Abstract:
A method of potentiating the activity of a drug which affects the central nervous system (CNS) comprising systemically administrating to a subject said drug together with an effective amount of a compound which stimulates peripheral chemoreceptors of vagal afferents and, optionally, with an effective amount of a stimulator of peripheral osmoreceptors of vagal afferents. Also disclosed are pharmaceutical compositions for systemic administration comprising a CNS drug together with the aforementioned compounds.

Description:
FIELD OF THE INVENTION  
       [0001]     This invention relates to compositions and methods useful for potentiating the activity of drugs affecting the Central Nervous System.  
       BACKGROUND OF THE INVENTION  
       [0002]     The following is a list of references which may be important in understanding the background of the invention: 
    1. U.S. Pat. No. 5,942,241;     2. Mancusi L. et al., Minerva Anestesiol, 53(1-2), 19-26, 1987;     3. Huang K S et al., Ma Tsui Hsueh Tsa Chi, 31(4), 245-8, 1993;     4. Goyagi T et al., Anesth Analg, 81(3), 508-13, 1995; 10     5. Niemi G et al., Acta Anaesthesiol Scand, 42(8), 897-909, 1998;     6. Russian Patent No. SU 2,088,233     7. 8 th  Sardinian Conference on Neuroscience.  Anxiety and depression neurobiology, pharmacology and clinic . Tanka Village, Villasimius, May 24-28 th  1995. Behavioral Pharmacology, Vol. 6 (Supplement 1), 1995, P.152.    
 
         [0010]     The references are referred to in the specification by their respective numbers.  
         [0011]     Currently, two principal methods of potentiation of the effect of central nervous system (CNS) active drugs (potentiated synergism) are known: (1) pharmacokinetic; and (2) pharmacodynamic.  
         [0012]     The pharmacokinetic method provides potentiation by creating a maximum concentration of the drug at the site of the primary pharmacological 5 response due to improved absorption, increased bioavailability, accelerated distribution and retarded elimination of the drug ( Goodman  &amp;  Gilman&#39;s The Pharmacological Basis of Therapeutics  9th ed. Hardman Paperback, McGraw-Hill Book Company, 1996). The known methods of pharmacokinetic potentiation are connected, as a rule, with the development of new and improved dosage forms and ways of drug administration.  
         [0013]     In recent years, the method of controlled extended release of active ingredients from micro-particles and microcapsules (e.g. U.S. Pat. No. 6,022,562) has been considered the most popular and promising of these methods. Each micro-particle generally represents a matrix of nontoxic polymer containing a drug and osmotically active polyatomic alcohols (e.g. U.S. Pat. No. 5,431,922). Micro-particles are included in traditional dosage forms for oral administration (tablets, capsules, suspensions, granules), which most frequently contain polymers such as polyvinylpyrilidone (PVP) or polyethylene oxide (PEO), and osmotically active alcohols such as sorbitol, xylitol and mannitol.  
         [0014]     The main drawback of this method is the necessity for permanent administration of a high dose of the active ingredient. This may lead, in the case of long-term administration, to the potentiation not only of its therapeutic action, but also of side effects in case of poor selectivity of the drug effect. In addition, the production of traditional oral dosage forms on the basis of micro-particles and microcapsules leads to a manifold increase in their cost, which often greatly exceeds the cost of-the active ingredient. Despite its numerous advantages, the aforementioned pharmacokinetic method does not achieve a manifold intensification of the effect of drugs.  
         [0015]     Osmotically active polymers (PVP, PEO) and polyatomic alcohols (xylitol, sorbitol, mannitol), included in the composition of both traditional monolithic dosage forms as well as forms intended for controlled release of active ingredients, play an important role in pharmacokinetic potentiation of CNS active drugs (e.g. U.S. Pat. Nos. 4,952,402 and 5,552,429). However, they are not active components of the compositions, but rather they only provide optimal conditions for the pharmacokinetics of a CNS active drug.  
         [0016]     A combined application of the α-1-adrenomimetics phenylephrine or midodrine, as well as the nonselective adrenomimetic adrenalin, together with narcotic analgesics and local anesthetics has been found to lead to a pharmacokinetic potentiation of analgesic and anesthetic effect. However, these compositions were only administered locally to intensify local anesthesia (1) or intrathecally to intensify spinal anesthesia (2-5). Intensification and prolongation of the effect of analgesics and anesthetics was caused by an increase in their local concentration, which is due to a decrease in the amount of analgesics and anesthetics entering the blood as a result of a local spasm of vessels caused by the adrenomimetics.  
         [0017]     The pharmacodynamic method also provides potentiation by a joint administration of active ingredients causing unidirectional pharmacological effects, but affecting different molecular substrates (having different mechanisms) (Goodman&amp;Gilman&#39;s The Pharmacological Basis of Therapeutics, op. cit.).  
         [0018]     Two main types of pharmacodynamic methods of the potentiation of 25 CNS active drugs are known:  
         [0019]     (1) Potentiation of the effects of CNS active drugs caused by joint administration of CNS active drugs only;  
         [0020]     (2) Potentiation of the effects of CNS active drugs caused by joint administration of a CNS active drug and a peripherally active drug.  
         [0021]     The well-known first method consists in joint administration of two CNS active drugs that act unidirectionally and mutually potentiate each other&#39;s effect. In cases of grave depressions, pain syndrome, parkinsonism, epilepsy and psychoses, potentiation of the maximal effect of antidepressants, neuroleptics, analgesics, psychostimulants, anti-parkinson and anticonvulsive agents is required. As a rule, potentiation is possible only by joint administration of CNS active drugs in submaximal doses. Potentiating of submaximal doses effects of CNS active drugs results in maximum possible intensification of their therapeutic activity. On the other hand potentiating of their central toxic effect is also caused resulting in multiple side effects and complications. (e.g. U.S. Pat. No. 4,788,189; Winter J C et al., Pharmacol Biochem Behav, 63(3), 507-13, 1999; Sills T S et al., Behav Pharmacol, 11(2), 109-16, 2000); Fredriksson A. et al., J Neural Transm Cen Sect, 97(3), 197-209, 1994).  
         [0022]     U.S. Pat. No. 3,947,579 discloses a method for potentiating the neuroleptic activity of drugs such as butyrophenone derivatives by administrating them together with an amino acid known to cross the blood brain barrier and have muscle relaxant properties useful in the treatment of spinal origin spasticity.  
         [0023]     At mild and moderate severity (or stage) of a disease, maximal or even submaximal effect caused by CNS active drug is quite sufficient. In this case therapeutic activity may usually be achieved by potentiating threshold doses of CNS active drugs. (e.g. U.S. Pat. No. 5,891,842; Freedman G M, Mt Sinai J Med, 62(3), 221-5, 1995; Kaminsky R et al., Pharmacol Res, 37(5), 375-81, 1998). The potentiation of the effect of threshold doses significantly reduces the probability of the development of side effects and complications inherent to CNS active drugs at maximal doses, as well as the development of tolerance and dependence due to their prolonged administration. However, even this, the safest of all known methods of pharmacodynamic potentiation has its own drawbacks: 
        1) The effect achieved by potentiating low doses of drugs does not exceed, as a rule, the maximal effect of the drug itself.     2) When the elimination of active ingredients is decelerated (childhood age, diseases of liver or kidneys) or the permeability of the hematoencephalic barrier is increased, threshold dosages of CNS active drugs can become submaximal and even toxic in their effect. Therefore, their combined administration even at such threshold doses becomes impossible due to the potentiation of their CNS side effects.     3) The risk of potentiating not only therapeutic, but also toxic effects of CNS active drugs by even small doses of other safe CNS active drugs.        
 
         [0027]     The potentiation of the effects of threshold doses of CNS active drugs can also be realized by a combined administration of a CNS active and a peripherally osmotically active drug. It is known that oral or intramuscular administration of osmotically active copolymers of N-vinyl-pyrrolidone with N,N,N,N, triethylmethacryloidoxyethylammonium iodide (6), potentiate the effects of threshold doses of analgesics, antidepressant, antishock and antihypoxic agents without any side effects and complications. Among the drawbacks of the method there should be mentioned the insufficient potentiation of the CNS active drugs when administered at threshold doses. Although potentiation occurs, it does not reach the level of the maximal effect of the CNS drug tested.  
         [0028]     Another drawback is the complexity of the synthesis and high cost of the polymers comprised in these compositions.  
         [0029]     In rats under urethan anaesthesia, peripherally administered serotonin produced cardiopulmonary reflex. Administration of phenylephrine or adrenaline to unaesthesized rats potentiated 5-10 fold the cardiopulmonary reflex caused by injection of serotonin in short-sleeping rats (7). This is a peripheral rather than a CNS effect, since peripherally administered serotonin cannot penetrate the hematoencephalic barrier.  
         [0030]     U.S. Pat. No. 4,631,284 discloses acetaminophen compositions containing a substantially high amount of acetaminophen and a low amount of pheniramine maleate. This patent teaches a method of tabletting using such compositions.  
       SUMMARY OF THE INVENTION  
       [0031]     It is an object of the invention to provide a pharmaceutical composition comprising a CNS active drug whose activity is potentiated.  
         [0032]     It is a further object of the invention to provide a method for potentiating CNS active drugs.  
         [0033]     In a first aspect of the invention, there is provided a pharmaceutical composition for systemic administration comprising: (a) an effective dose of a drug which affects the central nervous system (CNS); (b) a compound which stimulates peripheral chemoreceptors of vagal afferents; and, optionally, (c) a compound which stimulates peripheral osmoreceptors of vagal afferents.  
         [0034]     It has suprisingly been found that the activity of systemically administered CNS drugs may be significantly potentiated by the co-administration of a compound which stimulates peripheral chemoreceptors of vagal afferents and further by a compound which stimulates peripheral osmoreceptors of vagal afferents. The “active ingredients” of the invention are the CNS drug and the potentiating element, i.e. compound which stimulates peripheral chemoreceptors and a compound which stimulates peripheral osmoreceptors of vagal afferents.  
         [0035]     In the present specification, a CNS active drug is a drug that modifies the function of the CNS by directly affecting the CNS or a portion thereof. Such drugs include but are not limited to analgesics, antidepressants, neuroleptics, tranquilizers, psychostimulants, hypnotic drugs, anti-parkinson and anti-convulsive agents.  
         [0036]     The term “effective dose” with respect to the CNS drug refers to an amount of the drug which is effective in bringing about a desired effect in the CNS. This amount may be within the usual dosage range of the drug, or it may be less than the usual dosage range of the drug, as defined below, due to the potentiating effect(s) of the additional components of the composition.  
         [0037]     In one embodiment of the invention, the “effective dose” is less than the usual, conventional dosage range of the drug. The usual dose of a CNS drug may be ascertained by reference to standard drug and pharmacological handbooks, such as  Goodman  &amp;  Gilman&#39;s The Pharmacological Basis of Therapeutics  9th ed. Hardman Paperback, McGraw-Hill Book Company, 1996, the Physician&#39;s Desk Reference, the Israel Drug Index, or drug product inserts provided by the drug manufacturer. This information is well known and available to the average skilled man of the art.  
         [0038]     In a preferred embodiment, “less than the usual, conventional dosage range of the drug” means less than 50%, more preferrably less than 20%, still more preferably less than 10%, most preferably less than 5% of the usual dose of a CNS drug as defined above.  
         [0039]     The terms “compound which stimulates peripheral chemoreceptors of vagal afferents” and “compound which stimulates peripheral osmoreceptors of vagal afferents” are well known terms in the art, as appear, for example, in the following articles:  
         [0040]     BerthoucT, Hans-Rudolf and Neuhuber, W. L. (2000)  Functional and chemical anatomy of the afferent vagal system ; Autonomic Neuroscience: Basic and Clinical 85:1-17.  
         [0041]     Carlson, Scott H. and Osbom, J. W. (1998)  Splanchnic and vagal denervation attenuate central Fos but not A VP responses to intragastric salt in rats ; Am. J. Physiol. 274:R1243-R1252.  
         [0042]     Kobashi, M. and Adachi, A. (1995)  Chemosensitivity of neurons in the dorsal motor nucleus of the vagus that responded to portal infusion of hypertonic saline in rats ; Brain Research Bulletin 38:11-15.  
         [0043]     Schwartz, Gary J. (2000)  The role of gastrointestinal vagal afferents in the contol of food intake:current prospects ; Nutrition 16:866-873.  
         [0044]     Powley T L, Phillips R J.  Musings on the wanderer: what&#39;s new in our understanding of vago-vagal reflexes? L Morphology and topography of vagal afferents innervating the GI tract . Am J Physiol Gastrointest Liver Physiol. 2002 December; 283(6):G1217-25. Epub 2002 Jul. 31.  
         [0045]     Page, A. J., C. M. Martin, and L. A. Blackshaw.  Vagal Mechanoreceptors and Chemoreceptors in Mouse Stomach and Esophagus . J. Neurophysiol. 87: 2095-2103, 2002).  
         [0046]     The compounds which stimulate either chemoreceptors or osmoreceptors of the vagal afferents may be identified by one or more of the following methods:  
         [0047]     1. Direct registration of excitation of chemoreceptors or osmoreceptors of vagal afferents (electrophysiological measurement of action potentials in endings of vagal afferents) induced by compounds or osmotic agents (BerthoucT op. cit.; Verbeme, A. J. M., Saita, M. and Sartor, D. M. (2003)  Chemical stimulation of vagal afferent neurons and sympathetic vasomotor tone  Brain Research Reviews, 41:288-305; Powley T L, op. cit.)  
         [0048]     2. Measurement of action potentials in trunk of cardiopulmonary and subdiaphragmatic vagal afferents after stimulation of cardiac chemoreceptors or chemoreceptors or osmoreceptors of gastrointestinal mucosa by chemical compounds or osmotic agents (BerthoucT op. cit.; Verbeme, op.cit; Powley T L, op. cit.).  
         [0049]     3. Elimination of excitation of endings of vagal afferents, induced by compounds and osmotic agents, after local anaesthesia or deafferentation of endings of vagal afferents by lidocaine and the neurotoxin capsaicin (Powley T L, op. cit.; BerthoucT op. cit.; Uneyama, H, Niijima, A. Tanaka, T. and Torii, K. (2002)  Receptor subtype specific activation of the rat gastric vagal afferent fibers to serotonin , Life|Sciences 72:414-423). 
        4. Elimination of excitation of trunk of vagal afferents, induced by chemical compounds and osmotic agents, after local anaesthesia or deafferentation of endings of vagal afferents by lidocaine and the neurotoxin capsaicin.(Schwartz, op. cit.; Uneyama op. cit.; BerthoucT op. cit.; Verbeme, op. cit; Powley T L, op. cit. Blackshaw L A, Page A J, Partosoedarso E R.  Acute effects of capsaicin on gastrointestinal vagal afferents . Neuroscience. 2000; 96(2):407-16).        
 
         [0051]     5. Elimination of excitation of trunk of vagal afferents, induced by chemical compounds and osmotic agent after surgical trunk vagotomy and systemic administration of antagonists of CCKA receptors of subdiaphragmatic vagal afferents (proglumide, loxiglumide) (BerthoucT op. cit.; Verbeme, op.cit; Schwartz, op. cit. Moriarty P, Dimaline R, Thompson D G, Dockray G J.  Characterization of cholecystokinin A and cholecystokinin B receptors expressed by vagal afferent neurons . Neuroscience. 1997 August;79(3):905-13.)  
         [0052]     6. Indirect registration of activation of subdiaphragmatic vagal afferents by compounds and osmotic agents: measurement of growth of concentration of endogenous CCK in the blood caused stimulation of chemoreceptor and osmoreceptor vagal afferents in gastrointestinal mucosa (Moriarty P, op.cit., Schwartz, op. cit., Lal S, Kirkup A J, Brunsden A M, Thompson D G, Grundy D.  Vagal afferent responses to fatty acids of different chain length in the rat . Am J Physiol Gastrointest Liver Physiol. 2001 October;281 (4):G907- 15).  
         [0053]     7. Elimination of growth of concentration of endogenous CCK in the blood induced by compounds and osmotic agents after surgical vagotomy, local anaesthesia by lidocaine, or deafferentation of endings of vagal afferents by neurotoxin capsaicin.(BerthoucT op. cit.; Schwartz, op. cit., Blackshaw L A, op. cit., Moriarty P, op. cit.,)  
         [0054]     8. Measurement of cardiopulmonary and gastrointestinal reflex-induced stimulation of chemoreceptors and osmoreceptors of vagal afferents by compounds and osmotic agents (BerthoucT op. cit.; Verberne, op.cit; Schwartz, op. cit., Storr M, Sattler D, Hahn A, Schusdziarra V, Allescher H D.  Endogenous CCK depresses contractile activity within the ascending myenteric reflex pathway of rat ileum . Neuropharmacology. 2003 March;44(4):524-32; Travagli R A, Hermann G E, Browning K N, Rogers R C.  Musings on the wanderer: what&#39;s new in our understanding of vago - vagal reflexes ? III.  Activity - dependent plasticity in vago-vagal reflexes controlling the stomach . Am J Physiol Gastrointest Liver Physiol. 2003 February;284(2):G180-7; Serdiuk S E, Gmiro V E  The analgesic and antidepressant action of adrenaline - induced stress in the endogenous activation of the gastric afferent systems in rats  Ross Fiziol Zh Im I M Sechenova. 1997 August;83(8):111-20; Serdiuk S E, Gmiro V E  The participation of gastric afferents in the reflex mechanisms of immediate adaptation to stress exposures  Fiziol Zh Im I M Sechenova. 1995 September;81(9):40-51).  
         [0055]     9. Elimination of gastrointestinal and cardiopulmonary reflex induced by compounds and osmotic agents, after surgical vagotomy, local anaesthesia by lidocaine, or deafferentation of endings of vagal afferents by the neurotoxin capsaicin (BerthoucT op. cit.; Verbeme, op.cit; Powley T L, op. cit. Lal S, op.cit., Serdiuk S E, 1997 op.cit.. Serdiuk S E, 1995 op.cit.).  
         [0056]     10. Elimination of gastrointestinal reflex, induced by compounds and osmotic agent, after systemic administration of antagonists of CCKA receptors of subdiaphragmatic vagal afferents (proglumide,loxiglumide). (BerthoucT op. cit.; Verbeme, op.cit; Powley T L, op. cit.; Lal S, op. cit.; Moriarty P, op. cit.).  
         [0057]     11. Measurement of analgesic, anxiolitic, antidepressive, anticonvulsive, neuroprotective and stress-protective action, induced by stimulation of chemoreceptors and osmoreceptors of vagal afferents by compounds and osmotic agents (Hosomi N., Mizushige K., Kitadai M., Ohyama H., Ichihara S. I., Takahashi T., Matsuo H.  Induced hypertension treatment to improve cerebral ischemic injury after transient forebrain ischemia . Brain Res. 835(2): 188-196. 1999; Jensen R. A.  Modulation of memory storage processes by peripherally acting pharmacological agents . Proc. West Pharmacol. Soc. 39: 85-89. 1996; Krahl S. E., Senanayake S. S., Handforth A.  Seizure suppression by systemic epinephrine is mediated by the vagus nerve . Epilepsy Res. 38(2-3): 171-175. 2000; Randich A., Gebhart G. F.  Vagal afferent modulation of nociception . Brain Res. Brain Res. Rev. 17(2):77-99. 1992; Sevoz-Couche C., Hamon M., Laguzzi R.  Antinociceptive effect of cardiopulmonary chemoreceptor and baroreceptor reflex activation in the rat . Pain. 99(1-2): 71-81. 2002. Stacher G.  Effects of cholecystokinin and caerulein on human eating behavior and pain sensation: a review . Psychoneuroendocrinology, 11(1): 39-48. 1986; Tirassa P., Aloe L., Stenfors C., Turrini P., Lundeberg T.  Cholecystokinin -8  protects central cholinergic neurons against fimbria - fornix lesion through the up-regulation of nerve growth factor synthesis . Proc. Natl. Acad. Sci. U.S.A. 96(11): 6473-6477. 1999; Verbeme, op. cit, Watkins L. L., Grossman P. Association of depressive symptoms with reduced baroreflex cardiac control in coronary artery disease. Am. Heart. J. 137(3): 453-457. 1999; Serdiuk 1997 op. cit.; Serdiuk 1995 op. cit.).  
         [0058]     12. Elimination of analgesic, anxiolitic, antidepressive, anticonvulsive, neuroprotective and stress-protective action, induced by compounds and osmotic agent, after surgical vagotomy ,local anaesthesia by lidocaine and deafferentation ending of vagal afferents by neurotoxin capsaicin (Verbeme, op. cit.; Krahl S. E., op. cit.; Randich A., op. cit.; Sevoz-Couche C., op. cit.; Tirassa P., op. cit.; Serdiuk 1997 op. cit.; Serdiuk 1995 op. cit.)..  
         [0059]     13. Elimination of analgesic,anxiolitic,antidepressive, anticonvulsive, neuroprotective and stress-protective action induced by compounds and osmotic agent after systemic administration of antagonists of CCKA receptors of subdiaphragmatic vagal afferents (proglumide, loxiglumide) (Feinle C, Grundy D, Fried M.  Modulation of gastric distension - induced sensations by small intestinal receptors . Am J Physiol Gastrointest Liver Physiol. 2001 January;280(1):G51-7).Verbeme, op.cit.; Tirassa P op. cit.; Stacher op. cit.; Serdiuk, 1997 op. cit.; Serdiuk, 1995 op. cit.)  
         [0060]     Examples of types of compounds which stimulates peripheral chemoreceptors of vagal afferents are an α-1-adrenomimetic; a catecholamine; serotonin; a serotoninomimetic; gastrointestinal peptide or trypsin inhibitor; a bradykinin; an amino acid; stimulators of NMDA, AMPA/kainate or GABA receptors; metal cations; M-cholinomimetics; an acetylcholinesterase inhibitor; N-cholinomimetic; hystamine or hystaminomimetic; purine derivative; polyamines; stimulator of vanilloid receptors; stimulator of opioid receptors; prostoglandin; nitric oxide or stimulator of receptors of nitric oxide; surfactant; cytokine; carbohydrate; fatty acid; bile acid or salt; and potassium or cloride channel opener.  
         [0061]     Non-limiting examples of α-1-adrenomimetics are the compounds phenylephrine and midodrine. Non-limiting examples of catecholamines are epinephrine, norepinephrine, dopamine, and their combination. A non-limiting example of a serotoninomimetic is a stimulator of 5-HT3 receptors. Non-limiting examples of gastrointestinal peptides are cholecystokinin (CCK), calcitonin gene related peptide (CGRP), leptin, gastrin, substance P, somatostatin, vasointestinal peptide (VIP), and atrial natriuretic peptide (ANP). Non-limiting examples of amino acids are glutamate, aspartate, N-methyl-D-aspartate (NMDA), kainate, 1-arginine or Gamma- aminobutiric acid (GABA). Non-limiting examples of methal cation are Ca 2+ , H + , Mg 2+ , Na + , K + , Zn 2+ , Mn 2+ , Cu 2+ , Ag + , Hg 2+ , Cd 2+ , Ni + , Co 2+ , Al 3+ , Al 2+ , Fe 2+ , Fe 2+  or Bi 2+ . Non-limiting examples of M-cholinomimetic are acetylcholine, carbocholine, or pilocarpine. Non-limiting examples of N-cholinomimetic are subecholine or tetramethylammonium (TMA). Non-limiting examples of purine derivative are adenosine, adenosine monophospatis, adenosine diphosphatis, adenosine triphosphatis or inositol. Non-limiting examples of polyamine are spermine, spermidine, putrescine or agmatine. Non-limiting examples of stimulator of vanilloid receptors are capsaicin, palmitoylethanolamide or anandamide. A non-limiting example of a stimulator of opioid receptors is loperamide. Non-limiting examples of stimulators of receptor of nitric oxide are nitroglycerin or sodium nitroprusside. Non-limiting examples of cytokine are IL-1β, TNF, IL-6, IL-10 or IL-13. Non-limiting examples of carbohydrates are glucose, sucrose or polycose.  
         [0062]     In one embodiment of the invention, the compound which stimulates peripheral chemoreceptors of vagal afferents does not include one or more of the following compounds: an α-1-adrenomimetic such as phenylephrine or midodrine; a catecholamine such as epinephrine, norepinephrine and dopamine; serotonin; a serotoninomimetic; gastrointestinal peptide or trypsin inhibitor; a bradykinin; an amino acid; stimulators of NMDA, AMPA/kainate or GABA receptors; metal cations; M-cholinomimetics; an acetylcholinesterase inhibitor; N-cholinomimetic; hystamine or hystaminomimetic; purine derivative; polyamines; stimulator of vanilloid receptors; stimulator of opioid receptors; prostoglandin; nitric oxide or stimulator of receptors of nitric oxide; surfactant; cytokine; carbohydrate; fatty acid; bile acid or salt; and potassium or cloride channel opener, or one or more of the compounds listed above.  
         [0063]     In another embodiment of the invention, the compound which stimulates peripheral chemoreceptors of vagal afferents does not include specific carbohdrates and/or amino acids such as, for example, glucose, sucrose, tyrosine, phenylalanine and tryptophan.  
         [0064]     In a further embodiment of the invention, the compound which stimulates peripheral chemoreceptors of vagal afferents poorly penetrates the blood-brain barrier (BBB) and has a brain/plasma concentration ratio of less than 0.3.  
         [0065]     The penetration level of compounds through the blood-brain barrier may be estimated by the following method.  
         [0066]     A comparison is made between the maximal concentration of a drug in the blood and in the brain, and the brain/blood concentration ratio is calculated. The main advantage of this method of estimating BBB permeability for compounds is the extended period of time of measurement (up to 90 min, preferably 30-60 min) after systemic drug administration. Therefore, the brain/blood concentration ratio really shows penetration of the BBB by compounds at pike concentration in the blood after systemic administration.  
         [0067]     For example, morphine which is an effective CNS drug has a brain/blood concentration ratio of 0.4-0.5. Compounds which poorly penetrate the BBB usually have a brain/blood concentration ratio of less than 0.3.  
         [0068]     A description of the measurement of brain/plasma concentration ratio may be found in Fox, E. et al. (2002)  Zidovudine Concentration in Brain Extracellular Fluid Measured by Microdialysis Steady - State and Transient Results in Rhesus Monkey  Journal of Pharmacology And Experimental Therapeutics, 301:1003-1011.  
         [0069]     Non limiting examples of a compound which stimulates peripheral osmoreceptors of vagal afferents include PVP, dextran, PEO, xylitol, mannitol, glycerinum, urea, sorbitol, or a combination of two or more stimulators.  
         [0070]     In one embodiment of the invention, the compound which stimulates peripheral osmoreceptors of vagal afferents does not include osmotically active copolymers of N-vinyl-pyrrolidone with N,N,N,N, triethylmethacryloidoxyethylammonium iodide.  
         [0071]     In one embodiment of the invention, when the compound which stimulates peripheral chemoreceptors of vagal afferents is an α-1-adrenomimetic such as phenylephrine or midodrine; a catecholamine such as epinephrine, norepinephrine and dopamine; or serotonin, the compound which stimulates peripheral osmoreceptors of vagal afferents is not PVP, dextran, PEO, xylitol, mannitol or sorbitol.  
         [0072]     The composition of the invention is systemically administered to the subject (patient). Techniques of administration include systemic parenteral (e.g. intravenous, intramuscular, subcutaneous, inhalation) and systemic enteral (e.g. oral, sublingual, rectal) administration.  
         [0073]     In a second aspect of the invention, there is provided a pharmaceutical composition for systemic administration comprising: (a) an effective dose of a drug which affects the central nervous system (CNS); and (b) a compound which stimulates peripheral chemoreceptors of vagal afferents; wherein the dose of the drug in the composition is less than the usual dose of the drug.  
         [0074]     In this aspect of the invention, the “effective dose” of the drug is less than the usual, conventional dosage range of the drug. The usual dose of a CNS drug may be ascertained by reference to standard drug and pharmacological handbooks, such as  Goodman  &amp;  Gilman&#39;s The Pharmacological Basis of Therapeutics  9th ed. Hardman Paperback, McGraw-Hill Book Company, 1996, the Physician&#39;s Desk Reference, the Israel Drug Index, or drug product inserts provided by the drug manufacturer. This information is well known and available to the average skilled man of the art  
         [0075]     A compound which stimulates peripheral chemoreceptors of vagal afferents is as defined above.  
         [0076]     In the present invention, the term “composition” may be understood in its usual meaning, i.e. a product of mixing or combining the active ingredients, or the term may be understood as meaning that the active ingredients are administered separately but within a period of time which allows them to interact in the body. For example, in the second aspect of the invention, the compound which affects peripheral chemoreceptors and the CNS active drug may be administered either both parenterally or both orally or else one of them parenterally and the other orally. In the first aspect of the invention, the CNS active drug, the compound which affects peripheral chemoreceptors and the stimulator of osmoreceptors may be administered either all enterally or all parenterally, or else one of them parenterally and the other two enterally, or the reverse.  
         [0077]     Preferred compositions according to the invention comprise α-1-adrenomimetic and PVP or dextran for intramuscular administration, and α-1-adrenomimetic and xylitol, PVP or dextran for oral administration.  
         [0078]     In a third aspect of the invention, there is provided a method of potentiating the activity of a drug which affects the CNS comprising systemically administrating to a subject the drug together with an effective amount of a compound which stimulates peripheral chemoreceptors of vagal afferents and, optionally, with an effective amount of a compound which stimulates peripheral osmoreceptors of vagal afferents.  
         [0079]     An “effective amount” of a compound which affects peripheral chemoreceptors or osmoreceptors as used in the method of the invention is an amount which results in a significant decrease of a minimal effective dose of the CNS drug administered together with these components. For example, the effective amount of a peripherical chemoreceptor stimulating component administered together with a CNS active drug may decrease by 10-100 fold the minimal effective dose of a CNS active drug required in order to elicit a maximal therapeutic effect (i.e. potentiates the effect of the CNS active drug threshold dose to give the effect of a maximal dose). The effective amount may also be an amount that potentiates the magnitude of the maximal effect of the CNS drug. Including the osmoreceptor stimulator into the composition results in a substantial additional decrease in the effective dose of the CNS active drug.  
         [0080]     Preferred concentration ranges (in weight %) of the active ingredients in a composition according to the invention for systemic parenteral administration are as follows: for the CNS active drug: from 0.0005% to the upper limit of the usual dose for each drug; for α-1-adrenomimetic: from 0.0005% to 0.04%, and for stimulants of osmoreceptors from 0.1% to 10%. Compositions for oral administration preferably comprise each active ingredient in the amount of 0.0001% to 10% of the total weight of the composition. The remaining weight of the composition may comprise standard excipients.  
         [0081]     In a fourth aspect of the invention, there is provided a method of treating a disease affecting the CNS comprising systemically administrating to a subject an effective dose of a drug which affects the CNS together with an effective amount of a compound which stimulates peripheral chemoreceptors of vagal afferents and an effective amount of a compound which stimulates peripheral osmoreceptors of vagal afferents.  
         [0082]     In a fifth aspect of the invention, there is provided a method of treating a disease affecting the CNS comprising systemically administrating to a subject an effective dose of a drug which affects the CNS together with an effective amount of a compound which stimulates peripheral chemoreceptors of vagal afferents, wherein the dose of the drug in the composition is less than the usual dose of the drug.  
         [0083]     In a sixth aspect of the invention, there is provided a method for preparing a pharmaceutical composition for systemic administration of a drug which affects the CNS, said method comprising adding to an effective dose of said drug a compound which stimulates peripheral chemoreceptors of vagal afferents; and a compound which stimulates peripheral osmoreceptors of vagal afferents.  
         [0084]     In all of the aspects of the invention, the compound which stimulates peripheral chemoreceptors of vagal afferents and compound which stimulates peripheral osmoreceptors of vagal afferents are as defined in the first aspect above.  
     
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       [0000]     Materials and Methods  
         [0085]     The potentiation of the effect of CNS active drugs was studied in experiments on breedless white male rats having a mass of 180-200 g. For these studies, solutions of the composition of the invention were used, which were prepared using distilled water immediately before administration. The solutions were administered either orally (IG), by a rigid metal probe into the cardiac section of the stomach at a total amount of 0.8 ml, or intramuscularly (IM) at an amount of 0.2 ml, 30 min before testing.  
         [0086]     To determine the potentiation effect of the composition on the CNS drug, a minimal effective dose of the CNS drug within the composition causing a maximal possible effect for a given model was determined. The potentiation degree was estimated by the magnitude of the decrease in the minimal effective dose of the CNS drug within the composition causing the given effect of CNS active drug.  
         [0087]     The analgesic effect of the components was estimated by an extension of the latent period of the reflex of tail flicking in the “tail-flick” test [Woolf C. J., Barret G. D., Mitchel D., Myers R. A. (1977)  Eur. J Pharmacol.  45(3):311-314] and of the reflex of hind leg flicking in the hyperalgesia test [Coderre T. J., Melzack R.  Brain Res . (1987) 404(1-2):95-106].  
         [0088]     For the “tail-flick” test, hyperalgesic rats were selected (latent period of tail flicking on placing into water with a temperature of 51° C. was 3-4 sec). To estimate the potentiation effect of Dipyrone or morphine, the minimal effective dose of these drugs in compositions causing a maximal analgesia was determined (latent period of the reflex above 30 s).  
         [0089]     Hyperalgesia of a leg was developed by placing it into hot water (56° C.) for 20-25 sec under the conditions of ether anesthesia. Hyperalgesia was developed 30 min after the bum (latent period of leg flick reflex on its being placed into water at a temperature 47° C. was reduced from 15-20 s to 2-4 s). To estimate the potentiation effect of Dipyrone, the minimal effective dose of Dipyrone in the composition causing a maximal analgesic effect was determined (latent period of the leg-flick reflex above 30s).  
         [0090]     Antidepressive effects was studied by Porsolt&#39;s test [Porsolt R. D., Anton G., Blavet N., Jalfre M.  Eur. J. Pharmacol . (1978), 47(4):379-91]. For each rat under study, the total immobilization time was determined during 10 min of forced swimming in a glass vessel at a water temperature of 22° C. The animals were subdivided into three groups according to their immobilization time: highly-, medium- and low-active (immobilization time below 80 sec, 100-140 sec and above 150 sec, respectively). For a repeated study by Porsolt&#39;s test, on the second day low-active and highly active rats were selected.  
         [0091]     A model of depression was created by administration to a group of highly active rats of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [Krupina N. A., Orlova I. N., Kryzhanovskii G. N.  Biull. Eksp. Biol. Med . (1995) 120(8):160-3] 30 min before testing at a dose of 15 mg/kg. In the 30 min after the administration of MPTP, MPTP depression was developed in 100% of the highly active rats, since they passed into the category of low-active “depressive” rats (immobilization time—above 150 sec). Antidepressants (amitriptyline or Fluoxetine), as well as their compositions were administered to highly active rats 30 minutes before MPTP administration (60 min before a repeated examination in Porsolt&#39;s test), and also to low-active rats 30 min before a repeated study in Porsolt&#39;s test.  
         [0092]     To determine the degree of potentiation of the effect of antidepressants, their minimal effective dose within the compositions, which caused a maximal antidepressive effect (immobilization time—below 80 s) in low-active rats and in rats with MPTP-depression was determined.  
         [0093]     In a forced swimming test, the ability of amitriptyline and its compositions to eliminate the effect of toxic doses of MPTP was studied. Single administration of high MPTP doses (30 mg/kg) causes acute suppression of motor activity (akinesis), catalepsy, and muscular rigidity. Antidepressants reduce behavioral depression caused by a single administration of toxic doses of MPTP. The behavioral depression was studied in a forced swimming test of a group of active rats after the administration of a toxic dose of MPTP (30 mg/kg IM). Swimming duration (maximal swimming duration—10 min) and the time of forced immobilization during the first 5 min of swimming (under the condition that swimming duration exceeds 5 min) was estimated in the forced swimming test 30 min after MPTP administration. Drugs were administered IM or IG 30 min before MPTP administration.  
         [0094]     To estimate the potentiation of the effects of amitriptyline (its ability to reduce toxic effects of MPTP), the minimal effective dose of amitriptyline in the composition, which increased swimming time up to 9-10 min and reduced immobilization time during the first 5 min of swimming down to 20-30 sec was determined.  
         [0095]     Haloperidol catalepsy is a test for selecting anti-parkinson agents [Campbell A., Baldessarini R. J., Cremens M. C.  Neuropharmacology  (1988), 27(11):1197-9; Ossowska K.  J. Neural. Transm. Park. Dis. Dement. Sect . (1994) 8(1-2):39-71]. Catalepsy degree was estimated by the immobilization time (in sec) of a rat placed on a coarse-mesh grid at an angle of 45° during a 3-minute exposition [Campbell A., Baldessarini R. J., Cremens M. C.  Neuropharmacology  (1988) 27(11):1197-9] 30, 60, 90 and 120 minutes after haloperidol administration. Maximal catalepsy was attained in 40-60 minutes after haloperidol administration (immobilization time on the grid was 140-180 sec) and lasted from 2 to 6 hours depending on the dose of haloperidol (1 or 3 mg/kg). The minimal effective dose of the anti-parkinson agent memantine causing a maximal anticataleptic effect (immobilization time on an inclined grid less than 40 sec) 1 hour after haloperidol administration at a dose of 1 and 3 mg/kg was calculated.  
         [0096]     To estimate the potentiation effect of memantine, the minimal effective dose of memantine in the composition causing a maximal anticataleptic effect was determined.  
         [0097]     Anticonvulsive effects of drugs and their compositions was studied on the model of pentetrazole seizures [Parsons C. G., Quack G., Bresink I., Baran L., Przegalinski E., Kostowski W., Krzascik P., Hartmann S., Danysz W.  Neuropharmacology  (1995) 34(10):1239-1258). The capacity of the anticonvulsive drug diazepam and its compositions to prevent generalized clonico-tonic and clonic seizures in 80% of the rats 30 minutes after pentetrazole administration at a dose of 70 mg/kg IM (minimal effective dose) was estimated.  
         [0098]     To estimate the potentiation of diazepam effect, its minimal effective dose in the composition preventing clonico-tonic and clonic seizures in 80% of rats was determined.  
         [0099]     Antipsychotic effect of neuroleptics was studied using the model of behavioral toxicity “NK-toxicity” caused by a blocker of NMDA receptors MK-801 (Lapin I. P., Rogawski M. A.  Behav. Brain Res . (1995) 70(2):145-151) and a model of phenaminic stereotypy caused by phenamine (Kuczenski R., Schmidt D., Leith N.  Brain Res . (1977), 126(1):117-129).  
         [0100]     The minimal effective dose of the neuroleptic haloperidol necessary to completely prevent the development of “MK-toxicity” (MK-801 at a dose of 0.4 mg/kg IM) and phenaminic stereotypy (phenamine at a dose of 10 mg/kg IM) in 80% of the rats was calculated. To estimate the potentiation of the antipsychotic effect of haloperidol, the minimal effective dose of haloperidol in compositions, which completely prevents the development of MK-toxicity and phenaminic stereotypy in rats, was determined.  
         [0101]     The potentiation of the effect of psychostimulants was studied using the model of phenaminic stereotypy [Kuczenski R., Schmidt D., Leith N.  Brain Res . (1977), 126(1):117-29]. Phenamine at a dose of 10 mg/kg IM, or 20 mg/kg IG, causes a marked behavioral stereotypy. To estimate the potentiation effect of phenamine, a phenamine dose in the IM or IG introduced composition was determined, which causes the same stereotypy as phenamine alone at a dose of 10 mg/kg, IM or 20 mg/kg, IG. The potentiation degree of the psychostimulating effect of phenamine was estimated by the magnitude of the decrease of an equally effective dose of phenamine in the composition.  
       EXAMPLES  
     Example 1  
     Potentiation of the Effect of Analgesics  
       [0000]     a. Intramuscular Administration of Compositions  
         [0102]     A non-narcotic analgesic named Dipyrone at a dose of 20 mg/kg and the narcotic analgesic morphine at a dose of 3 mg/kg completely eliminate algesia in the tail-flick test (latent period of tail-flicking reflex increases from 3 to 30 sec and more). In the hyperalgesia test Dipyrone does not cause 20 complete analgesia even in a limiting dose of 40 mg/kg (latent period of leg flicking reflex increases from 3-4 s to 12.6 s). The results of administrating compositions in accordance with the invention are summarized in Table I.  
         [0103]     The α-1-adrenomimetics phenylephrine or midodrine at a threshold dose (0.008-0.01 mg/kg), which does not affect analgesia, in a composition with Dipyrone decrease the minimal effective dose of the drug 100 and 132 fold, respectively, causing maximal analgesia in the tail-flick test. In the hyperalgesia test, they potentiate the incomplete effect of the maximal dose of Dipyrone (30 mg/kg), which leads to the development of maximal analgesia in this model, that is more rigorous than the tail-flick model (the latent period of leg flicking reflex becomes longer than 30 s). An increase in α-1-adrenomimetic dose up to 0.02 mg/kg does not considerably increase the effect of Dipyrone in the tail-flick test, but decreases the minimal effective dose of Dipyrone causing a maximal analgesic effect in the hyperalgesia test 6-6.9 fold.  
         [0104]     Inclusion of a stimulant of osmoreceptors, such as PVP, dextran or PEO, into the composition of Dipyrone with the α-1-adrenomimetics phenylephrine or midodrine at a dose that does not cause analgesia leads to an additional 2-3.5-fold decrease in the minimal effective dose of Dipyrone, as well as a 3.3-4-fold decrease of a dose of phenylephrine or midodrine in the composition.  
         [0105]     Concentrations of the active ingredients in a solution of the composition of the invention potentiating the effect of Dipyrone were as follows: Dipyrone—from 0.005% to 3%, α-1-adrenomimetics—from 0.003% to 0.02%, and stimulants of osmoreceptors—from 0.25% to 2%. A decrease in the contents of α-1-adrenomimetics and stimulants of osmoreceptors in a composition with Dipyrone below the indicated limits leads to a dramatic decrease in the composition activity, whereas an increase in their concentration does not lead to a considerable intensification of the effect of the composition.  
         [0106]     The minimal effective dose of morphine in the tail-flick test decreases 75-fold in a composition with threshold doses of phenylephrine, and 214-fold in a composition with threshold doses of phenylephrine and PVP.  
         [0000]     b. Intragastric (Oral) Administration of Compositions  
         [0107]     In the tail-flick test, Dipyrone at a dose of 20 mg/kg and morphine at a dose of 3 mg/kg cause a maximal analgesia (latent period of tail flicking reflex exceeds 30 s). In the hyperalgesia test, IG administration of Dipyrone at its maximal possible dose of 40 mg/kg causes a mild analgesic effect (latent period of tail flicking reflex—13 s).  
         [0108]     Phenylephrine or midodrine at a threshold dose of 0.004-0.005 mg/kg in a composition with Dipyrone decreases its minimal effective dose, causing maximal analgesia in tail-flick test 133-167 times. In the hyperalgesia test they potentiate a mild analgesic effect of the maximal dose of Dipyrone (29 mg/kg) up to a complete analgesia (the latent period of leg flicking reflex becomes longer than 30 s).  
         [0109]     A further increase in phenylephrine or midodrine dose up to 0.01 mg/kg in the hyperalgesia test causes not only a potentiation of the effect of Dipyrone, but also decreases 9 and 7.9 times, respectively, the minimal effective dose of Dipyrone in the composition.  
         [0110]     Inclusion of stimulants of osmoreceptors such as PVP, dextran, PEO, xylitol or sorbitol into the composition of Dipyrone with α-1-adrenomimetics at a dose that does not cause analgesia leads to an additional 2.3-4.6-fold decrease in the minimal effective dose of Dipyrone and also to a 2.5-5-fold decrease in the threshold dose of phenylephrine or midodrine in the composition.  
         [0111]     Concentrations of the active ingredients in a solution of the composition for potentiation were as follows: Dipyrone—from 0.003% to 3%, α-1-adrenomimetics—from 0.001% to 0.01%, and stimulants of osmoreceptors—from 0.1% to 0.8%. A decrease in the contents of α-1-adrenomimetics and stimulants of osmoreceptors in a composition with Dipyrone below the indicated limits leads to a drastic decrease in the composition activity, whereas an increase in their concentration does not lead to a considerable potentiation of the effect of the composition.  
         [0112]     The minimal effective dose of morphine in the tail-flick test decreases 100-fold in a composition with threshold doses of phenylephrine, and 300-fold—in a composition with threshold doses of phenylephrine and xylitol.  
                                                           TABLE I                           Potentiation of analgesic effect of morphine and Dipyrone                    “Tail-flick” test   Hyperalgesia test       Drug or   Way of   Dose causing maximal   Dose causing maximal       composition   administration   analgesia*   analgesia*                    Dipyrone   IM***   20 ± 2.2   mg/kg   40   mg/kg****       Dipyrone + phenylephrine   IM   5.5 ± 0.6   mg/kg   31 ± 3.4   mg/kg           IM   0.004   mg/kg   0.008   mg/kg       Dipyrone + phenylephrine   IM   0.20 ± 0.023   mg/kg   5.2 ± 0.56   mg/kg           IM   0.01   mg/kg   0.02   mg/kg       Dipyrone + midodrine   IM   5.1 ± 0.55   mg/kg   29 ± 3.2   mg/kg           IM   0.004   mg/kg   0.008   mg/kg       Dipyrone + midodrine   IM   0.15 ± 0.018   mg/kg   4.2 ± 0.46   mg/kg           IM   0.01   mg/kg   0.02   mg/kg       Dipyrone + phenylephrine + PVP   IM   0.06 ± 0.007   mg/kg   1.6 ± 0.19   mg/kg           IM   0.003   mg/kg   0.005   mg/kg           IM   5   mg/kg   10   mg/kg       Dipyrone + midodrine + PVP   IM   0.05 ± 0.006   mg/kg   1.2 ± 0.15   mg/kg           IM   0.003   mg/kg   0.005   mg/kg           IM   5   mg/kg   10   mg/kg       Dipyrone + phenylephrine + dextran   IM   0.06 ± 0.007   mg/kg   1.9 ± 0.22   mg/kg           IM   0.003   mg/kg   0.005   mg/kg           IM   2.5   mg/kg   5   mg/kg       Dipyrone + phenylephrine + PEO   IM   0.09 ± 0.01   mg/kg   2.5 ± 0.29   mg/kg           IM   0.003   mg/kg   0.005   mg/kg           IM   10   mg/kg   20   mg/kg       Dipyrone   IG*****   20 ± 2.3   mg/kg   40   mg/kg******       Dipyrone + phenylephrine   IG   7.1 ± 0.74   mg/kg   34.2 ± 3.6   mg/kg           IG   0.002   mg/kg   0.004   mg/kg       Dipyrone + phenylephrine   IG   0.12 ± 0.014   mg/kg   3.8 ± 0.4   mg/kg           IG   0.005   mg/kg   0.01   mg/kg       Dipyrone + midodrine   IG   6.5 ± 0.72   mg/kg   32.2 ± 3.6   mg/kg           IG   0.002   mg/kg   0.004   mg/kg       Dipyrone + midodrine   IG   0.15 ± 0.018   mg/kg   4.1 ± 0.45   mg/kg           IG   0.005   mg/kg   0.01   mg/kg       Dipyrone + phenylephrine + PVP   IG   0.05 ± 0.0068   mg/kg   1.2 ± 0.14   mg/kg           IG   0.001   mg/kg   0.002   mg/kg           IG   8   mg/kg   16   mg/kg       Dipyrone + phenylephrine + dextran   IG   0.04 ± 0.005   mg/kg   1.4 ± 0.16   mg/kg           IG   0.001   mg/kg   0.002   mg/kg           IG   4   mg/kg   8   mg/kg       Dipyrone + phenylephrine + PEO   IG   0.05 ± 0.0055   mg/kg   1.9 ± 0.23   mg/kg           IG   0.001   mg/kg   0.002   mg/kg           IG   16   mg/kg   32   mg/kg       Dipyrone + phenylephrine + xylitol   IG   0.03 ± 0.004   mg/kg   0.8 ± 0.09   mg/kg           IG   0.001   mg/kg   0.002   mg/kg           IG   4   mg/kg   8   mg/kg       Dipyrone + midodrine + xylitol   IG   0.05 ± 0.006   mg/kg   1.0 ± 0.12   mg/kg           IG   0.001   mg/kg   0.002   mg/kg           IG   4   mg/kg   8   mg/kg       Dipyrone + phenylephrine + sorbitol   IG   0.06 ± 0.07   mg/kg   2.5 ± 0.20   mg/kg           IG   0.001   mg/kg   0.002   mg/kg           IG   8   mg/kg   16   mg/kg       Morphine   IM   3.0 ± 0.37   mg/kg       Morphine + phenylephrine   IM   2.4 ± 0.028   mg/kg           IM   0.004   mg/kg       Morphine + phenylephrine   IM   0.04 ± 0.0045   mg/kg           IM   0.01   mg/kg       Morphine + phenylephrine + PVP   IM   0.014 ± 0.0017   mg/kg           IM   0.003   mg/kg           IM   5   mg/kg       Morphine   IG   3 ± 0.35   mg/kg       Morphine + phenylephrine   IG   0.8 ± 0.09   mg/kg           IG   0.002   mg/kg       Morphine + phenylephrine   IG   0.03 ± 0.0035   mg/kg           IG   0.005   mg/kg       Morphine + phenylephrine + xylitol   IG   0.01 ± 0.0012   mg/kg           IG   0.001   mg/kg           IG   4   mg/kg                 *Latent period of tail flicking reflex more than 30 sec.            **Latent period of leg flicking reflex more than 30 sec.            ***Hereinafter the IM administered volume is 0.2 ml.            ****Latent period of leg flicking reflex 12.6 ± 1.4 sec.            *****Hereinafter the IG administered volume is 0.8 ml.            ******Latent period of leg flicking reflex 13.1 ± 1.6 sec.             
 
       Example 2  
     Potentiation of the Effect of Antidepressants  
       [0000]     a. Intramuscular Administration of Compositions  
         [0113]     IM administration of the antidepressant amitriptyline causes a maximal antidepressive effect in Porsolt&#39;s test (during 10 min of forced swimming, the immobilization time is below 80s) both in a group of low-active rats and in a group of highly active rats with MPTP depression (MPTP—15 mg/kg IM) at doses of 5.0 and 7.2 mg/kg, respectively. An increase of MPTP dose up to 30 mg/kg causes an acute suppression of motor activity and behavioral depression 15-30 min after IM administration. In a forced swimming test, the duration of swimming decreases from 550-600 s to 157-160 s.  
         [0114]     Amitriptyline at a dose of 20 mg/kg does not influence the effects of toxic doses of MPTP. Amitriptyline at a maximal dose of 30 mg/kg only partially decreases the toxic effect of MPTP, increasing swimming duration up to 410 s. The total immobilization time after the administration of 30 mg/kg of amitriptyline with 30 mg/kg of MPTP during the first 5 min of swimming was equal to 61 s. This corresponds to the immobilization time of medium-active rats and testifies to a mild antidepressive effect of amitriptyline in the maximal dose in case of administration of toxic doses of MPTP. The results of administrating compositions in accordance with the invention are summarized in Tables II and III.  
         [0115]     Phenylephrine or midodrine at a threshold dose (0.002-0.003 mg/kg) in a composition with amitriptyline decrease the minimal effective dose of amitriptyline causing maximal antidepressive effect in low-active rats and rats with MPTP-depression (MPTP 15 mg/kg IM) 87 and 70 times, respectively. Subsequent to the administration of a toxic dose of MPTP (30 mg/kg IM), phenylephrine at a threshold dose of 0.003 mg/kg in the composition with amitriptyline (30 mg/kg) potentiates a mild effect of amitriptyline in the maximal dose and eliminates completely the behavioral depression caused by the toxic dose of NPTP (swimming time increases up to 565 s, and the immobilization time is reduced from 61 s to 28 s). An increase of a dose of phenylephrine up to 0.006 mg/kg in the composition with amitriptyline makes it possible to decrease 3-fold the maximal effective dose of amitriptyline, which totally eliminates the effect of the toxic dose of MPTP.  
         [0116]     Additional inclusion of a stimulant of osmoreceptors into the composition of amitriptyline with α-1-adrenomimetic allows decreasing both the minimal effective dose of amitriptyline (2.5-3.3-fold) and the dose of α-1-adrenomimetic (2-3.3-fold), which is observed in all the models under study.  
         [0117]     Active ingredient contents in solution of the compositions for potentiation was as follows: amitriptyline—from 0.002% to 3%, α-1-adrenomimetics—from 0.0006% to 0.006%, and stimulants of osmoreceptors—from 0.5% to 2%. A decrease in the contents of α-1-adrenomimetics and stimulants of osmoreceptors in a composition with amitriptyline below the indicated limits leads to a drastic decrease in the composition activity, whereas an increase in their concentration does not lead to a considerable potentiation of the effect of the composition.  
         [0118]     IM administration of Fluoxetine causes a maximal antidepressive effect in low-active rats and rats with MPTP depression at a doses of 10.6 and 16.2 mg/kg, respectively. The minimal effective dose of Fluoxetine in Porsolts test in a composition with phenylephrine and PVP is decreased 46-63-fold.  
         [0000]     b. Intragastric Administration of Compositions  
         [0119]     IG administration of amitriptyline causes a maximal antidepressive effect in Porsolt&#39;s test (immobilization time below 80 s during 10 min of forced swimming) both in a group of low-active rats and in a group of highly active rats with MPTP depression (IM 15 mg/kg of MPTP) at a dose of 2-2.5 mg/kg, respectively. Amitriptyline at a dose of 30 mg/kg IG in the forced swimming test only partially eliminates the behavioral depression caused by a toxic dose of MPTP (30 mg/kg IM) (swimming time increased from 157 s to 340 s in comparison with reference group, and the immobilization time during 5 min of swimming amounted to 78 s).  
         [0120]     Phenylephrine or midodrine at a threshold dose of 0.002-0.003 mg/kg) in a composition with amitriptyline decrease 25-33-fold the minimal effective dose of amitriptyline causing a maximal antidepressive effect in low-active rats and rats with MPTP-depression. On the administration of a toxic dose of MPTP (30 mg/kg IM), phenylephrine at a threshold dose of 0.004 mg/kg in the composition with amitriptyline (30 mg/kg) potentiates the incomplete effect of amitriptyline at the maximal dose and eliminates completely the behavioral depression caused by a toxic dose of MPTP (swimming time increases up to 560 s, and the immobilization time is reduced from 78 s to 30 s). An increase in phenylephrine dose up to 0.008 mg/kg in composition with amitriptyline makes it possible to decrease 3-fold the minimal effective dose of amitriptyline, eliminating completely the effect of the toxic dose of MPTP.  
         [0121]     Addition of a stimulant of osmoreceptors to the composition of amitriptyline with α-1-adrenomimetic makes it possible to decrease both the minimal effective dose of amitriptyline (2.2-4-fold) and the dose of α-1-adrenomimetic (2-5-fold) in all the models under study.  
         [0122]     Active ingredient contents in solutions of the compositions for potentiation was as follows: amitriptyline—from 0.001% to 3%, α-1-adrenomimetics—from 0.0005% to 0.008%, and stimulants of osmoreceptors—from 0.2% to 1%. A decrease in the contents of α-1-adrenomimetics and stimulants of osmoreceptors in a composition with amitriptyline below the indicated limits leads to a drastic decrease in the composition activity, whereas an increase in their concentration does not lead to a considerable potentiation of the effect of the composition.  
         [0123]     IG administration of Fluoxetine causes a maximal antidepressive effect in low-active rats and rats with MPTP depression at doses of 5.5 mg/kg and 10.7 mg/kg, respectively. The minimal effective dose of Fluoxetine in Porsolt&#39;s test in a composition with phenylephrine and PVP decreases 50-59-fold.  
                                                           TABLE II                           Potentiation of antidepressive effect of amitriptyline and       Fluoxetine in Porsolt&#39;s test                        Porsolt&#39;s test.                   Dose*.               Porsolt&#39;s test.   Group of highly-active       Drug or   Way of   Dose*.   rats*** with MPTP       composition   administration   Group of low-active rats**   depression****                    Amitriptyline   IM*****   5.2 ± 0.6   mg/kg   7.0 ± 0.8   mg/kg       Amitriptyline + phenylephrine   IM   2.1 ± 0.24   mg/kg   2.4 ± 0.27   mg/kg           IM   0.001   mg/kg   0.0015   mg/kg       Amitriptyline + phenylephrine   IM   0.06 ± 0.0066   mg/kg   0.1 ± 0.013   mg/kg           IM   0.002   mg/kg   0.003   mg/kg       Amitriptyline + midodrine   IM   3.1 ± 0.34   mg/kg   4.2 ± 0.47   mg/kg           IM   0.001   mg/kg   0.0015   mg/kg       Amitriptyline + midodrine   IM   0.1 ± 0.012   mg/kg   0.12 ± 0.014   mg/kg           IM   0.002   mg/kg   0.003   mg/kg       Amitriptyline + phenylephrine + PVP   IM   0.02 ± 0.0023   mg/kg   0.03 ± 0.0035   mg/kg           IM   0.0006   mg/kg   0.001   mg/kg           IM   10   mg/kg   10   mg/kg       Amitriptyline + midodrine + PVP   IM   0.03 ± 0.   mg/kg   0.04 ± 0.005   mg/kg           IM   0.0006   mg/kg   0.001   mg/kg           IM   10   mg/kg   10   mg/kg       Amitriptyline + phenylephrine + dextran   IM   0.02 ± 0.0023   mg/kg   0.03 ± 0.0035   mg/kg           IM   0.001   mg/kg   0.0015   mg/kg           IM   5   mg/kg   5   mg/kg       Amitriptyline + phenylephrine + PEO   IM   0.025 ± 0.004   mg/kg   0.04 ± 0.005   mg/kg           IM   0.001   mg/kg   0.0015   mg/kg           IM   15   mg/kg   15   mg/kg       Fluoxetine   IM   10.6 ± 1.2   mg/kg   16 ± 2.1   mg/kg       Fluoxetine + PVP   IM   1.4 ± 0.17   mg/kg   1.9 ± 0.23   mg/kg           IM   20   mg/kg   20   mg/kg       Fluoxetine + phenylephrine + PVP   IM   0.12 ± 0.015   mg/kg   0.17 ± 0.021   mg/kg           IM   0.001   mg/kg   0.001   mg/kg           IM   10   mg/kg   10   mg/kg       Amitriptyline   IG******   2.0 ± 0.24   mg/kg   2.5 ± 0.5   mg/kg       Amitriptyline + phenylephrine   IG   0.92 ± 0.095   mg/kg   1.1 ± 0.25   mg/kg           IG   0.001   mg/kg   0.0015   mg/kg       Amitriptyline + phenylephrine   IG   0.06 ± 0.0065   mg/kg   0.10 ± 0.012   mg/kg           IG   0.002   mg/kg   0.003   mg/kg       Amitriptyline + midodrine   IG   1.2 ± 0.15   mg/kg   1.3 ± 0.15   mg/kg           IG   0.001   mg/kg   0.0015   mg/kg       Amitriptyline + midodrine   IG   0.06 ± 0.0067   mg/kg   0.11 ± 0.013   mg/kg           IG   0.002   mg/kg   0.003   mg/kg       Amitriptyline + phenylephrine + xylitol   IG   0.016 ± 0.0021   mg/kg   0.03 ± 0.0035   mg/kg           IG   0.0005   mg/kg   0.001   mg/kg           IG   8   mg/kg   8   mg/kg       Amitriptyline + midodrine + xylitol   IG   0.018 ± 0.0022   mg/kg   0.035 ± 0.0041   mg/kg           IG   0.0005   mg/kg   0.001   mg/kg           IG   8   mg/kg   8   mg/kg       Amitriptyline + phenylephrine + PVP   IG   0.022 ± 0.0026   mg/kg   0.04 ± 0.0045   mg/kg           IG   0.0007   mg/kg   0.001   mg/kg           IG   12   mg/kg   12   mg/kg       Amitriptyline + phenylephrine + dextran   IG   0.012 ± 0.0014   mg/kg   0.018 ± 0.0023   mg/kg           IG   0.0005   mg/kg   0.001   mg/kg           IG   8   mg/kg   8   mg/kg       Amitriptyline + phenylephrine + PEO   IG   0.025 ± 0.003   mg/kg   0.045 ± 0.0053   mg/kg           IG   0.0007   mg/kg   0.0014   mg/kg           IG   32   mg/kg   32   mg/kg       Amitriptyline + phenylephrine + sorbitol   IG   0.025 ± 0.0029   mg/kg   0.038 ± 0.0046   mg/kg           IG   0.0006   mg/kg   0.0012   mg/kg           IG   16   mg/kg   16   mg/kg       Fluoxetine   IG   5.5 ± 0.7   mg/kg   10.7 ± 1.1   mg/kg       Fluoxetine + xylitol   IG   1.8 ± 0.23   mg/kg   3.2 ± 0.36   mg/kg           IG   20   mg/kg   20   mg/kg       Fluoxetine + phenylephrine + xylitol   IG   0.11 ± 0.013   mg/kg   0.18 ± 0.022   mg/kg           IG   0.001   mg/kg   0.001   mg/kg           IG   8   mg/kg   8   mg/kg                 *Minimal effective dose of drug causing a maximal antidepressive effect (immobilization time below 80 sec).            **Total immobilization time more than 140 sec during 10 min of forced swimming in Porsolt&#39;s test.            ***Total immobilization time below 80 sec during 10 min of forced swimming in Porsolt&#39;s test.            ****MPTP in the dose of 15 mg/kg IM 30 min after its administration prolongs the immobilization time up to 150 and more seconds during 10 min of forced swimming in Porsolt&#39;s test.            *****Hereinafter the IM administered volume is 0.2 ml.            ******Hereinafter the IG administered volume is 0.8 ml.             
 
         [0124]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE III 
               
             
             
               
                   
               
               
                   
               
               
                 Potentiation of amitriptyline effect in a forced swimming test in 
               
               
                 rats with behavioral depression caused by a toxic dose of MPTP 
               
             
          
           
               
                   
                   
                   
                   
                 Total 
               
               
                   
                   
                   
                   
                 immobilization 
               
               
                   
                   
                   
                   
                 time during the 
               
               
                   
                   
                   
                   
                 first 5 minutes of 
               
               
                   
                   
                   
                 Maximal duration of 
                 forced 
               
               
                   
                 Way of 
                 Dose 
                 forced swimming* 
                 swimming** 
               
               
                 Drug 
                 administration 
                 mg/kg 
                 sec 
                 sec 
               
               
                   
               
               
                 Distilled water 
                 IM*** 
                 — 
                 160 ± 22 
                 — 
               
               
                 Amitriptyline 
                 IM 
                 20 
                 220 ± 25 
                 — 
               
               
                 Amitriptyline 
                 IM 
                 30 
                 410 ± 46 
                 61 ± 6.3 
               
               
                 Amitriptyline + phenylephrine 
                 IM 
                 30 
                 560 ± 63 
                 28 ± 3.0 
               
               
                   
                 IM 
                 0.002 
               
               
                 Amitriptyline + phenylephrine 
                 IM 
                 10 
                 565 ± 61 
                 25 ± 2.7 
               
               
                   
                 IM 
                 0.006 
               
               
                 Amitriptyline + phenylephrine + PVP 
                 IM 
                 5 
                 590 ± 65 
                 17 ± 1.9 
               
               
                   
                 IM 
                 0.003 
               
               
                   
                 IM 
                 20 
               
               
                 Distilled water 
                 IG**** 
                 — 
                 157 ± 18 
                 — 
               
               
                 Amitriptyline 
                 IG 
                 30 
                 340 ± 37 
                 78 ± 8.5 
               
               
                 Amitriptyline + phenylephrine 
                 IG 
                 30 
                 565 ± 59 
                 30 ± 3.4 
               
               
                   
                 IG 
                 0.004 
               
               
                 Amitriptyline + phenylephrine 
                 IG 
                 10 
                 558 ± 64 
                 28 ± 3.2 
               
               
                   
                 IG 
                 0.008 
               
               
                 Amitriptyline + phenylephrine + xylitol 
                 IG 
                 5 
                 585 ± 61 
                 20 ± 2.3 
               
               
                   
                 IG 
                 0.004 
               
               
                   
                 IG 
                 40 
               
               
                   
               
               
                   *Duration of forced swimming of rats in sec until drowning 30 min after MPTP administration in the dose of 30 mg/kg to active rats. Maximal recorded time of forced swimming 600 seconds.    
               
               
                   **Immobilization time was recorded during the first 5 minutes of forced swimming, 30 min after MPTP administration in the dose of 30 mg/kg to active rats.    
               
               
                   ***Hereinafter the IM administered volume is 0.2 ml.    
               
               
                   ****Hereinafter the IG administered volume is 0.8 ml.    
               
             
          
         
       
     
       Example 3  
     Potentiation of the Effect of Antiparkinson Agents  
       [0000]     a. Intramuscular Administration of Compositions  
         [0125]     The anti-parkinson agent memantine at a dose of 7.5 mg/kg completely eliminates the catalepsy caused by haloperidol at a dose of 1 mg/kg (immobilization time of a rat on an inclined grid is below 40 s). However, even at a dose of 15 mg/kg, memantine eliminates the catalepsy caused by haloperidol at a dose of 3 mg/kg only partially (immobilization time—60-70 s). The results of administrating compositions in accordance with the invention are summarized in Table IV.  
         [0126]     Phenylephrine or midodrine at a threshold dose (0.02 mg/kg) in a composition with memantine decrease its minimal effective dose causing a maximal effect (total elimination of catalepsy caused by haloperidol at a dose of 1 mg/kg) 18.8 and 17.9 times, respectively. They also potentiate an incomplete effect of memantine in the maximal dose (15 mg/kg) up to a complete elimination of catalepsy caused by haloperidol at a dose of 3 mg/kg. Further increase of a dose of phenylephrine or midodrine up to 0.04 mg/kg, which also does not cause an independent effect, not only potentiates the effect of memantine, but also decreases its maximal effective dose 4.5-4.8 times eliminating catalepsy caused by haloperidol at a dose of 3 mg/kg.  
         [0127]     The inclusion of stimulants of osmoreceptors—PVP, dextran or PEO—into the composition with memantine and α-1-adrenomimetics causes an additional decrease in the minimal effective dose of memantine for both models of catalepsy 2.1-2.7 times and at a dose of α-1-adrenomimetic in a tertiary composition 3-4 times.  
         [0128]     Active ingredient contents in solutions of the compositions for potentiation was as follows: memantine—from 0.015% to 1.5%, α-1-adrenomimetics—from 0.005% to 0.04%, and stimulants of osmoreceptors—from 1% to 4%. A decrease in the contents of α-1-adrenomimetics and stimulants of osmoreceptors in a composition with memantine below the indicated limits leads to a drastic decrease in the composition activity, whereas an increase in their concentration does not lead to a considerable Potentiation of the effect of the composition.  
         [0000]     b. Intragastric Administration of Compositions  
         [0129]     Memantine at a dose of 11.5 mg/kg eliminates completely the catalepsy caused by haloperidol at a dose of 1 mg/kg (immobilization time of a rat on an inclined grid is below 40 s). However, at a dose of 16 mg/kg, memantine eliminates the catalepsy caused by haloperidol at a dose of 3 mg/kg only partially (immobilization time—60-70 s).  
         [0130]     Phenylephrine or midodrine at a threshold dose of 0.02 mg/kg) in a composition with memantine decrease 10-11-fold its minimal effective dose causing a maximal effect (total elimination of catalepsy caused by haloperidol at a dose of 1 mg/kg). They also potentiate the incomplete effect of memantine in the maximal dose (16 mg/kg) up to a complete elimination of catalepsy caused by haloperidol at a dose of 3 mg/kg.  
         [0131]     A further increase of a threshold dose of phenylephrine or midodrine up to 0.04 mg/kg causes both the potentiation of the effect of memantine and a 3.7-4-fold decrease of its minimal effective dose eliminating catalepsy caused by haloperidol at a dose of 3 mg/kg.  
         [0132]     The inclusion of stimulants of osmoreceptors—PVP, dextran, PEO, xylitol or sorbitol—into the composition with memantine and α-1-adrenomimetic causes an additional decrease of the minimal effective dose of memantine in both models of catalepsy 2.1-4 times and the dose of α-1-adrenomimetic 4 times.  
         [0133]     Active ingredient contents in solutions of the compositions for potentiation was as follows: memantine—from 0.02% to 1.6%, α-1-adrenomimetics—from 0.005% to 0.04%, and stimulants of osmoreceptors—from 1% to 10%. A decrease in the contents of α-1-adrenomimetics and stimulants of osmoreceptors in a composition with memantine below the indicated limits leads to a drastic decrease in the composition activity, whereas an increase in their concentration does not lead to a considerable potentiation of the effect of the composition.  
                                                                     TABLE IV                           Potentiation of the effect of antiparkinson drugs                Minimal effective dose of drug*           eliminating catalepsy caused by:                Way of   a) haloperidol   b) haloperidol       Drug   administration   at a dose of 1 mg/kg**   at a dose of 3 mg/kg**                    Memantine   IM***   7.5 ± 0.7   mg/kg   15.0   mg/kg****       Memantine + phenylephrine   IM   5.7 ± 0.6   mg/kg   13.5 ± 1.5   mg/kg           IM   0.01   mg/kg   0.02   mg/kg       Memantine + phenylephrine   IM   0.4 ± 0.045   mg/kg   3.1 ± 0.04   mg/kg           IM   0.02   mg/kg   0.04   mg/kg       Memantine + midodrine   IM   6.2 ± 0.7   mg/kg   13.8 ± 1.5   mg/kg           IM   0.01   mg/kg   0.02   mg/kg       Memantine + midodrine   IM   0.42 ± 0.05   mg/kg   3.3 ± 0.37   mg/kg           IM   0.02   mg/kg   0.04   mg/kg       Memantine + phenylephrine + PVP   IM   0.15 ± 0.02   mg/kg   1.3 ± 0.17   mg/kg           IM   0.005   mg/kg   0.01   mg/kg           IM   10   mg/kg   20   mg/kg       Memantine + midodrine + PVP   IM   0.17 ± 0.021   mg/kg   1.4 ± 0.17   mg/kg           IM   0.005   mg/kg   0.01   mg/kg           IM   10   mg/kg   10   mg/kg       Memantine + phenylephrine + dextran   IM   0.18 ± 0.022   mg/kg   1.4 ± 0.16   mg/kg           IM   0.005   mg/kg   0.01   mg/kg           IM   10   mg/kg   20   mg/kg       Memantine + phenylephrine + PEO   IM   0.19 ± 0.023   mg/kg   1.5 ± 0.18   mg/kg           IM   0.005   mg/kg   0.015   mg/kg           IM   20   mg/kg   40   mg/kg       Memantine   IG*****   11.5 ± 1.2   mg/kg   16.0   mg/kg****       Memantine + phenylephrine   IG   8.5 ± 0.9   mg/kg   15.0 ± 1.7   mg/kg           IG   0.01   mg/kg   0.02   mg/kg       Memantine + phenylephrine   IG   1.0 ± 0.12   mg/kg   4.0 ± 0.046   mg/kg           IG   0.02   mg/kg   0.04   mg/kg       Memantine + midodrine   IG   8.8 ± 0.9   mg/kg   15.2 ± 1.8   mg/kg           IG   0.01   mg/kg   0.02   mg/kg       Memantine + midodrine   IG   1.1 ± 0.13   mg/kg   4.3 ± 0.05   mg/kg           IG   0.02   mg/kg   0.04   mg/kg       Memantine + phenylephrine + xylitol   IG   0.24 ± 0.047   mg/kg   1.5 ± 0.18   mg/kg           IG   0.005   mg/kg   0.01   mg/kg           IG   80   mg/kg   120   mg/kg       Memantine + midodrine + xylitol   IG   0.26 ± 0.03   mg/kg   1.6 ± 0.19   mg/kg           IG   0.005   mg/kg   0.01   mg/kg           IG   80   mg/kg   120   mg/kg       Memantine + phenylephrine + PVP   IG   0.28 ± 0.034   mg/kg   1.8 ± 0.22   mg/kg           IG   0.005   mg/kg   0.01   mg/kg           IG   40   mg/kg   80   mg/kg       Memantine + phenylephrine + dextran   IG   0.2 ± 0.024   mg/kg   1.3 ± 0.15   mg/kg           IG   0.005   mg/kg   0.01   mg/kg           IG   40   mg/kg   80   mg/kg       Memantine + phenylephrine + PEO   IG   0.35 ± 0.044   mg/kg   2.0 ± 0.24   mg/kg           IG   0.005   mg/kg   0.01   mg/kg           IG   200   mg/kg   400   mg/kg       Memantine + phenylephrine + sorbitol   IG   0.32 ± 0.036   mg/kg   1.9 ± 0.23   mg/kg           IG   0.005   mg/kg   0.01   mg/kg           IG   160   mg/kg   320   mg/kg                 *Dose of the drug corresponding to the immobilization time of a rat on an inclined grid (at an angle of 45°) below 40 seconds.            **Haloperidol in the doses of 1 mg/kg and 3 mg/kg IM causes after 60 minutes the immobilization of rats on an inclined grid for 140-180 seconds during 3 minutes of exposition.            ***Hereinafter the IM administered volume is 0.2 ml.            ****The immobilization time of rats on an inclined grid amounts to 60-70 seconds.            *****Hereinafter the IG administered volume is 0.8 ml.             
 
       Example 4  
     Potentiation of the Effect of Anticonvulsive Agents  
       [0000]     a. Intramuscular Administration of Compositions  
         [0134]     Diazepam at a dose of 6.7 mg/kg completely eliminates the generalized (clonico-tonic) seizures caused by pentylenetetrazole at a dose of 70 mg/kg in 80% of rats. Diazepam at the maximal endurable dose of 10 mg/kg eliminates clonic seizures preceding the generalized seizures caused by pentylenetetrazole at a dose of 70 mg/kg only in 20% of rats. The results of administrating compositions in accordance with the invention are summarized in Table V.  
         [0135]     Phenylephrine or midodrine at a threshold dose (0.012 mg/kg) in a composition with diazepam decrease its minimal effective dose causing a maximal anticonvulsive effect (elimination of clonico-tonic seizures caused by pentylenetetrazole at a dose of 70 mg/kg in 80% of rats) 74 and 85 times, respectively. They also potentiate a mild (only in 20% of rats) anticonvulsive effect of diazepam in the maximal dose (10 mg/kg) with respect to clonic pentylenetetrazole seizures (ensures a complete protection against clonic seizures in 80% of rats).  
         [0136]     Further increase of a dose of phenylephrine or midodrine up to 0.024 mg/kg, which also does not cause an independent effect, not only potentiates the effect of diazepam, but also decreases 5.5-6.3 times its minimal effective dose eliminating clonic seizures in 80% of rats.  
         [0137]     The inclusion of stimulants of osmoreceptors—PVP, dextran or PEO—into the composition with diazepam and α-1-adrenomimetics causes an additional decrease in the minimal effective dose of diazepam for both kinds of seizures 2.3-4.5 times and at a dose of α-1-adrenomimetic in a tertiary composition 2-2.4 times.  
         [0138]     Active ingredient contents in solutions of the compositions for potentiation was as follows: diazepam—from 0.002% to 1%, α-1-adrenomimetics—from 0.005% to 0.024%, and stimulants of osmoreceptors—from 1% to 10%. A decrease in the contents of α-1-adrenomimetics and stimulants of osmoreceptors in a composition with diazepam below the indicated limits leads to a drastic decrease in the composition activity, whereas an increase in their concentration does not lead to a considerable potentiation of the effect of the composition.  
         [0000]     b. Intragastric Administration of Compositions  
         [0139]     Diazepam at a dose of 2.5 mg/kg eliminates completely clonico-tonic seizures caused by pentylenetetrazole at a dose of 70 mg/kg in 80% of rats. Diazepam in the maximal dose of 10 mg/kg eliminates clonic seizures preceding the generalized seizures caused by pentylenetetrazole at a dose of 70 mg/kg only in 20% of rats.  
         [0140]     Phenylephrine or midodrine at a threshold dose of 0.012 mg/kg) in a composition with diazepam decrease 42 and 50 times, respectively, its minimal effective dose causing a maximal effect with respect to clonico-tonic seizures. They also intensify the anticonvulsive effect of diazepam in the maximal dose (10 mg/kg) with respect to clonic pentylenetetrazole-induced seizures (the number of rats without clonic seizures increasing from 20% to 80%).  
         [0141]     A further increase at a threshold dose of phenylephrine or midodrine up to 0.024 mg/kg causes both the potentiation of the effect of diazepam and a 5.0-5.9-fold decrease of its minimal effective dose eliminating clonic seizures in 80% of rats.  
         [0142]     The inclusion of stimulants of osmoreceptors—PVP, dextran, PEO, xylitol or sorbitol—into the composition with diazepam and α-1-adrenomimetics causes an additional decrease of the minimal effective dose of diazepam in both kinds of seizures 2.3-4.6 times and a decrease at a dose of α-1-adrenomimetic 2.1-3 times.  
         [0143]     Active ingredient contents in solutions of the compositions for potentiation was as follows: diazepam—from 0.0013% to 1%, α-1-adrenomimetics—from 0.004% to 0.024%, and stimulants of osmoreceptors—from 0.5% to 5%. A decrease in the contents of α-1-adrenomimetics and stimulants of osmoreceptors in a composition with diazepam below the indicated limits leads to a drastic decrease in the composition activity, whereas an increase in their concentration does not lead to a considerable potentiation of the effect of the composition.  
                                                                         TABLE V                           Potentiation of anticonvulsive effect of diazepam.                    Minimal effective dose* eliminating               seizures caused by pentylenetetrazole           Way of   (pentylenetetrazole dose 70 mg/kg IM)            Drug   administration   clonico-tonic seizures   clonic seizures                    Diazepam   IM**   6.7 ± 0.7   mg/kg   10   mg/kg***       Diazepam + phenylephrine   IM   1.2 ± 0.14   mg/kg   8.8 ± 0.9   mg/kg           IM   0.006   mg/kg   0.012   mg/kg       Diazepam + phenylephrine   IM   0.09 ± 0.011   mg/kg   1.8 ± 0.23   mg/kg           IM   0.012   mg/kg   0.024   mg/kg       Diazepam + midodrine   IM   0.78 ± 0.084   mg/kg   8.6 ± 0.95   mg/kg           IM   0.006   mg/kg   0.012   mg/kg       Diazepam + midodrine   IM   0.08 ± 0.009   mg/kg   1.6 ± 0.20   mg/kg           IM   0.012   mg/kg   0.024   mg/kg       Diazepam + phenylephrine + PVP   IM   0.03 ± 0.0033   mg/kg   0.5 ± 0.06   mg/kg           IM   0.005   mg/kg   0.01   mg/kg           IM   10   mg/kg   20   mg/kg       Diazepam + midodrine + PVP   IM   0.02 ± 0.0024   mg/kg   0.41 ± 0.05   mg/kg           IM   0.005   mg/kg   0.01   mg/kg           IM   10   mg/kg   20   mg/kg       Diazepam + phenylephrine + dextran   IM   0.02 ± 0.0026   mg/kg   0.45 ± 0.055   mg/kg           IM   0.005   mg/kg   0.01   mg/kg           IM   10   mg/kg   20   mg/kg       Diazepam + phenylephrine + PEO   IM   0.04 ± 0.045   mg/kg   0.70 ± 0.078   mg/kg           IM   0.005   mg/kg   0.01   mg/kg           IM   50   mg/kg   100   mg/kg       Diazepam   IG****   2.5 ± 0.3   mg/kg   10   mg/kg***       Diazepam + phenylephrine   IG   0.82 ± 0.089   mg/kg   8.6 ± 0.9   mg/kg           IG   0.006   mg/kg   0.012   mg/kg       Diazepam + phenylephrine   IG   0.06 ± 0.007   mg/kg   2.0 ± 0.22   mg/kg           IG   0.012   mg/kg   0.024   mg/kg       Diazepam + midodrine   IG   0.55 ± 0.062   mg/kg   8.5 ± 0.88   mg/kg           IG   0.006   mg/kg   0.012   mg/kg       Diazepam + midodrine   IG   0.05 ± 0.006   mg/kg   1.7 ± 0.21   mg/kg           IG   0.012   mg/kg   0.024   mg/kg       Diazepam + phenylephrine + xylitol   IG   0.02 ± 0.0024   mg/kg   0.65 ± 0.07   mg/kg           IG   0.004   mg/kg   0.01   mg/kg           IG   80   mg/kg   120   mg/kg       Diazepam + midodrine + xylitol   IG   0.015 ± 0.0017   mg/kg   0.62 ± 0.07   mg/kg           IG   0.004   mg/kg   0.01   mg/kg           IG   80   mg/kg   120   mg/kg       Diazepam + phenylephrine + PVP   IG   0.022 ± 0.0025   mg/kg   0.72 ± 0.082   mg/kg           IG   0.004   mg/kg   0.01   mg/kg           IG   40   mg/kg   80   mg/kg       Diazepam + phenylephrine + dextran   IG   0.013 ± 0.0016   mg/kg   0.6 ± 0.07   mg/kg           IG   0.004   mg/kg   0.01   mg/kg           IG   20   mg/kg   40   mg/kg       Diazepam + phenylephrine + PEO   IG   0.026 ± 0.003   mg/kg   0.82 ± 0.1   mg/kg           IG   0.004   mg/kg   0.01   mg/kg           IG   120   mg/kg   200   mg/kg       Diazepam + phenylephrine + sorbitol   IG   0.024 ± 0.028   mg/kg   0.80 ± 0.094   mg/kg           IG   0.004   mg/kg   0.01   mg/kg           IG   120   mg/kg   200   mg/kg                 *Minimal dose of diazepam preventing pentylenetetrazol seizures in 80% of rats.            **Hereinafter IM administered volume of the solution is 0.2 ml.            ***Prevents clonic pentylenetetrazole seizures in 20% of rats.            ****Hereinafter IG administered volume of the solution is 0.8 ml.             
 
       Example 5  
     Potentiation of the Effect of Neuroleptics  
       [0000]     a. Intramuscular Administration of Compositions  
         [0144]     The neuroleptic haloperidol at a dose of 0.15 mg/kg completely prevents the development of phenaminic stereotypy in 80% of rats. At a dose of 1 mg/kg haloperidol only partially eliminates behavioral toxicity caused by MK-801 (completely eliminates ataxia in 80% of rats, but insignificantly reduces stereotypy and hyperactivity). The results of administrating compositions in accordance with the invention are summarized in Table VI.  
         [0145]     Phenylephrine at a threshold dose (0.02 mg/kg) in a composition with haloperidol decrease its minimal effective dose causing a maximal antipsychotic effect (elimination of phenamine stereotypy in 80% of rats) times, respectively. They also potentiate an incomplete antipsychotic effect of haloperidol in the maximal dose (1 mg/kg) in MK-toxicity test (completely eliminates not only ataxia, but also hyperactivity and stereotypy in 80% of rats).  
         [0146]     A further increase at a dose of phenylephrine up to 0.04 mg/kg, which also does not cause an independent effect, not only potentiates the effect of haloperidol, but also decreases 4.4 times its minimal effective dose, eliminating MK-toxicity.  
         [0147]     The inclusion of a stimulant of osmoreceptors PVP into the composition with haloperidol and phenylephrine causes an additional decrease in the minimal effective dose of haloperidol in both tests of 3.0-3.1 times and at a dose of α-1-adrenomimetic in a tertiary composition by 4 times.  
         [0148]     Active ingredient contents in solutions of the compositions for potentiation was as follows: haloperidol—from 0.0005% to 0.1%, alpha-1-adrenomimetic—from 0.005% to 0.04%, and stimulants of osmoreceptors—from 1% to 2%. A decrease in the contents of phenylephrine and PVP in a composition with haloperidol below the indicated limits leads to a drastic decrease in the composition activity, whereas an increase in their concentration does not lead to a considerable potentiation of the effect of the composition.  
         [0000]     b) Intragastric Administration of Compositions  
         [0149]     Neuroleptic haloperidol at a dose of 0.18 mg/kg completely prevents the development of phenaminic stereotypy in 80% of rats. At a dose of 1 mg/kg haloperidol eliminates behavioral toxicity caused by MK-801 only partially (completely eliminates ataxia only).  
         [0150]     Phenylephrine at a threshold dose of 0.02 mg/kg in a composition with haloperidol decrease 13 times its minimal effective dose causing a maximal antipsychotic effect (elimination of phenaminic stereotypy in 80% of rats). They also potentiate a partial antipsychotic effect of haloperidol in the maximal dose (1 mg/kg) in MK-toxicity test (completely eliminates not only ataxia, but also hyperactivity and stereotypy in 80% of rats).  
         [0151]     A further increase at a threshold dose of phenylephrine up to 0.04 mg/kg causes both the potentiation of the effect of haloperidol and a 3.8-fold decrease of its minimal effective dose eliminating M-toxicity.  
         [0152]     The inclusion of a stimulant of osmoreceptors PVP into the composition with haloperidol and phenylephrine causes an additional decrease of the minimal effective dose of haloperidol in both tests 3.2-3.3 times and a decrease at a dose of phenylephrine 4 times.  
         [0153]     Active ingredient contents in solutions of the compositions for potentiation was as follows: haloperidol—from 0.0005% to 0.1%, α-1-adrenomimetics—from 0.005% to 0.04%, and stimulants of osmoreceptors—from 1% to 2%. A decrease in the contents of phenylephrine and PVP in a composition with haloperidol below the indicated limits leads to a drastic decrease in the composition activity, whereas an increase in their concentration does not lead to a considerable potentiation of the effect of the composition.  
                                                           TABLE 6                           Potentiation of antipsychotic effect of haloperidol                    Minimal dose of the drug   Minimal dose of the drug               preventing the   preventing the development           Way of   development of phenamine   of Mk-toxicity** in 80% of       Drug   administration   stereotypy* in 80% of rats.   rats.                    Haloperidol   IM***   0.15 ± 0.017   mg/kg   1   mg/kg****       Haloperidol + phenylephrine   IM   0.09 ± 0.01   mg/kg   0.89 ± 0.093   mg/kg           IM   0.01   mg/kg   0.02   mg/kg       Haloperidol + phenylephrine   IM   0.015 ± 0.0017   mg/kg   0.22 ± 0.026   mg/kg           IM   0.02   mg/kg   0.04   mg/kg       Haloperidol + phenylephrine + PVP   IM   0.005 ± 0.0006   mg/kg   0.07 ± 0.0076   mg/kg           IM   0.005   mg/kg   0.01   mg/kg           IM   10   mg/kg   20   mg/kg       Haloperidol   IG****   0.18 ± 0.022   mg/kg   1   mg/kg****       Haloperidol + phenylephrine   IG   0.14 ± 0.016   mg/kg   0.88 ± 0.095   mg/kg           IG   0.01   mg/kg   0.02   mg/kg       Haloperidol + phenylephrine   IG   0.016 ± 0.002   mg/kg   0.26 ± 0.029   mg/kg           IG   0.02   mg/kg   0.04   mg/kg       Haloperidol + phenylephrine + PVP   IG   0.005 ± 0.00056   mg/kg   0.08 ± 0.01   mg/kg           IG   0.005   mg/kg   0.01   mg/kg           IG   40   mg/kg   80   mg/kg                 *Phenamine in the dose of 10 mg/kg IM causes a behavioral stereotypy after 30-60 minutes.            **MK-801 (disocylpin) in the dose of 0.4 mg/kg IM causes a strong hyperactivity, stereotypy and ataxia after 20-30 minutes.            ***Hereinafter IM administered volume of the solution is 0.2 ml.            ****In the dose of 1 mg/kg (IM and IG) haloperidol eliminates ataxia in 80% of rats.            *****Hereinafter IG administered volume of the solution is 0.8 ml.             
 
       Example 6  
     Potentiation of the Effect of Psychostimulants  
       [0154]     The psychostimulant phenamine at a dose of 10 mg/kg IM and 20 mg/kg IG causes a marked behavioral stereotypy. IM or IG administration of phenamine in the composition with a threshold dose (0.02 mg/kg) of phenylephrine makes it possible to decrease the minimal effective dose of phenamine causing a maximally expressed stereotypy 4-5.3 times. The results of administrating compositions in accordance with the invention are summarized in Table VII.  
         [0155]     Additional inclusion of a stimulant of osmoreceptors PVP (IM, IG) into the composition of phenamine with phenylephrine at a doses, which do not potentiate independently the effect of phenamine, decreases 2.3-2.4 times the minimal effective dose of phenamine and, at the same time, decrease 3.3-4 times the dose of phenylephrine in the composition.  
         [0156]     A decrease at a dose of phenylephrine below 0.002 mg/kg and PVP below 20 mg/kg drastically decreases the activity of compositions with phenamine. An increase at a dose of phenylephrine above 0.02 mg/kg and PVP above 80 mg/kg does not considerably increase the activity of compositions with phenamine, but increases the risk of complications.  
                                               TABLE VII                           Potentiation of phenamine stereotypy in rats                    Minimal. dose of           Way of   phenamine causing       Drugs   administration   a behavioral stereotypy*                    Phenamine + distilled   IM   10.0 ± 1.1   mg/kg       water       Phenamine + PVP   IM   8.5 ± 0.9   mg/kg       20 mg/kg       Phenamine + phenylephrine   IM   9.2 ± 0.97   mg/kg       0.01 mg/kg       Phenamine + phenylephrine   IM   2.5 ± 0.29   mg/kg       0.02 mg/kg       Phenamine + phenylephrine   IM   1.1 ± 0.13   mg/kg       0.005 mg/kg + PVP       10 mg/kg       Phenamine + distilled   IG   20.2 ± 2.3   mg/kg       water       Phenamine + PVP   IG   17.8 ± 1.9   mg/kg       80 mg/kg       Phenamine + phenylephrine   IG   16.9 ± 1.8   mg/kg       0.01 mg/kg       Phenamine + phenylephrine   IG   3.8 ± 0.44   mg/kg       0.02 mg/kg       Phenamine + phenylephrine   IG   1.6 ± 0.14   mg/kg       0.005 mg/kg + PVP       40 mg/kg                 *Behavioral stereotypy caused by phenamine in the dose of 10 mg/kg IM.            **Hereinafter IM administered volume of the solution is 0.2 ml.            ***Hereinafter IG administered volume of the solution is 0.8 ml.             
 
       Example 7  
     Potentiation of CNS Drug by Cathecholamines  
       [0157]     It may be concluded from Table VIII, below, that catecholamines (e.g. epinephrine, dopamine, serotonin) potentiate the anticonvulsive action of diazepam threshold doses, when administered i.m. in a double composition with diazepam or triple composition with diazepam and PVP.  
                                               TABLE VIII                           Potentiation of anticonvulsive effect of diazepam by       cathecholamines                    Minimal effective dose*               eliminating clonicotonic               seizures caused by               pentylenetetrazole           Way of   (pentylenetetrazole       Drugs   administration   dose 70 mg/kg IM)                    Diazepame    IM**   6.7 ± 0.7   mg/kg       Diazepame + epinephrine   IM   1.5 ± 0.18   mg/kg           IM   0.01   mg/kg       Diazepame + epinephrine   IM   0.25 ± 0.3   mg/kg           IM   0.02   mg/kg       Diazepame + epinephrine+   IM   0.09 ± 0.01   mg/kg       PVP   IM   0.01   mg/kg           IM   10   mg/kg       Dizepame + dopamine   IM   1.3 ± 0.15   mg/kg           IM   0.01   mg/kg       Dizepame + dopamine   IM   0.12 ± 0.014   mg/kg           IM   0.02   mg\kg       Diazepame + dopamine +   IM   0.04 ± 0.0046   mg/kg           IM   0.01   mg\kg       PVP   IM   10   mg/kg       Diazepame + serotonin   IM   1.4 ± 0.16   mg\kg           IM   0.006   mg\kg       Diazepame + serotonin   IM   0.17 ± 0.02   mg/kg           IM   0.012   mg\kg       Diazepame + serotonin + PVP   IM   0.06 ± 0.007   mg/kg           IM   0.005   mg\kg           IM   10   mg\kg                 *Minimal dose of diazepam preventing pentylenetetrazol seizures in 80% of rats..            **Hereinafter IM administered volume of the solution is 0.2 ml             
 
       Example 8  
     Comparison of Prior Art Compositions and Composition of the Invention  
       [0158]     Although it is known to potentiate CNS active drugs by osmoreceptor stimulators, the results obtained by combining the above two components together with a compound which affects peripheral chemoreceptors are significantly and unexpectedly improved, as illustrated in the following tables.  
                                                                   TABLE IX                           Comparative results of potentiation of analgesic effect of       Dipyrone:                        “tail-flick” test   Hyperalgesia test           Drug or   Way Of   Dose causing maximal   Dose causing maximal           Composition   Administration   analgesia   analgesia                        a   Dipyrone   IM   1.5 ± 0.18   mg/kg   20.2 ± 2.3   mg/kg           PVP   IM   20   mg/kg   40   mg/kg       b   Dipyrone   IM   0.06 ± 0.007   mg/kg   1.6 ± 0.19   mg/kg           PVP   IM   5   mg/kg   10   mg/kg           phenylephrine   IM   0.003   mg/kg   0.005   mg/kg       a   Dipyrone   IM   2.0 ± 0.24   mg/kg   24.5 ± 2.8   mg/kg           dextran   IM   10   mg/kg   20   mg/kg       b   Dipyrone   IM   0.06 ± 0.007   mg/kg   1.9 ± 0.22   mg/kg           Dextran   IM   2.5   mg/kg   5   mg/kg           phenylephrine   IM   0.003   mg/kg   0.005   mg/kg       a   Dipyrone   IM   2.5 ± 0.29   mg/kg   31.2 ± 3.5   mg/kg           PEO   IM   30   mg/kg   60   mg/kg       b   Dipyrone   IM   0.09 ± 0.01   mg/kg   2.5 ± 0.29   mg/kg           PEO   IM   10   mg/kg   20   mg/kg           phenylephrine   IM   0.003   mg/kg   0.005   mg/kg       a   Dipyrone   IG   6.2 ± 0.7   mg/kg   20.4 ± 2.2   mg/kg           PVP   IG   20   mg/kg   40   mg/kg       b   Dipyrone   IG   0.05 ± 0.0068   mg/kg   1.2 ± 0.14   mg/kg           PVP   IG   8   mg/kg   16   mg/kg           Phenylephrine   IG   0.001   mg/kg   0.002   mg/kg       a   Dipyrone   IG   3.9 ± 0.44   mg/kg   17.5 ± 1.9   mg/kg           Dextran   IG   10   mg/kg   20   mg/kg       b   Dipyrone   IG   0.04 ± 0.005   mg/kg   1.4 ± 0.16   mg/kg           Dextran   IG   4   mg/kg   8   mg/kg           phenylephrine   IG   0.001   mg/kg   0.002   mg/kg       a   Dipyrone   IG   6.5 ± 0.73   mg/kg   27.4 ± 2.9   mg/kg           PEO   IG   40   mg/kg   80   mg/kg       b   Dipyrone   IG   0.05 ± 0.0055   mg/kg   1.9 ± 0.23   mg/kg           PEO   IG   16   mg/kg   32   mg/kg           phenylephrine   IG   0.001   mg/kg   0.002   mg/kg       a   Dipyrone   IG   4.5 ± 0.5   mg/kg   14.6 ± 1.6   mg/kg           xylitol   IG   20   mg/kg   40   mg/kg       b   Dipyrone   IG   0.03 ± 0.004   mg/kg   0.8 ± 0.09   mg/kg           xylitol   IG   4   mg/kg   8   mg/kg           phenylephrine   IG   0.001   mg/kg   0.002   mg/kg       a   Dipyrone   IG   5.2 ± 0.5   mg/kg   18.5 ± 1.9   mg/kg           sorbitol   IG   40   mg/kg   80   mg/kg       b   Dipyrone   IG   0.06 ± 0.007   mg/kg   2.5 ± 0.20   mg/kg           sorbitol   IG   8   mg/kg   16   mg/kg           phenylephrine   IG   0.001   mg/kg   0.002   mg/kg                 a) Dipyrone + osmoreceptor stimulant            b) Dipyrone + osmoreceptor stimulant + peripheral α-1-adrenomimetic ingredient             
 
         [0159]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE X 
               
             
             
               
                   
               
               
                   
               
               
                 Comparative results of potentiation of anti-depressive 
               
               
                 effect of amitryptiline 
               
             
          
           
               
                   
                   
                   
                   
                 Porsolt&#39;s test. Dose.Group 
               
               
                   
                   
                 Way of 
                 Porsolt&#39;s test. Dose. 
                 of highly-active rats with 
               
               
                   
                 Drug 
                 Administration 
                 Group of low-active rats 
                 MPTP depression 
               
               
                   
                   
               
             
          
           
               
                 a 
                 Amitriptyline 
                 IM 
                 0.4 ± 0.045 
                 mg/kg 
                 0.6 ± 0.07 
                 mg/kg 
               
               
                   
                 PVP 
                 IM 
                 20 
                 mg/kg 
                 20 
                 mg/kg 
               
               
                 b 
                 Amitriptyline 
                 IM 
                 0.02 ± 0.0023 
                 mg/kg 
                 0.03 ± 0.0035 
                 mg/kg 
               
               
                   
                 PVP 
                 IM 
                 10 
                 mg/kg 
                 10 
                 mg/kg 
               
               
                   
                 phenylephrine 
                 IM 
                 0.0006 
                 mg/kg 
                 0.001 
                 mg/kg 
               
               
                 a 
                 Amitriptyline 
                 IM 
                 0.3 ± 0.035 
                 mg/kg 
                 0.5 ± 0.06 
                 mg/kg 
               
               
                   
                 Dextran 
                 IM 
                 10 
                 mg/kg 
                 10 
                 mg/kg 
               
               
                 b 
                 Amitriptyline 
                 IM 
                 0.02 ± 0.0023 
                 mg/kg 
                 0.03 ± 0.0035 
                 mg/kg 
               
               
                   
                 Dextran 
                 IM 
                 5 
                 mg/kg 
                 5 
                 mg/kg 
               
               
                   
                 phenylephrine 
                 IM 
                 0.001 
                 mg/kg 
                 0.0015 
                 mg/kg 
               
               
                 a 
                 Amitriptyline 
                 IM 
                 0.5 ± 0.07 
                 mg/kg 
                 0.8 ± 0.09 
                 mg/kg 
               
               
                   
                 PEO 
                 IM 
                 30 
                 mg/kg 
                 30 
                 mg/kg 
               
               
                 b 
                 Amitriptyline 
                 IM 
                 0.025 ± 0.003 
                 mg/kg 
                 0.04 ± 0.005 
                 mg/kg 
               
               
                   
                 PEO 
                 IM 
                 15 
                 mg/kg 
                 15 
                 mg/kg 
               
               
                   
                 phenylephrine 
                 IM 
                 0.001 
                 mg/kg 
                 0.0015 
                 mg/kg 
               
               
                 a 
                 Amitriptyline 
                 IG 
                 0.5 ± 0.06 
                 mg/kg 
                 0.72 ± 0.084 
                 mg/kg 
               
               
                   
                 PVP 
                 IG 
                 30 
                 mg/kg 
                 30 
                 mg/kg 
               
               
                 b 
                 Amitriptyline 
                 IG 
                 0.022 ± 0.0026 
                 mg/kg 
                 0.04 ± 0.0045 
                 mg/kg 
               
               
                   
                 PVP 
                 IG 
                 12 
                 mg/kg 
                 12 
                 mg/kg 
               
               
                   
                 Phenylephrine + B57 
                 IG 
                 0.0007 
                 mg/kg 
                 0.001 
                 mg/kg 
               
               
                 a 
                 Amitriptyline 
                 IG 
                 0.33 ± 0.037 
                 mg/kg 
                 0.52 ± 0.06 
                 mg/kg 
               
               
                   
                 Dextran 
                 IG 
                 20 
                 mg/kg 
                 20 
                 mg/kg 
               
               
                 b 
                 Amitriptyline 
                 IG 
                 0.012 ± 0.0014 
                 mg/kg 
                 0.018 ± 0.0023 
                 mg/kg 
               
               
                   
                 Dextran 
                 IG 
                 8 
                 mg/kg 
                 8 
                 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.0005 
                 mg/kg 
                 0.001 
                 mg/kg 
               
               
                 a 
                 Amitriptyline 
                 IG 
                 0.55 ± 0.06 
                 mg/kg 
                 0.75 ± 0.09 
                 mg/kg 
               
               
                   
                 PEO 
                 IG 
                 80 
                 mg/kg 
                 80 
                 mg/kg 
               
               
                 b 
                 Amitriptyline 
                 IG 
                 0.025 ± 0.003 
                 mg/kg 
                 0.045 ± 0.0053 
                 mg/kg 
               
               
                   
                 PEO 
                 IG 
                 32 
                 mg/kg 
                 32 
                 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.0007 
                 mg/kg 
                 0.00014 
                 mg/kg 
               
               
                 a 
                 Amitriptyline 
                 IG 
                 0.31 ± 0.035 
                 mg/kg 
                 0.45 ± 0.05 
                 mg/kg 
               
               
                   
                 xylitol 
                 IG 
                 20 
                 mg/kg 
                 20 
                 mg/kg 
               
               
                 b 
                 Amitriptyline 
                 IG 
                 0.016 ± 0.0021 
                 mg/kg 
                 0.03 ± 0.0035 
                 mg/kg 
               
               
                   
                 xylitol 
                 IG 
                 8 
                 mg/kg 
                 8 
                 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.0005 
                 mg/kg 
                 0.001 
                 mg/kg 
               
               
                 a 
                 Amitriptyline 
                 IG 
                 0.63 ± 0.071 
                 mg/kg 
                 0.91 ± 0.1 
                 mg/kg 
               
               
                   
                 sorbitol 
                 IG 
                 40 
                 mg/kg 
                 40 
                 mg/kg 
               
               
                 b 
                 Amitriptyline 
                 IG 
                 0.025 ± 0.0029 
                 mg/kg 
                 0.038 ± 0.0046 
                 mg/kg 
               
               
                   
                 sorbitol 
                 IG 
                 16 
                 mg/kg 
                 16 
                 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.0006 
                 mg/kg 
                 0.0012 
                 mg/kg 
               
               
                   
               
               
                   a) Amitriptyline + osmoreceptor stimulant    
               
               
                   b) Amitriptyline + osmoreceptor stimulant + peripheral α-1 adrenomimetic stimulant    
               
             
          
         
       
     
         [0160]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE XI 
               
             
             
               
                   
               
               
                   
               
               
                 Comparative results of potentiation of antiparkinson 
               
               
                 effect of memantine: 
               
             
          
           
               
                   
                   
                   
                 Minimal Effective dose of drug 
               
               
                   
                   
                 Way of 
                 eliminating catalepsy caused by 
               
               
                   
                 Drug 
                 Administration 
                 haloperidol at a dose of 1 mg/kg 
               
               
                   
                   
               
             
          
           
               
                 a 
                 Memantine 
                 IM 
                  1.4 ± 0.16 mg/kg 
               
               
                   
                 PVP 
                 IM 
                   20 mg/kg 
               
               
                 b 
                 Memantine 
                 IM 
                 0.15 ± 0.02 mg/kg 
               
               
                   
                 PVP 
                 IM 
                   10 mg/kg 
               
               
                   
                 phenylephrine 
                 IM 
                 0.005 mg/kg 
               
               
                 a 
                 Memantine 
                 IM 
                  1.8 ± 0.2 mg/kg 
               
               
                   
                 dextran 
                 IM 
                   20 mg/kg 
               
               
                 b 
                 Memantine 
                 IM 
                 0.18 ± 0.022 mg/kg 
               
               
                   
                 Dextran 
                 IM 
                   10 mg/kg 
               
               
                   
                 phenylephrine 
                 IM 
                 0.005 mg/kg 
               
               
                 a 
                 Memantine 
                 IM 
                  2.2 ± 0.24 mg/kg 
               
               
                   
                 PEO 
                 IM 
                   40 mg/kg 
               
               
                 b 
                 Memantine 
                 IM 
                 0.19 ± 0.023 mg/kg 
               
               
                   
                 PEO 
                 IM 
                   20 mg/kg 
               
               
                   
                 phenylephrine 
                 IM 
                 0.005 mg/kg 
               
               
                 a 
                 Memantine 
                 IG 
                  4.5 ± 0.5 mg/kg 
               
               
                   
                 PVP 
                 IG 
                   80 mg/kg 
               
               
                 b 
                 Memantine 
                 IG 
                 0.28 ± 0.034 mg/kg 
               
               
                   
                 PVP 
                 IG 
                   40 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.005 mg/kg 
               
               
                 a 
                 Memantine 
                 IG 
                  4.8 ± 0.54 mg/kg 
               
               
                   
                 dextran 
                 IG 
                   80 mg/kg 
               
               
                 b 
                 Memantine 
                 IG 
                  0.2 ± 0.024 mg/kg 
               
               
                   
                 Dextran 
                 IG 
                   40 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.005 mg/kg 
               
               
                 a 
                 Memantine 
                 IG 
                  4.9 ± 0.55 mg/kg 
               
               
                   
                 PEO 
                 IG 
                   400 mg/kg 
               
               
                 b 
                 Memantine 
                 IG 
                 0.35 ± 0.044 mg/kg 
               
               
                   
                 PEO 
                 IG 
                   200 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.005 mg/kg 
               
               
                 a 
                 Memantine 
                 IG 
                  5.2 ± 0.56 mg/kg 
               
               
                   
                 xylitol 
                 IG 
                   160 mg/kg 
               
               
                 b 
                 Memantine 
                 IG 
                 0.24 ± 0.047 mg/kg 
               
               
                   
                 xylitol 
                 IG 
                   80 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.005 mg/kg 
               
               
                 a 
                 Memantine 
                 IG 
                  5.7 ± 0.63 mg/kg 
               
               
                   
                 sorbitol 
                 IG 
                   320 mg/kg 
               
               
                 b 
                 Memantine 
                 IG 
                 0.32 ± 0.036 mg/kg 
               
               
                   
                 sorbitol 
                 IG 
                   160 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.005 mg/kg 
               
               
                   
               
               
                   a) memantine + osmoreceptor stimulant    
               
               
                   b) memantine + osmoreceptor stimulant + peripheral α-1 adrenomimetic stimulant    
               
             
          
         
       
     
         [0161]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE XII 
               
             
             
               
                   
               
               
                   
               
               
                 Comparitive results of potentiation of anticonvulsive 
               
               
                 effect of diazepam: 
               
             
          
           
               
                   
                   
                   
                 Minimal Effective dose 
               
               
                   
                   
                   
                 of drug eliminating 
               
               
                   
                   
                   
                 seizures caused by 
               
               
                   
                   
                 Way of 
                 pentylentetrazole 
               
               
                   
                 Drug 
                 Administration 
                 (D9 70 mg/kg I.M.) 
               
               
                   
                   
               
             
          
           
               
                 a 
                 diazepam 
                 IM 
                  1.5 ± 17 mg/kg 
               
               
                   
                 PVP 
                 IM 
                   20 mg/kg 
               
               
                 b 
                 diazepam 
                 IM 
                  0.03 ± 0.0033 mg/kg 
               
               
                   
                 PVP 
                 IM 
                   10 mg/kg 
               
               
                   
                 phenylephrine 
                 IM 
                 0.005 mg/kg 
               
               
                 a 
                 diazepam 
                 IM 
                  1.0 ± 0.12 mg/kg 
               
               
                   
                 dextran 
                 IM 
                   20 mg/kg 
               
               
                 b 
                 diazepam 
                 IM 
                  0.02 ± 0.0026 mg/kg 
               
               
                   
                 Dextran 
                 IM 
                   10 mg/kg 
               
               
                   
                 phenylephrine 
                 IM 
                 0.005 mg/kg 
               
               
                 a 
                 diazepam 
                 IM 
                  1.3 ± 0.16 mg/kg 
               
               
                   
                 PEO 
                 IM 
                   50 mg/kg 
               
               
                 b 
                 diazepam 
                 IM 
                  0.04 ± 0.0045 mg/kg 
               
               
                   
                 PEO 
                 IM 
                   25 mg/kg 
               
               
                   
                 phenylephrine 
                 IM 
                 0.005 mg/kg 
               
               
                 a 
                 diazepam 
                 IG 
                  0.4 ± 0.0045 mg/kg 
               
               
                   
                 PVP 
                 IG 
                   80 mg/kg 
               
               
                 b 
                 diazepam 
                 IG 
                 0.022 ± 0.0025 mg/kg 
               
               
                   
                 PVP 
                 IG 
                   40 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.004 mg/kg 
               
               
                 a 
                 diazepam 
                 IG 
                  0.2 ± 0.023 mg/kg 
               
               
                   
                 dextran 
                 IG 
                   40 mg/kg 
               
               
                 b 
                 diazepam 
                 IG 
                 0.013 ± 0.0016 mg/kg 
               
               
                   
                 Dextran 
                 IG 
                   20 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.004 mg/kg 
               
               
                 a 
                 diazepam 
                 IG 
                  0.53 ± 0.58 mg/kg 
               
               
                   
                 PEO 
                 IG 
                   240 mg/kg 
               
               
                 b 
                 diazepam 
                 IG 
                 0.026 ± 0.003 mg/kg 
               
               
                   
                 PEO 
                 IG 
                   120 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.004 mg/kg 
               
               
                 a 
                 diazepam 
                 IG 
                  0.38 ± 0.044 mg/kg 
               
               
                   
                 xylitol 
                 IG 
                   160 mg/kg 
               
               
                 b 
                 diazepam 
                 IG 
                  0.02 ± 0.0024 mg/kg 
               
               
                   
                 xylitol 
                 IG 
                   80 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.004 mg/kg 
               
               
                 a 
                 diazepam 
                 IG 
                  0.52 ± 0.055 mg/kg 
               
               
                   
                 sorbitol 
                 IG 
                   240 mg/kg 
               
               
                 b 
                 diazepam 
                 IG 
                 0.024 ± 0.0028 mg/kg 
               
               
                   
                 sorbitol 
                 IG 
                   120 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.004 mg/kg 
               
               
                   
               
               
                   a) diazepam + osmoreceptor stimulant    
               
               
                   b) diazepam + osmoreceptor stimulant + peripheral α-1-adrenomimetic stimulant    
               
             
          
         
       
     
         [0162]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE XIII 
               
             
             
               
                   
               
               
                   
               
               
                 Comparative results of potentiation of antipsychotic 
               
               
                 effect of haloperidol: 
               
             
          
           
               
                   
                   
                   
                 Minimal dose of 
                 Minimal dose of 
               
               
                   
                   
                   
                 the drug preventing 
                 the drug preventing 
               
               
                   
                   
                 Way of 
                 the development of 
                 the development of MK- 
               
               
                   
                 Drug 
                 Administration 
                 phenamine stereotypy 
                 toxicity in 80% of rats 
               
               
                   
                   
               
             
          
           
               
                 a 
                 haloperidol 
                 IM 
                  0.07 ± 0.008 mg/kg 
                 0.45 ± 0.05 mg/kg 
               
               
                   
                 PVP 
                 IM 
                   20 mg/kg 
                   40 mg/kg 
               
               
                 b 
                 haloperidol 
                 IM 
                 0.005 ± 0.0006 mg/kg 
                 0.07 ± 0.008 mg/kg 
               
               
                   
                 PVP 
                 IM 
                   10 mg/kg 
                   20 mg/kg 
               
               
                   
                 phenylephrine 
                 IM 
                 0.005 mg/kg 
                 0.01 mg/kg 
               
               
                 a 
                 haloperidol 
                 IG 
                  0.05 ± 0.006 mg/kg 
                 0.48 ± 0.055 mg/kg 
               
               
                   
                 PVP 
                 IG 
                   80 mg/kg 
                  160 mg/kg 
               
               
                 b 
                 haloperidol 
                 IG 
                 0.005 ± 0.00056 mg/kg 
                 0.08 ± 0.01 mg/kg 
               
               
                   
                 PVP 
                 IG 
                   40 mg/kg 
                   80 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.005 mg/kg 
                 0.01 mg/kg 
               
               
                   
               
               
                   a) haloperidol + osmoreceptor stimulant    
               
               
                   b) haloperidol + osmoreceptor stimulant + peripheral α-1-adrenomimetic stimulant    
               
             
          
         
       
     
         [0163]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE XIV 
               
             
             
               
                   
               
               
                   
               
               
                 Comparative results of potentiation of psychostimulant 
               
               
                 effect of phenamine: 
               
             
          
           
               
                   
                   
                   
                 Minimal dose of 
               
               
                   
                   
                 Way Of 
                 phenamine causing 
               
               
                   
                 Drug 
                 Administration 
                 behavioral stereotypy 
               
               
                   
                   
               
             
          
           
               
                 a 
                 phenamine 
                 IM 
                  8.5 ± 0.9 mg/kg 
               
               
                   
                 PVP 
                 IM 
                   20 mg/kg 
               
               
                 b 
                 phenamine 
                 IM 
                  1.1 ± 0.13 mg/kg 
               
               
                   
                 PVP 
                 IM 
                   10 mg/kg 
               
               
                   
                 phenylephrine 
                 IM 
                 0.005 mg/kg 
               
               
                 a 
                 phenamine 
                 IG 
                 17.8 ± 1.9 mg/kg 
               
               
                   
                 PVP 
                 IG 
                   80 mg/kg 
               
               
                 b 
                 phenamine 
                 IG 
                  1.6 ± 0.14 mg/kg 
               
               
                   
                 PVP 
                 IG 
                   40 mg/kg 
               
               
                   
                 phenylephrine 
                 IG 
                 0.005 mg/kg 
               
               
                   
               
               
                   a) phenamine + osmoreceptor stimulant    
               
               
                   b) phenamine + osmoreceptor stimulant + peripheral α-1-adrenomimetic stimulant