Anesthetic composition comprising nmda-antagonist and alpha-2-adrenergic agonist

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention proposes the composition comprising xenon as NMDA-antagonist and alpha-2-adrenergic agonist used for treatment of tetanus or narcotics (alcohol) withdrawal syndrome, states with chronic pain syndrome. Also, invention relates to the anesthetic composition comprising xenon and alpha-2-adrenergic agonist and to a method for anesthesia. The synergistic interaction of xenon as NMDA-antagonist and alpha-2-adrenergic agonist provides reducing the dose and to maintain the prolonged effectiveness by prevention for arising the drug habitation to the claimed preparation.

EFFECT: valuable medicinal properties of composition.

9 cl, 6 dwg, 6 ex

 

Background of invention and prior art

The present invention relates to a new composition which is able to provide one or more beneficial therapeutic effects. As an example, the new composition can provide any one or more effects, including General anesthesia, analgesia, sedation with maintaining wakefulness and neuroprotection.

The state of General anesthesia involves several elements, namely, analgesia (or insensitivity to malicious stimulus), loss of consciousness (hypnosis reaction), the weakening of the reactions of the sympathetic nervous system on the harmful stimulus (sympatholysis), interrupt memory formation in an adverse event and relaxation of muscles.

The state of General anesthesia is usually caused by a combination of several drugs from different pharmacological classes, because there is currently no single class of compounds alone provides the ideal properties that are required. For example, potent volatile anesthetic agents such as halogenated ethers, and haloalkane, can undergo biological transformation in potentially toxic agents. These agents also cause agitation after the release of anesthesia. Inhalation means,such as nitrous oxide and xenon, not considered sufficiently active for use as monotherapy, while sedative/hypnotics means (including propofol, benzodiazepines and Barbiturate) are devoid of analgesic properties. Analgesic agent or cause severe respiratory depression requiring auxiliary artificial lung ventilation (in the case of the use of opioids) or not give hypnotic reactions (not opioids), while perifericheskie acting muscle relaxants (e.g., vecuronium and atracurium) have no analgesic or hypnotic properties.

With regard to the prior art, it is clear that there are a number of disadvantages associated with currently used drugs for General anesthesia. First, there is a need for specialized delivery systems of drugs, in particular, to potent volatile anesthetics. This necessity can be avoided by use of the intravenous route of administration (General intravenous anesthesia, otherwise known as the TIVA). However, current schemes TIVA inevitably include analgesic tools (e.g., opiate drugs), which cause respiratory depression, and sleeping pills (propofol and barbiturates), which cause suppression of cardiac activity, thus requiring equipment for auxiliary artificially the ventilation and auxiliary circulation at the time of their application. Secondly, the termination of the clinical effect TIVA requires or biological transformation and/or excretion of basic drugs and their metabolites, which can lead to problems associated with toxic effects on organs. Other disadvantages of these drugs (all except propofol) include the long exit anesthesia, associated with agitation, nausea and vomiting, high potential dependencies along with a narrow window of therapeutic efficacy. Finally, there is also a threat to the environment, associated with the destruction of the ozone layer nitrous oxide.

The present invention is directed to providing an improved composition for General pharmaceutical applications, in particular for use in anesthesia.

A statement of the substance of the invention

Aspects of the present invention represented in the accompanying claims and the following description.

Detailed description

In a broad aspect the present invention provides a pharmaceutical agent comprising a NMDA antagonist and alpha-2 adrenergic agonist.

In the preferred embodiment implementation of the present invention provides an anesthetic comprising a NMDA antagonist and alpha-2 adrenergic agonist.

Unexpectedly, it was found that co-administration of the antagonist of NMDA receptors and alpha-2 adrenergic the ski agonist, preferably in the form of a single combination of drugs, not only enhances the effectiveness of individual compounds through a synergistic mechanism, but also reduces the likelihood of adverse and unwanted side effects that these drugs can cause, when applied separately.

One of the essential components of the composition is an antagonist of NMDA receptors.

The term “antagonist” is used in its ordinary sense in this area, ie, a chemical compound that prevents the functional activation of the receptor by its agonist (in this case, NMDA).

NMDA receptor (the receptor N-methyl-D-aspartate) is the subclass of glutamate receptors, the most important excitatory neurotransmitter in the Central nervous system of mammals). It is important that the activation of NMDA receptors, as has been shown, is the Central phenomenon that leads to toxicity, leading to neuronal death in many pathological conditions, and also as a result of hypoxia and ischemia after head injury, shock, and after the heart stops.

In this area it is known that NMDA receptors play an important role in many higher cognitive functions such as memory and learning, as well as in specific nociceptive pathways and pain perception (Collingridge et al., The NMDA eceptor, Oxford University Press, 1994). In addition, certain properties of NMDA receptors suggests that they may participate in information processing in the brain, which lies at the basis of consciousness as such.

Antagonists of NMDA receptors in the context of the present invention have advantages for a number of reasons, such as the following three specific reasons. First, antagonists of NMDA receptors provide profound analgesia, being a very desirable component of General anesthesia and sedative action.

Secondly, antagonists of NMDA receptors exert a neuroprotective effect in many clinically relevant to the issue of the circumstances (including ischemia, brain trauma, neuropathic pain condition and certain types of seizures). Thirdly, antagonists of NMDA receptors provide a significant degree of amnesia.

The composition may include one or more antagonists of NMDA receptors.

In contrast to previously known methods of application of antagonists of NMDA receptors in the practice of General anesthesia was unexpectedly found that compositions of the present invention to their application there are no serious obstacles, despite their accompanying psychotomimetics effects and other unwanted side effects. The problems of the prior art associated with this class of compounds included singing is of involuntary movements, stimulation of the sympathetic nervous system, neurotoxic effects, which they caused in high doses (significantly as antagonists of NMDA receptors have low activity as a General anesthetics), depression of the myocardium, predatory in some epileptic conditions, for example, “increasing excitation” (Wlaz P, et al., Eur.J.Neurosci. 1994; 6: 1710-1719). The complexity of creating antagonists, which penetrate through the blood-brain barrier, also limited their practical application.

In more detail, the antagonists of the NMDA receptor of the present invention can provide a competitive antagonists such as 2-amino-5-phosphonopentanoate and 2-amino-7-phosphonopentanoate, or their derivatives or structural analogues. Antagonists of NMDA receptors can also be a non-competitive antagonists, such as dizocilpine, ketamine, ON-966 [(+/-)-3-amino-l-hydroxy-2-pyrrolidone] or their derivatives or structural analogues.

Preferably, the antagonist of NMDA receptors is a xenon.

The advantage of using an inert, volatile gas, such as xenon, as a means of General anesthesia is that its molecule can rapidly excreted through the breath.

In this regard, it was recently revealed that xenon (which quickly reaches equilibrium in the brain) NMDA antagonist (Franks NP, et al., Nature 1998;396:324), which makes it a particularly attractive candidate in the context of the present invention.

Xenon is a chemically inert gas, anaesthetic properties which have been known for more than 50 years (Lawrence JH, et al., J.Physiol. 1946; 105:197-204). Since its first application in surgery (Cullen SC et al, Science 1951; 113: 580-582), several research groups have shown that it has an excellent pharmacological profile, including the absence of metabolic by-products, profound analgesia, rapid onset of anesthesia and logoff, and minimal effects on the cardiovascular system (Lachmann In et al., Lancet 1990; 335: 1413-1415; Kennedy RR, et al., Anaesth. Intens. Care 1992; 20: 66-70; Luttropp HH et al., Acta Anaesthesiol. Scand. 1994; 38: 121-125; Goto T et al., Anesthesiology 1997; 86: 1273-1278; Marx T, et al., Br. J. Anaesth. 1997; 78: 326-327). Mechanistic studies on cultured hippocampal neurons showed that xenon at a concentration of 80%, which will maintain surgical anesthesia, reduces the currents activated NMDA, until the level reaches 60%. This is a powerful inhibition of NMDA receptors explains some of the important characteristics of the pharmacological profile and can probably contribute to the anesthetic and analgesic effects of this inert gas.

To date a significant problem that prevented the use of xenon as a new anesthetic, was it the high cost and the need to use complex devices to minimize the volume used (low flow system), along with the need to collect landfill gas for reuse. Another problem was that the activity of xenon is relatively low. As a consequence, it was assumed that the volatile General anesthetics can solubilisates in the lipid emulsion and injected intravenously (Eger RP et al., Can.J.Anaesth. 1995; 42:173-176). In this area it is known that local anesthesia can be caused vnutriaortalina injection microdroplets General anesthetic in liquid form (Haynes DH, U.S. patent No. 4725442 and 4622219). Usually these microcephaly covered unimolecularly phospholipid layer and remain sustainable in physiologically compatible solutions. A similar approach is described in a recently filed patent application, in which there is the possibility of introducing xenon thus (Georgieff M, the application for the European patent No. 864329 A1).

It should be noted that in the prior art was not disclosed and was not offered the use of an antagonist of NMDA receptors with alpha-2 adrenergic agonist in the composition, which would have wide applicability, especially for use as an anesthetic, not to mention unexpected properties associated with it.

Another essential component of the composition is alpha-2 adrenergic agonist. The term “agonist” is used in its ordinary sense in this area, ie, the chemical is connected to the e, which functionally activates the receptor, with which it is associated.

Alpha-2 adrenergic receptors (adrenoceptors) are widely distributed in both the nervous system and all other systems in the body. Including three different receptor subtypes (called a, b and C), alpha-2 adrenoceptor activated non-selective endogenous adrenergic agonists epinephrine and norepinephrine, which also activate six other subtypes adrenoceptors.

To date, the interest of anesthesiologists focused on reducing needs anesthetics, because experimental and clinical studies have shown that alpha-2 agonists have potent analgesic (Guo T, et al., Anesthesiology 1991; 75: 252-6) and anesthetic effects. It is believed that the hypnotic response is mediated by activation of alpha-2 adrenoceptors in the locus coeruleus, while analgesia caused by the modulation of the nociceptive pathway at the level of the dorsal horn of the spinal cord and in other areas not yet fully characterized (Guo T, et al., ibid.).

Thus, in the period associated with surgery, alpha-2 adrenergic agonists are effective to reduce the requirements for volatile anesthetics (Aho M, et al., Anesthesiology 1991; 74: 997-1002), opioid (Ghignone M, et al., Anesthesiology 1986; 64: 36-42) and hypnotic agents (Aantaa R, et al., Anesthesiology 1990; 73: 230-5. In addition, alpha-2 adrenergic agonists are also effective as anxiolytics (Uhde TW et al, Arch Gen Psychiatry 1989; 46: 170-7) and to provide preoperative sedation (Flaske JW et al., Anesthesiology 1987; 67: 11-9) in the period associated with the operation.

More specifically, exogenous alpha-2 agonists, such as dexmedetomidine cause loss of consciousness in experimental animals by activating alpha-2A subtype of adrenoceptors (Lakhlani PP, et al., Proc. Nat. Acad. Sci. 1997; 94: 9950-9955) in a discrete area in the brain stem (Correa-Sales et al., Anesthesiol s; 76: 948-52). Upon activation by its agonist of this receptor subtype also reduces anxiety (anxiolytic effect) (Salonen M, et al., Psychopharmacology 1992; 108: 229-234) and activity in the sympathetic nervous system (sympatholysis). Alpha-2 agonists are also anticonvulsant drugs in some types of epileptic disorders (Halonen T, et al., Brain Res. 1995; 6932: 17-24) and are neuroprotective agents during ischemic lesions (Maier With et al., Anesthesiology 1993; 79: 306-12).

The state of sleep caused by alpha-2 agonist, may be immediately removed selective alpha-2 adrenergic antagonists (e.g., yohimbine). Alpha-2 agonists decrease the excitation associated with the exit from the state of anesthesia, caused by volatile anaesthetic agents (Bruandet N et al., Anesth. Play mode display. 1998; 86: 240-5).

Up to the present time, p is the physical alteration of agonists alpha-2 adrenoceptors a total anaesthetic practice was hampered by their lack of anesthetic activity and side effect profile. Insufficient activity requires the use of very high doses, which can not activate alpha-2A adrenoceptor, which leads to constriction of peripheral blood vessels to increase blood pressure (Bloor SU et al., nsthesiology 1992; 77: 1134-1142) and reduced tissue perfusion. In addition, alpha-2 agonists are agents that cause seizures, on some models of epilepsy (“pentylenetetrazole” [reserve] epileptic seizures) (Mirski MA et al., Anesthesiology 1994; 81: 1422-8).

In this field it is well known that such alpha-2 agonists like clonidine, dexmedetomidine and with the systemic administration, and neuroaxial introduction relieve pain in humans and in experimental animal models. Alpha-2 agonists cause analgesia supraspinally (Guo TZ et al., ibid.), as well as local spinal action (Eisenach J, et al., Anesthesiol. 1993: 277-87). Unlike local anesthetics, alpha-2 agonists do not alter motor or sensory function, and, unlike opiates, they do not cause respiratory depression (Jarvis DA, et al., Anesthesiology 1992; 76: 899-905) or do not cause behavior in search of the drug (i.e. dependence). As a result of these signs of an alpha-2 adrenergic agonists are attractive candidates for the treatment of pain, and they are effective for reducing postoperative pain syndrome (Bonnet F, et al., Br J Anaesth 1989; 63: 465-9) and the La pain relief during and after childbirth (Eisenach JC, et al., Anesthesiology 1989; 71: 640-6; Filos KS, et al., Anesthesiology 1992; 77: 267-74).

The possibility of long-term treatment with alpha-2 agonists for chronic pain syndromes has been subjected to limited testing (Eisenach JC, et al., Anesthesiology 1989; 71: 647-52), but it seems very promising (Eisenach JC, et al., Anesthesiology 1996; 85: 655-74). Clinical research aimed at studying the duration of the analgesic effects of epidural injection of alpha-2 agonists after long-term administration, has yet to be undertaken, although currently commented in defense of long periods of injection of alpha-2 agonists (Segal et IS al., Anesthesiology 1991; 74: 220-5) because of their potential actions at each stage associated with the operation of the treatment of surgical patients. However, biologically important adaptation to the direct effects of alpha-2 agonists can lead to a reduction over time of effect of the drug; this is generally referred to as tolerance. Although tolerance to the sedative action of clonidine is developing rapidly and is considered to be desirable in the treatment of hypertension, it can reduce the clinical applicability of alpha-2 agonists for relief of chronic pain syndromes and long-term sedation in intensive care units (RTO) (Maze M, Redefining sedation. International Congress and Symposium, edited by Maze M, Morrison P. London, The Royal Society of Medicine Press, 1998, pp. 3-11). Ustoichivosti analgesic effect of spinal entered alpha-2 agonists may be minimal, as long epidural injection of clonidine caused a clinically acceptable analgesia for the treatment of chronic pain syndrome during treatment (Eisenach JC, et al., Anesthesiology 1989; 71: 640-6).

The composition of the present invention may include one or more alpha-2 adrenergic agonists.

Alpha-2 agonist of the present invention may be clonidine (which can be sold in the form of medications called Catapress™ Boehringer Ingelheim; Duraclon™ Roxanne). Clonidine, a prototype of the alpha-2 adrenergic agonist used as an antihypertensive since the beginning of 1970-ies because of its sympatholytic properties. These sympatholytic, and anxiolytic properties used for the use of clonidine to facilitate withdrawal of the drug and/or alcohol (Gold MS, et al., Psychiatr.Clin. North Am. 1993; 16: 61-73). Later it was used as an analgesic and sedative agents in connection with surgical treatment (Kamibayashi T, et al, Current Opinion in Anaesthesiology 1996; 9: 323-327) and for the treatment of psychological conditions such as disorder as hyperactivity with attention deficit (van der Meere J, et al., J. Child Psychol. Psychiatry 1999; 40: 291-8). In particular, it was shown that clonidine adding to funds for local anesthesia increases the analgesic effects to a much greater extent than with the systemic administration is similar to the eskers (Bernard JM, et al., Can Anaesthesiol 1994; 42 [2]: 223-8). This effect is probably a consequence of the local concentration of clonidine. In addition, extradural injection of clonidine are even more effective than systemic injection, at least during injection of high doses.

In addition, or alternatively, the alpha-2 agonist of the present invention can represent detomidine, medetomidine, dexmedetomidine (which can be sold in the form of Primadex, Abbott Labs.), brimonidine (which can be sold in the form of Alphagan, Allergon), tizanidine, mivazerol (UCB-Pharma, Belgium), guanabenz (which can be sold in the form of Wytensin™, Wyeth Ayerst), guanfacine (which can be sold in the form of Tepeh™, EN Robins), or a derivative or structural equivalent.

Preferred alpha-2 adrenergic agonist is dexmedetomidine.

It should be noted that in the prior art was not disclosed and was not offered the use of alpha-2 adrenergic agonist with an antagonist of NMDA receptors in the composition, which has a wide range application, especially for use as an anesthetic, not to mention unexpected properties associated with it.

Thus, the present invention therefore relates to compositions comprising alpha-2 adrenergic agonist and antagonist of NMDA receptors. While alpha-2 adrenergic agonists can prevent aromaticheskie side effects of NMDA antagonists on the back waist retrosplenial cortex (PC/RS) (Jevtovic-Todorovic V et al., Brain Res. 1998, Jan 19; 781[1-2]: 202-11). In particular, the alpha-2 adrenergic agonist such as clonidine and/or dexmedetomidine, which specifically alleviates neuropathic pain can increase the ease neuropathic pain NMDA antagonist such as MK-801, at the same time protecting against the adverse effects of the NMDA antagonist in the form of neurotoxicity and hyperactivity. In addition, it is known that, as it has been shown that oral clonidine premedication reduces hemodynamic effects associated with the introduction of ketamine anesthesia people (Doak JG et al., Can. J. Anaesth. 1993 Jul; 40[7]: 612-8).

Preferably, the antagonist of NMDA receptors is not ketamine.

Preferably the alpha-2 adrenergic agonist is not a drug.

More preferably, the composition does not include a combination of ketamine and xylazine. In this regard, a veterinary anesthetic practice NMDA antagonist ketamine was used in the presence of the drug, relatively weak alpha-2 agonist (Radde GR et al., Lab. Anim. 1996; 30:220-7). However, these drugs cannot be used in high enough doses to cause anesthesia, because of their side effect profile, which includes a direct depression of the myocardium and hypertension. As with other schemes TIVA, the introduction of these drugs requires kinetic mechanisms for the cessation of effect and clothe ing out of the anesthesia. In addition, extrapolation to promote General anesthesia in patients with complicated people involuntary movements and psychotomimetics effects.

Components of combination products of the present invention can be administered separately, sequentially or simultaneously, or a combination of these techniques.

Preferably the components of the compositions of the present invention are introduced simultaneously, i.e. in the form of a single composition.

Thus, in accordance with a preferred aspect of the present invention, General anesthesia may be induced and maintained by one composition (monotherapy). This has the advantage that it does not require the use of expensive equipment for delivery or for auxiliary artificial lung ventilation. The favorable pharmacokinetic profile of the present invention allows to provide a quick and easy selection of a dosage to achieve the desired effect and a smooth and rapid recovery from General anesthesia. In particular, when using General anesthesia as a treatment (e.g., the output from alcohol syndrome and/or drug abuse; to treat tetanus) the invention reduces hyperactivity in the sympathetic nervous system, and also provides all the other features, which are provided with a General anesthetic.

In accordance with the tvii with the present invention, rational sedative effect may be caused and supported by monotherapy, do not require expensive equipment to ensure delivery, or for control of artificial ventilation of the lungs. In addition, relief of chronic pain syndrome can be provided by monotherapy without the possibility of the development of dependence and without respiratory depression. In addition, neuroprotection can be achieved with monotherapy, which does not lead to the degree of suppression of cardiac activity and respiration, which requires resuscitation interventions to maintain the function of the cardiovascular and respiratory systems. As a result of further actions of the two components neuroprotective effect more efficiently.

Preferably, the composition of the present invention is presented in liquid form. For parenteral administration, the composition can be applied in the form of a sterile aqueous solution which may contain other substances, for example, the amount of salts or monosaccharides, sufficient to make the solution isotonic with blood.

More preferably, the composition is presented in the form of a lipid emulsion. In the case of using such a volatile anesthetic, as xenon, a composition for intravenous administration usually contains lipid emulsion (such as a commercially available emuls and Intralipid®10, Intralipid®20, Intrafat®, Lipofundin®S or Liposyn® or emulsion, specially designed to ensure maximum solubility) to adequately increase the solubility of the gas or volatile anesthetic to achieve the desired clinical effect. For more information on the lipid emulsions of this type can be found in the publication G.Kleinberger and H.PamperI, Infusionstherapie, 108-117 (1983)3.

The lipid phase of the present invention, which dissolves or disperses the gas, usually formed from esters of saturated or unsaturated long - and medium-chain fatty acids containing from 8 to 30 carbon atoms. These lipids form liposomes in aqueous solution. Examples include fish oil and vegetable oils such as soybean oil, butter artichoke or oil of cotton seeds. The lipid emulsion of the present invention are usually emulsions of oil in water, in which the proportion of fat in the emulsion is generally from 5 to 30 wt.%, and preferably 10 to 20 mass%. Emulsion of oil in water of this type often get in the presence of an emulsifying agent, such as soy phosphatid.

The lipids that form the liposomes of the present invention may be natural or synthetic and include cholesterol, glycolipids, sphingomyelin, glycolipids, glycosphingolipids, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine,phosphatidylglycerol, phosphatidylinositol.

The lipid emulsion of the present invention may also include additional components. They may include antioxidants, additives that make the osmolarity of the aqueous phase surrounding the lipid phase is isotonic with blood, or polymers that modify the surface of liposomes.

It was found that detectable amounts of xenon can be added to the lipid emulsion. Even using the most simple tools, at 20°and normal pressure, the xenon can be dissolved or dispersed in concentrations of from 0.2 to 10 ml or more per 1 ml of the emulsion. The concentration of dissolved gas depends on a number of factors, including temperature, pressure and concentration of lipid.

The lipid emulsion of the present invention can be loaded gaseous or volatile anesthetic. Typically, the device is filled with the emulsion, and anesthetics in the form of gases or vapors are passed through the bubblers made of tempered glass, immersed in the emulsion. The emulsions are able to be balanced against gas or vapor anesthetic at a selected partial pressure. When stored in sealed containers for gas these lipid emulsions have sufficient stability without allocation of anesthetic in the form of gas during normal periods of storage.

The lipid emulsion of the present invention can be loaded so that h is of xenon headlights will be on the level of saturation. Alternatively, the xenon may be present in lower concentrations provided, for example, that the introduction of the emulsion (in combination with alpha-2 agonist) provides the desired pharmaceutical activity.

The present invention also relates to pharmaceutical compositions comprising a composition of the invention and a pharmaceutically acceptable diluent, excipient or carrier. As an example, in the pharmaceutical compositions of the present invention the composition of the present invention can be mixed with any suitable binding agent (agents), lubricating substance (substances), suspenders agent (agents)covering agent (agents), solubilizers agent (agents), selected with regard to the intended route of administration and standard pharmaceutical practice.

In some cases, the composition of the present invention may further include optional components such as, for example, an inhibitor of nitric oxide synthase (NO).

In some cases, the presence of an inhibitor of NO synthase is a preferable aspect. It was found that the sedative and analgesic effects of alpha-2 adrenergic agonists may decrease, which is a form of synaptic plasticity that is called tolerance (Reid To t al., Pharmacol. Biochem. Behav. 1994; 47: 171-175).

Changes in biological reactivity in the Central nervous system, for example, long-term potentiation (LTP), Central sensitization (“inflation”) and tolerance collectively referred to as synaptic plasticity, and their molecular mechanisms may be the same, despite different causing their impact. Previous studies have revealed that the complex of NMDA receptors (Asztely F, et al., Mol Neurobiol 1996; 12: 1-11), and synthase nitric oxide (NOS) (Meller ST et al., J. Neurosci. 1997; 17: 2645-51; Boxall AR et al., Eur J Neurosci 1996; 8: 2209-12) are essential for some forms of synaptic plasticity. Studies have also shown that to achieve tolerance to snotvornogo action requires less exposure to alpha-2 agonists than for tolerance to the analgesic action (Hayashi Y et al., Anesthesiology 1995; 82: 954-62), which suggests that these two forms of tolerance may have different biological substrates.

In particular, studies have revealed that the induction of tolerance to snotvornogo effect of dexmedetomidine is blocked by the joint introduction or desrcibing, or an inhibitor of NOS NO2-arginine. However, after tolerance has developed, a single injection desrcibing, or NO2-arginine does not prevent the expression of tolerance, ie, either NMDA receptors or NOS may not affect the expression of Tole is astnosti to snotvornogo and analgesic effects, suggesting that there are multiple mechanisms through which may be caused and maintained behavioral tolerance to alpha-2 agonists.

Further studies using pharmacological probes MK-801, ketamine and NO2-arginine is also strong evidence that tolerance has at least two distinct phases (induction and expression), as observed in other forms of synaptic plasticity (e.g., LTP), and that the components of the signaling pathway is followed in an orderly time sequence.

Previous work has identified key areas of hypnotic and analgesic actions of alpha-2 agonists. Locus coeruleus (LC) is the major site for the development of sleep States caused by alpha-2-agonists (Correa-Sales et al., ibid.). However, the analgesic effects of alpha-2 agonists is mediated both spinal and supraspinal. Analgesic effect of dexmedetomidine, injected directly into the LC, is the result of activation of alpha-2 adrenoceptors in the spinal cord, as this analgesia can be blocked by intrathecal injection of alpha-2 antagonist atipamezole, as well as intrathecal introduction of pertussis toxin (Guo TZ et al., ibid), which reboilered and, through this, inactivates defined in the dy G proteins. Intrathecal injection of alpha-2 agonists, such as clonidine (Post et al., J Anesth play mode display 1987; 66: 317-24; Ossipov MH, et al., Pharmacol Exp Ther 1990; 255: 1107-16) or dexmedetomidine (Guo TZ et al., ibid.; Fisher In et al., Eur J Pharmacol 1991; 192: 221-5) also causes analgesia. These data indicate spinal alpha-2 adrenoceptor as the “final common pathway” when anesthesia.

Initially it was believed that the alpha-2 adrenoceptors has many similarities with the system of opiate receptors on the basis of the similarities of their physiological actions in LC (Aghajanian GK, et al., Neuropharmacol 1987; 26: 793-9; Williams JT, et al., J Neurosci 1988; 8: 4299-306) and in the spinal cord (Yoshimura M, et al., Nature 1983; 305: 529-30; North RA, et al., J Physiol (Lond) 1984; 349: 43-55) and their effect on the processing of painful stimuli in the spinal cord (Kendig JJ, et al., Eur J Pharmacol 1991; 192: 293-300; Feng J et al., Pain 1996; 66: 343-9). However, unlike tolerance to the analgesic action of alpha-2 agonists, the development of tolerance to the analgesic action of opiates sensitive to antagonists of NMDA receptors (Marek P et al., Brain Res 1991; 558: 163-5; Ben-Eliyahu S, et al., Brain Res 1992; 575: 304-8; Tiseo PJ, et al., J Pharmacol Exp Ther 1993; 264: 1090-6; Trujillo KA, et al., Science 1991; 251: 85-7) and NOS inhibitors (Kumar S et al., Gen Pharmacol 1997; 29: 223-7; Highfield DA, et al., Synapse 1998; 29: 233-9; Bhargava HN, Pharmacology 1994; 48: 234-41). Therefore, the lack of effect of inhibitors of NMDA and NOS when tolerance to the analgesic action of alpha-2 agonists strong evidence that the mechanisms underlying the tol is rennosti to alpha-2 agonists and opiates, different.

Pharmacological composition of the present invention may also include other active ingredients. Examples of such other ingredients include calcium channel blockers L-type, calcium channel blockers, N-type, antagonists, substance P antagonists, sodium channel blockers purinergic receptors or combinations thereof.

Preferably, the composition or pharmaceutical composition of the present invention can be delivered intravenously (bolus dosing or injection), neuroaxial (or subdural, or subarachnoid) or transdermal.

The composition of the present invention may also be administered in the form of ointment or cream (lipid emulsions or liposomes), applied transdermal. For example, the composition of the present invention can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. Alterantive, the composition of the present invention may be included in a concentration from 1 to 10 wt.% in an ointment consisting of a white wax or white soft paraffin together with such stabilizers and preservatives that may be required. These ointments or creams are suitable for local pain relief and can be applied directly to the damaged tissue, often with optional sealed wound dressing.

Use the e in the composition concentration can be minimal concentrations, required to achieve the desired clinical effect. Typically, concentrations of both drugs (antagonists of NMDA receptors and alpha-2 adrenergic agonists) will be lower, and in some cases significantly lower than the concentration required if each of the drugs would be used separately. Usually the doctor determines the actual dosage which will be most suited to this patient, and this dose will vary with age, weight and response of the particular patient. You can, of course, be some cases, when justified by the application of a higher or lower ranges of dosages, and are within the scope of the claims of this invention.

The composition of the preparations of the present invention may be intended for administration to humans or to the introduction of animals.

Thus, the composition of the present invention may also be used as a medicine for animals. In this aspect of the invention, furthermore, relates to veterinary compositions comprising a composition of the present invention and a veterinary acceptable diluent, excipient or carrier.

For veterinary use composition of the present invention or veterinary acceptable composition is usually introduced in accordance with normal veterinary practice and the veterinary surgeon will determine the scheme entered the I and the route of administration, which best suits an individual animal.

In a broad aspect the present invention provides a pharmaceutical composition comprising a combination of a NMDA antagonist and alpha-2 adrenergic agonist.

This pharmaceutical composition may be intended for any one or more of the following purposes:

a) to reduce the damaging effects of shock (such as a shock caused by reduced blood supply to the brain);

b) to provide neuroprotection after injury;

c) to relieve pain, such as chronic pain syndrome;

d) to provide sedation and/or General anesthesia;

e) to alleviate withdrawal symptoms in patients with drug and drug dependence;

f) to reduce anxiety - like disorders in the form of panic syndrome;

g) to prevent seizures and sympathetic hyperactivity in patients with tetanus.

Thus, the present invention also encompasses the use of combinations of drugs of the present invention in the manufacture of a medicinal product:

a) to reduce the damaging effects of shock (such as a shock caused by reduced blood supply to the brain); and/or

b) to provide neuroprotection after injury; and/or

c) to relieve pain, such as chronic pain syndrome; and/is Lee

d) to provide sedation and/or General anesthesia; and/or

e) to alleviate withdrawal symptoms in patients with drug and drug dependence; and/or

f) to reduce anxiety - like disorders in the form of panic syndrome; and/or

g) to prevent seizures and sympathetic hyperactivity in patients with tetanus.

In the preferred embodiment implementation of the present invention provides an improved composition for use in anesthesia, in which the antagonist of NMDA receptors and alpha-2 adrenergic agonist is combined, preferably in a form suitable for intravenous administration.

The present invention also relates to the use of anesthetic (or pharmaceutical compositions) of the invention for induction of anesthesia and/or its maintenance.

The composition of the present invention can also be applied to General anesthesia to facilitate surgical treatment, treatment of the syndrome of drugs/alcohol, treatment of tetanus and other diagnostic/therapeutic interventions. In particular, the present invention can be used to maintain General anesthesia for extended periods (24-48 h) in patients with addiction, during which provoked the development of the syndrome of drugs/alcohol. The invention can be applied to supports is Rania General anesthesia for long periods (days or weeks) in the treatment of patients with tetanus. Anesthetic invention can also be applied to ensure patients sedation and analgesia to facilitate surgical and other therapeutic interventions (including endotracheal mechanical ventilation, change wound dressings in patients with burns or diagnostic procedures (including endoscopy and imaging techniques), which do not require loss of consciousness (sedation without disconnecting consciousness).

In addition, the composition of the invention can be used for the prevention and/or treatment of damage (including ischemic and traumatic) of the nervous system. In this area it is known that the combination of intravenous agents used to counteract the toxic effects of mediating excitatory amino acids, including glutamate. However, although it has been shown that blockade of NMDA receptors is effective in experimental models, clinical trials showed that this class of compounds constitutes a significant neurotoxicity. This neurotoxicity can be prevented through neuroprotective effects of alpha-2 agonists used in the present invention.

The composition of the invention can also be used to treat conditions involving chronic pain syndrome. In this area it is known that money is of many classes of drugs (including opioids and neobiota) was used in several different ways or separately, or in combination. However, the synergistic interaction between NMDA antagonist and alpha-2 agonist of the present invention can limit the dose and maintain long-term effectiveness by preventing the occurrence of tolerance.

The composition of the present invention can also be used in the treatment of optic nerve damage caused by acute glaucoma. Reduction of intraocular pressure alpha-2 agonist in combination with a protective effect of the NMDA antagonist against neuronal damage can lead to treatment that is highly effective.

The powerful combination of alpha-2 agonist and quickly removed NMDA antagonist (such as xenon) may have an advantage for several other reasons. First, the convergence of two radically different ways of transmembrane signaling (alpha-2 adrenoceptor and NMDA receptors) on the same or different neurons in the molecular mechanism of anesthesia can lead to increased efficiency many times over. For example, alpha-2 agonists have a double effect and a decrease in excitability of membranes directly through the opening of potassium channels and closing of calcium channels (Nacif-Coelho With et al., Anesthesiology 1994; 81:1527-1534), and as a consequence caused by adrenoceptors of hyperpolarization, making it less likely that the release of glutamate will start potential is l actions by activation of NMDA receptors. Similarly, inhibition of NMDA receptors by NMDA antagonists will reduce anxiety and inhibition of depolarization through the channels of the NMDA receptor, as well as due to the fact that blocking basal activation of NMDA receptors will lead to a decrease in membrane conductance, the hyperpolarization due to the actions of alpha-2 agonist will be strengthened. In addition, the release of glutamate at NMDA synapses can be ingibirovalo presynaptic effects of alpha-2 agonists, again ensuring synergies. Finally, these two classes of agents may have a synergistic effect on muscle relaxation by inhibition of release (alpha 2 agonist) and the modulatory action of glutamate (NMDA antagonist) in the neuromuscular synapse (El Tamer A et al., J. Neurochem. 1996; 67: 636-44; Koyuncuoglu H et al., Pharmacol. Res. 1998; 37: 485-91).

Adverse effects of each agent (from NMDA antagonist and alpha-2 agonist) can counteract the other of them. Thus, the resilient and conducive to seizures effect of one drug may be compensated by another agent. Vasoconstrictor properties of alpha-2 agonists transducers through the subtype of the alpha-2B adrenergic receptor (Link RE et al., Science 1996; 273: 803-5), which may be diametrically opposite signal path relative to the path found by transduction of b is appopriate anesthetic effects, which are mediated by a subtype of the alpha-2A adrenoceptors. Thus, signaling through alpha-2B adrenoceptor can be interrupted by NMDA antagonists, relaxing and thus the voltage developed in vascular smooth muscle cells under the influence of activation is not selective for subtypes of alpha-2 agonists (Caue AD et al., Anesth. Play mode display. 1998; 87: 956-62). The development of tolerance to the anesthetic effects of alpha-2 agonist may require the involvement of NMDA receptors that simultaneous blockade may terminate this biological process.

Because xenon kinetically inert, it should not adversely impact on the kinetic profile of alpha-2 agonists and, therefore, the output of anesthesia may be predictable, smooth, and quick.

Hereinafter the invention will be described only as an example and with reference to the accompanying drawings, in which:

figure 1 shows the relationship between dose and response for a hypnotic and analgesic actions of dexmedetomidine rats subjected false surgery, or after chronic use of dexmedetomidine;

figure 2 shows the results of the introduction of MK-801 during sleep, caused by dexmedetomidine;

figure 3 shows the effects of the introduction of ketamine during sleep, caused by dexmedetomidine;

figure 4 show the us the impact of the introduction of MK-801 on analgesic effects, caused by dexmedetomidine;

figure 5 shows the effects of the introduction of NO2-arginine at bedtime caused by dexmedetomidine;

figure 6 shows the effects of the introduction of NO2-arginine on the analgesic effects induced by dexmedetomidine.

More detail on figa presents the results of rats of dexmedetomidine (5 µg/kg/h) for 1 day, followed by injection of resolving doses of dexmedetomidine, and registration of the duration of loss of reflex remedy the situation. All values represent the average ± the standard error of measurement at 4-11 rats. On FIGU presents the results of rats of dexmedetomidine (10 µg/kg/h) for 14 days followed by injection permissive doses of dexmedetomidine for 30 min before the test analgesia. All values represent the average ± the standard error of measurement at 5-14 rats.

More detail on figa presents the results of a single injection of MK-801 (10-200 µg/kg) on sleep time caused by a single introduction of dexmedetomidine (100 mg/kg intraperitoneally), *p<0,05 - unlike saline, n=6. Figv illustrates that the single injection of MK-801 does not block caused by dexmedetomidine tolerance snotvornogo effect of dexmedetomidine, *p<0,05 - contrast controlling the salt solution, n=6-7. Figs illustrates that co-administration of MK-801 (100 and 400 mg/kg/h) blocks tolerance to the hypnotic effects of the resolving dose of dexmedetomidine (100 µg/kg, intraperitoneally), *p<0,05 - contrast control, n=6-8. All values represent the average ± the standard error of measurement at 7-8 rats.

In more detail, figa shows that a single injection of ketamine has no effect on sleep time caused by dexmedetomidine (150 mg/kg intraperitoneally). figv shows that a single injection of ketamine (10 and 20 mg/kg) does not block caused by dexmedetomidine tolerance snotvornogo effect of dexmedetomidine. *=p<0,05 - difference results injection of ketamine at a dose of 10 mg/kg compared to animals subjected to false treatment, ***<0,001 - difference results injection of ketamine at a dose of 20 mg/kg compared to animals subjected to false treatment. Pigs shows that co-injection of ketamine (400 µg/kg/h) eliminates the tolerance to the hypnotic effects of the resolving dose of dexmedetomidine (150 mg/kg intraperitoneally), without giving effect to the sedative effect of dexmedetomidine when a stand-alone introduction, p<0,05 indicates statistically significant difference from the false treatment n=6-8. All values represent the average ± the standard error of measurement at 7-8 rats.

More sublattice is BNO, on figa shows the effect of a single injection of MK-801 on the analgesic action of dexmedetomidine in the intact rats. MK-801 was administered 15 min prior to the introduction of dexmedetomidine dose of 50 mg/kg and test pulling down the tail was completed in 40 min, **=p<0,01, n=6-7. Figv shows that a single injection of MK-801 does not prevent the development of tolerance. In rats, in which the tolerance was induced by implantation of minnesoto, who delivered dexmedetomidine (10 µg/kg/h) within 14 days, MK-801 (50 µg/kg) does not prevent the expression of tolerance. This dose of MK-801 was chosen because it had no effect on caused by dexmedetomidine sleep, ***=p<0,001, n=6-7. Figs illustrates that co-administration of MK-801 (0.4 µ g/kg/h) with dexmedetomidine (10 µg/kg/h) for 14 days does not prevent the development of resistance. This dose of MK-801 separately has no effect on the analgesic action of dexmedetomidine, ***=p<0,001 - statistically significant difference from the control. All values represent the average ± the standard error of measurement at 7-8 rats.

In more detail, figa shows that NO2-arginine dose-dependent increases sleep time caused by dexmedetomidine, in rats not treated with the drug. NO2-arginine was administered 15 min prior to the introduction of dexmedetomidine (100 mg/kg intraperitoneally), **=p<0,01, n=8. Figure 5 is shows that a single dose of NO2-arginine has no effect on sleep time caused by dexmedetomidine, and does not eliminate tolerance snotvornogo effect of dexmedetomidine (100 µg/kg), *=p<0,05 - statistically significant difference from control, n=8. Pigs shows that the simultaneous introduction of NO2-arginine (0.4 to 4 mg/kg/h) with dexmedetomidine (5 µg/kg/h) for 7 days dose-dependent blocks the development of tolerance to snotvornogo effect of dexmedetomidine, *=p<0,05 - statistically significant difference from control, #=p<0,05 statistically significant difference from the control group and from the group, tolerant dexmedetomidine, n=7-8. Treatment of NO2-arginine at a dose of 1.25 mg/kg/h (last column) does not affect the sleep time caused by dexmedetomidine, n=8. All values represent the average ± the standard error of measurement at 7-8 rats.

In more detail, figa shows that a single injection of NO2-arginine has no effect on the analgesic action of dexmedetomidine in the intact rats. NO2-arginine was administered intraperitoneally 15 min prior to the introduction of dexmedetomidine (50 mg/kg intraperitoneally), 40 min test conducted pulling down the tail. All values represent the average ± the standard error of measurement in 6 rats. Figv shows that NO2-argini is (1 and 20 mg/kg intraperitoneally) does not eliminate the tolerance to the analgesic action of dexmedetomidine (100 mg/kg intraperitoneally) in rats tolerant dexmedetomidine, *=p<0,05 - statistically significant difference from control, n=7-8. Pigs shows that the joint dose of NO2-arginine (4 µg/kg/h), which effectively counteracts tolerance snotvornogo effect (see figs), has no effect on tolerance to the analgesic effect caused by dexmedetomidine (10 µg/kg/h) for 14 days. Increasing doses of NO2-arginine to 8 mcg/kg/h, was also ineffective. All values represent the average ± the standard error of measurement at 7-8 rats. *=p<0,05, **p<0,01 - statistically significant difference from the control.

Examples

An example of a composition

A typical composition of the present invention includes from 5 to 30 mm xenon, and from 7 to 70 μm of dexmedetomidine 10-20% emulsion Intralipid™. In each of the following examples gaseous xenon dissolved in a lipid emulsion.

Example 1

In order to induce General anesthesia, adult intravenously for 2 min to produce an injection of a composition containing 5-20 ml of gaseous xenon and 15-300 μg of dexmedetomidine. Introductory anesthesia may contribute [s] to surgical treatment, [b] to exit the condition of drug and/or alcohol dependence, [with] the treatment of tetanus.

Example 2

To maintain General anesthesia (to promote [and] carrying the structure of surgical treatment, [b] to exit the condition of drug and/or alcohol dependence, [with] the treatment of tetanus) adult patient receives an intravenous infusion of a composition which is configured to deliver 10-50 ml of xenon and 10-150 µg dexmedetomidine during each hour.

Example 3

For sedative effect when saved conscious adult patient intravenously produce injection composition containing 1-10 ml of gaseous xenon and 5-100 µg dexmedetomidine for 10 min, and the patient receives an intravenous infusion of a composition which is configured for delivery during each hour of 5-20 ml of gaseous xenon and 2-30 µg dexmedetomidine. Sedation with preserved consciousness can facilitate diagnostic or therapeutic (surgical and nonsurgical) procedures.

Example 4

To protect against ongoing damage to the nervous tissue due to trauma or ischemia, adult intravenously produce injection composition containing 5-20 ml of gaseous xenon and 15-300 μg of dexmedetomidine for 10 minutes followed by continuous infusion of a composition which is configured for delivery during each hour of 10-50 ml of gaseous xenon and 10-150 µg dexmedetomidine.

Example 5

In the treatment of chronic pain syndrome in an adult patient epidurally PR is harass the injection of the composition, containing 1-10 ml of gaseous xenon and 5-60 µg dexmedetomidine for 10 minutes followed by continuous infusion of a composition which is configured for delivery during each hour 2-20 ml of gaseous xenon and 1-20 µg of dexmedetomidine.

Example 6

An alternative treatment for chronic pain syndrome in an adult patient a composition used transdermal, and the rate of administration set for delivery during each hour of 5-20 ml of gaseous xenon and 2-30 µg dexmedetomidine.

The effect of inhibitors of NMDA receptors in tolerance to alpha-2 agonists.

The experimental Protocol was approved by the Committee on care and use of animals of the health care System Department of veterans in Paio Alto. Used male rats Sprague-Dawley (B&K, Fremont, CA) weighing 250-350 g Rats were divided into groups for selection as much as possible the distribution of mass. All the tests were carried out from 10 a.m. till 16 o'clock the Number of animals in each experiment are indicated in the legend.

The development of tolerance

In rats caused the development of tolerance to anesthetic action of alpha-2 agonist of dexmedetomidine as described Reid To et al. (ibid.). Briefly, rats were continuously introduced, dexmedetomidine using osmotic minnasota Alzet® (model 2002 or 1007D, Alza, Palo Alto, CA), which vydeliautsia content and the average rate of pumping of 0.48±0.02 ul/H. The pumps were injected subcutaneously during anesthesia with isoflurane in the posterior thoracic region and filled for delivery of drug at a speed of 5 µg/kg/h for 7 days to induce tolerance to snotvornogo effect, and 10 µg/kg/h for 14 days to induce tolerance to the analgesic effect. It was previously shown that these schemes are optimal in order to cause the development of tolerance to the sleep state or analgesia (Hayashi Y et al, ibid.). At joint application of MK-801 or Nω-nitro-L-arginine (NO2-arginine) with dexmedetomidine MK-801 included in the same pump. In previous studies (Hayashi Y et al., ibid.) reported that behavioral responses, determined in animals subjected to false operation did not differ from reactions in rats that were implanted with pumps containing saline solution, and therefore used the first of these animals. For the experiments on snotvornogo effect of MK-801 and Nω-nitro-L-arginine (NO2-arginine) pumps were removed 1 day before behavioral testing. In all other experiments pumps before testing was not deleted.

Loss of reflex redress

The reaction in the form of sleep on dexmedetomidine was determined by loss of reflex redress rats (LORR), and its duration is measured in minutes and called wremen is sleep. The duration of LORR was assessed as the time from the onset of the rat's inability to fix its position when placed on her back until she spontaneously completely turned upside down in a prone position on his stomach. Test reactions in the form of sleep served from 10 a.m. till 18 h, as described by Reid et al., 1994.

Procedure painful testing

Pain response was assessed by response to the pulling down of the tail to painful thermal stimulus through 40 minutes after administration of the resolving dose of dexmedetomidine. A beam of light of high intensity focused on the tail and the time after which the rat was removed his tail from the light, was recorded as latency pulling down the tail. This method was previously described in the literature (Guo TZ et al., ibid.). Has averaged three values of the latency obtained with the three sections on the tail. To prevent tissue damage was asked the time of the cutoff of 10 C. the Original measure consisted of a set of three definitions pulling down the tail in 2-minute intervals. The original value of the latency pulling down the tail was in the range of from 3 to 4 seconds.

Preparation of medicines

The NOS inhibitor Nω-nitro-L-arginine (NO2-arginine) (Sigma), the NMDA antagonist MK-801 (RBI) and ketamine (Sigma) was dissolved in physiological saline and was administered intraperitoneally once or introduced continuously via osmotic the ini pumps Alzet® (model 2002 or 1007D, Alza, Palo Alto CA). These compounds were introduced together with dexmedetomidine inclusion of both drugs in one pump.

Statistical analysis

Data LORR and straightening the tail were analyzed using analysis of variance (ANOVA) followed by the application of retrospective criteria Bonferroni or, depending on feasibility, test Dunnett multiple comparisons or t criterion.

The connection between dose and response for dexmedetomidine in animals subjected to false and chronic treatment. The relationship between the dose and response in relation to the hypnotic and analgesic effect of dexmedetomidine shown in figure 1. The hypnotic effect of dexmedetomidine dose-dependent increased in animals subjected to false treatment, but almost completely absent in rats receiving continuous treatment for 7 days, even when administered large doses (figa). Was previously demonstrated biphasic curve dose-response for this type of action dexmedetomidine with a maximum efficiency of about 300 μg/kg, and, as has been shown, it is associated with stimulating effect of dexmedetomidine-mediated activation α1receptors (Guo TZ et al., ibid.).

Permanent impact of dexmedetomidine within 14 days moved the curve based analgesic effect of the dose of dexmedetomidine CA is approximately half and reduced the maximum effect (pigv).

Prevent the induction of tolerance to the hypnotic effects of dexmedetomidine antagoniste NMDA receptors with MK-801 and ketamine.

Single injection of MK-801 intact animals did not affect the sleep time (figa). After the development of tolerance single injection of MK-801 did not affect the expression of tolerance (pigv). However, co-administration of MK-801 with dexmedetomidine was able to prevent the development of tolerance (figs). In this experiment, the osmotic pump was removed 1 day before behavioral testing.

Ketamine had a similar profile in that single administration, it did not affect the sleep time induced by a single injection of dexmedetomidine (figa). A single injection of ketamine at a dose of 10 or 20 mg/kg could not eliminate tolerance, which previously developed (pigv), but ketamine eliminated tolerance to the sedative effect of dexmedetomidine simultaneous introduction (figs). The same dose of ketamine by itself had no effect. In this experiment, the Alzet pumps were left in place for behavioral testing.

The lack of prevention MK-801 induction of tolerance to the analgesic effects of decoratetoday.

Single injection of MK-801 for 15 minutes before resolving dose of dexmedetomidine suppressed its analgesic effect in the two is the very high doses (figa). To determine whether MK-801 to influence the expression of tolerance, it once was injected control and tolerant animals. Low dose MK-801, which separately had no effect on caused by dexmedetomidine analgesia, did not prohibit the expression of tolerance (pigv). A higher dose of MK-801 (400 µg/kg), which opposed the analgesic action of dexmedetomidine control animals, was also unable to resolve the tolerance. Joint dose of MK-801, which prevented the development of tolerance to snotvornogo effect of dexmedetomidine and represented the maximum dose that is tolerated by the rats, had no effect on the development of tolerance to the analgesic action (figs). This dose of MK-801 had no effect on latency pulling down the tail with an individual introduction.

Prevent the induction of tolerance to the hypnotic effects of dexmedetomidine inhibitor of NO synthesis. With the introduction of the intact animals NO2-arginine increased the sleep time only at high doses (figa). After the development of tolerance on the 7th day of the introduction of dexmedetomidine single injection of low doses of NO2-arginine, which is not subjected to sleep in the intact animals, did not prohibit the expression of tolerance (pigv). In a joint introduction NOsub> 2-arginine with dexmedetomidine induction of tolerance to the hypnotic effects of dexmedetomidine weakened (figs). Treatment only NO2-arginine at a dose of 1.25 mg/kg/h (last column) are not affected during sleep, caused by dexmedetomidine.

No prevent NO2-arginine induction of tolerance to the analgesic effects of dexmedetomidine. Single injection of NO2-arginine did not affect the analgesic action of dexmedetomidine (50 mg/kg intraperitoneally) (figa). To determine whether NO2-arginine to influence the expression of tolerance, it once was injected control and tolerant animals. NO2-arginine (1 and 20 mg/kg intraperitoneally) did not prohibit the expression of tolerance (pigv). Joint dose of NO2-arginine (4 µg/kg/h), which prevented the development of tolerance to snotvornogo effect of dexmedetomidine, had no effect on caused by dexmedetomidine analgesia in control rats and had no effect on tolerance to analgesia (figs). This dose NO2-arginine had no effect on latency pulling down the tail in a stand-alone introduction (data not shown). Further increase in the dose of NO2-arginine to 8 mcg/kg/h was also ineffective in the elimination of tolerance.

<> For specialists in this field will be apparent various modifications and changes of the described methods of the invention without deviating from the scope of the claims and the invention. Although the invention has been described in connection with specific preferred variant implementation, it is assumed that various modifications of the described methods of carrying out the invention that are obvious to experts in their respective fields, are within the scope of the following claims claims.

1. Composition for anesthesia, including xenon and alpha-2 adrenergic agonist.

2. The composition according to claim 1, wherein the alpha-2 adrenergic agonist is dexmedetomidine.

3. Composition according to any one of the preceding paragraphs, characterized in that it is presented in a liquid form.

4. The composition according to claim 3, characterized in that it presents in the form of a lipid emulsion.

5. Composition according to any one of the preceding paragraphs, characterized in that it comprises a pharmaceutically acceptable diluent, excipient or carrier.

6. Method of induction of anesthesia in in need of a subject, characterized in that the specified entity enter the xenon and alpha-2 adrenergic agonist in an amount sufficient to induce anesthesia.

7. The method according to claim 6, characterized in that the CNS is he and alpha-2 adrenergic agonist is administered in the form of a composition according to any one of claims 1 to 5.

8. The method according to claim 7, characterized in that the composition is injected, neuroaxial or transdermal.

9. A pharmaceutical composition comprising a composition including xenon and alpha-2 adrenergic agonist.



 

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