Analgesic compositions containing non-narcotic analgesic and amplifier analgesia

 

The invention relates to medicine and can be used for pain relief. The method is a simultaneous introduction of a mammal experiencing pain, except such conditions as colds, flu, cough, sore mouth and/or dysmenorrhea, acetaminophen in quantities sufficient to induce analgesia, and at least one amplifier analgesia in number, resulting in enhanced analgesia selected from the group consisting of dextromethorphan, dextrorphan and their pharmaceutically acceptable salts. The proposed method can improve the effectiveness of the treatment. 2 C. and 8 C.p. f-crystals, 1 tab., 9 Il.

Background of invention the Invention relates to a method and to compositions used to reduce pain. More specifically, the present invention relates to a method of pain relief, particularly arthritic pain, lumbosacral pain, musculoskeletal pain, pain associated with angina, and others, through the introduction of the needy in this volutrauma exposed to the mammal a non-narcotic analgesic (so-called cl tar analgesics) such as acetaminophen or nastroenogo anti-inflammatory drugs (NSPs), takatori N-methyl-D-aspartate, in particular morphinan, such as dextromethorphan or dextrorphan, or nontoxic substance that blocks a major intracellular activation sequence of the receptor N-methyl-D-aspartate, i.e., ganglioside, such as ganglioside GM1or ganglioside GT1b.Non-narcotic analgesics, such as NSPs represent a broad category of drugs, including aspirin, ibuprofen, flurbiprofen, and others , proved to be good for analgesic and anti-inflammatory characteristics. However, all NSPs tend to cause side effects such as gastro-intestinal tract, which may vary in a wide range from relatively weak effects (dyspepsia, heartburn) to very serious (ulceration of the stomach or duodenum). Acetaminophen is the most widely used in home medicine chest drug. However, it is known that acute overdose of this medication can cause serious hepatotoxic lesions. The risk of such side reversible reactions and their severity can be increased substantially at long application of the drug. And for relieving arthritic pain shows just detica, such as NSPs or acetaminophen, to significantly improve low level dosing of these drugs and thus their safety, without losing their analgesic efficacy? Dextromethorphan is a d-isomer of the codeine analog of Levorphanol. Unlike 1-dimensions, dextromethorphan, as reported, has no analgesic or addictive properties (Goodmen and Gilman''s, "The Pharmacological Basis of Therapeutics", 8 th ed., McGraw-Hill, Inc. 1999, R. 518).

Antitussive activity of dextromethorphan allows the use of this drug in a large number of oral dosage formulations (tablets, syrups) for pain relief for colds, flu and/or coughing. Many, if not most of these funds also contain non-narcotic analgesic, such as NSPs. For example, in U.S. patent 5164398 disclosed various oral dosage forms pharmaceutical compositions containing as an analgesic component (S)-ibuprofen in the form of its (S)-lysine salt and dextromethorphan in the form of its hydrobromide as antitussive component, and the use of this composition for the treatment of pain and/or inflammation colds, flu and/or coughing.

In U.S. patent 4446140 disclosed method and various injuries to the mucous surface of the lips, tongue and mouth, which arise as a result of dental pain, painful sensitivity of the dental prosthesis, aphthous stomatitis, irritation associated with inflammation of the gums, orthodontic procedures, oral surgery, and others, through the introduction of dextromethorphan, single or in combination with traditional analgesic, such as acetaminophen, indomethacin, ibuprofen, or naproxen, or with traditional anesthetic, such as benzocaine or butagain.

In the application for the European patent 0081823 reveals the way you can temporarily reduce the pain and discomfort associated with dysmenorrhea, through the introduction of dextromethorphan, single or in combination with one or more complementary action of drugs, in particular analgesic, such as acetaminophen, indomethacin, ibuprofen, or naproxen.

Previously it was not known that the analgesic effectiveness NSPs can be significantly increased when the input NSPs or acetaminophen before, together or after administration of dextromethorphan in a quantity sufficient to enhance the analgesic activity. Thus, in U.S. patent 5164398 and 4446140 and in the application for the European patent 0081823 disclosed dosage of dextromethorphan, which are not effective from the point replicacoach also reveals dosage of dextromethorphan, which, as shown in the present invention, lead to greater efficiency NSPs or acetaminophen, this result can be attributed to the unit and be considered completely random.

A brief description of the invention the Present invention relates to a method of alleviating pain which comprises the administration to a mammal experiencing pain, (a) non-narcotic analgesic such as NSPs or acetaminophen, in a quantity sufficient to induce analgesia, (b) at least one amplifier analgesia in number, resulting in enhanced analgesia, selected from the group consisting of non-toxic receptor antagonist N-methyl-D-aspartate and non-toxic substance that blocks a major intracellular activation sequence of the receptor N-methyl-D-aspartate, (a) can be administered before, concurrently or after administration of (b).

The method of the present invention and a pharmaceutical composition for it is applicable to treat all kinds of pain, and not only those activities which accompany the common cold, flu, cough, oral pain and/or dysmenorrhoea in accordance with the level of equipment. Thus, in a mammal in need of relief of pain, which is alentinoj dose non-narcotic analgesic or an equivalent level of analgesia with the introduction of low dose non-narcotic analgesic can be achieved, if the mentioned non-narcotic analgesic to take before, concurrently, or after the input of the amplifier analgesia. In addition, the method of reducing pain in accordance with the present invention, and used in medical practice pharmaceutical composition provides high efficiency analgesia in the case of a large number of States, not just those that are determined by the level of equipment. Thus, the present invention makes it possible to achieve significantly greater pain reduction at a given dosage non-narcotic analgesic than in the case of using only one analgesic for the treatment of conditions such as arthritic pain, lumbosacral pain, musculoskeletal pain, pain in the throat, resulting in angina, and others, each of which is accompanied by inflammation of the active sites.

The expression of the receptor N-methyl-D-aspartate" should be understood in context, including all subcategories binding site associated with the NMDA receptor (N-methyl-D-aspartate), i.e., the glycine-binding site, phenylcyclidine (PCP) binding site, and so on, as well as the NMDA channel. Thus, the present invention considers the use of nontoxic substances that block binding say.

The term "non-toxic" used in the context of the invention should be understood with respect to: any substance approved by the U.S. food and drug products [FDA (FDA)], for reception by the person or which, maintaining the established criteria and practices that corresponds to the parameters for which it can be approved by the FDA for administration to man. In this context, the term "non-toxic" is also used for the separation of antagonists of the NMDA receptor, or blockers, used according to the method of the present invention, antagonists of the NMDA receptor, such as MK 801 (compound 5-methyl-10,11-dihydro-SH-dibenz[a,d]cyclohepten-5,10-Imin), RAF (compound 3-[2-carboxypeptidase-4-yl]propyl-1-phosphonic acid) and PCP (compound 1-(phenylcyclohexyl)piperidine), the toxicity of which explicitly removes the question about their therapeutic use.

The term "ease the pain" in the context of the present description includes the phrase "overwhelming pain and inhibits the pain, because the invention relates to alleviate existing pain and suppression (suppression) or inhibition of pain, which can develop as a result of the progression taking place in organisms is highlighted difference (expressed in points) in the development of mechanical hyperalgesia, observed in laboratory animals with induced arthritis before and after the introduction of the method of percutaneous injection of each of the number of investigated substances; Fig. 2 is a histogram illustrating the difference (ranking) in the spontaneous behavior of animals in response to pain (duration of lifting the patient's feet) another indicator arthritic pain observed in animals before and after injection of each of the number of investigated substances; Fig. 3 is a histogram illustrating the difference in the average number toogoogling joints, which performs the function of another indicator arthritic pain, before and after injection the animals of each of the investigated substances; Fig.4 is a histogram illustrating the difference in the development of mechanical hyperalgesia in animals before and after oral administration of each of the investigated substances; Fig. 5 is a histogram illustrating the difference in the spontaneous behavior of animals in response to pain (rating) before and after oral administration of each of the investigated substances;
Fig. 6 is a histogram illustrating the difference in the average rating of tugopodvizhnostju replacement, which performs the function of another indicator arthritic pain, before and after oral administration to animals of each of the investigated substances;
figmas in laboratory animals with induced arthritis before and after oral administration of each of the number of investigated substances;
Fig. 8 is a histogram illustrating the difference in the spontaneous behavior of animals in response to pain (rating) before and after oral administration of each additional investigational agents; and
Fig. 9 is a histogram illustrating the difference in average stiffness of the joints, which performs the function of another indicator arthritic pain, before and after oral administration to animals of each additional investigational agents.

Description of the preferred embodiments of the invention
In accordance with the present description can be used by any non-narcotic analgesic. As already mentioned, NSPs represents one of the classes of such non-narcotic analgesics, which can be used according to the method of the present invention. An extensive list NSPs given in the book by Goodman and Gilman (Goodman and Gilman's "The Pharmacological Basis of Therapeutics", 8th ed., McGraw-Hill, Inc. 1990, p.638-670, "Remington's Pharmaceutical Sciences", 17 th ed., Mack Publishing Company (1985), PP.1116-1122) and in U.S. patent 4777174. Specific examples NSPs that can be used according to the method of the present invention include aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indometacin, Ketoprofen, Ketorolac, mndk, tolmetin, zomepirac, their mixtures and their pharmaceutically acceptable salts. Such "coal tar" analgesics like acetaminophen, constitute another class of non-narcotic analgesics, is suitable for use in the described method.

Among nontoxic substances that block the NMDA receptor, which in this context can be used as amplifiers actions considered analgesics - NSPs or acetaminophen, it should be noted dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) and its metabolite, dextrorphan ((+)-3-hydroxy-N-methylmorphinan), their mixtures and their pharmaceutically acceptable salts. Other suitable for use nontoxic substances that block the NMDA receptor include memantine, pyrroloquinoline, quinone and CIS-4-(postmetal)-2-piperidinylcarbonyl acid. Preferred for use according to the method of the present invention among the antagonists of the NMDA receptor is dextromethorphan in the form of hydrobromide in connection with proved for him a high safety and good availability. Despite the fact that dextrophan and its pharmaceutically acceptable salts also show good results, to date, no data on their commercial production.

In addition to the blocker of the NMDA receptor or instead of, blokiruyet basic sequence of activation of the NMDA receptor.

Activation of the NMDA receptor, which belongs to the subtype receptors excited amino acids, induces changes in the functional activity of nerve cells and, in particular, their ability to excitation or inhibition in the presence of addictive substances by increasing the intracellular concentration of CA++. The main sequence of activation of the NMDA receptor consists of the following sequence or cascade of events occurring in nerve cells;
a) the movement and activation of protein kinases such as protein kinase C, --> phosphorylation of substrate proteins such as cytosolic enzymes, channel proteins, receptor proteins, and others, --> change in functional activity;
b) initiation of expression of the early gene (C-fos, c-jun, zif-268 and others) or by increasing the intracellular content of CA++or Sa++-activated protein kinases --> the expression of functional genes responsible for the production of cellular enzymes (such as protein kinase) receptor proteins (such as the NMDA-receptor), a protein channel transport of ions (such as+, PA+, CA++- channels), neuropeptides (such as denomin) and others --> change in functional activity;
in)p>++-binding proteins), --> activation of CA++/calmodulin-proteinkinase systems, such as CA++/calmodulins II --> autophosphorylation of enzymes (in particular, CA++/calmodulins II) or other functional proteins --> change in functional activity;
g) activating constitutive synthase nitric oxide induced CA++/calmoduline, as well as the induction of inducible synthase nitric oxide --> the production of nitric oxide --> i) the production of cyclic guanosine monophosphate via activation of guanosines, leading to activation of protein kinases and the expression of early gene; (ii) direct modification of proteins, such as enzymes, receptor and/or channel proteins; (iii) modification of the lipid membrane and/or modification of nucleic acids through the deoxidation of free radicals; (iv) induction of neurotoxicity at high levels of nitric oxide; and (v) the inhibitory effect on adjacent neurons or glial cells, such as facilitating the release of glutamate/activation of NMDA receptors and/or inhibition of post-synaptic the NMDA receptor --> change in functional activity;
d) interaction with cyclic adenosinemonophosphate-protein kinase, system phospholipase A2-arachidonic acid /prostanoids/ leukotrienes --> change in functional activity induced secondary systems messengers other than the NMDA-receptor /CA++/Sa++-calmodulin/proteinkinase systems;
(e) interaction with other receptor subtypes excited amino acids, including receptors not the NMDA-type and metabotropic receptors, as well as the sequence of intracellular events that occur after activation of these receptor subtypes excited amino acid changes in the functional activity induced by activation of the receptor is not the NMDA-type and metabotropic receptor.

A substance that blocks the NMDA-receptor, will effectively prevent the passage of the main chain of intracellular processes associated with this receptor. However, even when the activation of the NMDA-receptor may, in accordance with the present invention, to treat the painful condition by introducing a non-narcotic analgesic and substance that blocks at least one link in the main sequence of intracellular processes. Thus, such a substance that inhibits the translocation and activation of protein kinase C or inducion the s of nitric oxide, will also be useful for implementing the present invention.

Nontoxic substances that block basic sequence of intracellular processes occurring after activation of the NMDA-receptor and are useful in this regard from the point of view of implementation of the present invention include inhibitors of protein kinase C, i.e., gangliosides, such as ganglioside DM1(monosialoganglioside) and ganglioside GT1b(trisiloxanes); amputations long-chain bases such as sphingosine, N,N,N-trimethylpyrazine, sphinganine and psychosis; finalisation-2-ones, such as 4-methyl-5-(3-chinoline)-2-(3H)-oxazolone and phenyl-5-(2-chinoline)-2-3(3H)-oxazolone; 1,4-bis-(aminohydroxylation)-anthraquinones, such as 1,4-bis-(3-propylamino-2-hydroxypropylamino)-9,10-anthracenedione and 1,4-bis-(3-benzylamino-2-hydroxypropylamino)-9,10-anthracenedione; mixtures and pharmaceutically acceptable salts of each of the above substances.

Other nontoxic substances that block the main chain of intracellular processes that occur after activation of the NMDA-receptor, and as such are useful for implementing the present invention include inhibitors of calmoduline, such as phenothiazines, particularly chlorproma is phenazine, the decanoate fluphenazine, thioridazine, besilate mezoridazina, piperacetazine, demolet acetophenazine, demolet Karenina, demolet butaperazine and sulfoxide fenotiazina; naphthalenesulfonate, such as N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonate, N-(6-aminohexyl)-5-chloro-2-naphthalenesulfonate and N-(6-aminohexyl)-5-bromo-2-naphthalenesulfonate; 4-substituted-4H,6N-pyrrolo[1,2-a][4,1]benzoxazepine, such as 1,3-dihydro-1-{ 1-[(4-methyl-4H, 6N-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)methyl]-4-piperidinyl)2H-benzimidazole-2-he; benzhydryl, such as N-[2] (diphenylmethyl] -2-(trifluoromethyl) benzenediamine, N-[2-(bis(4-forfinal)methylthio)ethyl] -2-(trifluoromethyl)benzenediamine and N-[2-(bis(4-forfinal)methylthio)ethyl] -3-(trifluoromethyl)benzenediamine; tricyclic antidepressants, such as imipramine, 2-chlorimipramine and amitriptyline; penfluridol; haloperidol; pimozide, clozapine; culmination; mixtures and pharmaceutically acceptable salts of each of the above substances.

Two groups of amplifiers analgesia preferred antagonists of the NMDA-receptor and among them for the above reasons, the most preferred dextromethorphan.

For the manifestation of enhancing the analgesic activity of the actions of non-toxic antagonist of the NMDA-reaktywacja the NMDA-receptor, must be present in sufficient quantity to enhance analgesia. This is the number for the substance of this type may be determined experimentally for each specialist with the average level of knowledge in this field when performing routine procedures of selection dosages, using the description of the experimental data. In the case of use as an antagonist of the NMDA-receptor dextromethorphan usual recommended adult dose of at least 15 mg, and preferably about 20 mg Unit dosage forms may contain less than the specified number of of dextromethorphan when it must be practiced daily use doses, to ensure the specified minimum dose of of dextromethorphan. So, 1 or 2 tablets, each of which contains 325 mg aspirin or acetaminophen (or other non-narcotic analgesic) and 15 mg of dextromethorphan, can be entered at the same time (up to 4 times within a 24-hour period) to ensure the strengthening process of analgesia according to the method of the present invention.

Level metering for non-narcotic analgesic should be sufficient to induce an efficient level and the beam aspirin, if diflunisal this dose will vary from about 125 mg to about 500 mg, sodium-zomepirac it will vary from about 25 to 100 mg for ibuprofen: from about 50 to about 400 mg of naproxen from about 125 to about 500 mg, for flurbiprofen: from about 25 to about 50 mg, for fenoprofen: from about 60 to about 200 mg, for piroxicam: from about 10 to about 20 mg for mefenamovoy acid: from about 125 to about 250 mg, for fenbufen: from about 100 to about 400 mg, for Ketoprofen: from about 25 to about 50 mg and acetaminophen this dose will vary from about 50 to about 650 mg. If you can use other dosage narcotic analgesic that can be more or less than the above.

Although non-narcotic analgesic and amplifier analgesia does not need to be entered together, they nevertheless must be present in the body at the same time and in effective quantities. Although separate, with the purpose of convenience, the introduction of analgesic and amplifier analgesia included in the scope of the present invention, it is preferable to introduce them together as a single therapeutic composition. In the invention within the intramuscular, subcutaneous, intrathecal, epidural or intracerebroventricular injection.

A therapeutic composition comprising a non-narcotic analgesic and amplifier analgesia, in the normal case, are prepared using one or more pharmaceutically acceptable ingredients in accordance with the accepted and well-known practice. Thus, the composition can be in the form of liquid, powder, elixir, solution for injection and other Preparations for oral use can be made in the form of tablets or hard capsules, in which the pharmacologically active ingredients are mixed with an inert solid filler, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredients are mixed with an oil medium, in particular with liquid paraffin or olive oil.

Aqueous suspensions may contain pharmaceutically acceptable carriers, such as suspendresume agents, in particular sodium carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragant and Arabian gum; dispersing or wetting agents such as natural gums, in particular lecithin, or prodali of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit, in particular polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of exit, such as polyoxyethylene servicemanual. Aqueous suspensions may also contain one or more preservatives, in particular, it may be ethyl or n-propyl-p-hydroxybenzoate, one or more dyes, one or more flavoring agents and one or more sweeteners, such as sucrose, saccharin or cyclamate or calcium.

Analgesic pharmaceutical composition of the present invention is prepared in the form of a metered dose of the prolonged forms, various types of which are known, in particular, they have been described in U.S. patents 4788005, 4816264, 4828836, 4834965, 4834985, 4996047, 5071646 and 5133974. Furthermore, in addition to the non-narcotic analgesic (a) and amplifier analgesia (b), the medicinal composition of the present invention may contain at least one other pharmacologically active substance (b), in particular narcotic analgesic such as codeine, or local anesthetic, such as lidocaine, dibucaine sludge which forms are typical for the described in the present invention is a therapeutic composition.

The following examples illustrate the method and composition of the present invention on the example of reducing arthritic pain induced in rats sprag-Share (Sprague-Dawley).

A. testing Procedure
Arthritic pain (monoarthritis) was induced in rats intracapsular injection of complete adjuvant (Butler et al., Pain, 48, 1992, PP.73-81). Complete adjuvant was obtained on the basis of 60 kg of killed cells of Mycobacterium butyricum in a mixture of paraffin weight (6 ml), 0.9% NaCl (4 ml) and Tween 80 (1 ml). Rats were subjected to mild anesthesia with isoflurane, injected in a mixture gas of N2O/O2. Drop complete adjuvant (0.05 ml) were injected with tracebale in the ankle joint (arsotibial) needle 26 size. 7 days after injection develops monoarthritis pain, which reaches a peak approximately through 2 weeks (Butler et al., ibid.).

To 12-th day after injection complete adjuvant were performed following behavioral tests for the presence of arthritic pain in order to establish the baseline level (point values) in accordance with the techniques described in the literature (Butler et al., ibid., Perrot et al., Pain, 52, 1993, PP.41-47).

(1) Mechanical hyperalgesia
To determine the mechanical hyperalgesia was used by the text of the Randall-Selitto (Randall-Selitto test) (Butler et al., ibid; Perrot et al., ibid). The area Pekoe impact. Rat drawing back a foot or uttered a sound, when imposed by force reached the pain threshold. This force was recorded as the degree of mechanical hyperalgesia.

(2) Spontaneous behavior associated with pain elevation (feet)
Each rat was allowed to move freely without restriction in the Plexiglas cylinder with an open top (cylinder diameter 19 cm, height 30 cm) and allowed to habituate to the cylinder for 5 minutes before monitoring begins. Within a 10-minute observations were recorded the total duration (in seconds) the period during which the animal was raised an arthritic foot.

(3) Quantitative evaluation (in points) stiffness of the joints
Investigated the existence of restrictions in the full range of flexion or extension of the joint after the injection. Subjected to injection joint is freely bent and open up to a certain point, after which the animal was resisting further movement of the examined joint. In rats with arthritis maximum stiffness of the joints is 2 points, in the case where there is a limitation in the full range of motion, as in flexion and extension porgey in the form of a single dose intraperitoneally or orally with one of the following investigational substances: (1) one ibuprofen, (2) one dextromethorphan-HBr, (3) a combination of ibuprofen and dextromethorphan-HBr or (4) one saline (control). After 1 hour (in the case of intraperitoneal injection) or 2 hours (in the case of oral administration) after each injection are the same as described behavioral tests to determine the impact of each input substances on the severity of arthritic pain.

B. test Results
In Fig.1-6 presents the results of these tests.

In Fig.1-3 and 4-6 shows the results observed with intraperitoneal injection and oral administration (n=5-6/group), respectively.

Fig.1: Mechanical hyperalgesia - intraperitoneal administration
To Express the degree of mechanical hyperalgesia was used, the difference in the quantitative assessment (value for the contralateral hind limb minus the value for the affected limb), reflecting the impact of the force ( in grams), superimposed on the region of the ankle joint, which leads to a sound response of an animal or otdergivanija feet. Between groups prior to the introduction of the substances under study there were no differences in scores. In the study within one hour after administration of the substances, the difference in scores was significantly decreased in rats, the saline controls. Combined intraperitoneal injection of ibuprofen and dextromethorphan-HBr (25 mg/kg each) resulted in significantly stronger lower rating than in the case of the introduction alone ibuprofen and dextromethorphan-HBr, which indicates a significant enhancement of therapeutic effect of the combination of ibuprofen and dextromethorphan-HBr, x=P<0,05, K - coefficient of the Waller-Duncan t-test (Waller-Duncan K ratio t-test ("SAS Procedures Guide, Version 6,34-d ed., Sas Instityte Inc., Cary, NC, 1990, p.705, et seg Mao et. al., Brain Res., 576, 1997, pp.254-262), compared to saline controls. (x)= p<0,05, K - coefficient of the Waller-Duncan t test in comparison with the data obtained for the groups treated separately ibuprofen and dextromethorphan-HBr, respectively, and also with saline controls.

Fig. 2: Spontaneous behavior associated with pain, intraperitoneal administration
Recorded the duration (in seconds) period of time during which the animal is raised from the surface as affected or not affected hind paw within a 10-minute observations and considered this as a sign that indicates the presence of spontaneous arthritic pain. While all examined rats did not lift not affected hind leg during the entire period of observing the bedroom intraperitoneal injection of ibuprofen and dextromethorphan-HBr (25 mg/kg each), and not separately (also in a dose of 25 mg/d) significantly reduced the duration of lifting the hind legs within 1 hour after injection, x=P<0,05; K - coefficient of the Waller-Duncan t test in comparison with groups that were injected separately ibuprofen and dextromethorphan-HBr, respectively, and also with saline controls.

Fig.3: Stiffness - intraperitoneal administration
The limitation in the full range of processes such as flexion or extension of the affected joint was scored as one point. In rats with arthritic lesions of the maximum stiffness of the joint is evaluated at two points, if you have restricted movement in the full range as in flexion and extension of the affected joint. Average stiffness of the joints at the points shown in Fig.3. Joint stiffness was observed both in flexion and extension of the affected hind limb prior to treatment. Combined intraperitoneal injection of ibuprofen and dextromethorphan-HBr (25 mg/kg each), but not these two tools alone (in a dose of 25 mg/kg), significantly reduced the severity (in points) stiffness of the joints in the study through the hours after injection, indicating a significant reduction in tagapo the groups, received only ibuprofen or only dextromethorphan-HBr, respectively, and with saline controls.

Fig.4: Mechanical hyperalgesia - oral administration
For all groups prior to the introduction of the investigated substances was not observed differences in the point rankings. Combined single oral administration of ibuprofen and dextromethorphan-HBr (50 mg/kg each), but not separately each of the two substances (also in a dose of 50 mg/kg each), resulted in a significant decrease in the difference in the ranking (in points) in the study two hours after injection, indicating a considerable increase in the level of analgesia with the introduction of the combination of ibuprofen and dextromethorphan-HBr in comparison with other investigated substances, x=P<0,05, K - coefficient of the Waller-Duncan t-test, in comparison with saline controls.

Fig.5: Spontaneous behavior associated with pain, oral administration
While the investigated animals are not raised in the monitoring process is not affected hind limbs, they often raised the rear of the affected foot when observed before the introduction of drugs. Combined oral single administration of ibuprofen and dextromethorphan-HBr (50 mg/kg each), but not two substances separately (also in d is observing two hours after administration, x=P<0,05, K - coefficient of the Waller-Duncan t-test, when compared with saline controls.

Fig.6: Stiffness - oral administration
In Fig. 6 shows the average stiffness of the joints in points. Joint stiffness observed during flexion and during the extension of the affected limb before the introduction of the investigated substances. Combined single oral administration of ibuprofen and dextromethorphan-HBr (50 mg/kg each), but not individually, each of these substances (in doses of 50 mg/kg), resulted in a significant decrease in the severity of stiffness of the joints (in points) in the study two hours after injection, indicating a significant reduction in stiffness of the affected joint, x= P<0,05, U-test Mann-Whitney, compared with the group who received only ibuprofen or only dextromethorphan respectively, as well as with saline controls.

Example 2
For each of the three And the tests were conducted baseline estimation. Disclosed in accordance with the procedures (1) to (3), the passage of time more than 14 days after adjuvant injection, each rat received an oral dose investigated the following substances: (1) acetaminophen (ACE), one in different doses, (2) dextro is 1.5 hours after each injection was repeated the above behavioral tests to determine the impact of each analyte on the severity of arthritic pain.

B. test Results
In Fig.7-9 presents the results of the above tests.

Fig.7: Mechanical hyperalgesia
To Express the degree of mechanical hyperalgesia was used the percentage change in pain threshold at which an animal was pulling back his foot, both before and after the introduction of each substance. 1.5 hours after administration of the compounds under investigation threshold otdergivanija feet was reduced in rats receiving a single oral dose of 50-400 mg/kg of acetaminophen or 50 mg/kg dextromethorphan-HBr compared to saline controls. Combined oral administration of acetaminophen (400 mg/kg) and dextromethorphan-HBr (50 mg/kg) resulted in a significant increase thresholds otdergivanija feet, indicating a significant increase terapevticheskii effect of the combination of acetaminophen and dextromethorphan-HBr, x= P<0,05, K - coefficient of the Waller-Duncan t-test (SAS Procedures Guid", Version 6, 34 ed., SAS Institute Inc., Cary, NC, 1990, pp. 705 et sed. Mao et al, Brain Res., 576, 1997, PP.254-262) in comparison with saline controls.

Fig.8: Spontaneous behavior associated with pain
The duration (in seconds) lifting from the surface as affected or not affected hind legs during the 10-minute observation period were recorded as pokazati, they often, in the course of the observations prior to the introduction of medicines, raised the affected hind leg. Combined oral administration of acetaminophen (400 mg/kg) and dextromethorphan-HBr (50 mg/kg), but not two substances separately, significantly reduced the duration of elevation of the affected hind paws while watching 1.5 hours after injection, x=P<0.5, the K - factor Waller-Duncan t-test, compared with groups receiving one acetaminophen or one dextromethorphan-HBr, and with saline controls.

Fig.9: joint Stiffness
The restriction of the full range of either flexion or extension of the affected joint was regarded as one point. In rats with arthritis maximum stiffness of the joints is two points in the case, if there is a restriction in the full range of motion in flexion and extension of the affected joint. Average stiffness of the joints at the points shown in Fig.9. Before treatment of stiffness of the joint was observed both in flexion and extension of the hind legs. Combined oral administration of acetaminophen (400 mg/kg) and dextromethorphan-HBr (50 mg/kg), but not two substances separately, significantly reduced the severity of twala to significantly reduce the stiffness of the affected joint, x=<0,05, U-test Mann-Whitney ("SAS Procedures Guide, ibid.; Mao et al., ibid.), in comparison with the groups of animals treated only acetaminophen or only dextromethorphan-Nug, as well as with saline controls.


Claims

1. The method of pain relief, which includes simultaneous administration to a mammal experiencing pain, except such conditions as colds, flu, cough, sore mouth and/or dysmenorrhea, acetaminophen in quantities sufficient to induce analgesia and at least one amplifier analgesia in number, resulting in enhanced analgesia selected from the group consisting of dextromethorphan, dextrorphan and their pharmaceutically acceptable salts.

2. The method according to p. 1, characterized in that the specified acetaminophen and amplifier analgesia prepared for the joint administration in the form of dosage forms for sustained release.

3. The method according to p. 1 or 2, characterized in that the amplifier analgesia is introduced in an amount not less than 15 mg/dose.

4. The method according to p. 3, characterized in that the amplifier analgesia is introduced in an amount not less than 20 mg/dose.

5. The method according to any of paragraphs.1-4, characterized in that the pain is determined by the active sites of FOTS is l, lumbosacral pain, musculo-skeletal pain or sore throat associated with angina.

7. therapeutic composition, intended for the relief of pain in a mammal experiencing pain, except such conditions as colds, flu, cough, sore mouth and/or dysmenorrhea, including at least one amplifier analgesia selected from the group consisting of dextromethorphan, dextrorphan and their pharmaceutically acceptable salts, and non-narcotic analgesic acetaminophen, characterized in that the above composition is prepared on the non-narcotic analgesic, in a quantity sufficient to induce analgesia, and amplifier analgesia of dextromethorphan, dextrorphan or their pharmaceutically acceptable salts in a quantity sufficient for potentiation of the analgesic effectiveness of this non-narcotic analgesic.

8. therapeutic composition according to p. 7, containing at least about 20 mg of dextromethorphan, dextrorphan or their pharmaceutically acceptable salts.

9. therapeutic composition according to p. 7 or 8 are presented in the form of dosage forms for sustained release.

10. therapeutic composition according to claim what no other arthritic pain, lumbar-sacral pain, musculo-skeletal pain or sore throat associated with angina.

 

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