Drug for analgesia
(57) Abstract:The invention relates to the field of pharmaceutical drug substances. The invention provides amplification analgesic effect of morphine and the reduction of dependence and tolerance. The invention consists in that the preparation contains in its composition of inhibitors CA++activatable endopeptidase-antipain or nupentin in relation to the morphine of 1: 20. This drug is superior to morphine in analgesic effect. In a lengthy introduction of this drug signs of tolerance and physical dependence, compared with morphine, are much weaker. Furthermore, addition of inhibitors of CA++activatable endopeptidase to morphine solution dramatically reduces the positively-reinforcing properties of the latter. Thus, the developed product is an effective tool for analgesia. Low dose with a low toxicity cause broad prospects for its application in clinical practice, especially in Oncology, for relief of strong long-lasting pain syndromes. 2 C. p. F.-ly, 5 Il. The present invention relates to oblakovo of morphine to reduce the risk of the development of dependence and tolerance.We already know the purpose of morphine together with atropine, metacin and other cholinergic substances (M. D. Mashkovsky. Medicinal product. I. Medicine, 1987, T. 1, S. 170).However, these drugs are used to reduce the side effects arising from the use of large doses of morphine (nausea, vomiting, respiratory depression), and not to enhance the analgesic effect of the latter. Additionally, the use of a combination of morphine with anticholinergic does not reduce the formation of tolerance and dependence with long-term, multiple doses of the drug.The aim of the present invention is increased analgesic effect of morphine and the reduction of dependence and tolerance.This goal is achieved by the fact that the drug contains an inhibitor of CA++activatable endopeptidase.As an inhibitor of CA++activatable endopeptidase use antipain ([(S)-1-Carboxy-2-phenylenthyl] -carbamoyl-Arg-Val-Arg-al) in relation to the morphine of 1:20.Also as an inhibitor of endopeptidase drug use leupeptin (Acethy-Leu-Leu-Arg-al) in relation to the morphine of 1:20.In Fig.1 shows the change in the latent period of otdergivanija tail of a rat durgiana tail in percent latent period with the introduction of morphine;
in Fig.2 shows the change in the latent period of otdergivanija tail in rats when added to a solution of morphine leupeptin. On the x-axis dose leupeptin. On the y-axis of the latent period otdergivanija tail in percent latent period with the introduction of morphine;
in Fig.3 shows the change in pain threshold under the influence of morphine and leupeptin from tolerant rats (2) compared with the intact (1). On the x-axis dose leupeptin. On the y-axis of the latent period otdergivanija tail in interest to the original;
in Fig. 4 shows the index of the withdrawal syndrome in animals, which together with the morphine was administered to antipain at a dose of 0.5 mg/kg (1), leupeptin at a dose of 0.5 mg/kg (2), and physiologic solution (3);
in Fig.5 presents the time spent in the non-preferred compartment during the test control animals (1), and in rats that were administered antipain at a dose of 10 mg/kg (2) and 50 mg/kg (3) once before testing and 10 mg/kg (4) and 25 mg/kg (5) daily before administration of morphine.The invention is illustrated by the following specific examples of its implementation:
Example 1.Strengthening the analgesic activity of morphine adding in its solution antipain
Experiments privale, using "test otdergivanija tail. Before testing, animals were placed in individual houses for 15 min, after which the tip of the tail of each animal was immersed in hot water (56oC). Analgesic effect was evaluated by the change of the time of latent period otdergivanija tail.The first group of animals before testing were injected intraperitoneally with 10 mg/kg morphine. The second group solution containing 10 mg/kg morphine and 0.05 mg/kg antipain. The third group solution containing 10 mg/kg morphine and 0.1 mg/kg antipain. The fourth group solution containing 10 mg/kg morphine and 0.5 mg/kg antipain. A fifth group, for 30 min before the introduction of a solution containing 10 mg/kg morphine was administered 1.0 mg/kg antipain. The sixth group for 30 minutes before administration of a solution containing 10 mg/kg morphine was administered 10 mg/kg antipain. The seventh group for 30 min before the introduction of a solution containing 10 mg/kg morphine was administered 50 mg/kg antipain.It was found that only the addition of solution of morphine 0.5 mg/kg antipain dramatically increases its analgesic effect (Fig. 1). The application of a combination of morphine with other doses antipain did not cause increased analgesia.Thus, adding a solution containing 10 mmer 2.Strengthening the analgesic activity of morphine adding in its solution leupeptin
The experiments were carried out on 7 groups of Wistar rats, male, weighing about 200 g, 8 rats in each group. Analgesic effect was evaluated using the test otdergivanija tail. Before testing, animals were placed in individual houses for 15 min, after which the tip of the tail of each animal was put into a hot hearth (56oC). Analgesic effect was evaluated by the change of the time of latent period otdergivanija tail.The first group of animals before testing were injected intraperitoneally with 10 mg/kg morphine. The second group solution containing 10 mg/kg morphine and 0.05 mg/kg leupeptin. The third group solution containing 10 mg/kg morphine and 0.1 mg/kg leupeptin. The fourth group solution containing 10 mg/kg morphine and 0.5 mg/kg leupeptin. A fifth group, for 30 min before the introduction of a solution containing 10 mg/kg morphine was administered 1.0 mg/kg leupeptin. The sixth group for 30 min before the introduction of the solution containing 10 mg/kg morphine was administered 10 mg/kg leupeptin. The seventh group for 30 min before the introduction of a solution containing 10 mg/kg morphine was administered 50 mg/kg leupeptin.It was found that only the addition of solution morphine doses leupeptin did not cause increased analgesia.Thus, adding a solution containing 10 mg/kg morphine 0.5 mg/kg leupeptin (ratio 20: 1), enhances the analgesic effect of morphine.Example 3.Reducing the development of tolerance for the analgesic action of morphine in the introduction of animals leupeptin
The experiments were conducted in 64 rats Fuscher-344, male, weighing 180-200, All animals were divided into groups of 8 rats each, depending on substances, injectable later. group 1 isotonic sodium chloride solution; group 2 morphine, group 3 isotonic sodium chloride + 1 mg/kg leupeptin; group 4 isotonic sodium chloride <10 mg/kg leupeptin; group 5 isotonic sodium chloride + 50 mg/kg leupeptin; group 6 morphine + 1 mg/kg leupeptin; 7 group morphine + 10 mg/kg leupeptin; 8 group morphine + 50 mg/kg leupeptin.At the first stage of the experiments, all animals were tested on the hot platform to study the latent period of painful reaction. Before testing for 30 minutes intraperitoneally injected morphine or physiologic solution, and 1 hour before testing leupeptin. In the second phase, rats were formed tolerance to morphine by twice daily injections (9 and 19 hours)ery, for 0.5 hour before the last injection of morphine to rats were administered an appropriate dose leupeptin or physiologic solution. Then defined pain sensitivity to "hot"platform.It has been shown that repeated injections of morphine in increasing doses caused the formation of tolerance to analgesic effect of morphine effect of morphine in a dose of 50 mg/kg almost completely absent. Introduction leupeptin at doses of 10 and 50 mg/kg in tolerant animals led to the emergence of reliable analgesic effect of morphine (Fig. 3).Thus, the injection leupeptin rats formed with tolerance to morphine in analgesic effect, reduces the tolerance.Example 4.Reducing the formation of physical dependence on morphine adding in its solution antipain and leupeptin
The experiments were conducted on a 64 Wistar rats, male, weighing 180-200, All animals were divided into groups of 8 rats each, depending on substances, injectable later. group 1 isotonic sodium chloride solution; group 2 morphine; group 3 isotonic sodium chloride + 0.5 mg/kg antipain; group 4 isotonic sodium chloride + 0.5 mg/kg l the ü from morphine by twice daily injections (9 and 19 hours) morphine in doses increasing from 10 to 50 mg/kg with the addition of an appropriate inhibitor of the protease or physiologic saline for 8 days. Control animals were injected with physiologic solution (the third and the fourth group with the addition of antipain or leupeptin). After 35 hours after the last injection was determined behavioral signs of withdrawal syndrome in the open field. Recorded the presence of such signs, as ptosis, cramps, convulsions, Bouncing out of the field, otrajjjenie "wet dog", gnashing of teeth, dispos, piloerection, impaired posture, rhinorrhea, shaking paws, diarrhea. To calculate the total index abstinence.It has been shown that repeated injections of morphine in increasing doses caused the development of physical dependence on morphine in animals showed marked the syndrome. Add in the morphine solution antipain or leupeptin at a dose of 0.5 mg/kg led to lower signs of withdrawal (Fig. 4).Thus, the addition of solution of morphine antipain or leupeptin reduces the formation of physical dependence on morphine.Example 5.Reducing narcotic potential of morphine adding to it antipain
The experiments were performed in 5 groups roadways and lighted compartments. All animals were chosen for their stay dark compartment. Then the animals were produced by an injection of morphine and was placed in the light (non-preferred) compartment, with access to the dark compartment was blocked. Animals 1, 2 and 3 groups for 0.5 hours before administration of morphine produced an injection of physiologic saline. Animals 4 and 5 groups were introduced 10 or 25 mg/kg antipain respectively. The procedure was repeated daily for 5 days. On day 6 animals 1, 4 and 5 groups were made with the injection of physiologic saline and animals 2 and 3 groups of 10 or 25 mg/kg antipain respectively, and after 1 hour was placed in an experimental setting with free access to both compartments. Recorded during their stay in the initial reproduction compartment.in the result it was found that the presence of rats in the initially non-preferred compartment after injection of morphine increases dramatically (up to 70%). This time is significantly decreased in all animals, which at one time or another has introduced antipain. To a greater extent in animals that were administered 10 mg/kg antipain before each injection of morphine and to a lesser extent in animals that were administered antipain at a dose of 25 mg/kg once before the last test (Fig. 5).Thus, antipain with a joint introduction is s, caused by morphine.Developed the drug for analgesia based on the morphine has not only a novelty, but a distinct significant differences. This is reflected in the fact that with the same amount of current start of morphine analgesic activity increases, and the formation of dependency and tolerance is significantly reduced. Such properties of the claimed product are unexpected for professionals, many of whom are convinced of the impossibility of such effect.Developed the drug, thus, represents a creative solution to the problems resulting from painstaking study of the mechanisms of action of morphine in combination with various biologically active substances, in particular inhibitors of CA++activatable endopeptidase. A careful analysis of this group of substances, to protect the presented antipain and leupeptin, as shown most stable results on the effectiveness and dose ratio with the main current top morphine.the invention allows to modify existing views about the use of narcotic analgesics in different areas of clinicalchemistry morphine and lower tolerance reduces the cost of treating patients. However, decreases the danger of drug abuse that can have great social value to solve struggle with drug addiction. 1 1. Drug for analgesia based on morphine, characterized in that, in order to enhance analgesic effect and reduce the formation of tolerance and dependence, it additionally contains inhibitors of CA++activated endopeptidase.2 2. The drug under item 1, characterized in that as an inhibitor of CA++activated endopeptidase use antipain ([(S)-1-Carboxy-2-phenylethyl] -carbamoyl-Arg-Val-Arg-al) in relation to morphine 1 20.2 3. The drug under item 1, characterized in that as an inhibitor of CA++activated endopeptidase use leupeptin (Acethyl-Leu-Leu-Agr-al) in relation to morphine 1 20.
FIELD: medicine, pharmacy.
SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.
EFFECT: valuable properties of tablet, expanded assortment of medicinal formulations of opioid analgesics.
19 cl, 4 tbl, 4 ex
FIELD: organic chemistry, pharmacology.
SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I
[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.
EFFECT: new compounds with value bioactive effect.
31 cl, 2 tbl, 32 ex
FIELD: pharmaceutical industry.
SUBSTANCE: invention discloses solid oral dozed pharmaceutical form of hydrocodon with controlled release. Pharmaceutical form comprises analgetically effective amount of hydrocodon or pharmaceutically acceptable salt thereof and controlled-release material. Pharmaceutical forms of hydrocodon are suitable to be administered once a day and provides early commencement of therapeutical effect, which lasts at least about 24 h.
EFFECT: enhanced analgetic action.
44 cl, 3 tbl, 3 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to medicine preparations that are used for treatment of opiomania or opiate dependence being especially heroin dependence. Diamorphine and/or one of pharmaceutically acceptable salts addition of acid are used as active substance. Also, invention relates to a method for treatment of opiate dependence. Invention provides the more long release of an active substance that is not decomposed and not loss activity in storing.
EFFECT: enhanced effectiveness of preparation, valuable medicinal properties.
12 cl, 1 tbl, 2 dwg, 3 ex
FIELD: medicine, anesthesiology, traumatology, orthopedics, thoracic surgery.
SUBSTANCE: about 1.5-2 min before spreading the affected lung it is necessary to deepen anesthesia due to injecting phenthanyl at the dosage of 10-12 mcg/kg body weight. The present innovation provides safety of operations of ventral spondyledesis out of transthoracic and thoracodiaphragmatic accesses, stability of arterial pressure level and patient's heart rate, decreases stress loading upon a patient that, in its turn, favors the prophylaxis of intraoperative complications.
EFFECT: higher efficiency of anesthesiological protection.
2 cl, 1 ex
FIELD: medicine, pharmacology, pharmacy.
SUBSTANCE: invention relates to the injection solution based on nalbuphine hydrochloride eliciting the expressed analgesic effect, and to a method for its preparing. The injection solution comprises the following components, wt.-%: nalbuphine hydrochloride, 0.8-2.2; buffer mixture, 0.5-3.5; stabilizing agent, 0.15-0.25; Trilon B (chelating component), 0.001-0.2, and water, the balance. Invention provides preparing the domestic preparation with analgesic effect and stability for above 2.5 years.
EFFECT: improved and valuable medicinal properties of solution.
11 cl, 1 tbl, 5 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention describes analgesic compositions containing buprenorphine in the level of subclinic analgesic doses in combination with naloxone, naltrexone or nalmephene. The mass ratio buprenorphine to naloxone is in the range from 12.5:1 to 27.5:1, and the mass ratio buprenorphine to naltrexone or to nalmephene is in the range from 12.5:1 to 22.5:1. Compositions are prepared as the parenteral or sublingual medicinal formulation or as a medicinal formulation that can be delivered through mucosa. Analgesic effect of buprenorphine is enhanced by low dose of naloxone, naltrexone or nalmephene.
EFFECT: enhanced effectiveness of compositions, valuable medicinal properties.
7 cl, 3 dwg, 21 ex