RU2559777C2 - Agent for managing pain and inflammation accompanying neurodegenerative disorders - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacy, pharmacology and medicine. What is presented is using N-(2-adamantyl)-hexamethylenimine hydrochloride (Gimantan) as an analgecis and anti-inflammatory agent.

EFFECT: increasing a pain limit in rats and anti-exudate activity; unlike sodium diclofenac, gimantan has shown no ulcerogenic action.

7 tbl

Description

The invention relates to medicine, in particular to pharmacology, and relates to the new use of the known substance - N- (2-adamantyl) -hexamethyleneimine hydrochloride (patent No. 1825499, patent No. 2423981) as an analgesic and anti-inflammatory agent.

The present invention describes a new use of the antiparkinsonian drug Himantan, an adamantane derivative, which is a non-competitive low-affinity ion channel blocker of NMDA receptors and has a number of additional components in the mechanism of action and the spectrum of pharmacological activity, in particular, exhibiting neuroprotective, immunotropic and antiradical properties (E.A. Waldman. Abstract of thesis of the doctor of medical sciences, 2001, Moscow). It was shown that a 14-day administration of hematan in doses of 10 and 20 mg / kg to rats inside causes an increase in the threshold of pain sensitivity. It was found that gimantan in the dose range of 10-40 mg / kg shows a pronounced analgesic activity against visceral pain in mice. In a model of peripheral inflammation in mice, gimantan found antiexudative activity, the severity of which is maximum at a dose of 20 mg / kg and is comparable to the anti-inflammatory effect of diclofenac sodium at a dose of 10 mg / kg. At the same time, gimantan, unlike diclofenac sodium, did not show ulcerogenic action. In addition, 10 mg / kg gimantan reduces the severity of neuroinflammation induced by intracerebral administration of lipopolysaccharide.

Chronic inflammatory diseases of the joints and spine affects at least 1-1.5% of the population; more than 10% - osteoarthritis and more than 10% - chronic pain associated with dorsopathies. Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are effective for symptomatic treatment of pain and inflammation of acute and chronic diseases of the musculoskeletal system (level of evidence A). However, oral administration (by mouth) of NSAIDs is associated with a high risk of serious side effects - primarily lesions of the gastrointestinal tract (A. E. Karateev, N. N. Yakhno, L. B. Lazebnik and others. Use of non-steroidal anti-inflammatory drugs. Clinical recommendations.M .: IMA-PRESS, 2009. - 168 p.). Thus, at present, the problem of safe and effective analgesic and anti-inflammatory therapy is not solved, and a search for new safe and effective painkillers and anti-inflammatory drugs is required.

The closest analogue of the present invention is 1-adamantylamine hydrochloride (midantane) - a NMDA receptor blocker related to centrally acting non-opioid analgesics (V. Churyukanov, M. Churyukanov, Vrach, 2002, No. 4, 29-33), but lacking anti-inflammatory activity .

The essence of the present invention is the proposal to use gimantan as a new analgesic and anti-inflammatory drug with no gastrotoxicity and is illustrated by examples.

Example 1

The effect of subchronic administration of hematan on the threshold of pain sensitivity in rats.

The experiment was carried out on male mongrel white rats weighing 210-240 g. The animals of the experimental groups were injected daily for 14 days with Gimantan dissolved in physiological saline in doses of 10, 20, 40 mg / kg, and the animals of the control group received physiological saline in an equivalent volume. On the 14th day of the experiment, the threshold of pain sensitivity of rats was recorded in a special chamber with an electrode floor measuring 30 × 50 cm. An alternating electric current was applied to the chamber floor, gradually increasing the voltage. The threshold of pain sensitivity of animals was recorded at the time of raising the limb from the electrode floor. Statistical processing of the results was carried out using Student's criterion using the software package Statistica v. 6.0.

It was found that gimantan with subchronic administration at doses of 10 and 20 mg / kg significantly increased the threshold of pain sensitivity in rats (Table 1). The maximum increase in the threshold of pain sensitivity was recorded when it was administered at a dose of 10 mg / kg and amounted to 35% relative to the values of the control group.

Example 2

The effect of hematan on visceral pain in mice.

The experiments were carried out on male mongrel white mice weighing 27-30 g. To reproduce visceral pain, a model of cramps was used, which was caused by intraperitoneal injection of a 1% solution of acetic acid at a rate of 1 ml per 100 grams of animal body weight (G.Ya. Schwartz, R.D. Syubaev, A Guide to the Experimental (Preclinical) Study of New Pharmacological Substances. - M.: Medicine (2005), pp. 695-709). Hymantanum dissolved in physiological solution at doses of 10, 20 and 40 mg / kg and a comparison drug diclofenac sodium at a dose of 10 mg / kg were administered intraperitoneally one hour before the introduction of acetic acid solution. Control mice were injected with saline in an equivalent volume. Within 15 minutes after injection of the acetic acid solution, the number of writhing was calculated for each mouse. The severity of the analgesic activity of the compounds was evaluated by reducing the average number of writhing in the group relative to the control. Statistical processing was performed using the Mann-Whitney test using the Statistica v software package. 6.0.

It was shown that gimantan in the dose range of 10–40 mg / kg exhibited a pronounced analgesic effect (Table 2). With the introduction of gimantan at a dose of 10 mg / kg, the pain response in mice decreased by 44.4%, at a dose of 20 mg / kg - by 60.4%, at a dose of 40 mg / kg - by 50.2%. The effectiveness of gimantan did not significantly differ from the activity of the drug diclofenac sodium, which at a dose of 10 mg / kg reduced the pain response in animals by 61.3%.

Example 3

The effect of gimantan on the exudative stage of inflammation in mice. The effect of gimantan on the exudative stage of inflammation was evaluated using a model of acetic peritonitis in mice, which was induced by intraperitoneal injection of a 1% solution of acetic acid at a rate of 1 ml per 100 g of animal body weight (G. Ya. Schwartz, R. D. Syubaev. Experimental Guide ( preclinical) study of new pharmacological substances. - M .: Medicine, (2005), pp. 695-709). Gimantan dissolved in physiological solution at doses of 10, 20, and 40 mg / kg and a comparison drug diclofenac sodium at a dose of 10 mg / kg were administered an hour before the introduction of acetic acid solution. The animals in the control group were injected with physiological saline in an equivalent volume. 3 hours after the introduction of the acetic acid solution, the mice were sacrificed, the abdominal cavity was opened, exudate was collected and its weight was measured. Statistical processing was performed using the Mann-Whitney test using the Statistica v software package. 6.0.

A significant anti-inflammatory effect of gimantan was revealed in the dose range from 10 to 40 mg / kg (Table 3). The most pronounced activity of gimantan was recorded when it was administered at a dose of 20 mg / kg and was manifested in a 1.9-fold decrease in the exudative reaction compared to the control group. This effect did not significantly differ from the effect of the comparison drug diclofenac sodium, which caused a 2.4-fold decrease in the exudate mass in mice compared to the control.

Example 4

The effect of hematan on neuroinflammation in rats.

The experiment was carried out on male mongrel white rats weighing 380-420 g before the start of the experimental work. Neuroinflammation was modeled by the unilateral administration of lipopolysaccharide (LPS; Escherichia Coli, Serotype 0, SIL2630, Sigma) into the substantia nigra of rats (A. Castano, A. Herrera, J. Cano et al., J Neurochem, 1998, 70, 4, 1584-1592 ) Anesthetized Nembutalum (45 mg / kg) rats were injected with LPS (10 μg in 2 μl of Ringer's solution) or Ringer's solution (control) in the black substance of the left hemisphere according to the following stereotactic coordinates: AP - 4.0 mm, ML - 2.0 mm, DV - 8.0 mm (J. Bures, M. Petran and J. Zachar, Electrophysiological methods in biological research, Academic Press, New York, 1960). Animals were divided into 3 groups: 1. Passive control (falsely operated, LO); 2. Active control (LPS); 3. Gimantan 10 mg / kg + LPS. Gimantan was administered intraperitoneally previously the day before the operation, immediately before the operation, and then daily for 14 days. Throughout the experiment, the dynamics of rat body weight were monitored. On the 7th day after surgery, the behavior of rats was evaluated in the test "Cylinder" (T. Schallert and T.A. Jones, J Neural Transparent Plas, 1993, 4, 193-198), which is used to analyze ankinesia of the forelimbs of animals. The rat was placed in a transparent cylinder with a diameter of 18 cm and a height of 45 cm (NPK Open Science, Moscow, Russia). Then, with free behavior, the contact of each cylinder with the front paw was recorded during two minutes of observation, after which the percentage of paw touches of the contralateral damage to the side relative to the total number of contacts was calculated. Three weeks after the operation, the effect of hematan on the impaired sense of LPS administration in rats was evaluated under the conditions of the modified method proposed by M. Lemasson et al. (M. Lemasson, C. Delbe, G. Gheusi et al., Behav Processes, 2005, 68, 1, 13-23). Rats were placed on a square arena measuring 60 × 60 cm and a wall height of 30 cm, divided into 9 equal squares. In one of the squares (the corner of the arena) a drop of essential citrus oil was applied. The arena was divided into 3 zones, depending on the decreasing odor intensity: zone 1 - the square marked directly by smell; zone 2 - three squares located at a distance of 20 to 40 cm from the source of the smell; zone 3 - squares distant from 40 to 60 cm from the source of smell. Within two minutes, the time spent by the animal in each zone and the number of entries into the first zone were recorded. Statistical data processing was performed using Student, Mann-Whitney and χ2 criteria using the Statistica v. Software package. 6.0.

Unilateral intranigral administration of LPS led to a significant loss in animal body weight. In the group of rats treated with LPS, the decrease in body weight on the 3rd day after the operation relative to the baseline values (on the eve of the operation) was 12.2 g. The negative dynamics of the body weight of rats of the LPS group continued in the future, which was reflected in an average loss of 11 more , 9 g on the 8th day after surgery (table. 4). Against the background of hematan, the decrease in rat body weight was less pronounced compared with the active control group. Loss of body weight on the 3rd and 8th day after surgery was 1.27 and 3.5 times less than the corresponding indicators in the LPS group. In false-operated rats, negative dynamics of body weight after the procedure was not observed.

In the “Cylinder” test, ankinesia of the forelimb, the contralateral side of LPS administration, was revealed in animals of the active control group, which was expressed in a significant decrease in touches of the cylinder walls with the right paw compared to the corresponding data in the group of falsely operated rats (Table 5). The noted fact indicates the defeat of dopaminergic neurons in the left substantia nigra of animals that received LPS. Against the background of hematan, the number of touches of the cylinder walls to the right, contralateral side of the lesion, with the limb was almost 2 times greater than in the active control group and did not differ from the values of the group of falsely operated animals.

Table 5.

The effect of gimantan when administered intraperitoneally on the ankinesia of the anterior extremity of rats, the contralateral side of the intraligral administration of lipopolysaccharide, in the test "Cylinder"

When assessing changes in the behavior of rats in response to an annoying smell, it was found that in the active control group there was a tendency to increase the duration of animals in the 1st and 2nd zones of the arena and the number of entries into the 1st zone, the intensity of the irritating smell in which maximum (table. 6). Against the background of hematan, a significant increase in the time spent in the 3rd zone farthest from the annoying odor-marked zone and a decrease in the number of entries into the 1st zone of the arena as compared to the LPS group was found.

The model of intraviginal LPS-induced neuroinflammation, also considered as a model of Parkinson's syndrome, revealed the corrective effect of gimantan with respect to endotoxin-induced decrease in body weight, akinesia of contralateral damage to the forelimb, and changes in animal behavior in response to irritating odor.

Example 5

The effect of gimantan on the mucous membrane of the gastrointestinal tract of rats.

The experiment was carried out on male mongrel white rats weighing 210-240 g. The effect of rats on the mucous membrane of the stomach of animals dissolved in physiological solution of hematan and the comparison drug diclofenac sodium was studied in animals deprived of food 16 hours before the experiment, with a single oral dose of 0. 2 LD50, which corresponded to 114 mg / kg for gimantan and 74 mg / kg for diclofenac sodium (G.Ya. Schwartz,

R.D. Syubaev. Guidelines for the experimental (preclinical) study of new pharmacological substances. - M.: Medicine (2005), p. 695-709). The animals in the control group were injected with physiological saline in an equivalent volume. The severity of the effect of hematan and diclofenac sodium on the gastric mucosa was assessed 3 hours after their administration on a 4-point scale: 0 - no damage; 0.5 - hyperemia; 1 - single minor injuries (1 or 2 point hemorrhages); 2 - multiple injuries (erosion, pinpoint hemorrhage); 3 - significant and multiple damage to the mucosa (erosion, hemorrhage); 4 - gross damage covering the entire surface of the mucosa (massive hemorrhage, erosion, perforation). Statistical processing was performed using the Mann-Whitney test using the Statistica v software package. 6.0. It was found that gimantan had no effect on the state of the mucous membrane of the stomach of rats: against the background of its administration, as in the control group, ulceration of the mucous membrane in animals was not observed (Table 7). In contrast to the group of animals treated with gimantan, in the group of rats that were injected with the diclofenac sodium comparison drug, ulceration averaged 2 points.

Claims (1)

The use of N- (2-adamantyl) -hexamethyleneimine hydrochloride as an analgesic and anti-inflammatory agent.