LT4799B - Anti-ishaemic preparation - Google Patents

Abstract

The invention is connected with medical pharmaceutical industry and is related to means that affect cardio vascular systems. N-carbamoylmethyl-4-phenyl-2-pyrrolidone is offered for usage in the pharmaceutical industry for ischaemic disease treatment. Previously, its hypotensic and nootropic activity was described. It is shown that anti-ischaemic activity of this medication exceeds the activity of obsidian. However, differently from obsidian, the medication does not have a negative inotropic impact.<IMAGE>

Description

The invention relates to the field of medicine and pharmaceutical industry and relates to devices acting on the cardiovascular system.

There are many biologically active substances known for their chemical structure and, in particular, for their pharmacological action on the cardiovascular system.

For example, 2-morpholino-5-phenyl-6H-1,3,4-thiadizine hydrochloride described in RU patent no. 2054938 (TPK A61 K 31/41, 1996) has a pronounced inotropic effect which results in reduced heart rate. Cis-1- (3a-acetylthiopropinyl) -6-methylpithecamic acid is disclosed in RU patent no. 2058144 (TPK A61K 31/445, 1996). From RU patent no. 1827067 (TPK A61K 31/41, 1994) known instrument such as

3-Methyl- [2,3-tert-butylamino- (2-oxypropoxy) phenoxymethyl] -1,2,4-oxadiazole with antihypertensive, antiarrhythmic, coronary-expanding, anisemic and anti-glaucomatous effects. However, it is not known whether these measures have an anti-ischemic effect or their anti-ischemic effect is not high enough.

One of the major groups in pharmacotherapy for ischemic disease (the most common cardiovascular disease) is β-blockers. One of the most commonly used preparations of the β-blocker group is obzidane (propranolol, anapriline) (M. fl. MaiuKOBCKmži. JleKapcTBeHHbie cpeącTBa. Vol. 1. M. MeąnqnHa, 1993, C. 258). The anti-ischemic effect of Obzidan is linked to its ability to reduce myocardial oxygen demand by decreasing heart rate, reducing myocardial contractility and increasing coronary blood flow. However, the use of obidan is restricted to patients with pulmonary obstructive disorders with bronchospasm or patients with peripheral vascular obliteration due to adverse inotropic effects. The ability of β-adrenergic blockers to increase the blood levels of atherogenic lipids is also known.

It is an object of the present invention to provide an effective anti-ischemic agent, thereby expanding the range of such agents.

This object is achieved by using N-carbamoylmethyl-4-phenyl-2-pyrrolidone as an anti-ischemic agent.

N-Carbamoylmethyl-4-phenyl-2-pyrrolidone (FP) is known to have hypotensive activity (Former USSR Certificate No. 797219, TPK C07D 202/26, _F 5 A61K 31/41, 1995). Its nootropic activity is described in K). Γ. Bo6kob, MC Mopo3OB, OM Tno3MaH m flp., <t> apMaKonorMHecKafl xapaKTepncTHKa ηοβογο φθΗΜΠΒΗΟΓΟ aHanora nupaaueiaMa - 4-cbeHnnnnpaųeTaMa .// Bran. invite. 6nonornn u MeflMųMHbi. - 1983, ΧΟΫ. C. 50-53. The anti-ischemic activity of this compound is not described.

A study of the anti-ischemic activity of N-carbamoylmethyl-4-phenyl-2-pyrrolidone

The anti-ischemic activity of N-carbamoylmethyl-4-phenyl-2-pyrrolidone (FP) was investigated in an experimental model of myocardial infarction by myocardial infarction induced by rat downstream coronary artery occlusion (ONVLKA). FP was administered intraperitoneally at a dose of 50 mg / kg 30 minutes before ONVLKA. (FP has a low toxicity and a therapeutic dose of ~ 1/50 LD ₅₀ , ie 50 mg / kg was chosen). The anti-ischemic activity of the product was evaluated on the third day after administration to the necrosis zone, the ischemia zone and the total myocardial zone (necrosis zone plus ischemia zone). Areas of ischemia and myocardial injury were determined by morphometric method. Results in the FP-injected animal group were compared with those in the saline-treated animal (FT) and obididan 0.5 mg / kg dose, as well as in the abdominal cavity 30 minutes prior to ONVLKA. (The therapeutic dose of obzidan in man is 80-320 mg per

-25 days, which is about 1-4 mg / kg / day, i.e. y. single dose amounts to about 0.25-1, 00 mg / kg).

The results of the studies are presented in Table 1.

table. Effects of FP and obididan on the ischemic area, lesion, and total myocardial injury area of the rat experimental myocardial infarction

Group Area of myocardium (Mm ² ) Area of ischemic zone (Mm ² ) The ratio Ischemia zone / Miok face eco onos area Mm ² ) The ratio Necrosis area / Myocardium Impact area (Mm ² ) The ratio Necrosis / Ischemia Control (FT) 435.97 + 4.87 233.09 + 11.34 0.479 0.022 + 6.00 ± 5.84 0.074 + 0.012 269.09 9.07 + 0.165 ± 0.036 Obzidan 481.13 + 8.12 175.21 +4.01 0.365 0.009 * + 8.48 +4.08 ' 0.059 ± 0.009 203.68 6.08 + 0.163 + 0.024 ' FP 492.55 + 4.85 163.33 ± 7.84 0.332 0.017 ' ± 9.21 + 6.35 ' 0.039 + 0.013 182.53 12.16 + 0.113 ± 0.036 '

* - The differences are statistically significant compared to the saline-treated (FT) group (p <0.05, Dannett's test).

According to the study results, the use of FP reliably reduced the area of the ischemia zone and the total area of the lesion area (ischemia plus necrosis). In the study, the anti-ischemic effect of FP was superior to the anti-ischemic effect of obidan. It should be noted that F P injection almost reduced the area of myocardial necrosis almost twice, although these data were not statistically reliable. It can be concluded that the patented preparation has an anti-ischemic effect that outperforms the activity of obidan.

In contrast to obsidian, there is no negative inotropic effect on FP subfamilies. Another study evaluated rat central hemodynamics (MOK blood flow / minute, UO - stroke volume, SI - heart index) after FP administration. Hemodynamic indices were evaluated by direct method on day 4 after FP administration at 50 mg / kg.

table. Indices of rat central hemodynamics at day 4 after FP administration

Indicators Values (% relative to pre-FP data) Circulation Volume Per Minute (MOK) 110.8 ± 3.2 Heart Index (SI) 133.8 ± 9.8 Stroke Volume (UO) 161.8 + 12.7 Heart rate (CHSS) 115.4 ± 3.1

The introduction of FP improved cardiac performance, mainly due to improved stroke volume. It follows that the proposed preparation has a positive inotropic effect.

FP toxicity study

The acute LD50 toxicity was studied in rats by intraperitoneal and oral administration. It has been shown that the FP ₅₀ in the abdominal cavity is 538 mg / kg for male and 522.4 mg / kg for female. [Obzidan toxicity (LD ₅₀ ) in rats is 364-533 mg / kg] by oral administration in rats (males and females) of 2464.8 mg / kg and in oral dosage form 3185.8 mg / kg.

Chronic toxicity at doses of 50 and 100 mg / kg in rats and rabbits showed no effect of FP on peripheral blood parameters, electrolyte composition and other biochemical parameters. Chronic toxicity studies in 160 rats and 28 dogs revealed no significant effects on peripheral blood and cardiac function, liver and kidney in both sexes following oral administration of FP at doses of 50, 250 and 500 mg / kg.

The agent may be administered in any dosage form containing an effective amount of FP and pharmacologically compatible carriers and / or excipients.

Thus, the present agent is of low toxicity, has anti-ischemic activity, which is more effective than obidan activity. In addition, FP has no negative inotropic effects. The existing hypotensive and nootropic activity makes N-carbamoylmethyl-4-

Claims (1)

DEFINITION OF INVENTION Use of N-Carbamoylmethyl-4-phenyl-2-pyrrolidone in the manufacture of a medicament for use in. 5 for the treatment of ischemic disease.