JPS63196517A - Antihypoxic and application - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides antihypoxic drugs (antihypoxlc d
rug). More specifically, the present invention relates to a medicament having cerebral and hepatoprotective effects for use in the treatment of acute or chronic diseases and poisonings that lead to complex damage to the entire body.

Orotic acid, uracil-4-carboxylic acid or vitamin B13, acts like a vitamin and aids in the anabolic, detoxifying and regenerative functions of liver cells.
It is known to exhibit a protective effect in cases of various poisonings and injuries of the liver. This orotic acid has a weak antihypoxic effect (Krug, M. et al., Ps.
ychophala+aco1. .

1977, 53. p, 73-78).

In addition, 2-oxo-pyrrolidine-2-oxo-pyrrolidine, a non-steroidal tropin preparation whose generic name is piracetam,
1-acetamide is associated with disease disorders of memory processes and learning abilities in the case of various injuries of the central nervous system, such as memory impairment, reduction of retention capacity, for example in toxic or alcoholic delirium, nervous fatigue, coma, acute neurological disorders, etc. It is known that it has a beneficial effect on (P a
tent G BN o, 1039113).

When used independently, orotic acid has only a weak antihypoxic effect on the liver parenchyma and an even weaker effect on the central nervous system.

The object of the present invention is to provide an antihypoxic drug, in particular a medicament with cerebroprotective and hepatoprotective effects, and to provide an antihypoxic drug for acute or chronic diseases and intoxication to achieve an enhanced antihypoxic effect. The object of the present invention is to provide a method of using the drug when the combination of

This objective is achieved by an antihypoxic drug, in particular a drug with cerebroprotective and hepatoprotective effects, containing piracetam and orotic acid or a pharmaceutically acceptable salt thereof in a weight ratio of 500:1 to 1=2. Ru.

It was confirmed that when piracetam and orotic acid are used simultaneously, both components interact completely favorably, resulting in a higher antihypoxic effect than the action of these drugs alone. The synergistic effect of the compositions of the invention, expressed as an enhanced antihypoxic effect, was confirmed by the results of the pharmacological studies and the individual clinical data shown in Table 1.

Table 1 Antihypoxic effects of piracetam and orotic acid in a mouse model of hypobaric hypoxia Dosage Substance against hypoxia (mg/kg) Increase in tolerance (%) Piracetam 500 29 Orotic acid 25 5 Viracetam + 500 + 25 76 .6 Piracetam orotate 1000 37.9 Orotic acid
50 9.7 Viracetam+ 1000+
50 91.5 Orotic Acid The medicament of the present invention is preferably administered to a living body as a ready-made drug.

The active substance combination compositions according to the invention are suitable for the production of pharmaceutical compositions and preparations. The ready-made dosage forms may contain, together with the active substance or its pharmaceutically acceptable salt, other additives or excipients according to conventional pharmaceutical technology, as shown in the examples below.

Compositions of the invention can be administered orally or parenterally. The latter is preferred for the treatment of serious diseases and acute exogenous poisoning. For oral administration, tablets, capsules, pills, solutions,
and can be made as an emulsion, suitable for the treatment of mild exogenous poisonings or for application after parenteral administration in the prophylaxis or acute phase of the disease.

One dose of Piracetam is 0.05 to 5 g and 0.01 to 0.1 g of orotic acid, and the daily dose is 0.150 to 50 g and 0.030 g to 0.30 g, 3 to 6 times. Administer in divided doses.

A study was conducted on the acute toxicity of the composition of the present invention, and when administered at 2500 mg/kg intramuscularly, 1
000 mg/kg when administered intravenously, 30
No toxic effects were observed in each case when 00 mg/kg was administered intraperitoneally.

Therefore, the composition is practically non-toxic. 100 mg/kg and 500 mg/kg to rats.
A photomorphological study of subchronic toxicity for 1 month with intramuscular administration of 1 kg showed no pathological changes in internal organs and hematological parameters.

This composition did not cause local irritation at the site of administration.

The composition of the present invention was applied both clinically and in the laboratory to the treatment of 15 patients who suffered from acute poisoning by a phytotoxin derived from phalloid mushrooms leading to toxic injury of the liver. The results are shown in the example below.

With several modern diseases that produce acute and chronic hypoxia that affect the central nervous system and the liver, or other organs and such systems that need to act simultaneously with the liver and brain. It has been found that the medicament of the invention can be used in cases of poisoning and certain complex effects on the human organism of ecological nature with pathological changes or fluctuations.

The advantage of the antihypoxic drug according to the invention is that it exhibits an enhanced antihypoxic effect that is simultaneously expressed in cases of acute and chronic diseases or poisonings and in cases of interrelated brain and liver damage. It is.

By administering this composition as a ready-made medicament,
Various doses of these ingredients can be used quickly and in a timely manner in such ratios as to achieve the most advantageous synergistic effect;
It is therefore possible to reduce the development of secondary effects of exogenous substances, which in many cases cause liver diseases and intoxications that cause damage of secondary properties to brain structures. In pharmaceutical administration, the average daily dose of Piracetam can be reduced by 30% compared to when used alone. Furthermore, the overall treatment period is shortened and the risk of complications is avoided.

Next, the present invention will be explained in more detail using specific examples.

Example 1 The experiment consisted of 60 white mice of the H strain (10 in each group).
in a glass airtight container using Rapidly reduce air pressure to 210 mmHg using a vacuum pump. This pressure corresponds to 10,000 meters above sea level. The pharmaceutical composition is administered intraperitoneally 30 minutes before the onset of hypoxia. Record the life duration of the mouse in seconds. The results obtained from the experimental group are recorded as % change relative to the control group (Table 1). As seen in the table, when 500 mg/kg piracetam is combined with 25 mg/kg orotic acid, the additive effect of antihypoxic action is 42.6% and 10
00 mg/kg piracetam 50mg/k
When combined with g of orotic acid, this additional effect is 43
．． It is 9%.

Example 2 Clinical Data Patients: G, D, 0. 19 years old (file number 21)
848/ 1984, Hospital for
first aid.

Medical In5titude'N,
Diagnosis: Phalloid mushroom poisoning, acute gastrointestinal colitis, toxic liver damage, toxic brain damage Overview of course, symptoms and treatment 2 With three friends I ate wild mushrooms prepared over an oven fire. 6-7
After an incubation period of hours, the first symptoms of intoxication, characteristic of toxic gastrointestinal colitis, appeared. Nausea, vomiting, diarrhea, general symptoms of toxicity - weakness, dizziness, asthenia, symptoms of liver toxicity - tension and pain in the right subcostal area, enlargement of the liver up to 3-4 cm below the costal eye.

At the time of admission, the patient's pulse was 108/min, and the arterial pressure was 120/80°. Some analysis data is shown below.

October 1984 date 4th 5th 8th 10th 31st 5GOT (U#) 80 88 22
11 8SGOT (U/)) 23 8
6 or more 77 5g 2 Serum bilirubin 39
．． 31 27.9 18.6 25.9 17(μa
+ol/)) The following treatments were performed. Gastric lavage, forced diuresis, hyperbaric oxygen therapy,
Common detoxification measures: up to 4 g of piracetam and orotic acid per day, 1% 1% solution, administered intramuscularly twice. The patient was discharged clinically well.

Example 3 Patient: 1. T, N, 19 years old (file number 2
1850/1984, Medical I n5
Titute'N.

Diagnosis: Phalloid mushroom poisoning, acute gastrointestinal colitis, toxic liver damage, toxic brain damage Overview of course, symptoms and treatment: 3 patients. My friend and I ate wild mushrooms prepared over an open fire. 7-8
After an incubation period of hours, symptoms of toxic gastrointestinal colitis appeared. Nausea, vomiting, diarrhea, general symptoms of toxicity - weakness, dizziness, symptoms of liver toxicity - tension and pain in the right subcostal area, enlargement of the liver 2-3 cm below the costal eye. Pulse at admission was 96 per minute.
Arterial pressure is 100/60°. Some analysis data is shown below.

October 1984 date 4th 5th 8th 7th
18th 5GOT (U/)) 38 47 10
17 4 Serum bilirubin 32.07 10
．． 4 7.2 11.4 13.4 (μmol/)) Urea (μmol/)) 8.09 − --
4. The following treatment was performed. Gastric lavage, forced diuresis, hyperbaric oxygen therapy, general detoxification measures, 4 g of piracetam and orotic acid per day, 1% solution of llt' twice, intramuscularly, 10
days. The patient was discharged clinically well.

Example 4 Patient: S, S, 7. 19 years old (file number 21)
651/1984, Medical In5t
1tute'N.

Pirogov', Sofias admitted 1984
Diagnosis: Phalloid mushroom poisoning, acute gastrointestinal colitis, toxic liver damage, toxic brain damage The course and symptoms were the same as in the above case. Only the more characteristic analysis data are shown.

October 1984 date 4th 6th 7th 11th
22nd 5GOT (U#) 24 43 38
13 108GPT(U/Jl) 33
811 72 79 4 Serum bilirubin
18.1 30.19 10.3 14J 8.2
(μmol/)) The following treatments were performed. Gastric lavage, forced diuresis, hyperbaric oxygen therapy,
Common detoxification measures: 4 g of piracetam and orotic acid per day, 1% solution of IWi twice, intramuscularly, for 10 days. The patient was discharged clinically well.

Example 5 Patient: 1. E.1. (File number 21647/198
4.Medical In5titude'N
, Pirogov'.

5ofias, hospitalized October 4, 1984, discharged 19
(October 19, 1984) Diagnosis: Phalloid mushroom poisoning, acute gastrointestinal colitis, toxic liver damage The course and symptoms were the same as in the above case. Only the more characteristic analysis data are shown.

October 1984 date 4th 5th 6th 7th 11th 18th 5GOT (U/)) 8080 or more
16 24 10 4SGPT (U/))48
86 or higher 36 23 33 5 Serum bilirubin 2g, 08 16.55 32.1 25.9
14.5 15.5 The following treatments were performed. Gastric lavage, forced diuresis, hyperbaric oxygen therapy, general detoxification measures, 4 g of piracetam and orotic acid per day, 1% solution of 1111 administered intramuscularly twice for 10 days. The patient was discharged clinically well.

Example 6 A clinical trial was conducted on a pharmaceutical composition combining viracetam and orotic acid (from August 5, 1984 to December 1985).
Until April 4th, I I Neurolog1ca
! Cl1n1cof Medlcal Ac
ademy, 5ofia) o 32 patients were treated. Of these, 21 underwent acute and chronic treatment, and 11 underwent chronic treatment. Table 2 shows the gender and age distribution of these patients.

Table 2 Gender Age 40 or younger Male 41-5051-6060 or older
2 5 5 2 Female 4
9 4 1 total 614
93 Table 3 shows the distribution of disease classifications.

Table 3 Status after cerebral attack 5 Chronic and transient cerebrovascular insufficiency 14 Vasomotor headache
10 Conditions after brain injury 2 Description of the methods used a) Acute procedure = performed on 21 patients.

After recording the background rheogram (volume and differential (velocity) right anterior mastoid, and left calf volume and longitudinal velocity), a five-red ampoule of piracetam and orotic acid was injected intramuscularly. Using the same induction, rheographic changes were observed at 5, 15, 30, 60, and 120 minutes after drug administration.

In the quantitative analysis, the following parameters were used.

Amplitude of the rheographic wave (Hl), credence index and diastolic index, relative portion of the ascending prominence, velocity of propagation of the REG wave. After these measurements were completely completed, all the obtained data were statistically processed. After completion of acute treatment, all patients underwent chronic treatment.

b) Chronic treatment: All patients were given twice a day (8:00 and 18:00)
30 minutes) One ampoule of viracetam orotic acid was administered intramuscularly. This is the second time for nine of them (
The administration at 18:30 was performed orally.

Treatment periods ranged from 10 to 29 days. For chronic treatments, rheographic measurements were taken before and after the treatment period. The main results obtained are shown below.

(1) Headache completely disappeared or headache symptoms decreased in 22 out of a total of 24 patients. All treated patients with vasomotor headache had their headaches reduced or disappeared during or after treatment.

(2) For 14 of the 19 patients whose main symptoms were dizziness, the dizziness decreased to varying degrees or disappeared.

(3) Twelve patients reported increased mental performance, improved memory, and improved attention.

(4) Six patients who had symptoms of light and short sleep, i.e., insomnia, or after the second drug administration of the day (at 16:30), without further hypnotics or other drugs, the night He reported to his doctor that his sleep had improved. This is noteworthy.

(5) Two patients (46 and 52 years old) reported improved sexual performance to their doctors.

(6) No patients exhibited allergies, gastrointestinal disorders, or other side effects.

(7) 60 without strongly changing the rheograph.
The efficacy of viracetam orotic acid was confirmed in patients under the age of 10.

Example 7 Pharmaceutical composition A, ampoulepiracetam 20 kg orotic acid 1 kg ethanolamine
0.80kg citric acid pH5.5~
Distilled water for injection up to 6.5 80 tablets up to 100 Piracetam 0.05-1.0 g Orotic acid 0.01-0.10 g Microcrystalline cellulose
0.05-0.10g Lactose 0.05
~0.10g Aerosll 0.001-0.008g Talc 0.003-0.006g Magnesium Stearate 0.002-0.004g C2 Solid Gelatin Capsules Piracetam 0.005-0.600g Orotic Acid 0. 01-0.100g Microcrystalline cellulose 0.05-0.100g Lactose 0.05-0.100g High molecular weight polymer 0.001-0.05g Talc 0.0
04 to 0.05g Magnesium stearate 0.002 to 0.025g

Claims (2)

[Claims] (1) An antihypoxia drug, especially for the brain, characterized in that it contains 2-oxo-pyrrolidine-1-acetamide and orotic acid or a pharmaceutically acceptable salt thereof in a weight ratio of 500:1 to 1:2. Medicines with protective and hepatoprotective effects. (2) an acute disease characterized by administering the medicament according to claim 1 at a total daily dose of 0.150 g to 50 g and 0.030 g to 0.30 g, respectively; Methods of treatment of chronic diseases and exogenous poisonings.