UA20555U - Method for pharmacological correction of closed craniocerebral injury - Google Patents

Abstract

The method for the pharmacological correction of the closed craniocerebral injury provides for the intraperitoneal double administration of the coordination substance of germanium and tartaric and nicotinic acids, OK-3 used as 4% aqueous solution at a dose of 100 mg/kg in 30 minutes and 8.5 hours after the graduated strike of the parietal area of the rat's skull delivered by the freely falling weight.

Description

Description of the invention

The useful model refers to medicine, namely to the solution of methodological issues of medical tactics in 2 treatment of patients with closed craniocerebral trauma (TBI).

One of the most urgent problems of modern medicine remains the search for an adequate pharmacological correction of oxidative stress, which is the basis of the pathogenesis of ZChMH (2, 12, 16Y. Despite the fact that the pharmaceutical market currently has a sufficient arsenal of drugs for the treatment of traumatic brain disease, the mortality rate of patients with this extreme condition remains very high - 7039-4595 (15).

At the current level of medical support for intensive care of brain injury, the greatest preference is given to such means of conservative therapy as nootropic, anti-edematous, ashinociceptive, neuroprotective, corticosteroid, antibacterial, antifibrinolytic, antihypertensive, antioxidant, etc. 8, 11, 14). Despite the large number of drugs offered, all of them have the following significant disadvantages: 12 1. Inability to correct the development of membrane-destructive processes in nervous tissue at a certain level. 2. Insufficient ability to prevent the occurrence and development of endogenous intoxication.

Q. The possibility of achieving the necessary therapeutic effect only under conditions of combined use of medicines. 4. A large number of adverse reactions, especially in conditions of polypharmacy, when the possibility of drug interaction increases and, as a result, the development of various complications of pharmacotherapy. 5. Low pharmacotherapeutic effectiveness at the pre-hospital stage due to the lack of proper pharmacological activity in the early post-traumatic period.

The purpose of the useful model is to experimentally develop a new, pathogenetically based, highly effective and safe means of pharmacological correction of ZUMG.

To achieve this goal, we conducted screening studies among coordination compounds of germanium 7) with various bioligands synthesized at Odesa State Medical University. I.I. Mechnikova.

17 coordination compounds of germanium with various bioligands and microelements were included in the pharmacological screening program under the corresponding laboratory codes: ОЕ-1 (based on germanium and oxyethylenediphosphanic acid with ammonium); OE-2 (with sodium), OBE-3 (with potassium), OE-4 (with zinc); OK-1 (based on germanium and citric acid with nicotinic acid). OK-2 (with nikaginamide); OK-Z (based on germanium with tartaric and nicotinic acids), OK-4 (with nicotinamide); OK-5 (based on germanium with malic and nicotinic acids, OK-b (with nicotinamide); DT-1 (based on germanium and diethylenetriaminepentoacetic acid with ammonium), (DH-2) (with sodium), DT-Z ( with potassium), DT-4 (with magnesium); DH-5 (with zinc); as well as ("with coordination compounds of germanium with nicotinic acid (MIGU-1) and nicotinamide (MIGU-2). 3o The experiments were performed on white unrelated non-linear rats of both sexes weighing 160-200g according to the requirements of the State Scientific Pharmacological Center of the Ministry of Health of Ukraine |4).

ZCHMG was simulated with the help of a special device, its own original design, which allows delivering a force-dosed and localization-oriented impact with a load weighing 45 g, freely falling from a height of 8Osm on the parietal region of a rat's skull, fixed in an improved Kogan camera (9) . The studied 50 coordination compounds of germanium were injected intraperitoneally twice at a dose of 10 Ω/kg in the form of 490 aqueous no) s solutions 30 minutes and 8.5 hours after the start of the simulation of ZChMH |, 17, 6).

I» As a comparison drug (standard), a nootropic drug was used - piracetam (manufactured by Farmak, Ukraine), which, according to the literature 5, 7, is widely used in the implementation of early measures of cerebral protection in conditions of traumatic brain damage. Piracetam was administered to the reference group of animals in a dose that was similar to that for the experimental compounds in the same time regime. No treatment was carried out in the control series of rounds after the creation of ZChMG. The intact group consisted of "healthy" animals. av | Quantitative criteria for the peribroprotective effectiveness of the use of coordination compounds of germanium with bioligands in the conditions of ZUMG were the concentration indicators of the end products of lipid peroxidation in the cortex and brain (TBK-reactants), which were determined by the photoelectrocalorimetric method |13)| and the level of markers of sl 20 eadotoxicosis in blood serum - medium-mass molecules (MSM), which were studied using spectrophotometric analysis |10Ї1. All these indicators were evaluated 10.5 hours later (corresponding to the sl previously established peak concentration of MSM in the control series of rats) after simulation of this extreme state.

Statistical processing of the obtained results was carried out using the Student's i-criterion according to the program 29 "Vadgarpisv" (ZI. c It was experimentally established that 9 coordination compounds of germanium out of 17 studied have sufficient cerebroprotective activity: OK-2, OK-3, OK-6 OBE-1, OE-2, OB-4, DH-2, DT-3, MIGU-1, which is realized by a decrease in the level of MSM in blood serum and TBK-reactants in the cerebral cortex (see table). 65 average masti (MSM) and TBC-reactants in the body of rats with ZCHMT (p-b) 65 t 0.003 vo -D-

2. Control 0.140 897.40

(Se-tartaric acid-Mis) 0004 10.80

(Se-malic acid-Mis) 0004 33 50 ооо о у з сх ос тітр исо " (Zbe-Ovartmna оооя no) - ооо m 1 с оо s (e-Ovarp-t) 0002 bo Z 65 Raz 20.01 " 0.001 -5B-

(ze-dtpA-Mo) 0.005 2 (Sesyame) ooo Z

IF) zo t. Migo ogo vv,67 (besigamav) ogooya in poyu yu oo o 20. Piracetam omo7 284.00 s zo o

Note: Roux - compared to intact animals; - with Ro - in comparison with the control;

Once - in comparison with the reference group of rats; )» This is germanium;

Mis - nicotinic acid;

Mad - nicotinamide;

Oeary - oxyethylenediphosphonic acid; ke DTPA - diethylenetriamipentacetate. o From the data presented in the table, it can be seen that the maximum cerebroprotective effect in conditions of craniocerebral injury is manifested by the coordination compound of germanium with wine and nicotinic acids under the laboratory code

OK-3, which is evidenced by the ability of the latter to reduce the level of MSM almost by half, and the concentration of TBK-reactants by 89,690 in comparison with the control series of rats. In addition, it should be noted that the neuroprotective activity of OK-3 is probably superior to the reference drug (standard) (Р»0.05) and, in terms of the level of MSM, it does not differ from intact animals (Р»0.05)3. In our opinion, the ability of this compound to restrain "oxidative stress" and prevent manifestations of endotoxicosis of traumatic genesis is due to the effect of the cationic form of nicotine

ACIDS. Compounds based on oxyacids - OK-2, OK-6 have a less pronounced protective effect.

As for other substituents, OE and DT, they are ionic associates consisting of a complex germanium-containing anion and an inorganic cation, so they can be considered as salts of the corresponding complex acids. That is probably why they are all active, and their activity is determined both by the complex anion, in which Ce-O bonds are realized, and by the cation. A number of compounds that were used in the screening program, in terms of the expressiveness of their cerebroprotective activity, can be imagined in a decreasing sequence: OK-3, DT-2, OB-2, OK-2, OBE-4, OK-6, MIGU -1, 3-1,

DtT-4, OB-3, DT-3, OK-4, DT-1, DT-5, MIGU-2, OK-5, OK-1.

Conclusion:

The introduction of a substitute - OK-3 with a therapeutic purpose in the conditions of TBI shows a pronounced cerebroprotective effect, which is realized, apparently, due to the synergism of the pharmacological action of germanium with ligands (nicotinic and tartaric acids) and to a large extent prevails over the comparison drug - piracetam and differs: 1 .The ability to effectively correct the manifestations of oxidative stress and endogenous intoxication under the conditions of traumatic brain disease, which is realized by a probable (Р«0.001, compared to the control) decrease in the level of medium molecular weight peptides in blood serum and end products of lipid peroxidation (TBK-reactants) in nervous tissue. 2. The possibility of use as a means of monotherapy due to high therapeutic efficiency, which makes it possible to prevent the development of undesirable reactions of various nature.

Q. The expediency of using the investigated compound at the pre-hospital stage, which is very important for 7/0 pharmacological support of early cerebral protection.

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Claims (1)

The formula of the invention The method of pharmacological correction of a closed craniocerebral injury, which is characterized by the fact that it includes a two-time intraperitoneal administration of a coordination compound of germanium with tartaric and nicotinic acids c - 0K-3, in the form of 4 95 aqueous solution at a dose of 100 mg/kg, After 30 minutes and 8 .5 hours after applying a dosed impact with a freely falling load on the parietal area of the rat's skull. in the Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 1, 15.01.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. b5