A means of having an anti-shock activity

 

(57) Abstract:

The invention relates to medicine and the application of known drug emoxipin (hydrochloride of 2-ethyl-6-methyl-3-oksipiridina) for a new purpose, namely as antishock funds. Previously emoxipin been used in ophthalmology for the treatment of, for example, burns in the retina of various etiologies. 8 table.

The invention relates to medicine, in particular to pharmacology, and can be used in the treatment of shock of various etiologies.

Currently, the number of known compounds that prevent the development of endotoxin shock. However, none of them has a high therapeutic effect against the background of developing shock.

The complexity of the pathogenetic picture endotoxin shock, resulting from the introduction into the body of pathogenic organisms or the products of its life activity of various nature and rapidity of development and the variety of clinical manifestations are seen as the main obstacles to the creation of pharmacological agents with effective medicinal properties.

In recent years, much hope is pinned on the blockers of prostaglandin synthesis, prid is).

Works Halushka et al. it is shown that the introduction of acetylsalicylic acid for 30 min before the induction of endotoxin shock sublethal doses of Salmonella enteritidis increases survival of animals up to 70%

The application at the same time ibuprofen and imidazole increases the survival rate to 80% [1]

At a later date either aspirin or other prostaglandin synthesis inhibitors do not inhibit the development of endotoxin shock and does not have a significant impact on the percentage of mortality, which is probably related not only with the rapid deployment of the clinical picture of shock, but also the inclusion in the pathogenetic chain of mechanisms that are independent products cyclooxygenase cascade.

Now remains the problem of the treatment of acute poisoning, accompanied by the emergence of ekzoticheskogo shock.

Acute toxicity of chemical substances, according to different authors, ranges from 40 to 85% of all cases of poisoning. To chemicals most frequently causing poisoning include, for example, strong acids, alkalis, drugs, household cleansers. Therapy when the shock is symptomatic.

Currently, when the shock conduct is of Oseni, for example, prednisolone, dexamethasone; narcotic analgesics for pain; buffer solutions for the correction of water-electrolyte balance; blood substitutes for inflammation of the circulating blood, as well as hemodialysis, the method of forced diuresis, peritoneal dialysis.

Currently in medical practice does not exist antishock drugs.

The purpose of the invention antishock tool.

The objective is achieved by the application of known medicinal substance hydrochloride 2-ethyl-6-methyl-3-occipied (international name emoxipin) of formula I:

HCl (I) for a new purpose, namely as antishock tools.

Currently, emoxipin finds application in ophthalmic practice, for example for the treatment of burns of the retina.

The mechanism is known therapeutic action emoxipin associated with inhibition of platelet aggregation in the blockade them in the activity of the phosphodiesterase of cyclic 3,5-AMP. Our study first showed that the emoxipin able to inhibit the development endotoxin and toxic shock. Based antishock action of the drug are completely different mechanisms for the cada, in particular, leukotriene fully4that is a powerful inducers of the septic process.

Due to the fact that medical practice has no means of pathogenetic therapy of shock, comparing the proposed drug, prednisolone, dexamethasone, drugs used for symptomatic treatment of shock.

The following examples illustrate antishock action emoxipin.

P R I m e R 1. Antishock activity emoxipin on the model of endotoxin shock. The experiments were performed on two kinds of animals: mice (weighing 20-24 g) and rabbits (weight 2.5-3.0 kg) contained in vivarium on a normal diet.

Model of endotoxin shock was created by the method (I) intravenous injection of sublethal doses of lipopolysaccharide (LPS) of Salmonella typhimurium L-3629 "Sigma" (USA), caused 90% mortality of the animals within 24 hours, Mice received LPS at a dose of 30 mg/kg, rabbits 7.5 mg/kg of LPS was dissolved in physiological sodium chloride solution, the pH was brought to 7.5.

Sterile solution emoxipin was injected intravenously: mice at doses of 50 and 100 mg/kg (tail vein), rabbits at doses of 20 and 50 mg/kg (ear vein) in amounts of, respectively, 0.1 ml and 1.0 ml after 1 h after westmore TWEEN-80 (or TWEEN-80 with physiological sodium chloride solution), ibuprofen (the"decision Upjohn Company, USA; 5 and 20 mg/kg) or dexamethasone (0.5 and 5.0 mg/kg).

Antishock activity of the preparations was assessed by the percentage of survival of animals 24 h after the beginning of the experiment, as well as visually (by changing the behavior of animals) and the histological studies. In experiments on rabbits was conducted continuous registration indices of Central and peripheral hemodynamics during 5 h from the start of the experiment with the help of special sensors connected with mingograph-34 ("Siemens"). Experimental data were processed statistically. The first clinical signs of endotoxin shock developed in animals by the end of 1 h after injection of endotoxin.

Subjectively, this was manifested by sudden braking of motor activity (in some cases, convulsive twitching), shortness of breath, excessive defecation in the form of loose stools, loss of appetite.

Objectively in rabbits was recorded a drop in blood pressure of more than 20% decrease heart rate, on average, 15%

Mortality of animals began with 3-5 hours during this period in the control group died 24% of mice and 30% of rabbits (table. 1 and 2).

After 12 h, the mortality of the mice reached the 50 and 90%

At necropsy, animals were detected plethora of parenchymatous organs, swelling of the lungs, multiple hemorrhages in internal organs.

With the introduction of emoxipin through 1 h after the development of shock dose of 50 mg/kg mortality of mice for 5 hours did not exceed 12% and by the end of the day 30% (table. 1). At a higher dose (100 mg/kg) emoxipin was much less effective.

Antishock activity of aspirin in doses of 50 and 100 mg/kg did not exceed 30% of the ibuprofen in doses of 5 and 20 mg/kg 35% in both groups of mice treated with dexamethasone (0.5 and 5 mg/kg), survival after 24 h was 29.4% (table. 1).

In experiments on rabbits optimal therapeutic effect emoxipin was observed at a dose of 20 mg/kg (table. 2). The blood pressure began to stabilize within one hour after drug administration and for 4 h was close to normal (Fig.).

Mortality of rabbits receiving the emoxipin and aspirin at a dose of 20 mg/kg, was in the first 5-8 h after shock 20% and after 24 h did not exceed 33% for the group of animals treated with emoxipin, and for the group of animals treated with aspirin and ibuprofen, the death of animals was 80% (table. 2).

The effectiveness of emoxipin and aspirin in a dose of 50 mg/kg and ibuprofen (Siena model ekzoticheskogo shock, caused by intragastric introduction of acetic acid. The experiments were performed at 150 outbred white rats-males weighing 180-240 g Endotoxic shock caused by well-known methods by oral administration of 40% acetic acid (0.4 ml per 100 g weight of the animal) under geksenalovy anesthesia. The emoxipin were injected once intraperitoneally in a volume of 1 ml at doses of 10, 15, 20, 40, 60 and 100 mg/kg for 1 h before and 1 h after injection of acetic acid. Control animals received prednisolone at a dose of 5 mg/kg

The results are shown in table. 3. The death of animals was observed after 24 h from the beginning of the experiment. Maximum shock effect emoxipin was observed at a dose of 40 mg/kg, regardless of the time of administration of the drug.

So, after 28 h from the beginning of the experiment died only 10% For the same period in the group of animals treated with prednisolone (maximum effective dose of 5 mg/kg), were killed 60-70% of the animals. After 36 hours from the start of the experiment in the group of animals treated with maximally effective dose of emoxipin (40 mg/kg), killed 40% of the animals, and prednisolone (5 mg/kg) 100% of the animals.

From table. 3 shows that increasing doses of emoxipin to 60-100 mg/kg did not increase antishock effect.

The results are shown in table. 4.

The most effective dose of emoxipin in this case was 20 mg/kg. So, with the introduction of emoxipin at this dose after 24 h from the beginning of the experiment, the death of animals was decreased by more than 3 times (killed 20% of the animals) compared with the group of animals treated with maximally effective dose of prednisolone (died 60 and 70% of the animals) depending on the time of administration of prednisolone). After 24 h from the beginning of the experiment in the group of animals treated with prednisolone, killed 100% and in the group of animals treated with emoxipin, 50-80% Increase in dose emoxipin to 100 mg/kg did not lead to an increase antishock effect.

The cause of deaths shocks of different etiologies is the development of respiratory distress syndrome, or so-called "shock lung". The formation of this complex of symptoms caused by the aggregation of neutrophils in microvessels mussomeli enzymes of neutrophils and reactive forms OF2. Examples 4-6 illustrate the ability of emoxipin to inhibit the aggregation of neutrophils induced in vitro substances with different mechanisms of action.

P R I m e R 4. The suppression of emoxipin aggregation of neutrophils induced by lipopolysaccharide In Salmonella typhimurium. Peripheral blood neutrophils were isolated according to the method, modified by the authors. During selection was used FCM buffer (II) without calcium and magnesium. Donors were the males rabbits breed grey chinchilla (weight of 3.0-3.5 kg). Blood (40-60 ml) were taken from the marginal vein of the ear in 1/10 volume of 3.8% solution of sodium citrate. Platelets were separated by centrifugation, removal of erythrocytes was used sedimentation in the dextran solution and hypotonic lysis. The resulting suspension of cells was fractionally by centrifugation in a density gradient (60% percoll, "harmacia, Sweden). Cells that have passed through the gradient, washed twice, and then resuspendable, bringing the density of the suspension to 1,11107cells/ml 98% of the cells were heterophily (count conducted in smears stained by Romanovsky). Cell viability averaged 97% (judging by the exception tepanovoi blue). Basophils and mononuclear cells were absent, contaminazione glassware. The selection procedure was carried out at 4aboutC.

Aggregation of neutrophils were recorded turbidimetric using standard aggregometry firm "Chronolog Corporation (model 330, USA) equipped with a data logger (sensitivity 10 mV, the tape speed 25.3 mm/min). In silikonizirovannaya cell covered with a Teflon magnetic stir bar was placed 0,45 ml suspension of neutrophils, was then added to 5 μl of concentrated solutions of calcium chloride and magnesium chloride, 20 μl of a solution emoxipin in 0.15 M sodium chloride solution (20 μl of 0.15 M sodium chloride) and warmed up in the device cell for 2 min at 37aboutWith, after which included a recorder and added into the cuvette 20 µl solubilizing of lipopolysaccharide (LPS; ConECs. conc. 200 μg/ml). With such a ratio of volumes of the final density of the suspension was 107cells/ml, calcium and magnesium, respectively, 1.3 and 1.0 mm and the final concentration of emoxipin 3, 5 or 10 mm. To set maximum light transmission enjoyed divorced twice a suspension of neutrophils. Neither LPS nor emoxipin in the used concentrations did not show toxic effects when a half-hour of incubation (except tepanovoi blue).

Each is Navali unsuitable for the experiment. After the onset of aggregation, recording was performed for 5 minutes quantify the aggregation response was given by the following parameters:

1) the lag-period L-the length of time between introduction of the inducer in the cell and the beginning of the aggregation;

2) the maximum light transmission INm(in percent relative to the transmittance divorced twice suspension);

3) the initial velocity of aggregation v is determined by the magnitude of the slope of the tangent conducted to the curve through the initial point, mm/min

The assessment of the significance of the obtained results was performed using t-student test.

Preincubate with emoxipin caused dose-dependent inhibition of aggregation. As can be seen from the table. 5, emoxipin at a concentration of 3-5 mm increased the lag period on average 1.9 times (p < 0,01). Preincubated with 10 mm emoxipin led to the prolongation of the lag is about 3 times (p < 0,001).

If we accept 100% of the maximum increase in light transmission caused by 200 μg/ml LPS, preincubate with emoxipin at a concentration of 3 mm caused a decrease of this parameter by 42% (p < 0,001), 5 mm by 55% (p < 0,001), 10 mm by 76% (p < 0,001).

The rate of aggregation of neutrophils during incubation with 3 mm emoxipin was decreased by half (p < 3 (p < 0.001) and 4 (p < 0,001) times.

P R I m e R 5. The suppression of emoxipin arachidonate-induced aggregation of neutrophils. Neutrophils were isolated from stable citrate venous blood of normal donors who in the past 7-10 days of medications. Neutrophils accounted for about 95% of the allocated cell viability in all cases more than 95% of Contaminating platelets met not more than 1/100. Experience set in the same way as described in example 4, with minor changes (the density of the suspension was brought to 1,09107cells/ml in the cuvette was made and 0.46 ml of a suspension, a solution of emoxipin was added in a volume of 25 μl). Inductor served as arachidonic acid (Fluka, Switzerland), which was stored in the form of a concentrated solution in absolute ethanol at -70aboutC. the working solution was prepared before each experiment so that when it is added in an amount of 5 μl, the concentration of arachidonic acid in the cell was 510-5M

The influence of emoxipin on arachidonate-induced aggregation of neutrophils was even more pronounced. Preincubate with 3 mm emoxipin led to the lengthening of the lag-period 2.9-fold (p < 0,001); at concentrations of 5-10 mm emoxipin increased the evoked decrease of maximum light transmission on average by 66% (p < 0,001). Preincubated with 10 mm of the drug is practically prevented aggregation (reduction INm92% p < 0,001).

During the incubation of neutrophils with 3, 5, 10 mm of the claimed substances the rate of aggregation decreased, respectively, in 2 (p < 0,001), 3 and 6-fold (p < 0,001).

P R I m e R 6. The suppression of emoxipin aggregation of neutrophils induced by calcium ionophores And 23187. Ionophor And 23187 ("Calbiochem-ehring, USA) was dissolved in dimethyl sulfoxide ("Serva, Germany) and stored at -70aboutC. Before each experiment the mother liquor was diluted 10 times with buffer. The experiments were set as described in example 4. The object of the study were rabbit and human neutrophils. The inductor was made into a cuvette in a volume of 20 µl. The magnitude of the lag period was not used for quantitative characterization of the suppression And 23187-induced aggregation.

As can be seen from the table. 7, preincubate rabbit and human neutrophils with 10 mm emoxipin reduced maximum light transmission in two times (p < 0,001). Judging by the changes in the initial velocity of aggregation, human neutrophils were more sensitive to the protective effects of emoxipin. Treatment with the drug (10 mm) reduced the rate of aggregation of rabbit granulocytes 1,atom, the emoxipin in concentrations of 5-10 mm inhibits the aggregation of neutrophils caused by different inducers. Dexamethasone, which is one of the most powerful drug of the group of steroids, inhibits the aggregation of neutrophils by 50% at a concentration of 80 mm (32 mg/ml). Cyclo-oxygenase inhibitors do not affect the aggregation ability of neutrophils.

The following example illustrates the ability of emoxipin block lipoxygenase way of arachidonic acid metabolism. Lipoxygenase products are as mediators of the activation of neutrophils (15-17), and mediators of shock.

P R I m e R 7. The suppression of emoxipin products leukotriene4and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (fully and 5-NET).

Experience set in the same way as described in example 4, but the size of the sample was increased by half. After 5 min incubation of intact or protected by emoxipin of neutrophils with LPS or 0.15 M solution of sodium chloride the reaction was stopped by adding 1.5 volumes of ice-cold methanol. Samples were incubated 15 min at 4aboutC, and then centrifuged (2000g, 4aboutC, 10 min), supernatant was acidified using 1 M hydrochloric acid to pH 3.5, and kept at -70aboutTo set the d nitrogen, and the residue was dissolved in the buffer for the corresponding radioimmunoassay.

FULLY4and 5-NET defined radioimmunochemical using commercial kits (3N-LtB4assay reagent system, Amersham UK; 5-NET3N-RIA Kit, "Seragen, USA). In each sample were made by two parallel dimension. The level of both products was expressed in PG/107cells/ml. Significance was evaluated using a t-test, t-test for pairwise related option.

As can be seen from the table. 8, cells stimulated by LPS, was formed by 1,4 times less 5-NET (p < 0.001) and 1.6 times more fully4(p < 0.01) compared with native neutrophils.

Preincubated with 10 mm emoxipin led to an even more dramatic decrease in the production of 5-NET (1.4-fold compared with cells treated with LPS, p < 0,05; 1.9 times compared to restimulating cells, p < 0,001. Under the influence of emoxipin products fully4decreased in 2 times in comparison with LPS-induced (p < <0.05) and was 1.3 times less than in unstimulated cells (p < 0,05).

Thus, even a two-minute contact of neutrophils with emoxipin completely blocks the leukotriene production induced by LPS. Dexamethasone inhibits the synthesis of the maturity of dexamethasone as an inhibitor of leukotriene production is determined by the ability of cells to protein synthesis. However, endotoxin shock protein synthesis is disrupted and even high-dose dexamethasone does not inhibit the production of metabolites of arachidonic acid. And, for example, inhibiting the activity of corticoids may depend on which agent is used as a trigger of arachidonic acid metabolism. For example, dexamethasone does not inhibit the production of leukotrienes in the cells of the lung tissue, stimulated by antibodies, and hydrocortisone leukemia in the rat basophils stimulated iodoform And 23187. To drugs, inhibiting cyclooxygenase and thromboxane-a synthase, enzyme of the biosynthesis of leukotrienes not sensitive.

The presented data allow to conclude that for the first time found a highly effective means of pathogenetic therapy of shock.

A MEANS of HAVING an anti-SHOCK ACTIVITY, characterized in that it is a hydrochloride of 2-ethyl-6-methyl-3-oksipiridina (emoxipin).

 

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