RU2228194C2 - Means for preventing from hemorrhagic blood-coagulating and edematous necrotic activity of snake venom - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves administering octreotide as synthetic octapeptide for preventing from hemorrhagic bloodcoagulating and edematous necrotic activity of snake venom of viper or rattlesnake family. The result is achieved with single application of the means. EFFECT: wide range of functional applications. 4 cl, 3 dwg

Description

The invention relates to emergency medicine.

The use of hemorrhagic and hemotoxic effects of isotonic sodium chloride solution, 5% glucose solution or 10% albumin solution for poisoning snake poisons is known. Prednisone or hydrocortisone can be added to infused solutions (“Handbook of emergency and emergency care” / Chazov E.I., Eliseev OM - M., 1988. - P.499-502; “Emergency care” / Under the editorship of Khramov Yu.A. - Novosibirsk. 1991. - P.38-39).

All these substances soften manifestations of intoxication. Prednisolone and hydrocortisone, in addition, prevent a possible anaphylactic reaction if the patient is further given specific antivenom serum (ATP). However, none of these agents (except ATP) prevents the development of hemorrhagic syndrome due to the action of the poison.

A known application for the treatment of venom poisoning snakes ATP (Chazov E.I., Eliseev O.M. ibid.). The use of ATP is indicated for poisoning with poisons the most dangerous snakes - cobra, gyurza, efa, viper. The most effective monovalent sera containing antibodies against one or another poison (for example, “anti-cobra”, “anti-gyurza”, “anti-efa”, “anti-viper”).

The specificity of sera, being their advantage, also presents some inconvenience for their use due to the lack of universality - in those areas where snakes of different species and genera are common. In practice, monovalent sera are used to treat poisoning by the poisons of various snakes within the same genus. For example, anti-gyurza serum is used for poisoning not only gyurza, but also other vipers of the Russian fauna, although with less efficiency.

The use of serums against snake venoms with hemorrhagic, hemotoxic effects, in addition to a number of advantages, has disadvantages. It is known that in 1-2% of patients, the administration of serum can cause anaphylactic shock, which is more dangerous than snake venom poisoning. Therefore, ATP is used mainly in assisting bitten children under the age of 3-4 years and in rare cases with severe poisoning in adults (Chazov E.I., Eliseev O.M. ibid.). The shelf life of serum is 2 years.

SUMMARY OF THE INVENTION

According to the mechanism of action, the poisons of all snakes are divided into two main groups:

1. Poisons that primarily affect the nervous system are neurotoxic (curare-like) poisons that cause paralysis of the motor and respiratory muscles, inhibition of the respiratory and vasomotor centers of the brain (venom of the cobra and other snakes of the aspid family, as well as poisons of marine poisonous snakes).

2. Poisons, mainly causing hemorrhagic, blood-clotting, edematous-necrotic effect. They mainly affect the walls of blood vessels and blood, cause extensive local and general hemorrhages, edema and necrosis of tissues, intravascular coagulation and other disorders, and therefore they are referred to the group of “hemorrhagic and hemotoxic poisons” (viper, viper, , vipers, etc. and poisonous rattlesnakes).

The picture of the defeat by poisons of the second group is as follows (observation of people bitten by snakes). There is a deep damage to the walls of blood vessels and other tissues in the area of the bite and away from it. Many point hemorrhages appear in the skin. Hemorrhages merge, forming extensive bruises and bruises that extend to most or all of the affected limb (when a person bites a limb), and in severe poisoning - to the trunk. Starting from 10-15 minutes after the bite, edema of the affected part of the body is clearly defined. It sometimes reaches enormous size and captures not only the entire affected limb, but also a significant part of the body. The volume of tissue in the area of edema increases by 1.5-3 times. Not only blood plasma, but also formed elements of blood: red blood cells and other cells come out of the vessels from the blood vessels. There is a big internal blood loss, which determines, to a large extent, the severity of the patient's condition and the outcome of the disease. Blood vessels are damaged not only in the bite zone, but also in all internal organs, where tissue edema and many small hemorrhages are also detected. An extremely unfavorable situation is created for the victim’s body: on the one hand, the walls of blood vessels are sharply damaged, because of which blood flows easily, and, on the other hand, the blood loses its ability to coagulate and clog destruction in the walls of blood vessels. Those. hemorrhagic syndrome is associated with both the hemorrhagic effect of poisons and coagulation - the development of disseminated intravascular coagulation, with short-term initial hypercoagulation and subsequent prolonged and deep hypocoagulation. In the area of the snake bite, bubbles appear, filled with bloody liquid, tissue necrosis with the formation of long healing ulcers.

The essence of the invention lies in the fact that it is proposed to use octreotide for the treatment of poisoning by snake venom causing hemorrhagic, blood-clotting, edematous and necrotic effects (venom of the snake of the viper family: viper, efa, viper, etc.). Prevention of hemorrhagic, hemotoxic effects is achieved by a single administration of the drug.

Compared with a solution of sodium chloride, glucose, albumin, the proposed tool prevents the development of hemorrhagic syndrome. Compared with ATP - with the same effectiveness as with the introduction of ATP, the risk of anaphylactic shock with a single administration of octreotide is excluded, because octreotide, unlike serum, is not an protein, but an octapeptide. In addition, the proposed tool is characterized by universality - the ability to use snakes of various species when poisoned by a bite, the poison of which causes hemorrhagic syndrome. Octreotide has a longer shelf life compared to PCA (5 years).

Octreotide (“The Register of Medicines of Russia. Encyclopedia of Medicines: annual. Collection. - LLC“ RLS-2002. ”- 2002, issue 9, p. 633-634) is a synthetic octapeptide that is a derivative of the natural hormone somatostatin, but has a more powerful and prolonged (up to 8-12 hours) action. Available in ampoules and vials for subcutaneous and intravenous administration. The drug suppresses pathologically increased secretion of growth hormone, as well as peptides and serotonin, produced in the gastro-entero-pancreatic endocrine system. The following octreotide prescriptions are known: acromegaly; alleviating the symptoms of endocrine tumors of the gastrointestinal tract and pancreas (carpinoid tumors; tumors characterized by hyperproduction of the vasoactive intestinal peptide (VIPoma); glucagonomas, gastrinomas / Zollinger-Ellison syndrome; insulinomas; tumors that are hyperproducing; AIDS; prevention of complications after operations on the pancreas; to stop bleeding from varicose veins of the esophagus and stomach in patients with cirrhosis of the liver.

The use of octreotide to prevent the development of hemorrhagic syndrome and the treatment of poisoning by snake venom causing hemorrhagic, blood-clotting and edematous-necrotic effects is unknown.

Information confirming the possibility of carrying out the invention with the implementation of the appointment

Dynamic monitoring of the effectiveness of the use of octreotide in case of poisoning with hemorrhagic poison

Clinical and morphological studies were conducted on rats of the Wistar strain weighing 150-200 g. Animals were divided into 4 groups of 11 animals in each group. The first group was the control, the rest were experienced. The animals of the control group were injected only with hemorrhagic, hemotoxic poison poison in a lethal dose (viper venom), simulating a snake bite. The animals of the experimental groups were also given poison in a lethal dose and, in addition, octreotide was administered. Octreotide was administered once. The animals of the first experimental group were slaughtered after 24 hours, the second experimental one after three, the third experimental group after 14 days. The procedures for the introduction of poison and octreotide, as well as the nature and dynamics of the observed changes in the control and experimental groups are described below.

The control group (simulation of snake venom poisoning hemorrhagic, hemotoxic effects). Animals under general ether anesthesia underwent median laparotomy and under the parietal peritoneum of the anterior abdominal wall, a solution of viper venom in a dose of 0.4 mg / 100 g of the animal’s body weight (lethal dose) was administered on one side (right or left). After 4-5 minutes (here and below, the time intervals counted from the moment of the introduction of the poison), serous edema developed in the area of poison injection, gradually increasing to 2-2.5 cm in diameter with the development (after 15-17 minutes) of the hemorrhagic rim on the periphery of the edema. After 20-40 minutes, point-type hemorrhages appeared on the serous membrane of the internal organs, as well as hemorrhages in the greater omentum. By the end of the third hour, hemorrhagic edema spread to the entire lateral surface of that side of the anterior abdominal wall (right or left) where the poison was injected. In the central part of the edema, a continuous hemorrhage was observed with signs of developing necrosis of the peritoneum and deeper lying tissues (muscles). On the periphery of the edema, the intensity of imbibition (hemorrhagic impregnation) was less intense.

About 50% of the animals died during the first three hours from the moment of the introduction of the poison, during which the dynamics of the development of edema and changes in the internal organs of the animal with an open stomach were monitored. The following changes in the internal organs were observed in these animals: the liver became darker, and almost black before the death of the animal. This indicated toxic liver damage - from toxic hepatitis to necrosis. The kidneys also acquired a darker color, becoming loose, swollen, which corresponds to the picture of toxic jade. Multiple point hemorrhages were observed in the lungs, the heart turned darker due to vascular stasis, and a thrombus was observed in the atria.

After a three-hour observation, the abdominal cavity in animals was sutured tightly. The animals were inactive, inhibited, their hair was ruffled. Animals did not take food or water.

All animals of the control group died during the first days from the moment of the introduction of the poison.

The autopsy of these animals that died after three hours (most of them died 5-7 hours after the introduction of the poison) revealed extensive hemorrhagic impregnation of the tissue of the lateral abdominal wall, extending down to the inguinal region and up the side wall of the chest. In the peritoneal section, the muscle of the anterior abdominal wall was necrotic. The central part of the edema had the appearance of a continuous hematoma, hemorrhages in separate areas over the entire thickness of the lateral abdominal wall were observed along its periphery. On the serous membrane of the internal organs there were point hemorrhagic hemorrhages. The kidneys were black, flabby, a clay -ish liver, indicating the development of necrosis in these organs. Point hemorrhages, swelling of the tissues were observed in the lungs and heart.

The first experimental group of animals (daily observation). According to the scheme described above, the animals of the experimental group were also injected with poison. Immediately after the introduction of the poison, octreotide was administered to the animal on the other side of the abdominal wall (i.e., if the poison was injected under the parietal peritoneum of the anterior abdominal wall on the right, then octreotide was administered under the parietal peritoneum of the anterior abdominal wall on the left). Octreotide was administered at a dose of 50 μg / 100 g body weight. After 8-15 minutes, i.e. later than in the control, a serous edema up to 2-2.5 cm in diameter with the presence of a hemorrhagic rim (spot hemorrhage) developed in the area of poison injection. Within 30-40 minutes from the introduction of the poison and octreotide, serous edema in the area of the introduction of the poison gradually increased in size to 3 cm with an evenly increasing hemorrhagic rim on the periphery. By the third hour, the diameter of the hemorrhagic edema stabilized within 3.5 cm. Sometimes hemorrhagic impregnation occupied the entire area of the edema, which was a bruise. Unlike control, the color of the edema did not take a black tint. By the end of the third hour from the introduction, single hemorrhages appeared on the serous membrane of the internal organs. There was a slight darkening of the liver and kidneys, but in no animal did they acquire such a dark color as in the control. This indicates the neutralization of the toxic effect of the poison.

Three hours after the introduction of substances, the abdominal cavity was sutured. In the first 1-2 hours after the abdominal cavity in animals was sewn up and placed in a cage, the animals remained inactive, inhibited, weakly responding to external stimuli. The hair was disheveled, animals did not accept food and water. Gradually, the animals became more active and after a day, their behavior and appearance practically did not differ from those in healthy animals.

The survival rate of animals in a day was about 80% (2 animals died).

After 24 hours (from the introduction of poison and octreotide) under general ether anesthesia, the sutures were removed from the anterior abdominal wall and a relaparotomy was performed to study further results of the treatment. At the injection site on the parietal peritoneum against the background of serous edema, the rim of hemorrhagic tissue imbibition was determined in the form of point hemorrhages with a diameter of up to 1.5-2 cm and a width of up to 1.2 mm. Sometimes, serous edema of the peritoneum spread down to the pelvis. The color of the swollen tissues is more pale than in the control, without signs of necrosis. Some changes in the internal organs were observed. The liver was swollen, friable, rarely - clay in nature. The kidneys are a slightly darker shade compared with a three-hour observation, but lighter than in the control; slightly swollen and loose. The picture indicated the presence of residual effects of toxic hepatitis, nephritis. No other changes in the internal organs of the abdominal and pleural cavities were found.

Thus, the daily experiment in animals allows us to draw the following conclusions:

- the introduction of octreotide leads to 80% survival of animals;

- locally, the process is limited - in the experiment, hemorrhagic edema does not exceed 1.5 cm, while in the control it is extensive, spreading to the entire lateral surface with the transition to the chest wall and deep into the entire thickness of the tissue. Unlike control, in the experiment there is no necrosis;

- changes on the part of internal organs are in the nature of residual manifestations in the form of edema (edematous hepatitis, edematous nephritis).

The second experimental group (three-day observation).

The nature and dynamics of changes in animals of this group during the first three hours from the introduction of substances, when the abdominal wall was not sutured, were similar to those observed in the first experimental group. A day after the administration of hemorrhagic poison and octreotide, 10 animals survived. As experiments showed, animals that survived on the first day, then almost all remain alive during the observation period.

Three days after the administration of substances to animals under ether anesthesia, they performed relaparotomy along the old scar with the removal of ligature sutures. In the area of injection of the snake venom solution, serous edema of the peritoneum with a diameter of 1.5-2 cm with the presence of point hemorrhages on the rim was observed. No effusion in the abdominal cavity was observed, indicating the absence of an inflammatory process in the internal organs. The liver and kidneys were of normal color, but somewhat loose (edematous) - residual effects of poisoning by poison. No changes were found from other organs. The behavior and appearance of animals did not differ from the behavior and appearance of healthy animals.

The third experimental group (observation period - 14 days).

During the first day 2 animals died. The remaining 9 animals after 14 days under ether anesthesia underwent relaparotomy and examined internal organs and local changes in the area of snake venom injection. In the area of injection of the poison there was edema of the peritoneum of a serous (not hemorrhagic) nature. There was no effusion in the abdominal cavity. When revising the liver, kidneys and other organs of the abdominal and pleural cavities, macroscopic changes were not detected. The behavior and appearance of animals did not differ from the behavior and appearance of healthy animals.

The experiments show that the use of octreotide leads to 80% survival of animals, and changes in the internal organs are minimal. The behavior and appearance of animals poisoned by snake venom of hemorrhagic, hemotoxic action, and treated with octreotide, does not differ from the behavior and appearance of healthy animals.

Claims (4)

1. The use of octreotide as a means with the properties to prevent the development of hemorrhagic, blood-clotting and edematous-necrotic action of snake venom in case of poisoning the body. 2. The use according to claim 1, characterized in that the poison is the venom of a snake of the viper family. 3. The use according to claim 2, characterized in that the poison is the venom of an ordinary viper. 4. The use according to claim 1, characterized in that the poison is the poison of a snake of the family of rattlesnakes.