RU2762495C1 - Application of hydrochloride n,n-diethyl-5,5-diphenyl-2-pentinylamine for treating non-cardiogenic pulmonary oedema - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to the field of medicine, in particular, to pulmonology and resuscitation, and is intended for treating non-cardiogenic pulmonary oedema. An aqueous 1% solution of hydrochloride N,N-diethyl-5.5-diphenyl-2-pentinylamine, injected in the form of an aerosol with a particle distribution range from 0.2 to 8 microns, is used as a treatment agent.

EFFECT: invention ensures a significant increase in the effectiveness of treatment of non-cardiogenic pulmonary oedema.

1 cl, 1 dwg, 1 tbl, 4 ex

Description

The invention relates to medicine, more precisely to pulmonology and resuscitation, and can be used for the treatment of non-cardiogenic pulmonary edema in the intensive care units and intensive care units of various hospitals, as well as for the relief of acute conditions caused by respiratory failure of a non-cardiogenic nature, both in a hospital setting and in non-stationary conditions.

Non-cardiogenic pulmonary edema is a life-threatening critical condition caused by respiratory failure of a non-cardiogenic nature, which means, first of all, the acute pulmonary injury syndrome (ARS) and its most severe form - adult respiratory distress syndrome (ARDS) [Bernard GR, Artigas A., Brigham KL E.A. The American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination // Amer. J. Resp. Crit. Care Med., 1994 - V. 149, N 3, pt. 1 - P. 818-824.], As well as severe bilateral pneumonia. These conditions are characterized by the rapid development of hypoxemia, refractory to oxygen therapy. Pulmonary edema is one of the most common causes of death in various diseases and pathological conditions. Primary diseases against which noncardiogenic pulmonary edema can develop can be, for example, viral pneumonia, bacterial pneumonia, septic shock, hemorrhagic shock, pulmonary toxicity poisoning, multiple organ failure and other causes.

In the treatment of pulmonary edema, the method of hyperbaric oxygenation is widely used [Mashkovsky M.D. Medicines. - 15th ed., M: "New Wave", 2006, 1206 p. ]. The following groups of drugs are also used:

- ganglion blockers (pentamin), which provide peripheral vasodillation, while improving the outflow of blood from the lungs;

- narcotic analgesics (morphine); their therapeutic effect is associated with adequate anesthesia, sedation and significant peripheral vasodillation, which ensures the deposition of blood in the systemic circulation, relieving the small circle;

- cardiac glycosides (strophanthin, digoxin) increase the contractility of the myocardium and reduce the heart rate;

- diuretics (lasix), reducing the volume of circulating blood, relieve the large and small circles of blood circulation;

- corticosteroids (prednisone) are used to reduce the permeability of the alveolar-capillary membranes of the lungs;

- defoaming (inhalation of antifomsilan aerosol) and ensuring airway patency, - adequate oxygen therapy, in severe cases, transferring patients to mechanical ventilation in the mode of positive outlet pressure.

However, the use of traditional treatment regimens has its drawbacks:

- these methods are not always effective in the treatment of pulmonary edema;

- they do not have a predominant effect on the shock organ, since they all act at the organismic level;

- weakly affect the processes of lymph circulation and lymph formation in the lungs;

- for the most part, they do not have a beneficial effect on the rheological properties of blood and lymph, do not prevent and do not eliminate thrombus formation in the system of pulmonary (primarily lymphatic) vessels;

- do not affect the reabsorption from the interstitial space of the lungs of large-molecular protein compounds released in large quantities from the blood capillaries due to their increased permeability;

- the use of ganglion blockers against the background of normal or low blood pressure is not always effective, it can be accompanied by severe, difficult to control hypotension. In addition, cerebral blood flow may decrease to a critical level, causing impaired consciousness in the patient [Obolensky S.V., Zaborov A.M., Dobrovolskaya R.V., Gomberg V.G., Domanskaya I.A., Malakhova M. I AM. METHOD FOR PULMONARY Edema TREATMENT. RU 2116799 Application: 95109321/14, 1995.06.13 Published: 1998.08.10].

As a prototype of the present invention, the method of hyperbaric oxygenation (HBO), which is most widely used to combat respiratory failure, has been selected. It should be noted that along with the positive aspects, the latter has a number of disadvantages. Firstly, the cause leading to the dysfunction of external respiration is not always eliminated, and secondly, with hyperbaric oxygenation, as a rule, it is impossible to carry out infusion therapy. Thirdly, HBO is performed by persons with special training. The hyperbaric oxygenation chamber is installed in a separate room, isolated from electrical devices [Voloshko IG, Berenshtein SS, Dzhenalayev BK, Dosmagambetov S.P. Oxygen therapy device with counterpressure in the expiratory phase. Patent RU (51) 5 A61M16 00], and therefore the HBO method is not applicable at the pre-hospital stage. The latter is especially important, since pulmonary edema requires the most prompt help, and even a few minutes of delay can cost the patient his life.

Thus, the development of new, more effective methods of treating pulmonary edema is an urgent task for modern medicine.

Disclosure of the invention.

The objective of the invention is to improve the effectiveness of the treatment of noncardiogenic pulmonary edema.

The problem is solved by inhalation of the drug substance - N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride using a nebulizer generating particles in the range of 5 microns.

The structural formula of the active substance is shown in Fig. 1.

N, N-Diethyl-5,5-diphenyl-2-pentylamine hydrochloride is an acetylenic amine with the gross formula C ₂₁ H ₂₅ N _* HCl with a molecular weight of 327.9. Let's very well dissolve in water, stable in aqueous solutions.

N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride was synthesized at the Federal State Budgetary Institution of Science “Institute of Toxicology of the Federal Medical and Biological Agency” (FGBUN IT FMBA of Russia). The substance is registered and produced under the name "Pedifen" by the Federal State Unitary Enterprise Scientific and Production Center "Pharmzashchita" of the FMBA of Russia, No. Р N002888 / 01 dated 06.06.2008.

N, N-Diethyl-5,5-diphenyl-2-pentynylamine hydrochloride possesses:

- antioxidant properties;

- membrane stabilizing action;

- pronounced local anesthetic effect;

- pronounced antispasmodic activity, exceeding papaverine by 6.5 times for this indicator;

- anti-inflammatory properties;

- mild stimulating effect on the central nervous system;

- properties that improve microcirculation.

In therapeutic doses, it does not have allergenic and irritating effects.

Pharmaco-toxicological assessment of N, N-diethyl-5,5-diphenyl-2-pentynyl-amine hydrochloride is given in theses [Onufrienko ME, Pharmaco-toxicological assessment of pedifen, St. Petersburg, 1995], [K. S., Experimental substantiation of a complex drug for inhalation use in lesions caused by pulmonotoxicants. SPb., 2016].

The closest in essence to this technical solution is the method of hyperbaric oxygenation (HBO), which is widely used to combat respiratory failure [Mashkovsky M.D. Medicines. - 15th ed., M: "New Wave", 2006, 1206 S.], which was chosen as the prototype of the present invention.

According to the present invention, the following agent and method of treatment is provided for the treatment of noncardiogenic pulmonary edema:

- N, N-Diethyl-5,5-diphenyl-2-pentynylamine hydrochloride aqueous solution with an active substance concentration of at least 0.5%;

- a nebulizer that generates liquid aerosol particles, the size of which is distributed in the range of 5 microns.

A nebulizer that generates particles, the size of which is distributed in the range of 1-50 microns.

The applicant is not aware of any sources of information that would contain information about the use of N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride for the treatment of noncardiogenic pulmonary edema. Thus, the claimed technical solution is not obvious to specialists, which makes it possible to conclude that the claimed invention meets the "Novelty" condition of patentability.

As the examples below show, the claimed agent and method of treatment provide an important technical result consisting in a significant increase in the effectiveness of the treatment of noncardiogenic pulmonary edema.

The applicant has not identified any sources of information containing information about the influence of the aggregate of the declared distinctive features on the achieved technical result. This, according to the applicant, testifies to the compliance of this technical solution with the patentability condition "Inventive level".

The implementation of the invention is illustrated by examples.

Experimental models and research methods.

Pharmacological agents.

- Oxygen-air mixture with an oxygen content of 50%.

- N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride, substance 99%.

- Carbon monoxide (CO) cylinder.

- Water for injections.

Experimental animals.

The experiments were carried out on white outbred male rats, age 3 months, weight 200-220 g, obtained from the Rappolovo nursery. The animals were kept under standard conditions under a 12-hour light regime with free access to water and food.

Animals were selected for the experiment by randomization and divided into 5 groups.

Example 1. Modeling of pulmonary edema.

A toxic model was used to model acute noncardiogenic pulmonary edema (NOL) in rats. Noncardiogenic pulmonary edema was induced by intraperitoneal administration of thiourea to animals. This model is characterized by the rapid development of pulmonary edema, minimal pathological changes in other organs and systems, as well as good reproducibility (according to literature data up to 80%) [Torkunov PA, P.D. Shabanov. Toxic pulmonary edema: pathogenesis, modeling, study methodology // https://cyberleninka.ru]. In order to enhance pulmonary hypoxia, the rats were inhaled with carbon monoxide. In general, the modeling of noncardiogenic pulmonary edema looked like this:

Rats were injected intraperitoneally with a 10% thiourea solution at a dose of 100 mg / kg. Immediately thereafter, the animals were placed in a 100 L chamber for 30 minutes for inhalation exposure to carbon monoxide at a concentration of 1500 mg / m ³ . In the course of the experiment, instrumental control of the concentrations of CO, CO ₂ , O ₂ , temperature and humidity, as well as the air flow through the chamber was carried out.

Example 2. Conditions of treatment by the method of hyperbaric oxygenation (HBO).

In the experiment, a pressure chamber with a working volume of 100 l was used, connected to a cylinder with an oxygen-air mixture with an oxygen content of 50%, equipped with a fine adjustment outlet valve. Experimental animals were placed in the pressure chamber, after which the chamber was saturated with an oxygen-air mixture, while the pressure in the chamber was maintained at 1.5 atm. After keeping the animals at a given pressure of the oxygen-air mixture for 40 minutes, the pressure was released and the animals were removed from the chamber and the survival rate and postmortem examinations were assessed.

Example 3. Conditions for treatment with inhalation of N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride

For experiments with laboratory rats, a compressor-type metered-dose inhaler was used, described in AS No. 320550 dated 01.11.90. The average particle size of the generated aerosol was 1.5 µm, the distribution range of aerosol particles was from 0.2 to 3.0 µm.

Example 4

The results of the study obtained when assessing the effectiveness of pharmaceutical substances in the treatment of noncardiogenic pulmonary edema

Animals were selected for the experiment by randomization and divided into 5 groups:

1. Group 1 - animals with induced pulmonary edema and HBO treatment (oxygen 50% at a pressure of 1.5 atm. For 30 minutes) 5 minutes after modeling of edema.

2. Group 2 - N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride 0.5% solution (the claimed method, according to the active component dose of 1-3 mg / kg) by inhalation 5 minutes after modeling the edema. A solution of the drug was prepared in distilled water immediately before administration and filtered through a cotton filter.

3. Group 3 - N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride 1.0% solution (the claimed method, according to the active component dose of 2-5 mg / kg) by inhalation 5 minutes after modeling the edema. A solution of the drug was prepared in distilled water immediately before administration and filtered through a cotton filter.

4. Group 4 - Water for injection 0.1 ml / rat inhalation after simulating edema.

5. Group 5 - Control (water for injection 0.1 ml / rat by inhalation without modeling of pulmonary edema).

Table 1 shows the survival rates and gravimetric lung coefficients in animals with OOL after treatment with a pharmacological substance.

The analysis of the presented results indicates the effectiveness of the treatment of NOL with the help of inhalation of a 0.5-1% solution of N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride (the claimed method of treatment). There is a statistically significant decrease in the gravimetric coefficients of the lungs in animals that received a pharmaceutical substance as a means of therapy. At the same time, the dependence of the effectiveness on the dose of the administered substance is traced. The introduction of a higher dose of 5 mg / kg causes a decrease in the degree of lung hydration (LHF) by 40.2% compared to the prototype, while the introduction of a dose of 3 mg / kg reduces lung hydration by 35.2%, respectively. The SHL coefficient indicates a less pronounced hydration of the lungs in animals of these groups, which can be regarded as an indicator of the effectiveness of the therapy. Significant differences were registered both with the group of control animals and with the group of HBO (prototype) [6 - Guidelines for conducting preclinical studies of drugs, Part 1. - M .: Grif and K, 2012. - P. 46].

Clinical picture and data of pathomorphological studies

After induction of NOL and removal of the animals from the CO chamber, the animals were placed in the containment cage for further observation. In 40-60 minutes from the moment of administration of the thiourea solution, hypodynamia was noted and shortness of breath was recorded. Subsequently, the condition of the animals continued to progressively deteriorate: shortness of breath with the participation of auxiliary muscles, weakness, cyanosis, and tousled coat. The death of animals occurred in conditions of increasing acute respiratory failure. Three rats died within 1.3-2.0 hours.

Clinical manifestations and dynamics of their development in animals before inhalation in all groups coincide with the data recorded in "model" animals with NOL.

In animals treated with HBO (prototype), the death of 2 rats was recorded 20-40 minutes after the simulation of edema.

In animals that received 0.5-1% solution of N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride as therapy, immediately after inhalation, the state stabilized and further deterioration from the respiratory system was not observed. Locomotor activity and grooming were recorded in animals.

When assessing the macroscopic picture of the lungs of animals with model toxic edema in all experimental groups, the lungs were enlarged in volume, the separation of a burgundy liquid was observed on the parenchyma section. In the chest cavity, the presence of a dark red exudate in a volume of up to 5 ml was noted. In the group of animals with model toxic pulmonary edema, where the substance N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride was used as therapy, the effusion in the pleural cavity was light yellow, without a hemorrhagic component. The gravimetric coefficients of the lungs of animals of these groups indicate less pronounced hydration of the lungs than in the case of the prototype, which can be regarded as an indicator of the effectiveness of the therapy.

Thus, in the course of the study, it was found that the proposed method of treatment using inhalation of a solution of the substance N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride according to the criteria of animal survival and the clinical picture of pulmonary edema has a significant advantage over the prototype (known treatment with hyperbaric oxygenation). The greatest effect was observed in the treatment of noncardiogenic pulmonary edema with 1% solution of N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride. In animals, after inhalation, the state stabilized and further deterioration from the respiratory system was not observed. The death of animals during treatment with the claimed method was not recorded for the entire observation period.

Claims (1)

A method of treating noncardiogenic pulmonary edema, characterized in that an aqueous 1% solution of N, N-diethyl-5,5-diphenyl-2-pentynylamine hydrochloride is used as a treatment agent, which is administered as an aerosol with a particle distribution range of 0, 2 to 8 microns.

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