Pharmacological studies of the new triazinoindole tompasline (3-(2-morpholinoethylthio)-1,2,4-triazino-[5, 6-b]indole dihydrochloride monohydrate) showed that it has high antihypoxic activity which is not species-specific. The activity of the agent is comparable to that of guthimine in hypoxic and circulatory hypoxia and is greater than that of guthimine in the "loading" model of hypoxia. The high efficacy of the protective effect of tompasline on the function of the sound analyzer allows this agent to be regarded as a potential specific antisurditant in acute sensorineural hearing loss. A preparative synthesis was developed for material of pharmacopeia quality, along with methods for its qualitative detection and quantitative estimation in substance and solutions, including biological fluids, which satisfy pharmacopeia requirements for therapeutic solution for intravenous injection. The technique for producing tompasline can be implemented more readily than the preparation of the antihypoxic agents guthimine and amtizol, which have not been yet introduced into production.The present report addresses our development of the first Russian antisurditant -tompasline -to be introduced into medical practice. The agent is (3-(2-morpholinoethylthio)-1,2,4-triazino[5,6-b]indole dihydrochloride monohydrate) (I), which has antihypoxic and anti-inflammatory activities [1,2].Compound I is one of the most effective antihypoxic agents among triazinoindole derivatives [3], which affect transmembrane ion transport [4]. Despite the fact that I is not the most active of these, it has a series of positive features, including a high therapeutic index, adequate solubility in water, and technical feasibility. I has been shown to have a wide spectrum of pharmacological activities, and is more active than guthimine and amtizol. Reports of several of the actions of I -analgesic, antiarrhythmic, antiaggregant, and neuroendocrine-optimizing in stress and hyperthermia -have been described in our previous reports (see the properties of the compound designed T-468) [5 -7]. Of particular note is the ability of I to relieve, in short periods of time (4 -5 days), acute sensorineural hearing loss and deafness [2].The aim of the present work was to study the antihypoxic action of I, as well as its protective effects on the auditory analyzer. We have undertaken experimental studies of the protective actions of I on auditory function in different pathological states. Despite the large number of studies addressing questions of the etiology, nature, and features of auditory afflictions, there are no pathogenetic substances for the treatment of acute sensorineural hearing loss. Given that the major pathogenetic component in the pathogenesis of sensorineural hearing loss in vascular, infectious, toxic, and other pathological actions on the hearing analyzer consists of intracochlear hypoxia [8,9], the most suitable approach to preventing functional degenerative changes in structures of the peripheral compartment of the auditory analyzer in acute sensorine...

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Objective of the study. To investigate the effect of triazino-indole derivative on the parameters of glycolysis in the endolymph during preventive and therapeutic use on the model of acoustic trauma. Experimental animals and methods. The experiments were carried out on 82 mice, female F1 hybrids of the CBA and C57BL/6 lines weighing at least 17 g at the age of 4–12 weeks. When simulating an acute acoustic trauma, an animal was exposed to white noise with a level of 107 dB SPL and frequency band 3–100,000 kHz. For therapeutic purposes, a single intravenous injection of a triazino-indole derivative was carried out immediately after noise exposure. The drug was administered at doses of 5, 7, and 10 mg/kg of animal weight. For prophylactic purposes, the intramuscular drug injection was administered before the acoustic trauma application. The drug was administered at doses of 5, 7, and 10 mg/kg of animal weight once a day for 3 days before noise exposure. The Cytoflavin was a reference drug. A normal saline was administered to the control group. When using the acoustic trauma models, the metabolic processes level in the cochlea was assessed by the glucose and lactic acid (lactate) content in the labyrinth fluid before and 2 hours after pathological exposure. Results and discussion. The triazino-indole derivative, both during preventive and therapeutic administration, significantly corrects changes in the glycolysis (glucose, lactate) indicators in the endolymph, thereby improving the bioenergetics of the inner ear cells. The best effect is observed when the drug is administered at a dose of 10 mg/kg. When compared with Cytoflavin, the antihypoxic effect of the triazino-indole derivative is more pronounced.

The specifics of military labor, the effect of harmful, and sometimes dangerous factors in the form of impulse noise, shock waves, constant high-level noise, leads to the risk of developing acutraumatic damage to the hearing organ in military personnel. The urgency of the problem is caused by the lack of a unified theory of the pathogenesis of the disease, the low efficiency of currently existing treatment approaches and the insufficient implementation of a system of preventive measures aimed at hearing preservation and health improvement of people working in conditions of increased noise load. The effect of high-intensity noise causes a disorder of microcirculation in the inner ear resulting in the development of hypoxia. As a result of the above-mentioned processes, there are changes in bioenergetics of cells, accumulation of reactive oxygen and nitrogen forms, leading to oxidative stress, and then to their programmed and/or necrotic death. In addition to hair cell damage, irreversible damage to spiral ganglion neurons also occurs. According to current studies, it has been established that the key role in the regulation of oxygen homeostasis under hypoxia is played by a molecule of the factor induced by it. This undoubtedly stimulates the search for drugs acting on it as a target molecule for the treatment of hearing loss of noise etiology. The paper presents data on the incidence of acutraumatic damage to the hearing organ due to noise of high intensity in military personnel, as well as the current views on the pathogenesis of the disease. Particular attention is paid to the analysis of approaches to the treatment of acute sensorineural hearing loss and the prospects for preventive and therapeutic use of antihypoxants.

The effect of triazino-indole derivative (Trisan) on hypoxia-inducible factor (HIF) expression level in the organ of Corti, when administering it for therapeutic and preventive purposes, was investigated using an acoustic trauma model in experimental animals (female F1 hybrids of CBA and C57BL/6 lines). Cytoflavin was used as a comparator product. Study product Trisan (1% solution) was injected intravenously, intramuscularly and intraperitoneally, in the dose of 5, 7 and 10 mg/kg 2 h after the acoustic trauma for therapeutic purposes and in the dose of 5, 7 and 10 mg/kg for 3 days before the acoustic trauma for preventive purposes. IHC methods were used to investigate the organ of Corti. Trisan was observed to increase HIF expression in hair cells and neurons of the spiral ganglion in case of acoustic trauma. Depending on the dose, the increased HIF-1 expression in hair cells and spiral ganglion occurred both after therapeutic and preventive use of Trisan. Maximum HIF expression in hair cells and ganglion was noted at the therapeutic and preventive drug dose of 10 mg/kg. Following experimental results, we conclude that the otoprotective effect of triazino-indole derivative is realized via its effect on HIF metabolism, which makes it a target molecule for the drug.