Acute Intoxications Involving Synthetic Psychoactive Substances

1 Северо-Западный государственный медицинский университет им. И. И. Мечникова Минздрава России, Россия, 191015, г. Санкт-Петербург, ул. Кирочная, д. 41 2 Уральский государственный медицинский университет Минздрава России, Россия, Свердловская область, 620028, г. Екатеринбург, Ключевская ул., д. 17 3 Ханты-Мансийская государственная медицинская академия Минздрава России, Россия, 628011, г. Ханты-Мансийск, ул. Мира, д. 40

Conclusion.Inclusion of cytoflavin in a protocol of a complex treatment of patients with synthetic drugs poisoning increased the effectiveness of the therapy.Data demonstrate that inclusion of the drug can be recommended for treatment of acute synthetic narcotic poisoning.Keywords: acute poisoning; synthetic narcotics; methadone; cannabinoids; therapy; naloxone; cytoflavin DOI:10.15360/1813-9779-2018-1-23-28

Introduction
The problem of drug addiction is still an urgent one not only because of a growing number of people using drugs, but also because of changes in the consumed drugs spectrum.Statistics demonstrates that the number of acute methadone and synthetic cannabinoids poisoning cases keeps growing each year.In some regions of Russia (Moscow, St. Petersburg), methadone is the leading problem in clinics dealing with acute poisoning and resuscitation; in others (Ural, Siberia), synthetic cannabinoids (cannabimimetics) are more common.Clinical presentation of such intoxication develops rapidly.It is difficult to treat and in some cases it ends with a fatal outcome.Acute poisoning with synthetic cannabinoids is commonly associated with significant psychomotor agitation.Lethal outcomes are associated with either dangerous disorders of perception, or with a direct or indirect cardiotoxic effect of cannabinoids [1][2][3].At that, the antidote therapy is imperfect: the treatment of respiratory failure during acute opioid (methadone) poisoning involves a prolonged mechanical ventilation; the use of naloxone requires exceptional accuracy and is possible only in the absence of severe hypoxia [4].
Drug cytoflavin (POLYSAN, St. Petersburg, Russia), which contains in a one-ml flask succinic acid (100 mg), nicotin amide (10 mg), inosine (20 mg) and riboflavin mononucleotide (2 mg) has been shown to correct the intracellular energy metabolism during tissue hypoxia-ischemia and post-ischemic reperfusion due to modifying the free radical oxidation processes.These data raised interest to the drug because omn its potential for treatment of patients with acute narcotic intoxication.
The purpose of this study was to evaluate the effectiveness of a succinic acid derivate, a substrate metabolic agent cytoflavin, in patients with acute poisoning with synthetic psychoactive drugs.
Анализ полученных данных выявил положительную динамику всех показателей, более выраженную в группе пациентов, получивших Цитофлавин: в 1,5 раза меньше времени нахождения в коме days.Patients of the reference group (510 subjects, median age 37.6±14.1 years) received treatment according to the «classical scheme».In addition to conventional examination, all patients underwent duplex scanning of cerebral vessels, examination of changes in the cerebral blood circulation and electroencephalogram.The severity of somatic disorders was assessed using criteria of the Glasgow coma scale.The severity of the asthenic syndrome was assessed according to the MFI-20 scale [5].
The statistical analysis was performed using the SPSS 17.0 software (IBM, USA) Data were processed using descriptive statistics and presented as arithmetic means and standard errors (M±m).The dynamics of parameters during the treatment was assessed by the average shift of the tested parameters from the baseline level.The statistical significance of differences between related samples was assessed using the Wilcoxon pair test.The effect of cytoflavin on the dynamics of studied parameters during the treatment was assessed by determining the significance of intergroup differences by Mann-Whitney U-test.The relationship between individual parameters was studied by calculation of Spearman's rank correlation coefficients (rs).The verification of statistical hypotheses was carried out at a critical significance level of P=0.05 and less.

Results and Discussion
It was shown that the average exposure of poison/drug in patients of the main group by the time of the initiation of the intensive detoxification therapy was 7.5±4.1 hours, in the reference group it was 9.9±4.3hours, which was comparable with the severity of pathological changes in the central nervous system: the level of consciousness measured by the Glasgow coma scale at the time of admission was 3.2±2.1 points in patients of the main group and 4.0±2.2points in the reference group patients and the severity of EEG disorders was 4.2±1.5 points in the main group and 4.7±1.2points in the reference group.The need in mechanical ventilation (MV) was found in 85 (75.8%) patients in the main group and 364 (71.4%) in the reference group.
The positive dynamics of the studied parameters was observed due to the therapy performed, it was more pronounced in patients receiving cytoflavin (table 1).
The analysis of the obtained data demonstrated the positive dynamics of all parameters; the most significant differences were noticed in patients who received Cytoflavin: they demonstrated a more rapid recovery from coma (by 1.5-fold: 23.5±3.1 days, versus 15.1±3.0 days in the reference group, P<0.05); the duration of psychotic disorders was shorter (by 1.8-fold: 15.5±4.2 hours vs 8.3±2.5 hours in the reference group, P<0.05).The severity of the asthenic syndrome in patients of the main group after treatment was estimated as 23.0±4.9rel.units, while in the reference group it was more severe (by 2.8-fold) and was 64.1±3.3 rel.units (P<0.05).The incidence of psychoorganic disorders was 6.25% (7 patients) in the main group and 10.6% (54 patients) in the reference group.
Therefore, inclusion of cytoflavin in intensive care regimen for patients with acute drug poisoning has reduced the duration of coma, psychotic and asthenic disorders, which can be explained by its metabolic and cytoprotective effect.
The main goals of management of acute synthetic chemicals poisoning are elimination of acute respiratory, cardiovascular and cerebral failure.Acute respiratory failure was a consequence of both direct inhibition of the respiratory center in the brain stem (methadone effect) and impairment of the water-electrolyte and/or acid-base balance.The resulting acute hypoxia of a combined genesis serves as the main universal pathogenetic factor and leading mechanism in development of clinical presentation of the intoxication syndrome and the development of cardiovascular and cerebral failure [6].
In a current drug therapy of narcotic poisoning, naloxone is the most widely used drug.Its use is limited due to a certain risk of adverse effectsthat include pulmonary and brain edema with convulsions, tachycardia, and cardiac arrest.Detailed pathogenesis of pulmonary and brain edema development is not fully understood yet.It could be associated with excessive rapid elimination of a depressive effect of the opioid on CNS after administration of naloxone followed by a sharp activation of sympathetic centers and release of catecholamines, redistribution of blood to the small circulation, increased wedge pressure in lung capillaries and an increase in their permeability [7].The above factors limit the potential of the use of the drug in patients with acute synthetic drug poisoning.
By producing a complex effect due to its ingredients, cytoflavin has demonstrated a good therapeutic effect: sodium succinate in its formulation activates the circulation in the tricarboxylic acids cycle increasing the amount of energy necessary for ATP and γaminobutyric acid synthesis, improves tissue respiration, and increases the antioxidant function of the glutathione system.Being an agonist of purinergic receptors, Riboxin/Inosine leads to production of additional amounts of energy, regardless of its glycolytic formation.Due to adenosine metabolites, activation w w w .r e a n i m a 2 0 1 8 , 1 4 ;  Таким образом, суммарные эффекты компонентов препарата обусловливают его фармакологическую активность при церебральной ишемии, стимулируют гликолиз, опосредованно активируют системы защиты от свободнорадикального повреждения и апоптоза.Препарат показан к назначению в составе комплексной терапии острого нарушения мозгового кровообращения; дисцир-of glycolysis may also occur, which serves as an effective source of energy with additional infusions of exogenous glucose.Riboflavin has both antioxidant and antihypoxic effects.Nicotinamide, a precursor of coenzymes dehydrogenases NAD and NADP, is a selective inhibitor of the poly-ADP-ribosyl synthetase formed in tissue ischemia, which is involved in cellular apoptosis initiation.
To conclude, the total effect of drug components explains its pharmacological activity in cerebral ischemia, they stimulate glycolysis, indirectly activate the free radical defense system and apoptosis.The drug can be recommended for patients who require complex therapy for acute cerebrovascular circulation disorders, 1-2 stage discirculatory encephalopathy, consequences of cerebral circulatory disorders (chronic cerebral ischemia) and for patients with toxic and hypoxic encephalopathy, acute and chronic poisoning, endotoxicosis, and consciousness depression after anesthesia [8].

Conclusion
Inclusion of cytoflavin into a complex therapy scheme for treatment of patients with synthetic drugs poisoning increased the effectiveness of the therapy.It indicates that inclusion of the drug can be recommended for the treatment of acute synthetic narcotic poisoning.