Algorithm of selection of compounds and formulations for development of multi-purpose CNS targeted medicinal products for emergency field and civil therapy is justified on the example of potent analgesics. Key criteria and quantitative parameters for selection of substances and dosage forms are singled out. The advantages of strong synthetic opioids vs traditionally used morphine, its derivatives and analogues are demonstrated. Advantages of multi-target formulations are shown. Choice of transmucosal dosage forms of analgesics, antiemetics and antidotes for urgent therapy is substantiated. Approaches to development of universal pharmacological platform for creating drugs acting on CNS are proposed. The current situation in the field of potent analgesics and other limited use medicines in the Russian Federation is described, problems are noted and possible solutions are suggested.

The article describes acute problem - absence of reference standards (Federal Reference Standards) of controlled ingredients of some potent pharmaceuticals (especially narcotic and psychotropic substances) in Russia. Authors present an algorithm for solving this task. According to regulatory documents providing traceability and technical regulation in Russian Federation requires use of the Federal Reference Standards for any official quantitative studies of narcotic and psychotropic substances. Lack of the reference standards does not allow provide: legally meaningful assessment of quality of medical products; to ensure industrial safety of work with substances belonging to list of dangerous goods; to conduct quantitative forensic analysis using instrumental methods, etc. Development of the Federal Reference Standards should be organized in the framework of technological cooperation of organizations (laboratories) which has necessary licenses. Production of the highest quality standards should be organized on a specialized facility where Federal S&T Center "Inversiya" has already made Federal Reference Standards of toxic chemicals. Creation and introduction in practices Federal Reference Standards of the controlled substances will provide scientific, technical and methodological foundations in development and implementation technologies for production of potent pharmaceutical ingredients in Russian Federation and solutions in the field of criminology and chemical safety and security.

The article describes some approaches to choice of the most potent non-narcotic analgesics among agents investigated in various R&D stages. Preparations non-narcotic analgesics for relief of severe and moderate pain are relatively new area of pharmaceuticals. Their application is very important as an alternative to opiates. However, the actual number of drug candidates is very limited. As a result of the authors analysis one of the most potent non-narcotic analgesics (PNS neurons sodium channel blocker) - Tetrodotoxin (TTX) was recognized as the most promising. Currently FSUE «GosZMP» conducting preclinical studies of injectable preparation of TTX.

According to comparative analysis of medical consumption of potent analgesics in economically developed countries was justified the need to increase production of active ingredients of potent analgesics in Russia by more than ten times. Also a list of the most relevant analgesics for production for chronic patients and for use in emergency situations was provided. It was shown that the production of substances of potent analgesics in Russia by 2020 should be increased up to 5-6 tons in morphine equivalent. This amount takes into account the need to expand diversity of dosage forms suitable for patient, including transdermal, transmucosal, intranasal, and others. The proportion of natural and semi-synthetic opioid analgesics should be at least 50% of the total production in morphine equivalent. Use of genetically modified varieties of opium poppy allows to obtain the raw material with a predetermined content of target alkaloids. It is proposed to organize production of active analgesics ingredients at one of repurposed military facilities, as well as recreate biotechnological production of raw materials on the basis of genetically modified varieties of poppy. This approach allows to produce active analgesics ingredients for all pharmaceutical manufacturers of Russian Federation. It is proposed to organize production of certified reference materials of significant pharmaceutical drugs and psychotropic substances for all Russian consumers - more than 250 licensed organizations in industry, health care, law enforcement, chemical safety and security.

Medicines based on opioid analgesics are the basic means of pharmacotherapy of severe pain at present. Approaches to increase efficacy and safety of complex opioid analgesia are described and classified based on analysis of medicinal and veterinary analgesics acting on different CNS biotargets. Principles of creation multitargeted fixed-dose combinations (FDC) and some schemes of multimodal analgesia are demonstrated by the example of opioid combinations with ligands of alpha-2 adrenergic receptors, antagonists of excitatory amino acid receptors, GABA ligands, their derivatives and analogues, cannabinoids, monoamines reuptake inhibitors and opiate receptor antagonists. Importance of multitargeted substances in general including codrug approach for facilitating of drug delivery and bioactivity enhancement were demonstrated. Development of opioid formulations with low level of dependency and tolerance and also principles to protect opioid formulations against non-medical use were described. Methodology of multitargeted analgesia is one of the drivers in drug development on the background of low progress in the development of new effective molecules for relief of severe and moderate pain. The greatest interest is development of FDC with drug potentiation and efficacy at low doses. It allows creating wide variety of analgesics formulations.

Application of luminescent reagents for detection of toxicants including warfare agents, pesticides and their degradation products and precursors has been systematically reviewed. Methods of organophosphorus toxicants and products of their destruction (OP) detection based on lanthanide luminescent complexes (primarily Eu3+) have the similar sensitivity as the most advanced instrumental chromatographic and biochemical assays with detection level in the range of several ppts that allows to determine supertoxicants at the safety requirements concentration levels and at appropriate analysis duration from a few seconds to 10 minutes. High selectivity of toxicants identification is achieved by means of imprinted materials, modified cyclodextrins and luminescent sensor arrays. This is the basis for development of new technologies for trace analysis of toxicants and their decomposition products, including possible technology of luminescent contrast agents’ application to increase sensitivity of spectroscopic methods and remote determination of toxicants on the ground. Further possibilities to develop next generation materials for protective gear, equipment and multifunctional contact surfaces providing visualization and identification of toxicants and simultaneous catalytic self-decontamination is discussed. Relationship between technologies for improving safety and security at the crossroads of analytical chemistry of warfare agents, criminalistics, chemical safety and pharmaceutics has been demonstrated.

The global opioid crisis requires a paradigm shift in medical use of opioids, the development of methodology to reduce illicit drug use, and development of drug addiction treatment and antidotes. USA target program - HEAL Initiative is implemented under the scientific guidance of NIH with active participation of FDA, CDC and military medicine institutions. The situation in Russian Federation is characterized by a combination of high illegal consumption of dangerous opioids with an extreme shortage of potent analgesics, drugs for treatment addiction and overdose and rudimentary choice of drug formulations. There isn’t any development of innovative substances and preparations of strong analgesics and antidotes, but also a competent analysis of the subject area and vision of directions for the development. The data analysis shows need to replace some of traditionally used mostly natural and semi-synthetic narcotic analgesics (with low therapeutic index, unsatisfactory pharmacokinetics and severe side effects) to promising synthetic opioids and non-narcotic analgesics. Use of prodrugs, synergistic combinations, conjugates and co-drugs is justified. Prospective dosage forms of compounds and pharmaceutical preparations for development of wide range of improved therapeutics should combine: high analgesicactivity, high therapeutic index, minimum values of Tmax and t1/2ke0, positive values of LogBB, distribution coefficient logD7,4 in the interval from 1 to 3. This combination of key properties is necessary for effectiveness and safety of CNS-specific drugs and also allows development on their basis wide range of dosage forms (injectable and non-injectable drugs, fast-acting and prolonged drugs). First of all it is desirable to replace some obsolete injecting and oral preparations (especially with fast and uncontrolled release) to fast-acting transmucosal formulations with targeted pharmacokinetic properties. In order to analyze best practices, develop a strategy for highly effective controlled medicinal and veterinary drugs (analgesics, anesthetics, antidotes and other vital therapies) and coordinate theirdevelopment and production it is necessary to create competent management structure combining the tasks of provision of civilian population and personnel of national defense agencies of effective and safe drugs.

The development of new antinociceptive agents and new approaches to pain relief based on potent non-narcotic analgesics is one of the most in demand and urgent directions of modern pharmacology. This work substantiates the choice of the clinically most relevant representative of non-narcotic analgesics from the α2-adrenoreceptor agonist class - dexmedetomidine, which acts at low doses and demonstrates high therapeutic index for various modes of administration. An analgesic efficacy of dexmedetomidine in single intranasal administration of the original experimental pharmaceutical formulation was evaluated in models of acute thermal and visceral pain in laboratory animals (female outbred white mice). A pronounced dose-dependent analgesic effect of the dexmedetomidine preparation in the 10 and 50 μg/kg dosage was revealed in the test models of visceral pain. The analgesic effect of dexmedetomidine was accompanied by a dose-dependent sedative (but not anesthetic) effect in mice, with peak at 30 minutes for intranasal administration of 50 μg/kg of drug. In the doses used, dexmedetomidine did not exert any acute toxic effects in mice.

The global opioid crisis requires a paradigm shift in medical use of opioids, the development of methodology to reduce illicit drug use, and development of drug addiction treatment and antidotes. USA target program - HEAL Initiative is implemented under the scientific guidance of NIH with active participation of FDA, CDC and military medicine institutions. The situation in Russian Federation is characterized by a combination of high illegal consumption of dangerous opioids with an extreme shortage of potent analgesics, drugs for treatment addiction and overdose and rudimentary choice of drug formulations. There isn’t any development of innovative substances and preparations of strong analgesics and antidotes, but also a competent analysis of the subject area and vision of directions for the development. The data analysis shows need to replace some of traditionally used mostly natural and semi-synthetic narcotic analgesics (with low therapeutic index, unsatisfactory pharmacokinetics and severe side effects) to promising synthetic opioids and non-narcotic analgesics. Use of prodrugs, synergistic combinations, conjugates and co-drugs is justified. Prospective dosage forms of compounds and pharmaceutical preparations for development of wide range of improved therapeutics should combine: high analgesicactivity, high therapeutic index, minimum values of T max and t 1/2 k e 0 , positive values of LogBB, distribution coefficient logD 7,4 in the interval from 1 to 3. This combination of key properties is necessary for effectiveness and safety of CNS-specific drugs and also allows development on their basis wide range of dosage forms (injectable and non-injectable drugs, fast-acting and prolonged drugs). First of all it is desirable to replace some obsolete injecting and oral preparations (especially with fast and uncontrolled release) to fast-acting transmucosal formulations with targeted pharmacokinetic properties. In order to analyze best practices, develop a strategy for highly effective controlled medicinal and veterinary drugs (analgesics, anesthetics, antidotes and other vital therapies) and coordinate theirdevelopment and production it is necessary to create competent management structure combining the tasks of provision of civilian population and personnel of national defense agencies of effective and safe drugs.

The development of new antinociceptive agents and new approaches to pain relief based on potent non-narcotic analgesics is one of the most in demand and urgent directions of modern pharmacology. This work substantiates the choice of the clinically most relevant representative of non-narcotic analgesics from the α 2 -adrenoreceptor agonist class - dexmedetomidine, which acts at low doses and demonstrates high therapeutic index for various modes of administration. An analgesic efficacy of dexmedetomidine in single intranasal administration of the original experimental pharmaceutical formulation was evaluated in models of acute thermal and visceral pain in laboratory animals (female outbred white mice). A pronounced dose-dependent analgesic effect of the dexmedetomidine preparation in the 10 and 50 μg/kg dosage was revealed in the test models of visceral pain. The analgesic effect of dexmedetomidine was accompanied by a dose-dependent sedative (but not anesthetic) effect in mice, with peak at 30 minutes for intranasal administration of 50 μg/kg of drug. In the doses used, dexmedetomidine did not exert any acute toxic effects in mice.

Application of luminescent reagents for detection of toxicants including warfare agents, pesticides and their degradation products and precursors has been systematically reviewed. Methods of organophosphorus toxicants and products of their destruction (OP) detection based on lanthanide luminescent complexes (primarily Eu 3+ ) have the similar sensitivity as the most advanced instrumental chromatographic and biochemical assays with detection level in the range of several ppts that allows to determine supertoxicants at the safety requirements concentration levels and at appropriate analysis duration from a few seconds to 10 minutes. High selectivity of toxicants identification is achieved by means of imprinted materials, modified cyclodextrins and luminescent sensor arrays. This is the basis for development of new technologies for trace analysis of toxicants and their decomposition products, including possible technology of luminescent contrast agents’ application to increase sensitivity of spectroscopic methods and remote determination of toxicants on the ground. Further possibilities to develop next generation materials for protective gear, equipment and multifunctional contact surfaces providing visualization and identification of toxicants and simultaneous catalytic self-decontamination is discussed. Relationship between technologies for improving safety and security at the crossroads of analytical chemistry of warfare agents, criminalistics, chemical safety and pharmaceutics has been demonstrated.

The article describes acute problem - absence of reference standards (Federal Reference Standards) of controlled ingredients of some potent pharmaceuticals (especially narcotic and psychotropic substances) in Russia. Authors present an algorithm for solving this task. According to regulatory documents providing traceability and technical regulation in Russian Federation requires use of the Federal Reference Standards for any official quantitative studies of narcotic and psychotropic substances. Lack of the reference standards does not allow provide: legally meaningful assessment of quality of medical products; to ensure industrial safety of work with substances belonging to list of dangerous goods; to conduct quantitative forensic analysis using instrumental methods, etc. Development of the Federal Reference Standards should be organized in the framework of technological cooperation of organizations (laboratories) which has necessary licenses. Production of the highest quality standards should be organized on a specialized facility where Federal S&T Center Inversiya has already made Federal Reference Standards of toxic chemicals. Creation and introduction in practices Federal Reference Standards of the controlled substances will provide scientific, technical and methodological foundations in development and implementation technologies for production of potent pharmaceutical ingredients in Russian Federation and solutions in the field of criminology and chemical safety and security.

The article describes some approaches to choice of the most potent non-narcotic analgesics among agents investigated in various R&D stages. Preparations non-narcotic analgesics for relief of severe and moderate pain are relatively new area of pharmaceuticals. Their application is very important as an alternative to opiates. However, the actual number of drug candidates is very limited. As a result of the authors analysis one of the most potent non-narcotic analgesics (PNS neurons sodium channel blocker) - Tetrodotoxin (TTX) was recognized as the most promising. Currently FSUE «GosZMP» conducting preclinical studies of injectable preparation of TTX.

Разработана методика определения 2-эндо-(6-хлорпиридин-3-ил)-7-азабицикло-[2.2.1]гептана (эпибатидин) и 2-эндо-(6-хлорпиридин-3-ил)-7-азабицикло[2.2.1]гептан-7-ола (биомаркер эпибатидина) в плазме крови на уровне 1 ? 10-5 1 ? 10-3 мг/мл. Методика основана на извлечении компонентов из плазмы крови жидкостно-жидкостной экстракцией и газохроматографическом определении с использованием термоионного или масс-спектрального детекторов. С целью снижения предела обнаружения эпибатидина и его биомаркера при использовании масс-спектрометрического детектора в методику включена стадия дериватизации с помощью N,O-бис(триметилсилил)трифторацетамида или 2,3,4,5,6-пентафторбензилбромида.

A method has been developed for the determination of 2-endo(6′-chloropyridin-3′-yl)-7-azabicyclo[2.2.1]heptane (epibatidine) and 2-endo(6′-chloropyridin-3′-yl)-7-azabicyclo[2.2.1]heptane-7-ol (epibatidine biomarker) in blood plasma at a level of 1 × 10−5–1 × 10−3 mg/mL. The method is based on the extraction of components from blood plasma by liquid-liquid extraction followed by gas-chromatographic determination using thermionic or mass spectrometric detectors. To reduce the limit of detection for epibatidine and its biomarker in using the mass-spectrometric detector, a derivatization stage using N,O-bis(trimethylsilyl)trifluoroacetamide or 2,3,4,5,6-pentafluorobenzyl bromide has been included into the procedure.

A new chemical series was identified via high-throughput screening as having antiproliferative activity on DU-145 human prostate carcinoma cell line (hit compound potency - 2.9 microM). Medicinal chemistry optimization of two peripheral diversity vectors of the hit molecule, independently, led to SAR generalizations and identification of the 'best' moieties. The latter were merged in a single compound that exhibited an over 100-fold better potency than the hit compound. For the most potent compounds it was confirmed that the observed antiproliferative potency was not associated with the compounds' non-specific cytotoxicity.