CC BY
59
THE PROBLEM OF ENSURING SAFETY IN THE USE OF NARCOTIC ANALGESICS IN THE RUSSIAN FEDERATION
GROUP OF AUTHORS, 2018
V.V. Uyba1, D.V. Krivorotov2, M.V. Zabelin1, A.S. Radilov2, V.R. Rembovskiy2, S.A. Dulov2, V.A. Kuznetsov2, G.G. Erofeev1, N.N. Martinovitch2, A.V. Sosnov3
OPIOID RECEPTOR ANTAGONISTS. FROM THE PRESENT TO THE FUTURE
1 Federal Medical-Biological Agency of Russia, Moscow, 123182, Russian Federation;
2 Research Institute of Human Hygiene, Occupational Pathology, and Ecology,
Saint Petersburg, 188663, Russian Federation;
3 Institute of Physiologically Active Compounds Russian Academy of Sciences,
Chernogolovka, 142432, Russian Federation
The article considers information indicating an increase in the danger of "designer drugs" created on the basis of highly active narcotic analgesics of the central action, to the human life and health. Aspects of the use of opioid receptor antagonists in the treatment of acute opioid poisoning and in the treatment of socially significant diseases such as alcoholism and drug addiction are discussed. The adequacy of naloxone use in the emergency treatment of the acute poisoning with narcotic analgesics has been evaluated. Approaches to the improvement of drugs for the treatment of acute opioid poisoning have been determined. The task of the directional design and chemical synthesis of drugs more effective than naloxone was formulated, and the prospect of using nalmefene to develop innovative drugs for the treatment of acute poisonings and socially significant diseases was evaluated.
Keywords: opioid receptors; narcotic analgesics; acute poisonings; drug addiction; alcoholism;
opioid receptor antagonists; lipophilicity; partition-coefficients; naloxone; naltrexone; nalmefene; dosage form.
For citation: Uyba V.V., Krivorotov D.V, Zabelin M.V, Radilov A.S., Rembovskiy V.R., Dulov S.A., Kuznetsov V.A., Erofeev G.G., Martinovitch N.V., Sosnov A.V Opioid receptor antagonists. From the present to the future. Meditsina ekstremal'nykh situatsiy (Medicine of Extreme Situations) 2018; 20(3): 371-382. (In Russ.).
For correspondence: Denis V. Krivorotov, Ph.D., Research Institute of Human Hygiene, Occupational Pathology, and Ecology, Saint Petersburg, 188663, Russian Federation. E-mail: denhome@bk.ru
Conflict of interest. The authors declare no conflict of interest Acknowledgments. The study had no sponsorship. Received 01June 2018 Accepted 19 September 2018
In 1817 the isolation of morphine from opium was a breakthrough in the development of European pharmacology, which determined the progress of science and technology for many years to come [1]. Opioids in modern medicine do not have an adequate alternative due to their unique analgesic and other pharmacological properties. There are more than ten drugs, except morphine, which relate to the pharmacological group of opioid narcotic analgesics (HA) in Russian Federation. A number of highly active opioid analgesics, such as sufentanil, are considered by the native pharmaceutical industry as promising medicines [2]. Despite the invaluable medical importance of opioid analgesics, their use poses a certain danger to human life and health.
In some countries, even clinically valid doses determine up to 43% of cases of lethal HA poisoning, and uncontrolled morphine's use gave rise to the first outbreaks of opioid epidemics in the XVIII-XIX centuries [1, 3]. The pathogenesis of the lethal and addictive potential of opioid analgesics of the central action is determined by the nature of neurochemical regulation of the organism with the system of opioid receptors (OP) and endogenous opioids (Table 1) [4].
^-opioid receptors are the most widely represented in the central nervous system; when taking opioids, they are responsible for the implementation of the analgesic effect, euphoria, miosis, respiratory depression and peristalsis. By the 5-opioid
ПРОБЛЕМА ОБЕСПЕЧЕНИЯ БЕЗОПАСНОСТИ ПРИ ИСПОЛЬЗОВАНИИ НАРКОТИЧЕСКИХ АНАЛЬГЕТИКОВ В РОССИЙСКОЙ ФЕДЕРАЦИИ
Table 1 Classification of opioid receptors and their ligands [4]
Receptor Agonist Antagonist Agonist's effect
Standard ligand - morphine Morphineceptin DAGO Normorphine Sufentanil Naloxone Naltrexone (-) - Cyclophane Samodorf Naldemidine (PNS) Alvimopan (PNS) Methylnaltrexone (PNS) 6-beta-Naltrexol BU-128 Analgesia Respiratory depression Miosis Disturbance / decreased motility of the gastrointestinal tract Nausea Vomiting Euphoria
5 Standard ligand - deltorphin DPDPE DADLE ICI 154.126 ICI 174.864 7-benzylidenenaltrexone Supraspinal analgesia
к Standard ligand - ketocyclozacin Agonist U50,488 Trifluadom MR2266 CERC-501 Antagonist LY-255582 5'-ghuanidinonaltrindole MR2266 BU-10119 3-methoxynaltrexone Supraspinal analgesia Miosis (weak) Agonist's effect Respiratory depression (weak) Dysphoria
Note. PNS - antagonists of the peripheral nervous system OR; DAGO, Tyr-D-Ala-Gly-ol; DPDPE, [D-Pen2, D-Pen5] enkephalin; Pen, penicillamine; DADLE, [D-Ala2, D-Leu5] encephalin; deltorphin II, Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2; morphiceptin, p-casomorphin- (1-4) - amide or Tyr-Pro-Phe-Pro-NH2. BU-128; ICI 154,126; ICI 174,864; MR2266; CERC-501; LY-255582; MR2266; BU-10119 - Pharmacological agents (OP's antagonists).
receptors the analgesic and antidepressant effect is realized; stimulation of K-opioid receptors provides analgesia and sedation, dysphoria and suppression of arginine vasopressin production. The expressed physiological response under the action of single molecules of opioids on the organism is provided biochemical cascades of signal amplification, described by the concept of «secondary messengers» - signal molecules, the content of which determines the excited or depressed state of the nerve cell, the key of which is: cyclic 3 <, 5-adenosine monophosphate ( cAMP), cyclic 3 <, 5>-guanosine monophosphate (cGMP), intracellular free Ca2 +, metabolic products of phosphoinositides, in particular inosi-toltriphosphates and diacylglycerol and others [5].
According to the hypothesis of cAMP-opioid's dependence, the chronic effects of opioids lead to pathological changes in the production of cAMP in nerve cells, as a result of which the initial cause of the development of opioid dependence at the cellular level is a painful reaction to a sharp decrease in the induction of adenylatecyclase when opioids are cancelled [6]. In acute poisoning, NA inhibits the activity of the chemoreceptor neurons and the respiratory center of the brain, disrupting the generation of the respiratory rhythm and
decreasing the sensitivity to the increase in the content of carbon dioxide in the blood, causing a violation in the reflex mechanism of respiration, the development of acute respiratory failure and death of an organism [7]. Clinical symptoms of acute opioid poisoning include oppression of consciousness to coma, respiratory depression, apnea, cyanosis of the skin, miosis, atony, areflexia. The development of hypoxia leads to heart failure and death. Poisoning is often accompanied by manifestations of convulsive syndrome, hypothermia, pyrogenic reactions and vomiting, which contributes to the development of severe complications of intoxication, including toxic pulmonary edema and pneumonia, cerebral edema, aspiration syndrome and sepsis [8]. The most life-threatening factor of acute poisoning by NA is respiratory depression, up to a complete stop, which determines the importance of conducting emergency resuscitation in the treatment of patients with opioid poisoning, including the use of antidotes [9]. As the interaction of opioid analgesics with receptors is reversible, opioid antagonists, such as naloxone, can interfere with these processes, restoring the vital functions of the nervous system and respiration [7].
THE PROBLEM OF ENSURING SAFETY IN THE USE OF NARCOTIC ANALGESICS IN THE RUSSIAN FEDERATION
CD
m o
IE
CD >
O T3
O t/5
"ci-c O ro 4— CD O-ö
CD CT CO
CD O
CD cl
100 90 80 70 60 50 40 30 20 10 0
I I Fentanyl ■ Fentanyl analog
State
Fig. 1. The contribution of fentanyl and its analogs to the overall statistics of deaths from overdose of HA
in some US states in December 2016. (https://www.cdc.gov/mmwr/volumes/66/wr/mm6643e1.htm).
100-250 thousand people worldwide die from drug overdose every year. In 2016, in Russia, about 10% of patients of the total quantity of poisoning were hospitalized with this diagnosis, but in the statistic of fatal poisoning, opioids became the leading cause of death. According to the UN and WHO position, the growing public health problem associated with HA poisoning can be controlled by increasing the use of the OP antagonist - naloxone, as well as taking actions for limiting the availability of illicit opioids while ensuring the availability of opioids used in medical and scientific purposes [10-11].
The Russian medical community believes that an available assortment of drugs based on OP antagonists responds to the problems of treating acute opioid poisoning and treatment of socially significant diseases, such as alcoholism, drug addiction [11-12]. At the same time, there are threatening trends that require systematic analysis and assessment of the adequacy of available antidotes to changes in the spectrum of medical and illegal HA. At the same time, there are threatening trends that require systematic analysis and confirmity assessment of available antidotes to changes in the spectrum of medical and illegal HA.
In recent decades, there has been an increase in the symptoms of acute HA poisoning with a multiple increase in the death rate of patients and in the
treatment of overdoses in specialized toxicological hospitals. The reason for this situation is associated with the replacement of illegal morphine and heroin with synthetic drugs, such as methadone, fentan-yl derivatives and "designer drugs" based on them [13-15]. In Russia, from 2000 to 2015 the frequency of heroin poisoning decreased by 5.8 times, with a 4.4- times increase in the incidence of methadone poisoning. There is currently no adequate antidote in the arsenal of medical drugs for methadone poisoning, as naloxone has an incommensurably short therapeutic time [16].
In addition to the "methadone threat" growth in Russia and the United States, "design drugs" based on fentanyl and its more potent analogues, which variety can not be reliably controlled, make a negative contribution to the total quantity of fatal poisonings [14, 17, 18]. Figure 1 presents a comparative picture of mortality from HA in some US states, illustrating the contribution of fentanyl and its analogues to the "opioid crisis" of 2016.
The increase of accidents of acute overdoses of fentanyl indicates the need to revise the approaches, ways and methods of treating pain with the use of HA. It can be expected that the medical use of fentanyl itself in the US and worldwide will be decreased in the next 5-10 years with its replacement by safer and more effective analgesics of the fen-tanyl series with a high therapeutic index [2]. At
ПРОБЛЕМА ОБЕСПЕЧЕНИЯ БЕЗОПАСНОСТИ ПРИ ИСПОЛЬЗОВАНИИ НАРКОТИЧЕСКИХ АНАЛЬГЕТИКОВ В РОССИЙСКОЙ ФЕДЕРАЦИИ
the same time, the experience of naloxone using in treating the consequences of the "fentanyl epidemic" of 2016 in the North American continent, which killed more than 60,000 people, has not shown satisfying results [19], which also points to the need to revise the approaches, ways and methods of treatment of acute poisoning by opioids. Thus, high physiological activity and the variety of biological effects of NA determine the relevance of the problem of finding effective ways of prevention and treatment of the poisonings caused by them [20]. The therapeutic potential of naloxone does not fully correspond to the task of stopping severe overdoses with "designer drugs" of the opioid series, justifying the need to develop more adequate antidotes. An analysis of the reasons that hamper the treatment with naloxone of acute intoxications with some narcotic analgesics and substantiation of ways to create more effective agents for the treatment of acute poisoning is devoted to this article.
Materials and methods
The connection between the strength of the narcotic effect of chemical substances and their lipophilicity was noted by the outstanding Russian toxicologist N.V. Lazarev [21], and today the distribution coefficients of opioids in the organism play a key role in predicting their physiological effects [2]. In this work, narcotic analgesics and their antagonists are examined through the prism of a comparative evaluation of parameters that determine the ability of molecules to penetrate across the blood-brain barrier (BBB) into the brain and exyend a central effect. The transfer through the blood-brain barrier plays an important role for all drugs, independently of the therapeutic category. To quantify and simulate this process, the parameters of the lipophilicity of molecules, as well as the experimentally more complex kinetic and thermo-dynamic parameters characterizing the rate of drug diffusion into the brain - LogPS and characterizing their equilibrium distribution in the brain and blood tissues - LogBB are used [22]. The lipophilicity of the pharmacological agents is described by the partition coefficients in the octanol / water (LogP) system at the physiological pH of the human blood (pH = 7.4, LogD7.4). The magnitude of the distribution coefficients for substances of central action in the optimal range of 1 <logD7.4 <5, as a rule, en-
374
sures their effective entry into the target tissues of the central nervous system. The kinetic parameter characterizing the rate of diffusion of substances into the brain - LogPS is in the range of -5 for molecules that are not able to penetrate through the BBB to -1 for substances that easily penetrate through this barrier. The most relevant for development are preparations of central action, the equilibrium concentration of which in the CNS tissue is higher than its equilibrium concentration in the blood, which corresponds to the value LogBB > 0. Given the fact that studying the kinetics of drug delivery in brain tissue is a time-consuming procedure, determining the lipophilicity of poisons and their antidotes can be the primary method for screening, predicting and assessing their effect on the central nervous system. Experimentally, the distribution coefficients of pharmaceutical agents are determined by extraction methods, titration, HPLC simulation of redistribution processes and computer simulation methods, taking into account the fact that their values are significantly influenced by temperature and pH fluctuations within physiological values [2326]. In this work, a complex of software for ADME profiling of Absorption, Distribution, Metabolism and Excretion) ACD / Percepta (ACD / Labs) [26] was used to predict lipophilicity parameters and parameters describing the penetration capacity of agonists and OP antagonists into the brain.
The results and discussion
The results of calculating the values of LogP and LogD7.4, presented in Table 2, allow to locate streclinically significant agonists and OP antagonists by increasing their lipophilicity (Table 2) and comparing the effectiveness of their admission from the bloodstream to the CNS tissue. The connection between the potency of the pharmacological action of opioids and the magnitude of their li-pophilicity is demonstrated by the experimentally found rate of admission to the brain of naloxone (LogD7.4 1.53, Table 2); it is 8-10 times higher than the rate of entry into the brain of morphine (LogD7.4 -0.12) and exceeding the rate of admission to the brain of naltrexone (LogD7.4 0.70) [27].
The analysis of the distribution coefficients LogP and LogD7.4 given in Table 2 indicates a slight lipophilicity of naloxone, which, in comparison with the lipophilicity of the analgesics of the
THE PROBLEM OF ENSURING SAFETY IN THE USE OF NARCOTIC ANALGESICS IN THE RUSSIAN FEDERATION
Table 2 The distribution coefficients of opioid receptor ligands (ACD / Percepta)
Preparation Biological role LogD7.4 LogP LogPS LogBB
Calc. Ref. Calc. Ref. Calc. Ref. Calc. Ref.
Morphine Narcotic analgesic -0,18 -0,12 0,69 0,76 -2,90 -2,7 -0,03 -0,12
Codeine Narcotic analgesic 0,34 0,61 1,21 1,14 -2,48 - 0,08 0,55
Hydromorphone Narcotic analgesic 0,53 - 1,29 0,92 -2,36 - 0,17 -
Dihydrocodeine Narcotic analgesic 0,67 - 1,54 - -2,32 - 0,07 0,55
Naltrexone Opioids antagonist 0,71 - 1,63 1,92 -2,59 - 0,26 -
Tramadol Narcotic analgesic 0,71 - 2,54 2,63 -2.00 - 0,59 0,53
Tapentadol Narcotic analgesic 0,77 - 2,63 - -1,84 - 0,57 -
Nalorphine Opioids antagonist 0,79 - 1,22 1,86 -2,40 - 0,01 -
Naloxone Opioids antagonist 0,86 1,53 1,53 2,09 -2,51 - 0,21 -
Nalboufine Narcotic analgesic 0,98 - 2,03 - -2,64 - 0,24 -
Heroin Narcotic analgesic 1,16 - 1,88 1,58 -2,11 - 0,28 -
Pethidine Narcotic analgesic 1,22 1,59 2,44 2,45 -1,75 -1,1 0,30 0,85
Nalodein Opioids antagonist 1,23 - 1,65 - -2,03 - 0,17 -
Nalmefene Opioids antagonist 1,23 - 2,42 - -2,20 - 0,44 -
Thebaine Raw materials for production 1,44 - 2,44 - -1,79 - 0,42 -
Remifentanil Narcotic analgesic 1,77 - 1,85 - -1,81 - 0,20 -
Promedol Narcotic analgesic 1,86 - 2,99 3,13 -1,54 - 0,56 -
Butorphanol Narcotic analgesic 1,96 - 3,52 - -1,73 - 0,77 -
Alfentanil Narcotic analgesic 1,99 - 2,04 2,16 -1,89 - -0,08 0,09
Diprenorphine Opioids antagonist 2,33 - 3,30 - -1,87 - 0,35 -
Prosidol Narcotic analgesic 2,62 - 2,88 - -1,33 - 0,55 -
Sufentanil Narcotic analgesic 2,91 - 3,77 3,95 -1,33 - 0,41 0,68
Acetylfentanil [17] Narcotic analgesic 2,98 - 3,74 -1,25 - 0,42 -
Methadone Narcotic analgesic 3,12 2,07 4,44 3,93 -1,20 -1,3 0,83 0,69
Carfentanil Narcotic analgesic 3,17 - 3,49 -1,27 - 0,42 -
Fentanyl Narcotic analgesic 3,32 2,86 4,08 4,05 -1,20 -1,0 0,55 0,65
Buprenorphine Narcotic analgesic 3,48 - 4,45 4,82 -1,52 - 0,70 0,52
fentanyl series and in combination with its not too high affinity for opiate receptors, can make it difficult to treat poisonings with such toxicants. Figure 2 shows the changes in LogD of naloxone, naltrex-one, nalmefene, and fentanyl, depending on the pH of the medium.
The dependences shown in Fig. 2 show the significant influence of the pH medium, including the pH blood, on the ability of opiates to penetrate biological membranes, which affects the strength of their analgesic or antidote effect in clinical conditions.
Consideration of the values of LogPS and Log-BB for the antagonists of ORs characterizing their
ability to penetrate the BBB (Table 2) showed that their ability to overcome the BBB is a fewha lower than that of most modern HA. At the same time, they all have a positive value for LogBB, with the highest value among them in the nalmefene molecule, which indicates its high antidot potential.
The assessed lipophilicity and parameters characterizing the penetration through the BBB agonists and antagonists of opioid receptors allow predicting high antidotal efficacy in lipophilic, highly affinity in vitro therapy agents for acute NA poisoning and substantiates the need to develop lipo-philic antagonists with a high affinity for the recep-
ПРОБЛЕМА ОБЕСПЕЧЕНИЯ БЕЗОПАСНОСТИ ПРИ ИСПОЛЬЗОВАНИИ НАРКОТИЧЕСКИХ АНАЛЬГЕТИКОВ В РОССИЙСКОЙ ФЕДЕРАЦИИ
Naloxone LogD at:
pH 1,7 (stomach): -1,57 pH 4,6 (duodenum): -1,38 pH 6,5 (jejunum and ileum): 0,06 pH 7,4 (blood): 0,86
Naltrexone LogD at:
pH 1,7 (stomach): -1,47 pH 4,6 (duodenum): -1,37 pH 6,5 (jejunum and ileum): -0,12 pH 7,4 (blood): 0,71
Nalmefene LogD at:
pH 1,7 (stomach): -0,68 pH 4,6 (duodenum): -0,62 pH 6,5 (jejunum and ileum): 0,4 pH 7,4 (blood): 1,23
Fentanyl LogD at:
pH 1,7 (stomach): 0,99 pH 4,6 (duodenum): 1,14 pH 6,5 (jejunum and ileum): 2,51 pH 7,4 (blood): 3,33
Fig. 2. Dependence of LogD agonists and antagonists on the pH of the medium (ACD / Percepta).
tor. The ability to model and analyze the distribution coefficients and the parameters of penetration through the BBB given in Table 2 allows one to select both individual compounds and chemotypes of antagonists that are relevant for the management of poisoning and the side effects of the most potent opioid agonists. Thus, the target design, synthesis and study of the high-affinity antagonists of opioid receptors that are adequate for their lipophilicity are of practical interest for solving the problems of emergency medicine and resuscitation.
Evolution of opioid antagonists -from chemistry to medicine
The pharmacology of opioids and their antagonists always keep up to the level of development of biology and medical chemistry, and the danger of opioid analgesics determined the request for a decrease in their addictive and toxic potential [28]. The principal possibility of controlling the dangerous manifestations of morphine and heroin was first demonstrated in 1915 when studying the phar-
macological antagonism of N-allyl-norcodeine (nalodein, Figure 3) [29], which laid the foundation for the construction of future theories of opioid receptors, their experimental discovery and structural description in 2012. Today, it is believed that the molecules of antagonists competitively displace and inhibit receptor population by other opiates, transferring the receptors to an inactive state, showing the properties of receptor, and not only pharmacological antagonists [30].
Antagonists have been used since the 1950s for the treatment of acute poisoning with opiates , starting with N-allyl-normorphine (nalorphine, Figure 3), which was no less toxic than morphine, prevented or completely abolished analgesia and respiratory depression mediated by morphine, showing the properties of a preventive and therapeutic antidote [31]. Using in the chemical design of new opioid antagonists, more powerful than morphine, the oxy-morphone analgesic predetermined the creation of the main OP antagonists - naloxone, naltrexone and
THE PROBLEM OF ENSURING SAFETY IN THE USE OF NARCOTIC ANALGESICS IN THE RUSSIAN FEDERATION
Table 3
Parameters of binding of antagonists to opioid receptors [41-45]
Compound (Ki, nM) MOR (p) (Ki, nM) KOR (K) (Ki, nM) DOR (S)
Naloxone 1,3 2,5 57
Naltrexone 0,26 5,15 117
Nalmefene 0,24 0,08 16
Fig. 3. Schematic diagram of antagonists synthesis of opioid receptors of the phenanthrene group.
nalmefene used in modern medicine [32]. Naloxone (N-allyl-noroxymorphone) (Figure 3, Tables 2, 3) is effectively used throughout the world for the treatment of acute HA poisoning [32]. Considering the medical significance of naloxone, drugs based on it are actively improved [33-34], but a short half-life, low bioavailability and metabolic stability do not allow using it in the treatment of drug addiction. For this purpose, naltrexone [32], a long-acting, orally available OP antagonist (Figure 3, Table 2, 3) was proposed. Naltrexone is the drug of choice in the treatment of opioid dependence in countries where legislation prohibits the use of opioid agonists for this purpose. However, a meta-analysis of his clinical studies did not show the benefits of naltrexone compared with placebo for both opioid dependence treatment and relapse prevention [35], while nal-trexone prolonged-effect implants clinically significantly reduce heroin intake, which gives them an advantage over the drugs replacement therapy due to the lack of legislative restrictions on use [36]. Naltrexone was unexpectedly clinically effective for the prevention of alcohol relapse, which opened new prospects for medical application to OP antagonists [37]. Low doses of naltrexone, modulating the nervous and immune systems, are considered for the treatment of certain autoimmune diseases [38].
The naltrexone molecule served as a prototype for the creation of the most modern OP antagonist -nalmefene (Figure 3), which has the potential to treat acute poisoning of HA and various states of dependence [39].
The substitution of the carbonyl group for methylene (= CH2) in the hydrophobic region of naltrexone (Figure 3) slightly increased the lipo-philicity of the obtained molecule and eliminated the center of the most active metabolism (Figure 4), which increased the lifetime of the drug in the organism, prevented the formation of a pharmacologically active metabolite of 6- beta-naltrexol and made the nalmefene molecule more predictable in clinical practice. The metabolism ways of naltrex-one and nalmefene are shown in Figure 3.
As a consequence, nalmefene shows the pharmacological properties of a long-acting, physiologically-active OP antagonist with no dose-dependent hepatotoxicity intrinsic to naltrexone [40]. Considering to the pharmacokinetic properties, an unique pharmacological profile of the nalmefene influence on the and k-OP system (Table 3) determined the main area of its modern medical use as a drug for reducing alcohol consumption [37].
At the same time, the ability of nalmefene to inhibit effectively the |-opioid receptor (IC50 1.0 nmol) together with its high metabolic stability and effective entry into the CNS tissue (Table 2) determined its antidote potential for the treatment of acute poisoning with potent HA [46]. The results of pilot clinical studies now allow us to consider nalmefene as a promising agent for first aid in acute poisoning with HA, including a range of fentanyl and methadone [47-50].
The most lipophilic of the practically used agonis t- OP antagonists is veterinary drug diprenor-phine (Table 2), which is 100-300 times more potent than naloxone, and is used as an antagonist-
ПРОБЛЕМА ОБЕСПЕЧЕНИЯ БЕЗОПАСНОСТИ ПРИ ИСПОЛЬЗОВАНИИ НАРКОТИЧЕСКИХ АНАЛЬГЕТИКОВ В РОССИЙСКОЙ ФЕДЕРАЦИИ
Fig. 4. Metabolism scheme of naltrexone and nalmefene (according to Thomson Reuters Integrity 2018).
antidote for highly active veterinary analgesics and immobilizing agents (ethorphin, thiofentanil, carfentanil, etc.) , for which naloxone is not effective enough. As these analgesics are not used in medicine, it has been considered that there is no urgent need for a clinical study of diprenor-phine [51], but the growing interest in analgesics and anesthetics with a high morphine equivalent makes it urgent to develop and study more potent antidotes from the class of opioid agonist antagonists [2].
Thus, from the clinically tested opioid receptor antagonists, only nalmefene now has the necessary and sufficient potential to develop the agents for treating acute poisoning with narcotic analgesics and "designer drugs" based on them. Considering the economically expedient strategy for the development and production of multi-purpose medicines within the framework of urgent therapy [2], the possibility of developing a line of medicines for the treatment of acute opioid poisoning and conditions of alcohol dependence based on high-tech native (отечественный) substance - nalmefene may be of practical interest to the pharmaceutical industry.
378
Drugs of the future. Perfection principles of drugs - antagonists of opioid receptors
In some cases, the antidote activity of naloxone is inadequate and the relevance of the development of innovative antidotes that correspond to the achievements of the pharmacology of opioid analgesics of the central action, considering the integration of advanced scientific approaches and technologies in the field of active pharmaceutical substances and their medicinal forms is defined [2].
Practical approaches to the development of high-activity, CNS-targeted OP antagonists can be based on the basic principles of medical chemistry of drugs, expressed by N.V. Lazarev, which, like the history of the creation of fentanyl, show the need for targeted design and synthesis of highly li-pophilic molecules [21, 28]. For this purpose, pharmacologically active molecules of naltrexone and nalmefene, having a number of reaction centers for possible functionalization and hydrophobization, are of greatest interest (Fig. 5).
The chemical functionalization of the "aromatic site" and the hydrophobic region of naltrexone and nalmefene are of greatest practical interest in order to ensure high affinity and selectivity of the action
THE PROBLEM OF ENSURING SAFETY IN THE USE OF NARCOTIC ANALGESICS IN THE RUSSIAN FEDERATION
Fig. 5. The pharmacophore of the three-point receptor model [30].
of the developed compounds on the ^-opioid receptors. The study of the heroin pharmacokinetics showed a positive effect of acyl groups in the structure of the morphine molecule on the change in the kinetics of its transport to the brain through the blood-brain barrier [52]. This approach substantiates the study of prodrugs of naltrexone or nalmefene [39, 53] with an improved penetration function through biological membranes, the use of which can increase the possibility of prosperous outcomes of acute intoxications. The change in the nature of the acyl substituent on naltrexone or nalmefene molecules on fatty (C6-16) or inorganic acids on the contrary makes it difficult for the molecules to penetrate through the BBB [54], allowing the creation of prodrugs of naltrexone and nalmefene as a way of controlling the features of the action of opioid receptor antagonists in the treatment of acute poisonings, and the states of dependence.
In searching for drugs aimed at the OP biotarget the methods of computer docking, previously not used because of the lack of an adequate model of the pharmacological target, have become relevant. The results of X-ray structural studies of OP complexes presented in 2012 became a significant breakthrough in understanding the nature of the structure of these targets, denoting a new direction of directed computer search for promising OP antagonists [55].
Improvement of the medicinal product for the treatment of acute poisoning includes not only the
choice of the active principle, but also the rational choice of a medicinal form adequate to the assigned task of pharmacotherapy. The main way of using naloxone drugs is the parenteral route of injection: intravenous, intramuscular or intraosseous. To ensure the simplicity and timeliness of injection of the antidote in the course of emergency treatment, alternative methods such as sublingual, transbuccal, intranasal or inhalation become actual [33, 34].
The intranasal route of CNS-specific drugs injection is a real alternative to intramuscular injection in terms of speed and effectiveness of therapy [56]. In 2015, the FDA approved a way of nalox-one introduction to treat overdoses caused by opi-oids; similar drugs are being developed in Russia [34]. Despite the first steps in developing alternative routes for the use of OP antagonists, their medicinal forms for intravenous or intramuscular injections remain the most reliable in the hands of a medical employee. In order to perform injections by unqualified personnel, automatic naloxone injectors ("Evzio", etc.) are offered in self-help and mutual assistance, but an unjustified increase in the cost of technical means of antidotes injection creates economic obstacles to struggle with NA poisoning [57]. A universal first-aid preparation can be considered pre-filled syringes that allow both nal-oxone injections and nasal administration with an atomizer, if vascular access is difficult [58]. These approaches to the development of innovative medicinal forms of naloxone are universal for other prospective OP antagonists, such as nalmefene.
Requirements for drug forms of OP antagonists, designed for the treatment of drug and alcohol dependence, are fundamentally different from the requirements for the treatment of acute poisoning with opioids. Such drugs should ensure the patient's adherence to treatment and long-term maintenance of therapeutic drug concentrations in the blood with minimal discomfort for the patient. Today, preparations of OR antagonists, such as prodrugs, conjugates and biopolymers of naloxone, naltrexone and nalmefene, with prolonged action in the form of transdermal therapeutic systems, subcutaneous implants and other innovative medicinal forms are being developed for the treatment of drug and alcohol dependence [53, 54, 59, 60]. Thus, the increasing demands on drugs for the treatment of acute poisoning with narcotic analgesics and socially
ПРОБЛЕМА ОБЕСПЕЧЕНИЯ БЕЗОПАСНОСТИ ПРИ ИСПОЛЬЗОВАНИИ НАРКОТИЧЕСКИХ АНАЛЬГЕТИКОВ В РОССИЙСКОЙ ФЕДЕРАЦИИ
significant diseases determine the need for innovative approaches to the development and production of active pharmacological substances and their pre-pered medicinal forms corresponding to the objectives of drug therapy.
The expected increase in the demand for potent drugs with a high therapeutic index, including HA, the risks of the emergence and illicit trafficking of increasingly strong and dangerous narcotic drugs and the growing need for reliable means of their antidote therapy justify the advisability of creating a unified expert system for predicting risks and interdepartmental coordination of work on development, production and use of potent controlled pharmaceutical and veterinary drugs and their antagonists for the purpose of operative response and ensuring national security of the Russian Federation with considering existing and potential threats.
Conclusion
The use of narcotic analgesics and anesthetics in medical practice is non-alternative, despite their side effects. The growth of recreational use and the increase in the level of danger of synthetic opioids appearing to replace heroin, as well as the paradigm shift in the medical use of strong analgesics and anesthetics, necessitate the creation of new, more effective antidotes, opioid receptor antagonists. Naloxone, widely used in medical practice, because of non-optimal pharmacodynamic and pharmacokinetic properties, is not always effective as an antidote to narcotic analgesics. Fundamental approaches to improving drugs based on opioid receptor antagonists are based on the principles of medical chemistry and are aimed at targeted design, synthesis and research of lipophilic high affinity antagonists of opioid receptors. Nalmefen has the greatest potential for the development of new agents for the treatment of acute poisoning with narcotic analgesics among pharmacological agents with experience in clinical use, which justifies the task of developing and registering on the unified market of the EAES a complex of its medicines for the treatment of acute poisoning and socially significant diseases associated with disorders in the opioidergic system.
The current trend of increasing the activity and chemical diversity of opioids requires the construction of an effective expert system for monitoring
380
and analyzing emerging risks for public health service and the creation of a unified system of coordination of work in the development and production of narcotic analgesics and adequate means of their antidote therapy.
REFERENCES
1. Huxtable R.J., Schwartz S.K.W. The Isolation of Morphine - First Principles in Science and Ethics Molecular. Interventions. 2001; 1: 189-91.
2. Sosnov A.V., Semchenko F.M., Vlasov M.I. et al. Development of non-injectable central drugs for emergency therapy. Razrabotka i registratsiya lekarstvennykh sred-stv. 2018; 22(1): 114-33. (in Russian)
3. Jones C.M., Mack K.A., Paulozzi L.J. Pharmaceutical overdose deaths, United States, 2010. Journal of the American Medical Association. 2013; 309(7): 657-9.
4. Brownstein M.J. A brief history of opiates, opioid peptides, and opioid receptors. Proceedings of the National Academy of Sciences of the United States of America. 1993; 90: 5391-3.
5. Lichtstein D., Rodbard D. A second look at the second messenger hypothesis. Life Sciences. 1987; 40(21): 2041-51.
6. Sharma S.K., Klee W.A., Nirenberg M. Dual regulation of adenylate cyclase accounts for narcotic dependence and tolerance. Proceedings of the National Academy of Sciences of the United States of America. 1975; 72: 3092-6.
7. White J.M., Irvine R.J. Mechanisms of fatal opioid overdose. Addiction. 1999; 94(7): 961-72.
8. Warner-Smith M., Darke S., Day C. Morbidity associated with non-fatal heroin overdose. Addiction. 2002; 97(8): 963-7.
9. Ivnitskiy Yu.Yu., Krasnov K.A., Rejnyuk VL. et al. The problem of the «golden hour» in the medical treatment of acute poisoning and the way to solve it. Rossiyskiy bio-meditsinskiyzhurnal. 2014; 15(3): 584-604. (in Russian)
10. Opioid overdose: prevention and reduction of opioid-induced deaths. UNODC/WHO discussion paper. [Peredozirovka opioidov preduprezhdenie i snizhenie smertnosti vyzvannoy peredozirovkoy opioidov 2013 god diskussionnyj dokument YUNODK/VOZ] «UNITED NATIONS»; 2013: 30.
11. Ostapenko Yu.N., Rozhkov P.G., Kazachkov V.I. et al. Acute poisoning in Russia and the state of toxicological help. In actual directions of the development of medical means of protection against extreme factors: a collection of materials of the All-Russian scientific and practical conference dedicated to the 25th anniversary of the FSUENPC "Farmzashita"FMBA of Russia. [Aktualnye napravleniya razvitiya meditsinskikh sredstv zashchity ot ekstremalnykh faktorov, sbornik materialov Vserosijskoj nauchno-prakticheskoj konferentsii posvyashchennoj 25-letiyu FGUP NPTS Farmzashchita FMBA Rossii]. 2017: 248. (in Russian)
THE PROBLEM OF ENSURING SAFETY IN THE USE OF NARCOTIC ANALGESICS IN THE RUSSIAN FEDERATION
12. Abuzarova G.R., Guseva O.I., Kovalev A.V et al. Forensic assessment of opiate toxicity in adults and children with persistent pain: Methodological recommendations. [Sudeb-no-meditsinskaya otsenka parametrov toksichnosti opiatov u vzroslykh i detej spersistiruyushchej bolyu Metodicheskie rekomendatsii]. Moscow: 2015. (in Russian)
13. Misailidi N., Papoutsis I., Nikolaou P. et al. Fentanyls continue to replace heroin in the drug arena: the cases of ocfentanil and carfentanil. Forensic Toxicology. 2018; 36(1): 12-32.
14. Zaikina O.L., SHilov V.V., Lodyagin A.N. et al. Features of detection of fentanyl derivatives in urine by gas and liquid chromatography-mass spectrometry. Toksiko-logicheskij vestnik. 2016; 3: 41-6. (in Russian)
15. Golovko A.I., Bonitenko E.Yu., Basharin VA. et al. Terminological and biological paradoxes of the phenomenon of "designer drugs". Narkologiya. 2015; 14(1): 69-83. (in Russian)
16. Muzurov K.V, Khalimov Yu.Sh., Basharin VA. et al. The dynamics of the structure of acute poisoning according to the department of resuscitation and intensive care clinic of the military field therapy of the Military Medical Academy. CM. Kirov for the period 2000-2015. Vestnik rossiyskoy voenno-meditsinskoy akademii. 2016; 55(3): 23-5. (in Russian)
17. Yoshiyasu Higashikawa, Shinichi Suzuki. Studies on 1-(2-phenethyl)-4-(N-propionylanilino)piperidine (fen-tanyl) and its related compounds. VI. Structure-analgesic activity relationship for fentanyl, methyl-substituted fen-tanyls and other analogues. Forensic Toxicology. 2008; 26(1): 1-5.
18. Mounteney J., Giraudon I., Denissov G. et al. Fentanyls: Are we missing the signs? Highly potent and on the rise in Europe. International Journal of Drug Policy. 2015; 26(7): 626-31.
19. Armenian, P., Vo K.T. Barr-Walker J., Kara L.L. Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review. Neuropharmacology. 2017.
20. Popovich V.I., Chepur S.V., Bykov V.N., Tamindarov R.R. et al. Medications for the prevention and treatment of poisoning with narcotic analgesics. In Actual problems of toxicology and radiobiology: Abstracts of the Russian scientific conference with international participation [Aktualnye problemy toksikologii i radiobiolo-gii. Tezisy dokladov Rossijskoj nauchnoj konferentsii s mezhdunarodnym uchastiem]. Sankt Petersburg: Foliant; 2011: 206. (in Russian)
21. Lazarev N.V. Drugs [Narkotiki]. L.: Izd-vo In-ta gigieny truda i profzabolevaniy Lengorzdravotdela; 1940: 399. (in Russian)
22. Bujaka R., Struck-Lewickaa W., Kaliszanb M. et al. Blood-brain barrier permeability mechanisms in view of quantitativestructure-activity relationships (QSAR). Journal of Pharmaceutical and Biomedical Analysis. 2015; 108: 29-37.
23. Andres A., Roses M., Rafols C. et al. Setup and validation of shake-flask procedures for the determination
of partition coefficients (logD) from low drug amounts. European Journal of Pharmaceutical Sciences. 2015; 30(76): 181-91.
24. Kalvass J.C., Olson E.R., Cassidy M.P. et al. Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC50, and Correlation of in Vitro, Precli-nical, and Clinical Data. Journal of Pharmacology and Experimental Therapeutics. 2007; 323(1): 346-55.
25. Kaufman J.J., Koski W.S., Benson D.W. et al. Narcotic and narcotic antagonist pKa's and partition coefficients and their significance in clinical practice. Drug and Alcohol Dependence. 1975; 1(2): 103-14.
26. Janicka M, Sztanke M, Sztanke K. Reversed-phase liquid chromatography with octadecylsilyl, immobilized artificial membrane and cholesterol columns in correlation studies with in silico biological descriptors of newly synthesized antiproliferative and analgesic active compounds. Journal of Chromatography A. 2013; 1318: 92-101.
27. Fishman J., Hahn E.F., Norton B.I. Comparative in vivo distribution of opiate agonists and antagonists by means of double isotope techniques. Life Sciences. 1975; 17(7): 1119-25.
28. Stanley T.H., Egan T.D., Aken H.V.A. A Tribute to Dr. Paul A.J. Janssen: entrepreneur extraordinaire, innovative scientist, and significant contributor to anesthesiol-ogy. Anesthesia & Analgesia. 2008; 106(2): 451-62.
29. Pohl J. Ueber das n-allylnorcodein, einen antagonisten des morphins. Zeitschrift für experimentelle Pathologie und Therapie. 1915; 17(3): 370-82.
30. Kuzmina N.E., Kuzmin VS. Development of ideas about the interaction of drugs with opiate receptors. Uspekhi khimii. 2011; 80(2): 157-81. (in Russian)
31. Unna K. Antagonistic effect of N-Allyl-normorphine upon morphine. Journal of Pharmacology and Experimental Therapeutics. 1943; 79(1): 27-31.
32. Blumberg H., Dayton H.B. Naloxone, naltrexone, and related noroxymorphones. Advances in Biochemical Psychopharmacology. 1973; 8: 33-43.
33. Vengerovich N.G., Yudin M.A., Bykov VN. et al. Investigation of the effectiveness of the microencapsulated form of naloxone with sustained release in the experimental model of fentanyl poisoning. Byulleten eksperi-mentalnyj biologii i meditsiny. 2017; 163(6): 702-6. (in Russian)
34. Bariev E.A., Bardakov A.I., Lyapunov N.A., Krasnyuk I.I. Justification of the choice of a non-injectable route of administration of naloxone. Vestnik VGU, seriya: Khimi-ya. Biologiya. Farmatsiya. 2017; 1: 133-7. (in Russian)
35. Mendelevich V.D., Zalmunin K.Y. Paradoxes of evidence in Russian addiction medicine. The International Journal of Risk & Safety in Medicine. 2015; 27(1): 102-3.
36. Sharma A., Kelly S.M., Mitchell S.G. et al. Update on Barriers to Pharmacotherapy for Opioid Use Disorders.
Current psychiatry reports. 2017; 19(6): 35.
ПРОБЛЕМА ОБЕСПЕЧЕНИЯ БЕЗОПАСНОСТИ ПРИ ИСПОЛЬЗОВАНИИ НАРКОТИЧЕСКИХ АНАЛЬГЕТИКОВ В РОССИЙСКОЙ ФЕДЕРАЦИИ
37. Shagiakhmetov F.S., Grishin S.A., Anokhin P.K., SHa-makina I.Y. The fundamental foundations of the therapeutic effects of opioid antagonists in the treatment of alcohol dependence: the role of kappa-opioid receptors. Voprosy narkologii. 2015; 4: 73-96. (in Russian)
38. Bihari B. Bernard Bihari, MD: low-dose naltrexone for normalizing immune system function. Alternative Therapies In Health And Medicine. 2013; 19(2): 56-65.
39. Hahn E.F., Fishman J., Heilman R.D. Narcotic antagonists. 4. Carbon-6 derivatives of N-substituted noroxy-morphones as narcotic antagonists. Journal of Medicinal Chemistry. 1975; 18(3): 259-62.
40. Ingman K., Hagelberg N., Aalto S. et al. Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing. Neuropsychopharmacology. 2005; 30(12): 2245-53.
41. Bart G., Schluger J.H., Borg L. et al. Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity? Neuropsychopharmacology. 2005; 30(12): 2254-62.
42. Li G., Aschenbach L.C., Chen J. et al. Design, Synthesis, and Biological Evaluation of 6a- and 6ß-N-Heterocyclic Substituted Naltrexamine Derivatives as д Opioid Receptor Selective Antagonists. Journal of Medicinal Chemistry. 2009; 52(5): 1416-27.
43. Maillet E.L., Milon N., Heghinian M.D. et al. Noribo-gaine is a G-protein biased к-opioid receptor agonist. Neuropharmacology. 2015; 99: 675.
44. Maillet E., Weis H. Methods and compositions for potentiating the action of opioid analgesics using iboga alkaloids: patent US 2016/0220579. 08.04.2016.
45. Roth B.L., Dengler D.G., Shoichet B.K. et al. mu Opi-oid receptor modulators: patent US WO 2017007695. 01.12.2017.
46. Yong Z., Gao X., Ma W. et al. Nalmefene reverses carfentanil-induced loss of righting reflex and respiratory depression in rats. European Journal of Pharmacology. 2014; 738: 153-7.
47. Kaplan J.L., Marx J.A., Calabro J.J. et al. Harchelroad FP Jr. Double-blind, randomized study of nalmefene and naloxone in emergency department patients with suspected narcotic overdose. Annals of Emergency Medicine. 1999; 34(1): 42-50.
48. Wang D.S., Sternbach G., Varon J. Nalmefene: a long-acting opioid antagonist. Clinical applications in emergency medicine. Journal of Emergency Medicine. 1998; 16(3): 471-5.
49. Kim S., Wagner H.N.J., Villemagne VL. et al. Longer oc-
cupancy of opioid receptors by nalmefene compared to naloxone as measured in vivo by a dual-detector system. Journal of Nuclear Medicine. 1997; 38(11): 1726-31.
50. Antidote therapy of poisoning by highly toxic substances in emergency situations. Manual. [Antidotnaya terapiya otravlenij vysokotoksichnymi veshchestvami usloviyakh chrezvychajnykh situatsij Rukovodstvo]. Pod redaktsiej V.D. Gladkikh, S.K. Sarmanaeva, Y.N. Ostapenko. Fed-eralnoe mediko-biologicheskoe agentstvo Moscow: Kommentarij; 2014: 272.(in Russian)
51. Haymerle A., Fahlman A., Walzer C. Human exposures to immobilising agents: results of an online survey. The Veterinary Record. 2010; 167(9): 327-32.
52. Halbsguth U., Rentsch K.M., Eich-Höchli D. et al. Oral diacetylmorphine (heroin) yields greater morphine bio-availability than oral morphine: bioavailability related to dosage and prior opioid exposure. British Journal of Clinical Pharmacology. 2008; 66(6): 781-91.
53. Stinchcomb A.L., Swaan P.W., Ekabo O. et al. Straight-chain naltrexone ester prodrugs: Diffusion and concurrent esterase biotransformation in human skin. Journal of Pharmaceutical Sciences. 2002; 91(12): 2571-8.
54. Gijom M.Z.M.A., Gakens T. Nalmefene prodrugs: patent RU2495042C2. 10.10.2013.
55. Kaserer T., Lantero A., Schmidhammer H. et al. д-Opioid receptor: novel antagonists and structural modeling. Scientific Reports. 2016; 6: 1-14.
56. Rudko O.I., Klimov E.A., Sobolev V.V. et al. The study of effects of the intranasal dexmedetomidine administration on pain sensitivity. Razrabotka I registraatsiya lek-arstvennykh sredstv. 2017; 19(2): 236-41. (in Russian)
57. Gupta R., Shah N.D., Ross J.S. Perspective: The Rising Price of Naloxone - Risks to Efforts to Stem Overdose Deaths. The New England Journal of Medicine. 2016; 375(23): 2213-5.
58. Edwards E.T., Edwards E.S., Davis E. et al. Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for Naloxone Delivery. Pain and Therapy. 2015; 4(1): 89-105.
59. Gaekens T., Guillaume M., Borghys H. et al. Lipophilic nalmefene prodrugs to achieve a one-month sustained release. Journal of Controlled Release. 2016; 232: 196202.
60. Petrova E.A., Kedik S.A., Alekseev K.V et al. Evaluation of the efficiency of the double emulsification method in the preparation of naltrexone microspheres based on a copolymer of lactic and glycolic acids. Vestnik MITKhT imM.V. Lomonosova. 2013; 8 (2): 58-63. (in Russian)
