Trazodone succinate — new opportunities for pharmacological correction of situational behavioral abnormalities in dogs and cats

Currently, the interest of veterinarians and owners in the pharmacological correction of situational behavioral disorders in companion animals has increased significantly. To quickly correct deviant behavior in dogs and cats, veterinarians use some of the psychotropic drugs used in human medicine, in particular, trazodone, an antidepressant antagonist/serotonin reuptake inhibitor.

Based on the analysis of literature sources, data on the history of creation and pharmacological properties, assessment of the safety and efficacy of drugs based on trazodone hydrochloride in behavioral medicine of small pets are provided.

The data on the prerequisites for the development, pharmaco-toxicological and clinical evaluation of a new drug for the modification of abnormal behavior in dogs and cats, Express Uspokoin® tablets based on trazodone succinate, which, with a high efficiency of the target action, made it possible to achieve the absence of side effects and significantly increase the tolerance of the dosage form by animals, are analyzed. compared with preparations based on trazodone hydrochloride.

Keywords: trazodone succinate, dogs, cats, behavior correction, behavioral abnormalities, safety, efficacy, Express Uspokoin® tablets.

Abbreviations: GABA: gamma-aminobutyric acid, AS: active substance, CA: companion animals, CNS: central nervous system, SA: succinic acid.

Relevance of misbehavior in companion animals

Between 2015 and 2019, the population of companion animals in Russia grew by 14%. Today, one in two households in Russia has a pet, representing 55.5 million households. There are 33.7 million pet cats, the third highest in the world after the United States and China, as well as 18.9 million pet dogs [19]. It is estimated that there is a steady increase in the number of pets worldwide [10]. In recent decades, there has been a clear trend of acquiring a pet to live with, with the animal beginning to serve as a social partner [5, 24] and a family member [42, 57]. Indeed, today 83% of cat owners and 76% of dog owners consider their pets to be family members, friends or even children [19].

regularly face a systemic problem that they are unable to manage on their own [6, 18], namely, the need for situational correction of certain behavioral deviations in dogs and cats due to the peculiarities of their cohabitation with humans. The situation is complicated by the evident lack of safe, effective and commercially available pharmacological remedies for treating problems of pet misbehavior, frequently encountered and associated with the state of fear, anxiety and stress.

At the same time, both owners and veterinary professionals need to effectively and safely manage typical pet behavior disorders that significantly impair the enjoyment of interaction with pets, such as fear of transportation [46], separation anxiety [27, 50], fear of visiting the veterinary clinic [32, 43], fear of stay in the clinic [40, 60], including after surgical interventions, fear of loud sounds [27, 29, 33, 56], cognitive dysfunction [53], etc.

In order to address this problem, veterinarians in recent years have often turned to the experience of human medicine and used some of the known neurotropic drugs for immediate situational correction of misbehavior in dogs and cats. Recently, trazodone has been considered a candidate for use as part of veterinary sedation medications [31].

Trazodone history and pharmacological properties

In 1966, chemists and psychopharmacologists of Angelini Pharma company, based on the known properties of phenylpiperazine derivatives, synthesized a new compound (2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4- triazolo[4,3-a]pyridin-3(2H)-one), which was named trazodone and was found to exhibit antidepressant properties [2]. Since 1971, trazodone in the form of a hydrochloride salt has found application in this capacity in Italy, and by the end of the 1980s it was registered as a medicinal product in many countries, including in the USSR [58] and became widespread enough in medical practice.

In the 70-90s, trazodone properties and its mechanism of action as an antidepressant were actively studied on experimental animals and humans, and its pharmacology and pharmacokinetics were studied in detail [30, 34...36, 41].

Studies conducted during this period confirmed that trazodone has sedative and myorelaxant effects, as well as a pronounced anxiolytic effect that eliminates both mental (fear, affective stress, insomnia) and somatic manifestations of anxiety in humans [3]. Due to these findings, the drug was recommended in psychiatry not only for the treatment of depressions of various origins (psychotic, neurotic, endogenous, somatogenic), but also for patients with phobias, panic attacks and anxiety, with compulsive disorders and posttraumatic stress [9].

It is now established that the mechanism of trazodone's antidepressant action is based on its ability to bind high-affinity to 5-HT2A and 5-HT2C-type serotonin receptors, for which it tradozone is a powerful antagonist, and to inhibit the reuptake of 5-hydroxytryptamine secreted by brain neurons, leading to an increase in serotonin content in the synaptic cleft [54]. In addition, it is known that trazodone and its active metabolite m-chlorophenylpiperazine have an agonist effect on type 1 serotonin receptors [47], and that trazodone can increase serotonin concentration by suppressing the inhibitory effect of GABA in the cerebral cortex [44].

Today, trazodone-containing medications are produced and used in various dosage forms in medical practice throughout the world. Trazodone is marketed under the trade name Desyrel in the United States and some other countries; Trittico in Europe and the CIS countries; Trazorel in Canada; Molipaxin in the United Kingdom and Ireland [2]. It is available as both immediate-release and sustained-release tablets, as well as oral drops and injectable solution [36]. At the same time, all known dosage include trazodone in the form of hydrochloride salt. In Russia and the CIS countries, only the oral controlled-release tablet form of the drug is available today for medical use.

Studies and evaluation of the results of the use of trazodone hydrochloride-based drugs in the behavioral medicine of companion animals

The experience of successful use of trazodone-containing drugs in psychiatry has sparked legitimate interest among veterinary specialists in evaluating the possibility of using trazodone for correction of the behavior of dogs and cats in various stressful situations. It was prompted, on the one hand, by the undoubted relevance of the problem of undesirable misbehavior in companion animals and the lack of effective and available means of its pharmacological correction, and on the other hand, by the data suggesting a connection between misbehavior observed in animals and serotonin metabolism. In particular, it is known that the development of acute distress and subsequent undesirable behavioral states in companion animals is neurophysiologically realized through the activation of the prefrontal cortex, amygdala, limbic system, and hypothalamus [49, 52], which on the biochemical level leads to an imbalance in neurotransmitters, including 5-hydroxytryptamine [49, 51, 61], the exchange of which is influenced by trazodone.

Since the end of 1990s, studies of trazodone influence on the behavior of dogs and cats in anxiety disorders typical for this group of animals have been conducted across the world [31, 38, 48, 53, 55].

pical for this group of animals have been conducted across the world [31, 38, 48, 53, 55]. It should be noted that in the absence of veterinary trazodone-containing drugs, animals were prescribed commercially available human drugs, which, as the experience of their use in dogs and cats has shown, in many cases led to the onset of various adverse effects, the most frequent of which were lethargy, excessive sedation, apathy, somnolence and depression [38, 39, 41]. These effects manifested 30 to 60 minutes after the ingestion and were often observed for the next 10 to 12 hours, and in some cases for more than 24 hours [59]. For example, unpublished data from the US Animal Poison Control Center (ASPCA) reported adverse effects associated with exposure to medical drug monotherapy with trazodone hydrochloride in 379 dogs from 2009 to 2013. Of the 104 dogs with adverse drug effects, excessive sedation and lethargy were reported in 43%, ataxia in 16%, and vomiting in 14% of the animals [37].

ТThe same organization reported adverse effects in dogs receiving commercial trazodone hydrochloride medications from January 2003 to November 2016, and the lowest dose at which each adverse effect was reported. It has also been noted that when Desyrel, which contains trazodone hydrochloride as an AS, is used in dogs concomitantly with other selective serotonin reuptake inhibitors and/or tricyclic antidepressants and/or monoamine oxidase inhibitors [31, 45], there is a potential risk of serotonin syndrome, which can be lifethreatening

Side effects associated with trazodone-containing medications in dogs

Side effectSide effect	Lowest dose, mg/kg, at which the side effect was observed
Lethargy	0,55
Depression/vomiting	1,35
Ataxia	1,7
Diarrhea	2,82
Hyperactivity	3,8
Hypotension	5,94
Hyperesthesia	6,06
Vocalization	6,6
Tremors	8,17
Tremors	8,28
Tachycardia/hypertension	8,83
Hyperthermia	11,8
Hyperthermia	12,99
Mydriasis/bradycardia	16,23
Seizure	78,7

Signs of serotonin syndrome include tachycardia, difficulty breathing, dilated pupils, and tremors.

The most common adverse effects of oral administration of known trazodone-containing drugs to cats are sedation and behavioral disinhibition (aggression and vocalization) [48, 55].

It is evident that in the context of situational use of commercial medical drugs in companion animals, the above effects disturb the habitual lifestyle of both the animal and its owner, and in many cases are highly undesirable and dangerous.

Considering the above, it hardly surprising that 50 years after trazodone became commercially available, there are still no trazodone-containing sedatives specifically designed for use in companion animals on the international veterinary market. As a result, veterinarians, particularly in the U.S. and Canada, continue to prescribe commercially available drugs for rapid correction of misbehavior in stressed cats and dogs, relying exclusively on the effectiveness of the drugs and ignoring their significant disadvantages, such as multiple adverse effects, prescription status and difficulty in precise dosing.

Ideology of developing a veterinary trazodone-containing drug for CA

The undoubted relevance of the issues of pharmacological correction of misbehavior in companion animals, on the one hand, and the results of international experience in the use of drugs hardly suitable for use in dogs and cats, on the other hand, have served as the driving force for creating a Russian trazodone-containing sedative for CA to address the problem of effective correction of misbehavior in the absence or at least minimal expression of the known adverse effects.

The main strategy in developing the world's first tradozone-based veterinary drug was to select such a derivative that would provide greater safety in its use by CA without impairing the effectiveness of trazodone's sedative action. The succinate salt of trazodone (trazodone succinate) turned out to be such a derivative, which, having high target efficacy, made it possible to substantially improve the toxicological profile of the new drug and significantly increase the tolerability of the drug form in animals as compared to trazodone hydrochloridebased drugs.

As the theoretical prerequisite, the synthesis and studies of the possibility of using trazodone succinate as a new AS were based on the known data on the beneficial properties of SA exhibited by this compound in humans and domestic animals [1, 4, 7, 25, 26]. Succinic (ethane-1,2-dicarboxylic, butanedione) acid and its salts (succinates) are universal intermediate intracellular metabolites formed during the interconversion of proteins, lipids and carbohydrates in animal cells, participants in energy metabolism in humans and animals [8, 11, 12]. SA is also a powerful endocrine stimulus; many organs and tissues, including the CNS, have succinate specific membrane receptors [4, 7, 21].

SA itself is a low-toxic compound and has no mutagenic or teratogenic effect [13]. It was found that SA acts Trazodone succinate — new opportunities for pharmacological correction of situational behavioral abnormalities in dogs and cats 4 • RVJ • № 4/2021 • as a regulator of physiological and biochemical processes, is a substrate antihypoxant, a component of antioxidant system of the body, has neurotropic activity [15, 22, 25]. In addition to antihypoxic and antioxidant effects, SA-based drugs have nootropic, anticonvulsant and anxiolytic effects. Drugs of this group modulate the activity of cell membrane enzymes, receptor complexes (benzodiazepine, GABA, acetylcholine), contributing to the binding of the latter to ligands, preserving the structural and functional organization of biomembranes, transport of neurotransmitters and improving synaptic transmission; increase the concentration of dopamine in the brain [22].

The positive effects of succinate on the CNS have been characterized in numerous clinical studies [14, 17, 20, 22, 23], which demonstrated their biological activity with a unique combination of manifestations: in a healthy body, succinate act as adaptogens and actoprotectors, while in the presence of pathological changes they demonstrate a therapeutic effect that is atypically high for adaptogens [12, 13, 26].

The successful solution of the problem of choosing a suitable form of trazodone for CA was possible due to the positive results obtained by specialists of RPC SKiFF (Moscow) after many years of research to assess safety, tolerability and efficacy of a number of derivatives, including pharmaceutically acceptable salts of trazodone, which resulted in the development and market launch of a new drug to correct behavioral disorders in dogs and cats: Express Uspokoin® tablets. This is the world's first patent-protected veterinary trazodone-containing drug for this purpose, the AS of which is trazodone succinate [16]. The new drug has a number of clear advantages compared to commercially available trazodone hydrochloride-based drugs

Pharmaco-toxicological parameters of new AS (trazodone succinate) significantly differ from those of trazodone hydrochloride traditionally used in medically similar drugs. For example, tests conducted during the development of the drug Express Uspokoin® tablets showed that the acute oral toxicity of trazodone succinate (active substance) for rats is characterized by an LD50 value of 2300 mg/kg, for mice 1200 mg/kg, which, in accordance with GOST 12.1.007-76, provides for the classification of the substance as Hazard Class III ("Moderately Hazardous Substances") which includes compounds having an LD50 value in the range of 151...5000 mg/kg. At the same time, the value of LD50 of trazodone hydrochloride, formally falling under the same hazard class, is only 690 mg/kg for rats and 610 mg/kg for mice [28], which is, respectively, 3 and 2 times lower than in trazodone succinate.

The significant difference in the quantitative toxicity of succinate and trazodone hydrochloride can be explained by the following reasons. Since the toxicity of both salts is entirely determined by the presence of the base in the trazodone molecule, the observed difference in LD50 may be the result of the difference in the amount of trazodone contained in equiponderant samples of the substances.

It follows from the comparison of the trazodone molecular weight to the molecular weights of its two salts that the mass fraction of trazodone in the hydrochloride molecule is approximately 91%, whereas it is only 75% in the succinate molecule. Accordingly, when recalculated with reference to "pure" trazodone, the same doses of salts used in acute toxicity studies will be much lower in succinate than in hydrochloride. We also cannot exclude the possibility that the observed decrease in toxicity (increased LD50 value) of trazodone succinate in comparison with trazodone hydrochloride is associated with the formation as a result of dissociation of water-soluble succinic salt of equimolar amounts of trazodone and negative ion of succinic acid, which is known to be able to accelerate the catabolism of many toxic compounds in mammals, i.e., to manifest detoxicant properties [4, 8, 13, 22, 25].

The study of subchronic toxicity of Express Uspokoin® tablets in rats showed that its administration for 90 days in the doses of 340 mg/kg, 170 mg/kg and 68 mg/kg, approximately 10...50 times higher than therapeutic, does not cause any significant changes in clinical condition and blood count (by the results of general clinical and biochemical tests) of experimental rats, which corresponded to generally accepted reference values for this type of animals during the whole experiment. No pathomorphological changes were found in rats receiving the drug. According to the results of postmortem macroscopic examination and morphometric analysis of the internal organs, their size and condition in the experimental and control animals had no reliable differences in the determined parameters

A significant achievement in the development of a new sedative for CA was the determination of an effective single dose of the drug for almost all specific situations encountered in everyday life, accompanied by manifestations of fear and anxiety in most dogs and cats, such as transportation, visits to the veterinary, loud noises, separation from the owner, stay in hospital, etc. Dose titration studies took into account the pharmacokinetic parameters of the AS, data from our own studies, as well as literature containing recommendations for the use of trazodone hydrochloride in veterinary practice. For the first time, relevant and systematized data on the range of optimal therapeutic doses of the AS recommended in dogs and cats in each case were obtained.

As the molecule of trazodone succinate contains equimolar quantities two active compounds: trazodone, which is a antidepressant, and SA, which has properties of detoxicant, antioxidant, antihypoxant and other qualities that can partially level the adverse effect of the primary AS on the body, the principal result of its choice as the AS is that while maintaining high anti-stress efficacy of the drug, the possibility of adverse effects typical for trazodone (pronounced sedation, lethargy, slowness, impaired movement coordination) observed when animals are treated with drugs containing trazodone hydrochloride, is excluded or significantly reduced. The absence of Beloglazov D.V., Mukaseev S.V., Zeinalov O.A. • RVJ • № 4/2021 • 5 the above mentioned undesirable reactions to the use of the drug Express Uspokoin ® tablets on the organism of dogs and cats ensures its safety, good tolerability of the target animals and possibility of course application, in contrast to trazodone hydrochloride.

As a result of tolerability tests of trazodone succinate as an ingredient of Express Uspokoin® tablets, it was found that its daily administration to dogs and cats for 90 days in therapeutic and double therapeutic dose has no negative impact on the general state of animals, their physiological status and behavior. No statistically significant changes in the morphological composition and biochemical blood parameters of the target animals were registered during the studies either.

Tolerability of dogs and cats receiving Express Uspokoin in increased doses in the long term is currently being evaluated. The effects of trazodone succinate in special conditions requiring a course of medication and in some cases a lifetime use of the drug, in particular in elderly dogs and cats, are currently being studied, with the prospects to expand the list of indications for its use in animals with age-related changes in behavior. In particular, we evaluated the effect of a course of use of Express Uspokoin in treating behavioral disorders in elderly cats and dogs, anxiety states and in post-operative management.

Express Uspokoin® tablets have a separating strip for facilitating precise dosing, coated with a coating with flavoring agent that provides attractive palatability of the drug for cats and dogs, thus significantly increasing the convenience of its use, both at home and in the conditions of a veterinary clinic or hospital. It should be noted that the substance of trazodone succinate has a moderately sour taste in contrast to the pronounced bitter taste of the trazodone hydrochloride, which further contributes to the good palatability of the drug for animals.

Conclusion

Thus, the use of trazodone tablet in the form of succinate in the drug Express Uspokoin ® has made it possible to achieve the absence of adverse effects characteristic of trazodone hydrochloride-based medical drugs that had no alternative until recently. This is due to the combination of the targeted trazodone action with the unique properties of SA in the AS molecule. High efficiency of sedative action of the new drug has been confirmed by clinical studies.

Express Uspokoin® tablets are distinguished from other commercially available drugs for correction of undesirable misbehavior in dogs and cats by good tolerability by animals of different ages, rapid onset of action with high sedative effect, absence of accumulative effect, withdrawal syndrome and tolerance development after a course of use.

Taking into account the above, as well as long (3 years) shelf life of the drug, Express Uspokoin® tablets may be recommended to be included in the veterinary medicine box of almost every pet owner for situational administration in order to quickly eliminate unwanted misbehavior associated with fear, anxiety and stress.

Conflict of Interes

The manufacturer of the drug Express Uspokoin® tablets and sponsor of this study is LLC RPC SKiFF. The decision to publish the results of the scientific work belongs to the originator company, LLC RPC SKiFF.

The drug was developed and introduced to the market with the financial support of The Foundation for Assistance to Small Innovative Enterprises in Science and Technology

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