Elsevier

Journal of Veterinary Behavior

Volume 2, Issue 5, September–October 2007, Pages 175-183
Journal of Veterinary Behavior

Research
Effects of alpha-casozepine (Zylkene) versus selegiline hydrochloride (Selgian, Anipryl) on anxiety disorders in dogs

https://doi.org/10.1016/j.jveb.2007.08.001Get rights and content

Abstract

After a first study showing efficacy on anxiety disorders in cats, the putative effects of alpha-casozepine (a tryptic bovine αs1-casein hydrolysate) on anxious disorders in dogs was investigated. The trial was conducted against a control molecule, selegiline. Thirty-eight dogs were recruited within veterinary practices by certified behaviorist surgeons. This 56 day trial, against the reference molecule, selegiline, showed that both products were efficient to decrease the EDED score and no statistical difference was found between their success score. Owners assessment was also statistically perfectly equivalent. Due to this efficacy, and to its safety, alpha-casozepine (Zylkene) should be considered an option by the veterinary surgeon for the biological management of anxiety beside the compulsory behavior modifications.

Introduction

Anxiety disorders in dogs are an important issue in veterinary behavioral medicine. Although various definitions for these disorders have been proposed, depending primarily on whether the authors believe that there exists such a thing as “normal anxiety” (Overall, 1997, Dodman and Shuster, 1998) or not (Pageat, 1995, Pageat, 1998, Mege et al., 2003), it is generally agreed that anxiety-related conditions are one of the main groups of behavioral disorders occurring in dogs.

The many possible causes of anxiety states range from internal causes such as hormonal imbalance (Clarke et al., 1998) and genetic vulnerability (Tancer et al., 1990, Uhde et al., 1992) to external causes such as species-inappropriate living conditions, ambiguous social relationships and inappropriate/unfair punishment.

The management of anxieties, fears and phobias may require inducing behavioral changes and possibly stress reduction training programs to improve dogs' abilities to cope with stressful situations. In addition to behavioral therapy, drugs have been developed to promote and speed the rate of animals' recovery. Drugs used currently as anxiolytics are numerous and belong to different classes (Loo et al., 1990) including:

  • anxiolytics:

    • beta-blockers

    • alpha-2 agonists

    • morpholines

    • benzodiazepines (the use of which varies considerably from one country to another); and

  • antidepressants

    • tricyclic antidepressants (TCAs)

    • selective serotonin reuptake inhibitors (SSRIs)

    • monoamine oxidase inhibitors (MAOIs).

However, the use of other compounds that have not been included in the classical drug classification scheme is now increasing. Two of these are:

  • pheromones

    • dog appeasing pheromone is used to deal with many anxious conditions, mainly during development (Mills et al., 2003, Pageat and Gaultier, 2003, Vienet-Legué, 2006); and

  • neutriceuticals

    • alpha-casozepine has been studied in classical laboratory rat models of anxiety (based on the use of conditioned defensive burying and elevated-plus maze paradigms, for instance) (Schroeder et al., 2003, Violle et al., 2006) and under various stress-inducing conditions in the case of human beings (Lanoir et al., 2002, Messaoudi et al., 2002, Messaoudi et al., 2005). This compound has proved to be an effective means of relieving anxiety in cats with social phobias (Beata et al., 2007).

Alpha-casozepine originated in the alpha S1 casein portion of milk. It is similar in spatial structure to gamma amino butyric acid (GABA) (Miclo et al., 2001), and is a decapeptide obtained from α-S1 casein by tryptic hydrolysis. It has an affinity for benzodiazepine receptors, particularly a sub-category of GABA-A receptors, as reviewed previously (Beata et al., 2007).

Many owners are reluctant to give their dogs psychotropic drugs and express concerns to veterinarians that they are worried about ‘addiction.’ Although few of the pharmaceuticals discussed have any addiction potential, and none is addictive at therapeutic levels, owners often feel reassured when veterinarians are able to offer ‘natural’ compounds. These compounds also must be shown to be efficacious. Efficacy data based on clinical trials provide practitioners with the evidence they require to prescribe such compounds with confidence.

We provided evidence recently of the efficacy of alpha-casozepine in cats in a study where the effects of the drug were compared with those of a placebo, so it seemed worthwhile to carry out similar trials with dogs. An initial study using a placebo showed promising effects in relieving anxiety in dogs (Beata et al., unpublished). For ethical reasons, we decided to conduct this study by comparing alpha-casozepine with a known, ‘control’ compound, selegiline, which is marketed in veterinary medicine for the treatment of anxiety disorders (in Europe) (Pageat, 1995, Pageat, 1998, Pageat, 2005, Mege et al., 2003) and old-age cognitive changes (in the United States) (Ruehl et al., 1998, Kitani et al., 2002, Landsberg, 2005). All work was done in compliance with the Good Clinical Practices guidelines (European Directive 92/18/CEE and European Directive III/3767/92).

Anxiety in dogs is an important issue. Although the definition of anxiety varies among studies, all authors agree that anxiety does exist in dogs. Pageat, 1995, Pageat, 1998 has defined anxiety as an emotional state characterized by an increase in the probability of fear-like emotional reactions being triggered in response to any change in the internal or external environment. This emotional state leads to a loss of self-control and adaptability. Based on our own records of more than 2,700 cases, anxious states account for up to 70% of all behavioral disorders occurring in dogs.

Anxiety in dogs is not only a psychological issue. The first signs of an anxious state often include visceral reactions. Many human and veterinary studies have been published about the relationships between dermatologic signs and anxiety (Hashiro and Okumura, 1997, Mege, 1997, Virga, 2003), gastro-intestinal signs and anxiety (Longstreth and Wolde-Tsadik, 1993, Levenstein, 1999, Marion, 2002), neurologic signs such as seizures and anxiety, and cardio-respiratory signs and anxiety (Pedersen et al., 1995, Yang et al., 1997, Toren et al., 1999, Tamam et al., 2000, Couture, 2001). Given this pattern, all veterinarians should be interested in relieving anxious states because they are often faced with the consequences of these states in their daily practice.

The management of anxiety is a challenge for veterinarians. To be as effective and efficient as possible an integrated treatment should include behavior modification targeting the roots of the anxiety-provoking situation, whenever possible, and the use of biologic agents (psychotropic drugs, pheromones, and nutraceuticals). Many veterinarians do not use biologic agents as a routine part of their treatment. This is regrettable because if we go back to our definition of anxiety, anxiety leads to a loss of adaptability. The use of biologic compounds may be the best way to quickly decrease the manifestation of the signs of anxiety while also increasing the plasticity or ability of the brain to learn a new set of reactions. This is why concurrent use of biologic agents and behavioral modification is so important. It is important that practitioners know and can explain relative side effects of all interventions involved. ‘Natural’ compounds are widely viewed to have fewer side effects, so owners may see these as welcome choice. Alpha-casozepine is worth studying more closely because it has the following advantages:

  • Safety

    • It is a naturally occurring decapeptide, it has been classified as food, and has therefore been given GRAS (Generally Recognized As Safe) status by the FDA in a self declaration process (FDA-21 CFR §184.1553; NDI #rpt242).

  • Efficacy

    • Experimental studies on rats have shown alpha-casozepine to be as efficacious as the control molecule, diazepam, on experimental models of anxiety such as those obtained using the conditioned defensive burying (CDB) paradigm and the elevated-plus maze paradigm (Schroeder et al., 2003, Violle et al., 2006).

    • Tests on healthy volunteers have shown that this substance can be used to prevent the physiologic effects of acute or chronic stress (Lanoir et al., 2002, Messaoudi et al., 2002, Messaoudi et al., 2005).

    • Initial studies on cats have yielded statistically significant results on the use of this molecule to control anxiety induced by social exposure (Beata et al., 2005, Beata et al., 2007).

Section snippets

Materials and methods

A multi-centre, French GCP-conducted, randomized, comparative trial was designed to compare the effects between alpha-casozepine at the daily dosage of 15 mg/kg by mouth every 24 h and the control molecule, selegiline hydrochloride at the daily dosage of 0.5 mg/kg by mouth every 24 h.

Methods

A case number was assigned to every dog that fulfilled the above requirements. This number determined what treatment would be given according to the treatment scheme (Table 2). To ensure that a blind protocol was applied, the selegiline and alpha-casozepine were packaged in 3 different kinds of capsules (25 mg, 75 mg, or 200 mg of alpha-casozepine or 0.75 mg, 2.5 mg, or 6.5 mg of selegiline hydrochloride). The treatment scheme ensured that the choice of drug was equally balanced across each

Results

Nineteen animals received each treatment.

Conclusion

Alpha-casozepine, a non-pharmaceutical compound, seems to be effective in treating anxiety in dogs and other species suffering from anxiety-related conditions (Beata et al., 2005, Violle et al., 2006). In this blinded study, the effects of treatment with selegiline and alpha-casozepine were shown to be equally effective.

For clients who worry about any potential side effects, the GRAS status of alpha-casozepine may provide reassurance. In this study, we had no adverse effect that is consistent

Acknowledgments

The authors thank Ingredia SA for sponsoring this study. They also want to thank all dogs and owners included in the study.

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