ResearchEffect of alpha-casozepine (Zylkene) on anxiety in cats
Introduction
Feline medicine is a growing field in which behavioral disorders are becoming better known every day. Cats are sometimes described as more territorial animals than social ones (Beata, 2005). Other authors postulate that cats have complex social interactions (Crowell-Davis et al 2004, Curtis et al 2003). Inadequate contact with unfamiliar people and uncontrolled access to other cats have been postulated as a classical factor of stress for this species (Carlstead et al., 1993).
Cats can exhibit many different signs related to their anxious state. Urine spraying, compulsive licking, and aggressive behaviors are some of the most obvious signs of stress and anxiety in cats (Pryor et al., 2001). Cat owners are often very sensitive to these behaviors and may wish to treat these cats, but they do not wish to use psychotropic drugs. If a nonpharmaceutical, natural biological compound were available, many owners would choose to use it.
Cow’s milk has long been considered a beverage with natural “tranquillizing” properties. Research has shown that some of the peptides present in the milk may have a calming effect (Brezinova and Oswald, 1972). This calming effect has been observed in babies and has been hypothesized to be associated with the specific way in which milk is digested by babies. Trypsin is more common in babies’ digestions, whereas pepsin is more active in adults.
Alpha-S1 casein is one of the major proteins in cows’ milk. Preliminary studies have demonstrated that many of the peptides that make up this protein have strong biological properties, including effects on opioid and immunologic systems (Morley et al 1985, Biziulevicius et al 2003, Sakaguchi et al 2003). The tryptic hydrolysis of the alpha-S1 casein produces a decapeptide whose spatial structure is known. This structure allows the decapeptide to fit into a segment of the GABA-B receptor thought to be responsible for anxiolytic activity (Lecouvey et al 1997a, Lecouvey et al 1997b).
The conditioned defensive burying paradigm (CDB) is a classic test to screen drugs for potential anxiolytic activity in rodents. Rats bury aversive stimuli, and burying activity can be linked with anxiety response (Pinel and Treit, 1978). Rats bury the electrode when they are under stress, and treatment with anxiolytics prevents burying behavior. This test is sensitive, as it allows for discrimination between any anxiolytic effect and an effect on general activity. The CDB paradigm has been validated as a test for clinical effects of anxiolytics (Treit et al., 1981). The strength of the response to the electrode can also be measured (Rohmer et al., 1990).
Alpha-casozepine was first tested in male Wistar rats (Rattus norvegicus). Using the CDB model, treatment with alpha-casozepine has been shown to be as effective as the reference molecule, diazepam. Neither an increase in aggression to cagemates nor a loss of working memory was seen with treatment with alpha-casozepine, but these effects have been noted for benzodiazepines (Schroeder et al., 2003). Similar results were found for rodents tested with the elevated-plus maze paradigm, another test used to evaluate putative anxiolytic effects of drugs (Violle et al., 2006).
Alpha-casozepine has been used in people with acute and chronic anxiety models. All studies were conducted according to Good Clinical Practices (GCP), and the designs of these studies were approved by an ethical committee (CCPPRB), as would be true for a drug trial. In both the cold pressure test and the Stroop test, 2 old but consistent anxiety tests in human beings, treatment with alpha-casozepine showed statistically significant effects (Lanoir et al 2002, Messaoudi et al 2002, Messaoudi et al 2005). Based on these results, it seemed logical to test this product on companion animals (e.g., dogs and cats) experiencing stressful conditions.
The role of anxiety in behavioral disorders of cats has been discussed (Houpt 1998, Horwitz and Landsberg 1998, Overall 1997). Composition of social groups within any given environment has been shown to be important to cats (Turner and Bateson 2000, Curtis et al 2003, Crowell-Davis et al 2004). Any modification to their living area and social environment can be stressful for cats and has been associated with various anxiety-related conditions, including obsessive-compulsive disorders (Overall and Dunham, 2002). Cats also have strong relationships with people (Beata, 2001), and separation anxiety has been described in this species (Schwartz 2002, Schwartz 2003). We define social phobia in cats as the situation where the cat disappears when a human or another cat enters the territory occupied by the cat, and during which the cat exhibits aggression or signs associated with autonomic activity. Social phobia, as defined here, is one of the main complaints of cat owners.
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Subjects, Materials, and Methods
A European multicentric, randomized, double-blind, placebo-controlled trial conducted according to GCP was designed to evaluate the efficacy of alpha-casozepine as an anxiolytic in cats. Cats were selected from general or specialist practices. Investigators ensured that cats were not subjected to inadequate living conditions. Inclusion criteria were based on a behavioral scale validated among the investigators, who were all behaviorist veterinary surgeons (Table 1).
Prior to including the first
Results
Thirty-four (34) cats were enrolled in and completed the trial. Accordingly, random assignment of cats resulted in 17 cats in each treatment group (placebo and alpha-casozepine).
Discussion
This study provides evidence for the efficacy of alpha-casozepine in the management of cats exhibiting anxiety in socially stressful conditions. Cats treated with alpha-casozepine sought contact with both familiar and unfamiliar people and showed improvement in fearful behaviors and in their associated autonomic signs.
No differences were seen in aggressive behaviors, but the study was relatively small. Behavior modification seemed to help manage or avoid the aggression, based on the data from
Conclusion
Alpha-casozepine, patented under the name of Zylkene (Ingredia, Arras, France), is a very interesting alternative in the management of anxiety in cats. In preclinical studies, it appears safe, and it is lactose free, making it suitable for most cats.
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