Safety evaluation of a new anxiolytic product containing botanicals souroubea spp. and platanus spp. In dogs(Article)

Canadian Journal of Veterinary ResearchVolume 82, Issue 1, January 2018, Article number 9, Pages 3-11 Masic, A.aEmail Author, Liu, R.b, Simkus, K.c, Wilson, J.c, Baker, J.d, Sanchez, P.e, Saleem, A.b, Harris, C.C.b, Durst, T.b, Arnason, J.T.b View Correspondence (jump link) aFaculty of Ecological Agriculture, Educons University, Sremska Kamenica, Serbia bFaculty of Science, University of Ottawa, Ottawa, ON, Canada cNovometrix Research, Moffat, ON, Canada View additional affiliations Abstract View references (30) Separation anxiety and noise aversion are common behavioral problems in dogs. They elicit fear responses such as cowering, seeking out the owner, and attempting to escape. This can result in property damage, injury to the dog, and disruption of the owner-pet bond, possibly leading to pet abandonment or euthanasia. A novel botanical anxiolytic product was evaluated for safety in dogs as the target animal species. Its intended use is for the treatment and prevention of anxiety and noise aversion in dogs. It contains a defined mixture of Souroubeaspp. vine and Platanus spp. bark, delivering the active principle, betulinic acid, at a recommended dose of 1 mg/kg body weight (BW). In the current target animal safety study, 16 healthy male beagle dogs were administered either a placebo or the newly formulated botanical tablets at 0.5×, 2.5×, or 5× the recommended dose (1 mg/kg BW) over 28 d. The dogs were monitored for occurrence of any systemic or local adverse events. In the investigation presented here, there were no clinically significant adverse effects following treatment, as determined by clinical observations, physical examinations, BW, hematology, clinical biochemistry, and urinalysis. Pharmacokinetic analysis demonstrated that the concentration of betulinic acid in serum was below 0.020 μg/mL in treated animals. Under the conditions of these studies, the formulated blend of S. sympetala and P. occidentalis, when administered up to 5× the intended dose for 28 consecutive d, showed no adverse effects on the health of dogs. © 2018, Canadian Veterinary Medical Association. All rights reserved. Indexed keywords EMTREE drug terms: anxiolytic agentbetulic acidmicrocrystalline celluloseplaceboplant extractPlatanus extractSouroubea extractunclassified drug EMTREE medical terms: acclimatizationamylase blood levelanimal experimentanimal modelanimal tissueanxietyArticleaspartate aminotransferase levelaversionbehavior changebiochemistrybody weightclinical evaluationcontrolled studycreatine kinase blood levelcreatinine blood leveldogdrug formulationdrug safetyerythrocytegamma glutamyl transferase blood levelglucose blood levelhematocrithematologyhigh performance liquid chromatographyinjuryleukocyte countleukocyte differential countmalemass spectrometrymean corpuscular hemoglobinmean corpuscular volumeneurologic examinationnoisenonhumanprotein blood levelSoxhlet extractionurinalysis Chemicals and CAS Registry Numbers: betulic acid, 472-15-1; microcrystalline cellulose, 39394-43-9, 51395-75-6 Funding details Funding number Funding sponsor Acronym Funding opportunities I2I Natural Sciences and Engineering Research Council of Canada NSERC See opportunities by NSERC Amorfix Life Sciences AMF Life Sciences Research Foundation LSRF Amorfix Life Sciences AMF Funding text #1 Funding was provided by the Natural Sciences and Engineering Research Council of Canada (I2I and CRD grant programs) and by Bioniche Life Sciences (Belleville, Ontario, Canada). The target animal safety study was conducted by Kingfisher International, a contract research facility in Stouffville, Ontario. It was supervised by Dr. Jonathan Hare and reported by Ms. Jennifer Caldwell. Funding text #2 Financial support was provided by Bioniche Life Sciences to Novometrix Research and to Paul Dick and Associates for their work. Since the corporate reorganization of Bioniche Life Sciences, leading to the sale of veterinary technologies, the product has been licensed to Souroubea Botanicals and several of the authors are principals in the new company (Arnason, Baker, Durst, Sanchez). Dr. Masic was employed by Bioniche Life Sciences at the time of study execution. ISSN: 08309000 CODEN: CJVRE Source Type: Journal Original language: English Document Type: Article Publisher: Canadian Veterinary Medical Association References (30) View in search results format All 1 Sherman, B.L., Mills, D.S. Canine Anxieties and Phobias: An Update on Separation Anxiety and Noise Aversions (2008) Veterinary Clinics of North America - Small Animal Practice, 38 (5), pp. 1081-1106. Cited 70 times. doi: 10.1016/j.cvsm.2008.04.012 View at Publisher 2 Shull-Selcer, E.A., Stagg, W. Advances in the understanding and treatment of noise phobias (1991) Veterinary Clinics of North America - Small Animal Practice, 21 (2), pp. 353-367. Cited 33 times. doi: 10.1016/S0195-5616(91)50038-3 View at Publisher 3 Thompson, S.B. Pharmacologic treatment of phobias (1998) Psychopharmacology of Animal Behavior Disorders, pp. 141-182. Cited 14 times. Dodman NH, Shuster L, eds., Malden, Massachusetts: Blackwell Science 4 Dreschel, N.A. The effects of fear and anxiety on health and lifespan in pet dogs (2010) Applied Animal Behaviour Science, 125 (3-4), pp. 157-162. Cited 36 times. doi: 10.1016/j.applanim.2010.04.003 View at Publisher 5 Puniani, E., Cayer, C., Kent, P., Mullally, M., Sánchez-Vindas, P., Poveda Álvarez, L., Cal, V., (...), Durst, T. Ethnopharmacology of Souroubea sympetala and Souroubea gilgii (Marcgraviaceae) and identification of betulinic acid as an anxiolytic principle (2015) Phytochemistry, 113, pp. 73-78. Cited 6 times. http://www.journals.elsevier.com/phytochemistry/ doi: 10.1016/j.phytochem.2014.02.017 View at Publisher 6 Mullally, M., Kramp, K., Cayer, C., Saleem, A., Ahmed, F., McRae, C., Baker, J., (...), Arnason, J.T. Anxiolytic activity of a supercritical carbon dioxide extract of Souroubea sympetala (Marcgraviaceae) (2011) Phytotherapy Research, 25 (2), pp. 264-270. Cited 15 times. doi: 10.1002/ptr.3246 View at Publisher 7 Carballo-Arce, A.F. (2013) Phytochemical Investigations of Costa Ricanmarcgraviaceae and Development of Insecticide Synergists [PhD, dissertation]. Ottawa, Ontario: University of Ottawa 8 Cayer, C. (2011) Vivo Behavioural Characterization of Anxiolytic. Cited 4 times. [MSc dissertation]. Ottawa, Ontario: University of, Ottawa 9 Mullally, M., Cayer, C., Kramp, K., Rojas, M.O., Vindas, P.S., Garcia, M., Alvarez, L.P., (...), Arnason, J.T. Souroubea sympetala (marcgraviaceae): A medicinal plant that exerts anxiolysis through interaction with the GABAA benzodiazepine receptor (2014) Canadian Journal of Physiology and Pharmacology, 92 (9), pp. 758-764. Cited 4 times. www.nrc.ca/cgi-bin/cisti/journals/rp/rp_desy_e?cjpp doi: 10.1139/cjpp-2014-0213 View at Publisher 10 Mullally, M. (2011) Anxiety-Reducing Tropical Plants: Phytochemicaland Pharmacological Characterization of Souroubea Sympetala Andpiper Amalago [PhD dissertation]. Ottawa, Ontario: University ofOttawa 11 Fujioka, T., Kashiwada, Y., Kilkuskie, R.E., Cosentino, L.M., Bailas, L.M., Jiang, J.B., Janzen, W.P., (...), Lee, K.-H. Anti-aids agents, 11. betulinic acid and platanic acid as anti-HIV principles from syzigium claviflorum, and the anti-HIV activity of structurally related triterpenoids (1994) Journal of Natural Products, 57 (2), pp. 243-247. Cited 347 times. doi: 10.1021/np50104a008 View at Publisher 12 Kashiwada, Y., Hashimoto, F., Cosentino, L.M., Chen, C.-H., Garrett, P.E., Lee -, K.H. Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents (1996) Journal of Medicinal Chemistry, 39 (5), pp. 1016-1017. Cited 220 times. doi: 10.1021/jm950922q View at Publisher 13 Mayaux, J.-F., Bousseau, A., Pauwels, R., Huet, T., Hénin, Y., Dereu, N., Evers, M., (...), Le Pecq, J. Triterpene derivatives that block entry of human immunodeficiency virus type 1 into cells (1994) Proceedings of the National Academy of Sciences of the United States of America, 91 (9), pp. 3564-3568. Cited 153 times. www.pnas.org doi: 10.1073/pnas.91.9.3564 View at Publisher 14 Mukherjee, P.K., Saha, K., Das, J., Pal, M., Saha, B.P. Studies on the anti-inflammatory activity of rhizomes of Nelumbo nucifera (1997) Planta Medica, 63 (4), pp. 367-369. Cited 148 times. doi: 10.1055/s-2006-957705 View at Publisher 15 Del Carmen Recio, M., Giner, R.M., Manez, S., Gueho, J., Julien, H.R., Hostettmann, K., Rios, J.L. Investigations on the steroidal anti-inflammatory activity of triterpenoids from Diospyros leucomelas (1995) Planta Medica, 61 (1), pp. 9-12. Cited 163 times. doi: 10.1055/s-2006-957988 View at Publisher 16 Pisha, E., Chai, H., Lee, I.-S., Chagwedera, T.E., Farnsworth, N.R., Cordell, G.A., Beecher, C.W.W., (...), Pezzuto, J.M. Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis (1995) Nature Medicine, 1 (10), pp. 1046-1051. Cited 615 times. doi: 10.1038/nm1095-1046 View at Publisher 17 Selzer, E., Pimentel, E., Wacheck, V., Schlegel, W., Pehamberger, H., Jansen, B., Kodym, R. Effects of betulinic acid alone and in combination with irradiation in human melanoma cells (Open Access) (2000) Journal of Investigative Dermatology, 114 (5), pp. 935-940. Cited 122 times. http://www.nature.com/jid/index.html doi: 10.1046/j.1523-1747.2000.00972.x View at Publisher 18 Zuco, V., Supino, R., Righetti, S.C., Cleris, L., Marchesi, E., Gambacorti-Passerini, C., Formelli, F. Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells (2002) Cancer Letters, 175 (1), pp. 17-25. Cited 328 times. doi: 10.1016/S0304-3835(01)00718-2 View at Publisher 19 Fulda, S., Debatin, K.-M. Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors (2000) Medical and Pediatric Oncology, 35 (6), pp. 616-618. Cited 116 times. doi: 10.1002/1096-911X(20001201)35:6<616::AID-MPO27>3.0.CO;2-N View at Publisher 20 Ramadoss, S., Jaggi, M., Siddiqui, M.J.A. (2000) Use of Betulinic Acid Andits Derivatives for Inhibiting Cancer Growth and a Method Ofmonitoring This. Cited 2 times. U.S. Patent 6048847 A filed March 18, 1998, and, issued April 11 21 Schühly, W., Heilmann, J., Çalis, I., Sticher, O. New triterpenoids with antibacterial activity from Zizyphus joazeiro (1999) Planta Medica, 65 (8), pp. 740-743. Cited 51 times. http://www.thieme-connect.com/ejournals/toc/plantamedica doi: 10.1055/s-1999-14054 View at Publisher 22 Chandramu, C., Manohar, R.D., Krupadanam, D.G.L., Dashavantha, R.V. Isolation, characterization and biological activity of betulinic acid and ursolic acid from Vitex negundo L. (2003) Phytotherapy Research, 17 (2), pp. 129-134. Cited 97 times. doi: 10.1002/ptr.1088 View at Publisher 23 Schultes, R.E., Raffauf, R.F. (1990) The Healing Forest: Medicinal Andtoxic Plants of the Northwest Amazonia. Cited 257 times. Portland, Oregon:, Dioscorides Press 24 Bourbonnais-Spear, N., Awad, R., Merali, Z., Maquin, P., Cal, V., Arnason, J.T. Ethnopharmacological investigation of plants used to treat susto, a folk illness (2007) Journal of Ethnopharmacology, 109 (3), pp. 380-387. Cited 28 times. doi: 10.1016/j.jep.2006.08.004 View at Publisher 25 Bourbonnais-Spear, N., Poissant, J., Cal, V., Arnason, J.T. Culturally important plants from Southern Belize: Domestication by Q'eqchi' Maya healers and conservation (2006) Ambio, 35 (3), pp. 138-140. Cited 6 times. doi: 10.1579/0044-7447(2006)35[138:CIPFSB]2.0.CO;2 View at Publisher 26 Arnason, T., Hebda, R.J., Johns, T. Use of plants for food andmedicine by Native Peoples of eastern Canada (1981) Can J Bot, 59, pp. 2189-2325. Cited 113 times. 27 Hamel, P.B., Chiltoskey, M.U. (1975) Cherokee Plants and Their Uses:, pp. 1-52. Cited 76 times. Sylva, NC: Herald Publishing 28 Villalobos, P., Baker, J., Sanchez Vindas, P., Durst, T., Masic, A., Arnason, T.J. Clinical observations and safety profile of oral herbal products, souroubea and platanus spp; A pilot-toxicology study in dogs (2014) Acta Veterinaria, 64 (2), pp. 269-275. Cited 3 times. http://www.degruyter.com/dg/viewjournalissue.articlelist.resultlinks.fullcontentlink:pdfeventlink/002fj002facve.2014.64.issue-2002facve-2014-0025002facve-2014-0025.pdf?t:ac=j002facve.2014.64.issue-2002fissue-files002facve.2014.64.issue-2.xml doi: 10.2478/acve-2014-0025 View at Publisher 29 Godugu, C., Patel, A.R., Doddapaneni, R., Somagoni, J., Singh, M. Approaches to improve the oral bioavailability and effects of novel anticancer drugs berberine and betulinic acid (Open Access) (2014) PLoS ONE, 9 (3), art. no. e89919. Cited 41 times. http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0089919&representation=PDF doi: 10.1371/journal.pone.0089919 View at Publisher 30 Udeani, G.O., Zhao, G.-M., Shin, Y.G., Cooke, B.P., Graham, J., Beecher, C.W.W., Kinghorn, A.D., (...), Pezzuto, J.M. Pharmacokinetics and tissue distribution of betulinic acid in CD-1 mice (1999) Biopharmaceutics and Drug Disposition, 20 (8), pp. 379-383. Cited 54 times. doi: 10.1002/1099-081X(199911)20:8<379::AID-BDD198>3.0.CO;2-C View at Publisher Masic, A.; Faculty of Ecological Agriculture, Educons University, Sremska Kamenica, Serbia; email:aleksander.masic@educons.edu.rs © Copyright 2018 Elsevier B.V., All rights reserved.