Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination of Scutellaria Extract and Acacia Extract in Rats

Young Chul Lee, Eujin Hyun, Mesfin Yimam, Lidia Brownell, Qi Jia

Unigen Inc., Cheonan, South Korea.
Unigen Inc., Seattle, USA.
Unigen Inc., Seattle, USA..

DOI: 10.4236/fns.2013.47A003                

Abstract

UP446 has been used in both joint supplements and prescription medical food. The purpose of this study was to evaluate the pharmaceutical safety of UP446 via acute and 26-week repeated oral dose toxicity study in SD rats. In acute toxicity study, UP446 was administered by oral gavage to Sprague-Dawley rats (5 males and 5 females) at a dose of 5000 mg/kg. In 26-week repeated oral dose toxicity study, UP446 at doses of 500, 1000 and 2000 mg/kg/day were given orally to groups of rats (10 rats/dose/sex) for 26-week. UP446 at a dose of 5000 mg/kg produced no treatment-related acute toxicity or mortality in any of the animals tested during 14 days of the study. In 26-week repeated dose toxicity study, there was no significant difference in body weight between the control and all treatment groups. Blackish stool and soft stool was observed in one male in the 1000 mg/kg group and in some males and females of 2000 mg/kg group. However, these changes of stool were not considered to be toxic effects because neither histopathological change in gastrointestinal tracks (GIT) nor body weight change were detected. No drug induced abnormalities were found as of body weights, food consumption, ophthalmological examinations, urinalysis, hematology, clinical chemistry, organ weights and gross necropsy in any animals in the dosing groups. These results suggest that the oral lethal dose of UP446 for male and female rats is in excess of 5000 mg/kg and the no observed adverse effect level (NOAEL) of the UP446 for both male and female rats is considered to be greater than 2000 mg/kg/day.

Keywords

Scutellaria baicalensis; Acacia catechu; Acute Oral Toxicity; Repeated Oral Toxicity

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	M. Modak, P. Dixit, J. Londhe, S. Ghaskadbi and T. P. Devasagayam, “Indian Herbs and Herbal Drugs Used for Treatment of Diabetes,” Journal of Clinical Biochemistry and Nutrition, Vol. 40, No. 3, 2007, pp. 163-173. doi:10.3164/jcbn.40.163
[2]	R. Morphy, C. Kay and Z. Rankovic, “From Magic Bullets to Designed Multiple Ligands,” Drug Discovery Today, Vol. 9, No. 15, 2004, pp. 641-651. doi:10.1016/S1359-6446(04)03163-0
[3]	P. A. Tatke, I. S. Nidhiya and S. G. Deshpande, “Safety Profile of Polyherbal Formulation in Female Rats by Subchronic Oral Ttoxicity Study,” Toxicology International, Vol. 19, No. 2, 2012, pp. 106-111. doi:10.4103/0971-6580.97196
[4]	P. G. Shekelle, S. C. Morton, M. J. Suttorp, N. Buscemi and C. Friesen, “Challenges in Systematic Reviews of Complementary and Alternative Medicine Topics,” Annals of Internal Medicine, Vol. 142, No. 12, 2005, pp. 1042-1047. doi:10.7326/0003-4819-142-12_Part_2-200506211-00003
[5]	R. Kroes and R. Walker, “Safety Issues of Botanicals and Botanical Preparations in Functional Foods,” Toxicology, Vol. 198, No. 1-3, 2004, pp. 213-220. doi:10.1016/j.tox.2004.01.028
[6]	E. Middleton, C. Kandaswami and T. C. Theoharides, “The Effects of Plant Flavonoids on Mammalian Cells: Implications for Inflammation, Heart Disease, and Cancer,” Pharmacological Review, Vol. 52, No. 4, 2000, pp. 673-751.
[7]	M. M. Cowan, “Plant Products as Antimicrobial Agents,” Clinical Microbiology Reviews, Vol. 12, No. 4, 1999, pp. 564-582.
[8]	P. Knekt, J. Kumpulainen, R. Jarvinen, H. Rissanen, M. Heliovaara, A. Reunanen, T. Hakulinen and A. Aromaa, “Flavonoid Intake and Risk of Chronic Diseases,” The American Journal of Clinical Nutrition, Vol. 76, No. 3, 2002, pp. 560-568.
[9]	L. Fu, B. T. Gan, Y. Zhang, X. R. Xu, E. Q. Xia and H. B. Li, “Total Phenolic Contents and Antioxidant Capacities of Herbal and Tea Infusions,” International Journal of Molecular Sciences, Vol. 12, No. 4, 2011, pp. 2112-2124. doi:10.3390/ijms12042112
[10]	Y. J. Moon, X. Wang and M. E. Morris, “Dietary Flavonoids: Effects on Xenobiotic and Carcinogen Metabolism,” Toxicological in Vitro, Vol. 20, No. 2, 2006, pp. 187-210. doi:10.1016/j.tiv.2005.06.048
[11]	T. G. Razina, S. N. Udintsev, I. I. Titutrin, T. G. Borovskaia and K. V. Iaremenko, “The Role of Thrombocyte Aggregation Function in the Mechanism of the Antimetastatic Action of an Extract of Baikal Skullcap,” Voprosy Onkologii, Vol. 35, No. 3, 1989, pp. 331-335.
[12]	N. Mahmood, C. Pizza, R. Aquino, N. De Tommasi, S. Piacente, S. Colman, A. Burke and A. J. Hay, “Inhibition of HIV Infection by Flavonoids,” Antiviral Research, Vol. 22, No. 2-3, 1993, pp. 189-199. doi:10.1016/0166-3542(93)90095-Z
[13]	I. M. Van Loon, “The golden Root: Rlinical Applications of Scutellaria Baicalensis GEORGI Flavonoids as Modulators of the Inflammatory Response,” Alternative Medicine Review, Vol. 2, No. 6, 1992, pp. 472-480.
[14]	B. H. Lee, S. J. Lee, T. H. Kang, D. H. Kim, D. H. Sohn, G. I. Ko and Y. C. Kim, “Baicalein: An in Vitro Antigenotoxic Compound from Scutellaria Baicalensis,” Planta Medica, Vol. 66, No. 1, 2000, pp. 70-71. doi:10.1055/s-0029-1243111
[15]	S. Shigeta, “Recent Progress in Antiviral Chemotherapy for Respiratory Syncytial Virus Infections,” Expert Opinion on Investigational Drugs, Vol. 9, No. 2, 2000, pp. 221-235. doi:10.1517/13543784.9.2.221
[16]	E. De Clercq, “Current Lead Natural Products for the Chemotherapy of Human Immunodeficiency Virus (HIV) Infection,” Medicinal Research Reviews, Vol. 20, No. 5, 2000, pp. 323-349. doi:10.1002/1098-1128(200009)20:5<323::AID-MED1>3.0.CO;2-A
[17]	Y. Huang, S. Y. Tsang, X. Yao and Z. Y. Chen, “Biological Properties of Baicalein in Cardiovascular System,” Current Drug Targets Cardiovascular & Haematological Disorder, Vol. 5, No. 2, 2005, pp. 177-184. doi:10.2174/1568006043586206
[18]	B. P. Burnett, Q. Jia, Y. Zhao and R. M. Levy, “ A Medicinal Extract of Scutellaria baicalensis and Acacia catechu Acts as a Dual Inhibitor of Cyclooxygenase and 5Lipoxygenase to Reduce Inflammation,” Journal of Medicinal Food, Vol. 10, No. 3, 2007, pp. 442-451. doi:10.1089/jmf.2006.255
[19]	S. L. Morgan, J. E. Baggott, L. Moreland, R. Desmond and A. C. Kendrach, “The Safety of Flavocoxid, a Medical Food, in the Dietary Management of Knee Osteoarthritis,” Journal of Medicinal Food, Vol. 12, No. 5, 2009, pp. 1143-1148. doi:10.1089/jmf.2008.0244
[20]	J. S. Sampalis and L. A. Brownell, “A Randomized, Double Blind, Placebo and Active Comparator Controlled Pilot Study of UP446, a Novel Dual Pathway Inhibitor Anti-Inflamatory Agent of Botanical Origin,” Nutrition Journal, Vol. 11, 2012, p. 21.
[21]	B. P. Burnett, S. Silva, M. H. Mesches, S. Wilson and Q. Jia, “Safety Evaluation of a Combination, Defined Extract of Scutellaria Baicalensis and Acacia Catechu,” Journal of Food Biochemistry, Vol. 31, No. 6, 2007, pp. 797-825. doi:10.1111/j.1745-4514.2007.00142.x
[22]	M. Yimam, L. Brownell, M. Hodges and Q. Jia, “Analgesic Effects of Standardized Bioflavonoid Composition from Scutellaria Baicalensis and Acacia Catechu,” Journal of Dietary Supplements, Vol. 9, No. 3, 2012, pp. 155165. doi:10.3109/19390211.2012.708713
[23]	M. Yimam, Y. Zhao, W. Ma, Q. Jia, S. G. Do and J. H. Shin, “90 Day Oral Toxicity Study of UP446, a Combination of Defined Extracts of Scutellaria Baicalensis and Acacia Catechu, in Rats,” Food and Chemical Toxicology, Vol. 48, No. 5, 2012, pp. 1202-1209. doi:10.1016/j.fct.2010.02.011
[24]	Q. Jia, “Formulation of a Mixture of Free-B-Ring Flavonoids and Flavans as a Therapeutic Agent,” US Patent No. 7514469, 2009.
[25]	A. A. Adeneyea, O. P. Ajagbonna, T. I. Adeleke and S. O. Bello, “Preliminary Toxicity and Phytochemical Studies of the Stem Bark Aqueous Extract of Musanga Cecropioides in Rats,” Journal of Ethnopharmacology, Vol. 105, No. 3, 2006, pp. 374-379. doi:10.1016/j.jep.2005.11.027
[26]	C. Bombardier, L. Laine, A. Reicin, D. Shapiro, R. Burgos-Vargas, B. Davis, R. Day, M. B. Ferraz, C. J. Hawkey, M. C. Hochberg, T. K. Kvien and T. J. Schnitzer, “Comparison of upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis,” The New England Journal of Medicine, Vol. 343, No. 21, 2000, pp. 1520-1528. doi:10.1056/NEJM200011233432103
[27]	R. S. Bresalier, V. E. Friedewald Jr., R. E. Rakel, W. C. Roberts and G. W. Williams, “The Editor’s Roundtable: Cyclooxygenase-2 Inhibitors and Cardiovascular Risk,” The American Journal of Cardiology, Vol. 96, No. 11, 2005, pp. 1589-1604. doi:10.1016/j.amjcard.2005.09.069
[28]	G. A. Elliott, A. Purmalis, D. A. VanderMeer and R. H. Denlinger, “The Propionic Acids. Gastrointestinal Toxicity in Various Species,” Toxicologic Pathology, Vol. 16, No. 2, 1988, pp. 245-250. doi:10.1177/019262338801600217
[29]	K. S. Mota, G. E. Dias, M. E. Pinto, A. Luiz-Ferreira, A. R. Souza-Brito, C. A. Hiruma-Lima, J. M. Barbosa-Filho and L. M. Batista, “Flavonoids with Gastroprotective Activity,” Molecules, Vol. 14, No. 3, 2009, pp. 979-1012. doi:10.3390/molecules14030979
[30]	A. A. Adeneyea, O. P. Ajagbonna, T. I. Adeleke and S. O. Bello, “Preliminary Ttoxicity and Phytochemical Studies of the Stem Bark Aqueous Extract of Musanga Cecropioides in Rats,” Journal of Ethnopharmacology, Vol. 105, No. 3, 2006, pp. 374-379. doi:10.1016/j.jep.2005.11.027
[31]	L. Johnson, C. S. Petty and W. B. Neaves, “A Comparative Study of Daily Sperm Production and Testicular Composition in Humans and Rats,” Biology of Reproduction, Vol. 22, No. 5, 1980, pp. 1233-1243.