Evaluation of safety of the herbal formula Ojeok-san: Acute and sub-chronic toxicity studies in rats
Graphical abstract
Introduction
Medicinal herbs are used for the prevention and treatment of diseases, and have a long history. However, the most commonly used herbal formulae have no indications of quality, safety and efficacy (Firenzuoli and Gori, 2007, Wang et al., 2009). Since 1990, 56 traditional herbal formulae have been supplied by the National Health Insurance Corporation (NHIC) in Korea. Of these 56 herbal prescriptions, Ojeok-san (OJS; wuji powder in China and goshaku-san in Japan) is first in ‘days of medication’ and ‘medical expenses’ over the last 20 years. It occupied 19% of the total ‘days of medication’ and 33% of the total ‘medical expenses’ in the ‘Oriental health treatments by 56 Prescription’ in 2008 (National Health Insurance Corporation, 2009). OJS has been used to treat the common cold and illness including fatigue and gastrointestinal disorders, among others. It has been reported that OJS has a variety of pharmacological activities such as analgesic, anti-pyretic, anti-phlogistic, anti-hyperlipidemic, anti-tumor and anti-blood stasis activity (Han and Lee, 1984, Park and Chae, 1992, Moon and Park, 1994, Jeon et al., 2003, Kim et al., 2004, Lee et al., 2008), however, there is very little information on its safety.
As a part of a safety evaluation of OJS, acute and sub-chronic oral dose toxicity studies were conducted to investigate the potential toxicity after single or 13-week repeated oral dosing of OJS in Sprague-Dawley rats. The present study was carried out in compliance with the Good Laboratory Practice (GLP) and Test Guidelines of the Organization for Economic Cooperation and Development (OECD, 1997) and the Korea Food and Drug Administration (KFDA, 2005a, KFDA, 2005b).
Section snippets
Preparation of Ojeok-san (OJS) extract
Seventeen constituents of OJS (Table 1) were chopped, mixed and extracted with water at 100 °C for 120 min in an herb extractor (COSMOS–660, KyungSeo Machine Co., Incheon, Korea) and filtered. The aqueous extract was lyophilized with a freeze drier (PVTFD100R, Ilshin Lab. Ltd., Korea) to yield a brown powder (yield of extract = 21.0%). Powders of OJS extract were stored at 4 °C.
Profiling the chemical contents of OJS by HPLC
The chemicals used for the identification and quantification of compounds in the OJS extract included the following:
Acute oral toxicity in rats
There were no animal deaths in any of the groups. Therefore, the approximate lethal dose of OJS extract in male and female rats was higher than 2000 mg/kg. Clinical signs observed included a loss of fur in 1/5 males from day 11 and 2/5 females from day 4 in the OJS 2000 mg/kg group. Normal body weight gains were observed in males and females of all dose groups (Fig. 2). No significant differences were observed between the vehicle control and OJS treatment groups. No abnormal gross findings were
Discussion
Complementary and alternative medicines (CAMs) such as herbal remedies require an influential and deep evaluation of their efficacies and safety due to their growing use all over the world (Firenzuoli and Gori, 2007, Lynch and Berry, 2007, Jordan et al., 2010). The increasing use of CAM is due to a variety factors, including limitations of current therapy and adverse effects of conventional drugs. Traditional herbal medicine is the most important part of CAM and has been practiced for thousands
Acknowledgement
This research was supported by a grant ‘The Evidence-based Medicine for herbal formulae’ from Korea Institute of Oriental Medicine (KIOM).
References (23)
- et al.
Assessment of herbal medicinal products: challenges, and opportunities to increase the knowledge base for safety assessment
Toxicology and Applied Pharmacology
(2010) - et al.
Subchronic toxicity of plant sterol esters administered by gavage to Sprague-Dawley rat
Food and Chemical Toxicology
(2002) - et al.
Differences in perceived risks and benefits of herbal, over-the-counter conventional, and prescribed conventional, medicines, and the implications of this for the safe and effective use of herbal products
Complementary Therapies in Medicine
(2007) - et al.
Toxicodynamics of subacute co-exposure to groundwater contaminant arsenic and analgesic–antipyretic drug acetaminophen in rats
Ecotoxicology and Environmental Safety
(2010) - et al.
Quality and safety of Chinese herbal medicines guided by a systems biology perspective
Journal of Ethnopharmacology
(2009) - et al.
Long-term effects of cage-cleaning frequency and bedding type on laboratory rat health, welfare, and handleability: a cross-laboratory study
Laboratory Animals
(2006) - et al.
Systematic review of Chinese herbal medicine for functional constipation
World Journal Gastroenterology
(2009) The Toxicologist's Pocket Handbook
(2008)- et al.
Herbal medicine today: clinical and research issues
Evidence Based Complement and Alternative Medicine
(2007) - et al.
Clinical Laboratory Parameters for Crl:CD (SD) Rats
(2006)
Study on the effects of Ojeogsan water extract upon antipyresis & analgesia
Journal of Korean Oriental Medicine
Cited by (24)
Safety assessment of Gyejibokryeong-hwan water extract: Study of acute and subacute toxicity, and influence on drug metabolizing enzymes
2019, Journal of EthnopharmacologyCitation Excerpt :The weight of the rats was measured immediately before initiation of dosing (day 1) and on days 2, 4, 8, and 15 using an electronic balance (Sartorius Co., Gottingen, Germany). On day 15, all rats were euthanized by exsanguination from the abdominal aorta and abdominal vena cava under CO2 anesthesia and observed for abnormality in the internal organs as described previously (Ha et al., 2010). GBHW did not cause animal death or abnormal responses or body weight change following a single dose in the acute toxicity study.
Six months chronic toxicological evaluation of naringin in Sprague-Dawley rats
2014, Food and Chemical ToxicologyCitation Excerpt :A study (Kim et al., 1998) reported that naringenin showed relatively low toxicity in the human hepatoma cell line HepG2, Macacus’ rhesus monkey kidney cell line MA-104, and human lung cancer cell line A549. Although a few studies have already revealed the chronic toxicity studies of naringin or herbal extracts which were contained naringin using rat models, there are no appropriated studies for the derivation of a NOAEL for pure compound naringin until recently (Ha et al., 2010; EFSA Panel on Additives and Products or Substances used in Animal Feed, 2011). An interim finding by EFSA, a Scientific Panel concerned with Food Contact Materials, Enzymes, Flavorings and Processing Aids, evaluated that it is considered safe for use in food (EFSA Panel on Additives and Products or Substances used in Animal Feed, 2011); however, more data relevant to safety assessment of naringin or naringenin is desirable.
Cardiovascular Effects of Hesperidin: A Flavanone Glycoside
2013, Polyphenols in Human Health and DiseaseOjeok-san, a traditional Korean herbal medicine attenuates airway inflammation and pulmonary fibrosis induced by repeated ovalbumin challenge
2013, Journal of EthnopharmacologyCitation Excerpt :Recently, it has been shown that VEGF plays a critical role in enhancing Th2 cell-mediated inflammation and TGF-β1 production (Vasquez-Pinto et al., 2010), which is consistent with the finding that inhibition of VEGF attenuates peribronchial fibrosis by blocking TGF-β1 production (Lee et al., 2008a). Ojeok-san, a traditional Korean herbal formula composed of 17 natural herbs, is used predominantly in China, Japan and Korea; however, during the past 20 years, its consumption has been highest in Korea (Ha et al., 2010). Ojeok-san is used for treatment of the common cold, gastrointestinal disorders and illnesses associated with fatigue, pain and fever (Ha et al., 2011).
Toxicity of Hydnora johannis Becca. dried roots and ethanol extract in rats
2011, Journal of Ethnopharmacology
- 1
These two authors contributed equally to this work.