A 4-week Repeated dose Oral Toxicity Study of Mecasin in Sprague-Dawley Rats to Determine the Appropriate Doses for a 13-week, Repeated Toxicity Test

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Abstract

Objectives:

In this study, we investigated the 4-week repeated-dose oral toxicity of gami-jakyak gamcho buja decoction (Mecasin) to develop safe treatments.

Methods:

In order to investigate the 4-week oral toxicity of Mecasin, we administered Mecasin orally to rats. Sprague-Dawley (SD) rats were divided into four groups of five male and five female animals per group: group 1 being the control group and groups 2, 3, and 4 being the experimental groups. Doses of Mecasin of 500, 1,000, and 2,000 mg/kg of body weight were administered to the experimental groups, and a dose of normal saline solution of 10 mL/kg was administered to the control group. We examined the survival rate, weight, clinical signs, and gross findings for four weeks. This study was conducted under the approval of the Institutional Animal Ethics Committee.

Results:

No deaths occurred in any of the four groups. No significant changes in weights or food consumption between the control group and the experimental groups were observed. Serum biochemistry revealed that some groups showed significant decrease in inorganic phosphorus (IP) ( P < 0.05). During necropsy on the rats, one abnormal macroscopic feature, a slight loss of fur, was observed in the mid dosage (1,000 mg/ kg) male group. No abnormalities were observed in any other rats. In histopathological findings, the tubular basophilia and cast of the kidney and extramedullary hematopoiesis of the spleen were found. However, those changes were minimal and had occurred naturally or sporadically. No other organ abnormalities were observed.

Conclusion:

During this 4-week, repeated, oral toxicity test of Mecasin in SD rats, no toxicity changes due to Mecasin were observed in any of the male or the female rats in the high dosage group. Thus, we suggest that the doses in a 13-week, repeated test should be 0, 500, 1,000, and 2,000 mg/kg respectively.

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Aconitum in traditional Chinese medicine: a valuable drug or an unpredictable risk?

Judith Singhuber, Ming Zhu, Sonja Prinz … (2009)

Aconitum species have been used in China as an essential drug in Traditional Chinese Medicine (TCM) for 2000 years. Reviewing the clinical application of Aconitum, their pharmacological effects, toxicity and detoxifying measures, herb-herb interactions, clinical taboos, famous herbal formulas, traditional and current herbal processing methods based upon a wide range of literature investigations serve as a case study to explore the multidisciplinary implications of botanicals used in TCM. The toxicological risk of improper usage of Aconitum remains very high, especially in countries like China, India and Japan. The toxicity of Aconitum mainly derives from the diester diterpene alkaloids (DDAs) including aconitine (AC), mesaconitine (MA) and hypaconitine (HA). They can be decomposed into less or non-toxic derivatives through Chinese traditional processing methods (Paozhi), which play an essential role in detoxification. Using Paozhi, the three main forms of processed aconite -- yanfuzi, heishunpian and baifupian -- can be obtained (CPCommission, 2005). Moreover, some new processing techniques have been developed in China such as pressure-steaming. The current development of fingerprint assays, in particular HPLC, has set a good basis to conduct an appropriate quality control for TCM crude herbs and their ready-made products. Therefore, a stipulation for a maximum level of DDA content of Aconitum is highly desirable in order to guarantee the clinical safety and its low toxicity in decoctions. Newly developed HPLC methods have made the accurate and simultaneous determination and quantification of DDA content interesting.

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Development and assessment of a complete-detoxication strategy for Fuzi (lateral root of Aconitum carmichaeli) and its application in rheumatoid arthritis therapy.

L Xiao, X. Wang, Peijian Tong … (2013)

Fuzi (lateral root of Aconitum carmichaeli) is a popular traditional Chinese medicine well known for its both therapeutic and high-toxic activities. Its toxic alkaloid ingredients, mainly aconitine, mesaconitine, and hypaconitine, are responsible for the high toxicity. However, to date, no detoxication strategy is available to completely eliminate Fuzi's toxicity, and, whether Fuzi's efficacy could be kept after detoxication, remain unknown and debatable. The purpose of this study was to establish and validate a complete-detoxication strategy for Fuzi via acute toxicity test, to clarify the detoxication mechanism by HPLC and titrimetric analyses, and to evaluate the therapeutic effect of detoxicated Fuzi on adjuvant arthritis (AA). Three processed Fuzi (Bai-fu-pian) with 30-min, 60-min, and 120-min decoctions, respectively, named dBfp-30, dBfp-60, and dBfp-120, were prepared for this study. For the acute toxicity test, their oral doses to male and female Kunming mice were up to 70-190g/kg body weight, and their toxicological profiles were evaluated by median lethal dose (LD50), maximal tolerance dose (MTD), minimal lethal dose (MLD), no-observed-adverse-effect-level (NOAEL), and time-concentration-mortality (TCM) modeling methods using a 14-day schedule with up to five doses. The HPLC analysis was performed to determine the detoxication-induced changes in composition and amount of aconitine, mesaconitine and hypaconitine in Fuzi, whilst the titrimetric method was adopted to estimate the amount changes of Fuzi's total alkaloids. AA model was established by incomplete Freund's adjuvant injection in Wistar rats, and the animal's physiological (body weight, food intake, etc.), clinical (hind paw volume), and immunological (IL-1 and TNF-α) parameters were assessed as markers of inflammation and arthritis. With increasing decoction time, the acute toxicity of detoxicated Fuzi became decreased in the following order: dBfp-30 (LD50 of 145.1g/kg; MTD of 70g/kg; MLD of 100g/kg; NOAEL of 70g/kg) >dBfp-60 (too large LD50; MTD of 160g/kg; MLD of 190g/kg; NOAEL of 100g/kg) >dBfp-120 (no LD50; unlimited MTD; unlimited MLD; NOAEL of 130g/kg). dBfp-30 and dBfp-60 displayed the toxicity at a dose-dependent manner with maximum mortalities reaching 100% and 50% respectively, whereas no mortality or signs of intoxication was induced by dBfp-120. The chemical analyses revealed a dramatic reduction of the toxic alkaloids as well as total alkaloids in Fuzi after the detoxication, from which no level of aconitine and only minimum residual of mesaconitine (0.56±0.02μg/g) and hypaconitine (8.73±0.13μg/g) were detected in dBfp-120. However, no significant difference of total alkaloid amount was found among dBfp-30, dBfp-60, and dBfp-120 (P>0.05), suggesting an equivalent conversion from toxic alkaloids to its non-toxic derivants in dBfp-120. Further, also no significant differences were seen among dBfp-30, dBfp-60, and dBfp-120 for the therapeutic effects on physiological, clinical, and immunological parameters in AA rat, indicating that dBfp-120 is of non-toxicity and efficacy. A complete-detoxication strategy has been developed successfully for ensuring the safe and effective use of Fuzi. The detoxication mechanism associated with elimination of toxic alkaloids has kept Fuzi's efficacy, indicating a non-interdependent relationship between its efficacy and toxicity. This is the first report on such an optimal detoxication strategy and on the application of detoxicated Fuzi in AA. It may provide in depth understanding to the toxicological and pharmacological profiles of Fuzi and further benefit the herbal drug development with safety and efficacy for disease especially RA therapy. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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Preclinical Evidence of Rapid-Onset Antidepressant-Like Effect in Radix Polygalae Extract

Im-Joon Shin, Sung Son, Hyunwoo Park … (2014)

Radix Polygalae (the root of Polygala tenuifolia) is a herb widely used in traditional Asian medicine that is thought to exert a variety of neuropsychiatric effects. Radix Polygalae extract can protect against N-methyl D-aspartate (NMDA) neurotoxicity and induce brain-derived neurotrophic factor (BDNF) expression, suggesting modulatory roles at glutamatergic synapses and possible antidepressant action. In accordance with this hypothesis, Radix Polygalae extract demonstrated antidepressant-like effects in 8-week-old male C57Bl/6 mice by decreasing behavioral despair in the forced swim and tail suspension tasks and increasing hedonic-like behavior in the female urine sniffing test 30 minutes after a single oral administration of 0.1 mg/kg. Reduced latency to acquire a food pellet in the novely suppressed feeding paradigm, without change in anxiety-like behaviors suggested a rapid-onset nature of the antidepressant-like effect. In addition, it decreased the number of failed escapes in the learned helplessness paradigm after two oral administrations 24 hours and 30 minutes before the first test. Finally, it reversed anhedonia as measured by saccharin preference in mice exposed to the chronic stress model after two administrations of 0.1 mg/kg, in contrast to the repeated administration generally needed for similar effect by monoamergic antidepressants. Immobility reduction in tail suspension task was blocked by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist NBQX, a pattern previously demonstrated by ketamine and other ketamine-like rapid-onset antidepressants. Also similarly to ketamine, Radix Polygalae appeared to acutely decrease phosphorylation of GluR1 serine-845 in the hippocampus while leaving the phosphorylation of hippocampal mTOR serine 2448 unchanged. These findings serve as preclinical evidence that Radix Polygalae extract exerts rapid-onset antidepressant effects by modulating glutamatergic synapses in critical brain circuits of depression and may be worthy of further evaluation as a safe substitute to other rapid-onset antidepressants known to have unacceptable side effects.

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Author and article information

Journal

Journal ID (nlm-ta): J Pharmacopuncture

Journal ID (iso-abbrev): J Pharmacopuncture

Journal ID (pmc): J Pharmacopunct

Journal ID (doi): 10.3831

Title: Journal of Pharmacopuncture

Publisher: KOREAN PHARMACOPUNCTURE INSTITUTE

ISSN (Print): 2093-6966

ISSN (Electronic): 2234-6856

Publication date (Print): December 2015

Volume: 18

Issue: 4

Pages: 45-50

Affiliations

[1 ]Department of Acupuncture & Moxibustion Medicine, Wonkwang University Gwangju Korean Medical Hospital, Gwangju, Korea

[2 ]Nervous & Muscular System Disease Clinical Research Center of Wonkwang University Gwangju Korean Medical Hospital, Gwangju, Korea

[3 ]Department of Nursing, Gwang-Ju Womens University, Gwangju, Korea

[4 ]Department of Neurology, Inam Neuroscience Research Center, Sanbon Medical Center, College of Medicine, Wonkwang University, Iksan, Korea

[5 ]Department of Internal Medicine, Wonkwang University Gwangju Korean Medical Hospital, Gwangju, Korea

[6 ]Department of Radiology, College of Korean Medicine, Wonkwang University, Iksan, Korea

Author notes

* Corresponding Author Department of Aupuncture & Moxibustion Medicine, Wonkwang Gwangju Oriental Medical Hospital, 543-8 Juweol 1-dong, Nam-gu, Gwangju 503-310, Korea. Tel: +82-62-670-6441 Fax: +82-62-670-6767 E-mail: kscndl@hanmail.net

Author information

Sungchul Kim http://orcid.org/0000-0003-3580-5290

Article

DOI: 10.3831/KPI.2015.18.037

PMC ID: 4797591

PubMed ID: 26998389

SO-VID: 2532bb0a-17d5-4b02-a0ee-9fff952a9941

License:

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

A 4-week Repeated dose Oral Toxicity Study of Mecasin in Sprague-Dawley Rats to Determine the Appropriate Doses for a 13-week, Repeated Toxicity Test

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Most cited references 26

Aconitum in traditional Chinese medicine: a valuable drug or an unpredictable risk?

Development and assessment of a complete-detoxication strategy for Fuzi (lateral root of Aconitum carmichaeli) and its application in rheumatoid arthritis therapy.

Preclinical Evidence of Rapid-Onset Antidepressant-Like Effect in Radix Polygalae Extract

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