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1.  Preclinical safety evaluation of the aqueous acetone extract of Chinese herbal formula Modified Huo Luo Xiao Ling Dan 
To investigate the safety of oral administration of Modified Huo Luo Xiao Ling Dan (HLXLD), a compound traditional Chinese herbal medicine.
The toxicological information of HLXLD and its individual constituent herbs was searched in cintcm or TCMlars (, PubMed (MEDLINE), Chinese Herbal Medicine (1999) and WHO Monographs on Selected Medicinal Plants (Vol. I—III). Single-dose acute toxicity was assessed by using the highest possible dosage. Motor function test was used to determine whether the herbal formula might cause motor impairment. Nine-day HLXLD repeat-dose sub-chronic toxicity/adverse effects, and 42-day chronic toxicity/adverse effects in rats were also assessed.
The literature searches showed that HLXLD and its eleven ingredient herbs had no side/adverse effects listed in the traditional Chinese medicine literature. Under the dosages proposed in the formula, the HLXLD formula had no side/adverse effects according to MEDLINE, Chinese Herbal Medicine and WHO Monographs on Selected Medicinal Plants. The studies in rats showed: (1) in single-dose acute toxicity assessment, the maximal feasible single oral dose, 9.20 g/kg HLXLD, showed no significant effect on clinical signs, or body weight and mortality over a 14-day period in rats; (2) during motor function test, nine-day repeat-dose of daily HLXLD treatment at 4.60 g/kg did not cause motor impairment; (3) in nine-day HLXLD repeat-dose sub-chronic toxicity/adverse effects assessment, there were no noticeable abnormal behavioral changes or obvious adverse reactions and signs in complete Freund's adjuvant inflamed rats (highest observed dosage: 4.60 g/kg), and no noticeable adverse effects were observed during, or 14 days after nine-day treatment at 4.60 g/kg in non-inflamed rats; (4) during 42-day chronic toxicity/adverse effects assessments, no noticeable abnormal behavioral changes, no obvious adverse reactions and signs were observed in normal rats administered with HLXLD at a dose of 2.30 g/kg and the values of serum biochemistry and histopathology were in normal range.
Both existing information and animal data support that Modified HLXLD is a safe herbal product for clinical application.
PMCID: PMC3739922  PMID: 20456842
Chinese herb formula; Modified Huo Luo Xiao Ling Dan; Safety; Literature investigation; Acute toxicity tests; Motor function; Sub-acute toxicity; Chronic toxicity tests; Rats
2.  Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7 
Toxicology Mechanisms and Methods  2011;21(7):520-532.
Menaquinone-7 (MK-7) is part of a family of vitamin K that are essential co-factors for the enzyme γ-glutamyl carboxylase, which is involved in the activation of γ-carboxy glutamate (Gla) proteins in the body. Gla proteins are important for normal blood coagulation and normality of bones and arteries. The objective of this study was to examine the potential toxicity of synthetic MK-7 in BomTac:NMRI mice and in Sprague-Dawley rats. In an acute oral toxicity test, mice were administered a single oral dose of 2000 mg/kg body weight (limit dose) and no toxicity was observed during the 14-day observation period. In the subchronic oral toxicity test in rats, animals were administered MK-7 for 90 days by gavage at the following doses: 0 (vehicle control, corn oil), 2.5, 5, and 10 mg/kg body weight/day. All generated data, including clinical observations, ophthalmology, clinical pathology, gross necropsy, and histopathology, revealed no compound-related toxicity in rats. Any statistically significant findings in clinical pathology parameters and/or organ weights noted were considered to be within normal biological variability. Therefore, under the conditions of this experiment, the median lethal dose (LD50) of MK-7 after a single oral administration in mice was determined to be greater than the limit dose level of 2000 mg/kg body weight. The no observed adverse effect level (NOAEL) of MK-7, when administered orally to rats for 90 days, was considered to be equal to 10 mg/kg body weight/day, the highest dose tested, based on lack of toxicity during the 90-day study period.
PMCID: PMC3172146  PMID: 21781006
Menaquinone-7; acute oral toxicity; 90-day oral subchronic toxicity study; histopathology
3.  Clinicopathological Studies on Vitamin D3 Toxicity and Therapeutic Evaluation of Aloe vera in Rats 
Toxicology International  2011;18(1):35-43.
A study was conducted to examine the clinical signs, hematological, biochemical and histopathological changes in vitamin D3 toxicity at a dose rate 2 mg/kg b.wt. of vitamin D3 and to assess the protective effect of Aloe vera in vitamin D3 toxicity. The clinical signs observed were anorexia, progressive weight loss, difficulty in movement and respiration, diarrhea, epistaxis, subnormal body temperature and nervous signs before death. Mortality was observed in treated rats between day 10 and day 19 of treatment. The gross postmortem changes observed were severe emaciation, white chalky deposits on epicardial surface of heart, pin point white deposits on cortical surface of kidneys with pale yellow discoloration and diffused white deposits on serosal surface of stomach and intestine with bloody ingesta in lumen. The hematological changes included non-significant increase in hemoglobin and total leukocyte count and significant increase in relative neutrophil count. The biochemical changes observed were significant increase in plasma concentration of calcium, phosphorus and blood urea nitrogen, whereas a significant decrease in the concentration of albumin and total plasma protein was observed. The histopathological lesions included calcification of various organs, viz., tongue, stomach, intestines, kidney, heart, aorta, larynx, trachea, lungs, spleen, choroid plexus arteries of brain and vas deferens. The Aloe vera juice (2.5% in drinking water) has no protective effect on vitamin D3 toxicity (2 mg/kg b.wt.).
PMCID: PMC3052582  PMID: 21430919
Aloe vera;  calcification; histopathological lesions; hypercalcemia; vitamin D3 toxicity
4.  Anti-malarial activity of a polyherbal product (Nefang) during early and established Plasmodium infection in rodent models 
Malaria Journal  2014;13(1):456.
The emerging resistance of Plasmodium species to currently available anti-malarials remains a public health concern, hence the need for new effective, safe and affordable drugs. Natural products remain a reliable source of drugs. Nefang is a polyherbal anti-malarial of the Cameroonian folklore medicine with demonstrated in vitro antiplasmodial and antioxidant activities. It is composed of Mangifera indica (bark and leaf), Psidium guajava, Carica papaya, Cymbopogon citratus, Citrus sinensis, Ocimum gratissimum (leaves). This study aimed at investigating the suppressive, prophylactic and curative activities of Nefang in Plasmodium infected rodent models.
Systemic acute oral toxicity of Nefang aqueous and ethanol extracts was assessed in mice up to a dose of 5,000 mgkg−1 body weight. BALB/c mice and Wistar rats were inoculated with Plasmodium chabaudi chabaudi and Plasmodium berghei, respectively, and treated with Nefang, the Mangifera indica bark/Psidium guajava combination and a Psidium guajava leaf aqueous extracts (75, 150, 300 and 600 mgkg−1 bwt). Their schizonticidal activity was then evaluated using the Peter’s 4-day suppressive test). The prophylactic and curative (Rane’s Test) activity of Nefang was also evaluated by determining the parasitaemia, survival time, body weight and temperature in pre-treated rodents.
Acute oral toxicity of the extract did not cause any observed adverse effects. Percent suppressions of parasitaemia at 600 mgkg−1 bwt were as follows (P. berghei/P. chabaudi): Nefang – 82.9/86.3, Mangifera indica bark/Psidium guajava leaf combination extract – 79.5/81.2 and Psidium guajava leaf – 58.9/67.4. Nefang exhibited a prophylactic activity of 79.5% and its chemotherapeutic effects ranged from 61.2 – 86.1% with maximum effect observed at the highest experimental dose.
These results indicate that Nefang has excellent in vivo anti-malarial activities against P. berghei and P. chabaudi, upholding earlier in vitro antiplasmodial activities against multi-drug resistant P. falciparum parasites as well as its traditional use. Hence, Nefang represents a promising source of new anti-malarial agents.
Electronic supplementary material
The online version of this article (doi:10.1186/1475-2875-13-456) contains supplementary material, which is available to authorized users.
PMCID: PMC4251988  PMID: 25421605
Medicinal Plants; Nefang; Acute toxicity; Malaria; In vivo antiplasmodial activity; Suppressive activity; Prophylactic activity; Curative activity; Combination phytotherapy
5.  Evaluation of hypoglycemic and anti-hyperglycemic potential of Tridax procumbens (Linn.) 
Diabetes is a metabolic disorder affecting carbohydrate, fat and protein metabolism. Tridax procumbens Linn. (Family-Asteraceae; common name-Dhaman grass) is common herb found in India. Traditionally, the tribal inhabitants of Udaipur district in Rajasthan (India) uses the leaf powder (along with other herb) orally to treat diabetes. There is a need to evaluate extracts of this plant in order to provide scientific proof for it's application in traditional medicine system.
Extraction of whole plant of T. procumbens using 50%methanol. The extract was tested for acute and sub-chronic anti-hyperglycemic activity in alloxan induced diabetic rats and for acute toxicity test among normal rats. Observations on body weight as well as on the oral glucose tolerance levels were also recorded.
Oral administration of acute and sub chronic doses (250 and 500 mg/kg b.wt.) of T. procumbens extract showed a significant (p < 0.05) reduction in fasting blood glucose levels in diabetic rats, however the decline in blood sugar levels in normal rats was not observed. In acute study the maximum percent blood glucose reduction (68.26% at 250 mg/kg and 71.03% at 500 mg/kg body weight) in diabetic rats was observed at 6 h. The anti-hyperglycemic effects were not dependent of dose and the OGTT and Body weight supported the antihyperglycemic action of the drug. The results of anti-diabetic effect of T. procumbens were compared with the reference standard drug Glibenclamide (10 mg/kg b.wt.).
These test results support traditional medicinal use of, T. procumbens for the treatment of diabetes mellitus with corrections in body weight and oral glucose tolerance and no visible signs or symptoms of toxicity in normal rats indicating a high margin of safety. These results warrant follow-up through bioassay-directed isolation of the active principles.
PMCID: PMC2790435  PMID: 19943967
6.  Acute and Subchronic Toxicity Study of Euphorbia hirta L. Methanol Extract in Rats 
BioMed Research International  2013;2013:182064.
Despite Euphorbia hirta L. ethnomedicinal benefits, very few studies have described the potential toxicity. The aim of the present study was to evaluate the in vivo toxicity of methanolic extracts of E. hirta. The acute and subchronic oral toxicity of E. hirta was evaluated in Sprague Dawley rats. The extract at a single dose of 5000 mg/kg did not produce treatment related signs of toxicity or mortality in any of the animals tested during the 14-day observation period. Therefore, the LD 50 of this plant was estimated to be more than 5000 mg/kg. In the repeated dose 90-day oral toxicity study, the administration of 50 mg/kg, 250 mg/kg, and 1000 mg/kg/day of E. hirta extract per body weight revealed no significant difference (P > 0.05) in food and water consumptions, body weight change, haematological and biochemical parameters, relative organ weights, and gross findings compared to the control group. Macropathology and histopathology examinations of all organs including the liver did not reveal morphological alteration. Analyses of these results with the information of signs, behaviour, and health monitoring could lead to the conclusion that the long-term oral administration of E. hirta extract for 90 days does not cause sub-chronic toxicity.
PMCID: PMC3872372  PMID: 24386634
7.  Gastroprotective and anti-Helicobacter pylori potential of herbal formula HZJW: safety and efficacy assessment 
A traditional Chinese Medicine (TCM) formula, HZJW, has been applied in clinics in China for gastrointestinal disorders. However, the therapeutic mechanism underlying its efficacy and safety remained to be defined. The present investigation was undertaken to evaluate the formula HZJW for its gastroprotective potential, possible effect on Helicobacter pylori along with safety to justify its anti-ulcer action and safe clinical application.
The gastroduodenal cytoprotective potential was evaluated in rodent experimental models (HCl/Ethanol and NSAID-induced ulcer protocols). The anti-H. pylori property was assessed by agar dilution assay in vitro and analysis in vivo including rapid urease test, immunogold test and histopathology. For toxicity assessment, acute toxicity study was performed according to fixed dose procedure with a single oral administration of HZJW to mice. In the oral chronic toxicity, rats (80 males, 80 females) were administrated HZJW orally in 0, 1000, 2500, or 5000 mg/kg/day doses for 26 weeks (n = 40/group of each sex). Clinical signs, mortality, body weights, feed consumption, ophthalmology, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined at the end of the 13- and 26-week dosing period, as well as after the 4-week recovery period.
In the HCl/Ethanol-induced ulcer model, it was observed that oral administration with HZJW (260, 520 and 1040 mg/kg) and ranitidine (250 mg/kg) significantly reduced the ulcerative lesion index (116.70 ± 36.4, 102.20 ± 18.20, 84.10 ± 12.1 and 73.70 ± 16.70) in a dose-dependent manner, respectively, with respect to control group (134.10 ± 31.69). Significant inhibition was also observed in ulcerative index from aspirin-induced ulcer model, with decreases of 35.40 ± 5.93, 31.30 ± 8.08, 26.80 ± 8.27and 20.40 ± 6.93 for the groups treated with HZJW and ranitidine, in parallel to controls (41.60 ± 10.80). On the other hand, treatment with HZJW efficaciously eradicated H. pylori in infected mice in rapid urease test (RUT) and immunogold antibody assay, as further confirmed by reduction of H. pylori presence in histopathological analysis. In the in vitro assay, MICs for HZJW and amoxicillin (positive control) were 125 and 0.12 μg/mL respectively. The LD50 of HZJW was over 18.0 g/kg for mice. No drug-induced abnormalities were found as clinical signs, body weight, food consumption, hematology, blood biochemistry, ophthalmology and histopathology results across three doses. No target organ was identified. The No Observed Adverse Effect Level (NOAEL) of HZJW was determined to be 5,000 mg/kg/day for both sexes, a dose that was equivalent to 50 times of human dose.
These results suggested the efficacy and safety of HZJW in healing peptic ulcer and combating H. pylori, which corroborated their conventional indications and contributed to their antiulcer pharmacological validation, lending more credence to its clinical application for the traditional treatment of stomach complaints symptomatic of peptic ulcer disease (PUD). HZJW might have the potential for further development as a safe and effective alternative/complementary to conventional medication in treating gastrointestinal (GI) disorders.
PMCID: PMC3679842  PMID: 23721522
HZJW; TCM; Cytoprotective; Helicobacter pylori; Gastroduodenal ulcer; Safety
8.  Biochemical and histopathological effects on liver due to acute oral toxicity of aqueous leaf extract of Ecliptaalba on female Swiss albino mice 
Indian Journal of Pharmacology  2013;45(1):61-65.
Limited data is available about the toxicity of herbal remedies used for self-medication. Since a popular medicinal plant Ecliptaalba contains various bioactive molecules, the present study aimed to observe the biochemical and histological changes in liver associated with acute oral toxicity (LD50) of aqueous extract of E. alba (L.) Hassk. in female Swiss albino mice.
Materials and Methods:
For the acute oral toxicity study, the animals were divided into six groups of 6 mice each. Group– I was normal control and the treatment groups were administered aqueous leaf extract of E. alba orally at different doses of 500 mg (group – I),1750 mg (group–III), 2000 mg (group- IV), 2500 mg (group- V) and 3000 mg/ kg/b.wt.(group- VI) for seven consecutive days. The mice were sacrificed on the eighth day and blood was collected for the analysis of ALP (alkaline phosphatase), SGPT (serum glutamic pyruvic transferase), total protein and albumin. The liver was dissected, weighed, and processed for histopathological analysis.
The LD50 was found to be 2316.626 mg/kg /body weight in female mice. Serum SGPT, total protein and albumin increased in treated group- IV (P < 0.05), V (P < 0.01), and VI (P < 0.01) as compared to the control (group- I). ALP level significantly decreased in the treated group- IV (P < 0.05), V (P < 0.01) and VI (P < 0.01). Histopathological changes were observed at dose of 2000 mg (group- IV), 2500 mg (group- V) and 3000 mg (group- VI).
It was concluded that oral administration of aqueous leaf extract of E. alba had detrimental effects on biochemical parameters and induced histopathological alterations in liver of female Swiss albino mice at doses higher than 2000 mg/kg/day indicating that its indiscriminate use should be avoided.
PMCID: PMC3608297  PMID: 23543876
Biochemical; Ecliptaalba; hepatotoxicity; histopathological
9.  A-90 Day Gavage Safety Assessment of Boswellia serrata in Rats 
Toxicology International  2012;19(3):273-278.
The present study deals with the evaluation and assessment of the safety/toxic potential of Boswellia serrata, a well known Ayurvedic herb used to treat disorders of digestive system, respiratory ailments and bone related diseases. A repeated dose oral (90 days) toxicity study of Boswellia serrata was carried out. For this, 10 rats of each sex were treated with the Boswellia serrata at three different doses i.e. 100, 500 and 1000 mg/kg B. wt. /day. As a control, 10 rats of each sex were treated with corn oil only which was the vehicle. Two groups consisting of five male and five female rats were kept as control recovery and high dose recovery group which were treated with the vehicle (corn oil) and the Boswellia serrata at the dose of 1000 mg/kg B. wt. Animals of control recovery and high dose recovery groups were further observed for 28 days without any treatment. From this study, it was found that the rats treated with high dose of the Boswellia serrata gained their body weight with much less rate than that of the control group. However, during the recovery period, the loss in body weight gain as observed during the study period exhibits a reversible effect on the metabolic activity and recovered. The results also indicate that Boswellia serrata is relatively safe in rat up to the dose of 500 mg/kg B.wt. as no adverse impact on health factors was observed. Thus, the No observed adverse effect level is 500 mg/kg B. wt.
PMCID: PMC3532773  PMID: 23293466
Boswellia serrata; NOAEL; safety; sub-chronic; toxicity; wistar rat
10.  Acute Oral or Dermal and Repeated Dose 90-Day Oral Toxicity of Tetrasodium Pyrophosphate in Spraque Dawley (SD) Rats 
Tetrasodium pyrophosphate (TSP) is used in processed meat products, as an emulsifier in cheese, and as a color preservative in soybean paste. However, little is known about its toxicity. This study was conducted to investigate the potential acute and repeated dose toxicity of TSP in Spraque Dawley (SD) rats.
In the acute study, animals were administered with oral or dermal doses of 2,000 mg/kg TSP. In the repeated dose study, animals were administered doses of 0, 250, 500, and 1,000 mg/kg by oral gavage five times a week for 90 days.
In acute toxicity studies, no dead animals or abnormal necropsy findings were found in the control or treated group. In the repeated dose toxicity study, there were no significant changes in body weight in the 1,000 mg/kg treatment group, or food consumption, urinalysis, and hematology in any group. With regards serum biochemistry, the levels of total protein, albumin, A/G ratio, triglyceride, calcium and inorganic phosphate were altered at doses of 500 and 1,000 mg/kg. However, no changes were observed at the dose of 250 mg/kg. With regards histopathological findings, cortical tubular basophilia of the kidney increased at the dose of 1,000 mg/kg, but not at doses of 250 and 500 mg/kg. No significant changes were observed in other organs at doses of 250, 500, and 1,000 mg/kg.
Based on the results, TSP is unclassified according to the Globally Harmonization System, with an LD50 value of over 2,000 mg/kg. The no observed effect level (NOEL) and no observed adverse effect level (NOAEL) were 250 and 500 mg/kg /day respectively and the target organ appears to be the kidney.
PMCID: PMC3214981  PMID: 22125775
Acute; Dermal toxicity; Oral toxicity; Rat; Repeated dose; Tetrasodium pyrophosphate
11.  Acute and subchronic toxicity as well as evaluation of safety pharmacology of eucalyptus oil-water emulsions 
Essential oil has performed a variety of indirect services used as insect/pest repellent. The present study investigated the acute and subchronic toxicity of eucalyptus oil emulsion in water (EOE). In addition, we conduct safety pharmacology evaluation of EOE to supplement the toxicity tests and provide a basis for a comprehensive understanding of the toxicity of EOE. Acute administration of EOE was done as single dose from 2772 mg to 5742 mg of EOE per kg/bodyweight (b.wt.) and subchronic toxicity study for thirty days was done by daily oral administration of EOE at doses of 396, 792 and 1188 mg/kg b.wt. In SPF SD rats. The acute toxicity study showed the LD50 of EOE was 3811.5 mg/kg. The subchronic toxicity study suggested the high-dose and middle-dose EOE slowed down the growth of male rats. The clinical pathology showed the high-dose and middle-dose EOE could cause damage to liver and kidney. The safety pharmacology indicated that EOE had no side effects on rats. These results suggest that EOE is a safe veterinary medicine for external use.
PMCID: PMC4307427  PMID: 25663980
Essential oil; acute toxicity; subchronic toxicity; safety pharmacology
12.  Evaluation of General Toxicity and Genotoxicity of the Silkworm Extract Powder 
Toxicological Research  2013;29(4):263-278.
The silkworm extract powder contain 1-deoxynojirimycin (DNJ), a potent α-glycosidase inhibitor, has therapeutic potency against diabetes mellitus. Therefore, natural products containing DNJ from mulberry leaves and silkworm are consumed as health functional food. The present study was performed to evaluate the safety of the silkworm extract powder, a health food which containing the DNJ. The repeated toxicity studies and gentic toxicity studies of the silkworm extract powder were performed to obtain the data for new functional food approval in MFDS. The safety was evaluated by a single-dose oral toxicity study and a 90 day repeated-dose oral toxicity study in Sprague-Dawley rats. The silkworm extract powder was also evaluated for its mutagenic potential in a battery of genetic toxicity test: in vitro bacterial reverse mutation assay, in vitro chromosomal aberration test, and in vivo mouse bone marrow micronucleus assay. The results of the genetic toxicology assays were negative in all of the assays. The approximate lethal dose in single oral dose toxicity study was considered to be higher than 5000 mg/kg in rats. In the 90 day study, the dose levels were wet at 0, 500, 1000, 2000 mg/kg/day, and 10 animals/sex/dose were treated with oral gavage. The parameters that were monitored were clinical signs, body weights, food and water consumptions, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weights, and histopathological examination. No adverse effects were observed after the 90 day administration of the silkworm extract powder. The No-Observed-Adverse-Effect-Level (NOAEL) of silkworm extract powder in the 90 day study was 2000 mg/kg/day in both sexes, and no target organ was identified.
PMCID: PMC3936179  PMID: 24578797
Single oral dose toxicity; 90 day repeated dose toxicity; Genotoxicity; Silkworm extract powder
13.  Acute and Subchronic Toxicity of Chantaleela Recipe in Rats 
Acute and subchronic toxicities of Chantaleela recipe were studied in both male and female rats. Oral administration of the extract at a single dose of 5,000 mg/kg body weight (5 females, 5 males) did not produce signs of toxicity, behavioral changes, mortality or differences on gross appearance of internal organs. The subchronic toxicity was determined by oral feeding the test substance at the doses of 600, 1,200 and 2,400 mg/kg body weight for 90 days (10 females, 10 males). No signs of abnormalities were observed in the test groups as compared to the controls. The test and control groups (on the 90th day) and the satellite group (on the 118th day) were analyzed by measuring their final body and organ weights, taking necropsy, and examining hematological parameters, blood clinical chemistry and histopathology features. The results suggest that Chantaleela recipe did not cause acute or subchronic oral toxicities to female and male rats.
PMCID: PMC3746366  PMID: 24082334
Acute toxicity; Subchronic toxicity; Chantaleela recipe
14.  Toxicity Studies of the Water Extract from the Calyces of Hibiscus Sabdariffa L. in Rats 
Acute and chronic toxicities of the water extract from calyces of Hibiscus sabdariffa were studied in male and female rats. After 14 days of a single oral administration of test substance 5,000 mg/kg body weight, measurement of the body and organ weights, necropsy and health monitoring were performed. No signs and differences of the weights or behaviour compared to the control rats were observed. The results indicated that the single oral administration of H. sabdariffa extract in the amount of 5,000 mg/kg body weight does not produce acute toxicity. The chronic toxicity was determined by oral feeding both male and female rats daily with the extract at the doses of 50, 100, and 200 mg/kg body weight for 270 days. The examinations of signs, animal behaviour and health monitoring showed no defects in the test groups compared to the control groups. Both test and control groups (day 270th) and satellite group (day 298th) were analysed by measuring their final body and organ weights, taking necropsy, and examining haematology, blood clinical chemistry, and microanatomy. Results showed no differences from the control groups. Overall, our study demonstrated that an oral administration of H. sabdariffa extract at the doses of 50, 100 and 200 mg/kg body weight for 270 days does not cause chronic toxicity in rat.
PMCID: PMC3794402  PMID: 24146512
Hibiscus sabdariffa L.; acute toxicity; chronic toxicity
15.  Genotoxicity and acute and subchronic toxicity studies of a standardized methanolic extract of Ficus deltoidea leaves 
Clinics  2013;68(6):865-875.
Ficus deltoidea leaves have been used in traditional medicine in Southeast Asia to treat diabetes, inflammation, diarrhea, and infections. The present study was conducted to assess the genotoxicity and acute and subchronic toxicity of a standardized methanol extract of F. deltoidea leaves.
Sprague Dawley rats were orally treated with five different single doses of the extract and screened for signs of toxicity for two weeks after administration. In the subchronic study, three different doses of the extract were administered for 28 days. Mortality, clinical signs, body weight changes, hematological and biochemical parameters, gross findings, organ weights, and histological parameters were monitored during the study. Genotoxicity was assessed using the Ames test with the TA98 and TA100 Salmonella typhimurium strains. Phytochemical standardization was performed using a colorimeter and high-performance liquid chromatography. Heavy metal detection was performed using an atomic absorption spectrometer.
The acute toxicity study showed that the LD50 of the extract was greater than 5000 mg/kg. In the subchronic toxicity study, there were no significant adverse effects on food consumption, body weight, organ weights, mortality, clinical chemistry, hematology, gross pathology, or histopathology. However, a dose-dependent increase in the serum urea level was observed. The Ames test revealed that the extract did not have any potential to induce gene mutations in S. typhimurium, either in the presence or absence of S9 activation. Phytochemical analysis of the extract revealed high contents of phenolics, flavonoids, and tannins. High-performance liquid chromatography analysis revealed high levels of vitexin and isovitexin in the extract, and the levels of heavy metals were below the toxic levels.
The no-observed adverse effect level of F. deltoidea in rats was determined to be 2500 mg/kg.
PMCID: PMC3674303  PMID: 23778480
Ficus deltoidea; Oral Toxicity; OECD; Genotoxicity; Isovitexin; Vitexin
16.  Pharmacokinetic interaction of garlic and atorvastatin in dyslipidemic rats 
Indian Journal of Pharmacology  2012;44(2):246-252.
To assess pharmacokinetic interaction of garlic with atorvastatin in dyslipidemic rats.
Materials and Methods:
Sprague Dawley rats with induced dyslipidemia were divided into five groups of eight rats each. Group 1 was given atorvastatin (10 mg/kg body weight (b.wt) orally), group 2 was given atorvastatin (10 mg/kg b.wt orally)+garlic (1% w/w in feed), group 3 was maintained on atorvastatin (5 mg/kg b.wt orally)+garlic (0.5% w/w in feed), group 4 was maintained on atorvastatin (7.5 mg/kg b.wt orally)+garlic (0.25% w/w in feed), and group 5 was maintained on atorvastatin (2.5 mg/kg b.wt orally)+garlic (0.75% w/w in feed) for 12 weeks. Blood samples were collected at predetermined time intervals for kinetic analysis after the first and last oral dosing of atorvastatin for single and multiple dose studies, respectively. Plasma samples were assayed for atorvastatin concentration by High-Performance Liquid Chromatography (HPLC) and then the concentration-time data were analyzed.
Maximum observed plasma concentration (Cmax), half-life, Area Under Plasma Concentration Time Curve (AUC), and Mean Resident Time (MRT) were significantly (P<0.05) increased during multiple dose kinetic study and elimination rate constant was significantly (P<0.05) decreased in comparison with their respective single-dose values, while there was no significant difference in time to achieve maximum concentration (tmax) in all groups during both phases of the study. The highest values for kinetic parameters were observed in group 2 with correspondingly low activity of Cytochrome P450 (CYP450).
The study revealed higher values [Cmax, AUC, Area Under The Moment Curve (AUMC), MRT, and half-life] of atorvastatin in garlic-treated groups.
PMCID: PMC3326922  PMID: 22529485
Atorvastatin; garlic; pharmacokinetics
17.  Evaluation of the Toxicity and Reversibility Profile of the Aqueous Seed Extract of Hunteria Umbellata (K. Schum.) Hallier F. in Rodents 
Hunteria umbellata (K. Schum.) Hallier f. (family: Apocynaceae) is reputed for the folkloric management of labour, pain and swellings, stomach ulcers, diabetes, obesity, and anaemia, with no scientific report of its toxicity and reversibility profile. The present study was, therefore, aimed at investigating the in vivo toxicity and reversibility profile of the aqueous seed extract of Hunteria umbellata (HU). The acute oral and intraperitoneal toxicity studies of HU were determined in Swiss albino mice while its 90-day oral toxicity and toxicity reversibility profile on anthropometric, biochemical, haematological and histopathological parameters were also assessed using standard procedures. Results showed that the LD50 values for the acute oral and intraperitoneal toxicity studies for HU were estimated to be 1000 mg/kg and 459.3 mg/kg, respectively. Visible signs of immediate and delayed toxicities including starry hair coat, respiratory distress, and dyskinesia were observed. For the chronic oral toxicity study, HU administered for 90 days produced significant (p<0.001) reductions in the weight gain pattern and significant (p<0.001) and dose related increases in the relative weights of liver, stomach, spleen, testis, lungs and heart, at the 100 and 500 mg/kg of HU. Chronic HU treatment also produced significant (p<0.05, p<0.001) dose related reductions in the serum levels of fasting blood glucose, bicarbonate, urea and creatinine while causing non-significant (p>0.05) alterations in the serum levels of sodium, potassium, alaninine transaminase, aspartate transaminase, alkaline phosphatase, total and conjugated bilirubin, total protein and albumin. Also, chronic oral treatment with HU produced significant (p<0.05, p<0.01, p<0.001) and dose-related increases in the red cell count, packed cell volume, haemoglobin concentration, platelet count, total leucocyte count and lymphocyte differential while producing significant (p<0.05) reductions in neutrophil and granulocyte differentials. HU also produced histological features of proliferations of the stomach epithelia, lung tissues, splenic white and red pulps, and testicular spermatogenic series. Following 14 days of oral toxicity reversibility test, there was no significant (p>0.05) reversal in the serum levels of the biochemical and haematological parameters investigated, including the HU-induced histological lesions.
Overall, results of this study showed that HU has a relatively low oral toxicity profile but its prolonged use, particularly, at high doses should be with great caution.
PMCID: PMC3005394  PMID: 21731167
Hunteria umbellata; Toxicity and reversibility profile; Haematology; Liver and Renal function tests; Histopathology; Rodents
18.  Safety Assessment of TLPL/AY/03/2008, A Polyherbal Formulation in Sprague Dawley Rats 
Toxicology International  2013;20(1):77-86.
TLPL/AY/03/2008 is a polyherbal formulation intended for treatment of osteoarthritis, rheumatoid arthritis, lumbago, spondylitis etc., Acute and repeated dose 90-days studies were conducted to evaluate the safety profile of TLPL/AY/03/2008 in rats.
Materials and Methods:
In acute study, TLPL/AY/03/2008 was orally administered to Sprague Dawley rats at 2000 mg/kg. In repeated dose study, TLPL/AY/03/2008 was administered to rats at 200, 500 and 1000 mg/kg through oral gavage for 90 days and assessed for treatment related changes in body weight, feed consumption, hematological, biochemical and pathological parameters. Histopathological examination was conducted for tissues from control and the high dose groups and was extended to target organs from the lower dose and recovery groups.
In acute study, the test item did not produce any mortality or adverse clinical signs. In the 90-days oral toxicity study, animals did not exhibit any toxicity symptoms and no deaths were observed. No significant changes were found in hematological and biochemical endpoints. Also, toxicologically significant alterations in relative organ weights were not observed. Microscopic findings of mild to marked, diffuse hepatocellular degeneration (vacuolar changes with granular of cytoplasm and pyknotic nuclei of hepatocytes) was noticed in males at 1000 mg/kg body weight. Animals of recovery group (1000 mg/kg) did not show any changes when compared with control group animals indicating the complete reversal.
Based on the findings of the study, the median lethal dose of TLPL/AY/03/2008 was found to be more than 2000 mg/kg. The No Observed Adverse Effect Level (NOAEL) of TLPL/AY/03/2008 can be considered as 1000 mg/kg in both male and female rats, under the experimental conditions and doses employed.
PMCID: PMC3702132  PMID: 23833442
Acute; polyherbal; subchronic; toxicity; TLPL/AY/03/2008
19.  Effects of Gelam and Acacia honey acute administration on some biochemical parameters of Sprague Dawley rats 
Since ancient times, honey has been used for medicinal purposes in many cultures; it is one of the oldest and most enduring substances used in wound management. Scientific evidence for its efficacy is widely studied, but systemic safety studies are still lacking. It is essential to study the impact of consumption of honey on the health and proper development of the consumer. Therefore, the present study was designed to observe the effects of acute administration (14 days) of Gelam honey (GH), a wild harvesting honey and Acacia honey (AH), a beekeeping honey, on male and female Sprague Dawley (SD) rats.
An acute oral study was performed following OECD test guideline 423, with minor modifications. In the study, GH, AH and sucrose (S) were administered at 2000 mg/kg body weight. Animals were observed for the next 14 days. Gross pathology was performed at the end of the study. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Clinical biochemistry, gross pathology, relative organ weight and histopathological examination were performed.
Rats fed with honey did not exhibit any abnormal signs or deaths. Results showed a decrease in weight gain and energy efficiency, but significantly increased in total food intake and total calories in female rats fed with GH, compared to control (p < 0.05). Nevertheless, a significant increase in body weight was observed in male rats in all honey-treated groups. Male rats fed with AH significantly decreased in total food intake, total calories and energy efficiency. Both male and female rats fed with GH displayed a significant decrease in triglycerides compared to control group. Hepatic and renal function levels were within acceptable range. The gross necropsy analysis did not reveal changes in any of the organs examined.
Our results suggest that acute consumption of GH and AH at 2000 mg/kg body weight of male and female SD rats has some discrepancy effects on biochemical parameters but in line with OECD regulation. Gelam honey may have potential in controlling weight gain and triglyceride levels in female rats compared to Acacia honey. SD rats have some effect on biochemical parameters, an exploration of which would make for intriguing analysis.
PMCID: PMC4028288  PMID: 24885010
Acacia honey; Acute consumption; Gelam honey; Sprague Dawley rats
20.  Evaluation of the Toxicological Profile of the Leaves and Young Twigs of Caesalpinia Bonduc (Linn) Roxb 
Acute and sub-acute toxicological effects of ethanolic extract of the leaves and young twigs of Caesalpinia bonduc were carried out on albino rats. Single extract doses from 2000 to 5000 mg/kg body weight were administered orally and monitored for 14 days in acute study, while extract doses from 200 to 1600 mg/kg body weight were orally administered daily for 28 days in sub-acute study and recovery was assessed 14 days after dosing. Biochemical, haematological and histopathological examinations were carried out. There was no mortality in the experimental animals in all acute treatment doses. However, there were significant alterations in the biomarkers and induced cellular damage to the liver in all acute treatment doses. In the sub-acute toxicity treatment, the assessed biomarkers were unaffected at extract dose of 200 mg/kg body weight compared to control, while significant changes were observed in rats administered with extract doses of 400 mg/kg body weight and above. No significant difference was observed between the tested groups and the recovery groups in the sub-acute toxicity study. In conclusion, the ethanolic extract of C. bonduc could be toxic to selected organs of the rat body in acute and sub-acute treatments.
PMCID: PMC3847393  PMID: 24311878
Caesalpinia bonduc; acute toxicity; sub-acute toxicity; biochemical; haematological and histopathological parameters
21.  Toxicological Evaluation of the Methanol Extract of Gmelina arborea Roxb. Bark in Mice and Rats 
Toxicology International  2012;19(2):125-131.
The present study was designed to evaluate acute and repeated dose toxicity of the methanol extract (ME) of the Gmelina arborea stem bark.
Materials and Methods:
For the acute toxicity study, ME of G. arborea was orally administered to Swiss albino mice at a dose range of 300–5000 mg/kg. For the repeated dose toxicity study, the Wistar rats of either sex were orally administered with ME of G. arborea at the doses of 300, 1000, and 2000 mg/kg/day for a period of 28 days. The effects on body weight, food and water consumption, organ weight, hematology, clinical chemistry as well as histology were studied.
The administration of ME from the G. arborea bark at 300–5000 mg/kg did not produce mortality or significant changes in the clinical signs. The no-observed adverse effect level (NOAEL) of ME was 5000 mg/kg. There were no significant differences in the general condition, growth, organ weights, hematological parameters, clinical chemistry values, or gross and microscopic appearance of the organs from the treatment groups as compared to the control group.
ME of G. arborea was found safe in acute and repeated dose toxicity studies when tested in mice and rats.
PMCID: PMC3388755  PMID: 22778509
Acute toxicity; Gmelina arborea; methanol extract; repeated dose toxicity
22.  Experimental studies on the effect of (Lambda-Cyhalothrin) insecticide on lungs and the ameliorating effect of plant extracts (Ginseng (Panax Ginseng) and garlic (Allium sativum L.) on asthma development in albino rats 
BMC Research Notes  2014;7:243.
Lambda-cyhalothrin (LTC) is a synthetic pyrethroid insecticide for agricultural and public health applications. This study was to determine the pathological alterations of LTC in lungs, which has not previously been studied, and the ameliorating effects of plant extracts (ginseng and garlic) on the development of asthma in albino rats.
Four groups (gps) of albino rats, (n = 20, average body weight = 200 gm with an age of 4 months), were formed. Gp 1 was kept as control. Gp 2 was injected intraperitoneally (i.p.) with LTC at a dose of 1/6 LD50 that is 9.34 mg/kg body weight (w.t.) daily for 21 days (d). Gp 3 & 4 were injected (i.p.) with ginseng at the dose of 200 mg/kg b.wt and garlic (Allium sativum L.) at the dose of 100 mg/kg b.wt., respectively, one hour before being given LTC at a dose of 1/6 LD50 (9.34 mg/kg b.wt.) daily. Each groups were divided into two sacrificed, at 15 and 21 d p.i. Blood and lung samples were collected for hematological and histopathological examinations.
Hematological findings showed that the animals in gps 2 and 3, which were treated for 21 days, showed a significant difference in RBC counts (P > .001), Hb (P > .007), PCV% (P > .004), (P > .008) in comparison with the control group. Signs of cough and nasal discharge were seen in gp 2, which became mild in gp 4. Grossly, the lungs showed congestion and consolidation in gp 2. Histopathologically, macroabscesses and interstitial alveolitis were seen in gp 2, which led to obstruction in the lumen of the bronchioles at 21 d p.i. Meanwhile, thickening in the interalveolar septa with mononuclear cells was seen in gps. 3 and 4 at 21d p.i.
The study shows 3 gps of rats injected with LHC alone or combined with garlic and ginseng extract, each group were divided into two sacrificed (15 and 21 d p.i.). Lambda cyhalothrin causes bronchial obstruction in the lungs of the rats (15 and 21 d p.i), which decreased into mild to moderate interstitial inflammation in the rats given garlic and ginseng, respectively.
PMCID: PMC3999737  PMID: 24739272
Albino rats; Airway inflammation; Asthma; LTC; Garlic; Ginseng plants; Pathology
23.  Single- and repeated-dose toxicities of aloe fermentation products in rats 
Laboratory Animal Research  2011;27(3):235-244.
In this study, aloe fermentation products were derived from mycelia from 3 mushrooms: Ganoderma lucidum (AG), Hericium erinaceum (AH), and Phellinus linteus (AP). Levels of aloin A and B increased with fermentation time. The highest levels were measured on the fifth day of fermentation. β-Glucan levels decreased with fermentation time. The safety of aloe fermentation products were examined in male and female Sprague-Dawley rats. Rats were orally administered the three aloe fermentation products at dose levels of 1, 2 or 5 g/kg for single-dose toxicity test and 0.5, 1, or 2 g/kg for repeated-dose toxicity test. There were no significant differences in body weight gain between vehicle control and AG-, AH- or AP-treated rats. Also, significant changes in daily feed intake and water consumption were not observed. In hematological analysis, none of the parameters were affected by aloe fermentation products with mushroom mycelia. This suggests that there are no negative effects on homeostasis and immunity. In blood biochemistry analysis, none of the markers were affected by feeding rats with AG, AH or AP. Similarly, there were no significant effects on markers for liver, kidney, skeletal and heart muscle functions. No remarkable lesions were observed in these organs at histopathology. Since there were no adverse effects of AG, AH and AP in single- or repeated-dose toxicity tests, even at higher doses than normal, we conclude that the aloe fermentation products with mushroom mycelia possess long-term safety and could be candidates as multifunctional nutrients for the improvement of intestinal function and immunity.
PMCID: PMC3188731  PMID: 21998613
Aloe fermentation; aloin; β-glucan; Ganoderma lucidum; Phellinus linteus; Hericium erinaceum; single-dose toxicity test; repeated-dose toxicity; Sprague-Dawley rat
24.  Acute and Sub-Acute Toxicological Assessment of the Aqueous Seed Extract of Persea Americana Mill (Lauraceae) in Rats 
The aqueous seed extract of Persea americana Mill (Lauraceae) is used by herbalists in Nigeria for the management of hypertension. As part of our on-going scientific evaluation of the extract, we designed the present study to assess its acute and sub-acute toxicity profiles in rats. Experiments were conducted to determine the oral median lethal dose (LD50) and other gross toxicological manifestations on acute basis. In the sub-acute experiments, the animals were administered 2.5 g/kg (p.o) per day of the extract for 28 consecutive days. Animal weight and fluid intake were recorded during the 28 days period. Terminally, kidneys, hearts, blood/sera were obtained for weight, haematological and biochemical markers of toxicity. Results show that the LD50 could not be determined after a maximum dose of 10 g/kg. Sub-acute treatment with the extract neither affected whole body weight nor organ-to-body weight ratios but significantly increased the fluid intake (P < 0.0001). Haematological parameters and the levels of ALT, AST, albumin and creatinine were not significantly altered. However, the concentration of total proteins was significantly increased in the treated group. In conclusion, the aqueous seed extract of P. americana is safe on sub-acute basis but extremely high doses may not be advisable.
PMCID: PMC2816474  PMID: 20606779
Persea americana seed; herbal medicine; safety profile
25.  Protective Effect of Psidium guajava in Arsenic-induced Oxidative Stress and Cytological Damage in Rats 
Toxicology International  2012;19(3):245-249.
This study was undertaken to evaluate the protective effect of aqueous extract of Psidium guajava leaves against sodium arsenite-induced toxicity in experimental rats. Animals were divided into four groups. Control group received arsenic free distilled water and three treatment groups (II, III, and IV) exposed to the arsenic (NaAsO2) (20 mg/kg b.wt) through drinking water. Group III and IV were administered a daily oral dose of P. guajava leaf extract 50 and 100 mg/kg b.wt. (AEPG50 and AEPG100) for the period of 6 weeks. Blood samples and organs were collected at the end of the experiment. Arsenic exposure resulted in significant rise in lipid peroxidation (LPO) levels in erythrocyte, liver, kidney, and brain. In addition toxin decreased (P<0.05) the level of reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities in the studied tissues. Residual effect of arsenic in various tissues was also observed. Histopathological results revealed mild to severe type of necrosis and degenerative changes in kidney and liver of arsenic intoxicated animals. Cytological alteration in brain tissue was also observed. Treatment with AEPG100 (aqueous extract of P. guajava) @100 mg/kg body weight) significantly restored activities of oxidative stress markers like LPO levels, GSH levels, SOD, and CAT activities but having the limited protective activity of the herbal extract was observed on tissues architecture. It is therefore concluded that prophylactic co-administration of AEPG could provide specific protection from oxidative injury and to some extent on tissue damage.
PMCID: PMC3532768  PMID: 23293461
Histopahtology; oxidative stress; Psidium guajava; rats; sodium arsenite

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