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Objective: To observe the toxic effects of cockle shell-derived calcium carbonate nanoparticles (CCNPs) on the SD rats, and to preliminarily explore the safe dose and biological effects of CCNPs. Methods: A total of 40 healthy male SD rats were randomly divided into control group, low, middle and high doses of CCNPs groups (given 0, 30, 60, and 120 mg middot; kg-1 CCNPs). The injection was consecutively given through the lateral tail vein once per day for 14 d. The body weights and daily feed intakes of the rats in various groups were measured. The haematology indexes, serum biochemical indexes, relative weights of organs and histopathology of main organs of the rats in various groups were detected. Results: In the 14-day repeated dose toxicity experiment, two rats died in high dose of CCNPs group, while no rats died in low and middle doses of CCNPs groups. The body weights and daily average intakes of the rats in different doses of CCNPs groups were slightly lower than those in control group, but the differences were not statistically significant (P>0. 05). There were no significant differences in the serum indexes of the rats between different doses of CCNPs groups and control group (P>0. 05). Compared with control group, the relative weights of lung of the rats in different doses of CCNPs groups were increased significant (P0. 05). The histopathological analysis results showed that the mild inflammatory infiltration was found in some organs of the rats in low dose of CCNPs group, while no obviously pathological changes were found. The obviously histopathological changes were observed in the main organs of the rats in middle and high doses of CCNPs groups, including inflammatory cell infiltration, slight disorder of hepatocytes arrangement, increased vacuoles in hepatocytes; thickening of alveolar interstitium and formation of granulomas in the lung tissue; swelling, rupture and even necrosis of cardiac muscle fibers; atrophy and fissures of glomerulus and so on. Conclusion: Intravenous administration of low dose of CCNPs couldn' t cause sever acute toxicity reaction.
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Ayapodi Elagam (A.E) was used in Siddha system of medicine for many years to treat Pandu (Anemia). This medicine contains Nellikai, Keezhanelli, Karisalai and Ayam. These herbs are helps to improve the blood to correct the anemia. This study was carried out to evaluate the acute and chronic toxic effect on Ayapodi Elagam and to determine the LD50. The toxicity study was done as per the guidelines of world health organization (WHO) guideline. As the herbs and Ayam were used for treating anemia by traditional practitioners for years together, the toxicity study was also proposed to study in both sexes. In acute study the animals were divided into two groups A.E was administered at 5000mg/kg orally and animals were observed for toxic sign at 0,5,1,4,24 hour and for 14 days. In chronic toxicity study A.E was administered at 450,900 and 1800 mg/kg body weight/day to 3 groups of animal, respectively. The distilled water was administered to control animals. The result showed that the acute toxicity study of A.E. at the dose level of 5000mg/kg does not produce any toxic sign and mortality among the experimental groups and the LD50 value of the drug was found to be more than 5000mg/kg bodyweight. The weight of rats, wellness parameters, mortality, hematological parameters, biochemical parameters and histological analysis of all vital organs were observed to know the chronic toxic effect of the drug. All the parameters of the study do not show the any significant chances between the control and experimental groups.
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Background and Aim: Different parts of Phyllanthus amarus are being used in the treatment of different diseases in several parts of Nigeria without considering its safety. This study was aimed at investigating the effect of ingestion of methanolic leaf extract of Phyllanthus amarus on the liver of Wistar rats. Materials and Methods: The acute oral toxicity of the leaf extract (LD50) was determined in 9 Wistar rats divided into 3 groups of 3 rats per group. Group 1 was the control and received distilled water. Different doses of 2000 mg/kg and 5000 mg/kg were administered orally once to the study groups 2 and 3 respectively. A sub-chronic toxicity study was carried out in 25 Wistar rats, divided into five groups of 5 rats per group. Group 1 served as control and received distilled water. The remaining 4 groups (2, 3, 4 and 5) served as the study groups and were administered different doses of 250 mg/kg, 500 mg/kg, 750 mg/kg and 1000 mg/kg of methanolic leaf extract of Phyllanthus amarus respectively on a daily basis for 28 days. Total protein (TP), albumin (ALB), total and conjugated bilirubin (TB and CB), aspartate and alanine transaminase (AST and ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were assayed using standard techniques. Results: In the acute oral toxicity study, no death or any sign of toxicities were recorded in the rats after 24 hours and up to 14 days post oral administration and there was no significant difference (P>0.05) in all the parameters analysed between the control and the study groups. In sub-chronic toxicity study, there was no significant difference (P>0.05) in all parameters analysed between the control and study groups. Histology of the liver of the rats in both the acute and sub-chronic study showed normocytic and normochromic cells. Conclusion: Methanolic leaf extract of Phyllanthus amarus is relatively non-toxic and is not likely to induce liver damage.
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Objective To obtain the basic data of Bama minipigs and provide basic reference for embryo-fetal developmental toxicity study. Methods Pregnant minipigs were sacrificed at different days during the gestation period respectively. The examinations included necropsy,count of corporea lutea,live and dead implantations,fetal body weight, and external,visceral, and skeletal examination of fetuses. Results The basic data of Bama minipigs, such as body weight, fetal development, and fetal malformation/variation were obtained. Conclusions We obtained the basic reproductive parameters of pregnant Bama minipigs and the indexes of fetal development, which can provide valuable reference data for embryo-fetal developmental toxicity tests of Bama minipigs.
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Objective To observe the repeat administration toxicity of Guanxinning Injection in rats.Methods Totally 120 rats (males and females) were randomly divided into vehicle control group and three Guanxinning Injection groups with different dosages (3.40,1.70,and 0.85 g/kg).Rats were administered with Guanxinning Injection by consecutive intravenous injection for 13 weeks.Besides the general conditions were observed,the related indexes were detected,such as body weight,the routine control of blood,hepatic function,renal function,the metabolism condition of lipids,the glycometabolism indexes,and histopathology analysis were determined at 13 weeks of treatments and 4 weeks after the withdrawal,respectively.Results Rats in the Guanxinning Injection group at 3.40,1.70 g/kg apperance shortness of breath,unsteady gait,lying motionless,and other symptoms.There was no obvious abnormal reaction in the 0.85 g/kg dose group.There were two male rats in the Guanxinning Injection group at 3.40 g/kg died at about week 4 of treatments,and there was no death in the 0.85 and 1.70 g/kg dose groups.Compared with vehicle control group,the related indexes of blood,blood biochemistry,organ relative quality,and histopathological showed no obvious abnormalities in Guanxinning Injection 0.85 and 1.70 g/kg group.The levels of urea nitrogen (BUN) and the relative weight of kidney in Guanxinning Injection 3.40 g/kg group were significantly higher than those in vehicle control group at 13 weeks.The change of these parameters regained to normal at 4 weeks after withdrawal and the rest of the detection index showed no obvious abnormality in 3.40 g/kg dase group.Conclusion Intravenous administration of Guanxinning Injection for 13 weeks at high dose could induce reversible damage to kidney.
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Daurian Thermopsis (Thermopsis daurica Czefr.),Gobian Thyme(Thymus gobicusTschern.) and Mogilev Mallow (Malva mohileviensis Downer) are separately used as mucolytic and anti- inflammatory treatment in non-conventional medicine. Therefore, we prepared infusion of these herbals compound called as a Tetima. It is important to produce new pharmaceutical preparation that mucolytic effective for upper and lower respiratory tract inflammatory disease. Despite the wide use of this plants as herbal medicine in the treatment of respiratory tract diseases, their toxicity is still unknown. Therefore, we evaluated the possiblesubchronic toxic effects of Tetima herbal compound inrats. Tetima herbal compound infusion was prepared in distilled water (1:10). We used 15 Wistar breed rats (230-370 gr) in this study. Subchronic toxicity study for 28 days was done by oral administration at doses of 0.5ml normal saline (control) and 200 mg/kg, 400 mg/kg of infusion in Wistar ratsThe obtained data revealed that oral administration of Tetima in rats for 28 successive days had no significant changes the hematological parameters in rats all over the period of the experiment, and there are no significant increases in the activity of aspartate aminotransferase, alanine aminotransferase, creatinine and urea, between control and treated groups (p>0.05). The histopathological studies of the major vital organs like liver, kidney and heart recovered from the control and treated groups showed normal architecture suggesting no detrimental changes and morphological disturbances. These results show that the Tetima herbal compound is low toxic in subchronic toxicity study.
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In recent years, with the rapid development of Chinese materia medica (CMM) industry, its clinical applications have become more and more widespread. While, adverse reactions of CMM have also become increasingly prominent. However, for adverse reactions of some CMM, the applications of conventional toxicology studies cannot draw definitive conclusions. These CMM, which were not defined as toxic drugs in traditional Chinese medicine (TCM) theories, have unknown potential toxicities and affect the safety in their clinical use. This paper reviewed recent advances in studies on potential toxicity of non-toxic CMM. It analyzed and summarized potential toxic compounds among them, and introduced application for metabolomics researches on potential toxicities in non-toxic CMM.
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Background: Polyscias fruticosa is been used in Ghanaian folkloric medicine for the management of asthma and its related complications. Aim: This study evaluated the muco-suppressant, anti-tussive, and safety profile of an ethanolic leaf extract of Polyscias fruticosa in its use as an anti-asthmatic. Place and Duration of Study: Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, KNUST, Kumasi, Ghana and the School of Physical Sciences, University of Cape-Coast, Cape-Coast, Ghana; between December, 2013 and May, 2014. Methodology: Preliminary phytochemical screening was carried out on the extract. Ammonium chloride-induced tracheal mucus phenol red secretion in ICR mice and the suppression of citric acid-induced cough in Dunkin-Hartley guinea pigs were determined after treatment of experimental animals with 100 mg/kg sodium cromoglycate, or 20 mg/kg dihydrocodeine respectively, as well as with 100, 250, or 500 mg/kg of the extract. A 100, 250, and 500 mg/kg dose of the extract was administered daily for 28 days to groups of guinea pigs to establish a safety profile in a sub-chronic toxicity study. Results: Phytochemical screening revealed the presence of saponins and cyanogenetic glycosides, alkaloids, and sterols. The extract significantly inhibited (P ≤ .01 - 0.001) tracheal mucus phenol red secretion, and suppression of citric acid-induced cough. There were no significant changes in body weight, haematological profile, as well as liver and kidney functions in the sub-chronic toxicity study. Conclusion: The findings indicate that the ethanolic leaf extract of Polyscias fruticosa has muco-suppressant and anti-tussive properties, and is safe to use; hence a suitable adjunct/remedy for the management of asthma.
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Nanoscience and Nanotechnology have found their way in the fields of pharmacology and medicine. The conjugation of drug to nanoparticles combines the properties of both. In this study, gold nanoparticle (GNP) was conjugated with NKCT1, a cytotoxic protein toxin from Indian cobra venom for evaluation of anti-arthritic activity and toxicity in experimental animal models. GNP conjugated NKCT1 (GNP-NKCT1) synthesized by NaBH4 reduction method was stable at room temperature (25±2 °C), pH 7.2. Hydrodynamic size of GNP-NKCT1 was 68–122 nm. Arthritis was developed by Freund's complete adjuvant induction in male albino rats and treatment was done with NKCT1/GNP-NKCT1/standard drug. The paw/ankle swelling, urinary markers, serum markers and cytokines were changed significantly in arthritic control rats which were restored after GNP-NKCT1 treatment. Acute toxicity study revealed that GNP conjugation increased the minimum lethal dose value of NKCT1 and partially reduced the NKCT1 induced increase of the serum biochemical tissue injury markers. Histopathological study showed partial restoration of toxic effect in kidney tissue after GNP conjugation. Normal lymphocyte count in culture was in the order of GNP-NKCT1>NKCT1>Indomethacine treatment. The present study confirmed that GNP conjugation increased the antiarthritic activity and decreased toxicity profile of NKCT1.
Subject(s)
Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/pathology , Edema/drug therapy , Edema/pathology , Elapid Venoms/administration & dosage , Elapid Venoms/chemistry , Elapidae , Gold/administration & dosage , Gold/chemistry , Humans , Lymphocyte Count , Metal Nanoparticles/administration & dosage , Metal Nanoparticles/chemistry , Mice , RatsABSTRACT
OBJECTIVE: To discuss early exploratory bridging studies between early screening phase and pivotal general toxicology studies and their application during new drug development. METHODS: The opinions on acute toxicity study from international counterparts and current application in domestic and overseas were briefly reviewed. At the same time, the study design and the strengths of an alternative maximum tolerated dose /dose range finding (MTD/DRF) study widely used abroad were fully discussed. Furthermore, considerations were also highlighted based on the authors' experience, which may aid in the design and the conduct of such bridging studies. RESULTS AND CONCLUSION: MTD/DRF study could provide more valuable information for subsequent non-clinical regulatory toxicity studies. It is a rational and practical general toxicological study with bridging character.
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To evaluate the toxicological implications of the administration of aqueous leaf extract of Chromolaena odorata. The aqueous leaf extract was administered three times per week, for 90 days at doses of 161.5mg/kg, 32 3mg/kg, 538,5mg/kg and 1077mg/kg body weight, respectively. The control animals received 0.5ml of deionised water alone. The animals were sacrificed at the end of 90days. Blood samples were collected for biochemical analysis, and the heart, testes and kidney harvested for histological analysis. Histopathological examination of the heart, lungs, testis and the kidneys did not show any observable morphological alterations. The biochemical parameters; amylase, albumin and total serum protein, and Na+ were found to be decreased at doses of 538.5mg/kg and 1077mg/kg, while the serum levels of creatine kinase, AST, K+, glucose, uric acid, urea and creatinine were increased at the same dose levels. The absence of exhibition of observable toxicity below 538.5mg/kg body weight suggests that the extract may be safe and non-toxic only at very low doses.
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Ipomoea Pes-caprae (L.) R.Br (IP) is a valuable medicinal plant, distributed in the tropics and subtropics regions and used in folk and tribal medicines. Traditionally IP is used in inflammatory conditions such as arthritis and also used to treat pain, ulcer, cancer and wounds. The acute anti-inflammatory activity of IP has been previously reported. The present study aims to discover the anti-inflammatory effect of ethanolic extracts from aerials parts of IP by sub-acute anti-inflammatory model. Completely dried leaves and stems of I.pes-caprae were extracted using ethanol by hot percolation method. The EELIP & EESIP (Ethanolic extract of Leaves & Stems of IP) thus obtained were subjected to preliminary phytochemical analysis and revealed the presence of alkaloids, carbohydrates, glycosides, flavonoids, tannins, sterols and terpenoids both in leaf and stem extracts. The LD50 of both EELIP & EESIP were found to be >2000 mg/kg by acute oral toxicity study. Both EELIP & EESIP exhibited significant anti-inflammatory activities in dose dependent manner.
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Objective: Terminalia chebula Retz. (combretaceae) is called the “King of Medicine” in Tibet and is always listed at the top of the list of “Ayurvedic Materia Medica” because of its extraordinary power of healing. The present study was carried out to evaluate the possible in vitro antibacterial potential of different solvent extracts of T. chebula fruit against multidrug-resistant uropathogens. Methods: A total of 52 multidrug-resistant uropathogenic bacteria were used in this study. Successive extractions of T. chebula fruits were performed with solvents of different polarities. Agar well diffusion and microbroth dilution assay methods were used for antibacterial susceptibility testing. Kill-kinetics study was done to know the rate and extent of bacterial killing. Qualitative phytochemical screening was done to know the major phytoconstituents present in the plant material. Acute oral toxicity study in mice was performed to evaluate the toxic potential of the plant material, if any. Results:The ethanol extract of T. chebula fruits demonstrated a strong antimicrobial activity against all the test isolates and found to be most effective over others. Kill-kinetics study showed dose and time dependent antibacterial activity of ethanol extract. Phytochemical analysis revealed the presence of high concentration of phenolics and low concentration of flavonoids and terpenoids. In acute oral toxicity study, no gross behavioral changes were observed in mice at recommended dosage level and 24 h LD50 of ethanol extract was found to be >4 g/kg, p.o. in mice. Conclusions: The results provide justification for the use of Terminalia chebula fruit in folk medicine to treat various infectious diseases and could be useful for the development of alternative/ complementary medicine for multidrug-resistant uropathogens.
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In the present study, an attempt was made to compare the statistical tools used for analysing the data of repeated dose toxicity studies with rodents conducted in 45 countries, with that of Japan. The study revealed that there was no congruence among the countries in the use of statistical tools for analysing the data obtained from the above studies. For example, to analyse the data obtained from repeated dose toxicity studies with rodents, Scheffé’s multiple range and Dunnett type (joint type Dunnett) tests are commonly used in Japan, but in other countries use of these statistical tools is not so common. However, statistical techniques used for testing the above data for homogeneity of variance and inter-group comparisons do not differ much between Japan and other countries. In Japan, the data are generally not tested for normality and the same is true with the most of the countries investigated. In the present investigation, out of 127 studies examined, data of only 6 studies were analysed for both homogeneity of variance and normal distribution. For examining homogeneity of variance, we propose Levene’s test, since the commonly used Bartlett’s test may show heterogeneity in variance in all the groups, if a slight heterogeneity in variance is seen any one of the groups. We suggest the data may be examined for both homogeneity of variance and normal distribution. For the data of the groups that do not show heterogeneity of variance, to find the significant difference among the groups, we recommend Dunnett’s test, and for those show heterogeneity of variance, we recommend Steel’s test.
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The generation and activity of serum neuralizing antibody in cynomolgus monkeys and SD rats undergoing long-term toxicity study with antitumor peptides HM-3 were investigated.The rats were administered intravenously with HM-3 at doses of 4.5 mg/kg,13.5 mg/kg,and 40.5 mg/kg for 6 months,and the cynomolgus monkeys were administrated intravenously with HM-3 at doses of 3 mg/kg,9 mg/kg and 27 mg/kg for 6 months,respectively.Anti-HM-3 antibodies and their neutralizing activities in serum samples taken every month after the administrations were determined by ELISA and cell migration assay,respectively.During the long-term administrations,anti-HM-3 antibodies were generated in some SD rats at high and moderate dose groups,and the antibody-neutralizing activities could be detected in a number of these samples (P ＜0.05).However,activity could be detected in very few monkeys (P ＜ 0.05),and the antibody titers were not correlated with the neutralizing activities.Therefore,we conclude that the antigenicity of HM-3 was low,but after long-term administration at high dose,low affinity neutralizing antibody could be generated in small number of samples.
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In repeated-dose 28-day oral toxicity study design, the low dose is fixed as the no observed effect level (NOEL). But, in practice the low dose usually shows significant difference in few measurable items in most of the studies. We investigated 109 of repeated-dose 28-day oral toxicity studies in rats conducted according to the Chemical Substance Control Law, Japan and examined the measurable items (functional observational battery, urinalysis, hematology, blood chemistry and absolute and relative organ weights) of the low dose group which showed a statistical significant difference (P<0.05) compared to the respective control groups. The investigation revealed that, 205/12,167 (1.6%) measurable items showed a significant difference in the low dose groups. The significant difference shown by urinalysis was high (3.3%), followed by clinical chemistry parameters, hematology, relative organ weights and absolute organ weights (1.8-1.1%). We conclude from the investigation that the low dose may be considered as NOEL, if the significant difference of measurable items of it is about 2% (maximum <5%), compared to the control. However, due consideration may be given to the clinical relevance of the items that showed a significant difference.
Subject(s)
Animals , Rats , Chemistry, Clinical , Hematology , Japan , Jurisprudence , No-Observed-Adverse-Effect Level , Organ Size , UrinalysisABSTRACT
In repeated-dose 28-day oral toxicity study design, the low dose is fixed as the no observed effect level (NOEL). But, in practice the low dose usually shows significant difference in few measurable items in most of the studies. We investigated 109 of repeated-dose 28-day oral toxicity studies in rats conducted according to the Chemical Substance Control Law, Japan and examined the measurable items (functional observational battery, urinalysis, hematology, blood chemistry and absolute and relative organ weights) of the low dose group which showed a statistical significant difference (P<0.05) compared to the respective control groups. The investigation revealed that, 205/12,167 (1.6%) measurable items showed a significant difference in the low dose groups. The significant difference shown by urinalysis was high (3.3%), followed by clinical chemistry parameters, hematology, relative organ weights and absolute organ weights (1.8-1.1%). We conclude from the investigation that the low dose may be considered as NOEL, if the significant difference of measurable items of it is about 2% (maximum <5%), compared to the control. However, due consideration may be given to the clinical relevance of the items that showed a significant difference.