血细胞形态及血常规指标MCV、MCH、MCHC、RDW对婴幼儿缺铁性贫血的诊断价值

目的 探讨血细胞形态检测及血常规指标MCV、MCH、MCHC、RDW对婴幼儿缺铁性贫血的诊断价值.方法 分别根据血细胞形态及血常规指标MCV、MCH、MCHC、RDW判定为小细胞低色素性贫血病例并收集,同时检测所有病例的血清铁蛋白和血清铁.分别分析两种方法所判定的小细胞低色素性贫血中缺铁性贫血的阳性率;再联合两种方法,观察它们在诊断缺铁性贫血中的价值.结果 根据血细胞形态所判定为小细胞低色素性贫血中最后确诊为缺铁性贫血的占70.5％;由血常规指标MCV、MCH、MCHC、RDW判定为小细胞低色素性贫血中最后确诊为缺铁性贫血的占83.8％;联合血细胞形态及血常规指标MCV、MCH、MCHC、RDW判定为小细胞低色素性贫血中最后确诊为缺铁性贫血的占94.9％.结论 分别检测血细胞形态及血常规指标MCV、MCH、MCHC、RDW对缺铁性贫血诊断具有一定的价值,若联合检测可显著提高缺铁性贫血的检出率.     

A two-year dietary carcinogenicity study of cyadox in Sprague-Dawley rats

To investigate the potential carcinogenicity of cyadox, an antimicrobial agent, four groups of Sprague-Dawley rats (50 rats/sex/group) were fed diets containing cyadox (0, 200, 600 or 2000 mg/kg) for up to two years. There were significant decreases in body weight, feed intake and feed efficiency in both genders during most of the period in the 2000 mg/kg group. Significant decreases in serum ALT were observed in the 2000 mg/kg group at weeks 52, 78 and 104. For the control, 200, 600, and 2000 mg/kg groups, the tumor incidence in females was 33.3%, 37.2%, 40.0% and 19.0%, while it in males it was 18.9%, 2.6%, 17.1% and 13.6%, respectively. At histopathology, no increases in tumor incidence were attributed to treatment with cyadox. The mild swelling and fatty degeneration in hepatocytes, and mild swelling and tubular necrosis in the kidney were observed in 2000 mg/kg group. The no-observed-effect-level (NOEL) for carcinogenicity of cyadox fed to rats was 2000 mg/kg diet (132.18–156.28 mg/kg b.w./day). In conclusion, cyadox was not carcinogenic to rats with the liver and kidney as the target organs, and the side chain may be involved in toxicity and carcinogenicity mediated by QdNOs.     

Development of safety profile evaluating pharmacokinetics, pharmacodynamics and toxicity of a combination of pioglitazone and olmesartan medoxomil in Wistar albino rats

Pioglitazone (PIO), an antidiabetic drug and olmesartan medoxomil (OLM), an antihypertensive drug were administered orally alone and in combination to Wistar albino rats for evaluation of pharmacokinetics, pharmacodynamics and repeated dose 28-day oral toxicity of individual drugs and their combination. Pharmacokinetic study was performed by orally administering PIO and OLM at single dose of 3 and 2mg/kg, respectively alone and in combination analyzing the plasma samples using LC-MS/MS. Antidiabetic activity evaluation was done in type-2 diabetes mellitus induced animals at same dose level as in pharmacokinetic study daily for 30 days. PIO and/or OLM were administered orally to animals at daily doses of 50, 100 and 150 mg/kg for 28 days for toxicity study. There was no significant alteration in the pharmacokinetic parameters of either drug indicating absence of any pharmacokinetic interaction when co-administered. Positive pharmacodynamic interaction between PIO and OLM was established in this study. Two drugs in combination showed no evidence of potentiation of 28-day repeated dose toxicity in animals. Again, drugs, alone and in combination, caused only minor changes in clinical-laboratory tests and histopathological change was not found in the experiment performed. In conclusion, PIO and OLM combination can primarily be stated as safe in terms of present toxicity and pharmacokinetics findings.     

Safety evaluation of fibermalt

Fibermalt is a new soluble fiber food ingredient produced with the use of an alternansucrase enzyme from Leuconostoc mesenteroides expressed in a non-pathogenic strain of Escherichia coli. Fibermalt is predominantly composed of indigestible maltose alternan oligosaccharides (?80%). Fibermalt was non-mutagenic in a bacterial reverse mutation test. In a 13-week dietary rat study, fibermalt was administered at 0 (control), 50,000, 100,000 or 150,000 ppm. Statistically significant increases in food consumption were generally observed throughout the study in males receiving 100,000 or 150,000 ppm and in females receiving 100,000 ppm. However, there was no effect of fibermalt on mean body weight, body weight gain or food efficiency. All animals survived to scheduled termination and no adverse clinical signs were attributed to administration of fibermalt. There were no toxicologically relevant changes in hematology, clinical chemistry or urinalysis parameters or organ weights in males or females ingesting any concentration of fibermalt. Any macroscopic or microscopic findings were considered incidental, of normal variation and/or of minimal magnitude for test substance association. Based on these results, fibermalt is not mutagenic as evaluated in a bacterial reverse mutation test and has an oral subchronic (13-week) no observable adverse effect level (NOAEL) of 150,000 ppm in rats.     

Dietary fat level affects tissue iron levels but not the iron regulatory gene HAMP in rats

Because dietary fats affect the regulation and use of body iron, we hypothesized that iron regulatory and transport genes may be affected by dietary fat. A model of early-stage I to II, nonalcoholic fatty liver was used in which rats were fed standard (35% energy from fat) or high-fat (71% energy from fat) liquid diets with normal iron content (STD/HF groups). In addition, intraperitoneal injections of iron dextran were given to iron-loaded (STD+/HF+ groups) and iron-deficient diets to STD−/HF− groups. Plasma osmolality, hemoglobin level, and mean corpuscular hemoglobin concentration were increased in all STD diet groups compared with all HF diet groups. Plasma iron and transferrin saturation were affected by an interaction between dietary fat and iron. They were high in the STD group (normal iron) compared with their respective HF group. Similarly, this group also showed a 4-fold increase in the messenger RNA expression of the hepatic hemochromatosis gene. Spleen iron was high in the iron-loaded STD+ group compared with all other groups. Hepatic iron and messenger RNA expression of peroxisome proliferator–activated receptor-γ, CCAAT/enhancer binding protein α, interleukin-6, and iron transport genes (transferrin receptor 2, divalent metal transporter 1 iron-responsive element, and divalent metal transporter 1 non–iron-responsive element) were increased, whereas tumor necrosis factor α was decreased in the HF diet groups. The expression of iron regulatory gene HAMP was not increased in the HF diet groups. Iron regulatory and transport genes involved in cellular and systemic iron homeostasis may be affected by the macronutrient composition of the diet.     

A 90-day oral (dietary) toxicity study of the 2R,4R-isomer of monatin salt in Sprague–Dawley rats

The root bark of Sclerochitin ilicifolius contains an intensely sweet substance analytically identified as isomers of 2-hydroxy-2-(indol-3-ylmethyl)-4-aminoglutaric acid and generically coined “monatin.” Groups of male and female Crl:CD(SD) rats were fed 0 (control), 5000, 10,000, 20,000 or 35,000 ppm R,R-monatin salt in the diet for 90 days. There were no toxicologically relevant clinical or histopathological findings in any of the test article-treated groups. Significantly lower cumulative body weight gains were noted in the 35,000 ppm group. Mean body weights in the 35,000 ppm group males and females were 7% and 12% lower, respectively, than the control group at study week 13. In the absence of other observations associated with systemic toxicity and lower food consumption, the magnitude of the body weight difference in the 35,000 ppm group females relative to the control group exceeded 10%, which indicated attainment of a maximum tolerated dose (MTD) level. Based on the results of this study, and conservatively assuming the body weight observations at the MTD to be indicative of an adverse effect, the dietary no-observed-adverse-effect level (NOAEL) of R,R-monatin salt for 90 days was 20,000 ppm in female rats (approximately 1544 mg/kg bw/day) and 35,000 ppm in male rats (approximately 2368 mg/kg bw/day).     

A subacute toxicity evaluation of green tea (Camellia sinensis) extract in mice

Green tea is believed to be beneficial to health because it possesses antioxidant, antiviral and anticancer properties. The potential toxicity of green tea when administered at high doses via concentrated extracts, however, has not been completely investigated. The objective of the present study was to evaluate the safety of green tea extract in ICR mice using a subacute exposure paradigm. In this study, mice were orally administered (gavage) green tea extract at doses of 0 (as normal group), 625, 1250 and 2500 mg/kg body weight/day for 28 days. The results showed that oral administration of green tea extract did not cause adverse effects on body weight, organ weights, hematology, serum biochemistry, urinalysis or histopathology. Additionally, administering green tea extract via gavage significantly reduced triglyceride and cholesterol levels. These observed effects could be attributed to the high levels of catechins present in green tea as these compounds have been reported to have beneficial health effects. The no-observed-adverse-effect level for green tea extract derived from the results of the present study was 2500 mg/kg body weight/day.     

Safety evaluation of a standardized phytochemical composition extracted from Bacopa monnieri in Sprague--Dawley rats.

BacoMind is an enriched phytochemical composition derived from Bacopa monnieri, a common medicinal plant having multiple uses in the traditional system of medicine and particularly used as a memory enhancing agent for centuries. The plant and its extracts have been evaluated for anti-inflammatory, cardio tonic, sedative and neuro-muscular blocking activities. In view of the extensive use of this plant, BacoMind , standardized to bioactive compounds was evaluated in a series of toxicity studies, to confirm the safety of its usage. BacoMind , on single oral administration had a median lethal dose of 2,400 mg/kg in Sprague-Dawley rats. In a 14 day repeated dose oral toxicity study in rats, except for mild lowering in body weight gain in male rats, it was found to be tolerated well up to the dose of 500 mg/kg. A subchronic oral toxicity study for 90 days in rats at the dose levels of 85, 210 and 500 mg/kg did not reveal any evidence of toxicity with respect to clinical signs, neurological examination, food consumption, body weight gain, haematological and blood biochemistry parameters. The absolute and relative organ weight of vital organs did not differ significantly from that of the control. Necropsy and histopathological examination, did not reveal any remarkable and treatment related changes. A no-observed adverse effect level of 500 mg/kg body weight was established in rats.     

Safety evaluation of AMP deaminase from Aspergillus oryzae

Adenosine-5′-monophosphate (AMP) deaminase is an enzyme used to increase concentrations of 5’-inosine monophosphate in certain foods and beverages for flavoring purposes. One commercial source of this enzyme is Aspergillus oryzae, a filamentous fungus with a history of safe use in Asia as a fermentation organism used in the production of miso sauce and sake liquors. Noting the use of the enzyme in food intended for human consumption and potential presence at trace levels in finished goods, a series of safety studies including an in vitro Ames test and chromosome aberration assay with Chinese hamster lung fibroblasts were conducted along with a 90-day oral toxicity study in rats. AMP deaminase showed no evidence of genotoxicity in the in vitro tests. Following gavage administration of Sprague–Dawley rats at dosages of 19.8, 198.4, or 1984 mg total organic solids (TOS)/kg body weight (bw)/day for 90 days, no adverse effects on body weight gain, food consumption, hematology, clinical chemistry, urinalysis, ophthalmological and histopathological examinations were observed. The no-observed-adverse-effect level was considered to be 1984 mg TOS/kg bw/day, the highest dose tested. Results of the genotoxicity studies and subchronic rat study support the safe use of AMP deaminase produced from A. oryzae in food production.     

Subchronic toxicity study of Coptidis Rhizoma in rats

Ethnopharmacological relevance

Coptidis Rhizoma (CR) is a medical herb from the family Ranunculacease that has been used to treat gastroenteritis, dysentery, diabetes mellitus, and severe skin diseases.

Aim of the study

To evaluate the no-observed-adverse-effect level (NOAEL) and the toxicity of CR, following repeat oral administration to rats for 13 weeks.

Materials and methods

CR was administered by oral gavage to groups of rats (n=10/group, each sex) at dose levels of 0 (control), 25, 74, 222, 667 or 2000 mg/kg/day 5 times per week for 13 weeks. Mortality, clinical signs, body weights, food consumption, hematology, serum chemistry, urinalysis, vaginal cytology and sperm morphology, organ weights, gross and histopathological findings were compared between control and CR groups.

Results

Urinalysis showed a significant increase in N-acety1-β-glucosaminidase in males in the 2000 mg/kg/day group (P<0.01). However, no mortality or remarkable clinical signs were observed during this 13-week study. No adverse effects on body weight, food consumption, hematology, serum chemistry, organ weights, gross lesion, histopathology, vaginal cytology, sperm motility, or deformity were observed in the males or female rats treated with CR.

Conclusions

On the basis of these results, the NOAEL of CR is determined to be 667 mg/kg/day for males and 2000 mg/kg/day for females.