Observations of alanine aminotransferase and aspartate aminotransferase in THRIVE studies treated orally with ximelagatran

Treatment of acute venous thromboembolism (VTE) and prophylaxis of recurrent events has been investigated in the THRIVE (THRombin Inhibitor in Venous Thrombe Embolism) Treatment and the THRIVE III trial using the oral direct thrombin inhibitor ximelagatran. Alanine aminotransferase (ALAT) increased in 9.6% and 6.4% of patients in the THRIVE Treatment and THRIVE III trials, respectively. The authors analysed the time course of the ALAT and in additionally of aspartate aminotransferase (ASAT) in blood from 52 and 23 patients participating in the THRIVE Treatment and the THRIVE III trials in Germany. Analysis of variance for repeated measures and t test were performed. In the THRIVE Treatment trial, ALAT was significantly higher at week 2 for enoxaparin/warfarin (p => .0039, t test) and at months 3 and 6 for ximelagatran (p = .0453, p = .0014, respectively). ASAT and ASAT/ALAT ratio values did not increase and not differ for both groups. In the THRIVE III trial, ALAT and ASAT did not increase and did not differ compared to the comparator placebo. 2 x 36 mg Ximelagatran, induced higher ALAT values at months 3 and 6 compared to 2 x 24 mg ximelagatran (p = .0105, p = .0063, respectively). ASAT did not differ between the two doses of ximelagatran. The ASAT/ALAT ratios were lower at week 2 for enoxaparin/warfarin (t-test, p = .0032) and at month 3 and 6 for 2 x 36 mg versus warfarin or 2 x 24 mg Ximelagatran (p between .0187 and .0002). The authors conclude that ALAT increases dose dependently during therapy with ximelagatran. The less frequent and lower increase of ASAT values compared to ALAT values indicates a nontoxic effect of ximelagatran on liver cells.     

Effects of Azadirachta indica leaves on the seminal vesicles and ventral prostate in albino rats

Oral administration of 20, 40, 60, mg of dry Azadirachta indica leaf powder for 24 days resulted in decrease in the weights of seminal vesicles and ventral prostate, reduction in epithelial height, nuclear diameter and the secretory material in the lumen. Biochemically, there was a decrease in total protein, acid phosphatase activities. Seminal vesicles and ventral prostate being androgen dependent, the regressive changes histologically as well as biochemically, suggests the antiandrogenic property of the neem leaves.     

Effect of Azadirachta indica (Neem) leaf aqueous extract on paracetamol-induced liver damage in rats

The effect of aqueous leaf extract of Azadirachta indica (A. indica) was evaluated in paracetamol induced hepatotoxicity in rats. Liver necrosis was produced by administering single dose of paracetamol (2 g/kg, p.o.). The liver damage was evidenced by elevated levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (gamma-GT) and by histopathological observations of liver sections. Aqueous A. indica leaf extract (500 mg/kg, p.o.) significantly (P < 0.01) reduced these elevated levels of AST, ALT and gamma-GT. Paracetamol induced liver necrosis was also found to be reduced as observed macroscopically and histologically.     

Effect of acarbose on alanine aminotransferase and aspartate aminotransferase activities in the liver of control and diabetic CBA mice

The purpose of this study was to examine the short-term effects of diet containing 0.1% (m/m) of acarbose in standard laboratory chow on specific liver enzyme activities: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in control and diabetic CBA mice. Diabetes was induced by intravenous injection of alloxan monohydrate in a dose of 75 mg kg(-1) mouse body mass seven days before the treatment with acarbose. There were four groups of CBA mice in the experiment: control (C) mice (n = 6) and diabetic (D) mice (n = 8) fed standard chow; control (C/A-100) mice (n = 8) and diabetic (D/A-100) mice (n = 8) fed standard chow containing 0.1% acarbose. Diabetes induced a decrease of the ALT catalytic activities to 69.6% of the control value. A similar level of decreased ALT catalytic activity was detected in the liver of control and diabetic mice fed chow containing 0.1% acarbose. No changes in the specific and total activities of AST in the liver of experimental groups were observed.     

Abamectin effects on aspartate aminotransferase and nitric oxide in rats

Abamectin is widely used as an insecticide and an anthelmintic. A previous report indicated that abamectin was used to commit suicide and led to death in Taiwan. This investigation focused on the toxicological effects of abamectin on serum aspartate aminotransferase (AST) and nitrate/nitrite (NO) levels in rats. After rats were gavaged with abamectin ranging from 1 to 20 mg/kg/body weight, AST and NO levels were examined within 12 h. AST and NO levels were elevated in abamectin-dosed rats in a dose-dependent manner. The least increase of AST corresponded to the highest enhancement of NO release at 6 h. A negative correlation coefficient (r=-0.55) between AST and NO was found. Both NG-nitro-L-arginine-methyl ester and aminoguanidine, inhibitors of nitric oxide synthase, increased the AST level induced by abamectin. These findings suggest that NO may be involved in the alteration of AST release induced by abamectin in rats.     

A study of cardiovascular effects of Azadirachta indica (neem) on isolated perfused heart preparations

The effects of aqueous leaf extract of Azadirachta indica were evaluated on isolated prefused frog and rabbit heart. Dose dependent negative inotropic and chronotropic effects were observed in both the heart preparation. An increase in coronary blood flow in isolated rabbit heart was observed. The effects were not blocked by atropine and mepyramine in both the preparations. The data suggests that A. indica could be of benefit in coronary artery disease and arrhythmias.     

Effect of aqueous extract of neem (Azadirachta indica) leaves on offensive and diffensive gastric mucosal factors in rats

Standardized aqueous extract of Neem (Azadirachta indica) leaves (AIE) has been reported to show both ulcer protective and ulcer healing effects in normal as well as in diabetic rats. To study the mechanism of its ulcer protective/healing actions, effects of AIE (500 mg/ kg) was studied on various parameters of offensive acid-pepsin secretion in 4 hr pylorus ligation, pentagastrin (PENTA, 5 microg/kg/hr)-stimulated acid secretion and gastric mucosal proton pump activity and defensive mucin secretion including life span of gastric mucosal cells in rats. AIE was found to inhibit acid-pepsin secretion in 4 hr pylorus ligated rats. Continuous infusion of PENTA significantly increased the acid secretion after 30 to 180 min or in the total 3 hr acid secretion in rat stomach perfusate while, AIE pretreatment significantly decreased them. AIE inhibited the rat gastric mucosal proton pump activity and the effect was comparable with that of omeprazole (OMZ). Further, AIE did not show any effect on mucin secretion though it enhanced life span of mucosal cells as evidenced by a decrease in cell shedding in the gastric juice. Thus, our present data suggest that the ulcer protective activity of AIE may be due to its anti-secretary and proton pump inhibitory activity rather than on defensive mucin secretion. Further, acute as well as sub acute toxicity studies have indicated no mortality with 2.5 g/kg dose of AIE in mice and no significant alterations in body or tissues weight, food and water intake, haematological profile and various liver and kidney function tests in rats when treated for 28 days with 1 g/kg dose of AIE.     

Ultrastructural changes induced by leaves of Azadirachta indica (Neem) in the testis of albino rats

The present work was designed to study the effect of Azadirachta indica (Neem) powder on rat testis using the electron microscope. Male albino rats received 100 mg each A. indica leaf powder orally (by gavage). On alternate days, a second group of rats received 0.125 mg testosterone dipropionate intramuscularly. A third group received both A. indica leaf powder by gavage and testosterone dipropionate intramuscularly. Suitable controls were maintained. After autopsy, ultrastructural analysis of the testis revealed that animals treated with testosterone dipropionate showed well-developed Sertoli cells and germ cells with well-developed cytoplasmic organelles. By contrast, in A. indica-treated rats, intracellular spaces and vacuolization were observed in Sertoli cells; whereas in Leydig cells, cytoplasmic inclusions appeared diminished, and the configuration of granular endoplasmic reticulum appeared as a single unbranched tubule. In late spermatids, defects were observed in the mitochondrial sheath. The ultrastructural changes seen in the A. indica-treated group provide a clue that A. indica leaves might affect spermatogenesis through antispermatogenic and antiandrogenic properties.     

A study of hypoglycaemic effects of Azadirachta indica (Neem) in normaland alloxan diabetic rabbits

Hypoglycaemic effect was observed with Azadirachta indica when given as a leaf extract and seed oil, in normal as well as diabetic rabbits. The effect, however, was more pronounced in diabetic animals in which administration for 4 weeks after alloxan induced diabetes, significantly reduced blood glucose levels. Hypoglycaemic effect was comparable to that of glibenclamide. Pretreatment with A. indica leaf extract or seed oil administration, started 2 weeks prior to alloxan, partially prevented the rise in blood glucose levels as compared to control diabetic animals. The data suggests that A. indica could be of benefit in diabetes mellitus in controlling the blood sugar or may also be helpful in preventing or delaying the onset of the disease.     

Phenolic acids in neem (Azadirachta indica): a major pre-existing secondary metabolites

High Performance Liquid Chromatographic (HPLC) analyses of various parts (fresh and dry bark of stem, mature and tender leaves, flower and different parts of fruit, i.e., raw and ripe fruit epicarp, mesocarp and seed) of neem (Azadirachta indica), which occupies an important place in socio-cultural-religious life in Indian communities, indicate that neem is rich in pre-existing secondary metabolites (phenolic acids). Dry bark showed only tannic acid but in fresh bark three phenolic acids were observed, i.e., gallic, tannic, and ferulic acids. In tender leaves only gallic and ferulic acids were detected, but the levels of these phenolic acids in mature leaves were about three times and fifty times greater, respectively. Flowers had only two phenolic acids in which gallic acid was maximum followed by chlorogenic acid. The level of phenolic acid was maximum in seeds followed by epicarp and pulp. In raw and ripe fruit seeds four phenolic acids were detected. Raw fruit seeds were rich in phenolic acids than ripe fruit seeds. Fruit epicarp was relatively richer than seed, seed pulp and flowers of the plants. Neem flowers were also rich in gallic and chlorogenic acids.     

Anti-leukemic activity of sulfonoquinovosyldiacylglyceride (SQDG): a constituent of Azadirachta indica leaves

The sulfonoquinovosyldiacylglyceride (SQDG) isolated from the leaves of Azadirachta indica showed significant anti-leukemic activity in human leukemic cell lines U937 and K562 with IC₅₀ of 9 μg/ml. SQDG treated leukemic cells showed chromatin condensation, apoptotic body formation, and increased caspase 3 production indicating apoptosis. Cell cycle study revealed that the treated leukemic cells accumulated in the sub-G₁ phase; the cell cycle was halted in this phase and the DNA content decreased in other phases.     

肝脏疾病患者血清中线粒体型天门冬氨酸氨基转移酶检测的临床意义

目的探讨线粒体型天门冬氨酸氨基转移酶（m—AST）以及m—AST与天门冬氨酸氨基转移酶（AST）比值在各类肝脏疾病中的变化规律及临床意义。方法用免疫抑制法测定各类肝脏疾病患者血清中m—AST和AST,计算出mAST／AST比值,观察其在入院时与治疗后的变化。结果患者入院时,mAST／AST比值从高到低依次为重型肝炎0．435±0．061、急性肝炎0．375±0．057、药物性肝炎0．321±0．035、慢性肝炎0．317±0．031、肝炎肝硬化0．276±0．031,均显著高于正常对照组（P〈0．05）;治疗后,急性肝炎组和药物性肝炎组mAST／AST比值明显下降,其他组无明显变化。结论动态监测血清mAST／AST比值的变化有利于急性肝炎、重型肝炎的预后判断和急性肝炎与慢性肝炎的鉴别诊断,对急性和药物性肝炎的评估和诊断治疗有指导价值。     

Neurobehavioural study of subchronic administration of oxydemeton-methyl (insecticide and acaricide) in rats

Oxydemeton-methyl, an organophosphate insecticide and acaricide produced decrease in the exploratory behaviour and prolongation of barbitone sodium induced hypnosis in rats after intermittent aerosol spray inhalational exposure, for 1/2 hour daily for 7 consecutive days, compared to the saline control group. Further, ED50 +/- SEM value for haloperidol induced catalepsy, CD50 +/- SEM value for pentylenetetrazole induced seizure and CI50 +/- SEM value for electroshock (i.e. the dose of haloperidol, PTZ and intensity of electroshock producing catalepsy or positive seizure response in 50% of rats) were significantly decreased after 7 days exposure to oxydemeton-methyl compared to that of saline control group. The study has established the central nervous system depressant effect, extrapyramidal effect and proconvulsant potential of oxydemeton-methyl which is widely used by the agricultural workers in the form of field spray.     

Acute and subchronic (28-day) oral toxicity study in rats fed with novel surfactants

The toxicity of 2 new synthetic lipids, 1,2-dioleoyl-rac-glycerol-3-dodecaethylene glycol, GDO-12 (lipid 1) and 1,2-distearoyl-rac-glycerol-3-dodecaethylene glycol, GDS-12 (lipid 2) has been evaluated in acute and subchronic toxicity studies. Acute oral toxicity studies in male and female rats documented no deaths or treatment-related signs at high doses. The lipids were individually administered (by gavage) to male and female Sprague-Dawley rats at concentrations of 250, 500, and 1000 mg/Kg bodyweight for 28 days. All animals survived the duration of the study, with no significant changes in clinical signs, hematological parameters, organ weights, ophthalmology evaluations, or histopathological findings. These studies establish that both GDO-12 (lipid 1) and GDS-12 (lipid 2) are nontoxic in rats following oral administration. The no-observed-adverse-effect level ranged between 250 mg/Kg and 1000 mg/Kg following oral administration.     

Toxicological evaluation of neem (Azadirachta indica) oil: Acute and subacute toxicity

Neem (Azadirachta indica), popularly known as traditional medicine is a native plant in India. Neem oil is a vegetable oil derived from seeds or fruits of the neem tree through pressing or solvent extraction, and largely used in popular medicine to have antifungal, antibacterial, antimalarial, antiparasitic, anti-inflammatory, as well as immunemodulatory properties in different animal species. In the present study, acute and 28-day subacute toxicity tests were carried out. In the acute toxicity test, the LD₅₀ values of neem oil were found to be 31.95 g/kg. The subacute treatment with neem oil failed to change body weight gain, food and water consumption. Serum biochemistry analysis showed no significant differences in any of the parameters examined under the dose of 1600 mg/kg/day. Histopathological exams showed that the target organs of neem oil were testicle, liver and kidneys up to the dose of 1600 mg/kg/day.     

A subchronic oral toxicity study on pyrroloquinoline quinone (PQQ) disodium salt in rats

A subchronic oral toxicity study on pyrroloquinoline quinone (PQQ) disodium salt was performed in rats. Sprague-Dawley rats were randomly divided into four groups (10 rats/sex/group) and administered with PQQ disodium salt at doses of 0 (control), 100, 200 and 400 mg/kg bw/day by gavage for 13 weeks. Daily clinical observations and weekly measurement of body weights and food consumption were conducted. Blood samples were obtained on day 46 and day 91 for measurement of hematology and serum biochemical parameters. Animals were euthanized for necropsy, selected organs were weighted and recorded. Histological examination was performed on all tissues from animals in the control and PQQ disodium salt treatment groups. No mortality or toxicologically significant changes in clinical signs, body weight, food consumption, necropsy findings or organ weights was observed. Differences between treated and control groups in some hematological and serum biochemical examinations and histopathological examination were not considered treatment-related. The no-observed-adverse-effect-level (NOAEL) of PQQ disodium salt in rats was considered to be 400 mg/kg bw/day for both sexes, the highest dose tested.     

A subchronic inhalation study with unleaded petrol in rats

The effect of intermittent 2 months' exposure to 2 g/m3 unleaded petrol on the hypothalamo-pituitary-thyroid-adrenal system was evaluated by measuring hypothalamic noradrenaline (NA), serum corticosterone (CS), thyroxine (T4) and adrenal catecholamine (CA) levels in male rats. Serum CS and adrenal CA were increased and hypothalamic NA was decreased by exposure. No changes were observed in serum T4. Exposure induced an increase in spleen, kidney, liver and lung weights; weights of adrenals and hypothalamus were not changed. All the petrol-induced effects depended on the length of exposure. Rats exposed to petrol gained less weight than controls. The results suggest a non-specific stress response in the rat.     

Effects of pyridoxal 5'-phosphate on plasma alanine aminotransferase determinations in toxicological studies

Alanine aminotransferase activities (ALT) were measured in rat plasma samples with three different reagent formulations. The inclusion of pyridoxal 5′-phosphate in the reagent produced higher ALT values, and altered the statistical relationships between control and treatment groups in three studies where plasma ALT values were reduced by xenobiotics.