Reproductive toxic impact of subchronic treatment with combined butylparaben and triclosan in weanling male rats

The effect of treatment with combined butylparaben and triclosan on male gonadal toxicity in weanling rats was investigated. All treated groups experienced atrophy in the ventral prostate and seminal vesicle, likewise significant depletion in the number and motility of sperm. Given individually or combined butylparaben and triclosan, significantly decreased testosterone, luteinizing hormone, and follicle‐stimulating hormone levels. Individual treatment with tested compounds caused significant elevation in the E₂ level, whereas combined treatment did not alter the E₂ level. Testicular DNA damage was recorded in all treated groups. Moreover, the testicular malondialdehyde level was significantly elevated, along with a significant decrease in catalase enzyme activity in all treated groups. Superoxide dismutase enzyme activity was significantly decreased in the butylparaben‐treated group, increased in the triclosan‐treated group, and nonsignificantly changed the butylparaben‐triclosan‐treated group. The combined treatment produced an endocrine disturbance with a concomitant induction of testicular oxidative stress, which may represent a common mechanism of endocrine disruptor‐mediated dysfunction.     

Effect of alcohol and kolanut interaction on brain sodium pump activity in Wistar Albino rats.

Effect of alcohol-kolanut interaction on Sodium Pump activity in wistar albino rats was studied. Thirty wistar albino rats were divided into six groups of five (5) rats per group and used for the study. The control group (1) received via oral route a placebo (4ml of distilled water). Groups 2 to 6 were treated for a period of 21 days, with (10% v/v) of alcohol (group 2), 50mg/kg body weight of kolanut (group 3), 50 mg/kg body weight of caffeine (group 4), 4ml of 10% v/v of alcohol and 50 mg/kg body weight kolanut (group 5), 4ml of 10% v/v of alcohol and 50 mg/kg body weight of caffeine in 4.0ml of the vehicle via gastric intubation respectively. A day after the final exposure, the brain of each rat was harvested and processed to examine several biochemical parameters, i.e., total ATpase, ouabain-insensitive ATpase, ouabain sensitive ATpase (Na(+)-K(+)ATPase), non-enzymatic breakdown of ATP and inorganic phosphate (Pi) released. The results showed that the essential enzyme of the brain responsible for neuronal function, Na(+)-K(+)ATPase, was inhibited by alcohol-kolanut co-administration relative to control, resulting in a decrease in Na(+)-K(+)ATPase activity, ATP production, ion transport and action potential, leading to loss of neuronal activities.     

Effect of chronic administration of phenytoin on regional monoamine levels in rat brain

Phenytoin (DPH) is a widely used anticonvulsant drug but a conclusive mode of action is not yet clear. This study was undertaken to assess the effects of chronic administration of DPH on monoamine levels. DPH (50 mg/kg body weight) was administered to adult male Wistar rats by intraperitoneal injections for 45 days and the regional brain levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were assayed using high performance liquid chromatographic (HPLC) method. The experimental rats revealed no behavioral deficits of any kind nor body and brain weight deficits were observed. Increased NE levels were observed after DPH administration in motor cortex (P<0.05), striatum-accumbens (P<0.01) and hippocampus (P<0.01), whereas, NE level was decreased in brain stem (P<0.05). DA levels were increased in striatum-accumbens (P<0.05), hypothalamus (P<0.001) and cerebellum (P<0.001) but decreased in brainstem (P<0.01). In DPH treated rats, 5-HT levels were increased in motor cortex (P<0.001) but decreased in cerebellum (P<0.001) when compared to control group of rats. The present study suggest that chronic administration of DPH induces alterations in monoamine levels in specific brain regions. DPH seems to mediate, its anticonvulsant action by selectively altering the monoamine levels in different brain regions.     

Probabilistic Estimates of Lifetime Daily Doses from Consumption of Drinking Water Containing Trace Levels of N,N-diethyl-meta-toluamide (DEET), Triclosan,or Acetaminophen and the Associated Risk to Human Health

Risk assessments were conducted for N,N-diethyl-meta-toluamide (DEET), triclosan, and acetaminophen to evaluate the risk from exposure to trace levels of these chemicals through drinking water consumption. We estimated exposure to these chemicals through drinking water consumption by generating distributions for key exposure parameters using Monte Carlo analysis. Body weight and water consumption was modeled using data from the U.S. Environmental Protection Agency (USEPA) Exposure Factor Handbook. Water concentrations were derived from reported concentrations in streams. Dose-response was evaluated through extensive literature searches for toxicology data for each chemical. Acceptable daily intakes (ADIs) were then derived from the available toxicology data. The exposure distributions were compared to the ADIs to evaluate the potential risk to the population from drinking water exposure. ADIs of 0.100, 0.153, and 0.05 mg/kg-day were derived for DEET, acetaminophen and triclosan, respectively. The maximum estimated exposures (0.082, 0.834, and 0.193 μ g/kg/day for DEET, acetaminophen, and triclosan, respectively) were at least 100-fold lower than the corresponding ADIs. Based on these assessments, we conclude that there is minimal risk to human health from exposure to these chemicals at the reported concentrations in U.S. streams.     

The effect ofl-deprenyl on behavior,cognitive function,and biogenic amines in the dog

Behavioral and pharmacological effects of oral administration ofl-deprenyl in the dog are described. Spontaneous behavior is unaffected at doses below 3 mg/kg while at higher doses there was stereotypical responding. There was evidence of improved cognitive function in animals chronically treated with a 1 mg/kg dose but the effectiveness varied considerably between subjects. Chronic administration produced a dose dependent inhibition in brain, kidney and liver monoamine oxidase B, and had no effect on monoamine oxidase A. There were also dose dependent increases in brain phenylethylamine and in plasma levels of amphetamine. Dog platelets did not have significant levels of MAO-B. Brain dopamine and serotonin metabolism were unaffected byl-deprenyl at doses up to 1 mg/kg. It appears that for the dog, deamination of catecholamines is controlled by MAO-A. Nevertheless, it is suggested thatl-deprenyl serves as a dopaminergic agonist, and there is also evidence that it affects adrenergic transmission. These catecholaminergic actions may account for the effects ofl-deprenyl on behavior and cognitive function.     

Assessment of female and male fertility in Sprague-Dawley rats administered vorinostat, a histone deacetylase inhibitor

BACKGROUND: Histone deacetylase (HDAC) inhibitors have been shown to mediate the regulation of gene expression, induce cell growth, cell differentiation, and apoptosis of tumor cells. These compounds are now marketed or are in clinical development. One such HDAC inhibitor, vorinostat (suberoylanilide hydroxamic acid [SAHA], Zolinza), was assessed for its potential effects on fertility in Sprague–Dawley rats. METHODS: Female rats were administered oral dose levels of 0 (vehicle only), 15, 50, or 150 mg/kg/day of vorinostat for 14 days before cohabitation, during cohabitation, and through Gestation Day (GD) 7. In a separate study, male rats were administered oral dose levels of 0 (vehicle only), 20, 50, or 150 mg/kg/day for 10 weeks before cohabitation, during cohabitation, and until the day before scheduled sacrifice (approximately 14 weeks total). In both studies, % peri‐implantation loss and % postimplantation loss were evaluated on GD 15–17. Testicular weight and histomorphology, cauda epididymal sperm count, and sperm motility were evaluated in the male rat study at termination. RESULTS: There were treatment‐related decreases in body weight gain at 150 mg/kg/day in both studies. There were no effects on mating or fertility indices in either study. In the female study there were increased numbers of corpora lutea in all drug‐treated groups (only 1 or 2 affected dams in low and mid‐dose groups), and a marked increase in percent postimplantation loss only in the high‐dose group. No treatment‐related effects were observed on litter or sperm parameters of the male study. CONCLUSIONS: Vorinostat had no effects on mating or fertility in rats up to 150 mg/kg/day. There were no indications of reproductive toxicity in drug‐treated male rats. Increases in corpora lutea or resorptions were observed in treated female rats. Birth Defects Res (Part B) 80:1–8, 2007. © 2007 Wiley‐Liss, Inc.     

Neuroprotective effect of rutin against colistin-induced oxidative stress,inflammation and apoptosis in rat brain associated with the CREB/BDNF expressions

The purpose of the current study was to examine the neuroprotective effect of rutin against colistin-induced neurotoxicity in rats. Thirty-five male Sprague Dawley rats were randomly divided into 5 groups. The control group (orally received physiological saline), the rutin group (orally administered 100 mg/kg body weight), the colistin group (i.p. administered 15 mg/kg body weight), the Col?+?Rut 50 group (i.p. administered 15 mg/kg body weight of colistin, and orally received 50 mg/kg body weight of rutin), the Col?+?Rut 100 group (i.p. administered 15 mg/kg body weight of colistin, and orally received 100 mg/kg body weight of rutin). Administration of colistin increased levels of glial fibrillary acidic protein and brain-derived neurotrophic factor and acetylcholinesterase and butyrylcholinesterase activities while decreasing level of cyclic AMP response element binding protein and extracellular signal regulated kinases 1 and 2 (ERK1/2) expressions. Colistin increased oxidative impairments as evidenced by a decrease in level of nuclear factor erythroid 2-related factor 2 (Nrf-2), glutathione, superoxide dismutase, glutathione peroxidase and catalase activities, and increased malondialdehyde content. Colistin also increased the levels of the apoptotic and inflammatoric parameters such as cysteine aspartate specific protease-3 (caspase-3), p53, B-cell lymphoma-2 (Bcl-2), nuclear factor kappa B (NF-κB), Bcl-2 associated X protein (Bax), tumor necrosis factor-α (TNF-α) and neuronal nitric oxide synthase (nNOS). Rutin treatment restored the brain function by attenuating colistin-induced oxidative stress, apoptosis, inflammation, histopathological and immunohistochemical alteration suggesting that rutin supplementation mitigated colistin-induced neurotoxicity in male rats.

     

Gastro-protective and Anti-stress Efficacies of Monomethyl Fumarate and a <Emphasis Type="Italic">Fumaria indica</Emphasis> Extract in Chronically Stressed Rats

Results of the very first experiments conducted to evaluate therapeutic potentials of a fumarate containing Fumaria indica extract and of fairly low daily oral doses of monomethyl fumarate for prevention of chronic unavoidable foot-shock stress-induced gastric ulcers, and possible involvement of diverse neuro-hormonal and oxidative process in their stress response desensitizing effects are reported and discussed in this article. Preventive effects of 21 daily oral 60, 120, and 240 mg/kg doses of a standardized 50 % methanolic F. indica extract (MFI) and 1.25, 2.50, and 5.00 mg/kg/day of pure monomethyl fumarate (MMF) were compared in rats subjected to one hour daily unavoidable foot-shocks. A pharmaceutically well-standardized Withania somnifera (WS) root extract was used as a reference herbal anti-stress agent in all experiments. Effects of the treatments on stress-induced alterations in body weight, adrenal and spleen weights, gastric ulcer and ulcer index, weight of glandular stomach, protective mucosal glycoprotein content, cellular proliferation, oxidative stress on stomach fundus, and brain tissues of male rats were quantified. Other parameters quantified were plasma corticosterone levels, brain monoamine levels, and expressions of the cytokines TNF-α, IL-10, and IL-1β in blood and brain of stressed and treated rats. Most but not every observed stress-induced anomalies were suppressed or completely prevented by both MFI and pure MMF treatments in dose-dependent manner. Qualitatively, the observed activity profiles of both of them were similar to those of WS dose tested. These results reveal that both MFI and MMF are potent gastro-protective agents against chronic unavoidable stress-induced ulcers and strongly suggest that they act as regulators or modulators of monoamine, corticosterone, and cytokine homeostasis.     

Plasmalogen Augmentation Reverses Striatal Dopamine Loss in MPTP Mice

Plasmalogens are a class of glycerophospholipids shown to play critical roles in membrane structure and function. Decreased plasmalogens are reported in the brain and blood of Parkinson’s disease (PD) patients. The present study investigated the hypothesis that augmenting plasmalogens could protect striatal dopamine neurons that degenerate in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in mice, a PD model. First, in a pre-treatment experiment male mice were treated for 10 days with the docosahexaenoic acid (DHA)-plasmalogen precursor PPI-1011 (10, 50 and 200 mg/kg). On day 5 mice received MPTP and were killed on day 11. Next, in a post-treatment study, male mice were treated with MPTP and then received daily for 5 days PPI-1011 (5, 10 and 50 mg/kg). MPTP treatment reduced serum plasmalogen levels, striatal contents of dopamine (DA) and its metabolites, serotonin, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). Pre-treatment with PPI-1011 (10 and 50 mg/kg) prevented all MPTP-induced effects. Positive correlations were measured between striatal DA contents and serum plasmalogen levels as well as striatal DAT and VMAT2 specific binding. Post-treatment with PPI-1011 prevented all MPTP-induced effects at 50 mg/kg but not at lower doses. Positive correlations were measured between striatal DA contents and serum plasmalogen levels as well as striatal DAT and VMAT2 specific binding in the post-treatment experiment. PPI-1011 treatment (10 days at 5, 10 and 50 mg/kg) of intact mice left unchanged striatal biogenic amine contents. These data demonstrate that treatment with a plasmalogen precursor is capable of protecting striatal dopamine markers in an animal model of PD.     

Reproductive activities of female albino rats treated with quassin, a bioactive triterpenoid from stem bark extract of Quassia amara

To evaluate the effect of quassin on female reproductive functions, 42 albino rats (35 females and 7 males) were used. The female albino rats were divided into seven groups of five rats each. Group I served as the control group and received distilled water while Groups II, III and IV rats were treatedorally with 0.1mg/kg, 1.0 mg/kg and 2.0 mg/kg body weight of quassin for 60 days respectively. Groups V, VI and VII rats were also treated orally with 0.1 mg/kg, 1.0mg/kg and 2.0 mg/kg body weight of quassin for 60 days but were left untreated for another 30 days, to serve as the recovery groups. At the end of each experimental period, blood samples were collected from each rat. Fertility study was done by cohabiting one untreated male with the five female rats in each group for 10 days. Quassin did not adversely affect the weight of the kidney, heart, liver and the body of the rats. However there was a significant decrease in the weight of the ovary and uterus in all the groups relative to the control. There was also a significant decrease in serum estrogen levels in quassin treated rats. The quassin treated rats had a significantly decreased mean litter number and weight. Histological studies show a disorganization and degeneration in the ovary while the uterus showed signs of vacuolation and disorganization. However, these effects were ameliorated after quassin was withdrawn from the rats. The results suggest that quassin has female anti-fertility properties, possibly acting via inhibition of estrogen secretion. Keyword: Quassin, Female rat, Reproduction, Estrogen.     

Hesperidin ameliorates heavy metal induced toxicity mediated by oxidative stress in brain of Wistar rats

Cadmium (Cd) induces neurotoxicity owing to its highly deleterious capacity to cross the blood brain barrier (BBB). Recent studies have provided insights on antioxidant properties of bioflavonoids which have emerged as potential therapeutic and nutraceutical agents. The aim of our study was to examine the hypothesis that hesperidin (HP) ameliorates oxidative stress and may have mitigatory effects in the extent of heavy metal-induced neurotoxicity. Cd (3 mg/kg body weight) was administered subcutaneously for 21 days while HP (40 mg/kg body weight) was administered orally once every day. The results of the current investigation demonstrate significant elevated levels of oxidative stress markers such as lipid peroxidation (LPO) and protein carbonyl (PC) along with significant depletion in the activity of non-enzymatic antioxidants like glutathione (GSH) and non-protein thiol (NP-SH) and enzymatic antioxidants in the Cd treated rats’ brain. Activity of neurotoxicity biomarkers such as acetylcholinesterase (AchE), monoamine oxidase (MAO) and total ATPase were also altered significantly and HP treatment significantly attenuated the altered levels of oxidative stress and neurotoxicity biomarkers while salvaging the antioxidant sentinels of cells to near normal levels thus exhibiting potent antioxidant and neuroprotective effects on the brain tissue against oxidative damage in Cd treated rodent model.     

Developmental Toxicity of the HMG‐CoA Reductase Inhibitor (PPD10558) in Rats and Rabbits

PPD10558 is an orally active, lipid‐lowering 3–hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor (statin) being developed as a treatment for hypercholesterolemia in patients who have not been able to tolerate statins because of statin‐associated myalgia. We have studied the potential developmental toxicity effects of PPD10558 in pregnant rats and rabbits given daily oral doses during the period of organogenesis. Rats were dosed with 0, 20, 80, or 320 mg/kg/day from Gestation Day (GD) 6 to 17 and rabbits received dose levels of 0, 12.5, 25, or 50 mg/kg/day from GD 6 to 18. Additional groups in both studies served as toxicokinetic animals and received the PPD10558 in the same manner as the main study groups at the same dose levels. Blood samples were collected from toxicokinetic animals at designated time points on GD 6 and 17 in rats and GD 6 and 18 in rabbits. Fetal exposure in rats was assessed on GD 20. Maternal and developmental parameters were evaluated in rats and rabbits on GD 20 and GD 29, respectively. No maternal and developmental toxicity was observed at any of the dose levels used in the rat study. Evidence of fetal exposure was determined in fetal plasma with mean fetal concentrations of PPD10558 and the metabolite (PPD11901) found to be between 1 and 6% of the mean maternal concentrations. In rabbits, marked maternal toxicity including mortality (eight deaths; 1 dose at 25 and 7 at 50 mg/kg/day), abortions (2 at 25 mg/kg/day and 6 at 50 mg/kg/day) and reduction in gestation body weight, gestation body weight changes and decreased food consumption were observed. In addition, fetal body weights of the combined sexes were significantly reduced at 50 mg/kg/day in comparison with the controls. Mean peak exposure (Cmax) and total exposure (AUC(0–24)) of PPD11901 in both rats and rabbits were higher than that of PPD10558 on GD 6 and GD 17 at each of the three dose levels.. Based on the results of these studies, the no observed adverse effect level (NOAEL) for maternal and developmental toxicity in rats was considered to be ≥320 mg/kg/day, the highest dose level used in the study. The NOAEL for maternal and developmental toxicity in rabbits was 12.5 mg/kg/day and 25 mg/kg/day, respectively.     

Untersuchungen über den Vitamin B2-Bedarf der Legehenne

Because of the well established function of carnitine possible effects of carnitine were studied in poultry. In trial I it was investigated if carnitine and its precursors (lysine, methionine) reduce the formation of abdominal fat in broilers. Chickens (10 groups of 10 chickens each) were fed different diets (control, lysine and methionine in excess and deficient, respectively, with or without 5% fat supplement, L‐carnitine and DL‐carnitine supplement, respectively).Performance (body weight gain, feed conversion), amount of abdominal fat and carnitine concentration in blood, muscles (M. sartorius, M.pectoralis superficialis, cardiac), liver and kidney were determined. Performance and abdominal fat were influenced by dietary fat, lysine and methionine as expected and were not altered by carnitine. Excess and deficiency of lysine and methionine did not influence, fat supplement reduced and carnitine supplementation significantly increased tissue concentration of carnitine.

In trial II it was studied if supplementation of a commercial layers’ ration with either 500 mg L‐carnitine or 500 mg nicotinic acid or both per kg reduces the cholesterol concentration in yolk. Influence on body weight, feed intake, laying performance, serum and yolk cholesterol concentration could not be observed, but yolk concentration of carnitine was significantly increased in supplemented groups.

Trial III should clarify if the L‐carnitine content in broiler parentstock ration influences hatchability. Four groups of 1350 hens each were fed a commercial all‐mash supplemented with 0, 20, 50 and 100 mg L‐carnitine, respectively. Hatching rate was increased from 83% to 87% and from 82.4% to 85.3% in groups supplemented with 50 and 100 mg L‐carnitine, respectively, and in randomly sampled eggs of these groups carnitine concentration in yolk was higher.     

Diethyl Hexyl Phthalate (DEHP) is associated with insulin resistance in adipose tissue of male rat: Protective role of antioxidant vitamins (C & E)

Diethyl hexyl phthalate (DEHP) is a plasticizer, commonly used in a variety of products, including lubricants, perfumes, hairsprays and cosmetics, construction materials, wood finishers, adhesives, floorings and paints. DEHP is an endocrine disruptor and it has a continuum of influence on various organ systems in human beings and experimental animals. However, specific effects of DEHP on insulin signaling in adipose tissue are not known. Adult male albino rats of Wistar strain were divided into four groups. Control, DEHP treated (dissolved in olive oil at a dose of 10, and 100 mg/kg body weight, respectively, once daily through gastric intubations for 30 days) and DEHP + vitamin E (50 mg/kg body weight) and C (100 mg/kg body weight) dissolved in olive oil and distilled water, respectively, once daily through gastric intubations for 30 days. After the completion of treatment, adipose tissue was dissected out to assess various parameters. DEHP treatment escalated H₂O₂ and hydroxyl radical levels as well as lipid peroxidation in the adipose tissue. DEHP impaired the expression of insulin signaling molecules and their phosphorelay pathways leading to diminish plasma membrane GLUT4 level and thus decreased glucose uptake and oxidation. Blood glucose level was elevated as a result of these changes. Supplementation of vitamins (C & E) prevented the DEHP‐induced changes. It is concluded that DEHP‐induced ROS and lipid peroxidation disrupts the insulin signal transduction in adipose tissue and favors glucose intolerance. Antioxidant vitamins have a protective role against the adverse effect of DEHP. J. Cell. Biochem. 114: 558–569, 2013. © 2012 Wiley Periodicals, Inc.     

腹腔注射乙酰唑胺对大鼠氧惊厥潜伏期的影响

为探讨脑血流调节与氧惊厥的关系,本研究在复制大鼠氧惊厥模型的基础上,采用行为学方法测定氧惊厥潜伏期,并测定脑皮质氧化指标内二醛（maleic dialdehyde,MDA）含量,采用腹腔注射不同剂量脑血管扩张药物乙酰唑胺（acetazolamide,ACZ）,以及联合注射ACZ及其拈抗刺吲哚美辛（indomethacin,IND）后,观察脑血管扩张对氧化状态以及氧惊厥潜伏期的影响。结果观察到：（1）腹腔注射ACZ（不小于7．5mg／kg体重）后,氧惊厥潜伏期明显缩短（P〈0．05）,剂量越大,缩短越明显。腹腔注射IND对氧惊厥潜伏期无显著影响。腹腔注射IND（20mg／kg体重）,30min后再注射ACZ（7．5mg／kg体重）,ACZ的氧惊厥潜伏期缩短作川被对抗（P〈0．05）。（2）腹腔注射ACZ7．5mg／kg后,与各组相比,6及16min暴露后,脑组织MDA含量明显增多（P〈0．01,P〈0．05）;腹腔注射IND对脑皮质MDA含量无显著影响;在预注射IND,再注射ACZ后,MDA含量显著降低（P〈0．01,P〈0．05）。结果表明,ACZ外周注射加重氧化损伤,缩短氧惊厥潜伏期;而IND可以对抗其氧惊厥潜伏期缩短作用以及氧化损伤加重作用,碳酸酐酶活力变化很可能是通过影响脑血管状态而影响氧化损伤以及氧惊厥潜伏期。     

Tenoxicam Modulates Antioxidant Redox System and Lipid Peroxidation in Rat Brain

We investigated effects of two doses of Tenoxicam, a type 2 cyclooxygenase inhibitor, administration on lipid peroxidation and antioxidant redox system in cortex of the brain in rats. Twenty-two male Wistar rats were randomly divided into three groups. First group was used as control. 10 and 20 mg/kg body weight Tenoxicam were intramuscularly administrated to rats constituting the second and third groups for 10 days, respectively. Both dose of Tenoxicam administration resulted in significant increase in the glutathione peroxidase activity, reduced glutathione and vitamins C and E of cortex of the brain. The lipid peroxidation levels in the cortex of the brain were significantly decreased by the administration. Vitamin A and β-carotene concentration was not affected by the administration. There was no statistical difference in all values between 10 and 20 mg Tenoxicam administrated groups. In conclusion, treatment of brain with 10 and 20 mg Tenoxicam has protective effects on the oxidative stress by inhibiting free radical and supporting antioxidant redox system.     

The effect of thyroid hormones on blood insulin level and metabolic parameters in diabetic rats

The effect of exogenous thyroid hormones on blood insulin and metabolic parameters in diabetic rats was investigated. Three groups of rats were treated with streptozotocin (STZ; 50 mg/kg b.w., intravenously) and one group receiving only saline served as control. Beginning with the third day after STZ treatment, until the last day before decapitation, i.e. for 11 days, two groups of diabetic rats were treated with T3 (50 microg/kg b.w., i.p.) or T4 (250 microg/kg b.w., i.p.). After two weeks, STZ injected rats had lower body weight, hyperglycemia with a simultaneous drop in blood insulin and decrease of T3 and T4 concentrations in comparison to control animals. Liver glycogen content was also reduced, whereas serum lactate, free fatty acids, triglycerides and cholesterol were elevated. Exogenous thyroid hormones given to diabetic rats substantially attenuated hyperglycemia without any significant changes in blood insulin concentration. An additional reduction of body weight gain and depletion in liver glycogen stores were also observed. Thyroid hormones augmented serum lactate and cholesterol and had no beneficial effect on elevated free fatty acids and triglycerides. It can be concluded that in spite of partial restriction of hyperglycemia, thyroid hormones evoked several unfavourable changes strongly limiting their potential use in diabetes.     

乙酰辅酶A羧化酶抑制剂联合非诺贝特对小鼠非酒精性脂肪肝的治疗效果

摘要 目的：探讨乙酰辅酶A羧化酶抑制剂（MK-4074）联合非诺贝特对小鼠非酒精性脂肪肝（NAFLD）的脂质含量以及肝功能的改善效果。方法：20只C57BL/6小鼠给予60%高脂饲料连续喂养8周构建NAFLD小鼠模型后，随机分为安慰剂组、MK-4074组、非诺贝特组以及MK-4074联合非诺贝特治疗组，每组各5只，继续高脂喂养并分别给予安慰剂（Placebo）、MK-4074（10 mg/kg/天）、非诺贝特（30 mg/kg/天）、以及MK-4074（10 mg/kg/天）+ 非诺贝特（30 mg/kg/天）治疗持续8周。治疗结束后对小鼠体重、肝指数、肝脏脂质含量、肝功能以及肝脏病理和肝脏中性粒细胞和巨噬细胞浸润情况进行分析。结果：与安慰剂组相比，单用MK-4074治疗可显著降低肝指数、肝脏甘油三酯（TG）、胆固醇（TC）、非酯化脂肪酸（NEFA）的含量以及血清ALT和AST水平，而对小鼠体重和血清TC没有显著影响；单用非诺贝特可显著降低小鼠体重，肝脏TG、TC、NEFA以及血清TG、 ALT和AST水平，对小鼠的肝指数、血清TC没有显著影响；而MK-4074与非诺贝特联合治疗可显著降低小鼠体重、肝脏TG、TC、NEFA，以及血清TG、ALT和AST水平，降低肝脏脂质积累以及中性粒细胞与巨噬细胞浸润，效果优于MK-4074或非诺贝特单药治疗。结论：MK-4074联合非诺贝特可显著减少NAFLD小鼠肝脏的脂质含量，改善肝功能。     

Ameltolide. I: Developmental toxicology studies of a novel anticonvulsant

Ameltolide, a novel anticonvulsant agent, has been shown in animal models to be effective in controlling seizures. The developmental toxicity of ameltolide was evaluated in two species. Naturally mated rats and rabbits were dosed once daily by gavage on gestation days (GD) 6-17 and 6-18, respectively. Rats were given doses of 0, 10, 25, or 50 mg/kg; rabbits were given 0, 25, 50, or 100 mg/kg. Laparotomy was performed on rats on GD 20 and on rabbits on GD 28. In rats, maternal toxicity was indicated at the 25- and 50-mg/kg dose levels by depressed body weight gain. Fetal body weight was depressed at the 50-mg/kg dose level. Fetal viability and morphology were not affected. The no-observed effect levels (NOEL) for adult and developmental toxicity in the rat were 10 and 25 mg/kg, respectively. In rabbits, maternal toxicity was indicated by a net loss in body weight at the 50- and 100-mg/kg dose levels. Fetal viability and body weight were depressed at the 100 mg/kg dose level. Shortened digits occurred on the right forepaw of one fetus at the 50-mg/kg dose level (in conjunction with severe maternal toxicity) and on the hindpaws of two fetuses from separate litters at the 100-mg/kg dose level. Incomplete ossification of the phalanges occurred on the forepaws of nine fetuses from four litters at the 100-mg/kg dose level. Ameltolide was weakly teratogenic in the rabbit. The NOEL for adult and developmental toxicity in the rabbit was 25 mg/kg.