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Toxic Dose (toxic + dose)
Selected AbstractsPrenatal developmental toxicity studies of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p, p,-DDT) in rats and rabbitsCONGENITAL ANOMALIES, Issue 4 2001Ken L. Takahashi ABSTRACT, The studies were conducted in rats and rabbits to elucidate the potential developmental toxicity of p, p'-DDT in general accordance with the improved Japanese MAFF guidelines (12-Nousan-No. 8147,2,1,18, 2000). p, p'-DDT suspended in 1% aqueous solution of CMC was administered orally to pregnant Jcl:SD rats on gestational days (GD) 6,19 at a dose of 0,5, 25, or 100 mg/kg/day and to pregnant KbI: JW rabbits on GD 6,27 at a dose of 0,5,20, or 80 mg/kg/day. Maternal animals were killed on the day after the last day of administration for morphological examination of their fetuses with special attention to the reproductive organs. Adverse effects on maternal animals were found only at the highest dose in both species; i.e., clonic convulsion (2/24 in rats, 5/22 in rabbits), mortality (1/24 in rats), abortion or premature delivery (4/22 in rabbits), and reduced body weight gains and food consumption. However, the control and treated groups showed comparable values for the numbers of corpora lutea and implants, percent preimplantation losses, number of live fetuses, percent resorptions and fetal deaths, sex ratio, fetal body weights, and placental weights in both species, and anogenital distance and testicular histology in rats. Although fetal examination revealed slightly increased incidence of 27 presacral vertebrae in the highest dose group in rats, there was no treatment-related increase in the incidence of malformations in any of the species. Based on these results, it is concluded that p, p'-DDT causes no malformations, including male reproductive organ abnormalities, in either rats or rabbits, although it results in an increased incidence of skeletal variations in rats at a maternally toxic dose. [source] Interactions Between Oxcarbazepine and Conventional Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic AnalysisEPILEPSIA, Issue 4 2003Jarogniew J. Luszczki Summary: ,Purpose: The aim of this study was to determine the types of interactions between oxcarbazepine (OCBZ) and conventional antiepileptic drugs (AEDs) against maximal electroshock-induced seizures (MES test) in mice, by using a method of isobolographic analysis. Methods: Adverse effects of combinations were evaluated in the chimney test (motor performance), also using the isobolographic method, which allowed determination of the median toxic dose (TD50) values for individual combinations; thus the protective indices could be determined. Results: OCBZ and phenytoin (PHT) at the fixed-ratio combination of 1:1 were significantly infraadditive (antagonistic) with respect to the antiseizure protection against MES and simultaneously additive in terms of side effects in the chimney test. Interestingly, combinations between OCBZ and clonazepam (CZP) in the MES test proved antagonistic or synergistic, depending on the proportion of both AEDs in the mixture. Low doses of OCBZ with high doses of CZP exerted antagonism. Conversely, high doses of OCBZ combined with low doses of CZP resulted in a synergistic interaction. Remaining combinations between OCBZ and phenobarbital, valproate, or carbamazepine were purely additive, either as regards the anticonvulsant activity against MES or in terms of motor impairment in the chimney test. Conclusions: The results of this study indicate that interaction of OCBZ and CZP at fixed-ratio combination of 1:1 might be profitable from a clinical point of view. Conversely, combinations of OCBZ with PHT may not be clinically efficient. [source] Neutrophil depletion protects against murine acetaminophen hepatotoxicity,,HEPATOLOGY, Issue 6 2006Zhang-Xu Liu We previously reported that liver natural killer (NK) and NKT cells play a critical role in mouse model of acetaminophen (APAP)-induced liver injury by producing interferon gamma (IFN-,) and modulating chemokine production and subsequent recruitment of neutrophils into the liver. In this report, we examined the role of neutrophils in the progression of APAP hepatotoxicity. C57BL/6 mice were given an intraperitoneal toxic dose of APAP (500 mg/kg), which caused severe acute liver injury characterized by significant elevation of serum ALT, centrilobular hepatic necrosis, and increased hepatic inflammatory cell accumulation. Flow cytometric analysis of isolated hepatic leukocytes demonstrated that the major fraction of increased hepatic leukocytes at 6 and 24 hours after APAP was neutrophils (Mac-1+Gr-1+). Depletion of neutrophils by in vivo treatment with anti-Gr-1 antibody (RB6-8C5) significantly protected mice against APAP-induced liver injury, as evidenced by markedly reduced serum ALT levels, centrilobular hepatic necrosis, and improved mouse survival. The protection was associated with decreased FasL-expressing cells, cytotoxicity against hepatocytes, and respiratory burst in hepatic leukocytes. In intracellular adhesion molecule (ICAM)-1,deficient mice, APAP caused markedly reduced liver injury when compared with wild-type mice. The marked protection in ICAM-1,deficient mice was associated with decreased accumulation of neutrophils in the liver. Hepatic GSH depletion and APAP-adducts showed no differences among the antibody-treated, ICAM-1,deficient, and normal mice. In conclusion, accumulated neutrophils in the liver contribute to the progression and severity of APAP-induced liver injury. (HEPATOLOGY 2006;43:1220,1230.) [source] Inflammation and drug hepatotoxicity: Aggravation of injury or clean-up mission?,HEPATOLOGY, Issue 5 2005Hartmut Jaeschke BACKGROUND & AIMS Inflammatory mediators released by nonparenchymal inflammatory cells in the liver have been implicated in the progression of acetaminophen (APAP) hepatotoxicity. Among hepatic nonparenchymal inflammatory cells, we examined the role of the abundant natural killer (NK) cells and NK cells with T-cell receptors (NKT cells) in APAP-induced liver injury. METHODS C57BL/6 mice were administered a toxic dose of APAP intraperitoneally to cause liver injury with or without depletion of NK and NKT cells by anti-NK1.1 monoclonal antibody (MAb). Serum alanine transaminase (ALT) levels, liver histology, hepatic leukocyte accumulation, and cytokine/chemokine expression were assessed. RESULTS Compared with APAP-treated control mice, depletion of both NK and NKT cells by anti-NK1.1 significantly protected mice from APAP-induced liver injury, as evidenced by decreased serum ALT level, improved survival of mice, decreased hepatic necrosis, inhibition of messenger RNA (mRNA) expression for interferon-gamma (IFN-gamma), Fas ligand (FasL), and chemokines including KC (Keratinocyte-derived chemokine); MIP-1 alpha (macrophage inflammatory protein-1 alpha); MCP-1 (monocyte chemoattractant protein-1); IP-10 (interferon-inducible protein); Mig (monokine induced by IFN-gamma) and decreased neutrophil accumulation in the liver. Hepatic NK and NKT cells were identified as the major source of IFN-gamma by intracellular cytokine staining. APAP induced much less liver injury in Fas-deficient (lpr) and FasL-deficient (gld) mice compared with that in wild-type mice. CONCLUSIONS NK and NKT cells play a critical role in the progression of APAP-induced liver injury by secreting IFN-gamma, modulating chemokine production and accumulation of neutrophils, and up-regulating FasL expression in the liver, all of which may promote the inflammatory response of liver innate immune system, thus contributing to the severity and progression of liver injury downstream of the metabolism of APAP and depletion of reduced glutathione (GSH) in hepatocytes. [source] Acute oral toxicity of colchicine in rats: effects of gender, vehicle matrix and pre-exposure to lipopolysaccharideJOURNAL OF APPLIED TOXICOLOGY, Issue 5 2007Paddy L. Wiesenfeld Abstract The oral toxicity of a single administration by gavage (10, 20 or 30 mg kg,1 body weight) of colchicine (COL) was determined in young, mature male and female Sprague-Dawley rats. The effect of COL was evaluated in the presence or absence of additional treatment variables that included vehicle and lipopolysaccharide (LPS) pre-exposure. The vehicle for COL was either Half and Half cream (H & H) or saline, and each group included pretreatment with either saline or a low, minimally toxic dose (83 µg kg,1 body weight) of LPS. Colchicine toxicity in both male and female age-matched rats was characterized by progressively more severe dose-related clinical signs of toxicity. These included mortality, decreased body weight and feed intake during the first several days after dosing, with recovery thereafter in surviving animals. There were differences in the severity of the toxic response to COL between male and female rats. The most notable sex-related difference was in COL lethality. Female rats were two times more susceptible to the lethal effects of COL than male rats. Saline or H & H delivery vehicles did not result in any apparent qualitative or quantitative differences in COL toxicity. LPS pretreatment significantly potentiated COL lethality in both males and females, although the potentiation in males was greater than in females. LPS pretreatment modestly increased the COL induced anorexic effect in surviving males, but not in surviving female animals. LPS did not appear to modulate either the body weights or clinical signs of COL induced toxicity in surviving males or females. Copyright © 2007 John Wiley & Sons, Ltd. [source] Effect of cyclosporin A in Lewis rats in vivo and HeLa cells in vitroJOURNAL OF APPLIED TOXICOLOGY, Issue 3 2002Andrea Sovcikova Abstract The aim of this study was to compare the effect of cyclosporin A (CsA) in inbred Lewis rats with published assessment of immunotoxicity in ,classical' outbred Wistar rats. A second purpose was to consider the contribution of a panel of in vitro assays in cell cultures when added to an immunotoxicity study in vivo. The in vivo effect of CsA was investigated in a 28-day subacute immunotoxicity study in male Lewis rats at three different concentrations: 1.25, 5 and 20 mg kg,1. The highest dose of CsA exceeded the maximum tolerated dose. A drop in body, spleen and popliteal lymph node weight of exposed animals displayed symptoms of toxicity. At a high toxic dose, haematological changes showed a decrease in the leucocyte count and in the percentage of lymphocytes, and an increase in the percentage of polymorphonuclear leucocytes. The haematocrit was significantly dose-dependently suppressed in all rats exposed to CsA. A similar dose-dependent depression of the mean cell volume of erythrocytes was found in rats given high and middle doses of CsA. The phagocytic activity of polymorphonuclear leucocytes and monocytes also was significantly dose-dependently suppressed. No significant changes in primary antibody response to sheep erythrocytes or in vitro proliferative response of spleen lymphocytes to mitogens were found in those rats. A battery of in vitro cytotoxicity methods was selected for the evaluation of metabolic and functional activity of subcellular organelles (mitochondria, lysosomes) and for the detection of drug-induced superoxide-mediated damage in HeLa cells. This cell line was chosen because it has a lower activity of superoxide dismutase (SOD) than normal cells and is sufficiently sensitive for the detection of the induction of oxygen radicals. The in vitro results indicated a direct relationship between CsA cytotoxicity and a change in the mitochondrial enzyme activity, as well as an induction of superoxide production. The results of the study indicated that a combination of selected in vivo and in vitro methods is an inexpensive way to obtain more complex information on cell status affected by xenobiotics. Copyright © 2002 John Wiley & Sons, Ltd. [source] BIOGENIC AMINE CONTENT OF SOME TURKISH CHEESESJOURNAL OF FOOD PROCESSING AND PRESERVATION, Issue 4 2002FÜGEN DURLU-ÖZKAYA Biogenic amines in ten samples of Ka,ar (aged), five samples of Ka,ar (fresh), four samples of Mihaliç, nine samples of Van Otlu (herbed), nine samples of Örgü, nine samples of Urfa and six samples of Civil cheeses were obtained from local supermarkets of Ankara. Tryptamine (TRY), phenylethylamine (PHA), putrescine (PUT), cadaverine (CAD), histamine (HIT), tyramine (TYA), spermine (SPM) and spermidine (SPD) contents of Turkish cheese samples were screened by high performance liquid chromatography (HPLC). PUT, CAD, HIT, TYA and SPD were the predominant biogenic amines in maturated Ka,ar (aged), vacuum-packed Ka,ar (fresh), Mihaliç, Otlu (herbed) and Örgü cheeses. PHA, CAD, TYA and SPD were the predominant biogenic amines in Urfa cheese samples. Civil cheeses were found to contain the highest HIT and TYA content with an average of 94.76 mg/100 g and 138.16 mg/100 g, respectively, much higher than the toxic dose. HIT level of Mihaliç cheeses were also higher than the accepted limit. The concentration of amines in all other cheeses was much lower than the toxic dose limits. [source] Treatment of mice with a herbal preparation (Mentat) protects against radiation-induced mortalityPHYTOTHERAPY RESEARCH, Issue 8 2003Ganesh Chandra Jagetia Abstract The effect of various doses (0, 5, 10, 20, 40, 80, 100, 120 and 160 mg/kg b. wt.) of 50% ethanolic extract of mentat (a herbal preparation) was studied on the survival of mice exposed to 10 Gy of , -radiation. Treatment of mice with different doses of mentat consecutively for ,ve days before irradiation delayed the onset of mortality and reduced the symptoms of radiation sickness when compared with the non-drug treated irradiated controls. Most of the doses of mentat provided protection against the gastrointestinal (GI) death, however, the highest protection against GI death was observed for 80 mg/kg mentat. This was also true for bone marrow deaths, where the highest number of survivors were observed at 30 days post-irradiation in this group (i.e. 80 mg/kg) when compared with the other doses of mentat. The evaluation of acute toxicity showed that mentat was non-toxic up to a dose of 1.5 g/kg b. wt., where no drug-induced mortality was observed. The LD50 dose of mentat was found to be 1.75 g/kg b. wt. Our study demonstrates that mentat can provide good radioprotection at a dose of 80 mg/kg, which is far below its toxic dose. Copyright © 2003 John Wiley & Sons, Ltd. [source] Subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, after single and 4-week repeated oral administration in dogsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2001Hyun J. Shim Abstract The subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, were evaluated after single (at the 1st day) and 4-week (at the 28th day) oral administration of the drug, in doses of 0 (to serve as a control), 12.5, 50 and 200 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). DA-8159 had an effect on the immune-related organs (or tissues), circulatory systems, liver, adrenal glands, ovaries and pancreas. The toxic dose was 200 mg/kg and no observed adverse effect level was less than 50 mg/kg for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of DA-8159 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DA-8159 were dose-independent after single oral administration; the time to reach a peak plasma concentration (Tmax) and the dose-normalized area under the plasma concentration,time curve from time zero to 24 h in plasma (AUC0,24 h) were not significantly different among three doses. However, accumulation of DA-8159 after 4-week oral administration was considerable at toxic dose, 200 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC0,24 h value at 200 mg/kg/day (4.71 and 15.3 ,g h/ml) was significantly greater than that at 12.5 mg/kg/day. After 4-week oral administration, the dose-normalized Cmax and AUC0,24 h at 200 mg/kg/day were significantly higher and greater, respectively, than those after a single oral administration. Copyright © 2001 John Wiley & Sons, Ltd. [source] Chromosomal antioxidant genes have metal ion-specific roles as determinants of bacterial metal toleranceENVIRONMENTAL MICROBIOLOGY, Issue 10 2009Joe J. Harrison Summary Microbiological metal toxicity involves redox reactions between metal species and cellular molecules, and therefore, we hypothesized that antioxidant systems might be chromosomal determinants affecting the susceptibility of bacteria to metal toxicity. Here, survival was quantified in metal ion-exposed planktonic cultures of several Escherichia coli strains, each bearing a mutation in a gene important for redox homeostasis. This characterized ,250 gene,metal combinations and identified that sodA, sodB, gor, trxA, gshA, grxA and marR have distinct roles in safeguarding or sensitizing cells to different toxic metal ions (Cr2O72,, Co2+, Cu2+, Ag+, Zn2+, AsO2,, SeO32, or TeO32,). To shed light on these observations, fluorescent sensors for reactive oxygen species (ROS) and reduced thiol (RSH) quantification were used to ascertain that different metal ions exert oxidative toxicity through disparate modes-of-action. These oxidative mechanisms of metal toxicity were categorized as involving ROS and thiol-disulfide chemistry together (AsO2,, SeO32,), ROS predominantly (Cu2+, Cr2O72,) or thiol-disulfide chemistry predominantly (Ag+, Co2+, Zn2+, TeO32,). Corresponding to this, promoter- luxCDABE fusions showed that toxic doses of different metal ions up- or downregulate the transcription of gene sets marking distinct pathways of cellular oxidative stress. Altogether, our findings suggest that different metal ions are lethal to cells through discrete pathways of oxidative biochemistry, and moreover, indicate that chromosomally encoded antioxidant systems may have metal ion-specific physiological roles as determinants of bacterial metal tolerance. [source] Evaluation of gastric toxicity of indomethacin acid, salt form and complexed forms with hydroxypropyl-,-cyclodextrin on Wistar rats: histopathologic analysisFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2009A.C. Ribeiro-Rama Abstract Indomethacin (IM) is a non-steroidal anti-inflammatory drug which inhibits prostaglandin biosynthesis. It is practically insoluble in water and has the capacity to induce gastric injury. Hydroxypropyl-,-cyclodextrin (HP-,-CD) is an alkylated derivative of ,-CD with the capacity to form inclusion complexes with suitable molecules. IM is considered to form partial inclusion complexes with HP-,-CD by enclosure of the p -chlorobenzoic part of the molecule in the cyclodextrin channel, reducing the adverse effects. The aim of this paper is to evaluate the gastric damage induced by the IM inclusion complex prepared by freeze-drying and spray-drying. A total of 135 Wistar rats weighing 224.4 ± 62.5 g were put into 10 groups. They were allowed free access to water but were maintained fasted for 18 h before the first administration until the end of the experiment. IM acid-form, IM trihydrated-sodium-salt and IM-HP-,-CD spray and freeze-dried, at normal and toxic doses, were administered through gastric cannula once/day for 3 days. Seventy-two hours after the first administration, the animals were sacrificed and the stomachs collected and prepared for morphological study by using the haematoxylin-eosin technique. Lesion indexes (rated 0/4) were developed and the type of injury was scored according to the severity of damage and the incidence of microscopic evidence of harm. Microscopic assessment demonstrated levels of injury with index one on 10,25%. The type of complexation method had different incidence but the same degree. The results show that IM inclusion complexation protects against gastric injury, reducing the incidence and the maximum degree of severity from 4 to 1, with a better performance of the spray-dried complex. [source] Vitamin D Hormone Inhibits Osteoclastogenesis In Vivo by Decreasing the Pool of Osteoclast Precursors in Bone MarrowJOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2002Takeshi Shibata Abstract Previous observations that vitamin D hormone induces the expression of the receptor activator of nuclear factor ,B (NF-,B) ligand (RANKL), thereby stimulating osteoclastogenesis in vitro, led to the widespread belief that 1,,25-dihydroxyvitamin D3 [1,,25(OH)2D3] is a bone-resorbing hormone. Here, we show that alfacalcidol, a prodrug metabolized to 1,,25(OH)2D3, suppresses bone resorption at pharmacologic doses that maintain normocalcemia in an ovariectomized (OVX) mouse model of osteoporosis. Treatment of OVX mice with pharmacologic doses of alfacalcidol does not increase RANKL expression, whereas toxic doses that cause hypercalcemia markedly reduce the expression of RANKL. When bone marrow (BM) cells from OVX mice were cultured with sufficient amounts of macrophage colony-stimulating factor (M-CSF) and RANKL, osteoclastogenic activity was higher than in sham mice. Marrow cultures from alfacalcidol- or estrogen-treated OVX mice showed significantly less osteoclastogenic potential compared with those from vehicle-treated OVX mice, suggesting that the pool of osteoclast progenitors in the marrow of vitamin D-treated mice as well as estrogen-treated mice was decreased. Frequency analysis showed that the number of osteoclast progenitors in bone marrow was increased by OVX and decreased by in vivo treatment with alfacalcidol or estrogen. We conclude that the pharmacologic action of active vitamin D in vivo is to decrease the pool of osteoclast progenitors in BM, thereby inhibiting bone resorption. Because of its unusual activity of maintaining bone formation while suppressing bone resorption, in contrast to estrogens that depress both processes, vitamin D hormone and its bone-selective analogs may be useful for the management of osteoporosis. [source] Clodronate treatment of vitamin D-induced hypercalcemia in dogsJOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 2 2006Bulent Ulutas DVM Abstract Objective: To determine the effects of clodronate on vitamin D3 -induced hypercalcemia in dogs. Design: Prospective experimental study. Settings: University research laboratory. Animals: Fourteen healthy intact adult male and female mixed breed dogs. Interventions: Dogs received 7.5 mg of vitamin D3/kg of body weight once orally and were randomly assigned to 2 groups of 7 dogs each. Dogs in the saline control group were given intravenous infusions of 150 mL 0.9% NaCl solution 24 hours after vitamin D3 administration. Dogs in the clodronate group were given an infusion of 4 mg/kg of clodronate in 150 mL 0.9% NaCl solution 24 hours after vitamin D3 administration. Measurements and main results: Clinical signs of vitamin D3 toxicosis were evaluated 48 hours after ingestion of vitamin D3. Dogs that were given clodronate had significantly lower serum calcium (Ca), phosphorus (P), urea, and Ca × P values than dogs in the control group on days 4, 7, and 12 after administration. Additionally, alkaline phosphatase activity was significantly lower in the clodronate group compared with dogs in the control group on days 4 and 7. Conclusions: Parenteral administration of clodronate, a biphosphonate compound and osteoclastic activity inhibitor, may be a useful therapy when administered within the first 24 hours after ingestion of toxic doses of vitamin D3. [source] Hepatoprotective and antioxidant activities of Tetracera loureiriPHYTOTHERAPY RESEARCH, Issue 7 2003Veerapol Kukongviriyapan Abstract Tetracera loureiri is one of the most valued herbs in Thai traditional medicine. In this study, we describe its in vitro and in vivo antioxidant and hepatoprotective activities. The ethanol extract of T. loureiri possessed potent antioxidant and strong free radical scavenging properties assayed using ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH), respectively. The cytoprotective effects of T. loureiri were demonstrated in ethanolic extracts of freshly isolated rat hepatocytes against the chemical toxicants paracetamol and tertiary-butylhydroperoxide. The cells pretreated with the extract maintained the GSH/GSSG ratio and suppressed lipid peroxidation in a dose dependent manner. Pretreating rats with the ethanol extract orally, one hour prior to intraperitoneal injection of toxic doses of paracetamol, signi,cantly prevented elevations of plasma ALT and AST. These results suggest that T. loureiri may be of potential therapeutic value in some liver disorders. Copyright © 2003 John Wiley & Sons, Ltd. [source] Acute toxicity in five dogs after ingestion of a commercial snail and slug bait containing iron EDTAAUSTRALIAN VETERINARY JOURNAL, Issue 7 2009SL Haldane This case series of five dogs describes the effects of ingesting large amounts of an iron EDTA snail-bait product. In all cases signs of toxicity occurred between 6 and 24 h after ingestion and included abdominal pain and haemorrhagic gastroenteritis. Two of the dogs had pretreatment serum iron levels measured and in both cases the levels were above normal limits. All of the dogs were treated with iron chelation therapy and supportive care including intravenous fluids, analgesics, gastric protectants and antibiotics. Chelation therapy with desferrioxamine mesylate did not cause adverse effects in any of the dogs and all survived to discharge. The effects of iron EDTA snail bait in dogs requires further study and minimum toxic doses need to be established. [source] Effects of therapeutic and toxic doses of levamisole on thyroid hormones and some biochemical parameters in sheepCELL BIOCHEMISTRY AND FUNCTION, Issue 5 2004Ahmet Atessahin Abstract This study was carried out to establish the effects of therapeutic and toxic doses of levamisole on thyroid hormone levels and some biochemical parameters in sheep. Twelve Akkaraman ewes were used. Levamisole was given orally at doses of 7.5,mg,kg,1 (group 1) and 40,mg,kg,1 (group 2) to the animals. Blood samples were taken from the jugular vein at 2, 4, 8, 24, 48, 96 and 144,h after the administrations. Serum thyroid hormones and some biochemical parameters were determined on these samples. When compared with the control levels, no significant changes were observed in triiodothyronine (T3) and thyroxin (T4) levels in group 1. Although levamisole was found to increase the levels of total T3, it decreased the levels of total T4 in group 2. On the other hand, free T3 and free T4 levels were not changed in either group. While serum alkaline phosphatase (ALP) activities were decreased, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and creatinine kinase (CK) activities were increased significantly by levamisole. However, it increased the serum albumin and cholesterol levels, but decreased the inorganic phosphate levels in groups 1 and 2. On the other hand, when compared with the control levels, no significant changes were detected in serum sodium, potassium and calcium levels. In conclusion, therapeutic and toxic doses of levamisole were determined to affect thyroid metabolism and some biochemical parameters in sheep. Copyright © 2004 John Wiley & Sons, Ltd. [source] Verapamil Toxicity Dysregulates the Phosphatidylinositol 3-Kinase PathwayACADEMIC EMERGENCY MEDICINE, Issue 4 2008Laura K. Bechtel PhD Abstract Objectives:, Recent animal research and clinical case reports suggest benefit from high-dose insulin therapy (HDIT) for the treatment of calcium channel blocker (CCB) toxicity. One molecular signaling pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, that contributes to CCB toxicity and the efficacy of HDIT, was examined for a role in this phenomenon. Methods:, A differentiated 3T3-L1 adipocyte model system was utilized to characterize metabolic and molecular signaling events dysregulated in response to acute CCB toxicity. Glucose uptake assays were performed in the presence of representatives of three classes of CCB drugs, and the ability of HDIT to reverse observed inhibition was assessed. Western blot analyses were utilized to probe which insulin-dependent signaling pathway was inhibited by CCB toxicity. Results:, Representative compounds from the dihydropyridine and phenylalkylamine classes of CCBs were more effective at inhibiting glucose uptake in differentiated 3T3-L1 adipocytes than a representative from the benzothiazepine class. Phosphorylation at serine 473 of the Akt protein (P-Akt), a protein representing a common pathway for insulin receptors (IR), insulinlike growth factor receptors (IGFR), and hybrid receptors formed by IR and IGFR subunits, was abolished in the presence of toxic doses of the phenylalkylamine CCB verapamil. Phosphorylation at serine 473 of Akt was rescued in the presence high concentrations of insulin. Conclusions:, These data suggest that dysregulation of the insulin-dependent PI3K pathway is partially responsible for insulin resistance and the hyperglycemic state observed in response to acute CCB toxicity. [source] | ||||||||||||||||||||||||||||