Human & Experimental Toxicology recent issues

Studies on hypoglycaemic effects of polyherbal preparation in streptozotocin-induced diabetic male albino rats

Mon, 16 Nov 2009 09:01:18 PST

Many traditional treatments have been recommended in the alternative system of medicine for diabetes mellitus. However, the mode of action of most of the herbals used has not been defined. It has been reported that sex hormones are important regulators of insulin-mediated events in skeletal muscles. In view of this, a novel herbal preparation containing antidiabetic and aphrodisiac plants was used in the present study. Adult male albino rats were divided into following groups after induction of diabetes. Rats were given an intraperitoneal (i.p.) injection of streptozotocin (STZ), at a dose of 65 mg/kg body weight after overnight fasting, to induce diabetic state with blood glucose levels >250 mg/dL. Group 1—Control rats treated with single i.p. injection of vehicle, Group 2—Rats treated with polyherbal preparation (PHP; 500 mg/kg body weight by oral intubation, morning and evening for 30 days), Group 3—STZ-diabetic rats treated orally with equal volumes of vehicle (water) alone and Group 4—STZ-diabetic rats treated with PHP after 10 days of diabetic induction. STZ-diabetes decreased the body weight, serum insulin level and glucose oxidation in liver and skeletal muscles but increased the fasting blood glucose level. After polyherbal treatment, body weight and glucose oxidation were completely restored to control level while serum insulin level was restored partially and the glucose tolerance was significantly improved. There was a significant decrease in total haemoglobin (Hb) level of diabetic rats when compared to control but polyherbal treatment significantly improved the same. However, the other parameters studied (red blood cell [RBC], white blood corpuscle [WBC], packed cell volume [PCV], mean corpuscular volume [MCV] and mean corpuscular haemoglobin [MCH]) were unaltered. In conclusion, the anti-diabetic properties of PHP appear to be mediated through pancreatic β-cell regeneration, resulting in maintenance of optimal blood glucose and its oxidation in liver and skeletal muscles.

Attenuation of Helicteres isora L. bark extracts on streptozotocin-induced alterations in glycogen and carbohydrate metabolism in albino rats

Kumar, G., Sharmila Banu, G., Murugesan, A. — Mon, 16 Nov 2009 09:01:18 PST

The present study was undertaken to assess the effect of Helicteres isora L. on four important enzymes of carbohydrate metabolism (glucokinase [GK], hexokinase [HK] phosphofructokinase [PFK] and fructose-1, 6-bisphosphatase [FBP]) along with glycogen content of insulin-dependent (skeletal muscle and liver) and insulin-independent tissues (kidneys and brain) in streptozotocin (STZ; 60 mg/kg)-induced model of diabetes for 30 days. Administration of bark extracts (100, 200 mg/kg) for 30 days led to decrease in plasma glucose levels by approximately 9.60% and 22.04% and 19.18% and 33.93% on 15th and 30th day, respectively, of the experiment. Liver and two-kidney weight expressed as percentage of body weight significantly increased in diabetics (P < 0.05) versus normal controls. Renal glycogen content increased by 10 folds while hepatic and skeletal muscle glycogen content decreased by 75% and 68% in diabetic controls versus controls. H. isora did not affect glycogen content in any tissue. The decreased activities of PFK, GK, FBP and HK in diabetic controls were 40%, 50%, 50% and 60% and bark extract of H. isora partially corrected this alteration. The efficacy of the bark extract was comparable with Tolbutamide, a well-known hypoglycemic drug.

Spider bite (latrodectism) in Mashhad, Iran

Afshari, R., Khadem-Rezaiyan, M., Balali-Mood, M. — Mon, 16 Nov 2009 09:01:18 PST

Background: Spider (Latrodectus tredecimguttatus) bites are relatively common in North East Iran. They induce morbidity and rarely mortality. We aimed to investigate clinical, electrocardiographic and para-clinical changes in patients with this bite. Methods: All consecutive patients admitted with suspected spider bites between September 2005 and September 2006 were studied prospectively. Results: Spider bites accounted for 56 cases (0.5% of all poisoning, 21% of all admitted envenomated). The patients’ mean (SD) age was 32 (16) years. The most common findings were pain (90%) mainly in their back (45%), stomach (35%), lower limbs (33%), upper limbs (19%) and chest (14%). Other clinical findings included were sweating (55%), chills (29%), dyspnea (25%), flushing (14%), spasm (12%), headache (12%), nausea (12%) and vertigo (12%). On electrocardiograph (ECG); ST segments were depressed in 25% of cases in at least two of the pre-cordial leads. Laboratory findings were in normal ranges. All the patients recovered following supportive and symptomatic treatment (no anti-toxin available in Iran), with a mean hospitalization period of 1.9 (1.3) days. Conclusions: Spider (L. Tredecimguttatus) bite is relatively common in Mashhad, which induces latrodectism with relatively different findings and cardiac toxicity. ECG monitoring should be considered, particularly when specific anti-toxin is not available.

Polybrominated diphenyl ethers cause oxidative stress in human umbilical vein endothelial cells

Kawashiro, Y., Fukata, H., Sato, K., Aburatani, H., Takigami, H., Mori, C. — Mon, 16 Nov 2009 09:01:18 PST

Polybrominated diphenyl ethers (PBDEs) are used as flame retardants to prevent combustion in consumer products, such as electronics, construction materials, and textiles and, therefore, have become important commercial substances. PBDEs were also detected in maternal blood, breast milk, umbilical cord blood, and cord tissue, thereby indicating that fetuses were also exposed to PBDEs. The purpose of this study is to identify the effect of PBDEs on human umbilical vein endothelial cells (HUVECs). Cultured HUVECs were exposed to a commercial mixture of penta-BDE (DE71), octa-BDE (DE79), and deca-BDE (DE83). Each gene expression that was altered in DNA microarray was confirmed by real-time reverse transcription—polymerase chain reaction and Western blotting analysis. The results indicated that gene expressions concerning antioxidant system, i.e., thioredoxin family, 24-dehydrocholesterol reductase (DHCR24), and tumor suppressor protein p53, were altered by PBDEs exposure in HUVECs. Moreover, it was demonstrated that thioredoxin-interacting protein (TXNIP) was a target gene in exposure to DE71 and DE79 in HUVECs, by drastically decreasing time-dependent TXNIP expression in HUVECs.

An atropine and glycopyrrolate combination reduces mortality in organophosphate poisoning

Arendse, R., Irusen, E. — Mon, 16 Nov 2009 09:01:18 PST

Anticholinergics are the mainstay of the pharmacological management of organophosphate poisoning (OPP). Atropine has the potential to cause central toxicity which may complicate the management of this life-threatening condition. A combination of atropine and glycopyrrolate in equivalent dosages titrated to the peripheral muscarinic signs, theoretically reduces the central effect of the anticholinergics by 50% and thereby the risk of central toxicity, while it provides effective control of the peripheral manifestations of OPP. This study reports the clinical morbidity and mortality associated with the management of OP with this anticholinergic combination over a 4-year period, 2003 to 2006, at Tygerberg Academic Hospital (TAH). Two of the 53 patients treated for OPP died, with this mortality lower than that previously reported at TAH. Atropine toxicity was evident in 12 (22.5%) patients and responded to a temporary cessation of the combination infusion. The demographic profile, presenting symptoms, duration of stay and complications encountered were similar to previous reports from TAH. Patients treated with the infusion of a combination of atropine and glycopyrrolate had a lower mortality rate compared with earlier reports from the same unit, but the occurrence of atropine toxicity was unchanged despite the hypothesized theoretical advantage.

Severe scorpion envenomation in children: Management in pediatric intensive care unit

Mon, 16 Nov 2009 09:01:18 PST

Background: Scorpion envenomation is a common public health problem worldwide and children are at greater risk of developing severe cardiac, respiratory and neurological complications. The aim of this study was to evaluate the effects of antivenin and/or prazosin use on prognosis of scorpion-envenomed children admitted to pediatric intensive care unit (PICU). Methods: The standardized medical records of 45 children hospitalized with severe scorpion sting in PICU were retrospectively evaluated. General characteristics of the children, clinical and laboratory findings, treatment approaches and prognosis were evaluated. Results: The mean age of the patients were 6.1 ± 4.1 years ranging between 4 month and 15 years. Male to female ratio was 1.8. Thirty-three (71.1%) cases of scorpion stings came from rural areas. Twenty-six (57.8%) of the patients were stung by Androctonus crassicauda. The most common sting localization was the foot-leg (55.6%). The mean duration from the scorpion sting to hospital admission was 4.5 ± 2.6 hours. The most common findings at presentation were cold extremities (95.5%), excessive sweating (91.1%) and tachycardia (77.7%). The mean leukocyte count, and serum levels of glucose, lactate dehydrogenase, creatine phosphokinase and international normalized ratio were found above the normal ranges. Prazosin was used in all patients, dopamine in 11 (24.4%) and Na-nitroprusside in 4 (8.8%) patients. Two children died (4.4%) due to pulmonary oedema. These children, in poor clinical status at hospital admission, needed mechanical ventilation, and death occurred despite use of antivenin and prazosin in both of them. Conclusion: The current management of children with severe scorpion envenomation consists of administration of specific antivenom and close surveillance in a PICU, where vital signs and continuous monitoring enable early initiation of therapy for life-threatening complications. The aggressive medical management directed at the organ system specifically can be effective. Our data indicated that when admission to hospital is late, the beneficial effect of antivenom and/or prazosin is questionable in severe scorpion stings.

Severe acetaminophen poisoning treated with a fractionated plasma separation and absorption system: A case report

Sebe, A., Satar, S., Rana Alpay, N., Murt, M., Guvenc, B. — Mon, 16 Nov 2009 09:01:18 PST

Acetaminophen is an analgesic drug that is frequently used in suicide attempts. In this paper, we report on a 17-year-old girl who was admitted to an emergency department 15 hours after taking acetaminophen pills in a suicide attempt. Her serum acetaminophen level was 73 mg/L on admission; she had elevated liver enzymes suggesting hepatic necrosis. She was started on N-acetyl cystein (NAC), and treated successfully with a fractionated plasma separation and absorption system.

Acrylamide-induced oxidative stress in human erythrocytes

Catalgol, B., Ozhan, G., Alpertunga, B. — Mon, 02 Nov 2009 05:59:36 PST

Acrylamide (AA), a widely used industrial chemical, is shown to be neurotoxic, mutagenic and carcinogenic. This study was carried out to investigate the effects of different doses of AA on lipid peroxidation (LPO), haemolysis, methaemoglobin (MetHb) and antioxidant system in human erythrocytes in vitro. Erythrocyte solutions were incubated with 0.10, 0.25, 0.50 and 1.00 mM of AA at 37°C for 1 hour. At the end of the incubation, malondialdehyde (MDA), an end product of LPO, was determined by liquid chromatography (LC) while total glutathione, reduced glutathione (GSH) levels, activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) enzymes and the rates of haemolysis and MetHb were determined by spectrophotometric methods. All of the studied concentrations of AA increased MetHb formation and SOD activity, and induced MDA formation and haemolysis due to the destruction of erythrocyte cell membrane. AA caused a decrease in the activities of GSH-Px, CAT and GSH levels. However, these effects of AA were seen only at higher concentrations than AA intake estimated for populations in many countries. We suggest that LPO process may not be involved in the toxic effects of AA in low concentrations, although the present results showed that the studied concentrations of AA exert deteriorating effects on antioxidant enzyme activities, LPO process and haemolysis.

Safety of a novel galacto-oligosaccharide: Genotoxicity and repeated oral dose studies

Kobayashi, T., Yasutake, N., Uchida, K., Ohyama, W., Kaneko, K., Onoue, M. — Mon, 02 Nov 2009 05:59:36 PST

A series of safety tests were undertaken on a novel galacto-oligosaccharide (GOS) produced from lactose by a two-step enzymatic process involving Sporobolomyces singularis and Kluyveromyces lactis. Bacterial reverse mutation and chromosomal aberration tests, with or without metabolic activation, were performed. These tests showed no mutagenesis in the Ames assay or in Escherichia coli WP2uvrA, and no chromosomal aberrations in cultured fibroblast cells from Chinese hamster lungs (CHL/IU). Micronuclei were not induced in the reticulocytes of mouse peripheral blood following oral administration of GOS. In a 90-day repeated oral dose toxicity study in rats, GOS was administered at 0, 500, 1000 and 2000 mg/kg to male and female Sprague-Dawley rats. There were no GOS-related changes in clinical signs, body weight, water intake, feed intake, urinalysis, ophthalmology, haematology, blood chemistry, organ weights, gross pathology or histopathology in any of the treatment groups compared to the control group. The no observed adverse effect level (NOAEL) of GOS was at least 2000 mg/kg/day in both males and females.

Cardiac biomarkers in a model of acute catecholamine cardiotoxicity

Mon, 02 Nov 2009 05:59:36 PST

Coronary heart disease and in particular its most serious form — acute myocardial infarction (AMI) — represents the most common cause of mortality in developed countries. Better prognosis may be achieved by understanding the etiopathogenetic mechanisms of AMI. Therefore, a catecholamine model of myocardial injury, which has appeared to be very similar to AMI in human in some aspect, was used. Male Wistar:Han rats were randomly divided into two groups: control group (saline) and isoprenaline group (ISO; synthetic catecholamine, 100 mg.kg^{— 1} subcutaneously [s.c.]). After 24 hours, functional parameters were measured, biochemical markers in the blood and metals content in the heart tissue were analysed and histological examination was performed. ISO caused marked myocardial injury that was associated with myocardial calcium overload. Close correlation between myocardial impairment (i.e. serum TnT, stroke volume index and wet ventricles weight) and the levels of myocardial calcium was observed. Direct reactive oxygen species (ROS) involvement was documented only by non-significant increase in malonyldialdehyde 24 hours after ISO injury. Moreover, myocardial element analysis revealed no significant changes as for the content of zinc and iron while selenium and copper increased in the ISO group although it reached statistical significance only for the latter.

The effects of subchronic lithium administration in male Wistar mice on some biochemical parameters

Nciri, R., Allagui, M., Vincent, C., Murat, J., Croute, F., El Feki, A. — Mon, 02 Nov 2009 05:59:36 PST

Lithium salts are efficiently used for treatment of psychiatric disorders. However, prolonged treatment frequently involves adverse side effects. In this study, effects of lithium carbonate administration on some biochemical parameters were studied in male mice. Lithium carbonate (20, 40, or 80 mg/kg body weight corresponding to 3.77, 7.54, or 15.08 mg Li element/kg body weight, respectively) was injected daily for 14 or 28 days. The following parameters were recorded: drinking water consumption, body weight, lithium and testosterone serum concentrations, activities of catalase (CAT), superoxide-dismutase (SOD), and glutathione-peroxidase (GPX), and level of lipid peroxidation (expressed as TBARS) in liver was performed. Lithium treatment, especially at the highest dose for 28 days, was found to induce weight gain and polydipsia and a significant decrease of plasma testosterone level. Lipid peroxidation level and activities of SOD and GPX were increased in liver, which suggests a perturbation of the antioxidative status. Our results indicate that subchronic exposure to lithium, which induces weight gain and polydipsia under our experimental conditions, also damages the male reproductive system and triggers an oxidative stress in the liver.

Time-dependent changes in lead and {delta}-aminolevulinic acid after subchronic lead exposure in rats

Kang, H. G., Jeong, S. H., Cho, M. R., Cho, J. H., Bischoff, K. — Mon, 02 Nov 2009 05:59:36 PST

The time-dependent changes in lead (Pb) concentrations in major tissues, serum and urine, and the Pb biomarker -aminolevulinic acid (ALA) concentration in urine were studied in rats after sub-chronic Pb exposure. Female Sprague-Dawley (SD) rats were exposed to Pb in drinking water at concentrations of 100 ppm and 1000 ppm for 30 days. The Pb concentration in muscle, liver, kidney, plasma and urine, and the ALA concentration in urine were determined during exposure and every 7 days after exposure for 3 weeks. The muscle Pb concentration did not change post exposure. The liver Pb concentration increased 2.2 to 2.8 times (100 ppm group) and 3.9 to 7.4 times (1000 ppm group) during exposure, then decreased rapidly. Kidney Pb concentrations were 8.0 to 14.3 times (100 ppm group) and 13.8 to 28.5 times (1000 ppm group) higher than controls during exposure and decreased for 1 to 2 weeks post exposure. Plasma Pb concentrations were 1.2 to 3.3 times (100 ppm group) and 2.9 to 5.8 times (1000 ppm group) higher than control concentrations during exposure and decreased time-dependently in the 1000-ppm group after exposure. Urine Pb concentrations were 8.5 to 10.7 times (100 ppm group) and 30.4 to 51.1 times (1000 ppm group) higher than control concentrations during exposure and rapidly decreased after exposure, though concentrations remained up to 4 times higher than controls in the 1000 ppm exposure group. Urine ALA concentrations increased 1.7 to 2.6 and 7.1 to 32.7 times during exposure in the 100 ppm and 1000 ppm groups respectively, and remained elevated for 21 days post exposure. Our data support that urine Pb concentration is a useful marker for acute Pb exposure or post exposure. Urine ALA may be a predicator of biological response to Pb exposure.

Effect of m-3M3FBS on Ca2+ movement in Madin-Darby canine renal tubular cells

Fang, Y.-C., Kuo, D.-H., Shieh, P., Chen, F.-A., Kuo, C.-C., Jan, C.-R. — Mon, 02 Nov 2009 05:59:36 PST

The effect of 2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl)-benzenesulfonamide (m-3M3FBS), a presumed phospholipase C (PLC) activator, on cytosolic free Ca²⁺ concentrations ([Ca²⁺]_i) in Madin-Darby canine kidney (MDCK) cells is unclear. This study explored whether m-3M3FBS changed basal [Ca²⁺]_i levels in suspended MDCK cells using fura-2 as a Ca²⁺-sensitive fluorescent dye. M-3M3FBS at concentrations between 0.1 and 20 µM increased [Ca²⁺]_i in a concentration-dependent manner. The Ca²⁺ signal was decreased by removing extracellular Ca²⁺. M-3M3FBS-induced Ca²⁺ influx was inhibited by the store-operated Ca²⁺ channel blockers nifedipine, econazole, and SK&F96365, and by the phospholipase A2 inhibitor aristolochic acid. In Ca²⁺-free medium, 20-µM m-3M3FBS pretreatment abolished the [Ca²⁺]_i rise induced by the endoplasmic reticulum Ca²⁺ pump inhibitors thapsigargin (TG) and cyclopiazonic acid (CPA). Conversely, pretreatment with TG or CPA partly reduced m-3M3FBS-induced [Ca²⁺]_i rise. The inhibition of PLC with U73122 did not alter m-3M3FBS-induced [Ca²⁺]_i rise. Collectively, in MDCK cells, m-3M3FBS induced [Ca²⁺]_i rises by causing PLC-independent Ca²⁺ release from the endoplasmic reticulum and Ca²⁺ influx via store-operated Ca²⁺ channels and other unidentified Ca²⁺ channels.

Comparison of arterial and capillary blood gas values in poisoning department assessment

Eizadi-Mood, N., Alfred, S., Yaraghi, A., Huynh, C., Moghadam, A. S. — Mon, 02 Nov 2009 05:59:36 PST

The aim of this study was to compare simultaneously obtained arterial and capillary blood gas (CBG) values in comatose-poisoned patients presented with stable vital signs. Forty-five adult patients with a diagnosis of coma because of poisoning and stable vital signs were included in this prospective study. With respect to pH, the arterial blood gas (ABG) and CBG values correlated satisfactorily (r² = .91) and had an acceptable limit of agreements (LOAs; —0.04 to 0.06). With respect to base excess (BE), the ABG and CBG values correlated well (r² = .85), but their 95% LOAs seem too wide to allow substitution (—4.4 to 2.7). PCO₂ (r² = .61), HCO₃ (r² = .71) and PO₂ (r² = .53) correlated less reliably. A capillary PCO₂ of 51.7 mm Hg had a sensitivity of 100% and a specificity of 95.12% for detecting hypercarbia (area under the curve, 0.99; 95% Confidence Interval, 0.90-0.99; p < .0001). In conclusion, CBG analysis for pH may be a reliable substitute for ABG analysis in the initial evaluation of patients presenting with coma and stable vital signs to the poisoning emergency department (PED). Subsequent ABG may be required in patients with capillary PCO₂ > 51.7 mm Hg.

Persistent organic pollutants (POPs) in Africa: Egyptian scenario

Mansour, S. A — Wed, 21 Oct 2009 07:40:53 PDT

Persistent organic pollutants (POPs) are organic (carbon-based) compounds that include synthesized substances (pesticides and polychlorinated biphenyls [PCBs]) and other by-product substances generated as a result of human and natural activity (dioxins and furans). Extensive scientific studies have shown that POPs are some of the most dangerous pollutants released into the environment by humans. Great efforts have been made since the early 1960s to enhance chemical management and safety issues. Various conventions have been adopted for this purpose: the Stockholm Convention (SC) is one of the well-known meetings in this context. The SC on POPs (May 2001) focuses on reducing and eliminating releases of 12 POPs coined the ‘Dirty Dozen’ by the United Nations Environment Program (UNEP). Persistence of such chemicals in soils, air, and water, together with natural processes such as evaporation to the atmosphere and washout by rain and flood, give rise to their ubiquitous distribution in the environment and eventual penetration into food chains and bio-accumulation in humans. Public concern about contamination by POPs increased recently because several of these compounds are identified as hormone disruptors, which can alter normal function of endocrine and reproductive systems in humans and wildlife. African countries are using pesticides, such as dichlorodiphenyltrichloroethane (DDT), lindane, toxaphene, endrin, dieldrin, heptachlor, since more than 50 years for combating agricultural pests and controlling disease vectors, especially malaria. The way in which pesticides are used in Africa caused serious environmental and health problems much more than elsewhere. These problems are represented by accumulation of organochlorine pesticide (OCP) residues in different environmental samples and hosting of at least 50,000 tons of obsolete pesticides, as well as tens of thousands of tons of contaminated soil. Within the framework of the Africa Stockpiles Program (ASP), huge quantities of pesticidal POPs have been completely or partially destroyed in a number of African countries (e.g. Egypt, Namibia, Niger, Senegal, Seychelles, South Africa, Sudan, Tanzania, Uganda, Zambia). At regional level (i.e. African Countries), a strategic plan for monitoring and getting rid of POPs in the continent should be set up and implemented through coordination between all governments. Among issues of top priorities are to find alternative non-combustion technologies for disposing obsolete pesticides, and to use alternative control measures for mosquitoes’ management and other vector-borne diseases.

Evaluation of calcium excretion in Brazilian infantile and young population environmentally exposed to lead

Wed, 21 Oct 2009 07:41:08 PDT

Lead exposure is an important issue in the research of several toxic effects resulting from the biochemical interaction between this metal and the organism. Calcium is a fundamental mineral for the maintenance of the organism homeostasis where there is interaction between lead and calcium in metabolic pathways. Environmental lead exposure by verifying the usefulness and applicability of urinary calcium/creatinine ratio (UCa/Cr) in this context was evaluated. This was an extensive socio-demographic study of the nutritional profile, lead exposure biomarkers in blood and the urine and UCa/Cr ratio. The children studied were from a low socio-economic group characterized by unsatisfactory nutritional diet. Lead environmental exposure was shown by biomarkers, with UCa/Cr ratio having positive and significant correlations with both lead and -aminolevulinic acid in urine (ALA-U), without colinearity diagnosis. There was a strong association between calcium excretion and lead exposure as a result of linear regression construction models. In children, lead increases calcium excretion which is an additional risk to infantile health. Urinary calcium/creatinine ratio may be a useful tool in the biological monitoring of lead exposure and health promotion programs.

Oxidative stress induced by morphine in brain of rats fed with a protein deficient diet

Wed, 21 Oct 2009 07:41:10 PDT

The objective of the study is to determine the damage by oxidative stress induced by morphine in brain of rats fed with a protein-deficient diet. Twenty-eight malnourished male Wistar rats, 30 days old, were used in the study. The animals were divided into four groups of 7 rats per group. Group I received NaCl and the groups II; III and IV intraperitoneally received 3, 6 and 12 mg/kg of morphine sulphate, respectively, in a single dose. Animals were sacrificed and the levels of glutathione (GSH), dopamine, tryptophan and 5-hydroxyindole-3-acetic acid (5-HIAA) as well as, Na⁺/K⁺ ATPase and total ATPase activity in the brain were measured. Tryptophan levels and Na⁺/K⁺ ATPase activity showed non-significant changes in the experimental group. Levels of 5-HIAA decreased significantly (p = .03) in animals that received 12 mg/kg of morphine and in animals that received 3 mg/kg, levels of GSH and dopamine were found to have a significant decrease (p < .05), but a significant increase in the group that received 12 mg/kg of morphine (p < .05). Total ATPase activity increased significantly in the groups that received 3 mg/kg (p = .015) and 6 mg/kg (p = .0001) of morphine. The results show that malnutrition induces changes in cellular regulation and biochemical responses to oxidative stress caused by morphine sulphate.

Glycogen content is affected differently in acute pulmonary and extra-pulmonary lung injury

Borges, E., Pinheiro, M., Eleto-Silva, A., Caliari, M., Rodrigues-Machado, M. — Wed, 21 Oct 2009 07:41:12 PDT

Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury (ALI). The aim of the present study was to investigate whether paraquat-induced acute pulmonary and extra-pulmonary lung injury (ALI-P and ALI-EX, respectively), in rats, affects glycogen content in different tissues. This measurement could indicate performance limitations of tissues, a new biochemical aspect of ARDS. ALI-P and ALI-EX were induced by injection into the trachea (0.5 mg/kg) and intraperitoneally (20 mg/kg) 24 hours prior to tissue collection. The control groups (CTRL) received the same volume of saline. Glycogen content (mg/g tissue) from different tissues was measured using the anthrone reagent. Glycogen content in the heart and kidney was higher in the ALI-EX group than the CTRL-EX group. Glycogen content in the gastrocnemius muscle was lower in the ALI-EX group than the CTRL-EX group. However, there were no significant differences in glycogen content in the diaphragm in the ALI-EX and ALI-P groups or in the gastrocnemius, heart and kidney in the ALI-P group when compared to the respective controls. ALI-EX caused a greater thickening of the alveolar walls, more areas of atelectasis and a greater abundance of inflammatory cells in comparison to ALI-P. These results demonstrate that glycogen content in ALI, induced by an herbicide that is highly toxic to humans and animals, is altered in different tissues depending on the location of the injury.

Toxicological implications of aqueous extract of Bambusa vulgaris leaves in pregnant Dutch rabbits

Yakubu, M., Bukoye, B., Oladiji, A., Akanji, M. — Wed, 21 Oct 2009 07:41:15 PDT

Aqueous extract of Bambusa vulgaris L. leaves at 250 and 500 mg/kg body weight was investigated for toxic effects in pregnant rabbits. Apparently healthy, female rabbits (Dutch) weighing between 1.62 and 1.70 kg as previously used in our abortifacient study were paired overnight with male rabbits in ratio 2:1 and those that became pregnant were completely randomized into three groups (A-C). Group A (the control), received orally 1.85 mL/kg body weight (3 mL) of distilled water thrice daily on days 1-9 of pregnancy while groups B and C were treated orally with the same volume corresponding to 250 and 500 mg/kg body weight of the extract. Clinical signs of toxicity were not observed in all the animals during the study. The extract did not significantly alter (p > .05) the serum follicle stimulating hormone and total protein content of the pregnant rabbits throughout the exposure period whereas, the concentrations of luteinizing hormone, progesterone, albumin, globulin, urea and calcium decreased in the serum of the rabbits. At 250 mg/kg body weight, the extract increased kidney alkaline phosphatase (ALP) activity whereas at 500 mg/kg body weight of the extract, the ALP level was similar to the control group. Liver ALP at all doses, as well as the activity of gamma glutamyl transferase (GGT) at 500 mg/kg body weight was reduced. This reduction was accompanied by an increase in serum ALP and GGT at these doses. At 250 mg/kg, the extract increased kidney GGT. Conversely, at 500 mg/ kg, kidney GGT activity decreased. Liver and serum GGT were not altered by the 250 mg/kg. The extract also increased the serum levels of creatinine, uric acid, sodium, potassium and bicarbonate ions as well as total and conjugated bilirubin. In the hepatocytes of extract-treated animals, there was no evidence of necrosis, inflammation, fibrosis and degenerative changes in the central vein and radiating hepatic cords, while the glomerulus and the tubules of the nephrons also remained intact. The alterations in biochemical parameters by the aqueous extract of B. vulgaris leaves suggests adverse effect on the synthetic, secretory, reabsorptive and excretory functions of liver and kidney of the animals. Therefore, the absence of histopathological lesions in the hepatocytes and nephrons implies that histopathological changes are not a sensitive assay for the assessment of tissue damage by the extract.

Use of pralidoxime without atropine in rivastigmine (carbamate) toxicity

Wed, 21 Oct 2009 07:41:19 PDT

Some experimental models suggest that the use of pralidoxime in carbamate toxicity is deleterious. Although pretreatment with atropine minimizes the adverse effect of pralidoxime reported in these models, concerns over the risks of pralidoxime in humans with carbamate poisoning continue. We present a unique case of carbamate toxicity treated successfully with pralidoxime alone. An 80-year-old woman with Alzheimer’s dementia presented to the emergency department with 3-4 days of lightheadedness, vomiting, diarrhea, and bilateral lower extremity muscle pain. Extensive review of systems was otherwise negative. Her vital signs were BP, 207/85 mmHg; pulse, 101 beats/min; rectal temperature, 36.6^°C; respirations, 18/min; and SpO₂, 95% breathing room air. Her bedside glucose measurement was 6.7 mmol/L. Physical examination revealed a confused, diaphoretic, ill-appearing woman with miosis and fasciculations of the tongue, eyelids, gastrocnemius and quadriceps bilaterally. The heart, lung, abdominal and head, eyes, ears, nose and throat examinations were otherwise unremarkable. Nine 5-cm² rivastigmine patches (9.5 mg/24-hour) were found adherent to her torso and lower extremities. The patches were immediately removed and underlying skin cleansed with soap and water. Laboratory values including complete blood count, basic metabolic panel, calcium, magnesium, phosphorus, troponin, coagulation studies and urinalysis were unremarkable. Due to the absence of pulmonary muscarinic findings, no atropine was administered. However, 1 g of pralidoxime was administered intravenously over 30 min to treat fasciculations. Within 30 min of this treatment, there was significant improvement in symptoms and resolution of fasciculations. She was admitted to the hospital, required no further pralidoxime therapy and was discharged after 3 days. Rivastigmine is a reversible (carbamate) cholinesterase inhibitor used to treat dementia. In overdose, cholinergic crisis is expected and in this case was precipitated by patch overuse. We believe there was a causal relationship between pralidoxime administration and the prompt resolution of symptoms and fasciculations. This case of apparently safe and effective pralidoxime use without concomitant atropine administration in a patient with carbamate toxicity reinforces recent data demonstrating the potential safety of pralidoxime in carbamate toxicity.

Effects of exposure to pesticides during pregnancy on placental maturity and weight of newborns: A cross-sectional pilot study in women from the Chihuahua State, Mexico

Acosta-Maldonado, B., Sanchez-Ramirez, B., Reza-Lopez, S., Levario-Carrillo, M. — Thu, 01 Oct 2009 07:50:57 PDT

It is known that pesticides cross the placental barrier and can cause alterations in the development of placental structures resulting in adverse effects in reproduction. The objectives of this study were to investigate the effects of pesticide exposure during pregnancy on placental maturity and to evaluate the relationship between placental maturity, gestational age and birth weight. We collected the placentas from singleton pregnancies from women exposed (n = 9) and non-exposed (n = 45 full-term and n = 31 preterm) to pesticides as evaluated geographically, by questionnaire and by acetylcholinesterase levels. Placental morphometry from the central and peripheral regions was examined by microscopy and staining with hematoxylin and eosin. The placental maturity index (PMI) was estimated by dividing the number of epithelial plates in terminal villi to their thickness in 1 mm² of the placental parenchyma. Gestational age, birth weight and the following characteristics of the mother were also recorded: pre-pregnancy body mass index, weight gain during pregnancy and hemoglobin concentrations. Birth weight and the gestational age were correlated with PMI (r = .54 and r = .44, respectively; p < .01). Pesticide exposure was associated with a higher PMI (beta = 7.38, p = .01) after adjusting by variables related to placental maturity. In conclusion, the results suggest a relationship between prenatal exposure to pesticides and placental maturity and may potentially affect the nutrient transport from the mother to the fetus.

Protective role of selenium supplementation against cardiac lesions induced by the combination of levomepromazine and risperidone in the rabbit

Thu, 01 Oct 2009 07:50:57 PDT

Neuroleptics are a suspected cause of sudden death in psychiatric patients, especially in those with pre-existing cardiac lesions. As these lesions were previously shown to be associated with selenium (Se) deficiency, the aim of the present study was to evidence the possible protective effect of Se supplementation against cardiac lesions induced by the combination of the neuroleptic drugs levomepromazine and risperidone in the rabbit. Two groups of 6 rabbits were treated with 3 mg/kg of levomepromazine daily intramuscularly combined with 1 mg/kg of risperidone intramuscularly every other week for 3 consecutive months, and one group additionally received a solution of sodium selenite (2 µg/kg/day) intramuscularly during the whole treatment period. Furthermore, one group of six untreated animals was given the Se supplementation and another group of six control animals received saline daily. Blood samples were drawn before and at the end of the treatment period for the measurement of serum Se levels. At the end of the study, all animals were sacrificed and their hearts were removed for the measurement of tissue Se concentrations. In addition, the hearts were prepared for histopathological examination. A variety of cardiac lesions was found in the neuroleptics-treated animals without supplementation and to a lesser extent in the control and Se-supplemented untreated animals. Importantly, only rare cardiac lesions were observed in neuroleptics-Se-treated animals. The most striking differences in Se concentrations were noted in the myocardium: as compared to controls, there was a 43% reduction in neuroleptics-treated, but non-Se-supplemented animals (p < .01), at the end of the treatment period, whereas only a 14% reduction (p < .05) was noted in the neuroleptics-Se-treated animals. These results confirm that neuroleptics induce cardiac lesions associated with Se deficiency. Selenium supplementation markedly decreased the incidence and severity of neuroleptics-induced cardiac lesions and these findings may serve as a basis for further evaluation of the protective role of Se supplementation in neuroleptics-treated patients. However, Se supplementation in normal animals without Se deficiency was also shown to be cardiotoxic.

Mode of cellular toxicity of aqueous extract of Fadogia agrestis (Schweinf. Ex Hiern) stem in male rat liver and kidney

Yakubu, M., Oladiji, A., Akanji, M. — Thu, 01 Oct 2009 07:50:57 PDT

The mode of cellular toxicity of aqueous extract of Fadogia agrestis stem in male rats was investigated. Rats were grouped into four: A, B, C and D where A (the control) received orally 1 mL of distilled water; B, C and D (test groups) received orally 18, 50 and 100 mg/kg body weight of the extract, respectively, for 28 days. Infrared spectroscopy indicated the presence of hydroxyl (OH) and primary amine (CONH). Clinical toxicity symptoms such as respiratory distress, epistasis, salivation, hypo- and hyperactivity were not observed at any period of the experiment. No mortality was also recorded. Extract administration significantly reduced (p < .05) the activities of alkaline phosphatase, lactate dehydrogenase and gamma glutamyl transferase in the liver and kidney with corresponding increases in the serum. Serum malondialdehyde also increased significantly in all the extract-treated groups. The liver and kidney body weight ratios of the extract-treated animals compared well (P > .05) with their controls throughout the experimental period. The extract did not cause any swelling, atrophy or hypertrophy of the organs. The other evidence in this study suggests disruption of the ordered lipid bilayer of the plasma membranes of the hepatocytes and nephrons. This might have resulted from peroxidation of the polyunsaturated fatty acids on the membranes of the hepatocytes and nephrons made possible by the functional groups or the product of metabolism of the extract. This may be responsible for the compromise of the integrity of the plasma membranes of the hepatocytes and nephrons.

Toxicology and biodistribution study of CIGB-230, a DNA vaccine against hepatitis C virus

Thu, 01 Oct 2009 07:50:57 PDT

CIGB-230, a mixture of a DNA plasmid expressing hepatitis C virus (HCV) structural antigens and a HCV recombinant capsid protein, has demonstrated to elicit strong immune responses in animals. The present study evaluated the plasmid biodistribution after the administration of CIGB-230 in mice, as well as toxicity of this vaccine candidate in rats. In the biodistribution study, mice received single or repeated intramuscular injections of CIGB-230, 50 µg of plasmid DNA mixed with 5 µg of Co.120 protein. Plasmid presence was assessed in ovaries, kidney, liver, pancreas, mesenteric ganglion, blood, and muscle of the injection site by a qualitative polymerase chain reaction. The toxicology evaluation included treatment groups receiving doses 5, 15, or 50 times higher, according to the body weight, than the expected therapeutic clinical dose. During the first hour after repeated inoculation, a promiscuous distribution was observed. However, 3 months later, plasmid could not be detected in any tissue. There was an absence of detectable adverse effects on key toxicology parameters and no damage evidenced in inspected organs and tissues. These results indicate that CIGB-230 is nontoxic at local and systemic levels and no concerns about persistence are observed, which support clinical testing of this vaccine candidate against HCV.

Quercetin-induced apoptosis acts through mitochondrial- and caspase-3-dependent pathways in human breast cancer MDA-MB-231 cells

Thu, 01 Oct 2009 07:50:57 PDT

There has been considerable evidence recently demonstrating the anti-tumour effects of flavonols. Quercetin, an ubiquitous bioactive flavonol, inhibits cells proliferation, induces cell cycle arrest and apoptosis in different cancer cell types. The precise molecular mechanism of quercetin-induced apoptosis in human breast cancer cells is unclear. The purpose of this study was to investigate effects of quercetin on cell viability and to determine its underlying mechanism in human breast cancer MDA-MB-231 cells. Quercetin decreased the percentage of viable cells in a dose- and time-dependent manner, which was associated with cell cycle arrest and apoptosis. Quercetin did not increase reactive oxygen species generation but increased cytosolic Ca²⁺ levels and reduced the mitochondrial membrane potential (_m). Quercetin treatment promoted activation of caspase-3, -8 and -9 in MDA-MB-231 cells. Caspase inhibitors prevented the quercetin-induced loss of cell viability. Quercetin increased abundance of the pro-apoptotic protein Bax and decreased the levels of anti-apoptotic protein Bcl-2. Confocal laser microscope examination indicated that quercetin promoted apoptosis-inducing factor (AIF) release from mitochondria and stimulated translocation to the nucleus. Taken together, these findings suggest that quercetin results in human breast cancer MDA-MB-231 cell death through mitochondrial- and caspase-3-dependent pathways.

Immediate- and controlled-release zolpidem ingestions reported to Texas poison centers

Forrester, M. B — Thu, 01 Oct 2009 07:50:57 PDT

Zolpidem is available in immediate-release (IR) and controlled-release (CR) formulations. This investigation examined whether there were differences in zolpidem IR and CR ingestions reported to poison control centers. Zolpidem ingestions that did not involve coingestants reported to Texas poison control centers during 2005-2008 were identified. The ingestions were grouped by IR and CR formulations and compared with respect to demographic and clinical factors. There were 734 IR and 163 CR ingestions. The mean dose ingested was 92.9 mg and 104.6 mg, respectively. IR and CR cases were, respectively, 56.9% and 58.3% male, 54.6% and 49.7% age >19 years, 65.0% and 65.0% already at or en route to a health care facility when the poison control center was contacted, and 30.1% and 39.3% involved no effect. The most frequently reported adverse clinical effects were, for IR and CR, respectively, drowsiness (54.4% vs 42.3%), tachycardia (10.6% vs 11.7%), ataxia (6.3% vs 11.7%), slurred speech (6.3% vs 6.7%), vomiting (5.0% vs 5.5%) and hallucinations/delusions (4.9% vs 3.1%). The distribution of zolpidem IR and CR ingestions reported to Texas poison control centers were similar. However, zolpidem CR ingestions appeared less likely to result in drowsiness and hallucinations but more likely to result in ataxia.

Risk assessment of severe tricyclic antidepressant overdose

Thu, 01 Oct 2009 07:50:57 PDT

Prognostic factors for severe complications in tricyclic antidepressant (TCA) overdose remain unclear. We therefore evaluated the value of clinical characteristics and electrocardiograph (ECG) parameters to predict serious events (seizures, arrhythmia, death) in severe TCA overdose of 100 patients using logistic regression models for risk assessment. The overall fatality rate was 6%, arrhythmia occurred in 21% and 31% of the patients developed seizures. Using an univariable logistic regression model, the maximal QRS interval (OR 1.22; 95% CI 1.06-1.41; p = .005), the time lag between ingestion and occurrence of first symptoms of overdose (OR 1.13; 95% CI 0.99-1.29; p = .072) and the age (OR 0.73; 95% CI 0.55-0.98; p = .038) were determined as the solely predictive parameters. In the multivariable logistic regression model, the QRS interval could not be established as independent predictor, however, the terminal 40-ms frontal plane QRS vector (T40) reached statistical significance regarding prediction of serious events (odds ration [OR] 1.70; 95% confidence interval [CI] 1.02-2.84; p = .041), along with age and time lag between ingestion and onset of symptoms of overdose with a sensitivity and specificity of 71% and 70%, respectively. Evaluation of both clinical characteristics and ECG-parameters in the early stage of TCA overdose may help to identify those patients who urgently need further aggressive medical observation and management.

Homicidal poisoning by injection of methidathion: The first ever report

Ozdemir, C., Kar, H., Bilge, Y., Batuk, G., Batuk, H. I. — Thu, 01 Oct 2009 07:50:57 PDT

We present the first ever case of homicidal poisoning due to injection of methidathion, an organophosphate insecticide. Case: A 4-month-old baby presented to the emergency department with chief complaints of unconsciousness and irregular respiration. A bitter odour and an injection site with a greenish blue colouration and two bullaous lesions were noticed by the emergency department physicians. Postmortem examinations revealed a wide shiny blue colouration of the antecubital region with oedematous muscular fascia and focal liquefaction necrosis. Blood and tissue levels were positive for methidathion. Our case report emphasizes the necessity of a detailed crime scene investigation and postmortem examination for the possibility of homicide in such cases. Although injection sites may be the expected results of medical treatment, dermal lesions also may be associated with injections of toxic substances.