Human & Experimental Toxicology

Acute poisoning continues to be an important public health problem. Medical records of 116 adult patients presented to Tikur Anbessa Specialized University Hospital from January 2007 to December 2008 were reviewed retrospectively. Females outnumbered males. Mean age was 21 years. Most (96.5%) were intentional self-harm poisonings. Household cleansing agents were the leading causes of poisoning (43.1%) followed by organophosphate (21.6%) and phenobarbitone (10.3%). Loss of consciousness, vomiting and epigastric pain were the common presenting features accounting 46.2%, 23.8% and 22.5%, respectively. A total of 13(11.2%) patients had already known mental illness and 12 of them poisoned by using their own medications. Among 65 patients who reported their reason of poisoning, temporary quarrel (57%) and emotional disturbance (26%) were frequently cited. The case fatality rate was 8.6%. Death was most occurred by organophosphate (5/25) and phenobarbitone poisoning (3/12). Awareness on proper handling of chemicals and prescribed agents should be forwarded to users of these agents. Majority of patients poisoned for intentional self-harm purposes so that linkage of suicidal patients to appropriate mental health service is recommended. The availability of psychiatry consultation in the hospital is also recommended.

Introduction: Lithium is a popular medication for bipolar disorder, but very little work has been done to study Asian patients with lithium poisoning. Methods: A total of 21 out of 7140 poisoned patients were referred for management of lithium poisoning between 2000 and 2009. Patients were stratified according to blood lithium level, that is mild-to-moderate (<2.5 mEq/L) or severe (≥2.5 mEq/L) poisoning. Demographic, clinical, and laboratory data were obtained for analysis. Mortality rates were also analyzed. Results: There were no significant differences between both groups for the baseline variables such as poisoning patterns, age, sex, smoking habit, alcohol consumption, or medical history of diabetes mellitus or hypertension (p > 0.05). Patients with severe poisoning had a greater distribution of severe neurological symptoms (mild/moderate/ severe: 11.1%/44.4%/44.4% versus 58.35%/16.65%/8.3%, p < 0.05), cardiovascular symptoms (66.6% versus 16.6%, p < 0.05), and renal impairment (urea nitrogen/creatinine: 27.1 ± 17.8/ 1.9 ± 1.3 mg/dL versus 14.1 ± 7.1/ 1.3 ± 0.6 mg/dL, p < 0.05) than patients with mild-to-moderate poisoning. Most patients were treated with saline diuresis (9 patients [100%] with severe poisoning versus 9 patients [75.0%] with mild-to-moderate poisoning, p > 0.05). Hemodialysis was initiated in 2 (22.2%) of 9 and 1 (8.3%) of 12 patients with severe and mild-to-moderate poisoning, respectively (p > 0.05). The treatment was successful and all patients recovered without chronic sequelae. Thus, these favorable outcomes were comparable to the data from other international Poison Centers. Conclusions: Given the excellent outcomes of detoxification protocols, patients undergoing lithium therapy must be closely monitored for its toxicity and treated immediately in case of poisoning.

Background: Naloxone, as a low-priced and available drug, may be useful in improvement of signs and symptoms of benzodiazepines intoxication. The aim of this study was assessment of its effect on benzodiazepines poisoning. Methods: In this clinical-trial study, patients with typical signs and symptoms of benzodiazepines poisoning, who were referred to a poisoning center in Tehran in 2008, were selected. After recording of patients’ characteristics, supportive treatment was initiated and patients were randomly assigned to the case group with intravenous (IV) injection of two 0.4 mg naloxone ampules or to the control group. Their signs and symptoms were evaluated again 0.5 hour later. Each of diazepam, clonazepam and alperazolam drug group had 30 patients and lorazepam drug group had 26 patients, half of which patients in each drug group received naloxone. Results: Most of the participants were female and the mean age was 28 years. There were no significant differences between case and control groups in age, sex, time of drug consumption, tablet counts, signs and symptoms and level of consciousness at the admission time in each drug types. After naloxone injection in case groups, all signs and symptoms significantly improved in all drug types in comparison to control groups except nystagmus. In addition, level of consciousness significantly improved in case groups in all drug types except lorazepam. Conclusion: Findings of the study showed that naloxone is effective in management of benzodiazepines poisoning. However, future clinical trials with greater sample size are recommened.

T-lymphocyte (T-LC)-derived cytokines have been implicated in asthmatic pathogenesis. Proteomic technology is now widely accepted as a complementary technology to genetic profiling. We investigated the changes of proteins in T-LC of asthmatic patients from the no typical therapy (uncontrolled) to typical therapy (controlled) level by using standard proteome technology. Methods: The proteins of CD4+ T-LC were isolated from the whole blood of six asthmatic patients from uncontrolled to controlled levels over 3 months. Two-dimensional polyacrylamide gel electrophoresis was performed and coomassie blue stained protein spots were comparatively analyzed by using an image analyzer. Some differentially expressed spots were identified by liquid chromatography/mass spectrometry and database search. Our results showed that 13 proteins showed different expression. Six protein spots in the CD4+ T-LC of the uncontrolled asthmatic patients were increased and 7 spots were decreased compared to those of the controlled subjects. In conclusion, the proteomic examination of the CD4+ T-LC revealed some differentially expressed proteins in the uncontrolled and controlled asthmatic patients. The possibility of using the differentially expressed proteins as important biomarkers and therapeutic targets warrants further study.

Background: Acetaminophen is one of the most commonly encountered medications in self-poisoning, with a high rate of morbidity. The prevalence and characteristics of acetaminophen intoxication associated with long hospital stay in patients are not well defined. Objectives: This study aims to identify the clinical and demographic factors associated with the length of in-hospital stay (LOS), and to evaluate the effect of early treatment of acetaminophen overdose patients (≤8 hours) by intravenous N-acetylcysteine (IV-NAC) on hospital stay. Methods: This is a retrospective cohort study of hospital admissions for acetaminophen overdose conducted over a period of 5 years from 1 January 2004 to 31 December 2008. Patients were divided into two groups: LS group patients had a long hospital stay (> median hours stay in hospital) and SS group patients had a short hospital stay (≤ median hours stay in hospital). Variables were abstracted from medical records for comparison between the two groups. A total of 20 variables were identified for comparison. Parametric and non-parametric tests were used to test differences between groups depending on the normality of the data. SPSS 15 was used for data analysis. Results: Of the 305 patients, 11 factors were identified in the univariate analysis as associated with LS. Three independent factors were found to be significant predictors of LS in the multivariate analysis. The factors associated with LS were seen among patients with a history of abdominal pain after ingestion of acetaminophen (p = 0.04), who were on IV-NAC administration (p < 0.001) and had an acutely depressed mood (p = 0.003). Late time to NAC infusion of more than 8 hours was associated with LS rather than SS (96 patients [57%] and 6 [24%], respectively; p = 0.003). Conclusion: Patients with long hospital stay have different clinical characteristics compared to patients with short hospital stay. We identified time to IV-NAC administration is a potentially modifiable factor that may lead to prolonged hospital stay. When risk assessment indicates that NAC is required, it is highly recommended that NAC be started in the first hours of admission to reduce the LOS.

Tumor necrosis factor (TNF)-α antibodies have been shown to reduce liver damage in different models. We investigated the effects of infliximab (a TNF-α antibody) on liver damage in thioacetamide (TAA)-induced hepatotoxicity in rats. Group 1 (n = 8) was the control group. In group 2 (n = 8), the TAA group, the rats received 300 mg/kg intraperitoneal (ip) TAA daily for 2 days. In group 3 (n = 8), the TAA + Infliximab (INF) group, infliximab (5 mg/kg ip daily) was administered 48 hours before the first dose of TAA daily for 2 days and was maintained for 4 consecutive days. In group 4 (n = 8), the INF group, the rats received only ip infliximab (5 mg/kg) daily. Livers were excised for histopathological and biochemical tests (thiobarbituric-acid-reactive substances [TBARS], and myeloperoxidase [MPO]). Serum ammonia, aspartate transaminase (AST), alanine transaminase (ALT), TNF-α, liver TBARS and MPO levels, and liver necrosis and inflammation scores in the TAA group were significantly higher than in the control and INF groups (all p < 0.01). All parameters except AST were not significantly different between TAA and TAA + INF. In conclusion, our results suggest that oxidative stress plays an important role in TAA-induced hepatotoxicity, and infliximab does not improve oxidative liver damage.

Dioxins like 2,3,7,8 tetrachlorodibenzo-p—dioxin (TCDD) impair male reproductive system by increasing the generation of reactive oxygen species (ROS). Glucocorticoids have been found to suppress male reproductive function and also influence TCDD pathway. As stress is characterized by an increase in the level and activity of glucocorticoids, the present experiments were conducted to evaluate the effect of restraint stress on TCDDinduced testicular and epididymal toxicity. Adult male Wistar rats were subjected to either restraint stress (5 hours/day) or TCDD treatment (100 ng/kg b.w./day) or both for 15 days. Restraint stress or TCDD treatment raised the serum level of corticosterone and suppressed the testicular level of steroidogenic acute regulatory (StAR) protein and serum level of testosterone significantly. In the testis and epididymis, restraint stress or TCDD treatment raised the levels of lipid peroxidation and hydrogen peroxide and suppressed the activities of antioxidant enzymes significantly. In rats subjected to both restraint stress and TCDD treatment, a significant increase in the serum level of corticosterone and a significant decrease in the testicular level of StAR protein and serum level of testosterone were observed as compared to rats treated with TCDD alone. A significant increase in the levels of lipid peroxidation and hydrogen peroxide and a significant decrease in the activities of antioxidant enzymes were observed in the testis and epididymis of rats subjected to both restraint stress and TCDD treatment as compared to TCDD alone treated rats. Thus, restraint stress potentiates the adverse effects of TCDD on male reproductive organs.

It has been reported that vascular endothelia cell damage is an important precursor to the morbidity and mortality associated with cardiovascular disease exposed to airborne particulate matter (PM). The present study investigated the hypothesis that urban fine (PM_2.5) particles could cause cytotoxicity via oxidative stress in human umbilical vein endothelial cells, EA.hy926. The concentrations of metal elements (Cr, Fe, Ni, Cu, Zn, Mo, Cd and Pb) in PM_2.5 suspension, water-soluble and water-insoluble fractions of PM_2.5 were determined by inductively coupled plasma - mass spectrometry (ICP-MS). Iron (Fe), Zn and Pb were highly enriched in all the samples. Exposure of the cultured EA.hy926 cells to PM_2.5 suspension, water-soluble and water-insoluble fractions of PM_2.5 led to cell death, reactive oxygen species (ROS) increase, mitochondrial transmembrane potential (ΔΨm) disruption and NF-κB activation, respectively. The ROS increase by exposure to PM _2.5 suspension, water-soluble and water-insoluble fractions of PM _2.5 triggered the activation of nuclear factor (NF)-κB, which means that PM_2.5 particles exert cytotoxicity by an apopotic process. However, the induction of cytotoxicity by PM_2.5 suspension, water-soluble and water-insoluble fractions of PM_2.5 was reversed by pretreatment with superoxide dismutase (SOD). These results suggest that each fraction of PM_2.5 has a potency to cause oxidative stress in endothelial cells. ROS was generated through PM_2.5-mediated mitochondrial apoptotic pathway, which may induce direct interaction between metal elements and endothelia cells.

The aim of this study was to investigate effects of lambda-cyhalothrin (LCT) on clinical, hematological, biochemical and pathological alterations in rabbits (Oryctolagus cuniculus). New Zealand white female rabbits (n = 24) of 4-5 months age having 997.92 ± 32.83 g weight were divided into four equal groups. Group A (control) received normal saline intraperitoneally (ip). Animals in groups B, C and D were treated with LCT 1.0, 4.0 and 8.0 mg/kg bw ip. Each group received seven consecutive doses at an interval of 48 hours. Blood and serum samples were collected at an interval of 96 hours. Blood analysis revealed a significant (p < 0.05) decrease in red blood cell and white blood cell counts, hemoglobin concentration and lymphocytes, while mean corpuscular hemoglobin concentration, mean corpuscular volume, neutrophils, monocytes and eosinophils were increased. Serum biochemical analysis revealed significant (p < 0.05) decrease in serum total proteins and serum albumin, while an increase was seen in serum alanine aminotransferase and aspartate aminotransferase activities compared with the control group. Serum globulin values varied non-significantly in all treatment groups as compared to control group. A dose-dependent increase in the incidence of micronucleated polychromatic erythrocyte was observed. All gross and histopathological lesions observed in LCT-treated rabbits were dose-dependent. Liver of the treated rabbits exhibited extensive perihepatitis, hyperplasia of bile duct, necrosis, hemorrhages and congestion. In lungs, there were hemorrhages, thickened alveolar walls, congestion, emphysema, collapsed alveoli and accumulation of extensive inflammatory cells. Kidneys were congested and hemorrhagic whereas renal parenchyma and stroma were normal. Microscopically, heart showed congestion of blood vessels and nuclear pyknosis, myodegeneration. It was concluded from the study that LCT produced toxicopathological alterations in rabbits in a dose-dependent manner. On the basis of the results, it can be suggested that overdosing of LCT be avoided while treating animals for ectoparasites.

We investigated whether pravastatin ameliorates renal damage induced by cisplatin (CP). Forty-three male Wistar rats were divided into four groups: rats treated with a control diet for 19 days and saline injection on day 14 (group1), group 1 with pravastatin treatment with 19 days (group 2), group 1 with CP injection on day 14 (group 3), and group 2 with CP injection (group 4). Renal function and serum lipids, renal malondialdehyde (MDA) and glutathione (GSH) levels, glutathione peroxidase (GPx) mRNA expression and activity, and kidney triglyceride (TG) concentrations were measured. Histology was evaluated by light microscopy with immunohistochemistry for p53, p53-upregulated modulation of apoptosis (PUMA), and terminal deoxynucleotide transferase dUTP nick end-labeling (TUNEL) staining. CP induced renal tubular damage with a higher MDA level, increased PUMA expression, p53- and TUNEL-positive cells counts, elevation of serum lipids, and decreased GSH level, GPx mRNA expression, and activity. Pravastatin partially ameliorated CP-induced renal injury, based on suppression of the renal MDA and TG levels, decreased p53 expression, and apoptosis in CP-treated rats. These findings suggest that pravastatin has a partial protective effect against CP nephrotoxicity via antioxidant activity as well as attenuation of the p53 response, and lipid-lowering effects.

Nephrotoxicity is one of the adverse side effects of cyclophosphamide (CP) chemotherapy. In a recent study, we have demonstrated that oxidative stress and glutathione depletion play important roles in CP-induced renal damage. The aim of the study was to verify whether glutamine, the precursor for glutathione synthesis, prevents CP-induced oxidative stress and renal damage using a rat model. Adult male rats were administered a single dose of 150 mg/ kg body weight of CP intraperitoneally. The glutamine-pretreated rats were administered 1 gm/kg body weight of glutamine orally 2 h before the administration of CP. Vehicle/glutaminetreated rats served as controls. All the rats were killed 16 h after the dose of CP/vehicle. The kidneys were removed and used for light microscopic and biochemical studies. The markers of oxidative stress including malondialdehyde content, protein carbonyl content, protein thiol, reduced glutathione and myeloperoxidase activity, a marker of neutrophil infiltration, were measured in kidney homogenates. CP treatment-induced damage to kidney involved the glomeruli and the tubules. Pretreatment with glutamine reduced CP-induced glutathione depletion and increased myeloperoxidase activity. However, it did not prevent CP-induced lipid peroxidation, protein carbonylation and renal damage. The results of the present study suggest that glutamine pretreatment does not prevent CP-induced lipid peroxidation and renal damage, although it prevents CP-induced glutathione depletion and neutrophil infiltration significantly. It is suggested that mechanisms other than oxidative stress may also be involved and/or oxidative stress may be consequence and not the cause of CP induced renal damage.

Various hepatotoxicants co-treated with lipopolysaccharide (LPS) have the potential to cause severe hepatic damage. Whether co-treatment with ostensibly ineffectual (without effect on customary clinical liver function tests, such as aspartate aminotransferase and alanine aminotransferase) doses of cadmium (Cd) and LPS cause liver damage is still unknown. We examined the effects of treating ostensibly ineffectual doses of Cd and LPS on liver dysfunction as well as on liver histopathology. We injected rats with saline only, Cd only, LPS only, or a single ostensibly ineffectual dose of Cd (100 μg/kg body weight) plus LPS (0.1 mg/kg body weight). After 6 h, the rats were killed and their liver damage was assessed. Co-treated with ostensibly ineffectual doses of Cd and LPS had higher levels of aspartate aminotransferase and alanine aminotransferase, hepatic lipid peroxidation, peroxynitrite, nitrite, and interleukin-1β (IL-1β), but lower levels of hepatic metallothionein (MT) than did that treated with saline only, Cd only, and LPS only. Histopathological analysis of Cd only and LPS only showed apparent liver damage, but Cd plus LPS showed marked hepatic damage. We conclude that co-treating the rats with ostensibly ineffectual doses of Cd and LPS is hepatotoxic. Cd promotes LPS-initiated oxidative-stress-associated liver damage by increasing IL-1β and decreasing MT levels in rats.

Environmental pollution is a complex issue because of the diversity of anthropogenic agents, both chemical and physical, that have been detected and catalogued. The consequences to biota from exposure to genotoxic agents present an additional problem because of the potential for these agents to produce adverse change at the cellular and organism levels. Past studies in virus have focused on structural damage to the DNA of environmental species that may occur after exposure to genotoxic agents and the use of this information to document exposure and to monitor remediation. In an effort to predict effects at the population, community and ecosystem levels, in the present study, we attempt to characterize damage occurring through genotoxic agents like 5-bromo-2-deoxyuridine, BrdU, using sister chromatid exchange technique and the formation of micronuclei (MN) in the peripheral lymphocytes of the post-polio syndrome sequelae affected by poliovirus. Analysis of structural chromosomal aberrations (CAs) and involvement of the specific chromosome break were pursued in this study. They revealed a significantly higher incidence of CAs (chromatid and chromosome breaks) in patients compared with controls, where the specific chromosome break has emerged as specific. Also, the maximum numbers of breaks were found to be in chromosome 1 at the position 1p36.1. The results also suggest a correlation between CAs and content of MN.

We examined how chemotherapy-induced myelotoxicity and the associated leukopaenia affect cancer metastasis in an animal model. Myelotoxicity was induced by a single injection of 5-fluorouracil (5-FU) or Cisplatin, administered to 7-week-old BALB/c mice. CT-26 murine colon carcinoma cells were injected into the lateral tail vein on days 0, 1, 3, 5, and 7 after anticancer drug injection. On day 14 after cancer cell injection, the number of pulmonary colonies was measured in a double-blind setting. Compared with Cisplatin, 5-FU induced severe leukopaenia and bone marrow suppression, while on day 5, both drugs induced severe myelotoxicity. The number of pulmonary colonies did not correlate with the severity of leukopaenia, regardless of the type or time of drug injection, except in the group pretreated with Cisplatin (3 days prior to cancer cell injection). Our results suggest that chemotherapy-induced myelotoxicity does not increase the incidence of cancer metastasis in this animal model.

We previously reported that the microsomal fraction from rat mammary tissue is able to oxidize ethanol to acetaldehyde, a mutagenic-carcinogenic metabolite, depending on the presence of NADPH and oxygen but not inhibited by carbon monoxide or other cytochrome P450 inhibitors. The process was strongly inhibited by diphenyleneiodonium, a known inhibitor of NADPH oxidase, and by nordihydroguaiaretic acid, an inhibitor of lipoxygenases. This led us to suggest that both enzymes could be involved. With the purpose of identifying natural compounds present in food with the ability to decrease the production of acetaldehyde in mammary tissue, in the present studies, several plant polyphenols having inhibitory effects on lipoxygenases and of antioxidant nature were tested as potential inhibitors of the rat mammary tissue microsomal pathway of ethanol oxidation. We included in the present screening study 32 polyphenols having ready availability and that were also tested against the rat mammary tissue cytosolic metabolism of ethanol to acetaldehyde. Several polyphenols were also able to inhibit the microsomal ethanol oxidation at concentrations as low was 10-50 μM. The results of these screening experiments suggest the potential of several plant polyphenols to prevent in vivo production and accumulation of acetaldehyde in mammary tissue.

Fenitrothion (FNT) is used throughout the world as an insecticide in agriculture. To investigate the effect of FNT on the splenocytes and the underlying mechanism, FNT and its main metabolite, 3-methyl-4-nitrophenol (MNP), were administered orally to Wistar rats in daily doses of 0, 5 and 10 mg/kg, 4-5 days/week for 9 weeks. Splenocytes were harvested from control and exposed rats, and the following cell phenotypes were quantified by flow cytometry: (1) B cells (PE-CD45RA), (2) T cells (FITC-CD3), (3) T cell subsets (PE-CD4 and PerCPCD8), (4) natural killer (NK) cells (FITC-CD161a), (5) macrophages (FITC-CD11b), and (6) granulocyte (PE-granulocyte). Body weight, weight of the spleen, and histopathological alterations of spleens were also examined. The percentage of splenic CD8+ T cells and the ratio of CD8/CD4 in the group receiving 10 mg/kg FNT, and the percentages of splenic CD3+ and CD8+ T cells in the group receiving 10 mg/kg MNP were significantly decreased compared with those in the controls. FNT exposure also significantly decreased the weight of the spleen and body weight. In addition, apoptotic lymphocytes in spleen were observed in FNT-exposed rats under transmission electron microscope. However, FNT and MNP exposures did not affect splenic NK cells, B cells, macrophages, and granulocytes. The above findings indicate that FNT and MNP may selectively affect splenic T cells in rats.

Free radicals production and oxidative stress play a central role in injuries caused by ethanol (EtOH) on gastric mucosal. Thus, strategies to counteract EtOH toxicity are highly desirable. This study was aimed at evaluating whether Vernonia cognata extract would reduce EtOH effects in rats. Rats received Vernonia cognata extract (0, 1 and 2 g/kg bw, by gavage) 1 hour after EtOH had been administered (0 or 70%, 0.5 mL/100 g bw, by gavage) and were killed 1 hour after Vernonia cognata extract administration. The stomach was removed for macroscopic and histopathological evaluation, as well as, oxidative stress markers such as lipoperoxidation (LPO) and non-protein thiol groups (NPSH) levels and catalase (CAT) activity. EtOH acute exposure increased LPO and decreased NPSH levels and CAT activity along with macroscopic and microscopic lesions in gastric tissue, confirming the involvement of oxidative stress in EtOH toxicity. Vernonia cognata extract attenuated oxidative and histopathological features induced by EtOH at all evaluated doses. Moreover, both studied doses of Vernonia cognata extract caused an increase in NPSH levels per se. However, only the dose of 2 g/kg reverted all macroscopic changes caused by EtOH toxicity. The protective effect of the extract could be attributed to antioxidant molecules present in the extract, such as flavonoids and phenolic acids, which were quantified by high performance liquid chromatography (HPLC). Thus, an antioxidant effect of the extract leads to a protection on gastric tissue. Our results indicate that Vernonia cognata hydroethanolic extract could have a beneficial role against EtOH toxicity by preventing oxidative stress and gastric tissue injury.

Three hundred 1-day-old Avian broilers were divided into four groups and fed on control diet (fluorine 23 mg/kg) and high-fluorine (F) diets (400 mg/kg, high-F group I; 800 mg/kg, high-F group II; 1200 mg/kg, high-F group III) for 42 days (n = 75/group). The growth index (GI) was obviously decreased in the three high-F groups, which indicated the inhibited development of thymus. Histopathologically, the population of thymocytes was decreased in the thymic lobule in the three high-F groups. As measured by flow cytometry, thymocytes in G₀/G ₁ phase were significantly increased while thymocytes in S phase, G ₂ + M phase and proliferating index (PI) value were obviously decreased in the three high-F groups. Also, the percentage of apoptotic thymocytes was greatly increased in the three high-F groups when compared with that of control group. At the same time, the occurrence frequencies of apoptotic thymocyte were markedly increased in the three high-F groups, with the appearance of dilated endoplasmic reticulum in high-F groups II and III ultra-structurally. The results showed that excess dietary F in the range of 400-1200 mg/kg caused histological lesions, G₀/G₁ arrest and cellular apoptosis in the thymus, which inhibited the development of thymus and finally led to impaired cellular immune function.

Maytenus heterophylla (Eckl & Zeyh.) Robson and Maytenus senegalensis (Lam). Exell are two African medicinal plants used to treat painful and inflammatory diseases. We evaluated the in vivo (per os) anti-inflammatory activity of M. heterophylla leaf, stem and root extracts and of M. senegalensis leaf and stem extracts. Additionally, we assessed their in vivo acute and sub-acute toxicities. Anti-inflammatory activities of ethanol extracts were determined in Wistar albino rats, by the carrageenan-induced paw oedema method. Acute and sub-acute toxicity screening of the extracts was evaluated in adult male CD-6 mice. Leaf extracts of M. heterophylla and M. senegalensis exhibited significant anti-inflammatory activity (120 mg/kg, per os), reducing oedema by 51% and 35%, respectively. While M. heterophylla extracts at 1200 mg/kg have shown to be non-toxic, M. senegalensis extracts indicated some toxicity. Our results show a significant anti-inflammatory effect of both M. heterophylla and M. senegalensis leaf extracts in a local model of acute inflammation and suggest the absence of acute and sub-acute toxicity signs of the M. heterophylla leaf extract (but not of M. senegalensis). Ongoing studies will surely shed some light into the mechanism of action of this active extract and establish its chemical fingerprint.

The increasing threat from terrorism has brought attention to the possible use of toxic industrial compounds (TICs) and other lung-damaging agents as weapons against civilian populations. The way in which these agents could be used favours the development of generic countermeasures. Improved medical countermeasures would increase survivability and improve the quality of recovery of lung damaged casualties. It is evident that there is a dearth of therapeutic regimes available to treat those forms of lung damage that currently require intensive care management. It is quite possible that mass casualties from a terrorist incident or major industrial accident involving the release of large quantities of inhaled TICs would place a severe burden on already scarce intensive care facilities. The development of effective pharmacological approaches to assist the recovery of casualties suffering from acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) may improve the prognosis of such patients (which is currently poor) and would ideally be used as a means of preventing subjects from developing the pulmonary oedema characteristic of ALI/ARDS. Many promising candidate pharmacological treatments have been evaluated for the treatment of ALI/ARDS, but their clinical value is often debatable. Thus, despite improvements in ventilation strategies, pharmacological intervention for ALI/ARDS remains problematical. A new approach is clearly required for the treatment of patients with severely compromised lungs. Whilst the pathology of ALI/ARDS associated with exposure to a variety of agents is complex, numerous experimental studies suggest that generic therapeutic intervention directed at approaches that aim to upregulate repair of the damaged alveolar blood/air barrier of the lung may be of value, particularly with respect to chemical-induced injury. To this end, keratinocyte growth factor (KGF), epithelial growth factor (EGF) and basic fibroblast growth factor (bFGF) are emerging as the most important candidates. Hepatocyte growth factor (HGF) does not have epithelial specificity for lung tissue. However, the enhanced effects of combinations of growth factors, such as the synergistic effect of HGF upon vascular endothelial growth factor (VEGF)-mediated endothelial cell activity, and the combined effect of HGF and KGF in tissue repair should be investigated, particularly as the latter pair of growth factors are frequently implicated in processes associated with the repair of lung damage. Synergistic interactions also occur between trefoil factor family (TFF) peptides and growth factors such as EGF. TFF peptides are most likely to be of value as a short term therapeutic intervention strategy in stimulating epithelial spreading activities which allow damaged mucosal surfaces to be rapidly covered by epithelial cells.

Epidemiological findings suggesting that formaldehyde exposure is associated with a higher risk of acute myelogenous leukemia (AML) and other hematological cancers have led to consideration of the potential mechanism of action by which inhalation of this rapidly reactive agent can cause bone marrow cancer. Two major mechanism-based arguments against formaldehyde as a leukemogen have been the difficulty in envisioning how inhaled formaldehyde might penetrate to the bone marrow; and the lack of similarity of non-cancer effects to other known human myeloleukemogens, particularly the absence of pancytopenia in humans or laboratory animals exposed to high levels. However, both of these arguments have been addressed by the recent finding of a pancytopenic effect and chromosomal abnormalities in heavily exposed Chinese workers which, if replicated, are indicative of a genotoxic effect of formaldehyde on hematopoietic stem cells that is in keeping with other known human leukemogens. Review of the body of evidence suggests an apparent discrepancy between studies in laboratory animals, which generally fail to show evidence of penetration of formaldehyde into the blood or evidence of blood or bone marrow genotoxicity, and studies of exposed humans in which there tends to be evidence of genotoxicity in circulating blood cells. One possible explanation for this discrepancy is species difference. Another possible explanation is that myeloid precursors within the nasal mucosa may be the site for leukemogenesis. However, chloromas, which are local collections of myeloid tumor cells, are rarely if ever found in the nose. Other proposed mechanisms for formaldehyde leukemogenesis are reviewed, and dose issues at the interface between the epidemiological and hematotoxicological findings are explored.

We review the dichotomous regulatory roles of natural imidazole-containing peptidomimetics (N-acetylcarnosine [NAC], carcinine, non-hydrolized carnosine) in maintaining skin homeostasis that determines whether keratinocytes survive or undergo apoptosis in response to various insults and in the development of skin diseases. General strategies addressing common ground techniques to improve absorption of usually active chaperone proteins or their dipeptide inducer (usually poorly absorbed) compounds include encapsulation into hydrophobic carriers, combination with penetration enhancers, active electrical transport or chemical modification to increase hydrophobicity. A growing evidence is presented that demonstrates the ability of NAC (lubricant eye drops) or carcinine to act as pharmacological chaperones, or being synergistically coupled in patented formulations with another imidazole-containing peptidomimetic (such as, Leucyl-histidylhydrazide), to decrease oxidative stress and ameliorate oxidative and excessive glycation stress-related eye disease phenotypes, suggesting that the field of chaperone therapy might hold novel treatments for age-related cataracts, glaucoma, age-related macular degeneration (AMD), and ocular complications of diabetes (OCD). Current efforts are being directed towards exploring therapeutic approaches of pharmacological targeting and human drug delivery for chaperone molecules based on innovative patented strategies.

4,4′-Methylenedianiline (MDA) is a chemical used in manufacturing and insulation processes and is a well-known hepatotoxin. We report the case of a 42-year-old construction-site worker who was accidentally exposed to large amounts of MDA and developed acute liver damage. The clinical course is described, with particular emphasis on the timely identification of the underlying cause and prompt management that led to an uneventful recovery. We review the relevant literature and discuss the safety measures necessary to minimize similar occupational hazards in industrial workers.

Mucopolysaccharidosis type VI (MPS VI), or Maroteaux-Lamy syndrome, is a lysosomal storage disorder that results from a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase or arylsulfatase B (ASB). It is a relatively rare disorder, with an estimated incidence of 1 in 248,000 to 1 in 300,000. The diagnosis is made on the basis of findings of elevated urine glycosaminoglycans and a deficiency of ASB activity in leukocytes or cultured fibroblasts. In treatment of MPS VI, enzyme replacement therapy (galsulfase; human recombinant ASB enzyme) became available. Infusions of galsulfase were generally well tolerated. But in some patients, infusion-associated reactions including rash, urticaria, headache, hypotension, nausea, and vomiting were documented and were managed successfully by interrupting or slowing the rate of infusion and/or by the administration of antihistamines, antipyretics, corticosteroids, or oxygen. Here, we report a case with MPS VI who developed thrombocytopenia after third dose of therapy. To the best of our knowledge, this is the first report about thrombocytopenia associated with galsulfase therapy in the literature. Additionally, with this report, we want to share our approach for this case.

Drugs containing 5-acetylsalicylic acid (5-ASA) have been commonly used for inflammatory bowel diseases for more than half a century, but no case about overdose of suppository form of mesalazine which was taken both orally and rectally has been reported in the related literature up to now. In the present case, a 20-year-old male patient who took 14.5 g of mesalazine rectally and orally for suicide purpose is discussed. He was an ulcerative colitis patient and depressed about his illness and routine life traffic. Although it was hard for him to take the suppository form orally because of its bad taste and structure, he took it with the help of water. In the patient’s colonoscopy, diffuse hyperemia and edema extending from the anal channel to the proximal rectal mucosa and a 1.5 cm diameter ulcer expanding from anal channel through the rectum were identified. No pathology was found in the upper gastrointestinal endoscopy. Routine laboratory examination was performed and no abnormality was identified in the patient’s total blood account, biochemical parameters and full-urine examination. In the control rectoscopy applied to the patient 15 days later, recovery of the ulcer was observed and he was discharged to be followed in the psychiatry clinic.

We report a curious double-suicide autopsy case of both male and female who died of potassium poisoning by intravenous administration of concentrated potassium aspartate solution. The plasma concentrations of potassium of the male and female subjects were as high as 49.7 and 62.8 mEq/L, respectively. In addition to the high concentrations of potassium, toxic levels of phenobarbital, promethazine and chlorpromazine, and relatively low levels of etizolam and brotizolam were also detected from whole blood and urine specimens of both cadavers. Twenty empty plastic bottles (10-mL capacity) labeled ‘ASPARA^® Potassium Injection 10 mEq’ were found at the suicide spot. To our knowledge, this is the first description for suicidal death by potassium aspartate; in all of the previous literature, they used potassium chloride intravenously or per os.

Introduction: Cardiotoxicity in acute aconitine intoxication is well known; however, elevation of troponin I level and abnormal scintigraphy findings had not previously been reported. Case report: A 60-year-old man developed chest tightness, syncope and convulsion after ingesting processed Aconitum carmichaeli (Chuanwu) extract for treatment of headache. Electrocardiogram showed first degree atrioventricular (AV) block. Troponin I level was elevated at 14.8 ng/mL 13 hours post-ingestion. Creatine kinase was also increased to 414 U/L. However, echocardiography did not show any abnormal cardiac wall motion. Tc-99m-PYP scintigraphy revealed diffusely increased uptake in the myocardium, suggesting the presence of myocardial necrosis or myocarditis. Discussion: Aconitine poisoning can mimic acute myocardial infarction with chest tightness and elevated cardiac enzymes. Increased cardiac markers and myocardial insult seen in this patient were likely to be related to the toxicity of aconitine. Care should be taken in making the diagnosis in such instances. Management is primarily supportive.

This study was designed to evaluate the effects of depleted uranium (DU) on 1α-hydroxylase in the kidney of rats and to delinerate the mechanism of damage to kidneys and bones by DU. Male Sprague-Dawley rats were surgically implanted with DU fragments at three dose levels (0.1 g, 0.2 g and 0.3 g). After 3, 6 or 12 months, the concentration of 1α,25(OH)₂D₃ in the kidney was measured by radioimmunoassay. The activity of 1α-hydroxylase was shown by the production of 1α,25(OH)₂D₃ after incubation. The results showed that the 1α-hydroxylase activity in the kidney was decreased after 3 months (27.2% at the medium dose DU group, p < 0.05; 33.4% at the high dose DU group, p < 0.01). In contrast, at 6 months and 12 months after implantation of DU, the activity of renal 1α-hydroxylase in DU-treated animals was not decreased significantly in comparison with the controls (p > 0.05). On the other hand, the activity of renal 1α-hydroxylase was decreased by 33.1% (p < 0.05) and 34.4% (p < 0.01) in blank control groups at 6 and 12 months, respectively, when compared with the blank control group at 3 months. In conclusion, this study showed that chronic DU exposure could induce renal damages and inhibit the synthesis of biologically active form of vitamin D, which may be the underlying mechanism of bone metabolic disorder caused by renal injury after DU exposure.