bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protection of A549 cells against the toxic effects of sulphur mustard by hexamethylenetetramine
Authors: Lindsay Christopher D , Hambrook Joy L 
Published: December 2008

The A549 cell line was used as a model of the deep lung to study the toxicity and mechanism of action of sulphur mustard (HD), using the neutral red (NR) dye retention and gentian violet (GV) assays as indices of cell viability. It was found that exposure to concentrations in excess of 40 μM HD resulted in a rapid onset of toxicity. Exposure to 1000 μM HD reduced viability in A549 cell cultures to 61% after 2 h (control cultures=100%), whereas exposure to 40 μM HD did not result in deleterious effects until 26 h at which point viability fell to only 84% (NR assay). Agarose gel electrophoresis of cell cultures exposed to 40 and 1000 μM HD and harvested at 4.5, 19 and 43 h after exposure to HD, indicated that cell death was due to necrosis, despite the observation that at the higher concentration of HD cells displayed many of the features common to cells undergoing apoptotic death. The ability of hexamethylenetetramine (HMT) to protect A549 cells against the effects of an LC50 challenge dose of HD was assessed using the GV and NR assays. It was found that HMT (15 mM) could protect cells against the effects of HD though HMT had to be present at the time of HD challenge. Cultures treated with HD only were 49% viable at 48 h after HD challenge, compared to 101% for protected cultures (NR assay) and 58% and 91% for unprotected and protected cultures respectively using the GV assay. Morphological observations of GV and NR stained cultures confirmed these findings. HMT concen trations of 2.5 to 25 mM were used. Maximal protection against the toxic effects of HD (LC50) was found at 10 to 25 mM HMT. Over this concentration range, HMT did not exert any toxic effects on A549 cells. Pretreatment of A549 cultures with HMT followed by its removal prior to HD challenge had no protective effect. Similarly, treating cultures with HD followed by addition of HMT did not increase the viability of the cultures, even if the HMT was added immediately after HD exposure. HMT was found to protect against the toxic effects ofHD, though it must be present at the time ofHD challenge. A549 cells were found to be a valuable experimental model for studying the toxicology of HD and other lung damaging agents, and for screening other compounds for potential therapeutic efficacy as a prelude to studies with non- transformed cell culture systems and in vivo models.
Effects of a diphenyl-ether herbicide, oxyfluorfen, on human BFU-E/CFU-E development and haemoglobin synthesis
Authors: Rio B. , Parent-Massin D. , Lautraite S. , Hoellinger H. 
Published: December 2008

The diphenyl-ether herbicides exert their phytotoxic activity by preventing chlorophyll formation in plants as a result of inhibition of protoporphyrinogen oxidase. This enzyme is the last step of the common pathway for chlorophyll and haem biosynthesis. The aim of this work is to determine whether herbicide inhibitors of plant protoporphyrinogen oxidase could act on the human protoporphyrinogen oxidase involved in haemoglobin synthesis and cause heamatologic diseases. Human erythroblastic progenitors (BFU-E/CFU-E: Burst Forming Unit-Erythroid and Colony Forming Unit-Ery throid) were exposed to oxyfluorfen, a diphenyl-ether herbicide in the presence of erythropoietin, and the haematoxicity evaluated in vitro by scoring the develop ment of BFU-E/CFU-E colonies after 7 and 14 days of culture. The toxic effect on differentiation has been evaluated using four criteria: morphology, total protein, total porphyrin, and haemoglobin content. The study of BFU-E/CFU-E proliferation and differentia tion showed a cytotoxic effect of oxyfluorfen only at very high concentrations. In contrast, haemoglobin synthesis can be inhibited by concentration of oxyfluorfen (10-4 M) that have no adverse effect on cellular proliferation.
Metabolism of n-hexane by rat liver and extrahepatic tissues and the effect of cytochrome P-450 inducers
Authors: Crosbie Sarah J , Blain PG , Williams Faith M 
Published: December 2008

1 The in vitro metabolism ofn-hexane was studied in rat liver, lung, brain and skeletal muscle microsomes and in microsomes prepared from cell lines expressing human cytochrome P-450 2E1 or 2B6. The hydro xylated metabolites ofn-hexane were quantified by gas chromatography-mass spectometry.2 Rat liver and extensor digitorum longus (EDL, fast- twitch skeletal muscle) microsomes and the CYP 2B6 microsomes produced the pre-neurotoxic metabolite of n-hexane, 2-hexanol as a major metabolite in contrast to the other rat tissues examined.3 Inhibition of 2- and 3-hexanol production from n- hexane by rat lung microsomes using metyrapone, an inhibitor of cytochrome P-450 2B1 activity, resulted in almost complete inhibition of lung microsomal activ ity.4 Production of all three hexanols was significantly increased with phenobarbital-induced rat liver micro somes, with a 10-fold increase in 2- and 3-hexanol production. A slight increase in 2-hexanol production with phenobarbital-induced rat EDL and brain micro somes was observed. No increase in n-hexane meta bolism was noted following induction with β- naphthoflavone or with ethanol.
An investigation into the role of rat skeletal muscle as a site for xenobiotic metabolism using microsomes and isolated cells
Authors: Crosbie Sarah J , Blain PG , Williams Faith M 
Published: December 2008

1 The role of skeletal muscle microsomes as a site of extrahepatic xenobiotic metabolism using n-hexane as a model substrate was investigated. The observed cytochrome P450-dependent metabolism was com pared with that found with liver, and brain micro somal fractions.2 Rat skeletal muscle microsomes metabolised n-hexane to 1-, 2- and 3-hexanol at rates 40 - 300 times lower than observed with rat liver microsomes.3 Fast-twitch extensor digitorum longus muscle (EDL) microsomes had twice as much n-hexane hydroxylase activity as the slow-twitch soleus and furthermore the EDL microsomes produced 2-hexanol, a bioactivation product of n-hexane, as a major metabolite.4 Metabolism of hexane to 1-, 2- and 3- hexanol and 2- hexanone was demonstrated in cultured rat myoblasts.5 Ethoxyresorufin and pentoxyresorufin O-dealkylation were not detected in either muscle microsomes or myoblasts although immunocytochemical localisation studies were suggestive of the presence of cytochrome P-450.6 In conclusion, rat skeletal muscle has a low level of xenobiotic metabolism activity. The relevance to neuromuscular toxicity of n-hexane is discussed.
Phenytoin-mediated oxidative stress in serum of female epileptics: A possible pathogenesis in the fetal hydantoin syndrome
Authors: Liu Chin-San , Wu Hong-Ming , Kao Shu-Huei , Wei Yau-Huei 
Published: December 2008

1 The concentration of serum malondialdehyde (MDA) was measured as the index of lipid peroxidation in female epileptics with phenytoin (PHT) monotherapy. Sera from 20 female epileptics with PHT monotherapy, 12 female epileptics without anticonvulsant therapy and 20 female healthy controls were sampled. The levels of serum copper (S-Cu), serum zinc (S-Zn), copper/zinc superoxide dismutase (CuZn-SOD), and reduced glutathione (GSH) were analyzed as inter active factors of the oxidative stress.2 For the female epileptics with PHT monotherapy, serum MDA concentration (2.6 ± 0.7 μM vs control 1.8 ± 0.6 μM, P < 0.05), CuZn-SOD activity (178.2 ± 63.5 U/dL vs control 97.1 ± 36.4 U/dL, P < 0.01), and S-Cu content (126.2 ± 36.1 μg/dL vs control 98.4 ± 16.7 μg/dL, P < 0.05) were significantly in creased, but GSH level (27.5±6.8 μM vs control 32.2 ± 5.7 μM, P < 0.05) was significantly decreased. The level of serum MDA was associated with the elevation of CuZn-SOD activity ( r=0.54, P < 0.05) and S-Cu content ( r=0.44, P < 0.05) in all the samples collected from epileptics and controls. However, there were no significant differences in all the above parameters between the female epileptics without anticonvulsant therapy and healthy controls.3 These results indicated that oxidative stress was enhanced in the female epileptics with PHT-mono therapy. Apart from the reactive PHT intermediate, the abnormal metabolism of S-Cu, CuZn-SOD, and GSH was highly involved in the PHT-mediated toxicity. Supplement of GSH, modification of CuZn-SOD enzyme activity and reduction of the absorption of copper may prevent the incidence of fetal hydantoin syndrome during pregnancy.
Granulocyte-colony stimulating factor in the treatment of colchicine poisoning
Authors: Critchley Julian AJH , Critchley Lester AH , Yeung Elce Au , Young Robert P , Young Robert J , Chan Thomas YK , Goh Victor KM 
Published: December 2008

1 Colchicine is a highly active alkaloid used in the treatment of gouty arthritis and pseudogout. In over dose colchicine inhibits cell division effecting organs with a high rate of cell turn-over, such as the gastrointestinal tract and bone marrow. Early fatality results from cardiovascular collapse and respiratory failure, however pancytopenia and overwhelming septicaemia can occur later.2 We describe a case of suicidal ingestion of 25 - 30 mg of colchicine in a previously healthy 43-year-old woman. Initial symptoms were mainly gastrointestinal. By day 5 she had developed severe pancytopenia and early sepsis, which were successfully treated using granu locyte colony stimulating factor (G-CSF) 600 μg s.c.3 In vitro G-CSF is produced by the haematopoietic system. However, G-CSF can now be produced by recombinant DNA cloning technology and thus is available clinically.4 There is no recognised antidote for colchicine poison ing and treatment is symptomatic. Fab fragments may have a promising future in eliminating colchicine from the body, but are currently not clinically available. In those patients that survive the initial phase of poisoning, G-CSF offers an effective method of treating the pancytopenia and preventing overwhelming septi caemia. Daily monitoring of the patient's haematolo gical status is strongly recommended.
Study of oxidative-stress in rifampicin-induced hepatic injury in growin rats with and without protein-energy malnutrition
Authors: Chhinder Pal Sodhi  , Rana Satyavati , Mehta Saroj , Vaiphei Kim , Ramesh Chand Goel  , Satish Kumar Mehta  
Published: December 2008

1 Rifampicin (RMP) induced hepatic injury was investi gated in growing rats. The interaction of moderate and severe protein-energy malnutrition (PEM) was also investigated. 2 Status of oxidative/antioxidative profile was studied by the mechanistic approach, to enumerate the nature of injury. 3 Successful hepatic injury in rats was produced by giving intraperitoneal injection of RMP (50 mg/kg/ day). 4 Hepatic lipid peroxidation was significantly increased in all the RMP treated rats. 5 Superoxide dismutase, catalase and glutathione per oxidase activities in the hepatic tissue decreased with RMP treatment. 6 Hepatic thiols represented as total and protein-bound thiols, showed significant elevation, whereas the non protein thiols remain unchanged with RMP treatment. 7 Glutathione-S-transferases also showed significant elevation against 1,2-dichloro-4 nitrobenzene (DCNB) and ethacrynic acid (EA) as substrates. 8 The oxidative/antioxidative profile was observed to be more severely affected with coexistence of malnutri tion. 9 Histopathological correlation showed an additional fatty infiltration of hepatocytes with coexistence of malnutrition. 10 Thus, in conclusion, it can be speculated that an altered oxidative/antioxidative profile is the closely associated with production of RMP induced hepatic injury.
Changes in the arterial blood pressure, heart rate and normal ECG parameters of rat after envenomation with Egyptian cobra (Naja haje) venom
Authors: Omran Mohamed Alaa A , Abdel-Nabi Ismail M 
Published: December 2008

1 The effect of Egyptian cobra (Naja haje) venom on the normal electrical activity of the cardiac muscles (ECG) and arterial blood pressure of envenomated rats were investigated in this study. 2 Rats were divided into three groups. The first group was injected im with saline and considered as control group. Rats of the second and third groups were injected IM with 0.02 μg and 0.04 μg cobra venom/ gim b.wt, respectively. 3 Mean blood pressure (MBP), heart rate (HR) and four different ECG parameters (PR and QT intervals, R and T wave amplitudes) were measured over 1 h following envenomation. 4 The low dose (0.02 μg/g) of N. haje venom caused hypotension accompanied by an increase in the HR, whereas hypertension and bradycardia developed after injection of the high dose (0.04 μg/g) of venom. 5 There was a decrease in the P-R interval after administration of the low dose and prolongation of it after the high dose. The Q-T interval and R-wave amplitude were significantly increased after injection of both doses. T-wave amplitude was significantly elevated only after injection of the high dose. 6 The present results indicate that the Egyptian cobra (N. haje) venom significantly alters the arterial blood pressure and ECG parameters of envenomated rats. This suggests that impairment of the electrical activity of cardiac muscle may be one of the reasons why victims of cobra bite die.
Are we ready to replace dimercaprol (BAL) as an arsenic antidote?
Authors: Mückter Harald , Lieb Bernhard , Reich Franz-Xaver , Hunder Göran , Walther Udo , Fichtl Burckhard 
Published: December 2008

1 Dimercaprol (BAL), 2,3-dimercaptopropanesulpho nate sodium (DMPS) and meso-2,3-dimercaptosucci nic acid (DMSA) are effective arsenic antidotes, but the question which one is preferable for optimal therapy of arsenic poisoning is still open to discussion. Major drawbacks of BAL include (a) its low therapeutic index, (b) its tendency to redistribute arsenic to brain and testes, for example, (c) the need for (painful) intramuscular injection and (d) its unpleasant odour. 2 The newer antidotes DMPS and DMSA feature low toxicity and high therapeutic index. They can be given orally or intravenously due to their high water solubility. While these advantages make it likely that DMPS and DMSA will replace BAL for the treatment of chronic arsenic poisoning, acute intoxication - espe cially with lipophilic organoarsenicals - may pose a problem for the hydrophilic antidotes, because their ionic nature can adversely affect intracellular avail ability. 3 This article focuses on aspects dealing with the power of BAL, DMPS, and DMSA to mobilize tissue-bound arsenic in various experimental models, such as monolayers of MDCK (=Madin-Darby canine kidney) cells from dog kidney, isolated perfused liver from guinea-pigs, and perfused jejunal segments from rat small intestine. 4 The results show that hydrophilic DMPS and DMSA may fail to rapidly and completely remove arsenic that has escaped from the extracellular space across tight epithelial barriers. However, owing to their low toxicity, which allows larger doses to be applied, and the potential modification of their pharmacokinetics by means of inert oral anion-exchange resins, DMPS and DMSA may advantageously replace BAL when ever intervention time is not critical. With severe intoxication by organic arsenicals, when the point-of- no-return is a limiting factor, BAL may still have a place as an arsenic antidote.
Cholinesterase status, pharmacokinetics and laboratory findings during obidoxime therapy in organophosphate poisoned patients
Authors: Thiermann H. , Mast U. , Klimmek R. , Eyer P. , Hibler A. , Pfab R. , Felgenhauer N. , Zilker T. 
Published: December 2008

1 The effectiveness of oxime therapy in organophos phate poisoning is still a matter of debate. It appears, however, that the often cited ineffectiveness of oximes may be due to inappropriate dosing. By virtue of in vitro findings and theoretical considerations we concluded in the preceding paper that oximes should preferably be administered by continuous infusion following an initial bolus dose for as long as reactiva tion of inhibited acetylcholinesterase (AChE) can be expected. This conclusion has called for a clinical trial to evaluate such oxime therapy on the basis of objective parameters. 2 Before transfer to the intensive care unit (ICU), 5 patients received primary care by an emergency physician. In the ICU, atropine sulphate was adminis tered IV upon demand according to the endpoints: no bronchorrhoea, dry mucous membranes, no axillary sweating, heart rate of about 100/min. Obidoxime (Toxogonin®) was given as an IV bolus (250 mg) followed by continuous infusion of 750 mg/24 h. 3 Intoxication and therapy were monitored by determin ing erythrocyte AChE (eryAChE) activity, reactivat ability of the patient's eryAChE ex vivo, plasma cholinesterase activity, the presence of AChE inhibit ing compounds, as well as the concentrations of obidoxime and atropine in plasma. 4 Obidoxime was effective in life-threatening parathion poisoning, in particular when the dose absorbed was comparably low. In mega-dose poisoning, net reacti vation was not achieved until several days after ingestion, when the concentration of active poison in plasma had declined. Reactivatability in vivo lasted for a longer period than expected from in vitro experiments. 5 Obidoxime was quite ineffective in oxydemeton- methyl poisoning, when the time elapsed between ingestion and oxime therapy was longer than 1 day. When obidoxime was administered shortly after ingestion (1 h) reactivation was nearly complete. 6 Obidoxime levels of 10-20 μM were achieved by our regimen, and atropine could rapidly be reduced to approx. 20 nM, as attained by continuous infusion of 1 mg atropine sulphate/h. Maintenance of the desired plasma levels was not critical even when renal function deteriorated. 7 Signs of transiently impaired liver function were observed in patients who showed transient multi- organ failure. In the present stage of knowledge, we feel it advisable to keep the plasma concentration of obidoxime at 10 - 20 μM, although the full reactivating potential of obidoxime will not then be exploited. Still, the reactivation rate, with an apparent half-time of some 3 min, is twice that estimated for a tenfold higher pralidoxime concentration.
Paracetamol poisoning in the North East of England: presentation, early management and outcome
Authors: Thomas Shl , Horner JE , Chew K. , Connolly J. , Dorani B. , Bevan L. , Bhattacharyya S. , Bramble MG , Han KH , Rodgers A. , Sen B. , Tesfayohannes B. , Wynne H. , Bateman DN 
Published: December 2008

1 Paracetamol is increasingly involved in self-poisoning in the United Kingdom and remains a common cause of fatal poisoning. 2 To document the epidemiology and early management of paracetamol poisoning data were collected on consecutive patients with suspected paracetamol poisoning presenting to 6 hospitals in the North East of England over 12 weeks in 1994. 3 There were 400 presentations (attendance rate 1.14/103 population/yr) involving 343 persons (45% male). Paracetamol concentrations at 4 h correlated weakly with reported paracetamol dose (R=0.49, P < 0.0001) and were similar comparing those treated and not treated by gastric decontamination. 4 In 38 (9%) cases paracetamol concentrations were above the appropriate nomogram treatment line, including 3% and 20% of patients who reported ingesting less than and more than 12 g respectively. In 21 patients acetylcysteine treatment was deferred until admission to the ward, the mean delay involved was 2.8 h. 5 One patient died, from arrhythmias caused by co- ingested dothiepin. 6 Paracetamol poisoning is common. Most cases do not have potentially toxic plasma paracetamol concentra tions, but those who do often present late and antidotal treatment may be delayed inappropriately.
The percutaneous absorption and skin distribution of lindane in man
Authors: Dick Ian P , Blain Peter G , Williams Faith M 
Published: December 2008

1 The absorption and distribution of lindane through skin was examined using human volunteers. Two different preparations were employed, one with acetone as the vehicle and the other, a commercial product, consisting primarily of white spirit as the solvent base. 2 The mean peak plasma concentrations of lindane following exposure to the acetone and white-spirit based applications were 0.91 and 0.47 ng/ml, respec tively. The similarity between these levels did not reflect the 40-fold higher dose of lindane in the acetone vehicle. White spirit enhanced the penetration of lindane with respect to the acetone vehicle, high lighting the influence of vehicle upon percutaneous absorption. Low levels of trichlorophenol glucuronide metabolites, but no lindane, were detected in the urine. 3 The exposure site was washed at 6 h to mimic a decontamination procedure at the end of a working day. The proportion of the applied dose unabsorbed by 6 h was 80% and 10% for the acetone and the white spirit-based formulation, respectively. Small areas of the exposed site were tape stripped at 6 and 24 h to assess any lindane that may be associated with the stratum corneum. High levels were observed in the stratum corneum at 6 h exposure (up to 30% of the applied dose for the white spirit based formulation). However, this level had decreased by 24 h (by at least 90% of the amount found at 6 h). A gauze or gauze/shirt combination covering the application site between 6 and 24 h did account for some of this loss of lindane from the stratum corneum attributed to friction and removal of exfoliated cells. The unaccounted propor tion was presumed to have been absorbed through the skin into the systemic circulation. This demonstrates the absorption of chemicals can occur from a depot in the stratum corneum even following a wash proce dure.
In vitro toxicity of trichothecenes on human erythroblastic progenitors
Authors: Rio B. , Lautraite S. , Parent-Massin D. 
Published: December 2008

Trichothecenes are mycotoxins produced by various species of fungi which can occur on various agricultural products. Among these compounds, T-2 toxin, HT-2 toxin, diacetoxyscirpenol (DAS) and deoxynivalenol (DON) are the most naturally encountered and potent trichothe cenes. Consumption of trichothecene contaminated foods by farm animals and humans leads to mycotoxicoses. Trichothecenes are known to induce haematologic dis orders such as neutropenia, thrombopenia, and aplastic anemia in human and animals.The aim of our investigations is to explore the effects of trichothecenes on the haematopoietic progenitors. The four trichothecenes previously demonstrated to be strongly cytotoxic for human CFU-GM have been tested on human BFU-E. For this purpose, a culture model of human erythroblastic progenitors (BFU-E) optimized for toxicological studies was used to determine the effects of T-2, HT-2, diacetoxyscirpenol (DAS) and deoxynivalenol (DON) on red blood cell precursor proliferation and differentiation. Results showed that human BFU-E are as sensitive to trichothecenes as human CFU-GM, except for DON, in the range of concentrations tested. Differentiation of erythroblastic progenitors could be perturbed by these mycotoxins. Human erythroblastic progenitors are also a target of trichothecenes.