Renal replacement therapy in acute poisonings--one center experience.

The authors described three groups of patients after acute poisonings. In the first group were 60 patients after carbon tetrachioride poisoning, the second group consisted of 81 patients after mushroom poisoning and 20 patients after ethylene glycol poisoning were in the third group. Besides two patients with rare poisonings after potassium dichromate and after paraquat poisoning were analysed. All groups of patients with the kidney damage were presented from the diagnostic, differential diagnostic, conservative, ntra- and extracorporeal elimination treatment point of view. In the group of patients suffering from acute carbon tetrachloride poisoning and with acute renal failure following therapy was used: conservative treatment, exchange blood transfusion--in 4 patients in hepatic coma, renal replacement therapy (peritoneal dialysis, haemodialysis, plasmapheresis). From the total number of 60 patients 58 survived and 2 patients died in liver coma. Survival of patients after mushroom poisoning depended on amount of oral use of mushroom (Amanita phalloides), on early admission in dialysis centre and on early beginning of renal replacement therapy within 24 hr after acute poisoning. Twenty four patients from 81 patients of this group died. Main clinical signs of ethylene glycol poisoning were various neurological symptoms (cramps, hemiparesis, coma), severe metabolic acidosis (pH = 7.06 +/- 0.14), leucocytosis (26.4 +/- 5.5x 10(9)/L) and the signs of acute toxic hepatitis and of acute renal failure. Calcium oxalic crystals in urine were present in 17 patients and leucocytosis was observed in every patient. In the first 4 patients we administered intravenously ethylalcohol as an antidotum and later in other patients we used ethylalcohol in dialysis solution. The concentration of ethylalcohol in dialysis solution was 100 mg%. Severe metabolic acidosis improved in 17 patients using bicarbonate haemodialysis and 3 patients died before the possibility to use bicarbonate haemodialysis. Eighty-four hours after acute potassium dichromate poisoning and 24 hours after exchange blood transfusion during haemodialysis a 41-year old man died in haemorhagic shock, which developed after the extensive chemical burns of mucous membrane of gastrointestinal tract caused by this poison. Our patient after paraquat poisoning was treated by repeated charcoal haemoperfusion and haemodialysis. Despite of that therapy the patient died in severe respiratory insufficiency.

Inhibition of cyclooxygenase-2 aggravates secretory phospholipase A2-mediated progression of acute liver injury.

Our previous study [Bhave, V. S., Donthamsetty, S., Latendresse, J. R., Muskhelishvili, L., and Mehendale, H. M. 2008-this issue. Secretory phospholipase A(2) mediates progression of acute liver injury in the absence of sufficient COX-2. Toxicol Appl Pharmacol] showed that in the absence of sufficient induction and co-presence of cyclooxygenase-2 (COX-2), secretory phospholipase A(2) (sPLA(2)) appearing in the intercellular spaces for cleanup of post-necrotic debris seems to contribute to the progression of toxicant-initiated liver injury, possibly by hydrolysis of membrane phospholipids of hepatocytes in the perinecrotic areas. To further test our hypothesis on the protective role of COX-2, male Fisher-344 rats were administered a selective COX-2 inhibitor, NS-398, and then challenged with a moderately toxic dose of CCl(4). This led to a 5-fold increase in the susceptibility of the COX-2 inhibited rats to CCl(4) hepatotoxicity and mortality. The CCl(4) bioactivating enzyme CYP2E1 protein, CYP2E1 enzyme activity, and the (14)CCl(4)-derived radiolabel covalently bound to the liver proteins were unaffected by the COX-2 inhibitor suggesting that the increased hepatotoxic sensitivity of the COX-2 inhibited rats was not due to higher bioactivation of CCl(4). Further investigation showed that this increased mortality was due to higher plasma and hepatic sPLA(2) activities, inhibited PGE(2) production, and progression of liver injury as compared to the non-intervened rats(.) In conclusion, inhibition of COX-2 mitigates the tissue protective mechanisms associated with COX-2 induction, which promotes sPLA(2)-mediated progression of liver injury in an acute liver toxicity model. Because increased sPLA(2) activity in the intercellular space is associated with increased progression of injury, and induced COX-2 is associated with hepatoprotection, ratios of hepatic COX-2 and sPLA(2) activities may turn out to be a useful tool in predicting the extent of hepatotoxicities.

Secretory phospholipase A2 mediates progression of acute liver injury in the absence of sufficient cyclooxygenase-2.

Previous studies have shown that injury initiated by toxicants progresses even after most of the toxicant is eliminated from the body. One mechanism of progression of injury is the extracellular appearance of hydrolytic enzymes following leakage or upon cell lyses. Under normal conditions, after exposure to low to moderate doses of toxicants, secretory phospholipase A(2) (sPLA(2)) and other hydrolytic enzymes are known to appear in the extracellular spaces in order to cleanup the post-necrotic debris in tissues. We tested the hypothesis that sPLA(2) contributes to progression of toxicant-initiated liver injury because of hydrolysis of membrane phospholipids of hepatocytes in the perinecrotic areas in the absence of sufficient cyclooxygenase-2 (COX-2). Male Sprague-Dawley rats were administered either a moderately hepatotoxic dose (MD, 2 ml CCl(4)/kg, ip) or a highly hepatotoxic dose (HD, 3 ml CCl(4)/kg, ip) of CCl(4). After MD, liver sPLA(2) and COX-2 were co-localized in the necrotic and perinecrotic areas and their activities in plasma and liver increased before decreasing in tandem with liver injury (ALT and histopathology) leading to 100% survival. In contrast, after the HD, high extracellular and hepatic sPLA(2) activities were accompanied by minimal COX-2 activity and localization in the liver throughout the time course. This led to progression of liver injury and 70% mortality. These data suggested a destructive role of sPLA(2) in the absence of sufficient COX-2. Time- and dose-dependent destruction of hepatocytes by sPLA(2) in isolated hepatocyte incubations confirmed the destructive ability of sPLA(2) when present extracellularly, suggesting its ability to spread injury in vivo. These findings suggest that sPLA(2), secreted for cleanup of necrotic debris upon initiation of hepatic necrosis, requires the co-presence of sufficiently induced COX-2 activity to prevent the run-away destructive action of sPLA(2) in the absence of the tissue protective mechanisms afforded by COX-2 induction.

Effect of oral dosing vehicles on the subchronic hepatotoxicity of carbon tetrachloride in the rat.

Previous studies in this laboratory have shown that corn oil delayed and prolonged the gastrointestinal absorption of carbon tetrachloride (CCl4) and reduced its acute hepatotoxicity in rats. The objective of the present study was to extend the duration of ingestion of CCl4 to assess vehicle effects on the subchronic oral toxicity of CCl4. Male Harlan Sprague-Dawley rats were given doses of 0, 25, or 100 mg CCl4/kg body weight by gavage in either corn oil or a 1% Emulphor aqueous emulsion 5 times a week for 13 wk. Blood was collected at 4, 8, and 13 wk for measurement of serum enzymes. Liver samples were also taken at 13 wk for measurement of triglyceride and microsomal enzyme levels, as well as for histopathological examination. Serum enzyme levels peaked at 8 wk in the high-dose groups, but not until 13 wk in the low-dose animals. Effects of CCl4 on serum and microsomal enzymes were of similar magnitude in the two vehicle groups. A comprehensive histopathological examination revealed no qualitative or quantitative differences between the corn oil and aqueous vehicle groups in hepatic lesions. Although CCl4 and chloroform have been reported by other investigators to be more hepatotoxic to mice when given for 90 d in corn oil, current findings indicate that corn oil does not significantly alter the subchronic hepatotoxicity of CCl4 in rats from that when the halocarbon is given in an aqueous medium.

[Mechanisms of hepatoprotective action of new nicotinic acid derivatives in experimental CCL4-induced liver injury]. / Mekhanizmy gepatoprotektornogo deistviia novykh proizvodnykh nikotinovoi kisloty pri éksperimental'nom porazhenii pecheni chetyrekhkhloristym uglerodom.

New biologically active compounds (BAC) created on the basis of nicotinic acid possess hepatoprotective action. The preparations were introduced preventively in doses of 10 mg/kg during 14 days. Litonit and nicogamol increased survival of experimental animals by 36.8% and nicotinic acid by 26.8%. ALT, AST, GGT activity in the blood serum was reduced. The activity of the main antioxidant enzymes (SOD and catalase) grew in the rat liver tissue in parallel with inhibition of DK and MDA activity. Morphological picture of the rat liver, most evident after application of litonit improved. Hepatoprotective action of these BAC are attributed to their membrano stabilizing effects.

[The effect of a fluorocarbon emulsion--an enzyme inducer of the cytochrome P-450-dependent monooxygenase system of the liver--on the acute toxicity of CCl4 and on the efficacy of the prophylactic use of antidotes in organophosphate pesticide poisoning]. / Vliianie ftoruglerodnoi émul'sii--induktora fermentov tsitokhrom P-450-zavisimosti monooksigenaznoi sistemy pecheni--na ostruiu toksichnost' CCl4 i na éffektivnost' profilakticheskogo primeneniia antidotov pri intoksikatsii fosfororganicheskimi pestitsidami.

The effect of intraperitoneal administration of perfluorocarbon emulsion, an inducer of cytochrome P-450-dependent monoxygenase system of the liver, on the resistance of rodents to the action of CCl4 and organophosphorus pesticides was studied. Perfluorocarbon emulsion potentiated CCl4 toxicity decreasing LD50 from 4.5 to 3.7 mg/kg mouse body weight without changing susceptibility of rats to organophosphorus pesticides. A preliminary administration of perfluorocarbon emulsion effectively increased the protective action of antidotes (atropine + dipyroxime) providing the resistance of the animals to 12-fold, 20-fold and 20-fold LD50 of dichlophos, methaphos and butiphos, respectively.

A mortality study of a research, engineering, and metal fabrication facility in western New York State.

The mortality experience of 8,146 male employees of a research, engineering, and metal fabrication facility in Tonawanda, New York state was examined from 1946 to 1981. Potential workplace exposures included welding fumes, cutting oils, asbestos, organic solvents, and environmental ionizing radiation, as the result of disposal of wastes during the Manhattan Project of World War II. External comparisons with the US male population were supplemented by regional comparisons. For the total cohort, deficits were observed for all causes of death (standardized mortality ratio (SMR) = 87) and most non-cancer causes. The observed number of cancer deaths was close to expected (SMR = 99). There was an excess of connective and soft tissue cancer deaths, most notably in hourly employees hired prior to 1946. Among all hourly employees, there was an excess of respiratory cancer, which did not appear to be associated with length of employment. Mesothelioma was recorded as the cause of death for three decedents, two of whom were hourly employees who worked in production areas with high potential for asbestos exposure. The standardized mortality ratio for cirrhosis of the liver was elevated among long-term hourly employees hired prior to 1946. The roles of carbon tetrachloride exposure in the 1940s and alcohol consumption are discussed as possible contributory risk factors for the cirrhosis findings. The data do not provide evidence of radiation-induced cancers within this employee population.

Uninterrupted protein synthesis is essential for survival in the early stages of carbon tetrachloride-induced hepatocellular necrosis in the mouse.

The fatal syndrome produced by cycloheximide given 6 h after a hepatonecrogenic dose of CCl4 is due neither to direct toxic synergism between CCl4 and cycloheximide nor to transient sinusoidal thrombosis. It is suggested that survival in the presence of unknown factors released from dying liver cells requires uninterrupted protein synthesis. The life-saving effect of sterilization of the intestine by antibiotics indicates that the gut flora or its products play a vital role in pathogenesis.

[Mortality from accidental poisoning in Budapest during 1961-1975. II. Carbon monoxide poisoning]. / Mérgezés okozta baleseti halálozás Budapesten az 1961--1975. években. II. Szénmonoxidmérgezés.

In the examined 15 year period accidental deaths from carbon monoxide poisoning amounted to 641 persons--341 males and 300 females. The number of poisonings increased evenly and at a progressive rate, although the frequency of carbon monoxide poisoning--among the accidental poisonings--decreased. The majority of the deceased from accidental carbon monoxide poisoning was older 60 years. 90.4 per cent of cases occurred at home. In 37.7 per cent of the cases the source of the gas appeared to be the gap-tap turned off wrongly and in 36.4 per cent the escape of gas. 4.4 per cent of the cases survived. 14.4 per cent of the deceased had alcohol in their blood.