Uri Taitelman

N-acetylcysteine increases the glutathione content and protects rat alveolar type II cells against paraquat-induced cytotoxicity

A protective effect of N-acetylcysteine in oxidative lung damage was reported by a number of workers; however, the mechanism underlying this effect was not thoroughly elucidated. The present research investigates the protection by N-acetylcysteine against paraquat-induced cytotoxicity to alveolar type II cells, which are known to be specific targets of paraquat toxicity in vivo. We found that addition of 1 mM N-acetylcysteine to alveolar type II cells incubated with 1 mM paraquat reduced the cytotoxic index from 17.4 +/- 1.3% to 9.3 +/- 1.5%. This effect could not be explained by the interference of N-acetylcysteine with the active uptake of paraquat by type II cells. Incubation of these cells with N-acetylcysteine enhances their glutathione content, thus reducing the paraquat- induced depletion of glutathione in these cells. These results suggest that N-acetylcysteine exerts its protective effect by acting as a precursor for glutathione in alveolar type II cells.

Evaluation of the role of ionized calcium in sodium fluoroacetate (“1080”) poisoning

Fluoroacetate, which is an inhibitor of the tricarboxilic acid cycle, is widely used as a rodenticide. Fluoroacetate is converted in the body to fluorocitrate, which is an inhibitor of the enzyme aconitate hydrase. As a result, energy production goes down, and citrate accumulates. As citrate is a potent chelator of calcium ion, we postulated that ionized calcium concentration in the blood would drop. Fluoroacetate, 0.03 mmol/kg, was injected iv into anesthetized cats. Ionized calcium concentration in anaerobically drawn arterial blood samples was measured with an ion-exchange electrode. Samples were taken immediately before and 40 min after the poisoning, after which the animals were either used as controls (six cats) or treated with an infusion of iv CaCl2 (another six cats), so as to restore ionized calcium levels to normal values. Forty minutes after fluoroacetate injection, the ionized calcium levels fell by an average of 27.2%, from 1.09 ± 0.07 to 0.79 ± 0.14 mM. There was a corresponding prolongation of the QTc interval of the ECG (r = 0.82). Treatment with CaCl2 significantly prolonged the life of the treated animals as compared to the control animals (p < 0.0016 by the Mann-Whitney rank sum test). Our findings suggest that reduced levels of ionized calcium play an important role in the pathogenesis of fluoroacetate poisoning. The reduced levels of Ca2+ are an adequate explanation for the toxic effects of fluoroacetate, and may be the missing link between the biochemistry of the poisoning and the clinical manifestations.

Combined carbon monoxide and cyanide poisoning: a place for treatment.

During fires, victims can inhale significant carbon monoxide (CO) and cyanide (CN) gases, which may cause synergistic toxicity in humans.Oxygen therapy is the specific treatment for CO poisoning, but the treatment of CN toxicity is controversial. To examine the indication for treatment of CN toxicity, we have established a canine model to delineate the natural history of combined CO and CN poisoning. In seven dogs (24 +/- 3 kg), CO gas (201 +/- 43 mL) was administered by closed-circuit inhalation. Then, potassium CN was intravenously (IV) infused (0.072 mg centered dot kg-1 centered dot min-1) for 17.5 +/- 3.0 min. Cardiorespiratory measurements were conducted before and after these toxic challenges. Despite significant CO poisoning (peak carboxyhemoglobin fractions [COHb] = 46% of total hemoglobin [Hb]; elimination t1/2 = 114 +/- 42 min) with attendant decrease in blood O2 content, CO had essentially little effect on any hemodynamic or metabolic variable. On the other hand, CN severely depressed most hemodynamic and metabolic functions. Compared to baseline values, CN caused significant (P < 0.01) decreases in cardiac output (6.4 +/- 2.0 to 3.1 +/- 0.5 L/min) and heart rate (169 +/- 44 to 115 +/- 29 bpm) and decreases in oxygen consumption (VO2) (133 +/- 19 to 69 +/- 21 mL/min) and carbon dioxide production (VCO2) (128 +/- 27 to 103 +/- 22 mL/min). However, these critical hemodynamic and metabolic variables recovered to baseline values by 15 min after stopping the CN infusion, except lactic acidosis which persisted for at least 25 min after the CN infusion. The elimination half-life of CN in the blood was 129 min and significant blood [CN] persisted at least 25 min after the CN infusion. We suggest that, after extraction of a victim from a fire, mechanical ventilation alone should facilitate the return of critical body functions, and that the presence of persistent blood [CN] and lactic acidosis indicate the need for specific therapy for CN toxicity. (Anesth Analg 1995;80:671-7)

Exposure to Paraquat Through Skin Absorption: Clinical and Laboratory Observations of Accidental Splashing on Healthy Skin of Agricultural Workers

Data concerning 15 consecutive cases of single exposures of the skin or eyes during work to paraquat solutions are presented. Urine and serum were analysed for paraquat in all these cases at the laboratory of the Israel Poison Information Center. From these data it is apparent that a single exposure of healthy skin to paraquat solutions caused only local lesions. No systemic effect was detected in these patients.

Meso-2,3-dimercaptosuccinic acid in the diagnosis and treatment of lead poisoning

Lead poisoning remains one of the hazards of industrialized civilization. CaNa2 EDTA and dimercaprol, the usual therapeutic measures, have many side effects and can be given by parenteral route alone. The authors present a case of chronic lead poisoning caused by ingestion of contaminated flour ground in a primitive flour mill. The diagnosis was confirmed by the CaNa2 EDTA provocative test. Dimercaptosuccinic acid (DMSA) was given orally as a further provocation and resulted in an 11-fold increase in urinary lead excretion. A 5-day course of treatment with DMSA was instituted, during which symptoms abated, urinary lead excretion increased and the blood lead level decreased. No side effects were noticed. There has been no relapse over several months of follow-up. The authors conclude that the oral use of DMSA is effective, safe and convenient both as a provocative test in establishing the diagnosis of lead poisoning and as a therapeutic tool.

Management of crush syndrome

Our experience in treating seven patients with severe crush injury of the lower limbs is described. They were brought to hospital 12 h after rescue and had no treatment until then. All seven developed acute renal failure due to myoglobinuria and dehydration. Five were anuric and three non-oliguric. All developed severe sepsis and two had also acute respiratory failure. No bleeding tendency was observed. They were treated along the following lines: early extensive fasciotomy and removal of dead tissues; early fluid challenge; early peritoneal dialysis and/or hemodialysis; high caloric, high protein nutrition; vigorous antibiotic therapy when infection was evident. There were no deaths in our patients. Our management and results are discussed and compared with those in the literature.

Evaluation of a Liposome System for the Delivery of Desferrioxamine to Lungs in Rats

Abstract— Liposomes with various lipid composition and sizes, prepared by two different techniques were evaluated for their potential to deliver desferrioxamine to lungs as a treatment against oxidative lung damage. Multilamellar vesicles (MLV) and reverse evaporation vesicles were prepared out of a lipid mixture containing dipalmitoyl phosphatidylcholine, stearyl amine, cholesterol and vitamin E. The administration of desferrioxamine‐encapsulated liposomes to rats by the intravenous route at a dose of 100 mg kg−1, significantly prolonged the presence of desferrioxamine in all the tested organs when compared with the administration of free desferrioxamine. The injection of reverse evaporation vesicles extruded through a 2 μm polycarbonate membrane exhibited a longer residence time of the desferrioxamine and of liposomal vitamin E in lungs compared with the other types of liposomes tested. The examination of liposome components in the bronchoalveolar lavage fluid (BALF) and the alveolar macrophages recovered from BALF revealed that about 7 × 10−3% of the administered desferrioxamine dose was recovered by this technique at 3 and 17 h after liposome administration. This high residual concentration in the alveolar space confirms the hypothesis that liposomes can be delivered to the lung tissue when encapsulated in alveolar macrophages.

Direct effects of phosphamidon on isolated working rat heart electrical and mechanical function

Phosphamidon (2-chloro-3-(diethylamino)-1-methyl-3-oxopropanyldimethyl phosphate) is widely used in agriculture as an organophosphate insecticide. It is a water-soluble cholinesterase inhibitor whose estimated rat LD50 is 9.2 mg/kg, ip. Mechanical and electrophysiologic direct effects of phosphamidon were studied in an isolated working rat heart model. Phosphamidon caused a positive inotropic effect, as indicated by increased maximum time derivative of left ventricular pressure and increased cardiac output. Stroke work and total pressure-volume area increased in a dose-dependent manner following perfusion with phosphamidon. Phosphamidon had in this preparation a biphasic effect on heart rate: at 10(-6) M concentration, heart rate increased, but at higher concentrations (10(-4)-10(-3) M) heart rate decreased significantly. High concentrations of phosphamidon caused a significant prolongation of the Q-T interval. We conclude that phosphamidon has potent cardiotoxic effects, both mechanical and electrophysiologic, on the isolated rat heart.

Measurement of blood CO2 concentration with a conventional PCO2 analyzer

OBJECTIVES CO2 content can be determined from the Pco2 in an acidified (forces all CO2 into solution) and diluted blood sample. However, Pco2 concentrations measured in conventional blood gas analyzers are only correct for samples with a significant buffer capacity (such as whole blood), so that mixing with the Pco2 in the rinse solution and tubing walls does not significantly change the sample Pco2. This study describes a calibration method and validation data for the Radiometer Medical ABL2 CO2 electrode system to accurately measure unbuffered blood samples used in the determination of blood CO2 content (or other aqueous fluids). DESIGN Prospective, criterion standard. SETTING Laboratory. MEASUREMENTS AND MAIN RESULTS Blood samples (0.4 mL) were acidified and diluted with 0.2 M lactic acid. After measuring Pco2, CO2 content was calculated using the CO2 solubility coefficient and the dilution factor of 20. CO2 content was determined in a series of sodium carbonate (Na2CO3) solutions spanning the physiologic range of CO2 content. Regression of the measured vs. the actual CO2 content data generated a straight line with a slope of 0.796 and y-intercept of 12.5 (r2 = .99; n = 48). These coefficients were successfully used to correct CO2 content determined in blood samples into which graduated amounts of sodium carbonate were added. CONCLUSIONS This calibration procedure allows accurate measurement of Pco2 in aqueous samples using the Radiometer ABL2 electrode system, and should be applicable to other blood gas analyzers. Necessary syringes and chemicals are readily available, the method is fast and simple, and the sample volume is small. In the practice of critical care medicine, accurate Pco2 measurement in aqueous acidified and diluted blood provides direct determination of blood CO2 content (useful in calculations of modified Fick cardiac output or tissue CO2 production). Determinations of absolute CO2 content in blood requiring complex methodology are not necessary. In addition, accurate measurement of aqueous gastric Pco2 can help determine gastric pH, which is an important marker of tissue perfusion.

Protective effect of stroma-free methemoglobin during cyanide poisoning in dogs.

Background During fire exposure, cyanide toxicity can block aerobic metabolism. Oxygen and sodium thiosulfate are accepted therapy. However, nitrite-induced methemoglobinemia, which avidly binds cyanide, decreases oxygen-carrying capacity that is already reduced by the presence of carboxyhemoglobin (inhalation of carbon monoxide in smoke). This study tested whether exogenous stroma-free methemoglobin (SFmetHb) can prevent depression of hemodynamics and metabolism during canine cyanide poisoning. Methods In 10 dogs (weighing 18.8 plus/minus 3.5 kg) anesthetized with chloralose-urethane and mechanically ventilated with air, baseline hemodynamic and metabolic measurements were made. Then, 137 plus/minus 31 ml of 12 g% SFmetHb was infused into five dogs (SFmetHb group). Finally, the SFmetHb group and the control group (n = 5, no SFmetHb) received an intravenous potassium cyanide infusion (0.072 mg *symbol* kg sup -1 *symbol* min sup -1) for 20 min. Oxygen consumption (V with dot sub O2) was measured with a Datex Deltatrac (Datex Instruments, Helsinki, Finland) metabolic monitor and cardiac output (Q with dot T) was measured by pulmonary artery thermodilution. Results From baseline to cyanide infusion in the control group, Q with dot T decreased significantly (p < 0.05) from 2.9 plus/minus 0.8 to 1.5 plus/minus 0.4 l/min, mixed venous PCO2 (Pv with barCO2) tended to decrease from 35 plus/minus 4 to 23 plus/minus 2 mmHg, Pv with barO2 increased from 43 plus/minus 4 to 62 plus/minus 8 mmHg, V with dotO2 decreased from 93 plus/minus 8 to 64 plus/minus 19 ml/min, and lactate increased from 2.3 plus/minus 0.5 to 7.1 plus/minus 0.7 mM. In the SFmetHb group, cyanide infusion did not significantly change these variables. From baseline to infused cyanide, the increases in blood cyanide (4.8 plus/minus 1.0 to 452 plus/minus 97 micro Meter) and plasma thiocyanate cyanide (18 plus/minus 5 to 65 plus/minus 22 micro Meter) in the SFmetHb group were significantly greater than those increases in the control group. SFmetHb itself caused no physiologic changes, except small decreases in heart rate and Pv with barO2. Peak SFmetHb reached 7.7 plus/minus 1.0% of total hemoglobin. Conclusions Prophylactic intravenous SFmetHb preserved cardiovascular and metabolic function in dogs exposed to significant intravenous cyanide. Blood concentrations of cyanide, and its metabolite, thiocyanate, revealed that SFmetHb trapped significant cyanide in blood before tissue penetration.