Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group.
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BACKGROUND: Ethylene glycol poisoning causes metabolic acidosis and renal failure and may cause death. The standard treatment is inhibition of alcohol dehydrogenase with ethanol, given in intoxicating doses, and adjunctive hemodialysis. We studied the efficacy of fomepizole, a new inhibitor of alcohol dehydrogenase, in the treatment of ethylene glycol poisoning. METHODS: We administered intravenous fomepizole to 19 patients with ethylene glycol poisoning (plasma ethylene glycol concentration, > or =20 mg per deciliter [3.2 mmol per liter]). Patients who met specific criteria also underwent hemodialysis. Treatment was continued until plasma ethylene glycol concentrations were less than 20 mg per deciliter. Acid-base status, renal function, the kinetics of fomepizole, and ethylene glycol metabolism were assessed at predetermined intervals. RESULTS: Fifteen of the patients initially had acidosis (mean serum bicarbonate concentration, 12.9 mmol per liter). Acid-base status tended to normalize within hours after the initiation of treatment with fomepizole. One patient with extreme acidosis died. In nine patients, renal function decreased during therapy; at enrollment, all nine had high serum creatinine concentrations and markedly elevated plasma glycolate concentrations (> or =97.7 mg per deciliter [12.9 mmol per liter]). None of the 10 patients with normal serum creatinine concentrations at enrollment had renal injury during treatment; all 10 had plasma glycolate concentrations at or below 76.8 mg per deciliter (10.1 mmol per liter). Renal injury was independent of the initial plasma ethylene glycol concentration. The plasma concentration of glycolate and the urinary excretion of oxalate, the major metabolites of ethylene glycol, uniformly fell after the initiation of fomepizole therapy. Few adverse effects were attributable to fomepizole. CONCLUSIONS: In patients with ethylene glycol poisoning, fomepizole administered early in the course of intoxication prevents renal injury by inhibiting the formation of toxic metabolites. (+info)
Examination on biological activities and fates of new steroids, steroid-17-yl methyl glycolate derivatives.
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A variety of acyl derivatives based on the "antedrug" concept were synthesized to evaluate their biological activities, in vitro fate in human serum and examine pharmacokinetics in rats. Among the prepared compounds, acetyl and pivaloyl derivatives (8 and 9) showed strong to vasoconstrictive activity in human, exceeding that of dexamethasone. In rats, topical administration of the compound 8 significantly reduced oxazolone-induced ear edema compared to that of control. These activities were almost equal to that of prednisolone, however 9 did not show any suppression of the oxazolone-induced edema. The in vitro half-lives of 8 and 9 in human serum were 18.2 and 43.8 hours, respectively. Prednisolone and dexamethasone were extremely stable under the used conditions. When compound 8 was intravenously administrated to rats, its metabolites, 20(R)-methyl dexamethasonate (4) and carboxylic acid (18), were found in the systemic blood. The total body clearance of 8 was 1734 ml x hr(-1) x kg(-1), which was about 12 times larger than that of dexamethasone. On the other hand, 9 was found to be metabolized instantaneously to methyl prednisolonate (1) in systemic serum. Acetyl derivative 8 derived from dexamethasone may thus be useful as a topical steroid which offers the advantage of a low potential for systemic and local side effects. (+info)
Favorable effects of glycolate conjugation on the biodistribution of humanized antiTac Fab fragment.
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One of the major limitations of using intact immunoglobulins for targeting tumors is poor penetration into tissues. Although Fab fragments have been used because of their improved kinetics, they have undesirable high renal accumulation. In this study we tested a new approach to block renal accumulation of Fab. METHODS: We conjugated humanized antiTac Fab fragments, which are directed against the interleukin-2 receptor, with glycolate. The biodistribution, pharmacokinetics and catabolism of glycolated Fab (glyco-Fab) were evaluated at two different levels of substitution (heavy and light) compared with nonglycolated Fab in Tac-antigen-positive (ATAC4) and -negative (A431) tumor-bearing nude mice. The mice received coinjections of 125I-labeled glyco-Fab (3 microCi/1 microg) and 131I-labeled nonglycolated Fab (5 microCi/1 microg). In addition, groups of mice receiving these reagents were also coinfused with 50 mg L-lysine. RESULTS: Significantly less glyco-Fab than nonglycolated Fab accumulated in the kidney (21 versus 189 %ID/g; P < 0.001). A higher proportion of glyco-Fab was excreted into the urine in its intact form. The glyco-Fab survived longer in circulation than nonglycolated Fab. The peak tumor accumulation of glyco-Fab was 2.3-fold greater than that of nonglycolated Fab. Furthermore, the ATAC4 tumor-to-normal tissue ratio of glyco-Fab was much higher in all organs than that of nonglycolated Fab. The heavily glyco-Fab accumulated less in the kidney than the lightly glyco-Fab. The coinjected lysine reduced the renal accumulation of both nonglycolated Fab and glyco-Fab. CONCLUSION: Glyco-Fab is a promising agent because of its lower renal accumulation, higher tumor uptake and higher tumor-to-normal tissue ratio. (+info)
Ethylene glycol developmental toxicity: unraveling the roles of glycolic acid and metabolic acidosis.
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This study sought to determine the relative roles of glycolic acid (GA), a toxicologically important metabolite of ethylene glycol (EG), and metabolic acidosis in causing developmental toxicity in Sprague-Dawley rats. To tease apart these two interrelated factors, we developed an experimental approach in which high blood glycolate levels could be achieved, in either the presence or absence of metabolic acidosis. Initially, rats previously implanted with a carotid artery cannula were given, on gestation day (gd) 10, 40.3 mmol/kg (2500 mg/kg) of EG via gavage, 8.5 mmol/kg (650 mg/kg) of GA via gavage, 8.5 mmol/kg (833 mg/kg) of sodium glycolate (NaG; pH 7.4) via subcutaneous (sc) injection, or distilled water via gavage (control). Peak serum glycolate was nearly identical (8.4-8.8 mM) in the EG, GA, and NaG groups and, as expected, EG and GA caused a metabolic acidosis, but acid base balance was normal with NaG. Subsequently, these treatments were given on gd 6-15 to groups of 25 time-mated rats, followed by fetal evaluation on gd 21. EG and GA decreased fetal body weights and caused a similar spectrum of developmental effects, including numerous axial skeleton malformations. NaG treatment also caused slight decreases in fetal body weight, increases in skeletal variations, and totally malformed fetuses. These results indicate that glycolate, in the absence of metabolic acidosis, can cause the most sensitive of EG's developmental effects, whereas metabolic acidosis appears to interact with glycolate at very high doses to markedly enhance teratogenesis. These results support previous studies, which indicated that glycolate is the proximate developmental toxicant for EG, and that GA toxicokinetic parameters can be used to define a quantitative, physiologically based threshold for EG-induced developmental effects. (+info)
Repair of apurinic/apyrimidinic sites by UV damage endonuclease; a repair protein for UV and oxidative damage.
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UV damage endonuclease (UVDE) initiates a novel form of excision repair by introducing a nick imme-diately 5" to UV-induced cyclobutane pyrimidine dimers or 6-4 photoproducts. Here, we report that apurinic/apyrimidinic (AP) sites are also nicked by Neurospora crassa and Schizosaccharomyces pombe UVDE. UVDE introduces a nick immediately 5" to the AP site leaving a 3"-OH and a 5"-phosphate AP. Apyrimidinic sites are more effectively nicked by UVDE than apurinic sites. UVDE also possesses 3"-repair activities for AP sites nicked by AP lyase and for 3"-phosphoglycolate produced by bleomycin. The Uvde gene introduced into Escherichia coli cells lacking two types of AP endonuclease, Exo III and Endo IV, gave the host cells resistance to methylmethane sulfonate and t-butyl hydroperoxide. We identified two AP endonuclease activities in S.pombe cell extracts. Besides cyclobutane pyrimidine dimers and 6-4 photoproducts, N. crassa UVDE also nicks Dewar photoproducts. Thus, UVDE is able to repair both of the major forms of DNA damage in living organisms: UV-induced DNA lesions and AP sites. (+info)
Improved method to measure urinary alkoxyacetic acids.
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OBJECTIVES: To simplify the current preparation of samples, and to improve the specificity and reliability of the conventional analytical methods to measure urinary alkoxyacetic acids. METHODS: Samples containing alkoxyacetic acids including methoxy, ethoxy, and butoxyacetic acids (MAA, EAA, and BAA) were acidified with HCl and extracted with a mixed solvent of methylene chloride and isopropyl alcohol, then analysed by gas chromatography/mass spectrometry (GC/MS). RESULTS: Optimal results were obtained when pH was 1.05-1.45, the ratio of methylene chloride and isopropyl alcohol was 2:1, and when extraction time was 10 minutes. Over the concentration range 0.3-200 micrograms/ml, MAA, EAA, and BAA could be determined with a pooled coefficient of variation (nine concentrations, six replicate samples) of 5.55%, 6.37%, and 6.41%, respectively. Urine samples were stable for at least 5 months and 3 freeze-thaw cycles at -20 degrees C. The limits of detection of MAA, EAA, and BAA were 0.055, 0.183, and 0.009 microgram/ml, respectively. The matrix effect of urine samples was negligible for MAA and EAA, but were marginally significant for BAA. The average recoveries of alkoxyacetic acids were 99%-101%. In urine samples MAA from 15 exposed workers showed a strong linear correlation (r = 0.999, slope = 1.01) between the new GC/MS method and Sakai's GC method. CONCLUSIONS: The simplified non-derivatisation pretreatment of samples coupled with GC/MS can provide a specific, sensitive, simple, safe, and reliable method for the biological monitoring of occupational exposure of ethylene glycol ethers. (+info)
Formation of anion-selective channels in the cell plasma membrane by the toxin VacA of Helicobacter pylori is required for its biological activity.
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The vacuolating toxin VacA, a major determinant of Helicobacter pylori-associated gastric diseases, forms anion-selective channels in artificial planar lipid bilayers. Here we show that VacA increases the anion permeability of the HeLa cell plasma membrane and determines membrane depolarization. Electrophysiological and pharmacological approaches indicated that this effect is due to the formation of low-conductance VacA pores in the cell plasma membrane and not to the opening of Ca(2+)- or volume-activated chloride channels. VacA-dependent increase of current conduction both in artificial planar lipid bilayers and in the cellular system was effectively inhibited by the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), while2-[(2-cyclopentenyl-6,7dichloro-2, 3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]acetic acid (IAA-94) was less effective. NPPB inhibited and partially reversed the vacuolation of HeLa cells and the increase of ion conductivity of polarized Madine Darby canine kidney cell monolayers induced by VacA, while IAA-94 had a weaker effect. We conclude that pore formation by VacA accounts for plasma membrane permeabilization and is required for both cell vacuolation and increase of trans-epithelial conductivity. (+info)
Simultaneous determination of ethylene glycol and glycolic acid in serum by gas chromatography-mass spectrometry.
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We describe a gas chromatographic-mass spectrometric (GC-MS) procedure for the simultaneous determination of ethylene glycol (EG) and its major toxic metabolite, glycolic acid (GA), in serum. In this method, serum (50 microL) is treated with 150 microL of glacial acetic acid/acetonitrile (1:10, v/v; contains internal standard, 1,3-propanediol, 15 mg/dL) to precipitate protein. After centrifugation, 10 microL of supernate is treated with 500 microL of 2,2-dimethoxypropane/dimethylformamide (80:20, v/v) to convert water to methanol, and the volume is then reduced to < 100 microL of dimethylformamide (but not to dryness). After formation of tertbutyldimethylsilyl derivatives, analysis is performed by capillary column GC-MS in selected ion mode. The method gives a linear response to 1000 mg/L each EG and GA (16.1 mmol/L and 13.2 mmol/L, respectively) and has a lower limit of detection and a lower limit of quantitation of 10 mg/L each EG and GA (0.16 mmol/L and 0.13 mmol/L, respectively). Total assay imprecision is CV < or = 6.4% (200 and 800 mg/L EG and GA [3.2 and 12.9 mmol/L EG; 2.6 and 10.5 mmol/L GA, respectively]). Absolute recovery from human serum was 91.1% for EG and 77.6% for GA. The procedure is free from any known interference. A complete analysis set (three calibrators, patient serum neat, patient serum diluted 1:5 (v/v), and two controls) may be completed in about 2 h. A preliminary result, based on a single calibrator and patient serum diluted 1:5 (v/v), is complete in about 1 h. The method has been used to aid the diagnosis and management in 34 cases of EG intoxication. Selected cases are briefly reviewed. (+info)