David A. Herold

Oxidation of polyethylene glycols by alcohol dehydrogenase

The present studies were undertaken to investigate the enzymology of a fatal toxic syndrome that resulted from the absorption and subsequent oxidation of polyethylene glycol (PEG). The presence of organic acids of PEG in the blood of poisoned patients and in an animal model suggested that the metabolism of PEG involved sequential oxidations by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. A key question concerned the ability of ADH to initiate this pathway for oxidation of PEG. In the present studies the oxidation of PEG homologues by ADH was characterized. The polymer homologues of ethylene glycol from n = 1 to n = 8 were used as substrates. ADH catalyzed the oxidation of each of these PEGs. The oxidation of PEG was inhibited by the ADH inhibitor 4-methylpyrazole. With the exception of diethylene glycol, the Km decreased as the homologue number increased, and the Vmax decreased progressively through the series. The concentrations of PEG in the blood of poisoned humans and animals were 0.06 to 0.8 Km of ADH for all the PEG homologues above the triethylene glycol. These investigations establish ADH as a candidate enzyme for mammalian metabolism of PEG and thus suggest that specific inhibitors of ADH may prove to be useful as tools to treat PEG poisoning.

Toxicity of topical polyethylene glycol

Abstract An animal model was developed to study the potential toxicity resulting from repeated, topical applications of a polyethylene glycol-based antimicrobial cream. Applications of this cream to open wounds in rabbits produced the same syndrome observed in the burn patients treated with this agent. This syndrome was characterized by (1) elevated total calcium, (2) elevated osmolality gap, (3) high anion gap metabolic acidosis, and (4) renal failure. Ten of twelve treated animals died within one week of therapy. This syndrome appears to result from the absorption of polyethylene glycols and their metabolism to nephrotoxic compounds and to mono- and diacids. We propose that the increased serum osmolality reflects the absorption of glycols and their presence in the circulation, while the acidosis reflects the presence in plasma of mono- and diacid metabolites of the glycols. The diacid metabolities of low-molecular-weight polyethylene glycols are excellent calcium chelators and can account for the hypercalcemia. Finally, we suggest that polyethylene glycol metabolites produce renal destruction via mechanisms similar to those involved in the renal failure associated with ethylene glycol poisoning.

Effect of Activated Charcoal in 70 Sorbitol in Healthy Hdiyiduals

Activated charcoal in 70% sorbitol enjoys wide use in the management of acute poisonings but the effects of the activated charcoal-sorbitol mixture in healthy individuals have not been characterized. We were concerned about the possibility of sorbitol causing changes in the routinely monitored serum chemistry and hematological parameters, either directly due to the absorbed polyol or due to the diarrhea induced by it, thus complicating the diagnosis and management in an overdose setting. We assessed the action of a single dose of 30g of activated charcoal in 150 ml of 70% sorbitol and its effects on serum osmolality, electrolytes, metabolic profile (SMAC), magnesium, hepatic enzymes, and complete blood count in healthy adult individuals. The only significant change in the laboratory parameters tested was the consistent rise in serum sodium and phosphorus concentrations four hours after drinking the charcoal-sorbitol mixture. However, a similarly consistent rise in the concentrations at the same hours on another day without ingestion of the charcoal-sorbitol mixture suggested the rise was due to circadian rhythm or other factors unrelated to the cathartic. The lack of effect on routinely monitored laboratory parameters, relative palatability and the rapid onset (40-225 minutes), and long duration (7 to 127 hours) of purgation, make charcoal-sorbitol an attractive combination for use as a gastrointestinal decontaminant. Possible effects of multiple dose regimens and the effects in pediatric and geriatric populations need further study.

Activated Charcoal in Oral Ethanol Absorption: Lack of Effect in Humans

Activated charcoal has been recommended for use in poisonings by ethanol, other toxic alcohols and glycols, but it has been avoided with therapeutic use of oral ethanol. Six healthy young adults drank a dose of ethanol designed to give a peak concentration of 125 mg/dl on two different days after overnight fasting. Each individual drank the same dose on both occasions; but on one of these days, the subjects drank an aqueous slurry of 60 g of superactive charcoal prior to ethanol ingestion. We compared the pharmacokinetic profile of ethanol with and without activated charcoal treatment. The fraction of ethanol absorbed was similar on both protocols. The mean peak ethanol concentration after pretreatment with activated charcoal was 8% greater than ethanol alone (p = 0.08). Thus oral activated charcoal does not significantly impair ethanol absorption and can be used in patients requiring oral ethanol. Our results do not support the use of activated charcoal in overdose of ethanol alone. Extending our results to poisonings by other toxic alcohols and glycols, the use of activated charcoal to reduce their absorption deserves evaluation.

Determination of isotope ratios of chromium nickel, zinc and copper by gas chromatography-mass spectrometry by using volatile metal chelates

A gas chromatographic-mass spectrometric (GC-MS) method involving thermally stable, volatile chelates was investigated for measurements of isotope ratios of chromium, nickel, zinc and copper. The chelating agents acetylacetone, trifluoroacetylacetone, sodium diethyldithiocarbamate and lithium bis (trifluoroethyl)dithiocarbamate [Li(FDEDTC])] were used. Experimental conditions for the preparation of chelates and the mass spectrometric operating parameters for precise and accurate measurement of isotope ratios were optimized using a general-purpose mass spectrometer. Imprecision values of 1–4% were obtained for measurements of different isotope ratios using chelates containing about 10 ng of metal. The capability of this technique for the accurate determination of natural and altered isotope ratios was also evaluated for these elements using Li(FDEDTC) as a chelating agent. This GC-MS method obviates the need for a more specialized mass spectrometer such as a thermal ionization or inductively coupled plasma mass spectrometer for trace metal determination. The technique gives detection limits down to parts per 109 levels and offers considerable potential for isotope dilution measurements.

Modulation of ethanol-induced central nervous system depression by ibuprofen

We investigated the effect of pretreatment with a prostaglandin synthetase inhibitor, ibuprofen, on the pharmacokinetics and pharmacodynamics of ethanol in six fasting subjects. Ibuprofen caused a 10% decrease in the maximum rate of elimination of ethanol. Visual memory, which is a function primarily mediated by the right cerebral hemisphere, was measured by the Benton Visual Retention test and was more impaired during combined ibuprofen and ethanol dosing than during ethanol dosing alone (P = 0.05). The auditory‐verbal memory of the subjects, which is primarily a function of the left cerebral hemisphere, was assessed by the Selective Reminding Test and showed decreased impairment during combined ibuprofen and ethanol dosing as compared with ethanol dosing alone (P = 0.04). The opposite effect of ibuprofen on ethanol‐induced cognitive impairment as measured by two lateralized functions is consistent with the reports in tissue and animal models that central nervous system effects of ethanol may be mediated at least in part by prostaglandins.

Isotope dilution gas chromatography/mass spectrometry for platinum determination in urine

The therapeutic importance of platinum (Pt) compounds, the growing accessibility of gas chromatography/mass spectrometry (GC/MS) systems in clinical laboratories, and the lack of a mass spectrometric method for the determination of Pt in biological samples motivated us to develop an isotope dilution GC/MS assay for Pt. The method is based on the use of lithium bis(trifluoroethyl) dithiocarbamate, Li(FDEDTC), as a chelating agent and enriched 192Pt for isotope dilution. Conditions were optimized for the precise and accurate determination of isotope ratios of Pt by using a 10-m DB-l fused silica capillary column and a reverse-geometry double-focusing mass spectrometer with selected ion monitoring. An overall precision of 1% was obtained by combining within-run precision and between-run precision at the 10-ng level. No appreciable memory effect was observed when samples with different isotope ratios were analyzed sequentially. The method was validated by the quantitation of Pt in National Institute of Standards and Technology freeze-dried urine sample SRM 2670. A concentration value of 125 ± 6 /Lg/L (n = 6) was obtained by using four different sets of isotope ratios in the molecular ion and supports the National Institute of Standards and Technology recommended value of 120 ± ? μg/L. Limits-of-quantitation, estimated at 3 μg/L, are made possible by the high sensitivity of the method and the low blank value for Pt.

Determination of cobalt in urine by gas chromatography-mass spectrometry employing nickel as an internal standard

A gas chromatographic-mass spectrometric method for the determination of cobalt in biological materials employing stable enriched 62Ni as an internal standard and using lithium bis(trifluoroethyl)dithiocarbamate as a chelating agent is described. The method involves the addition of a known amount (1 microgram) of 62Ni to the sample, the formation of the chelate and the determination by selected-ion monitoring of the m/z 571/574 ratio, which corresponds to 59Co/62Ni. No appreciable memory effect was observed, and an acceptable dynamic range of 100 was found. There was good agreement between the cobalt concentration values determined by gas chromatography-mass spectrometry and electrothermal atomic absorption spectrometry. The present method has high sensitivity and can be used for the quantitation of cobalt at concentrations as low as 1 microgram/l. The use of enriched 62Ni circumvents the problem caused by endogenous nickel and simultaneously provides data on the nickel concentration in the biological sample without any additional experimental effort.

Lidocaine permeability in silicone tissue expanders: an in vitro analysis

Tissue expansion has achieved a prominent role in soft-tissue reconstruction. Expansion-induced pain is often a limiting factor in this process and can affect patients for as long as 24 to 48 hours following each expansion session. Although lidocaine is known to be an effective analgesic, only anecdotal reports of its usefulness when placed within a tissue expander currently exist. This two-part study was designed first to determine if in fact silicone is readily permeable to lidocaine, and second to determine if the potential diffusion dynamics can be defined. In part 1 of the study, the silicone polymer was indeed found to be readily permeable to lidocaine as measured with fluorescence immunoassay technique. In part 2, two groups of Surgitek and Dow Corning expanders were filled with saline and lidocaine and placed in saline baths. At several intervals over a 48-hour period, aliquots of the surrounding saline were sampled and the lidocaine levels subsequently determined. A rather predictable and consistent diffusion curve was demonstrated. The significant difference in diffusion characteristics between the two expander types was apparently due to wall thickness differences inherent in the manufacturing. In this in vitro study, filler-valve leakage did not significantly contribute to lidocaine migration from within these tissue expanders. This basic in vitro work will now set the stage for further in vivo and clinical investigations to more precisely define the role of lidocaine in the tissue-expansion process.

Steroid and benzyl alcohol diffusion through tissue expanders and double lumen breast implants.

The rate of diffusion of benzyl alcohol (the bacteriostatic agent in the provided diluent) and methylprednisolone 21-hemisuccinate and related rearrangement and hydrolysis products (“steroid”) through tissue expanders was examined. The rate of diffusion of steroid through double lumen breast implants was also studied. It was found that benzyl alcohol rapidly diffused through tissue expanders into a saline bath. By 24 hours, one-half of the benzyl alcohol had diffused through the expander. The steroid was much slower to diffuse out of the expander. By 141 days, only 2% of the steroid was found in the bath. This rate was comparable for both the tissue expander and double lumen implants. In addition, a significant amount of the steroid is located in the expander wall, associated with the surface of the expander or precipitated out of solution or both. The clinical significance of these findings is discussed.