More on B-cell-depleting induction therapy and acute cellular rejection.

n engl j med 361;12 nejm.org september 17, 2009 1214 contribute to the discourse concerning the nuances of the clinical use of fomepizole. Rehman points out that the osmolal gap dissipates as ethylene glycol or methanol is metabolized. The reason is that only the parent compound contributes to this gap. Electroneutrality requires the acidic metabolites of ethylene glycol and methanol (primarily glycolate and formate), which are ionized to negatively charged carboxyl groups at physiologic pHs, to have a counter cation. In plasma, on a probabilistic basis, this would be a sodium ion. The equation for calculating the osmolal gap includes, for serum osmolarity, a term that is two times the sodium concentration, accounting for both the sodium ion itself and, by virtue of the coefficient, the metabolite anion (Table 3 of the article). Thus, these metabolites, unlike the parent compounds, will not contribute to the calculated osmolarity and hence decrease the osmolal gap. This event is important because the disappearance of the osmolal gap is evidence of metabolism of the parent compound, after which there is no benefit to inhibiting alcohol dehydrogenase. Rehman also correctly observes that the contribution of ethanol must be factored into the calculation of the predicted osmolarity (also explained in Table 3 of the article). González-Santiago and Garza-Ocañas speculate that the pharmacokinetic interaction between fomepizole and ethanol might exacerbate the potential adverse effects of the latter. When fomepizole is used, ethanol continues to be metabolized, but with a reduction in the clearance rate of approximately 40%.1 There have been a number of instances in which fomepizole was administered to patients with blood alcohol concentrations in the intoxication range with no reported adverse effect, including one instance in which the fomepizole nullified an adverse effect of ethanol on a patient’s level of consciousness.2 I agree with González-Santiago and GarzaOcañas that fomepizole should be used with caution if a patient is allergic to pyrazoles; however, no allergic reactions in patients with intolerance to this class of medications have been reported in the literature.