Excretion of tolbutamide metabolites in young and old subjects

Summary Tolbutamide (1 g/70 kg) was administered as a single intravenous dose to 31 healthy, non-smoking, drug-free males between 23 and 87 years old and the total amounts of hydroxy and carboxytolbutamide excreted in 24 h were measured. There was a significant decrease in the urinary recovery of both metabolites with age. The reason for these findings is not known at the present time and may be associated with the decrease in creatinine clearance observed in these subjects or other changes in the pharmacokinetics of tolbutamide which are currently being investigated.     

An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, beta-globin haplotypes, alpha-globin gene number, gender, and age

Five factors have been shown to influence the 20-fold variation of fetal hemoglobin (Hb F) levels in sickle cell anemia (SS): age, sex, the alpha-globin gene number, beta-globin haplotypes, and an X-linked locus that regulates the production of Hb F-containing erythrocytes (F cells), ie, the F-cell production (FCP) locus. To determine the relative importance of these factors, we studied 257 Jamaican SS subjects from a Cohort group identified by newborn screening and from a Sib Pair study. Linear regression analyses showed that each variable, when analyzed alone, had a significant association with Hb F levels (P < .05). Multiple regression analysis, including all variables, showed that the FCP locus is the strongest predictor, accounting for 40% of Hb F variation. beta-Globin haplotypes, alpha-globin genes, and age accounted for less than 10% of the variation. The association between the beta-globin haplotypes and Hb F levels becomes apparent if the influence of the FCP locus is removed by analyzing only individuals with the same FCP phenotype. Thus, the FCP locus is the most important factor identified to date in determining Hb F levels. The variation within each FCP phenotype is modulated by factors associated with the three common beta-globin haplotypes and other as yet unidentified factor(s).     

Effect of phenytoin on the pharmacokinetics of doxorubicin and doxorubicinol in the rabbit

Summary Doxorubicin is metabolized extensively to doxorubicinol by the ubiquitous aldoketoreductase enzymes. The extent of conversion to this alcohol metabolite is important since doxorubicinol may be the major contributor to cardiotoxicity. Aldoketoreductases are inhibited in vitro by phenytoin. The present study was conducted to examine the effect of phenytoin on doxorubicin pharmacokinetics. Doxorubicin single-dose pharmacokinetic studies were performed in 10 New Zealand White rabbits after pretreatment with phenytoin or phenytoin vehicle (control) infusions in crossover fashion with 4–6 weeks between studies. Infusions were commenced 16 h before and during the course of the doxorubicin pharmacokinetic studies. Phenytoin infusion was guided by plasma phenytoin estimation to maintain total plasma concentrations between 20 and 30 g/ml. Following doxorubicin 5 mg/kg by i.v. bolus, blood samples were obtained at intervals over 32 h. Plasma doxorubicin and doxorubicinol concentrations were measured by HPLC. The mean plasma phenytoin concentrations ranged from 17.4 to 33.9 g/ml. Phenytoin infusion did not alter doxorubicin pharmacokinetics. The elimination half-life and volume of distribution were almost identical to control. Clearance of doxorubicin during phenytoin administration (60.9±5.8 ml/min per kg, mean±SE) was similar to that during vehicle infusion (67.5±5.4 ml/min per kg). Phenytoin administration was associated with a significant decrease in doxorubicinol elimination half-life from 41.0±4.8 to 25.6±2.8 h. The area under the plasma concentration/time curve (AUC) for doxorubicinol decreased significantly from 666.8±100.4 to 491.5±65.7 n.h.ml^-1. These data suggest that phenytoin at clinically relevant concentrations does not alter the conversion of doxorubicin to doxorubicinol in the rabbit. The reduction in the AUC for doxorubicinol caused by phenytoin appears to be due to an increased rate of doxorubicinol elimination. Phenytoin or similar agents may have the effect of modifying doxorubicinol plasma concentrations by induction of doxorubicinol metabolism rather than by inhibition of aldoketoreductase enzymes.     

Electrocardiographic predictors of failure and recurrence in patients with idiopathic right ventricular outflow tract tachycardia and ectopy who underwent radiofrequency catheter ablation

This study reports new electrocardiographic (ECG) predictors of radiofrequency catheter ablation failure and recurrence in idiopathic right ventricular outflow tract (RVOT) ventricular tachycardia (VT) or ectopy based on 91 consecutive patients. Procedural success and failure rates were 85% (77/91) and 15% (14/91), respectively. Twenty three percent (18/77) had recurrence during the follow-up period of 1 to 120 months (mean 56 +/- 31 months). Baseline RVOT VT/ectopy on 12-lead ECG taken prior to ablation from 91 patients were retrospectively analyzed. Ablation performed with RVOT ectopy (isolated ectopies, bigeminy, trigeminy, or couplets) as template arrhythmia was more likely to fail (30% vs. 8%, P =.02) as opposed to RVOT VT (sustained or nonsustained). VT/ectopy-QRS morphology variation was more observed in failed ablations (36% vs. 7%, P =.001). Significantly wider mean VT/ectopy QRS in leads I, II, AVR, V2, V3, V5, and V6 were noted in failed ablation group. Mean R wave amplitude reached statistical significance only in lead II (22.0 +/- 5.1 mV for failed vs. 17.8 +/- 5.2 mV for successful outcomes; P =.009). QRS morphologic variation (47% vs. 16%; P =.009) was the only statistically significant ECG to be more common in patients with arrhythmia recurrence. In conclusion, ablation with ectopy over VT as template arrhythmia, presence of QRS morphologic variation, wider mean QRS width, and taller mean R-wave amplitude in lead II were identified ECG predictors of failed RVOT VT/Ectopy ablation. The only ECG predictor of recurrence was the presence of RVOT VT or ectopy QRS morphologic variation.     

Can sensitization to aeroallergens disappear over time in children with allergic disease?

Background: Remittance of aeroallergen sensitization has been shown in population‐based studies, but there is a common perception that sensitization to aeroallergens rarely if ever disappears in children with allergic disease. Methods: We retrospectively reviewed all specific IgE tests carried out in children aged 0–18 years at our hospital laboratory over a 14‐year period. Of 3115 children sensitized to one or more aeroallergens, 244 (7.8%) were retested after a mean (SD) period of 45 (28) months at their physician’s discretion. Results: Disappearance of sensitization to individual aeroallergens did occur, with remittance rates ranging from 3.1% for house dust mite to 17.5% for cat. However, complete remittance of aeroallergen sensitization was found in only one subject. In up to 35% of cases, remittance of sensitization was offset by the appearance of one or more new aeroallergen sensitizations. Remittance was only observed in children sensitized to multiple allergens (with a median of 3 aeroallergen sensitizations), and their median degree of sensitization was low (median 2.1 kU/L). Conclusion: Aeroallergen sensitization can disappear in children with allergic disease, but only in polysensitized individuals. Complete remittance of sensitization to aeroallergens is rare in symptomatic children.