Reduced Serum Theophylline Concentrations after Discontinuation of Azithromycin: Evidence for an Unusual Interaction

A 68-year-old man receiving long-term therapy with oral sustained-release theophylline 450 mg twice/day was admitted to the hospital after failing treatment with azithromycin for an acute exacerbation of obstructive lung disease. Peak serum theophylline concentration was 20 μg/ml (normal 10–20 μg/ml). Azithromycin was discontinued and the theophylline dosage reduced by 33%. The subsequent 80% decrease in serum theophylline to 4.6 μg/ml was unexpectedly large. Two rechallenges produced similar transient depressions of serum theophylline concentrations after withdrawal of azithromycin, suggesting an interaction. Withdrawal of azithromycin may leave an increased number of active enzyme sites available as the drug is cleared from the system. In some circumstances, it may be useful for pharmacokinetic interaction studies to continue measuring concentrations after the suspected interacting agent is stopped.     

Folding of the conserved domain but not of flanking regions in the integrin β2 subunit requires association with the α subunit

We have used immunoprecipitation with mAbs to probe folding during biosynthesis of the β₂ integrin subunit of lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) before and after association with the α_L subunit. An evolutionarily conserved region is present in the β₂ subunit between amino acid residues 102 and 344. mAbs to one subregion before the conserved region, and two subregions after the conserved domain, immunoprecipitated both the unassociated β′₂ precursor and mature α_L/β₂ complex, suggesting portions of these subregions are folded before association with α_L. An activating mAb to the C-terminal cysteine-rich region, KIM127, preferentially bound to the unassociated β subunit, suggesting that it may bind to an epitope that is in an αβ interface in unactivated LFA-1. By contrast, mAbs to five different epitopes in the conserved region did not react with unassociated β′₂ precursor, suggesting that this region folds after α_L association and is intimately associated with the α_L subunit in the α_L/β₂ complex. mAbs to two different epitopes that involve the border between the conserved region and the C-terminal segment, were fully or partially reactive with the β′₂ precursor, suggesting that this region is partially folded before association with α_L. The findings suggest that the conserved region is a distinct folding and hence structural unit, and is intimately associated with the α subunit.     

Realities in ossiculoplasty

The results of ossiculoplasty are frequently reported in terms of closure of the air-bone gap. This parameter is a reliable indicator of the degree of technical success, and is useful in comparing different materials and types of reconstructions. However, assessment of the operated ear alone does not evaluate the effect of surgery on binaural hearing ability, leading to the situation where sub-optimal advice may be given to patients pre-operatively. This article advocates a more patient orientated method of assessing the results of ossiculoplasty. Previous studies have indicated that the operated ear must reach an air conduction level of 30 dB for the speech frequencies, or be within 15 dB of the other ear, to ensure that the patient will gain significant benefit. A graphical method for the prediction of patient benefit is presented, and compared to the rule of thumb quoted above. The implications for surgeons and patients considering ossiculoplasty are obvious. Many statements routinely made to patients prior to surgery for conductive hearing loss are unduly optimistic and unrelated to the realities of reported results. There is a need to determine what types of such hearing losses can be helped surgically, and more importantly to what extent the patients hearing disability can be relieved.     

Erythromycin-Induced Immune Hemolytic Anemia

A 3-year-old female receiving Pediazole (erythromycin ethylsuccinate and sulfisoxazole) for tonsillitis and otitis media developed severe hemolytic anemia. No serum drug-dependent antibodies could be demonstrated with an in vitro 'immune-complex' method using Pediazole, pure erythromycin ethylsuccinate or pure sulfisoxazole. However, a method using red cells coated with erythromycin base showed in vitro lysis of the erythromycin-coated red cells. This is only the second case of immune hemolytic anemia associated with erythromycin and the first where in vitro drug-dependent hemolysis was demonstrable.     

Improved Scoring System to Assess Adult Donors For Cadaver Renal Transplantation

We previously proposed a quantitative approach to assess donor organs for cadaver renal transplantation. To improve on our original scoring system, we studied 34 324 patients who received cadaver renal transplants from adult donors between 1994 and 1999 and were reported to the UNOS Scientific Renal Transplant Registry. A scoring system was developed from five donor variables (age, 0-25 points; history of hypertension, 0-4; creatinine clearance before procurement, 0-4; cause of death, 0-3; HLA mismatch, 0-3) that showed a significant correlation with renal function and long-term graft survival. Cadaver kidneys were stratified by cumulative donor score: grade A, 0-9 points; grade B, 10-19; grade C, 20-29; and grade D, 30-39. The influence of donor score on renal function and graft survival was most severe above 20 points, designated 'marginal' kidneys. In summary, a donor scoring system developed from a large population database was useful in predicting outcome after cadaver renal transplantation. The improved system provides a quantitative approach to evaluation of marginal kidneys and may improve allocation of these organs in cadaver renal transplantation.