Does rapid dose titration affect the hepatic safety profile of Bosentan?

RATIONALE: Bosentan, a dual endothelin receptor antagonist, has proven efficacy in pulmonary hypertension. Due to an association with hepatic dysfunction, it is typically initiated at a sub-therapeutic dose for 4 weeks before titration to a therapeutic dose. At our institution some patients have undergone rapid titration, to potentially benefit from therapy earlier. This study assesses the impact of this practice on hepatic safety. METHOD: All patients initiated on bosentan therapy before April 2005 were included. Rapidly titrated patients achieved a therapeutic dose by 3 days, whereas standard titration patients were titrated at 4 weeks. All patients were monitored with monthly liver function tests. RESULTS: 149 patients commenced bosentan, of which 55 were rapidly titrated. At baseline, the two groups were similar in age, BMI, diagnosis, 6-min walking distance, alanine aminotransferase (ALT), cardiac index and pulmonary artery pressures. The rapid group had elevated right atrial pressures (9.7 mm Hg versus 7.4 mm Hg, p = 0.016) and worse WHO functional class (p = 0.008) and included less females (31% versus 69%, p = 0.024). The incidence of hepatic dysfunction in all patients was 12.8% at 12 months. There was no statistical difference in incidence between the rapid and standard groups (4% versus 11% at 3 months, p = 0.211 and 6% versus 15% at 12 months, p = 0.219). Of all patients on bosentan, hepatic dysfunction was most significantly associated with a higher baseline ALT (p = 0.021), female sex (p = 0.003) and underlying connective tissue disease (p = 0.025). Subgroup analysis suggested these factors were not confounders when comparing rapid and standard titration. CONCLUSIONS: Rapid and standard titration of bosentan resulted in similar hepatic safety profiles. Baseline ALT, female sex and the presence of connective tissue disease increased the risk of hepatic dysfunction independent of the titration method used.

A longitudinal study of the relation of lead in blood to lead in air concentrations among battery workers.

The relation between lead in air (PbA) and lead in blood (PbB), concentrations was investigated among 44 workers in five major operations in a United States high volume, lead acid battery plant. The study covered a 30 month period in which workers received frequent PbA and PbB determinations, workers remained in a single job, and PbA concentrations averaged below the US Occupational Safety and Health Administration (OSHA) permissible exposure limit of 50 micrograms/m3. In both univariate and multivariable linear regressions, longitudinal analyses averaging PbA concentrations over the 30 month study period appeared superior to cross sectional analyses using only six month PbA averages to model PbB concentrations. The covariate adjusted coefficient (alpha value) for PbA (mu/m3) in models of PbB (micrograms/100 g) was 1.14. This figure is strikingly higher than that reported in previous studies in the lead acid battery industry in all of which PbA concentrations were substantially higher than in the current study. Plausible explanations for the difference in alpha values include non-linearity of the PbA-PbB curve, a higher fraction of large size particulate associated with higher PbA concentrations, survivor bias among workers exposed to higher PbA concentrations, and the cross sectional designs of most previous studies. Despite previously reported problems with the model used by OSHA to predict PbA-PbB relations, the findings of this study are in good agreement with the predictions of that model.

The effect of airborne lead particle size on worker blood-lead levels: an empirical study of battery workers.

Theoretical models and experimental data suggest that the particle size distribution of lead aerosols should affect the lead dose absorbed by exposed workers. In the present study, 44 workers in five major operations in a high-volume, lead-acid battery plant were studied for the influence of lead aerosol size on lead-in-blood (PbB) levels. A multiple linear regression analysis based on particle size assumptions made in the model used by the Occupational Safety and Health Administration to help select the permissible exposure level (PEL) for lead showed no improvement in prediction of PbB over that already present without any consideration of particle size. The use of the American Conference of Governmental Industrial Hygienists (ACGIH) regional size-selective criteria also failed to improve the prediction of PbB. However, when deposition models developed by Heyder et al were used in which the lead aerosol was separated into alveolar and extra-alveolar fractions, corresponding to what is considered respirable and ingestible lead, the coefficient of determination (R2) associated with the fractionated lead particulate increased approximately 25% over that attributable to only the total lead concentration. In addition, the deposition model, which closely matched the ACGIH reference worker criteria, resulted in ratios of the coefficients for the respirable to ingestible lead contributions to PbB that appeared to agree with experimental data, suggesting approximately a 10 to 1 ratio in absorption efficiency of the lung versus the gastrointestinal tract.

Influence of high past lead-in-air exposures on the lead-in-blood levels of lead-acid battery workers with continuing exposure.

We investigated the relationship between air lead levels and blood lead levels in 132 lead-acid battery workers in two plants who were followed for 30 months between 1983 and 1985 with frequent air lead and blood lead determinations. Both plants converted to more modern, expanded-metal battery manufacturing technologies around 1978 with associated reductions in mean air lead exposures from greater than 100 to less than 30 micrograms/m3. In multiple regression analyses including consideration of job category, seniority, age, ethnicity, gender, and smoking habit as covariates, there was a highly significant association of blood lead in micrograms/dL with air lead in micrograms/m3 (partial R2 = .20, P less than .0001) among the 68 workers in plant B but no association (P = .91) in plant A. Restriction of the regression analysis to those 44 workers in plant B with less than or equal to 22 years of seniority yielded the most significant air lead-blood lead association (partial R2 = .36, P less than .0001). Among the remaining 24 plant B workers, seniority, but not air lead, had a significant positive association with blood lead. Despite very stable air lead levels over the 30-month study, the 51 workers in plant A with more than 20 years' seniority had a mean decline of 0.04 microgram/dL in mean blood lead over the study period, whereas the 13 workers in plant A with less than or equal to 20 years' seniority had a mean increase of 7.6 microgram/dL.(ABSTRACT TRUNCATED AT 250 WORDS)