Publications

OBJECTIVE

To track changes in the proportion of persons ages 18-64 with systemic lupus erythematosus (SLE) who were employed from diagnosis through 2004, to estimate changes in annual work hours during this time, and to describe risk factors for work loss among those employed at diagnosis.

METHODS

A structured telephone survey was administered to a cohort of 982 persons with SLE, which was assembled between 2002 and 2004. Of the 900 enrolled in 2002-2003, 832 (92%) were re-interviewed in 2004. We tabulated the proportion employed at diagnosis, at baseline interview, and at followup in 2004. Among individuals employed at each time frame, we estimated the hours of work per year. We then used the Kaplan-Meier method to estimate time until work loss among individuals employed at diagnosis and Cox proportional hazards regression to describe the risk factors for such work loss.

RESULTS

Between diagnosis and followup interview, the proportion employed declined from 74% to 54%. Over the same period, hours of work per year declined by 32.2% among all individuals with a work history, but by only 1% among those continuously employed. Among individuals working at diagnosis, the proportion employed declined by 15% and 63% after 5 and 20 years, respectively. Demographics (age, sex, and education) and work characteristics (physical and psychological demands of jobs and level of control) were the principal determinants of work loss.

CONCLUSION

Total cessation of employment, rather than reduced hours among employed persons, accounts for most of the decline in annual work hours among persons with SLE.

RATIONALE

Genes in the interleukin (IL)-4/IL-13/IL-4Ralpha pathway have been shown to be associated with asthma and related phenotypes in some populations, but not in others. Furthermore, interaction between these genes has been shown to affect asthma in white and Chinese populations.

OBJECTIVES

To determine whether there are IL-4/IL-13 and IL-4Ralpha gene-gene interactions that are associated with asthma in African Americans.

METHODS

Eighteen single-nucleotide polymorphisms (SNPs) in IL-4, IL-13, and IL-4Ralpha genes were genotyped in 264 African Americans with asthma and 176 healthy control subjects. We tested the SNPs for genetic associations and gene-gene interactions with asthma, baseline lung function, bronchodilator drug response, and total serum IgE levels.

MEASUREMENTS AND MAIN RESULTS

We identified 94 SNPs in IL-4, IL-13, and IL-4Ralpha genes by directly sequencing these genes in 24 African-American subjects with asthma. Seventeen SNPs were analyzed for association with asthma and related phenotypes. We found no evidence of association in the IL-4 gene. One SNP in the IL-13 gene (A-646G, rs2069743) and two SNPs in the IL-4Ralpha gene (A+4679G, rs1805010, and C+22656T, rs1805015) showed association with lung function (both baseline and post-bronchodilator). Although the association between individual SNPs and asthma-related phenotypes differed from previous studies performed in white and Chinese populations, significant gene-gene interaction was found between the IL-13 (A-646G) and IL-4Ralpha (A+4679G) SNPs for baseline lung function among African-American subjects with asthma.

CONCLUSIONS

Gene-gene interaction between the IL-13 and IL-4Ralpha genes may play an important role in asthma among African Americans.

Carboxylic acids may be metabolized to acyl glucuronides and acyl-coenzyme A thioesters (acyl-CoAs), which are reactive metabolites capable of reacting with proteins in vivo. In this study, the metabolic activation of tolmetin (Tol) to reactive metabolites and the subsequent formation of Tol-protein adducts in the liver were studied in rats. Two hours after dose administration (100 mg/kg i.p.), tolmetin acyl-CoA (Tol-CoA) was identified by liquid chromatography-tandem mass spectrometry in liver homogenates. Similarly, the acyl-CoA-dependent metabolites tolmetin-taurine conjugate (Tol-Tau) and tolmetin-acyl carnitine ester (Tol-Car) were identified in rat livers. In a rat bile study (100 mg/kg i.p.), the S-acyl glutathione thioester conjugate was identified, providing further evidence of the formation of reactive metabolites such as Tol-CoA or Tol-acyl glucuronide (Tol-O-G), capable of acylating nucleophilic functional groups. Three rats were treated with clofibric acid (150 mg/kg/day i.p. for 7 days) before dose administration of Tol. This resulted in an increase in covalent binding to liver proteins from 0.9 nmol/g liver in control rats to 4.2 nmol/g liver in clofibric acid-treated rats. Similarly, levels of Tol-CoA increased from 0.6 nmol/g to 4.4 nmol/g liver after pretreatment with clofibric acid, whereas the formation of Tol-O-G and Tol-Tau was unaffected by clofibric acid treatment. However, Tol-Car levels increased from 0.08 to 0.64 nmol/g after clofibric acid treatment. Collectively, these results confirm that Tol-CoA is formed in vivo in the rat and that this metabolite can have important consequences in terms of covalent binding to liver proteins.

PURPOSE

To test the tolerability, safety, and recommended phase II dose of CP-724,714, a reversible, highly selective, oral HER2 tyrosine kinase inhibitor in patients with advanced solid tumor malignancies that express HER2.

EXPERIMENTAL DESIGN

A phase I trial evaluated escalating doses of CP-724,714, administered daily in 21-day cycles. Pharmacokinetics/pharmacodynamics were evaluated in serial blood samples and in pretreatment and posttreatment tumor and skin biopsies.

RESULTS

Thirty female patients [median age, 51 years (range, 37-71); median performance status, 1 (range, 0-1)] received CP-724,714 at four dose levels: 250 mg once daily (4 patients), 250 mg twice daily (15 patients), 250 mg thrice daily (6 patients), and 400 mg twice daily (5 patients). Dosing at 400 mg twice daily and 250 mg thrice daily was not feasible due to reversible, cholestatic liver dysfunction. Treatment-related adverse events were nausea (58%), asthenia (23%), hyperbilirubinemia (27%), elevated transaminases (30%), and skin rash (30%); neither diarrhea nor cardiomyopathy was observed. No objective responses were observed in 28 evaluable patients; 8 (29%) patients had stable disease. Twenty-seven (96%) patients received prior trastuzumab and were heavily pretreated (median prior chemotherapy, 6; range, 1-11). Systemic exposure exceeded the in vivo efficacy threshold required in preclinical studies.

CONCLUSIONS

Dose-limiting toxicities included hyperbilirubinemia, elevated alanine aminotransferase, thrombocytopenia and pulmonary embolus. Although the protocol-specified maximum tolerated dose of CP-724,714 was 250 mg thrice daily, the recommended phase II dose was 250 mg twice daily due to excessive late-cycle hepatotoxicity. Despite extensive prior treatment, 29% of patients had stable disease. A phase II trial has been initiated in patients with breast cancer.

PURPOSE

Cardiovascular disease and obstructive lung disease are leading global causes of death. Despite this, the impact of secondhand smoke (SHS) exposure on pulmonary function and cardiovascular disease remains uncertain. Our goal was to elucidate the association between baseline SHS exposure and the risk of lung function decline and cardiovascular mortality over a period of nearly a decade.

METHODS

We used data from a longitudinal cohort study of 1,057 older adults to study the association between baseline SHS exposure and the risk of lung function decline and cardiovascular mortality. The effect of SHS exposure on cardiovascular mortality may be mediated by its influence on FEV1 and biological processes captured by measurement of FEV1. Alternatively, the effect of SHS may be mediated by baseline cardiovascular disease status, which reflects the combined effects of traditional cardiovascular risk factors. To correctly estimate the effect of SHS and FEV1 on cardiovascular mortality, we used marginal structural models (MSMs) that took into account the mediating effects of FEV1 and baseline cardiovascular disease in the causal pathway.

RESULTS

In longitudinal multivariate analyses, lifetime cumulative home and work SHS exposure were associated with a greater decline of FEV1 (-15 mL/s; 95% CI, -29 to -1.3 mL/s and -41 mL/s; 95% CI, -55 to -28 mL/s per 10-year cumulative exposure, respectively). Lifetime home SHS exposure was associated with a greater risk of cardiovascular mortality in both conventional multivariate analysis (HR, 1.10 per 10 years of exposure; 95% CI, 0.99 to 1.24) and the MSM for FEV1 (HR, 1.06; 95% CI, 0.95 to 1.19) and baseline cardiovascular disease (HR for subjects with no baseline cardiovascular disease, 1.39; 95% CI, 1.17 to 1.66).

CONCLUSIONS

Lifetime SHS exposure appears to result in a greater decline in lung function and risk of cardiovascular mortality, taking into account confounders and the mediating effect of FEV1 and baseline cardiovascular disease.

OBJECTIVE

To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model.

METHODS

Prospective randomized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy. Patients were randomly assigned to smoke either cannabis (3.56% tetrahydrocannabinol) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days. Primary outcome measures included ratings of chronic pain and the percentage achieving >30% reduction in pain intensity. Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model.

RESULTS

Fifty patients completed the entire trial. Smoked cannabis reduced daily pain by 34% (median reduction; IQR = -71, -16) vs 17% (IQR = -29, 8) with placebo (p = 0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p = 0.04). The first cannabis cigarette reduced chronic pain by a median of 72% vs 15% with placebo (p < 0.001). Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli (p < or = 0.05) but appeared to have little effect on the painfulness of noxious heat stimulation. No serious adverse events were reported.

CONCLUSION

Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain.