Publications

The Informatics and Computational Safety Analysis Staff at the US FDA's Center for Drug Evaluation and Research has created a database of pharmaceutical adverse effects (AEs) linked to pharmaceutical chemical structures and estimated population exposures. The database is being used to develop quantitative structure-activity relationship (QSAR) models for the prediction of drug-induced liver and renal injury, as well as to identify relationships among AEs. The post-market observations contained in the database were obtained from FDA's Spontaneous Reporting System (SRS) and the Adverse Event Reporting System (AERS) accessed through Elsevier PharmaPendium software. The database contains approximately 3100 unique pharmaceutical compounds and 9685 AE endpoints. To account for variations in AE reports due to different patient populations and exposures for each drug, a proportional reporting ratio (PRR) was used. The PRR was applied to all AEs to identify chemicals that could be scored as positive in the training datasets of QSAR models. Additionally, toxicologically similar AEs were grouped into clusters based upon both biological effects and statistical correlation. This clustering created a weight of evidence paradigm for the identification of compounds most likely to cause human harm based upon findings in multiple related AE endpoints.

This report describes the development of quantitative structure-activity relationship (QSAR) models for predicting rare drug-induced liver and urinary tract injury in humans based upon a database of post-marketing adverse effects (AEs) linked to approximately 1600 chemical structures. The models are based upon estimated population exposure using AE proportional reporting ratios. Models were constructed for 5 types of liver injury (liver enzyme disorders, cytotoxic injury, cholestasis and jaundice, bile duct disorders, gall bladder disorders) and 6 types of urinary tract injury (acute renal disorders, nephropathies, bladder disorders, kidney function tests, blood in urine, urolithiases). Identical training data sets were configured for 4 QSAR programs (MC4PC, MDL-QSAR, BioEpisteme, and Predictive Data Miner). Model performance was optimized and was shown to be affected by the AE scoring method and the ratio of the number of active to inactive drugs. The best QSAR models exhibited an overall average 92.4% coverage, 86.5% specificity and 39.3% sensitivity. The 4 QSAR programs were demonstrated to be complementary and enhanced performance was obtained by combining predictions from 2 programs (average 78.4% specificity, 56.2% sensitivity). Consensus predictions resulted in better performance as judged by both internal and external validation experiments.

We investigated the association of adherence to the Mediterranean diet and other risk factors for dyslipidemia in HIV-infected Croatian patients during the first year of highly active antiretroviral therapy (HAART). Adherence to the Mediterranean diet was determined by a 150-item questionnaire; a 0 to 9-point diet scale was created that stratified respondents as having low adherence (<4 points) and moderate to high adherence (> or = 4 points). We interviewed 117 participants between May 2004 and June 2005 and abstracted their serum lipid measurements taken during the first year of HAART The values of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides increased most prominently in the first 3 to 6 months after initiation of HAART (average increase at 3 months: 25% for total cholesterol, 22% for LDL-cholesterol, 18% for HDL-cholesterol and 43% for triglycerides). A Mediterranean diet and physical activity had no effect on serum lipids. The mean total cholesterol was higher in participants receiving a combination of a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor compared to participants receiving a combination of nucleoside analogs with a non-nucleoside analog or a combination of nucleoside analogs and a protease inhibitor Among individual drug treatments, indinavir/ritonavir had the most unfavorable lipid profile. We conclude that adherence to a Mediterranean diet does not influence serum lipid profiles during the first year of HAART.

OBJECTIVE

To determine whether the flight attendants who were exposed to secondhand tobacco smoke in the aircraft cabin have abnormal pulmonary function.

METHODS

We administered questionnaires and performed pulmonary function testing in 61 never-smoking female flight attendants who worked in active air crews before the smoking ban on commercial aircraft (preban).

RESULTS

Although the preban flight attendants had normal FVC, FEV1, and FEV1/FVC ratio, they had significantly decreased flow at mid- and low-lung volumes, curvilinear flow-volume curves, and evidence of air trapping. Furthermore, the flight attendants had significantly decreased diffusing capacity (77.5% +/- 11.2% predicted normal) with 51% having a diffusing capacity below their 95% normal prediction limit.

CONCLUSIONS

This cohort of healthy never-smoking flight attendants who were exposed to secondhand tobacco smoke in the aircraft cabin showed pulmonary function abnormalities suggestive of airway obstruction and impaired diffusion.

Current guidelines recommend beta blockers for patients after myocardial infarction (MI). Novel therapies for heart failure should be tested in combination with this medication before entering clinical trials. In this methodologic study, we sought to describe the time course of systolic and diastolic parameters of cardiac performance over a 6-wk period in closed-chest model of swine MI treated with a beta blocker. Myocardial infarction in pigs (n = 10) was induced by 90-min balloon occlusion of the left anterior descending coronary artery. Echocardiography and pressure-volume data were collected before and at 1 and 6 wk after MI; histopathology was assessed at 6 wk. Left-ventricular (LV) volume increased significantly over 6 wk, with significant decreases in ejection fraction, wall motion index, stroke work, rate of pressure development (dP/dt(max)), preload recruitable stroke work, and mechanical efficiency. Impairment of diastolic function was manifested by a significant increase in the exponential beta coefficient of the LV end-diastolic pressure-volume relation and reduction of LV pressure decay. At 6 wk, histopathologic analysis showed that the size of the infarct area was 16.3% +/- 4.4%, and the LV mass and myocyte cross-sectional area in both the infarct border and remote zones were increased compared with those of noninfarcted pigs (n = 5). These findings suggest a dynamic pattern of remodeling over time in a closed-chest ischemia-reperfusion swine model of acute MI on beta-blocker therapy and may guide future studies.

OBJECTIVE

To evaluate the effect of HIV infection on longitudinal changes in kidney function and to identify independent predictors of kidney function changes in HIV-infected individuals.

DESIGN

A prospective cohort.

METHODS

Cystatin C was measured at baseline and at the 5-year follow-up visit of the Study of Fat Redistribution and Metabolic Change in HIV infection in 554 HIV-infected participants and 230 controls. Control participants were obtained from the Coronary Artery Risk Development in Young Adults study. Glomerular filtration rate (eGFRcys) was estimated using the formula 76.7 x cysC(-1.19).

RESULTS

Compared with controls, HIV-infected participants had a greater proportion of clinical decliners (annual decrease in eGFRcys > 3 ml/min per 1.73 m2; 18 versus 13%, P = 0.002) and clinical improvers (annual increase in eGFRcys > 3 ml/min per 1.73 m2; 26 versus 6%, P < 0.0001). After multivariable adjustment, HIV infection was associated with higher odds of both clinical decline (odds ratio 2.2; 95% confidence interval 1.3, 3.9, P = 0.004) and clinical improvement (odds ratio 7.3; 95% confidence interval 3.9, 13.6, P < or = 0.0001). Among HIV-infected participants, a decrease in HIV viral load during follow-up was independently associated with clinical improvement; conversely, higher baseline and an increase in viral load during follow-up were associated with clinical decline. No individual antiretroviral drug or drug class appeared to be substantially associated with clinical decline or improvement.

CONCLUSION

Compared with controls, HIV-infected persons were more likely both to have clinical decline and clinical improvement in kidney function during 5 years of follow-up. The extent of viremic control had a strong association with longitudinal changes in kidney function.

Nephrogenic systemic fibrosis (NSF) is a disease of thickened, hard, hyperpigmented skin lesions with or without systemic fibrosis occurring in patients with renal insufficiency and associated with the administration of gadolinium-containing contrast. The pathogenesis of this disease is unclear, and there is no definitive treatment. We describe a 71-yr-old patient with stable chronic lymphocytic leukemia (CLL), end-stage renal disease (ESRD), and NSF who presented with hypercalcemia in 2006. Before onset of renal insufficiency in 2002, serum calcium, phosphorus, and PTH levels were normal. In 2004, the patient began hemodialysis, and he was diagnosed with NSF in 2005, shortly after undergoing an MRI with gadolinium contrast administration. Over the next 6 mo, albumin-corrected serum total calcium levels rose from 9.9 to 13.1 mg/dl (normal range, 8.5-10.5 mg/dl) with normal serum phosphorus levels. On admission in September 2006, 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were elevated at 130.7 pg/ml (normal range, 25.1-66.1 pg/ml). Biopsy of an NSF lesion showed increased 25-hydroxyvitamin D(3)-1-alpha hydroxylase (CYP27B1) immunostaining compared with the biopsy from a normal control. This is the first reported association of NSF with hypercalcemia caused by elevated 1,25(OH)(2)D levels. This metabolic disturbance should be sought in future cases to determine a connection between NSF, 1,25(OH)(2)D metabolism, and CYP27B1 activation in the skin, which may shed light on the pathogenesis of this unusual local and systemic fibrosing disorder.

STUDY OBJECTIVE

To examine obstructive sleep apnea (OSA) as a risk factor for work disability.

PATIENTS AND SETTING

Consecutive patients referred to the University of California San Francisco Sleep Disorders Center with suspected OSA (n = 183).

DESIGN

All patients underwent overnight polysomnography after completing a written survey which assessed work disability due to sleep problems, occupational characteristics and excessive daytime sleepiness (EDS) defined as an Epworth Sleepiness Scale score > 10.

RESULTS

Among 150 currently employed patients, 83 had OSA on polysomnography (apnea-hypopnea index > or = 5). Compared with patients in whom both OSA and EDS were absent, patients with the combination of OSA and EDS were at higher risk of both recent work disability (adjusted odds ratio [OR], 13.7; 95% confidence interval [CI], 3.9-48) and longer-term work duty modification (OR, 3.6; CI, 1.1-12). When either OSA or EDS were absent, the strength of the association with work disability was less than when both OSA and EDS were present. When OSA was examined without respect to EDS, patients with OSA were at increased risk of recent work disability relative to patients without OSA (OR 2.6; 95% CI 1.2-5.8), but the association of OSA with longer-term work duty modification did not meet standard criteria for statistical significance (OR = 2.0, 95% CI 0.8-5.0).

CONCLUSIONS

The combination of OSA and EDS contributes to work disability, and OSA by itself contributes to recent work disability. These findings should highlight to employers and clinicians the importance of OSA in the workplace to encourage patients to be screened for OSA, particularly in situations of decreased productivity associated with EDS.

BACKGROUND

The diagnosis of and criteria for the evaluation of asbestos-related disease impairment remains controversial after decades of research. Assessing agreement among experts who study pneumoconiosis, and diagnose and treat patients with asbestos-related respiratory conditions may be the first step in clarifying clinical and forensic/administrative issues associated with asbestos-related pulmonary conditions.

METHODS

We conducted a Delphi study, an iterative method of obtaining consensus among a group of experts. An expert panel was identified using an objective, nonbiased algorithm, based on the number of asbestos-related disease publications authored during the preceding 10-year period. Identified experts were invited to participate by accessing an Internet site. Each expert was presented statements developed by the authors regarding the diagnosis or treatment of asbestos-related disease; experts then ranked their degree of agreement or disagreement utilizing an 11-level modified Likert scale for each statement. Each expert was asked to justify their selection and to suggest references in support of their opinion. The Wilcoxon signed rank test and the interquartile range were used to define "consensus." The results of the collective Likert rankings, deidentified comments, and suggested references as well as the initial consensus results were then provided to the participating experts. Each panel member then ranked their extent of agreement with a modified statement for which consensus was not achieved. The process was repeated three times.

RESULTS

Consensus was achieved on all but 9 of 32 statements.

CONCLUSIONS

Consensus was not achieved for nine statements. These statements may be topics for future research.

Since the current standards for drug approval were established nearly half a century ago, no drug has been approved for the treatment of systemic lupus erythematosus (SLE). Despite this sobering history, interest in drug development for SLE has heightened in the past few years. This enthusiasm has been fueled in large part by the success of biologic therapy for rheumatoid arthritis and other autoimmune diseases. Unfortunately, despite considerable clinical trial activity, this interest has not yet translated into the discovery of an effective treatment for SLE. This article provides an analysis of the major clinical trials in SLE, and offers an interpretation of the results that could illuminate the path forward.