Publications by authors named "Alan Pan"

29 Publications

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Impact of mRNA vaccines in curtailing SARS-CoV-2 infection and disability leave utilisation among healthcare workers during the COVID-19 pandemic: cross-sectional analysis from a tertiary healthcare system in the Greater Houston metropolitan area.

BMJ Open 2021 10 12;11(10):e054332. Epub 2021 Oct 12.

Houston Methodist, Houston Methodist Academic Institute, Houston, Texas, USA.

Objectives: We provide an account of real-world effectiveness of COVID-19 vaccines among healthcare workers (HCWs) at a tertiary healthcare system and report trends in SARS-CoV-2 infections and subsequent utilisation of COVID-19-specific short-term disability leave (STDL).

Design: Cross-sectional study.

Setting And Participants: Summary data on 27 291 employees at a tertiary healthcare system in the Greater Houston metropolitan area between 15 December 2020 and 5 June 2021. The initial 12-week vaccination programme period (15 December 2020 to 6 March 2021) was defined as a rapid roll-out phase.

Main Outcomes And Measures: At the pandemic onset, HCW testing and surveillance was conducted where SARS-CoV-2-positive HCWs were offered STDL. Deidentified summary data of SARS-CoV-2 infections and STDL utilisation among HCWs were analysed. Prevaccination and postvaccination trends in SARS-CoV-2 positivity and STDL utilisation rates were evaluated.

Results: Updated for 5 June 2021, 98.2% (n=26 791) of employees received a full or partial dose of one of the approved mRNA COVID-19 vaccines. The vaccination rate during the rapid roll-out phase was approximately 3700 doses/7 days. The overall mean weekly SARS-CoV-2 positivity rates among HCWs were significantly lower following vaccine roll-out (2.4%), compared with prevaccination period (11.8%, p<0.001). An accompanying 69.8% decline in STDL utilisation was also observed (315 to 95 weekly leaves). During the rapid roll-out phase, SARS-CoV-2 positivity rate among Houston Methodist HCWs declined by 84.3% (8.9% to 1.4% positivity rate), compared with a 54.7% (12.8% to 5.8% positivity rate) decline in the Houston metropolitan area.

Conclusion: Despite limited generalisability of regional hospital-based studies-where factors such as the emergence of viral variants and population-level vaccine penetrance may differ-accounts of robust HCW vaccination programmes provide important guidance for sustaining a critical resource to provide safe and effective care for patients with and without COVID-19 across healthcare systems.
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http://dx.doi.org/10.1136/bmjopen-2021-054332DOI Listing
October 2021

National Trends in Transfer of Patients with Primary Intracerebral Hemorrhage: An Analysis of 12-Year Nationwide Data.

J Stroke Cerebrovasc Dis 2021 Sep 22;30(12):106116. Epub 2021 Sep 22.

Center for Outcomes Research, Houston Methodist, Houston, TX, United States; Houston Methodist Neurological Institute, Houston Methodist, Houston, TX, United States. Electronic address:

Objectives: The guidelines of the American Hospital Association encourage transferring intracerebral hemorrhage patients from community hospitals to centers with stroke expertise. However, research on the differences in outcomes between transferred intracerebral hemorrhage hospitalizations and directly admitted hospitalizations have been largely limited to small single-center studies. In this study, we explored the national trends in transferred intracerebral hemorrhage hospitalizations, as well as evaluated the differences, in terms of demographic characteristics, co-morbidity, resource utilization, and outcomes, between transferred intracerebral hemorrhage hospitalizations and directly admitted hospitalizations.

Materials And Methods: From the National Inpatient Sample (2004 - 2016), we assessed the linear trends in the proportion of interhospital transfers for intracerebral hemorrhage hospitalizations. We constructed a series of multivariate logistic regression models to explore the association of transfer status with inpatient mortality and discharge disposition, controlling for demographic, clinical, and hospital characteristics. We used survey design variables to report nationally weighted estimates.

Results: Among 786,999 hospitalizations, 137,340 (17.5%, 95% CI: 16.4-18.6) were transferred. Overall, interhospital transfers for intracerebral hemorrhage has been increasing over the 12-year period of this study. Patients in transferred hospitalizations were younger, more likely to be white, and more likely to have private insurance. Transferred hospitalizations were associated with significantly lower adjusted odds of inpatient mortality, compared to directly admitted hospitalizations.

Conclusions: As the US healthcare system continues shifting towards value-based care, evidence on the short- and long-term outcomes of transfer of intracerebral hemorrhage patients will inform optimal management of intracerebral hemorrhage patients.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106116DOI Listing
September 2021

Cognitive Impairment After Intracerebral Hemorrhage: A Systematic Review of Current Evidence and Knowledge Gaps.

Front Neurol 2021 27;12:716632. Epub 2021 Aug 27.

Center for Outcomes Research, Houston Methodist Research Institute, Houston Methodist, Houston, TX, United States.

Cognitive impairment (CI) is commonly observed after intracerebral hemorrhage (ICH). While a growing number of studies have explored this association, several evidence gaps persist. This review seeks to investigate the relationship between CI and ICH. A two-stage systematic review of research articles, clinical trials, and case series was performed. Initial search used the keywords ["Intracerebral hemorrhage" OR "ICH"] AND ["Cognitive Impairment" OR "Dementia OR "Cognitive Decline"] within the PubMed (last accessed November 3rd, 2020) and ScienceDirect (last accessed October 27th, 2020) databases, without publication date limits. Articles that addressed CI and spontaneous ICH were accepted if CI was assessed after ICH. Articles were rejected if they did not independently address an adult human population or spontaneous ICH, didn't link CI to ICH, were an unrelated document type, or were not written in English. A secondary snowball literature search was performed using reviews identified by the initial search. The Agency for Healthcare research and Quality's assessment tool was used to evaluate bias within studies. Rates of CI and contributory factors were investigated. Search yielded 32 articles that collectively included 22,631 patients. Present evidence indicates a high rate of post-ICH CI (65-84%) in the acute phase (<4 weeks) which is relatively lower at 3 (17.3-40.2%) and 6 months (19-63.3%). Longer term follow-up (≥1 year) demonstrates a gradual increase in CI. Advanced age, female sex, and prior stroke were associated with higher rates of CI. Associations between post-ICH CI and cerebral microbleeds, superficial siderosis, and ICH volume also exist. Pre-ICH cognitive assessment was missing in 28% of included studies. The Mini Mental State Evaluation (44%) and Montreal Cognitive Assessment (16%) were the most common cognitive assessments, albeit with variable thresholds and definitions. Studies rarely (<10%) addressed racial and ethnic disparities. Current findings suggest a dynamic course of post-ICH cognitive impairment that may depend on genetic, sociodemographic and clinical factors. Methodological heterogeneity prevented meta-analysis, limiting results. There is a need for the methodologies and time points of post-ICH cognitive assessments to be harmonized across diverse clinical and demographic populations.
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http://dx.doi.org/10.3389/fneur.2021.716632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429504PMC
August 2021

SARS-CoV-2 Susceptibility and COVID-19 Mortality Among Older Adults With Cognitive Impairment: Cross-Sectional Analysis From Hospital Records in a Diverse US Metropolitan Area.

Front Neurol 2021 22;12:692662. Epub 2021 Jul 22.

Center for Outcomes Research, Houston Methodist, Houston, TX, United States.

Persistent knowledge gaps exist as to the extent that preexisting cognitive impairment is a risk factor for susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mortality from the coronavirus disease 2019 (COVID-19). We conducted a cross-sectional analysis of adults tested for SARS-CoV-2 at a tertiary healthcare system. Cognitive impairment was identified utilizing diagnosis codes (mild cognitive impairment, Alzheimer's disease, vascular, and other dementias) or cognitive impairment-specific medication use. Propensity score (PS) matched analyses were utilized to report odds ratios (OR) and 95% confidence intervals (CI) for association of cognitive impairment with SARS-CoV-2 susceptibility and COVID-19 mortality. Between March-3rd and December-11th, 2020, 179,979 adults were tested, of whom 21,607 (12.0%) tested positive. We identified 6,364 individuals with preexisting cognitive impairment (mean age: 78.5 years, 56.8% females), among whom 843 (13.2%) tested positive and 139 (19.5%) of those hospitalized died. In the pre-PS matched cohort, cognitive impairment was significantly associated with increased SARS-CoV-2 susceptibility (OR, CI: 1.12, 1.04-1.21) and COVID-19 mortality (OR, CI: 2.54, 2.07-3.12). One-to-one matches were identified for 6,192 of 6,364 (97.3%) individuals with prior cognitive impairment and 687 of 712 (96.5%) hospitalized patients with prior cognitive impairment. In the fully balanced post-matched cohort, preexisting cognitive impairment was significantly associated with higher likelihood of SARS-CoV-2 infection (OR, CI: 1.51, 1.35-1.70); however, cognitive impairment did not confer higher risk of COVID-19 mortality (OR, CI: 0.96, 0.73-1.25). To mitigate the effects of healthcare catastrophes such as the COVID-19 pandemic, strategies for targeted prevention and risk-stratified comorbidity management are warranted among the vulnerable sub-population living with cognitive impairment.
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http://dx.doi.org/10.3389/fneur.2021.692662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344862PMC
July 2021

Disparities in COVID-19 hospitalizations and mortality among black and Hispanic patients: cross-sectional analysis from the greater Houston metropolitan area.

BMC Public Health 2021 07 6;21(1):1330. Epub 2021 Jul 6.

Center for Outcomes Research, Houston Methodist, Josie Roberts Administration Building, 7550 Greenbriar Drive, Suite 4.123, Houston, TX, 77030, USA.

Background: Disparate racial/ethnic burdens of the Coronavirus Disease 2019 (COVID-19) pandemic may be attributable to higher susceptibility to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or to factors such as differences in hospitalization and care provision.

Methods: In our cross-sectional analysis of lab-confirmed COVID-19 cases from a tertiary, eight-hospital healthcare system across greater Houston, multivariable logistic regression models were fitted to evaluate hospitalization and mortality odds for non-Hispanic Blacks (NHBs) vs. non-Hispanic Whites (NHWs) and Hispanics vs. non-Hispanics.

Results: Between March 3rd and July 18th, 2020, 70,496 individuals were tested for SARS-CoV-2; 12,084 (17.1%) tested positive, of whom 3536 (29.3%) were hospitalized. Among positive cases, NHBs and Hispanics were significantly younger than NHWs and Hispanics, respectively (mean age NHBs vs. NHWs: 46.0 vs. 51.7 years; p < 0.001 and Hispanic vs. non-Hispanic: 44.0 vs. 48.7 years; p < 0.001). Despite younger age, NHBs (vs. NHWs) had a higher prevalence of diabetes (25.2% vs. 17.6%; p < 0.001), hypertension (47.7% vs. 43.1%; p < 0.001), and chronic kidney disease (5.0% vs. 3.3%; p = 0.001). Both minority groups resided in lower median income (median income [USD]; NHBs vs. NHWs: 63,489 vs. 75,793; p < 0.001, Hispanic vs. non-Hispanic: 59,104 vs. 68,318; p < 0.001) and higher population density areas (median population density [per square mile]; NHBs vs. NHWs: 3257 vs. 2742; p < 0.001, Hispanic vs. non-Hispanic: 3381 vs. 2884; p < 0.001). In fully adjusted models, NHBs (vs. NHWs) and Hispanics (vs. non-Hispanic) had higher likelihoods of hospitalization, aOR (95% CI): 1.42 (1.24-1.63) and 1.61 (1.46-1.78), respectively. No differences were observed in intensive care unit (ICU) utilization or treatment parameters. Models adjusted for demographics, vital signs, laboratory parameters, hospital complications, and ICU admission vital signs demonstrated non-significantly lower likelihoods of in-hospital mortality among NHBs and Hispanic patients, aOR (95% CI): 0.65 (0.40-1.03) and 0.89 (0.59-1.31), respectively.

Conclusions: Our data did not demonstrate racial and ethnic differences in care provision and hospital outcomes. Higher susceptibility of racial and ethnic minorities to SARS-CoV-2 and subsequent hospitalization may be driven primarily by social determinants.
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http://dx.doi.org/10.1186/s12889-021-11431-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258471PMC
July 2021

Decade-Long Nationwide Trends and Disparities in Use of Comfort Care Interventions for Patients With Ischemic Stroke.

J Am Heart Assoc 2021 04 7;10(8):e019785. Epub 2021 Apr 7.

Center for Outcomes Research Houston Methodist Houston TX.

Background Stroke remains one of the leading causes of disability and death in the United States. We characterized 10-year nationwide trends in use of comfort care interventions (CCIs) among patients with ischemic stroke, particularly pertaining to acute thrombolytic therapy with intravenous tissue-type plasminogen activator and endovascular thrombectomy, and describe in-hospital outcomes and costs. Methods and Results We analyzed the National Inpatient Sample from 2006 to 2015 and identified adult patients with ischemic stroke with or without thrombolytic therapy and CCIs using validated ( codes. We report adjusted odds ratios (ORs) and 95% CI of CCI usage across five 2-year periods. Of 4 249 201 ischemic stroke encounters, 3.8% had CCI use. CCI use increased over time (adjusted OR, 4.80; 95% CI, 4.15-5.55) regardless of acute treatment type. Advanced age, female sex, White race, non-Medicare insurance, higher income, disease severity, comorbidity burden, and discharge from non-northeastern teaching hospitals were independently associated with receiving CCIs. In the fully adjusted model, thrombolytic therapy and endovascular thrombectomy, respectively, conferred a 6% and 10% greater likelihood of receiving CCIs. Among CCI users, there was a significant decline in in-hospital mortality compared with all other dispositions over time (adjusted OR, 0.46; 95% CI, 0.38-0.56). Despite longer length of stay, CCI hospitalizations incurred 16% lower adjusted costs. Conclusions CCI use among patients with ischemic stroke has increased regardless of acute treatment type. Nonetheless, considerable disparities persist. Closing the disparities gap and optimizing access, outcomes, and costs for CCIs among patients with stroke are important avenues for further research.
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http://dx.doi.org/10.1161/JAHA.120.019785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174182PMC
April 2021

Rapid Response to Drive COVID-19 Research in a Learning Health Care System: Rationale and Design of the Houston Methodist COVID-19 Surveillance and Outcomes Registry (CURATOR).

JMIR Med Inform 2021 Feb 23;9(2):e26773. Epub 2021 Feb 23.

Houston Methodist, Houston, TX, United States.

Background: The COVID-19 pandemic has exacerbated the challenges of meaningful health care digitization. The need for rapid yet validated decision-making requires robust data infrastructure. Organizations with a focus on learning health care (LHC) systems tend to adapt better to rapidly evolving data needs. Few studies have demonstrated a successful implementation of data digitization principles in an LHC context across health care systems during the COVID-19 pandemic.

Objective: We share our experience and provide a framework for assembling and organizing multidisciplinary resources, structuring and regulating research needs, and developing a single source of truth (SSoT) for COVID-19 research by applying fundamental principles of health care digitization, in the context of LHC systems across a complex health care organization.

Methods: Houston Methodist (HM) comprises eight tertiary care hospitals and an expansive primary care network across Greater Houston, Texas. During the early phase of the pandemic, institutional leadership envisioned the need to streamline COVID-19 research and established the retrospective research task force (RRTF). We describe an account of the structure, functioning, and productivity of the RRTF. We further elucidate the technical and structural details of a comprehensive data repository-the HM COVID-19 Surveillance and Outcomes Registry (CURATOR). We particularly highlight how CURATOR conforms to standard health care digitization principles in the LHC context.

Results: The HM COVID-19 RRTF comprises expertise in epidemiology, health systems, clinical domains, data sciences, information technology, and research regulation. The RRTF initially convened in March 2020 to prioritize and streamline COVID-19 observational research; to date, it has reviewed over 60 protocols and made recommendations to the institutional review board (IRB). The RRTF also established the charter for CURATOR, which in itself was IRB-approved in April 2020. CURATOR is a relational structured query language database that is directly populated with data from electronic health records, via largely automated extract, transform, and load procedures. The CURATOR design enables longitudinal tracking of COVID-19 cases and controls before and after COVID-19 testing. CURATOR has been set up following the SSoT principle and is harmonized across other COVID-19 data sources. CURATOR eliminates data silos by leveraging unique and disparate big data sources for COVID-19 research and provides a platform to capitalize on institutional investment in cloud computing. It currently hosts deeply phenotyped sociodemographic, clinical, and outcomes data of approximately 200,000 individuals tested for COVID-19. It supports more than 30 IRB-approved protocols across several clinical domains and has generated numerous publications from its core and associated data sources.

Conclusions: A data-driven decision-making strategy is paramount to the success of health care organizations. Investment in cross-disciplinary expertise, health care technology, and leadership commitment are key ingredients to foster an LHC system. Such systems can mitigate the effects of ongoing and future health care catastrophes by providing timely and validated decision support.
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http://dx.doi.org/10.2196/26773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903978PMC
February 2021

Sex differences in susceptibility, severity, and outcomes of coronavirus disease 2019: Cross-sectional analysis from a diverse US metropolitan area.

PLoS One 2021 13;16(1):e0245556. Epub 2021 Jan 13.

Department of Neurology, McGovern Medical School, UTHealth, Houston, TX, United States of America.

Introduction: Sex is increasingly recognized as an important factor in the epidemiology and outcome of many diseases. This also appears to hold for coronavirus disease 2019 (COVID-19). Evidence from China and Europe has suggested that mortality from COVID-19 infection is higher in men than women, but evidence from US populations is lacking. Utilizing data from a large healthcare provider, we determined if males, as compared to females have a higher likelihood of SARS-CoV-2 susceptibility, and if among the hospitalized COVID-19 patients, male sex is independently associated with COVID-19 severity and poor in-hospital outcomes.

Methods And Findings: Using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines, we conducted a cross-sectional analysis of data from a COVID-19 Surveillance and Outcomes Registry (CURATOR). Data were extracted from Electronic Medical Records (EMR). A total of 96,473 individuals tested for SARS-CoV-2 RNA in nasopharyngeal swab specimens via Polymerized Chain Reaction (PCR) tests were included. For hospital-based analyses, all patients admitted during the same time-period were included. Of the 96,473 patients tested, 14,992 (15.6%) tested positive, of whom 4,785 (31.9%) were hospitalized and 452 (9.5%) died. Among all patients tested, men were significantly older. The overall SARS-CoV-2 positivity among all tested individuals was 15.5%, and was higher in males as compared to females 17.0% vs. 14.6% [OR 1.20]. This sex difference held after adjusting for age, race, ethnicity, marital status, insurance type, median income, BMI, smoking and 17 comorbidities included in Charlson Comorbidity Index (CCI) [aOR 1.39]. A higher proportion of males (vs. females) experienced pulmonary (ARDS, hypoxic respiratory failure) and extra-pulmonary (acute renal injury) complications during their hospital course. After adjustment, length of stay (LOS), need for mechanical ventilation, and in-hospital mortality were significantly higher in males as compared to females.

Conclusions: In this analysis of a large US cohort, males were more likely to test positive for COVID-19. In hospitalized patients, males were more likely to have complications, require ICU admission and mechanical ventilation, and had higher mortality than females, independent of age. Sex disparities in COVID-19 vulnerability are present, and emphasize the importance of examining sex-disaggregated data to improve our understanding of the biological processes involved to potentially tailor treatment and risk stratify patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245556PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806140PMC
January 2021

Racial and ethnic disparities in SARS-CoV-2 pandemic: analysis of a COVID-19 observational registry for a diverse US metropolitan population.

BMJ Open 2020 08 11;10(8):e039849. Epub 2020 Aug 11.

Center for Outcomes Research, Houston Methodist Research Institute, Houston, Texas, USA.

Introduction: Data on race and ethnic disparities for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited. We analysed sociodemographic factors associated with higher likelihood of SARS-CoV-2 infection and explore mediating pathways for race and ethnic disparities in the SARS-CoV-2 pandemic.

Methods: This is a cross-sectional analysis of the COVID-19 Surveillance and Outcomes Registry, which captures data for a large healthcare system, comprising one central tertiary care hospital, seven large community hospitals and an expansive ambulatory/emergency care network in the Greater Houston area. Nasopharyngeal samples for individuals inclusive of all ages, races, ethnicities and sex were tested for SARS-CoV-2. We analysed sociodemographic (age, sex, race, ethnicity, household income, residence population density) and comorbidity (Charlson Comorbidity Index, hypertension, diabetes, obesity) factors. Multivariable logistic regression models were fitted to provide adjusted OR (aOR) and 95% CI for likelihood of a positive SARS-CoV-2 test. Structural equation modelling (SEM) framework was used to explore three mediation pathways (low income, high population density, high comorbidity burden) for the association between non-Hispanic black (NHB) race, Hispanic ethnicity and SARS-CoV-2 infection.

Results: Among 20 228 tested individuals, 1551 (7.7%) tested positive. The overall mean (SD) age was 51.1 (19.0) years, 62% were females, 22% were black and 18% were Hispanic. NHB and Hispanic ethnicity were associated with lower socioeconomic status and higher population density residence. In the fully adjusted model, NHB (vs non-Hispanic white; aOR, 2.23, CI 1.90 to 2.60) and Hispanic ethnicity (vs non-Hispanic; aOR, 1.95, CI 1.72 to 2.20) had a higher likelihood of infection. Older individuals and males were also at higher risk of infection. The SEM framework demonstrated a significant indirect effect of NHB and Hispanic ethnicity on SARS-CoV-2 infection mediated via a pathway including residence in densely populated zip code.

Conclusions: There is strong evidence of race and ethnic disparities in the SARS-CoV-2 pandemic that are potentially mediated through unique social determinants of health.
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http://dx.doi.org/10.1136/bmjopen-2020-039849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418666PMC
August 2020

Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non-Small Cell Lung Cancer.

Oncologist 2019 06 13;24(6):820-828. Epub 2019 Mar 13.

Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Background: Tissue tumor mutational burden (TMB) has emerged as a potential biomarker predicting response to anti-programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) therapy, but few studies have explored using circulating tumor DNA (ctDNA) TMB in non-small cell lung cancer (NSCLC).

Materials And Methods: A total of 136 patients with NSCLC with ctDNA testing were retrospectively evaluated from a single institution, along with a validation cohort from a second institution. ctDNA TMB was derived using the number of detected mutations over the DNA sequencing length.

Results: Higher ctDNA TMB was significantly correlated with smoking history ( < .05, chi-squared test). Among patients treated with immune checkpoint inhibitors ( = 20), higher ctDNA TMB was significantly correlated with shorter progressive free survival (PFS) and overall survival (OS; 45 vs. 355 days; hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.3-24.6;  < .01, and OS 106 days vs. not reached; HR, 6.0; 95% CI, 1.3-27.1;  < .01, respectively). In a small independent validation cohort ( = 12), there was a nonsignificant numerical difference for higher ctDNA TMB predicting shorter OS but not PFS. ctDNA TMB was not correlated with RECIST tumor burden estimation in the subset of patients treated with immune checkpoint blockade.

Conclusion: The findings indicate that higher ctDNA TMB, at the current commercial sequencing length, reflects worse clinical outcomes.

Implications For Practice: Biomarkers to identify patients who will respond to immune checkpoint blockade are critical. Tissue tumor mutational burden (TMB) has emerged as a viable biomarker to predict response to anti-PD-1/PD-L1 therapy, but few studies have explored the meaning and potential clinical significance of noninvasive, blood-based TMB. Here, we investigated circulating tumor DNA (ctDNA) TMB and present data demonstrating that current ctDNA TMB may reflect tumor burden and that ctDNA panels with a greater number of mutations may be necessary to more accurately reflect tissue TMB.
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http://dx.doi.org/10.1634/theoncologist.2018-0433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656496PMC
June 2019

Association of Tumor Mutational Burden With DNA Repair Mutations and Response to Anti-PD-1/PD-L1 Therapy in Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2019 03 25;20(2):88-96.e6. Epub 2018 Sep 25.

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.

Purpose: To examine clinical predictors of tumor mutational burden (TMB), to explore the association between TMB and DNA repair mutations, and to analyze TMB as a biomarker for response to immune checkpoint blockade in non-small-cell lung cancer.

Patients And Methods: TMB scores were determined retrospectively for 72 consecutive patients at our institution with next-generation sequencing comprehensive genomic profiling testing by Foundation Medicine. TMB scores were correlated with a number of clinical variables and presence of DNA repair mutations. Thirty-four patients were treated with anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies, and survival analyses based on TMB score were performed. In addition, tissue immunohistochemical analysis was performed for a subset of patients.

Results: History of smoking, but not other clinical variables, including prior treatment lines, stage of disease, and number of metastatic sites, predicted higher TMB score. Higher TMB score was significantly associated with greater number of DNA repair mutations. In the subset of patients treated with immune checkpoint blockade, higher TMB score significantly predicted overall survival, but not progression-free survival (hazard ratio = 0.10, P = .003; hazard ratio 1.1, P = .84, respectively). In a small subset of patients, PD-1/PD-L1 staining did not independently predict progression-free survival or overall survival.

Conclusion: Tissue TMB was significantly associated with smoking history and number of DNA repair mutations. TMB is a promising biomarker for response to anti-PD-1/PD-L1 therapy, with higher TMB score predicting longer overall survival.
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http://dx.doi.org/10.1016/j.cllc.2018.09.008DOI Listing
March 2019

Penumbral role of beta blockade on heart rate recovery in heart failure.

Authors:
Alan Pan

Clin Exp Pharmacol Physiol 2018 12;45(12):1328-1329

Presbyterian Intercommunity Hospital (PIH) Health, Whittier, CA, USA.

We would agree that Heart Rate Variability (HRR) is a measure of parasympathetic activity, which may need to be augmented in chronic management of Heart Failure (HF). A viable next step would be the determination of the relative strength of the sympathetic response versus the decrease of parasympathetic tone in HF, while taking into consideration the suppression of the sympathetic nervous system by virtue of Beta Blockade, which constitutes standard therapy.
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http://dx.doi.org/10.1111/1440-1681.12951DOI Listing
December 2018

Path toward Precision Oncology: Review of Targeted Therapy Studies and Tools to Aid in Defining "Actionability" of a Molecular Lesion and Patient Management Support.

Mol Cancer Ther 2017 Dec;16(12):2645-2655

Developmental Therapeutics Program, Division of Hematology Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Precision medicine trials and targeted therapies have shifted to the forefront of oncology. Although targeted therapies have shown initial promise, implementation across the broad landscape of oncology has many challenges. These limitations include an incomplete understanding of the functional significance of variant alleles as well as the need for clinical research and practice models that are more patient-centered and account for the complexity of individual patient tumors. Furthermore, successful implementation of targeted therapies will also be predicated on efforts to standardize the framework for patient management support. Here, we review current implementations of targeted therapies in precision oncology and discuss how "actionability" is defined for molecular targets in cancer therapeutics. We also comment on the growing need for bioinformatics tools and data platforms to complement advances in precision oncology. Finally, we discuss current frameworks for integrating precision oncology into patient management and propose an integrated model that combines features of molecular tumor boards and decision support systems. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0597DOI Listing
December 2017

The Influence of Exercise Therapy on the Heart Failure Disease Pathway.

Authors:
Alan Pan

J Am Coll Cardiol 2017 05;69(18):2350-2351

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http://dx.doi.org/10.1016/j.jacc.2016.12.048DOI Listing
May 2017

The real-world evidence of heart failure co-morbidities.

Authors:
Alan Pan

Eur J Heart Fail 2017 03;19(3):434

MemorialCare Health, 450 Spring Street, Long Beach, CA 90806, USA.

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http://dx.doi.org/10.1002/ejhf.751DOI Listing
March 2017

Recent Advances and Future Strategies for Immune-Checkpoint Inhibition in Small-Cell Lung Cancer.

Clin Lung Cancer 2017 03 9;18(2):132-140. Epub 2016 Jul 9.

Developmental Therapeutics Program of the Division of Hematology Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; Division of Hematology Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL; The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL.

Small-cell lung cancer (SCLC) is distinguished from non-small-cell lung cancer by its rapid growth and more frequent metastases. Although patients with SCLC are highly responsive to chemotherapy and radiation therapy, long-term prognosis remains poor, with relapse and disease recurrence occurring in almost all cases. Whereas combination chemotherapies continue to be the standard of care in extensive-stage SCLC, there is value in exploring whether immune-checkpoint inhibition is an effective treatment strategy, given the durable responses in non-small-cell lung cancer. Data from SCLC trials have shown clinical activity and response to cytotoxic T-lymphocyte antigen-4 protein and programmed cell death-1 blockade, suggesting that antibodies targeting these pathways may be effective in improving survival outcome. However, data on clinical activity by programmed cell death-1 ligand expression in SCLC are not widely available. Limited data indicate that programmed cell death-1 ligand expression may not be an ideal biomarker for patient selection. Continued research is necessary to better optimize patient selection and response to therapy.
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http://dx.doi.org/10.1016/j.cllc.2016.07.004DOI Listing
March 2017

Long-Term Outcomes of Single-Port Laparoscopic Placement of Peritoneal Dialysis Catheter.

Vasc Endovascular Surg 2016 Jul 2;50(5):343-8. Epub 2016 Jun 2.

Division of Vascular Surgery & Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA

Introduction: Laparoscopic insertion of peritoneal dialysis (PD) catheter has become a preferred method compared to the traditional open technique for PD catheter insertion. We retrospectively report the outcome of 1-port laparoscopic placement PD catheters in our institution.

Methods: A total of 263 patients with end-stage renal disease who underwent single-trocar laparoscopic PD catheter insertion during a recent 6-year period were reviewed. Laparoscopic technique involves introducing a PD catheter over a stiff guidewire into the abdominal cavity through a 10-mm laparoscopic port. Pertinent clinical variables, procedural complications, and follow-up outcome were analyzed.

Results: There were 182 men and 81 women. The mean age was 56 years. Technical success was 95.8%. Catheter occlusion was the most common early complications (<6 months) that occurred in 4 (1.5%) patients. Late complications (> 6 months) including catheter occlusion, cuff extrusion, catheter leakage, catheter migration, infection, and hernia occurred in 5 patients (1.9%), 2 patients (0.8%), 3 patients (1.1%), 3 patients (1.1%), 6 patients (2.3%), and 4 patients (1.5), respectively. Mean follow-up time was 39 ± 18 months. Catheter survival rate at 1, 2, 3, 4, and 5 years was 96%, 94%, 90%, 85%, and 82%, respectively.

Conclusion: Laparoscopic PD catheter implantation via a single-trocar utilizing a stiff guidewire technique is feasible and safe. This method can result in low complication and high catheter survival rate.
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http://dx.doi.org/10.1177/1538574416652245DOI Listing
July 2016

Biomarkers for PD-1/PD-L1 Blockade Therapy in Non-Small-cell Lung Cancer: Is PD-L1 Expression a Good Marker for Patient Selection?

Clin Lung Cancer 2016 09 6;17(5):350-361. Epub 2016 Apr 6.

Developmental Therapeutics Program of the Division of Hematology Oncology, Department of Medicine, Northwestern Medicine Developmental Therapeutics Institute, Northwestern University, Chicago, IL; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Northwestern University Feinberg School of Medicine, Chicago, IL.

Immunotherapy has emerged as a promising treatment modality in cancer therapy. With improved understanding of how to tip the balance of immune homeostasis, novel therapeutics targeting immune checkpoints have been developed, with durable responses observed in multiple solid tumors, including melanoma, renal cell carcinoma, and non-small-cell lung cancer. Clinical trials have reported favorable responses using programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) blockade as monotherapy and most impressively in combinatorial trials with cytotoxic T-lymphocyte antigen-4 protein blockade. Nonetheless, a clinical benefit has not been observed in all patients. Therefore, identifying the ideal biomarkers for patient selection would be of great value in optimizing and personalizing immunotherapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials and immunohistochemistry assays. In addition, the response to immune checkpoint inhibition has been complicated by PD-L1 expression as a marker influenced by the dynamic tumor microenvironment. No consensus has yet been reached on whether PD-L1 expression is an ideal marker for patient selection. Recent research has shown promise for alternative markers, including T-cell immunohistochemistry, other immunologic markers, T-cell receptor clonality, and somatic mutational burden. However, additional studies are needed to assess the value of these as practical predictive biomarkers for patient selection and treatment response.
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http://dx.doi.org/10.1016/j.cllc.2016.03.011DOI Listing
September 2016

A pharmacokinetic/pharmacodynamic investigation: assessment of edivoxetine and atomoxetine on systemic and central 3,4-dihydroxyphenylglycol, a biochemical marker for norepinephrine transporter inhibition.

Eur Neuropsychopharmacol 2015 Mar 5;25(3):377-85. Epub 2015 Jan 5.

Aepodia S.A., Rue Louis de Geer, 6, B-1348 Louvain La Neuve, Belgium.

Inhibition of norepinephrine (NE) reuptake into noradrenergic nerves is a common therapeutic target in the central nervous system (CNS). In noradrenergic nerves, NE is oxidized by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). In this study, 40 healthy male subjects received the NE transporter (NET) inhibitor edivoxetine (EDX) or atomoxetine (ATX), or placebo. The pharmacokinetic and pharmacodynamic profile of these drugs in plasma and cerebrospinal fluid (CSF) was assessed. In Part A, subjects received EDX once daily (QD) for 14 or 15 days at targeted doses of 6mg or 9mg. In Part B, subjects received 80mg ATX QD for 14 or 15 days. Each subject received a lumbar puncture before receiving drug and after 14 or 15 days of dosing. Plasma and urine were collected at baseline and after 14 days of dosing. Edivoxetine plasma and CSF concentrations increased dose dependently. The time to maximum plasma concentration of EDX was 2h, and the half-life was 9h. At the highest EDX dose of 9mg, DHPG concentrations were reduced from baseline by 51% at 8h postdose in CSF, and steady-state plasma and urine DHPG concentrations decreased by 38% and 26%, respectively. For 80mg ATX, the decrease of plasma, CSF, or urine DHPG was similar to EDX. Herein we provide clinical evidence that EDX and ATX decrease DHPG concentrations in the periphery and CNS, presumably via NET inhibition. EDX and ATX concentrations measured in the CSF confirmed the availability of those drugs in the CNS.
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http://dx.doi.org/10.1016/j.euroneuro.2014.12.009DOI Listing
March 2015

Visual assessment of brain magnetic resonance imaging detects injury to cognitive regulatory sites in patients with heart failure.

J Card Fail 2013 Feb;19(2):94-100

School of Nursing, University of California, Los Angeles, California 90095-1702, USA.

Background: Heart failure (HF) patients exhibit depression and executive function impairments that contribute to HF mortality. Using specialized magnetic resonance imaging (MRI) analysis procedures, brain changes appear in areas regulating these functions (mammillary bodies, hippocampi, and frontal cortex). However, specialized MRI procedures are not part of standard clinical assessment for HF (which is usually a visual evaluation), and it is unclear whether visual MRI examination can detect changes in these structures.

Methods And Results: Using brain MRI, we visually examined the mammillary bodies and frontal cortex for global and hippocampi for global and regional tissue changes in 17 HF and 50 control subjects. Significantly global changes emerged in the right mammillary body (HF 1.18 ± 1.13 vs control 0.52 ± 0.74; P = .024), right hippocampus (HF 1.53 ± 0.94 vs control 0.80 ± 0.86; P = .005), and left frontal cortex (HF 1.76 ± 1.03 vs control 1.24 ± 0.77; P = .034). Comparison of the visual method with specialized MRI techniques corroborates right hippocampal and left frontal cortical, but not mammillary body, tissue changes.

Conclusions: Visual examination of brain MRI can detect damage in HF in areas regulating depression and executive function, including the right hippocampus and left frontal cortex. Visual MRI assessment in HF may facilitate evaluation of injury to these structures and the assessment of the impact of potential treatments for this damage.
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http://dx.doi.org/10.1016/j.cardfail.2012.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249656PMC
February 2013

Effects of smoking cessation, acute re-exposure and nicotine replacement in smokers on AIR inhaled insulin pharmacokinetics and glucodynamics.

Br J Clin Pharmacol 2008 Apr 8;65(4):480-7. Epub 2007 Oct 8.

Lilly-NUS Centre for Clinical Pharmacology Pte Ltd, Singapore.

What Is Already Known About This Subject: * Only one other study (Becker et al.) has reported on the influence of smoking cessation and smoking resumption on inhaled insulin pharmacokinetics and glucodynamics, concluding that the rapid changes associated with smoking resumption carry the risk for hypoglycaemia and thus should not be used by active smokers.

What This Study Adds: * This is the first euglycaemic clamp study on the impact of smoking cessation, acute smoking re-exposure and nicotine replacement on AIR((R)) inhaled insulin pharmacokinetics and glucodynamics. * We demonstrate clinically and statistically significant shifts in glucodynamic response to acute re-exposure to a single cigarette, leading us to conclude that active smokers should be advised against inhaled insulin therapy until smoking abstinence is stable. * Additionally, these results are also the first to demonstrate an apparent independent effect of nicotine replacement therapy on insulin exposure and glucodynamic response.

Aims: To explore the effects of smoking cessation and acute smoking re-exposure on the pharmacokinetic (PK) and glucodynamic (GD) profiles of AIR inhaled insulin (AIR Insulin) with or without nicotine replacement therapy (NRT).

Methods: Nondiabetic smokers (n = 24) with normal pulmonary function completed a two-phase (four-period), open-label, randomized euglycaemic clamp study. During the initial study phase, subjects underwent glucose clamps following AIR Insulin dosing, shortly after smoking, 8-12 h after smoking, or following subcutaneous insulin lispro shortly after smoking. AIR Insulin PK and GD were again assessed during and after a 4-week smoking-cessation period with or without NRT. In the last study period, subjects smoked one cigarette shortly before final AIR Insulin dosing and glucose clamp, to study the effect of acute smoking re-exposure on inhaled insulin PK and GD.

Results: Compared with the preceding active smoking phase, the administration of AIR Insulin in nondiabetic subjects undergoing a 4-week period of smoking abstinence resulted in a decrease in PK and GD of approximately 25% (P = 0.008 for both), an effect which was greater in subjects using NRT. Following rechallenge with a single cigarette (without NRT), GD response to AIR Insulin increased significantly (P = 0.006) towards precessation levels, relative to smoking abstinence. In subjects using NRT, however, the increase in GD was less pronounced.

Conclusion: Smoking, smoking cessation and acute re-exposure with a single cigarette are associated with clinically significant alterations in AIR Insulin pharmacokinetics and glucodynamics. AIR Insulin should not be used by smokers or those at risk for recidivism.
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http://dx.doi.org/10.1111/j.1365-2125.2007.03041.xDOI Listing
April 2008

Pharmacokinetics and tolerability of duloxetine following oral administration to healthy Chinese subjects.

Clin Pharmacokinet 2007 ;46(9):767-75

Peking University Institute of Mental Health, Beijing, China.

Objectives: The objectives of the study were to characterise the pharmacokinetics and assess the tolerability of duloxetine in healthy Chinese subjects after single and multiple oral 60 mg dosing.

Methods: This was a single-centre, double-blind, randomised, placebo-controlled, single-period study in healthy native Chinese subjects. A total of 32 subjects, 19 men (14 on duloxetine, 5 on placebo) and 13 women (10 on duloxetine, 3 on placebo) between the ages of 20 and 39 years, participated in the study. Duloxetine 60 mg (enteric-coated pellets in a capsule) was given orally once on day 1 and once daily on days 4 to 9. Sequential blood samples were collected over 72 hours after the dose on days 1 and 9, and a predose sample was obtained on days 7 and 8. Duloxetine concentrations in plasma were determined by a validated liquid chromatography-tandem mass spectrometry method. The tolerability evaluation included a physical examination, vital signs, adverse event monitoring and clinical laboratory evaluations.

Results: Duloxetine disposition on oral administration is characterised by a one-compartment pharmacokinetic model. Duloxetine is well absorbed, with a median time of maximum plasma concentration at 6 and 4 hours following single and multiple dosing, respectively. At steady state, the mean apparent oral clearance (CL(ss)/F), mean apparent volume of distribution (V(ss)/F) and mean terminal elimination half-life (t((1/2))) were 86.8 L/h, 1570L and 11 hours, respectively. CL/F and V(ss)/F on single dosing were not statistically significantly different (p > 0.05) compared with multiple dosing. The linearity index, calculated as the ratio of the area under the plasma concentration-time curve (AUC) during the dosing interval tau at steady state (AUC(tau)(,ss)) to the AUC from time zero to infinity after single dosing (AUC(infinity,single dose)) was 1.15 (coefficient of variation 35.7%). The accumulation in duloxetine exposure was estimated to be 50% on multiple dosing compared with single dosing, consistent with the t((1/2)) and dosing interval (24 hours). The pharmacokinetic parameters of duloxetine in Chinese subjects were not statistically significantly different from those reported previously in Caucasian and Japanese subjects. There were no clinically significant adverse events, abnormal safety laboratory data or vital sign changes reported.

Conclusion: Duloxetine pharmacokinetics in healthy Chinese subjects given a 60 mg once-daily dosing regimen were well characterised and consistent with known duloxetine pharmacokinetics in healthy Caucasian and Japanese subjects. Both single dosing and multiple once-daily dosing of duloxetine 60 mg were well tolerated by healthy Chinese subjects in this study.
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http://dx.doi.org/10.2165/00003088-200746090-00004DOI Listing
November 2007

Atomoxetine pharmacokinetics in healthy Chinese subjects and effect of the CYP2D6*10 allele.

Br J Clin Pharmacol 2007 Oct 4;64(4):445-9. Epub 2007 Jul 4.

Department of Pharmacy, Peking University First Hospital, Beijing, PR China.

Aims: To characterize atomoxetine pharmacokinetics, explore the effect of the homozygous CYP2D6*10 genotype on atomoxetine pharmacokinetics and evaluate the tolerability of atomoxetine, in healthy Chinese subjects.

Methods: Twenty-four subjects, all CYP2D6 extensive metabolizers (EM), were randomized to receive atomoxetine (40 mg qd for 3 days, then 80 mg qd for 7 days) or matching placebo (2 : 1 ratio) in a double-blind fashion. Atomoxetine serum concentrations were measured following single (40 mg) and multiple (80 mg) doses. Adverse events, clinical safety laboratory data and vital signs were assessed during the study.

Results: Atomoxetine was rapidly absorbed with median time to maximum serum concentrations of approximately 1.5 h after single and multiple doses. Atomoxetine concentrations appeared to decrease monoexponentially with a mean apparent terminal half-life (t(1/2)) of approximately 4 h. The apparent clearance, apparent volume of distribution and t(1/2) following single and multiple doses were similar, suggesting linear pharmacokinetics with respect to time. Homozygous CYP2D6*10 subjects had 50% lower clearances compared with other EM subjects, resulting in twofold higher mean exposures. No clinically significant changes or abnormalities were noted in laboratory data and vital signs.

Conclusions: The pharmacokinetics of atomoxetine in healthy Chinese subjects appears comparable to other ethnic populations. Multiple dosing of 80 mg qd atomoxetine was well tolerated in this study.
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http://dx.doi.org/10.1111/j.1365-2125.2007.02912.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2048549PMC
October 2007

Duloxetine pharmacokinetics are similar in Japanese and Caucasian subjects.

Br J Clin Pharmacol 2007 Mar 12;63(3):310-4. Epub 2006 Sep 12.

Lilly-NUS Centre for Clinical Pharmacology, National University of Singapore, Singapore.

Aims: To compare single- and multiple-dose duloxetine pharmacokinetics between healthy Japanese and Caucasians.

Methods: Twenty-four subjects of each race were given single oral doses of duloxetine (20, 40 and 60 mg) in a randomized, double-blind study. Another 20 subjects of each race received 20, 40 mg or placebo (2 : 2 : 1) twice-daily for 5 days.

Results: Following single doses, the mean duloxetine C(max) and AUC were approximately 20% greater in Japanese. This difference could be explained by the 15% lower average body weight in Japanese. Similar results were observed following multiple dosing.

Conclusion: Duloxetine pharmacokinetics are not meaningfully different between Japanese and Caucasians.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2000724PMC
http://dx.doi.org/10.1111/j.1365-2125.2006.02770.xDOI Listing
March 2007

Identifying pharmacodynamic protein markers of centrally active drugs in humans: a pilot study in a novel clinical model.

J Proteome Res 2007 Mar 23;6(3):955-66. Epub 2007 Jan 23.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.

Recognizing specific protein changes in response to drug administration in humans has the potential for significant utility in clinical research. In spite of this, many methodological and practical questions related to assessing such changes are unanswered. We conducted a series of clinical studies to assess the feasibility of measuring changes in proteins related to drug administration using a mass-spectrometry proteomics technique capable of quantifying hundreds of proteins simultaneously in cerebrospinal fluid (CSF) and plasma. Initially, the normal variability of proteins in these compartments was characterized in 16 healthy volunteers over a 2-week period. Drug-associated changes were subsequently assessed in the plasma and CSF proteomes of 11 subjects given atomoxetine, which served as a selective, centrally active probe to test the model. Protein levels in the CSF and plasma were unchanged between visits in the normal variability study. In contrast, statistically significant changes were detected in the CSF protein pattern after drug treatment. These studies suggest that identification of changes in the CSF proteome associated with the administration of centrally active drugs is feasible, and may be of value in the development of new drugs, as well as broader clinical research.
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http://dx.doi.org/10.1021/pr0603710DOI Listing
March 2007

L-5-Hydroxytryptophan augments the neuroendocrine response to a SSRI.

Psychoneuroendocrinology 2006 May 27;31(4):473-84. Epub 2005 Dec 27.

Lilly-NUS Centre for Clinical Pharmacology, Level 6, Clinical Research Centre (MD11), National University of Singapore, 10 Medical Drive, Singapore, Singapore 117597.

The objective of the study was to assess l-5-hydroxytryptophan's (l-5HTP) augmentation effect on the neuroendocrine response to a SSRI (citalopram). A neuroendocrine challenge study was conducted in healthy Asian male subjects. The neuroendocrine response to oral citalopram and l-5HTP was measured primarily as the prolactin and cortisol area under the response curve (or AUC). The study comprised 2 studies: Study 1. A double blind, randomised dose ranging study was conducted with l-5HTP (50-200 mg) to explore the prolactin and/or cortisol dose response and select a dose that provided a threshold neuroendocrine response. Study 2. A randomized comparison of citalopram 20 vs 40 mg was used to assess the effect of these doses on prolactin and cortisol. Based on the results of the dose response assessments with l-5HTP and cortisol, 200 mg l-5HTP was subsequently used in Study 2 to explore the augmentation of the neuroendocrine response to 20 mg citalopram. Citalopram, but not l-5HTP, increased prolactin AUC(0-3h) while 5HTP and citalopram increased cortisol AUC(0-3h). A 200 mg dose of l-5HTP significantly augmented the prolactin and cortisol response AUC(0-3h) to 20mg oral citalopram. The results of the study suggest that an augmented neuroendocrine challenge may be a suitable marker to demonstrate increased 5-HT-mediated responses when exploring novel agents as improved SSRIs.
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http://dx.doi.org/10.1016/j.psyneuen.2005.11.005DOI Listing
May 2006

Effect of duloxetine on tolterodine pharmacokinetics in healthy volunteers.

Br J Clin Pharmacol 2004 May;57(5):652-6

Lilly NUS Centre for Clinical Pharmacology, National University of Singapore, Singapore.

Aim: To investigate the effect of duloxetine on the pharmacokinetics and tolerability of tolterodine and its active 5-hydroxymethyl metabolite (5-HM).

Methods: Sixteen healthy subjects received two 5-day treatment regimens in a randomized, double-blinded, crossover fashion: tolterodine (2 mg, BID) + duloxetine (40 mg, BID), tolterodine (2 mg, BID) + duloxetine placebo (BID). Plasma concentrations of tolterodine and 5-HM were measured on day 5. Adverse events, clinical safety laboratory data and vital signs were assessed during the study.

Results: Duloxetine increased the AUC(tau,ss) of tolterodine by 71%[geometric mean, 95% confidence interval (CI) 31, 123], and its C(max,ss) by 64% (CI 30, 106), and prolonged its t(1/2) by 14% (CI 1, 28). Duloxetine did not affect the plasma concentrations or t(1/2) of 5-HM. Laboratory data and vital signs did not reveal any clinically significant changes or abnormalities.

Conclusions: Duloxetine exhibited minor inhibitory effects on the pharmacokinetics of tolterodine but not 5-HM. Coadministration of these drugs was well tolerated and demonstrated no significant safety findings in the studied population. These findings suggest that there should not be a need for routine adjustment of tolterodine dosage in the presence of duloxetine.
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http://dx.doi.org/10.1111/j.1365-2125.2004.02068.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884503PMC
May 2004

Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers.

Clin Pharmacol Ther 2003 Mar;73(3):170-7

Lilly Laboratory for Clinical Research, Indiana University Hospital and Outpatient Center, 550 N. University Road, Indianapolis, IN 46202-5250, USA.

Background And Objectives: Duloxetine, a potent dual reuptake inhibitor of serotonin and norepinephrine currently undergoing clinical investigation for treatment of depression and stress urinary incontinence, has the potential to act as both a substrate and an inhibitor of cytochrome P4502D6 (CYP2D6). Our objectives were to determine the effect of duloxetine on the pharmacokinetics of desipramine, a tricyclic antidepressant metabolized by CYP2D6 (study 1), and the effect of paroxetine, a potent CYP2D6 inhibitor, on duloxetine pharmacokinetics (study 2).

Methods: Subjects were healthy men and women between 21 and 63 years old. All subjects were genotypically CYP2D6 extensive metabolizers. In study 1, 50 mg of desipramine was administered as a single dose alone and in the presence of steady-state duloxetine 60 mg twice daily. In study 2, steady-state pharmacokinetics of duloxetine 40 mg once daily were determined in the presence and absence of steady-state paroxetine 20 mg once daily.

Results: Duloxetine increased the maximum plasma concentration of desipramine 1.7-fold and the area under the concentration-time curve 2.9-fold. Paroxetine increased the maximum plasma concentration of duloxetine and the area under the concentration-time curve at steady state 1.6-fold. Reports of adverse events were similar whether duloxetine was administered alone or in combination with desipramine or paroxetine.

Conclusion: Duloxetine 60 mg twice daily is a moderately potent CYP2D6 inhibitor, intermediate between paroxetine and sertraline. The potent CYP2D6 inhibitor paroxetine has a moderate effect on duloxetine concentrations. The results of these 2 studies suggest that caution should be used when CYP2D6 substrates and inhibitors are coadministered with duloxetine.
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http://dx.doi.org/10.1067/mcp.2003.28DOI Listing
March 2003
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