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Health plan claims may provide complete longitudinal data for timely, real-world population-level COVID-19 assessment. However, these data often lack laboratory results, the standard for COVID-19 diagnosis.We assessed the validity of ICD-10-CM diagnosis codes for identifying patients hospitalized with COVID-19 in U.S. claims databases, compared to linked laboratory results, among six Food and Drug Administration Sentinel System data partners (two large national insurers, four integrated delivery systems) from February 20-October 17, 2020. We identified patients hospitalized with COVID-19 according to five ICD-10-CM diagnosis code-based algorithms, which included combinations of codes U07.1, B97.29, general coronavirus codes, and diagnosis codes for severe symptoms. We calculated the positive predictive value (PPV) and sensitivity of each algorithm relative to laboratory test results. We stratified results by data source type and across three time periods: February 20-March 31 (Time A), April 1-30 (Time B), May 1-October 17 (Time C).The five algorithms identified between 34 806 and 47 293 patients across the study periods; 23% with known laboratory results contributed to PPV calculations. PPVs were high and similar across algorithms. PPV of U07.1 alone was stable around 93% for integrated delivery systems, but declined over time from 93% to 70% among national insurers. Overall PPV of U07.1 across all data partners was 94.1% (95% CI, 92.3%-95.5%) in Time A and 81.2% (95% CI, 80.1%-82.2%) in Time C. Sensitivity was consistent across algorithms and over time, at 94.9% (95% CI, 94.2%-95.5%).Our results support the use of code U07.1 to identify hospitalized COVID-19 patients in U.S. claims data.

Background Recent suggestions of therapeutic inequivalence of brand and generic sertraline have raised concerns about disproportionately higher adverse events among generic users. Objective To assess the impact of confounding in a comparison of the risks of worsening depression and intentional self-harm (ISH) between users of brand name sertraline and its pharmaceutically equivalent authorized generic (AG). Methods Using a retrospective new-user cohort design, we identified patients with a diagnosis code for depression aged ≥12 years who were continuously enrolled in a Sentinel Data Partner health plan for ≥180 days before their first sertraline dispensing between June 30, 2006 and September 30, 2015. New use was defined as no evidence of sertraline dispensing in the 180 days before index date. We matched each brand name user to up to 10 AG users using propensity scores (PS) and conducted case-centered logistic regression to assess the risks of hospitalized depression and ISH. Results Before PS matching, brand name users were significantly less likely to be hospitalized for depression [Hazard Ratio (HR) = 0.70 (95% confidence interval (CI): 0.53-0.94)]. However, in the matched analysis, we observed no statistical difference between brand and AG users [HR = 0.84 (95% CI: 0.59-1.21)]. The risk of ISH did not significantly differ between the exposure groups in unmatched (HR = 0.99 (95% CI: 0.60-1.62) and matched analyses [HR = 0.91 (95% CI: 0.49-1.70). Conclusion In depressed patients receiving brand versus AG sertraline, patient characteristics confounded the association with hospitalization. Baseline differences were ameliorated by PS matching resulting in no statistical difference between brand and AG sertraline users.

Background We assessed the ability to identify key data relevant to influenza and other respiratory virus surveillance in a large-scale US-based hospital electronic medical record (EMR) dataset using seasonal influenza as a use case. We describe characteristics and outcomes of hospitalized influenza cases across three seasons. Methods We identified patients with an influenza diagnosis between March 2017 and March 2020 in 140 US hospitals as part of the US FDA's Sentinel System. We calculated descriptive statistics on the presence of high-risk conditions, influenza antiviral administrations, and severity endpoints. Results Among 5.1 million hospitalizations, we identified 29,520 hospitalizations with an influenza diagnosis; 64% were treated with an influenza antiviral within 2 days of admission, and 25% were treated >2 days after admission. Patients treated >2 days after admission had more comorbidities than patients treated within 2 days of admission. Patients never treated during hospitalization had more documentation of cardiovascular and other diseases than treated patients. We observed more severe endpoints in patients never treated (death = 3%, mechanical ventilation [MV] = 9%, intensive care unit [ICU] = 26%) or patients treated >2 days after admission (death = 2%, MV = 14%, ICU = 32%) than in patients treated earlier (treated on admission: death = 1%, MV = 5%, ICU = 23%, treated within 2 days of admission: death = 1%, MV = 7%, ICU = 27%). Conclusions We identified important trends in influenza severity related to treatment timing in a large inpatient dataset, laying the groundwork for the use of this and other inpatient EMR data for influenza and other respiratory virus surveillance.

Objectives To better understand patients' and pharmacists' preferences for and experiences with changes in pill appearance (size, shape, color, and markings). Study design Cross-sectional. Methods We conducted independent national surveys of patients 50 years and older taking generic drugs for depression, diabetes, epilepsy, HIV, hyperlipidemia, or hypertension and of licensed pharmacists practicing in chain, franchise, or independent pharmacies. Responses were collected between January and April 2016. Results Of 1000 patient respondents (30% response rate), most reported experiencing changes in pill appearance (51%) and preferred to be notified about them (82%), but less than half recalled being notified (verbally: 36%; via sticker: 45%). Among patients who reported experiencing a change, 12% reported stopping their medication or using it less frequently. Of 710 pharmacist respondents (33% response rate), many reported changes in pill appearance occurring frequently in their pharmacies (47% reported that changes occurred 6 or more times per month) and more than three-fourths reported notifying patients about them often (verbally: 88%; via sticker: 77%). Conclusions Our findings reveal opportunities to improve patients' experiences with pill appearance changes through better notification practices and patient education.

OBJECTIVE To estimate real-world off-label use of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with type 1 diabetes, estimate rates of diabetic ketoacidosis (DKA), and compare them with DKA rates observed in sotagliflozin clinical trials. RESEARCH DESIGN AND METHODS We identified initiators of SGLT2 inhibitors in the Sentinel System from March 2013 to June 2018, determined the prevalence of type 1 diabetes using a narrow and a broad definition, and measured rates of DKA using administrative claims data. Standardized incidence ratios (SIRs) were calculated using age- and sex-specific follow-up time in Sentinel and age- and sex-specific DKA rates from sotagliflozin trials 309, 310, and 312. RESULTS Among 475,527 initiators of SGLT2 inhibitors, 0.50% and 0.92% met narrow and broad criteria for type 1 diabetes, respectively. Rates of DKA in the narrow and broad groups were 7.1/100 person-years and 4.3/100 person-years, respectively. Among patients who met narrow criteria for type 1 diabetes, rates of DKA were highest for patients aged 25–44 years, especially females aged 25–44 years (19.7/100 person-years). More DKA events were observed during off-label use of SGLT2 inhibitors in Sentinel than would be expected based on sotagliflozin clinical trials (SIR = 1.83; 95% CI 1.45–2.28). CONCLUSIONS Real-world off-label use of SGLT2 inhibitors among patients with type 1 diabetes accounted for a small proportion of overall SGLT2 inhibitor use. However, the risk for DKA during off-label use was notable, especially among young, female patients. Although real-word rates of DKA exceeded the expectation based on clinical trials, results should be interpreted with caution due to differences in study methods, patient samples, and study drugs.

Objective:We describe the baseline characteristics and complications of individuals with influenza in the US FDA’s Sentinel System by antiviral treatment timing.Design:Retrospective cohort design.Patients:Individuals aged ≥6 months with outpatient diagnoses of influenza in June 2014–July 2017, 3 influenza seasons.Methods:We identified the comorbidities, vaccination history, influenza testing, and outpatient antiviral dispensings of individuals with influenza using administrative claims data from 13 data partners including the Centers for Medicare and Medicaid Services, integrated delivery systems, and commercial health plans. We assessed complications within 30 days: hospitalization, oxygen use, mechanical ventilation, critical care, ECMO, and death.Results:There were 1,090,333 influenza diagnoses in 2014–2015; 1,005,240 in 2016–2017; and 578,548 in 2017–2018. Between 49% and 55% of patients were dispensed outpatient treatment within 5 days. In all periods >80% of treated individuals received treatment on the day of diagnosis. Those treated on days 1–5 after diagnosis had higher prevalences of diabetes, chronic obstructive pulmonary disease, asthma, and obesity compared to those treated on the day of diagnosis or not treated at all. They also had higher rates of hospitalization, oxygen use, and critical care. In 2014–2015, among those aged ≥65 years, the rates of hospitalization were 45 per 1,000 diagnoses among those treated on day 0; 74 per 1,000 among those treated on days 1–5; and 50 per 1,000 among those who were untreated.Conclusions:In a large, national analysis, approximately half of people diagnosed with influenza in the outpatient setting were treated with antiviral medications. Delays in outpatient dispensed treatment were associated with higher prevalence of comorbidities and higher rates of complication.

Observational studies of oseltamivir use and influenza complications could suffer from residual confounding. Using negative control risk periods and a negative control outcome, we examined confounding control in a health-insurance-claims–based study of oseltamivir and influenza complications (pneumonia, all-cause hospitalization, and dispensing of an antibiotic). Within the Food and Drug Administration’s Sentinel System, we identified individuals aged ≥18 years who initiated oseltamivir use on the influenza diagnosis date versus those who did not, during 3 influenza seasons (2014–2017). We evaluated primary outcomes within the following 1–30 days (the primary risk period) and 61–90 days (the negative control period) and nonvertebral fractures (the negative control outcome) within days 1–30. We estimated propensity-score–matched risk ratios (RRs) per season. During the 2014–2015 influenza season, oseltamivir use was associated with a reduction in the risk of pneumonia (RR = 0.72, 95% confidence interval (CI): 0.70, 0.75) and all-cause hospitalization (RR = 0.54, 95% CI: 0.53, 0.55) in days 1–30. During days 61–90, estimates were near-null for pneumonia (RR = 1.04, 95% CI: 0.95, 1.15) and hospitalization (RR = 0.94, 95% CI: 0.91, 0.98) but slightly increased for antibiotic dispensing (RR = 1.14, 95% CI: 1.08, 1.21). The RR for fractures was near-null (RR = 1.09, 95% CI: 0.99, 1.20). Estimates for the 2016–2017 influenza season were comparable, while the 2015–2016 season had conflicting results. Our study suggests minimal residual confounding for specific outcomes, but results differed by season.

Purpose Lymphoma is a health outcome of interest for drug safety studies. Studies using administrative claims data require the accurate identification of lymphoma cases. We developed and validated an International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM)-based algorithm to identify lymphoma in healthcare claims data. Methods We developed a three-component algorithm to identify patients aged ≥15 years who were newly diagnosed with Hodgkin (HL) or non-Hodgkin (NHL) lymphoma from January 2016 through July 2018 among members of four Data Partners within the FDA's Sentinel System. The algorithm identified potential cases as patients with ≥2 ICD-10-CM lymphoma diagnosis codes on different dates within 183 days; ≥1 procedure code for a diagnostic procedure (e.g. biopsy, flow cytometry) and ≥1 procedure code for a relevant imaging study within 90 days of the first lymphoma diagnosis code. Cases identified by the algorithm were adjudicated via chart review and a positive predictive value (PPV) was calculated. Results We identified 8,723 potential lymphoma cases via the algorithm and randomly sampled 213 for validation. We retrieved 138 charts (65%) and adjudicated 134 (63%). The overall PPV was 77% (95% Confidence Interval: 69-84%). Most cases also had subtype information available, with 88% of cases identified as NHL and 11% as HL. Conclusions Seventy-seven percent of lymphoma cases identified by an algorithm based on ICD-10-CM diagnosis and procedure codes and applied to claims data were true cases. This novel algorithm represents an efficient, cost-effective way to target an important health outcome of interest for large-scale drug safety and public health surveillance studies.

ImportanceThe incidence of arterial thromboembolism and venous thromboembolism in persons with COVID-19 remains unclear.ObjectiveTo measure the 90-day risk of arterial thromboembolism and venous thromboembolism in patients hospitalized with COVID-19 before or during COVID-19 vaccine availability vs patients hospitalized with influenza.Design, Setting, and ParticipantsRetrospective cohort study of 41 443 patients hospitalized with COVID-19 before vaccine availability (April-November 2020), 44 194 patients hospitalized with COVID-19 during vaccine availability (December 2020-May 2021), and 8269 patients hospitalized with influenza (October 2018-April 2019) in the US Food and Drug Administration Sentinel System (data from 2 national health insurers and 4 regional integrated health systems).ExposuresCOVID-19 or influenza (identified by hospital diagnosis or nucleic acid test).Main Outcomes and MeasuresHospital diagnosis of arterial thromboembolism (acute myocardial infarction or ischemic stroke) and venous thromboembolism (deep vein thrombosis or pulmonary embolism) within 90 days. Outcomes were ascertained through July 2019 for patients with influenza and through August 2021 for patients with COVID-19. Propensity scores with fine stratification were developed to account for differences between the influenza and COVID-19 cohorts. Weighted Cox regression was used to estimate the adjusted hazard ratios (HRs) for outcomes during each COVID-19 vaccine availability period vs the influenza period.ResultsA total of 85 637 patients with COVID-19 (mean age, 72 [SD, 13.0] years; 50.5% were male) and 8269 with influenza (mean age, 72 [SD, 13.3] years; 45.0% were male) were included. The 90-day absolute risk of arterial thromboembolism was 14.4% (95% CI, 13.6%-15.2%) in patients with influenza vs 15.8% (95% CI, 15.5%-16.2%) in patients with COVID-19 before vaccine availability (risk difference, 1.4% [95% CI, 1.0%-2.3%]) and 16.3% (95% CI, 16.0%-16.6%) in patients with COVID-19 during vaccine availability (risk difference, 1.9% [95% CI, 1.1%-2.7%]). Compared with patients with influenza, the risk of arterial thromboembolism was not significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.04 [95% CI, 0.97-1.11]) or during vaccine availability (adjusted HR, 1.07 [95% CI, 1.00-1.14]). The 90-day absolute risk of venous thromboembolism was 5.3% (95% CI, 4.9%-5.8%) in patients with influenza vs 9.5% (95% CI, 9.2%-9.7%) in patients with COVID-19 before vaccine availability (risk difference, 4.1% [95% CI, 3.6%-4.7%]) and 10.9% (95% CI, 10.6%-11.1%) in patients with COVID-19 during vaccine availability (risk difference, 5.5% [95% CI, 5.0%-6.1%]). Compared with patients with influenza, the risk of venous thromboembolism was significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.60 [95% CI, 1.43-1.79]) and during vaccine availability (adjusted HR, 1.89 [95% CI, 1.68-2.12]).Conclusions and RelevanceBased on data from a US public health surveillance system, hospitalization with COVID-19 before and during vaccine availability, vs hospitalization with influenza in 2018-2019, was significantly associated with a higher risk of venous thromboembolism within 90 days, but there was no significant difference in the risk of arterial thromboembolism within 90 days.

Background Certain medications may increase the risk of death or death from specific causes (eg, sudden cardiac death), but these risks may not be identified in premarket randomized trials. Having the capacity to examine death in postmarket safety surveillance activities is important to the US Food and Drug Administration’s (FDA) mission to protect public health. Distributed networks of electronic health plan databases used by the FDA to conduct multicenter research or medical product safety surveillance studies often do not systematically include death or cause-of-death information. Objective This study aims to develop reusable, generalizable methods for linking multiple health plan databases with the Centers for Disease Control and Prevention’s National Death Index Plus (NDI+) data. Methods We will develop efficient administrative workflows to facilitate multicenter institutional review board (IRB) review and approval within a distributed network of 6 health plans. The study will create a distributed NDI+ linkage process that avoids sharing of identifiable patient information between health plans or with a central coordinating center. We will develop standardized criteria for selecting and retaining NDI+ matches and methods for harmonizing linked information across multiple health plans. We will test our processes within a use case comprising users and nonusers of antiarrhythmic medications. Results We will use the linked health plan and NDI+ data sets to estimate the incidences and incidence rates of mortality and specific causes of death within the study use case and compare the results with reported estimates. These comparisons provide an opportunity to assess the performance of the developed NDI+ linkage approach and lessons for future studies requiring NDI+ linkage in distributed database settings. This study is approved by the IRB at Harvard Pilgrim Health Care in Boston, MA. Results will be presented to the FDA at academic conferences and published in peer-reviewed journals. Conclusions This study will develop and test a reusable distributed NDI+ linkage approach with the goal of providing tested NDI+ linkage methods for use in future studies within distributed data networks. Having standardized and reusable methods for systematically obtaining death and cause-of-death information from NDI+ would enhance the FDA’s ability to assess mortality-related safety questions in the postmarket, real-world setting. International Registered Report Identifier (IRRID) DERR1-10.2196/21811

This cohort study compares the effectiveness of generic vs brand-name levothyroxine in achieving and maintaining normal thyrotropin levels among new users., Key Points Question What is the comparative effectiveness of generic vs brand-name levothyroxine in achieving normal thyrotropin levels? Findings In a cohort study of 17 598 patients from a national administrative claims database, a similar proportion of generic vs brand-name levothyroxine users achieved target thyrotropin levels. Meaning These findings suggest that initiation of generic or brand levothyroxine for mild thyroid dysfunction is associated with similar rates of achieving target laboratory outcomes., Importance Whether the use of generic vs brand levothyroxine affects thyrotropin levels remains unclear. Objective To compare the effectiveness of generic vs brand levothyroxine in achieving and maintaining normal thyrotropin levels among new users. Design, Setting, and Participants This retrospective, 1:1 propensity score–matched longitudinal cohort study used the OptumLabs Data Warehouse administrative claims database linked to laboratory results from commercially insured and Medicare Advantage enrollees throughout the United States. Eligible patients were adults (aged ≥18 years) with thyrotropin levels ranging from 4.5 to 19.9 mIU/L who initiated use of generic or brand-name levothyroxine from January 1, 2008, to October 1, 2017. Data were analyzed from August 13, 2018, to October 25, 2019. Exposure Patients received generic or brand-name levothyroxine. Main Outcomes and Measures Proportion of patients with normal vs markedly abnormal thyrotropin levels (10 mIU/L) within 3 months and with stable thyrotropin levels within 3 months after the thyrotropin value fell into the normal range. Results A total of 17 598 patients were included (69.0% female; 74.0% White; mean [SD] age, 55.1 [16.0] years), of whom 15 299 filled generic and 2299 filled brand-name levothyroxine prescriptions during the study period. Among 4570 propensity score–matched patients (mean [SD] age, 50.3 [13.8] years; 3457 [75.6%] female; 3510 [76.8%] White), the proportion with normal thyrotropin levels within 3 months of filling levothyroxine prescriptions was similar for patients who received generic vs brand-name levothyroxine (1722 [75.4%; 95% CI, 71.9%-79.0%] vs 1757 [76.9%; 95% CI, 73.4%-80.6%]; P = .23), as was the proportion with markedly abnormal levels (94 [4.1%; 95% CI, 3.4%-5.0%] vs 88 [3.9%; 95% CI, 3.1%-4.7%]; P = .65). Among 1034 propensity score–matched patients who achieved a normal thyrotropin value within 3 months of initiation of levothyroxine, the proportion maintaining subsequent normal thyrotropin levels during the next 3 months was similar for patients receiving generic vs brand-name levothyroxine (427 [82.6%] vs 433 [83.8%]; P = .62). Conclusions and Relevance Initiation of generic vs brand-name levothyroxine formulations was associated with similar rates of normal and stable thyrotropin levels. These results suggest that generic levothyroxine as initial therapy for mild thyroid dysfunction is as effective as brand-name levothyroxine.

Context Generic drugs account for 9 out of 10 prescriptions dispensed in the United States but for a lower proportion of commonly prescribed thyroid hormone replacement therapies. Objective Characterize temporal patterns of generic and brand-name thyroid hormone drug use, including patient and prescriber characteristics associated with brand-name use. Design and setting Cross-sectional longitudinal analysis of national data from a large administrative claims database from January 2007 through December 2016. Patients Adults with insurance coverage through commercial, Medicare Advantage, and Medicare Part D health plans. Main outcome measures Generic and brand-name thyroid hormone drug use. Results From 2007 to 2016, the annual number of thyroid hormone treatment pharmacy fills increased from 8,905,836 in 2007 to 11,613,923 in 2016, 73.6% of which were for generic levothyroxine, 23.4% for brand-name levothyroxine, and the remaining for other formulations. Dispensing of generic thyroid hormone drugs increased from 59.8% in 2007 to 84.9% in 2016 and was consistently higher among Medicare Advantage and Medicare Part D when compared with the commercial beneficiary population. For all three beneficiary populations, use of brand-name products was less common among older adults and more common among women and those receiving prescriptions from endocrinologists and was more common among those of white race and with greater household income for the Medicare Advantage and commercial beneficiary populations (P Conclusions Brand-name thyroid hormone product use declined from 2007 to 2016 among three large, national insurer beneficiary populations. Although certain patient characteristics were associated with brand-name use, prescriber specialty was the strongest predictor.

BACKGROUND: Generic versions of a drug can vary in appearance, which can impact adherence. OBJECTIVE: To assess the preferences, perceptions, and responses of patients who experienced a change in the appearance of a generic medication. DESIGN: Cross-sectional survey of patients from a large commercial health plan. PARTICIPANTS: Adults receiving generic versions of lisinopril, fluoxetine, lamotrigine, or simvastatin who experienced a change in the color or shape of their pills between March 2014 and November 2015. MAIN MEASURES: Likert-scale responses to questions concerning perceptions of generic drug safety and effectiveness, reliance on and preferences for pill appearance, and responses to pill appearance changes. Multivariable logistic regression-modeled predictors of seeking advice and adjusting use following a pill appearance change. KEY RESULTS: Of 814 respondents (response rate = 41%), 72% relied on pill appearance to ensure they took the correct medication. A similar percentage wanted their pills to remain the same color (72%), shape (71%), and size (75%) upon refill, but 58% would not have paid a $1 premium on a $5 co-pay to ensure such consistency. Most respondents (86%) wanted their pharmacists to notify them about pill appearance changes, but only 37% recalled such notification; 21% thought they received the wrong medication, and 8% adjusted medication use. Younger respondents (18–33 vs. 50–57 years) were more likely to seek advice (odds ratio [OR] = 1.91; 95% confidence interval [CI],1.02–3.59), and respondents with lower household income ( $100,000) were more likely to adjust medication use (OR = 3.40; 95% CI,1.09–10.67). CONCLUSIONS: Requiring uniform pill appearance may help increase adherence but presents challenges. Standardized pharmacy notification and education policies may be a more feasible short-term solution. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-018-4791-1) contains supplementary material, which is available to authorized users.

The transplant community is divided regarding whether substitution with generic immunosuppressants is appropriate for organ transplant recipients. We estimated the rate of uptake over time of generic immunosuppressants using US Medicare Part D Prescription Drug Event (PDE) and Colorado pharmacy claims (including both Part D and non-Part D) data from 2008 to 2013. Data from 26 070 kidney, 15 548 liver, and 6685 heart recipients from Part D, and 1138 kidney and 389 liver recipients from Colorado were analyzed. The proportions of patients with PDEs or claims for generic and brand-name tacrolimus or mycophenolate mofetil were calculated over time by transplanted organ and drug. Among Part D kidney, liver, and heart beneficiaries, the proportion dispensed generic tacrolimus reached 50%−56% at 1 year after first generic approval and 78%−81% by December 2013. The proportion dispensed generic mycophenolate mofetil reached 70%−73% at 1 year after generic market entry and 88%−90% by December 2013. There was wide interstate variability in generic uptake, with faster uptake in Colorado compared with most other states. Overall, generic substitution for tacrolimus and mycophenolate mofetil for organ transplant recipients increased rapidly following first availability, and utilization of generic immunosuppressants exceeded that of brand-name products within a year of market entry.

Background: Despite the availability of generic levothyroxine products for more than a decade, uptake of these products is poor. Objective: We sought to evaluate determinants of generic prescribing of levothyroxine. Methods: In a cross-sectional analysis of electronic health records data between 2010 and 2013, we identified adult patients with a levothyroxine prescription from a primary-care physician (PCP) or endocrinologist. We used mixed-effect logistic regression models with random intercepts for prescribing provider to examine predictors of generic levothyroxine prescribing. Models include patient, prescription, and provider fixed-effect covariates. Odds ratios (ORs) and 95% CIs were generated. Between-provider random variation was quantified by the intraclass correlation coefficient (ICC). Results: Study patients (n = 63 838) were clustered among 941 prescribing providers within 25 ambulatory care clinics. The overall prevalence of generic prescribing of levothyroxine was 73%. In the multivariable mixed-effect model, patients were significantly less likely to receive generic levothyroxine from an endocrinologist than a PCP (OR = 0.43; 95% CI = 0.33-0.55; P < 0.001). Women were less likely to receive generic levothyroxine than men from endocrinologists (OR = 0.68; 95% CI = 0.59-0.78; P < 0.001) but not from PCPs. Between-provider variation in generic prescribing was 18.3% in the absence of fixed-effect covariates and could be explained marginally by patient, prescription, and provider factors (ICC = 15.9%). Conclusions: Generic levothyroxine prescribing differed by PCPs and endocrinologists. Residual variation in generic prescribing, after accounting for measurable factors, indicates the need for provider interventions or patient education aimed at improving levothyroxine generic uptake.

tudy Objective Generic drugs contain identical active ingredients as their corresponding brand drugs and are pharmaceutically equivalent and bioequivalent, whereas authorized generic drugs contain both identical active and inactive ingredients as their corresponding brand drugs but are marketed as generics. The objective of this study was to compare generic-to-brand switchback rates between generic and authorized generic drugs. Design Retrospective cohort study. Data Source Claims and electronic health record data from a regional United States health care system. Patients The full cohort consisted of 5542 unique patients who received select branded drugs during the 6 months prior to their generic drug market availability (between 1999 and 2014), and then were switched to an authorized generic or generic drug within 30 months of generic drug entry; for these patients, 5929 unique patient-drug combinations (867 with authorized generic drugs and 5062 with generic drugs) were evaluated. Measurements and Main Results Ten drugs with authorized generics and generics marketed between 1999 and 2014 were evaluated. The date of the first generic prescription was considered the index date for each drug, and this date marked the beginning of follow-up to evaluate the occurrence of generic-to-brand switchback patterns over the subsequent 30 months. Switchback rates were compared between patients receiving authorized generics versus those receiving generics using multivariable Cox proportional hazards models, controlling for individual drug effects, age, sex, Charlson comorbidity score, pre-index drug use characteristics, and pre-index health care utilization. Among the 5542 unique patients who switched from brand-to-generic or brand-to–authorized generic, 264 (4.8%) switched back to the brand drug. Overall switchback rates were similar for authorized generics compared with generics (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.65–1.15). The likelihood of switchback was higher for alendronate (HR 1.64, 95% CI 1.20–2.23) and simvastatin (HR 1.81, 95% CI 1.30–2.54) and lower for amlodipine (HR 0.27, 95% CI 0.17–0.42) compared with the other drugs evaluated. Conclusion Overall switchback rates were similar between authorized generic and generic drug users, indirectly supporting similar efficacy and tolerability profiles for brand and generic drugs. Reasons for differences in switchback rates among specific products need to be further explored. This article is protected by copyright. All rights reserved.

BACKGROUND: Some classes of drugs have lower than optimal uptake of generic products. We aimed to understand the determinants of generic drug substitution across classes. METHODS: We conducted a cross-sectional analysis of data from the 2013 MarketScan Commercial Claims and Encounters Database from Truven Health Analytics. We quantified generic substitution rates (GSR) for 26 drug classes, choosing one representative week in November 2013. We used mixed-effects logistic regression to estimate the independent relationship between the determinants of interest and generic substitution for 8 classes with low generic utilization. RESULTS: The GSRs for most classes exceeded 90%, although some were much lower including thyroid hormones (64%), androgens (74%), estrogens (71%), and hydantoin-type anticonvulsants (72%). The determinants of generic substitution varied across classes, albeit with important patterns. Patients using a mail order pharmacy had significantly less generic substitution than patients filling at retail pharmacies for 5 of the 8 studied classes; two additional classes showed no relationship between pharmacy type and generic use. Men relative to women and patients taking more medications were more likely to use generics for most classes. State substitution laws and patient consent laws were largely inconsequential regarding generic substitution. CONCLUSIONS: Policies are needed to support the use of safe, effective and often lower cost generic drugs, when available. Mail order pharmacies, as often required by pharmacy benefits managers, lessen generic use for many classes. These pharmacies may require additional regulatory oversight if this adversely impacts patients.

Generic levothyroxine has been approved and available since 2004 but its substitution remains controversial. Therefore, the objective was to examine patterns of and identify factors associated with initiation and substitution of generic levothyroxine treatment. This was a retrospective observational study, including new users of brand and generic levothyroxine in 2013–2015 Medicare (n = 15,877) or 2011–2012 Medicaid (n = 9390) administrative claim databases. The primary outcomes included (1) generic levothyroxine initiation, and (2) among brand-new users, generic levothyroxine substitution in 12 months. The factors associated with generic levothyroxine initiation and substitution were measured. Among all levothyroxine new users, Medicare beneficiaries had a higher proportion of generic levothyroxine initiation than Medicaid beneficiaries (66.40% vs. 44.04%, respectively). Medicare beneficiaries’ demographic factors, and health service utilizations were associated with generic levothyroxine initiation. Medicaid beneficiaries who were male and residing in the northeast region and rural areas were more likely to initiate generic levothyroxine. Among brand levothyroxine new users, the generic substitution rate was higher in the Medicare than the Medicaid cohort (18.26 vs. 3.88%). Medicare brand levothyroxine new users’ demographic factors and health service utilizations were associated with generic levothyroxine substitution. Medicaid brand levothyroxine new users who were residing in the northeast region, with more prior hospitalization, and initiating a lower dosage of brand levothyroxine, had higher rates of generic substitution. Patient demographic factors and health service utilizations are associated with generic levothyroxine initiation and substitution. Educational outreach programs targeted to increase generic levothyroxine use and prescription savings should be tailored based on different patient populations.

The anticoagulant response to warfarin, a narrow therapeutic index drug, increases with age, which may make older patients susceptible to adverse outcomes resulting from small differences in bioavailability between generic and brand products. Using US Medicare claims linked to electronic medical records from two large hospitals in Boston, we designed a cohort study of ≥ 65-year-old patients. Patients were followed for a composite effectiveness outcome of ischemic stroke or venous thromboembolism, a composite safety outcome, including major hemorrhage, and a 1-year all-cause mortality outcome. After propensity score fine-stratification and weighting to account for > 90 confounders, hazard ratios comparing brand vs. generic warfarin initiators (95% confidence intervals) for the effectiveness, safety, and all-cause mortality outcomes, were 0.97 (0.65-1.46), 0.94 (0.65-1.35), and 0.84 (0.62-1.13), respectively. Results from subgroup analyses of patients with atrial fibrillation, CHADS-VASc score ≥ 3, and HAS-BLED score ≥ 3 were consistent with the primary analysis.

PURPOSE To describe utilization of filgrastim and infliximab, the first two products with biosimilars approved in the United States. METHODS We identified use of filgrastim (reference, tbo-filgrastim, and filgrastim-sndz) and infliximab (reference, infliximab-dyyb, and infliximab-abda) in the Sentinel Distributed Database using Healthcare Common Procedure Coding System (HCPCS) codes and National Drug Codes (NDCs) from January 2015 to August 2018. We calculated the proportion of use by code type and assessed uptake over time. We compared baseline patient characteristics and treatment indications. Among patients with >1 exposure episode, we characterized gaps between episodes. RESULTS Use was identified primarily via HCPCS codes (filgrastim: 86.4%-97.7%; infliximab: 87.8%-100%) although some was identified via NDCs (filgrastim: 2.2%-13.5%; infliximab

We sought to examine rates of clinical outcomes among patients before and after market introduction of generic versions of five drugs approved using product-specific equivalence determinations. We used data from a large national insurer to identify patients who initiated a study (acarbose tablets, salmon calcitonin nasal spray, enoxaparin injection, vancomycin capsules, venlafaxine extended-release tablets) or control drug (nateglinide, glimepiride, alendronate, fondaparinux, metronidazole, sertraline, paroxetine) in each calendar month between 2003 and 2012 and to determine rates of claims-based proxies for lack of effectiveness outcomes following initiation. We used segmented time-series analyses to evaluate level (short-term) and slope (longer-term) changes in outcomes upon introduction of a generic study or control drug. Among study drugs, we observed three increases (one with p

Objective We sought to examine rates of clinical outcomes among patients before and after market introduction of generic versions of five drugs approved using product-specific equivalence determinations.

Background To the extent that outcomes are mediated through negative perceptions of generics (the nocebo effect), observational studies comparing brand-name and generic drugs are susceptible to bias favoring the brand-name drugs. We used authorized generic (AG) products, which are identical in composition and appearance to brand-name products but are marketed as generics, as a control group to address this bias in an evaluation aiming to compare the effectiveness of generic versus brand medications. Methods and findings For commercial health insurance enrollees from the US, administrative claims data were derived from 2 databases: (1) Optum Clinformatics Data Mart (years: 2004–2013) and (2) Truven MarketScan (years: 2003–2015). For a total of 8 drug products, the following groups were compared using a cohort study design: (1) patients switching from brand-name products to AGs versus generics, and patients initiating treatment with AGs versus generics, where AG use proxied brand-name use, addressing negative perception bias, and (2) patients initiating generic versus brand-name products (bias-prone direct comparison) and patients initiating AG versus brand-name products (negative control). Using Cox proportional hazards regression after 1:1 propensity-score matching, we compared a composite cardiovascular endpoint (for amlodipine, amlodipine-benazepril, and quinapril), non-vertebral fracture (for alendronate and calcitonin), psychiatric hospitalization rate (for sertraline and escitalopram), and insulin initiation (for glipizide) between the groups. Inverse variance meta-analytic methods were used to pool adjusted hazard ratios (HRs) for each comparison between the 2 databases. Across 8 products, 2,264,774 matched pairs of patients were included in the comparisons of AGs versus generics. A majority (12 out of 16) of the clinical endpoint estimates showed similar outcomes between AGs and generics. Among the other 4 estimates that did have significantly different outcomes, 3 suggested improved outcomes with generics and 1 favored AGs (patients switching from amlodipine brand-name: HR [95% CI] 0.92 [0.88–0.97]). The comparison between generic and brand-name initiators involved 1,313,161 matched pairs, and no differences in outcomes were noted for alendronate, calcitonin, glipizide, or quinapril. We observed a lower risk of the composite cardiovascular endpoint with generics versus brand-name products for amlodipine and amlodipine-benazepril (HR [95% CI]: 0.91 [0.84–0.99] and 0.84 [0.76–0.94], respectively). For escitalopram and sertraline, we observed higher rates of psychiatric hospitalizations with generics (HR [95% CI]: 1.05 [1.01–1.10] and 1.07 [1.01–1.14], respectively). The negative control comparisons also indicated potentially higher rates of similar magnitude with AG compared to brand-name initiation for escitalopram and sertraline (HR [95% CI]: 1.06 [0.98–1.13] and 1.11 [1.05–1.18], respectively), suggesting that the differences observed between brand and generic users in these outcomes are likely explained by either residual confounding or generic perception bias. Limitations of this study include potential residual confounding due to the unavailability of certain clinical parameters in administrative claims data and the inability to evaluate surrogate outcomes, such as immediate changes in blood pressure, upon switching from brand products to generics. Conclusions In this study, we observed that use of generics was associated with comparable clinical outcomes to use of brand-name products. These results could help in promoting educational interventions aimed at increasing patient and provider confidence in the ability of generic medicines to manage chronic diseases., Rishi Desai & colleagues use data from two large US commercial insurance databases to compare brand-name versus authorised generic drugs and negative perception bias., Author summary Why was this study done? Empirical research investigating comparative outcomes of generic versus brand-name drug use in routine-care patient populations is limited. Many patients and providers perceive generics to be less effective and less safe than their brand-name counterparts. To the extent that outcomes are mediated through negative perceptions (the nocebo effect), observational studies comparing brand-name and generic drugs are susceptible to bias favoring the brand-name drugs. This study was done to assess the comparative effectiveness of generic versus brand-name drugs, while addressing the potential for perception bias. What did the researchers do and find? The authors used data from 2 large US commercial insurance databases to assess authorized generics, which are chemically identical to and share the same appearance as brand-name products, as proxies for brand-name drug use to account for potential bias due to negative perceptions towards generics in comparing the effectiveness of 8 brand-name versus generic products. After analyzing data from more than 3.5 million patients, the authors observed that use of generics provided comparable clinical outcomes to those of the brand-name products for chronic conditions including diabetes (glipizide), hypertension (amlodipine, amlodipine-benazepril, and quinapril), osteoporosis (alendronate and calcitonin salmon), and depression and anxiety (escitalopram and sertraline). What do these findings mean? These results may guide the development of educational interventions to address physicians’ and patients’ negative perceptions of generics and to increase awareness regarding the equivalence of generic and brand-name drugs.

Methodologic research evaluating confounding due to socioeconomic status (SES) in observational studies of medications is limited. We identified 7,109 patients who initiated brand or generic atorvastatin from Medicare claims (2011-2013) linked to electronic medical records and census data. We created a propensity score (PS) containing only claims-based covariates and augmented it with additional claims-based proxies for SES, ZIP code, and block group level SES. Cox models with PS fine-stratification and weighting were used to compare rates of a cardiovascular end point and emergency department visits. Adjustment with only claims-based variables substantially improved balance on all SES variables compared with the unadjusted. Although inclusion of SES in PS models further improved balance on SES variables compared with models with claims-based covariates only, it did not materially change point estimates for either outcome. Inclusion of claims-based proxies may mitigate confounding by SES when aggregate-level SES information is unavailable.

Nearly 90% of drugs dispensed in the US are generic products. The aim of this study was to develop and implement a tool for analyzing manufacturer-level drug utilization and switching patterns within the US Food and Drug Administration’s Sentinel system. A descriptive tool was designed to analyze data in the Sentinel common data model and was tested with two case studies—metoprolol extended release (ER) and lamotrigine ER—using claims data from four Sentinel data partners. We plotted initiators of each brand and generic product over time. For metoprolol ER, we evaluated rates of switching from generics around the time of manufacturing issues. For lamotrigine ER, we examined rates of switching back to the brand among those who switched from brand to generic. We identified 1,651,285 initiators of metoprolol ER products between July 2008 and September 2015. We observed a large decrease in monthly metoprolol ER initiators (from 25,465 in December 2008 to 13,128 in February 2009), corresponding to recalls by generic manufacturers. We observed simultaneous increases in utilization of the authorized generic and brand products. We identified 4266 initiators of lamotrigine ER with an epilepsy diagnosis between January 2012 and September 2015. Among those who switched from brand to generic, the cumulative incidence of switching back was close to 20% at 2 years. Switchback rates were higher for the first available generic products. This developed tool was able to elucidate novel utilization and switching patterns in two case studies. Such information can be used to support surveillance of generic drugs and biosimilars.

Objectives To compare rates of switchbacks to branded drug products for patients switched from branded to authorized generic drug products, which have the same active ingredients, appearance, and excipients as the branded product, with patients switched from branded to generic drug products, which have the same active ingredients as the branded product but may differ in appearance and excipients. Design Observational cohort study. Setting Private (a large commercial health plan) and public (Medicaid) insurance programs in the US. Participants Beneficiaries of a large US commercial health insurer between 2004 and 2013 (primary cohort) and Medicaid beneficiaries between 2000 and 2010 (replication cohort). Main outcome measures Patients taking branded products for one of the study drugs (alendronate tablets, amlodipine tablets, amlodipine-benazepril capsules, calcitonin salmon nasal spray, escitalopram tablets, glipizide extended release tablets, quinapril tablets, and sertraline tablets) were identified when they switched to an authorized generic or a generic drug product after the date of market entry of generic drug products. These patients were followed for switchbacks to the branded drug product in the year after their switch to an authorized generic or a generic drug product. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals after adjusting for demographics, including age, sex, and calendar year. Inverse variance meta-analysis was used to pool adjusted hazard ratios across all drug products. Results A total of 94 909 patients switched from branded to authorized generic drug products and 116 017 patients switched from branded to generic drug products and contributed to the switchback analysis. Unadjusted incidence rates of switchback varied across drug products, ranging from a low of 3.8 per 100 person years (for alendronate tablets) to a high of 17.8 per 100 person years (for amlodipine-benazepril capsules), with an overall rate of 8.2 per 100 person years across all drug products. Adjusted switchback rates were consistently lower for patients who switched from branded to authorized generic drug products compared with branded to generic drug products in the primary cohort (pooled hazard ratio 0.72, 95% confidence interval 0.64 to 0.81). Similar results (0.75, 0.62 to 0.91) were observed in the replication cohort. Conclusion Switching from branded to authorized generic drug products was associated with lower switchback rates compared with switching from branded to generic drug products.

OBJECTIVE To synthesize the existing literature on benefits and risks of anticoagulant use after traumatic brain injury (TBI). DESIGN Systematic review. A literature search was performed in MEDLINE, International Pharmaceutical Abstracts, Health Star, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) on October 11, 2012, and updated on September 2, 2013, using terms related to TBI and anticoagulants. MAIN MEASURES Human studies evaluating the effects of post-TBI anticoagulation on venous thromboembolism, hemorrhage, mortality, or coagulation parameters with original analyses were eligible for the review. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline was followed throughout the conduct of the review. RESULTS Thirty-nine eligible studies were identified from the literature, of which 23 studies with complete information on post-TBI anticoagulant use and patient outcomes were summarized in this review. Meta-analysis was unwarranted because of varying methodological design and quality of the studies. Twenty-one studies focused on the effects of pharmacological thromboprophylaxis (PTP) post-TBI on venous thromboembolism and/or progression of intracranial hemorrhage, whereas 2 randomized controlled trials analyzed coagulation parameters as the result of anticoagulation. CONCLUSION Pharmacological thromboprophylaxis appears to be safe among TBI patients with stabilized hemorrhagic patterns. More evidence is needed regarding effectiveness of PTP in preventing venous thromboembolism as well as preferred agent, dose, and timing for PTP.

Background: Social media offer a novel avenue to engage with and recruit research participants. Facebook in particular is a promising option given its popularity and widespread use. Objective: To explore the feasibility of using Facebook to recruit physicians and patients to participate in a survey to assess their perceptions about generic venlafaxine extended release (ER) tablet indicated for depression. Methods: Web-based surveys were developed to gauge physicians’ prescribing experiences with and patients’ perceptions of generic venlafaxine ER tablet. The surveys included questions specific to venlafaxine ER tablets, such as perceived safety and efficacy of the drug and overall comfort level with either prescribing or taking the drug. Survey links were then posted and advertised on Facebook to recruit physicians and patients. Results: Advertisement for physicians reached 1898 Facebook users and advertisement for patients reached 1144 users during a 10-day advertising period. However, only 14 and 35 users clicked on the survey for physicians and patients, respectively. No physician completed the physician survey while 3 patients completed the patient survey. Conclusions: The findings of this study suggest that Facebook may not be an effective method to recruit physicians. Facebook holds promise to recruit patients, but additional recruitment efforts, such as incentives, are needed.

Authorized generics are identical in formulation to brand drugs, manufactured by the brand company but marketed as a generic. Generics, marketed by generic manufacturers, are required to demonstrate pharmaceutical and bioequivalence to the brand drug, but repetition of clinical trials is not required. This retrospective cohort study compared outcomes for generics and authorized generics, which serves as a generic vs. brand proxy that minimizes bias against generics. For the seven drugs studied between 1999 and 2014, 5,234 unique patients were on brand drugs prior to generic entry and 4,900 (93.6%) switched to a generic. During the 12 months following the brand-to-generic switch, patients using generics vs. authorized generics were similar in terms of outpatient visits, urgent care visits, hospitalizations, and medication discontinuation. The likelihood of emergency department (ED) visits was slightly higher for authorized generics compared with generics. These data suggest that generics were clinically no worse than their proxy brand comparators.

Small changes in bioavailability of narrow therapeutic index (NTI) drugs can alter clinical outcomes, raising concern over generic NTI substitution. We surveyed pharmacists to identify their perceptions of generic NTI drugs, their frequency of performing generic NTI substitution, and predictors of this behavior. Of 710 respondents (33% response rate), 87% perceived generic NTI drugs as effective as their brand-name versions and 94% as safe. Whereas 82% almost always performed generic NTI substitution for initial prescriptions, only 60% did for refills. Pharmacists in non-chain settings (odds ratio (OR) = 2.37; 95% confidence interval (CI) = 1.40-4.02), in practice longer (per year OR = 1.04; 95% CI = 1.02-1.06), in states with affirmative patient consent laws (OR = 1.88; 95% CI = 1.06-3.32), and in states with NTI-specific substitution requirements (OR = 1.95; 95% CI = 1.16-3.26) were more likely not to substitute initial prescriptions. Education of non-chain and veteran pharmacists and elimination of affirmative patient consent and NTI-specific substitution requirements could increase generic NTI substitution.

Objectives: To assess the effectiveness of medications used in the management of Alzheimer's disease and related dementias (ADRD) on cognition and activity of daily living (ADL) trajectories and to determine whether sex modifies these effects. Design: Two-year (2007�2008) longitudinal study. Setting: Medicare enrollment and claims data linked to the Minimum Dataset 2.0. Participants: Older nursing home (NH) residents with newly diagnosed ADRD (n = 18,950). Measurements: Exposures included four medication classes: antidementia medications (ADMs), antipsychotics, antidepressants, and mood stabilizers. Outcomes included ADLs and cognition (Cognitive Performance Scale (CPS)). Marginal structural models were employed to account for time-dependent confounding. Results: The mean age was 83.6, and 76% of the sample was female. Baseline use of ADMs was 15%, antidepressants was 40%, antipsychotics was 13%, and mood stabilizers was 3%. Mean baseline ADL and CPS scores were 16.6 and 2.1, respectively. ADM use was not associated with change in ADLs over time but was associated with a slower CPS decline (slope difference: -0.09 points/year, 99% confidence interval (CI) = -0.14 to -0.03). Antidepressant use was associated with slower declines in ADL (slope difference: -0.36 points/year, 99% CI = -0.58 to -0.14) and CPS (slope difference: -0.12 points/year, 99% CI = -0.17 to -0.08). Sex modified the effect of both antipsychotic and mood stabilizer use on ADLs; female users declined most quickly. Antipsychotic use was associated with slower CPS decline (slope difference: -0.11 points/year, 99% CI = -0.17 to -0.06), whereas mood stabilizer use had no effect. Conclusion: Despite the observed statistically significantly slower declines in cognition with ADMs, antidepressants, and antipsychotics and the slower ADL decline found with antidepressants, it is unlikely that these benefits are of clinical significance.

Background Medication reconciliation has been recognized as an important process in care transitions to prevent adverse health outcomes. Because older adults have multiple comorbid conditions and use multiple medications, they are more likely to experience complicated transitions between acute and long-term care settings. Hence, it is important to develop effective interventions to protect older adults at transition points of care. Objective To systematically review the literature and evaluate studies performing medication reconciliation interventions in patients transferred to and from long-term care settings. Methods The literature search focused on studies that evaluated an intervention involving medication reconciliation in patients transferred to and/or from long-term care settings, such as nursing homes, skilled nursing facilities, residential care facilities, assisted living facilities, homes for the aged, and hospice care. A search was conducted on Ovid MEDLINE (1950-August 2010), Ovid HealthSTAR (1966-August 2010), Cumulative Index to Nursing and Allied Health Literature (1982-August 2010), PubMed (1980-August 2010), The Cochrane Database of Systematic Reviews (2005-August 2010), the Agency for Healthcare Research and Quality website, and reference lists of relevant articles were hand-searched. Two reviewers screened the titles and abstracts for potentially relevant studies. Data abstraction from the included articles was performed independently by 4 reviewers. Results Seven studies met the inclusion criteria. Four studies were performed in the United States, whereas 3 studies were performed in other countries. A clinical pharmacist proved to be useful in providing medication reconciliation interventions by adopting specialized responsibilities such as serving as a transition pharmacist coordinator or working through a call center. Although improvement in the outcome(s) examined was shown in all of the studies, there were study design flaws. Conclusion There is a need for well-designed studies demonstrating the effectiveness of medication reconciliation interventions in long-term care settings. Future studies should focus on employing appropriate methods so that their interventions can be evaluated more effectively.

The modification of protein and non-protein thiols by oxidants including hydrogen peroxide (H(2)O(2)), peroxynitrite anion (ONOO(-)) and hypochlorous acid (HOCl) is well documented. Using an aromatic thiol, 5-thio-2-nitrobenzoic acid, and biologically relevant oxidants, we have identified higher oxidation states of sulfur including the sulfonic acid derivative and the disulfide S-oxide, a thiosulfinate, by HPLC and mass spectrometry. The initial reaction of ONOO(-) with 5-thio-2-nitrobenzoic acid yielded a transient red intermediate, the sulfenate anion. The red intermediate was observed when ONOO(-) and H(2)O(2) were used to oxidize 5-thio-2-nitrobenzoic acid and it persisted for several seconds at pH 7. HOCl oxidized the disulfide, 5,5'dithiobis(2-nitrobenzoic acid) to the corresponding sulfonic acid and no additional products were detected. Using this system, we can directly compare the thiol-oxidizing abilities of several oxidants. Because 5-thio-2-nitrobenzoic acid is the product of the reaction of Ellman's reagent with protein thiols, a detailed study of its stability in biological matrices where oxidants may be generated is warranted.

US Food and Drug Administration approval for generic drugs relies on demonstrating pharmaceutical equivalence and bioequivalence; however, some drug products have unique attributes that necessitate product-specific approval pathways. We evaluated rates of patients' switching back to brand-name versions from generic versions of four drugs approved via such approaches.We used data from Optum LifeSciences Research Database to identify patients using a brand-name version of a study drug (acarbose tablets, salmon calcitonin nasal spray, enoxaparin sodium injection, and venlafaxine extended release tablets) or a control drug. We followed patients to identify switching to generic versions and then followed those who switched to identify whether they switched back to brand-name versions. We calculated switch and switch-back rates and used Kaplan-Meier and log-rank tests to compare rates between study and control drugs.Our cohort included 201 959 eligible patients. Brand-to-generic switch rates ranged from 66 to 106 switches per 100 person-years for study drugs and 80 to 110 for control drugs. Rates of switch-back to brand-name versions ranged from 5 to 37 among study drugs and 3 to 53 among control drugs. Switch-back rates were higher for venlafaxine vs. sertraline (p 0.01) and calcitonin vs. alendronate (p = 0.01). Switch-back rates were lower for venlafaxine vs. paroxetine (p 0.01) and acarbose vs. nateglinide (p 0.01). Rates were similar for acarbose vs. glimepiride (p = 0.97) and for enoxaparin vs. fondiparinux (p = 0.11).As compared to control drugs, patients were not more likely to systematically switch back from generic to brand-name versions of the four study drugs. Copyright © 2016 John WileySons, Ltd.

Older adults with dementia are vulnerable to the central deteriorating effects of drugs with anticholinergic properties (DAPs). These effects include falls and confusion and may exacerbate dementia-related symptoms. Many individuals with dementia also receive acetylcholinesterase inhibitors (AChEIs), indicated for mild to moderate Alzheimer’s disease. AChEIs have opposing effects to DAPs and, consequently, concomitant use of DAPs and AChEIs may further impair cognition among patients with dementia. Our objectives were to (1) evaluate the anticholinergic burden among nursing home (NH) residents with dementia; (2) characterize trends in use of DAPs and concomitant use of DAPs and AChEIs among NH residents with dementia; and (3) identify factors associated with the use of DAPs and concomitant use of DAPs and AChEIs. We conducted a retrospective analysis of Medicare data from 2007 to 2008 linked to the Minimum Data Set. During the study period, 53,805 (77 %) NH residents with dementia used at least one DAP each month. Sixty-seven percent of residents with dementia used Anticholinergic Cognitive Burden Scale (ACBS) level 1 DAPs, 3 % used level 2 DAPs, and 31 % used level 3 DAPs. Thirteen percent of NH residents with dementia concomitantly used ACBS levels 2 or 3 DAPs and AChEIs. This study sheds new light on the prevalence of DAP use and concomitant use of DAPs and AChEIs among NH residents with dementia. Clinicians should consider alternatives with lower anticholinergic effects, particularly in patients already taking DAPs.

Objectives: To describe population-based use of cognitive-enhancing and psychopharmacological medications across care settings in Medicare beneficiaries with dementia. Design: One-year (2008) cross-sectional study. Setting: Medicare administrative claims from a 5% random sample. Participants: Medicare beneficiaries with dementia aged 65 and older with continuous Medicare Parts A, B, and D coverage and alive throughout 2008. To ascertain dementia, one or more medical claims with a dementia International Classification of Diseases, Ninth Revision, Clinical Modification code was required before 2008, and an additional claim was required in 2008 to confirm active disease. Measurements: Use of medications commonly prescribed in managing dementia (cognitive enhancers, antidepressants, antipsychotics, and mood stabilizers) was assessed using three measures: annual prevalence of use, consistency of use, and count of psychopharmacological medication classes. Care setting was determined using the number of months of nursing home (NH) residency: no NH (0 months), partial NH (1�11 months), and full NH (12 months). Results: Community-dwellers represented 41.3% of the cohort, whereas 42.4% and 16.3% resided partially and fully in a NH, respectively. Annual prevalence of use was 57.1% for cognitive enhancers, 56.4% for antidepressants, 34.0% for antipsychotics, and 8.8% for mood stabilizers. Cognitive enhancer use was significantly lower in those with any NH stay (partial NH vs no NH, adjusted prevalence ratio (APR) = 0.84, 99% confidence interval (CI) = 0.83�0.86; full NH vs no NH, APR = 0.83, 99% CI = 0.81�0.85). In contrast, those with any NH residence had significantly higher use of all psychopharmacological medication classes than community-dwellers. More than half the cohort had consistent medication regimens during 2008 (64.8%). The number of psychopharmacological medication classes used increased with increasing NH stay duration. Conclusion: This population-based study documents significant differences in medication use for managing dementia between care settings and substantial use of psychopharmacological medications in older adults with dementia.

Cancers arising in pancreas, lung, liver and stomach are difficult to treat successfully. Wanting to understand the basis for such intractability, we previously performed comparative analyses of publicly available gene expression data from tumor biopsies. Expression of many cell adhesion genes correlated significantly with intractability of cancers, our surrogate of intractability being the SEER five-year survivals of patients with disseminated tumors. To model resistance mediated by cell adhesion, we evaluated HCT 116 cells grown in two modes differing in cell adhesion status: (i) as monolayers attached to plastic culture dishes, (ii) cells attached to one another in spheroids. We determined gene expression profiles of cells grown in these two modes, for three or six days, using the human genome U133A microarray (Affymetrix, Inc.). There was a striking overlap between (a) the genes expressed differentially between early monolayers and early spheroids and (b) those expressed differentially between early and confluent monolayers. However, there was no similarity between these overlaps and the genes that were differentially expressed in intractable, as opposed to more tractable, tumors. We hypothesize that the cytotoxicity resistance for polyHEMA spheroids and for confluent cells have a similar basis, one that differs from the resistance found in intractable solid tumors in patients. Cytotoxicity, cell cycle and immunohistochemistry assays on early and on confluent monolayers, and on spheroids, showed similarities between these latter two conditions. We conclude that while spheroids (and confluent monolayer cells) show drug resistance, the mechanisms underlying this resistance diverge from those conferring resistance to intractable cancers.