Serious cardiovascular adverse events with fluoroquinolones versus other antibiotics: A self-controlled case series analysis.

The objective of this study was to evaluate the association between fluoroquinolone (FQ) use and the occurrence of aortic aneurysm/dissection (AA/AD), acute myocardial infarction (AMI), ventricular arrhythmias (VenA), and all-cause mortality vs other commonly used antibiotics. We conducted a self-controlled case series analysis of patients who experienced the outcomes of AA/AD, AMI, and VenA, based on diagnosis codes from emergency department visits and hospitalizations within Veterans Health Administration, and death in FY2014-FY2018. These Veterans also received outpatient prescriptions for FQs. Conditional Poisson regression models were used to estimate the association between FQs and each of the outcomes vs antibiotics of interest (ie amoxicillin or amoxicillin/clavulanate, azithromycin, doxycycline, cefuroxime or cephalexin, or sulfamethoxazole-trimethoprim), adjusted for time-varying covariates. Using a 30-day risk period after each antibiotic prescription, adjusted incidence rate ratios (aIRRs) for FQs vs each comparator antibiotic were not statistically different for outcomes of VenA or AMI. For AA/AD, incidence was higher during FQ risk periods vs amoxicillin [aIRR 1.50 (95% CI 1.01, 2.25)] and azithromycin [aIRR 2.15 (95% CI 1.27, 3.64)] risk periods. A significantly increased risk of mortality was observed with FQs vs each antibiotic of interest. FQs were associated with an increased risk of AA/AD vs amoxicillin and azithromycin and an increased risk of all-cause mortality vs multiple antibiotics commonly used for outpatient infections. Although the differences in event rates are small, FQ use should be limited to serious infections without appropriate alternatives.

Assessment of Use and Safety of Edaravone for Amyotrophic Lateral Sclerosis in the Veterans Affairs Health Care System.

Importance: Using real-world data, the US Department of Veterans Affairs (VA) initiated a surveillance evaluation of edaravone after its approval for amyotrophic lateral sclerosis (ALS) in 2017. The use and safety of edaravone for patients with ALS in the VA health care system remain to be assessed. Objective: To describe a pharmacovigilance surveillance initiative with edaravone to monitor patient characteristics, utilization (edaravone cycles and riluzole use), and safety and to evaluate safety/effectiveness. Design, Setting, and Participants: This propensity score-matched cohort study used data on 369 patients with documented definite or probable ALS in the Veterans Health Administration (VHA) with at least 1 prescription for edaravone between August 1, 2017, and September 30, 2019. The analysis compared edaravone (alone or with riluzole) with riluzole only. For chronic users (≥6 months of drug), a time-to-event model evaluated ALS-related outcomes, with censoring at outcome, death, or end of evaluation. Patients with Parkinson disease, dementia, schizophrenia, or significant respiratory insufficiency per diagnosis codes within 2 years before prescription initiation were excluded. In overall matched cohorts, 223 patients treated with edaravone were 1:3 propensity score matched based on predefined confounders. For the chronic user subgroup analysis, 96 patients receiving edaravone and 424 patients receiving riluzole only were included. Exposures: Edaravone (alone or with riluzole) vs riluzole only. Main Outcomes and Measures: Patient characteristics, ALS drug use, and mortality. Acute outcomes (within 6 months of index) included proportion and mean time to event for death, discontinuation, or all-cause hospitalization, and outcomes for chronic users (receiving >6 months of treatment) included hazard ratios of outcomes related to disease-state progression. Results: Of 369 patients who received edaravone, most were older (mean [SD] age, 64.6 [11.3] years), male (346 [93.8%]), and White (261 [70.7%]). As of September 2019, 59.9% of edaravone patients had discontinued treatment; of those, 49.5% (108 of 218) received only 1 to 3 treatment cycles. Approximately 30% (110 patients) died. In a matched evaluation, significantly more acute all-cause hospitalization events occurred with edaravone (35.4% vs 22.0% for riluzole only); 72.6% of the edaravone cohort received edaravone with riluzole. Among chronic users, edaravone patients (70.8% edaravone with riluzole) had an increased hazard ratio of ALS-associated hospitalization (2.51; 95% CI, 1.18-8.16). The death rate was lower with edaravone but the difference was not statistically significant. Conclusions and Relevance: Early edaravone discontinuation was common in the VA. Although outcomes favored use of riluzole only in the matched analysis, results should be interpreted with caution, as unmeasured bias in observational data is likely.

Structure, heterogeneity and developability assessment of therapeutic antibodies.

Increasing attention has been paid to developability assessment with the understanding that thorough evaluation of monoclonal antibody lead candidates at an early stage can avoid delays during late-stage development. The concept of developability is based on the knowledge gained from the successful development of approximately 80 marketed antibody and Fc-fusion protein drug products and from the lessons learned from many failed development programs over the last three decades. Here, we reviewed antibody quality attributes that are critical to development and traditional and state-of-the-art analytical methods to monitor those attributes. Based on our collective experiences, a practical workflow is proposed as a best practice for developability assessment including in silico evaluation, extended characterization and forced degradation using appropriate analytical methods that allow characterization with limited material consumption and fast turnaround time.

Entacapone and prostate cancer in Parkinson's disease patients: A large Veterans Affairs healthcare system study.

BACKGROUND: An increased incidence of prostate cancer was observed in Parkinson's disease (PD) patients treated with entacapone during a pre-approval randomized clinical trial; the relation has not been robustly investigated in the U.S. ambulatory setting. OBJECTIVE: To investigate whether entacapone is associated with prostate cancer and to assess whether the associations are correlated with advanced disease at the time of cancer diagnosis. METHODS: Using data from the Department of Veterans Affairs healthcare system, new-user cohorts were created of PD patients treated with add-on entacapone or add-on dopamine agonist/monoamine oxidase B inhibitors between January 2000 and December 2014. Patients were followed on-treatment for occurrence of prostate cancer, identified via linkage to the VA cancer registry. RESULTS: Mean follow-up time was 3.1 and 4.0 years in the entacapone and control cohort, respectively. There were 17,666 subjects meeting study criteria (mean age, 74 (SD 8.6) years); the entacapone-treated group comprised 5,257 subjects. Twenty-three prostate cancer cases occurred in the entacapone cohort and ninety-seven in the control cohort. The overall incidence of prostate cancer was 1.8 per 1,000 person-years of risk. There was no difference in risk of prostate cancer between the cohorts for increased duration of entacapone intake (adjusted HR: 1.08; 95% confidence interval: 0.46-2.51 for cumulative exposure of ≥2 years). Time since starting drug therapy and cumulative dose (mg) also do not suggest a difference in prostate cancer risk between cohorts. CONCLUSIONS: Prolonged therapy with entacapone was not associated with increased prostate cancer incidence; however, findings suggest a higher severity of prostate cancer.

A comparison of neuropsychiatric adverse events during early treatment with varenicline or a nicotine patch.

AIMS: We compared the risk of mental health episodes requiring hospitalization (primary aim) or out-patient clinic visits (secondary aim) associated with varenicline versus the nicotine patch (NP) in an era prior to psychiatric boxed warnings. DESIGN: Retrospective cohort. SETTING: Department of Veterans Affairs (VA), USA. PARTICIPANTS: VA patients with or without psychiatric comorbidities and a new prescription for varenicline (15 255) were propensity score-matched (1 : 2) to new users of NP (123 054) between 1 May 2006 and 30 September 2007, resulting in 11 774 and 23 548 patients in the varenicline and NP groups, respectively. MEASUREMENTS: The primary outcomes were hospitalizations with a primary discharge diagnosis of a range of mental health disorders: depression, schizophrenia, bipolar disorder, suicide attempt, post-traumatic stress disorder, other psychosis and drug-induced mental disorders. Secondary outcomes were out-patient clinic visits with a primary diagnosis of the above list of mental health disorders. FINDINGS: Background characteristics of the treatment groups were similar after matching. There was no statistically significant difference in risk of hospitalization for any of the studied mental health disorders with varenicline compared with NP. Among secondary outcomes there was an increased risk of out-patient clinic visits for schizophrenia among patients who received varenicline [hazard ratio (HR) = 1.27; 95% confidence interval (CI) = 1.07, 1.51], this increase being evident only in those with a pre-existing mental health disorder. CONCLUSION: In US VA patients studied prior to the boxed warning being implemented, use of varenicline for smoking cessation was not associated with a detectable increase compared with nicotine patches in hospitalization for any mental health outcomes. There was an increased rate of out-patient attendances with a primary diagnosis of schizophrenia amounting to five per 100 person years of treatment. This increase was found only in patients with a pre-existing mental health disorder.

Maternal Chlamydia Infection During Pregnancy and Risk of Cyanotic Congenital Heart Defects in the Offspring.

OBJECTIVES: Genital Chlamydia is a common bacterial sexually-transmitted infection among reproductive aged women, particularly younger populations. Cyanotic congenital heart defects (CCHDs) constitute about one quarter of all cardiac malformations at birth, and are associated with high rate of morbidity and mortality. Epidemiological research on the association between maternal Chlamydia during pregnancy and CCHDs in the offspring is lacking. METHODS: Using data from the 2012 United States birth certificates, we examined the association between CCHDs and prenatal exposure to Chlamydia among live singleton births with CCHDs (n = 2487) and unaffected singleton births (n = 3,334,424). We estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis for all CCHDs combined, and isolated CCHDs (without other major congenital malformations). RESULTS: Overall 1.7% of case and 1.7% of control women reported having Chlamydia during their pregnancies. After controlling for potential confounders, we found a weak positive association between maternal Chlamydia during pregnancy and all CCHDs combined (aOR = 1.39; 95% CI 1.02-1.90). The positive association persisted for isolated CCHD cases, but with marginal significance (aOR = 1.34; 95% CI 0.96-1.74). Subgroup analyses for younger women showed an increased risk for CCHDs; however, the associations were not statistically significant. CONCLUSIONS: Maternal exposure to Chlamydia during pregnancy was weakly associated with a higher risk of CCHDs in the offspring. The finding should be interpreted with caution due to limitations of birth certificate data. Future studies using more robust data sources are warranted to further study the association between maternal Chlamydia during pregnancy and CCHDs in the offspring.

Effect of cleaning agents and additives on Protein A ligand degradation and chromatography performance.

Protein A chromatography, employing the recombinant Protein A ligand, is widely used as a capture step for antibody and Fc-fusion proteins manufacture. Protein A ligands in these matrices are susceptible to degradation/loss when exposed to cleaning agents such as sodium hydroxide, resulting in loss of capacity on reuse. In this study, MabSelect Protein A ligand and MabSelect SuRe Protein A ligand were chosen to evaluate the impact of alkaline cleaning solutions on the ligands and the packed columns. The Protein A ligands alone and the Protein A columns were incubated or cycled in different concentrations of sodium hydroxide solutions with and without additives, respectively. Ligand integrity (degradation) and ligand function (binding affinity) were studied using SDS-PAGE and customized Biacore technology, surface plasma resonance (SPR) and were successfully correlated with column performance measurement in terms of static binding capacity (SBC), dynamic binding capacity (DBC) and recovery as a function of exposure to cleaning agents with and without additives. The findings and the methodology presented in this study are not only able to determine appropriate cleaning conditions for Protein A chromatography, but also provided tools to enable systematic and rapid study of the cleaning solutions and conditions.

Severe dysglycemia with the fluoroquinolones: a class effect?

BACKGROUND: Although gatifloxacin is no longer available, other fluoroquinolones may significantly interfere with glucose homeostasis. The objective of the present study was to compare the risk of severe hypo- and hyperglycemia in a cohort of patients treated with gatifloxacin, levofloxacin, ciprofloxacin, or azithromycin. METHODS: This was a retrospective inception cohort study of outpatients with a new prescription for gatifloxacin, levofloxacin, ciprofloxacin, or azithromycin from 1 October 2000 through 30 September 2005 in the Veterans Affairs health care system. For patients who received one of these antibiotics, we identified outcomes of hospitalization with a primary diagnosis of hypo- or hyperglycemia. Multivariable logistic regression was used to determine the odds of hypo- and hyperglycemia with the individual fluoroquinolones versus azithromycin. RESULTS: The crude incidence rates for severe hypo- and hyperglycemia among those who received gatifloxacin, levofloxacin, ciprofloxacin, and azithromycin were 0.35 and 0.45, 0.19 and 0.18, 0.10 and 0.12, and 0.07 and 0.10 cases per 1000 patients, respectively. Among patients with diabetes, the odds ratios for hypoglycemia compared with azithromycin were 4.3 (95% confidence interval [CI], 2.7-6.6) for gatifloxacin, 2.1 (95% CI, 1.4-3.3) for levofloxacin, and 1.1 (95% CI, 0.6-2.0) for ciprofloxacin. The odds ratios for hyperglycemia were 4.5 (95% CI, 3.0-6.9) for gatifloxacin, 1.8 (95% CI, 1.2-2.7) for levofloxacin, and 1.0 (95% CI, 0.6-1.8) for ciprofloxacin. CONCLUSIONS: The odds of severe hypo- and hyperglycemia were significantly greater with gatifloxacin and levofloxacin, but not ciprofloxacin, than with azithromycin. Thus, the risk of a clinically relevant dysglycemic event appears to vary among the fluoroquinolones.

National utilization of antihypertensive medications from 2000 to 2006 in the Veterans Health Administration: focus on thiazide diuretics.

The authors sought to determine the prescribing practices of clinicians treating veterans with hypertension. A descriptive analysis was performed using a national pharmacy database of patients with a diagnosis of hypertension receiving antihypertensive medication in the fiscal years 2000 to 2006. Angiotensin-converting enzyme inhibitors were the most frequently prescribed antihypertensive class, with utilization increasing from 56.0% in fiscal year 2000 to 63.2% of patients in 2006. Utilization of thiazide-type diuretics increased from 31.9% of patients in fiscal year 2000 to 42.0% in 2006. When patient comorbidities were taken into consideration, 48.1% of patients defined as having uncomplicated hypertension had at least one prescription for a thiazide diuretic in fiscal year 2006. Utilization by monotherapy and combination therapy were also evaluated. The trends in utilization allowed for identification of areas in which a change in prescribing practices may improve blood pressure control and health outcomes in the Veterans Health Administration.

Functional analysis of the LXXLL motifs of the human glucocorticoid receptor: association with altered ligand affinity.

Although LXXLL motifs in coactivators mediate binding to liganded nuclear receptors, the roles of comparable motifs within nuclear receptors are less understood. We investigated the role of the LXXLL motifs in the human glucocorticoid receptor both in transcriptional activation and repression of gene expression. The two conserved LXXLL motifs within the ligand binding domain of the receptor, amino acids 532-536 (helix 1) and 718-722 (helix 10), were characterized by evaluating LXXLL mutant receptors as well as comparable mutants in other helices of the ligand binding domain. All mutant receptors were expressed at comparable levels to wild type in COS-1 cells. Mutation of 532-536 LXXLL to LXXAA completely disrupted dexamethasone induced transcription, whereas the 718-722 LXXAA mutant fully activated reporter genes at high ligand concentrations. Ligand binding analysis demonstrated that both LXXLL motif mutations resulted in disruption of ligand binding capacity without altering their association with hsp90. Proteolytic cleavage studies suggested that mutations of the LXXLL motifs introduced changes in the receptor conformation. Interestingly, the 532-536 LXXAA mutant was not able to transrepress NF-kappaB activity, whereas the 718-722 LXXAA mutant did so in the presence of ligand. These data suggest that although LXXLL motifs in helices 1 and 10 appear to lie outside the predicted ligand binding pocket they may contribute to receptor ligand binding affinity.

The initial development of the WebMedQual scale: domain assessment of the construct of quality of health web sites.

OBJECTIVE: To develop a comprehensive instrument assessing quality of health-related web sites. METHODS: Phase I consisted of a literature review to identify constructs thought to indicate web site quality and to identify items. During content analysis, duplicate items were eliminated and items that were not clear, meaningful, or measurable were reworded or removed. Some items were generated by the authors. Phase II: a panel consisting of six healthcare and MIS reviewers was convened to assess each item for its relevance and importance to the construct and to assess item clarity and measurement feasibility. RESULTS: Three hundred and eighty-four items were generated from 26 sources. The initial content analysis reduced the scale to 104 items. Four of the six expert reviewers responded; high concordance on the relevance, importance and measurement feasibility of each item was observed: 3 out of 4, or all raters agreed on 76-85% of items. Based on the panel ratings, 9 items were removed, 3 added, and 10 revised. The WebMedQual consists of 8 categories, 8 sub-categories, 95 items and 3 supplemental items to assess web site quality. The constructs are: content (19 items), authority of source (18 items), design (19 items), accessibility and availability (6 items), links (4 items), user support (9 items), confidentiality and privacy (17 items), e-commerce (6 items). CONCLUSION: The "WebMedQual" represents a first step toward a comprehensive and standard quality assessment of health web sites. This scale will allow relatively easy assessment of quality with possible numeric scoring.

Multicenter drug use evaluation of tamsulosin and availability of guidance criteria for nonformulary use in the veterans affairs health system.

OBJECTIVE: The U.S. Department of Veterans Affairs (VA) Pharmacy Benefits Management Strategic Healthcare Group (PBM-SHG) and its Medical Advisory Panel developed national criteria (guidelines) for the appropriate use of tamsulosin in the VA. Drug use evaluation (DUE) was performed to (a) determine the prescribing patterns (indications and patient follow-up monitoring as measured by a clinician.s note regarding evaluation of therapeutic response or report of adverse drug event) of tamsulosin, (b) assess the impact of the availability (not active dissemination) of national criteria for nonformulary use of tamsulosin, and (c) project the cost avoidance if generic terazosin was substituted for tamsulosin in those patients who were prescribed tamsulosin outside of appropriate use criteria. METHODS: Geographically dispersed VA medical centers were identified for which tamsulosin utilization was significantly above and below the national average (4.8% of all prescriptions for alpha [alpha]-blockers) in January 2001. A data collection form for medical record abstraction was designed to capture the patient.s diagnosis, reported indication for tamsulosin, history of previous alpha-blocker use, tamsulosin follow-up evaluation, and the individual facility.s method of implementation of criteria for nonformulary use. Patients receiving a prescription for tamsulosin during a 3-month period preceding the posting of national criteria, and patients with a first-time prescription for tamsulosin during a 3-month period after the national criteria were posted were randomly selected by the PBM and assigned for chart review at each site. RESULTS: Data for 332 patients were collected from 6 different sites over a 6-month period for each pregroup and postgroup beginning August 2001 and January 2002, respectively. Tamsulosin was prescribed for appropriate indications in 66% of patients, potentially appropriate indications in 4% of patients, and inappropriate indications in 30% of patients. Of the 206 patients (62%) who were prescribed tamsulosin as a result of a reported adverse event with a previous alpha-blocker, only 29% of the cases (N = 59) showed evidence that an attempt was made to reduce the dose of the first alpha-blocker to abate the side effects. Followup monitoring was conducted in 78% of tamsulosin patients, of whom 55% reported effectiveness of tamsulosin, and 6% reported side effects attributable to tamsulosin. No meaningful differences in prescribing patterns were found between the pregroups and postgroups relative to the posting of the criteria for nonformulary use. Two sites had some form of the criteria made available to physicians, while 4 sites had not implemented the national criteria. Extrapolation of the results to the VA system-wide yielded a conservative estimate of 480,993 dollars in potential cost avoidance for 1 quarter (July to September 2002) when corrected for patients prescribed tamsulosin outside of the criteria for nonformulary use. CONCLUSIONS: Despite the availability of national criteria for nonformulary use of tamsulosin, the results reveal that these criteria were not followed by prescribers. The DUE reinforced the need for more effective implementation and dissemination of criteria for appropriate use of tamsulosin. A formal education process is necessary to encourage appropriate use of formulary alpha-blockers and to attenuate the increased cost associated with the inappropriate prescribing of the nonformulary drug.