Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project.

Importance: The rapid spread and mortality associated with COVID-19 emphasized a need for surveillance system development to identify adverse events (AEs) to emerging therapeutics. Bradycardia is a remdesivir infusion-associated AE listed in the US Food and Drug Administration-approved prescribing information.

Objective: To evaluate the magnitude and duration of bradycardic events following remdesivir administration.

Considerations in Pfizer-BioNTech COVID-19 vaccine preparation in clinic: Quality vs quantity.

In an effort to expedite the publication of articles , AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

Remote Cardiac Safety Monitoring through the Lens of the FDA Biomarker Qualification Evidentiary Criteria Framework: A Case Study Analysis.

Clinical safety findings remain one of the reasons for attrition of drug candidates during clinical development. Cardiovascular liabilities are not consistently detected in early-stage clinical trials and often become apparent when drugs are administered chronically for extended periods of time. Vital sign data collection outside of the clinic offers an opportunity for deeper physiological characterization of drug candidates and earlier safety signal detection.

Evaluation of Deviation From Planned Cohort Size and Operating Characteristics of Phase 1 Trials.

Importance: The cohort size of phase 1 clinical trials and thus the timing of the interim decisions are typically prespecified in the trial protocol. During trial implementation, however, the cohort size often deviates from the planned one, which shifts the schedule of the interims. Despite its pervasiveness in phase 1 trials, the association of cohort size deviation with the operating characteristics of these trials is not clear.

Contents of US Food and Drug Administration Refuse-to-File Letters for New Drug Applications and Efficacy Supplements and Their Public Disclosure by Applicants.

Importance: Before reviewing drug applications, the US Food and Drug Administration (FDA) conducts "filing reviews" to assess whether they are complete enough for full review. If the applications are incomplete, the FDA issues refuse-to-file (RTF) letters identifying deficiencies. The FDA does not make these RTF letters public at the time of issuance.

Consensus on Language for Advance Informed Consent in Health Care-Associated Pneumonia Clinical Trials Using a Delphi Process.

Importance: Information to be included in advance informed consent forms for health care-associated pneumonia treatment trials remains to be determined.

Objective: To identify and determine how to describe information to be included in an advance informed consent form for an early-enrollment noninferiority hospital-acquired and/or ventilator-associated bacterial pneumonia (HABP/VABP) clinical trial.

Design, Setting, And Participants: A Delphi consensus process with stakeholders in HABP/VABP clinical trials was conducted using qualitative semistructured telephone interviews from June to August 2016, followed by 2 online surveys, the first from April to May 2017, and the second from September to October 2017.

Quantitative systems toxicology (QST) reproduces species differences in PF-04895162 liver safety due to combined mitochondrial and bile acid toxicity.

Many compounds that appear promising in preclinical species, fail in human clinical trials due to safety concerns. The FDA has strongly encouraged the application of modeling in drug development to improve product safety. This study illustrates how DILIsym, a computational representation of liver injury, was able to reproduce species differences in liver toxicity due to PF-04895162 (ICA-105665).

Lipidomics reveals a systemic energy deficient state that precedes neurotoxicity in neonatal monkeys after sevoflurane exposure.

Although numerous studies have raised public concerns regarding the safety of anesthetics including sevoflurane in children, the biochemical mechanisms leading to anesthetics-induced neurotoxicity remain elusive. Moreover, potential biomarker(s) for early detection of general anesthetics-induced brain injury are urgent for public health. We employed an enabling technology of shotgun lipidomics and analyzed nearly 20 classes and subclasses of lipids present in the blood serum of postnatal day (PND) 5 or 6 rhesus monkeys temporally collected after exposure to sevoflurane at a clinically relevant concentration or room-air as control.

Association Between Sickle Cell Trait With Selected Chronic Medical Conditions in U.S. Service Members.

Introduction: Sickle cell trait (SCT), the heterozygous carrier state for hemoglobin S, is present in an estimated 1.6% of all newborns and 7.3% in black individuals in the USA.

Lipid profiling as an effective approach for identifying biomarkers/adverse events associated with pediatric anesthesia.

Adverse effects related to central nervous system (CNS) function in pediatric populations may, at times, be difficult, if not impossible to evaluate. Prolonged anesthetic exposure affects brain excitability and anesthesia during the most sensitive developmental stages and has been associated with mitochondrial dysfunction, aberrant lipid metabolism and synaptogenesis, subsequent neuronal damage, as well as long-term behavioral deficits. There has been limited research evaluating whether and how anesthetic agents affect cellular lipids, the most abundant components of the brain other than water.

A headspace-gas chromatography method for isopropanol determination in warfarin sodium products as a measure of drug crystallinity.

Coumadin® a nd s everal generic products of warfarin s odium (WS) contain the crystalline form (clathrate) in which WS and isopropanol (IPA) are associated in a 2:1 molar ratio. IPA is critical in maintaining the WS crystalline structure. Physicochemical properties of the drug and drug product may change when the crystalline drug transforms to amorphous form.

Risk of Exertional Heat Illnesses Associated with Sickle Cell Trait in U.S. Military.

Introduction: A number of studies have found an association between sickle cell trait (SCT) and exertional heat illnesses (EHIs) including heat stroke, a potentially fatal condition. The strength of this association varied across studies, limiting the ability to quantify potential benefits of SCT-screening policies for competitive athletics and military service members. We determined the relative rate and attributable risk of developing EHI associated with being SCT positive and the EHI health care utilization.

Racial disparity in all-cause mortality among hepatitis C virus-infected individuals in a general US population, NHANES III.

There are few long-term nationally representative studies of all-cause mortality among those infected with hepatitis C virus (HCV). When an additional 5 years of data were made publicly available in 2015, the Third National Health and Nutrition Examination Survey Linked Mortality File became the longest nationally representative study in the United States. Our objective was to update the estimated HCV-associated all-cause mortality in the general US population and determine any differences by sex, age and race/ethnicity.

Protective effect of acetyl-L-carnitine on propofol-induced toxicity in embryonic neural stem cells.

Propofol is a widely used general anesthetic. A growing body of data suggests that perinatal exposure to general anesthetics can result in long-term deleterious effects on brain function. In the developing brain there is evidence that general anesthetics can cause cell death, synaptic remodeling, and altered brain cell morphology.

Particulate matter in injectable drug products.

Unlabelled: Clinicians have had concerns about particulate matter contamination of injectable drug products since the development of the earliest intravenous therapeutics. All parenteral products contain particulate matter, and particulate matter contamination still has the potential to cause harm to patients. With tens of millions of doses of injectable drug products administered in the United States each year, it is critical to understand the types and sources of particulate matter that contaminate injectable drug products, the possible effects of injected particulate matter on patients, and the current state of regulations and standards related to particulate matter in injectable drug products.

Sex-related differences in mast cell activity and doxorubicin toxicity: a study in spontaneously hypertensive rats.

Clinically, girls appear to be more sensitive than boys to the cardiotoxic effects of doxorubicin, whereas the opposite may be true for adults. To identify and characterize potential sex-related differences, adult male and female spontaneously hypertensive rats (SHR; some ovariectomized [OVX]) received 1 mg/kg of doxorubicin or saline iv weekly for 9, 10, or 12 weeks. Weight gain was slower in treated males.

Dysregulated ΔNp63α inhibits expression of Ink4a/arf, blocks senescence, and promotes malignant conversion of keratinocytes.

p63 is critical for squamous epithelial development, and elevated levels of the ΔNp63α isoform are seen in squamous cell cancers of various organ sites. However, significant controversy exists regarding the role of p63 isoforms as oncoproteins or tumor suppressors. Here, lentiviruses were developed to drive long-term overexpression of ΔNp63α in primary keratinocytes.

Using partial area for evaluation of bioavailability and bioequivalence.

Assessment of bioavailability/bioequivalence generally relies on the comparison of rate and extent of drug absorption between products. Rate of absorption is commonly expressed by peak concentration (C(max)) and time to peak concentration (T(max)), although these parameters are indirect measures of absorption rate. Recognizing the importance of systemic exposure to drug efficacy and safety, FDA recommended that systemic exposure be better used for bioavailability/bioequivalence assessment.

Comparing reporting rates of adverse events between drugs with adjustment for year of marketing and secular trends in total reporting.

The Food and Drug Administration has collected spontaneous reports on adverse events (AE) from manufacturers and individuals. These data provide useful information on the safety of marketed drugs. Due to many unique characteristics of this reporting system, the information is difficult to evaluate.