Identification and Determination of 1,3-Thiazinane-4-carboxylic Acid in Human Urine—Chromatographic Studies

It is well established that homocysteine (Hcy) and its thiolactone (HTL) are reactive towards aldehydes in an aqueous environment, forming substituted thiazinane carboxylic acids. This report provides evidence that Hcy/HTL and formaldehyde (FA) adduct, namely 1,3-thiazinane-4-carboxylic acid (TCA) is formed in vivo in humans. In order to provide definitive proof, a gas chromatography–mass spectrometry (GC–MS) based method was elaborated to identify and quantify TCA in human urine. The GC–MS assay involves chemical derivatization with isobutyl chloroformate (IBCF) in the presence of pyridine as a catalyst, followed by an ethyl acetate extraction of the obtained isobutyl derivative of TCA (TCA-IBCF). The validity of the method has been demonstrated based upon United States Food and Drug Administration recommendations. The assay linearity was observed within a 1–50 µmol L−1 range for TCA in urine, while the lowest concentration on the calibration curve was recognized as the limit of quantification (LOQ). Importantly, the method was successfully applied to urine samples delivered by apparently healthy volunteers (n = 15). The GC–MS assay may provide a new analytical tool for routine clinical analysis of the role of TCA in living systems in the near future.

A comparison of mutagenic potential of Aji-no-Moto with a traditional chemical mutagen on microsporogenesis in barley (Hordeum vulagre L.)

Aji-no-Moto or Mono Sodium Glutamate (MSG) is a flavour enhancer being used extensively in South East Asian cuisine. The Federation of American Societies for Experimental Biology for the United States Food and Drug Administration (FDA) has concluded that MSG is safe when "eaten at customary levels" but there is still great confusion regarding its toxicity at higher concentrations. Therefore, it was decided to assess the mutagenic efficacy of MSG on a plant system and present the findings as a model for probably similar effects in the animal model. For this, a traditionally popular genus for genetic studies, Hordeum vulgare L. or winter barley, was used as the model system. The studies of microsporogenesis were done in order to see the long term effect. The sets were compared with experimental sets of plants grown from seeds treated with a traditional chemical mutagen Ethyl Methane Sulphonate (EMS). The study revealed that MSG does not induce much genotoxic effects at lower doses and the chromosomal damages induced were very few. However, at higher doses, it almost equals the effects of EMS in terms of heritable genetic damage. The work is significant as MSG continues to be one of the most popular flavouring agents and does not face any challenge to its biosafe status. However, the clastogenic and chromotoxic effects of higher doses of MSG as observed in the study are in total contradiction to the popular belief.

Effects of feeding lubabegron on gas emissions, growth performance, and carcass characteristics of beef cattle housed in small-pen environmentally monitored enclosures during the last 3 months of the finishing period

The development of technologies that promote environmental stewardship while maintaining or improving the efficiency of food animal production is essential to the sustainability of producing a food supply to meet the demands of a growing population. As such, Elanco (Greenfield, IN) pursued an environmental indication for a selective β-modulator (lubabegron; LUB). LUB was recently approved by the United States Food and Drug Administration (FDA) to be fed to feedlot cattle during the last 14 to 91 d of the feeding period for reductions in gas emissions/kg of unshrunk final BW and HCW. A 4 × 2 factorial arrangement of treatments was used with the factors of dose (0.0, 1.38, 5.5 or 22.0 mg·kg-1 DM basis) and sex (steers or heifers). Three 91-d cycles were conducted (112 cattle/cycle) with each dose × sex combination being represented by a single cattle pen enclosure (CPE; 14 cattle/CPE) resulting in a total of 168 steers and 168 heifers (n = 6 replicates/dose). There were no interactions observed between dose and sex for any variable measured in the study (P ≥ 0.063). Five gases were evaluated for all pens based on CPE concentrations relative to ambient air: NH3, CH4, N2O, H2S, and CO2. Cumulative NH3 gas emissions were reduced by feeding cattle 5.5 and 22.0 mg·kg-1 LUB (P ≤ 0.023) and tended (P = 0.076) to be lower for the cattle fed 1.38 mg·kg-1 LUB compared to the negative controls (CON). The cumulative NH3 gas emission reductions of 960 to 1032 g, coupled with HCW increases (P ≤ 0.019) of 15 kg to 16 kg for all LUB doses vs. CON, led to reductions in NH3 gas emissions/kg HCW for all 3 LUB treatments (P ≤ 0.004). Similar to HCW, reductions in NH3 gas emissions/kg of unshrunk final BW were observed for all LUB doses (P ≤ 0.009) and were attributable to both decreases in NH3 gas emissions and numerical increases in BW. Dose had no effect on cumulative emissions or emissions standardized by BW or HCW for the other 4 gases (P ≥ 0.268). Lubabegron is a novel tool to reduce emissions of NH3 gas per kg of unshrunk live BW and hot carcass weight.

Remdesivir-Associated Significant Bradycardia: A Report of Three Cases

Recently, remdesivir was approved by the United States Food and Drug Administration for patients with Coronavirus disease 2019 (COVID-19). We herein describe 3 patients with COVID-19 who showed significant bradycardia and QTc prolongation after remdesivir administration. Bradycardia did not respond to atropine treatment in 2 of the patients, one of whom received theophylline and the other required a temporary pacemaker. Fortunately, the patients’ heart rate and rhythm returned to normal after the discontinuation of remdesivir, albeit it lengthened their hospital stays. Careful monitoring during remdesivir infusion may decrease the risk of adverse cardiovascular side effects.

Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going?

For decades, limited options existed to treat metastatic genitourinary cancers, including treatment options that could be classified as immunotherapy. Historically, immunotherapy centered on systemic cytokines for the treatment of metastatic kidney cancer, which had several adverse effects, as well as the Bacillus Calmette–Guérin vaccine for non-metastatic bladder cancer. Within the past decade, advances in immunotherapy have led to several approvals from the United States Food and Drug Administration, particularly in the field of immune checkpoint inhibition. Immune checkpoint inhibitors (ICIs) are now being used extensively to treat multiple solid tumors, including kidney and bladder cancers, and they are also being tested in many other cancers. Despite encouraging data from phase 2/3 clinical trials, less is known about biomarkers that may predict better response to ICIs. The effect of ICIs in genitourinary cancers is heterogeneous, with some tumor types having little clinical data available, or ICIs having limited activity in other tumors. In this review, we briefly discuss approved immunotherapy agents prior to the time of ICIs. Then, given the emergence of this class of agents, we summarize the several important ICIs and the clinical trials that led to their approval. Finally, we mention ongoing and future clinical trials.

How to manage incompleteness of nutritional food sources? A solution using FoodOn as pivot ontology

In order to correctly assess the nutritional quality of a raw or manufactured food product, the first step is to obtain the associated nutritional values. Food composition databases (FCDBs) managed at national level provide values for nutrients of foods. Unfortunately, values associated with some nutrients of interest may be lacking in the FCDB of the country in which the nutritional quality must be assessed and finding values associated with nutrients for similar foods in other FCDBs is a way to deal with incompleteness. An additional issue arises because the vocabulary used to denote a given food in a given FCDB is usually different from the one used in others. In this paper, the authors address the problem of retrieving the nutritional value of foods by querying different FCDBs through FoodOn used as pivot ontology. The article presents a new food source alignment method between two FCDBs. The method has been evaluated on the French and United States food nutritional evaluation. The proposed solution for the incompleteness management task has been assessed with a real use case.

How to Manage Incompleteness of Nutritional Food Sources?

In order to correctly assess the nutritional quality of a raw or manufactured food product, the first step is to obtain the associated nutritional values. Food composition databases (FCDBs) managed at national level provide values for nutrients of foods. Unfortunately, values associated with some nutrients of interest may be lacking in the FCDB of the country in which the nutritional quality must be assessed and finding values associated with nutrients for similar foods in other FCDBs is a way to deal with incompleteness. An additional issue arises because the vocabulary used to denote a given food in a given FCDB is usually different from the one used in others. In this paper, the authors address the problem of retrieving the nutritional value of foods by querying different FCDBs through FoodOn used as pivot ontology. The article presents a new food source alignment method between two FCDBs. The method has been evaluated on the French and United States food nutritional evaluation. The proposed solution for the incompleteness management task has been assessed with a real use case.

Abbreviated New Drug Application Process: A Gift for The Industry and The Patients

The United States Food and Drug Administration (USFDA) is one of the main regulated agencies wherein the submission and approval of the new drugs is done. This review is based on the process of submission to the ANDA as per FDA norms as described in paragraph IV submission in Federal Food, Drug, and Cosmetic Act (FD and C Act). No drug would exist in the market until it gets accepted by regulatory authorities. The ANDA submission is for those firms seeking to copy branded drugs before running out of patents to get profit on them. A generic applicant must provide in its application a "certification" that a patent submitted to FDA by the brand-name drug's sponsor and scheduled in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book). A Generic Product must meet the standards recognized by FDA in Reference listed drugs (RLD). This study concludes the process of ANDA submission to FDA and acts correlated to the submission in paragraph IV, the details of ANDA filling in the eCTD format and overview of the review process the checklist to the applicant.

Safety assessment of natural products in Malaysia: current practices, challenges, and new strategies

The belief that natural products are inherently safe is a primary reason for consumers to choose traditional medicines and herbal supplements for health maintenance and disease prevention. Unfortunately, some natural products on the market have been found to contain toxic compounds, such as heavy metals and microbes, as well as banned ingredients such as aristolochic acids. It shows that the existing regulatory system is inadequate and highlights the importance of thorough safety evaluations. In Malaysia, the National Pharmaceutical Regulatory Agency is responsible for the regulatory control of medicinal products and cosmetics, including natural products. For registration purpose, the safety of natural products is primarily determined through the review of documents, including monographs, research articles and scientific reports. One of the main factors hampering safety evaluations of natural products is the lack of toxicological data from animal studies. However, international regulatory agencies such as the European Food Safety Authority and the United States Food and Drug Administration are beginning to accept data obtained using alternative strategies such as non-animal predictive toxicological tools. Our paper discusses the use of state-of-the-art techniques, including chemometrics, in silico modelling and omics technologies and their applications to the safety assessments of natural products.

Physician Network Connections Associated With Faster De-Adoption of Dronedarone for Permanent Atrial Fibrillation

Background: Physicians’ professional networks are an important source of new medical information and have been shown to influence the adoption of new treatments, but it is unknown how physician networks impact the de-adoption of harmful practices. Methods: We analyzed changes in physicians’ use of dronedarone after the PALLAS trial (Palbociclib Collaborative Adjuvant Study; November 2011) showed that dronedarone increased the risk of death from cardiovascular events among patients with permanent atrial fibrillation. Deidentified administrative claims from the OptumLabs Data Warehouse were combined with physicians’ demographic information from the Doximity database and publicly available data on physicians’ patient-sharing relationships compiled by the Centers for Medicare and Medicaid Services. We used a linear probability model with an interrupted linear time trend specification to model the impact of the PALLAS trial on physicians’ dronedarone usage between 2009 and 2014. Results: Before the PALLAS trial, the use of dronedarone was increasing by 0.22 percentage points per quarter (95% CI, 0.19–0.25) in our Medicare Advantage sample (N=343 429 patient-quarter observations) and 0.63 percentage points per quarter (95% CI, 0.52–0.75) in our commercially insured sample (N=44 402 patient-quarter observations). After the PALLAS trial and subsequent United States Food and Drug Administration black box warning, physicians in the Medicare Advantage sample with an above-median number of network connections to other physicians decreased their quarterly usage of dronedarone by 0.12 percentage points more per quarter (95% CI, −0.20 to −0.04; P =0.031) than physicians with equal to or below the median number of network connections. Similar patterns existed in the commercially insured sample ( P =0.0318). Conclusions: After controlling for a wide range of patient, physician, and geographic characteristics, physicians with a greater number of network connections were faster de-adopters of dronedarone for patients with permanent atrial fibrillation after the PALLAS trial and subsequent United States Food and Drug Administration black box warning detailed the harmfulness of dronedarone for these patients. Policies for improving physicians’ responsiveness to new medical information should consider utilizing the influence of these important professional network relationships.