A case of COVID-19 diarrhea relieved by bile acid sequestrant administration.

Patients with coronavirus disease 2019 exhibit various gastrointestinal symptoms. Although diarrhea is reported in many cases, the pathophysiology of diarrhea has not been fully clarified. Herein, we report a case of coronavirus disease 2019 with diarrhea that was successfully relieved by the administration of a bile acid sequestrant. The patient was a 59-year-old man whose pneumonia was treated by the administration of glucocorticoids and mechanical ventilation. However, beginning on the 30th hospital day, he developed severe watery diarrhea (up to 10 times a day). Colonoscopy detected ulcers in the terminal ileum and ascending colon. The oral administration of a bile acid sequestrant, colestimide, improved his diarrhea quickly. Ileal inflammation is reported to suppress expression of the gut epithelial apical sodium-dependent bile acid transporter. It decreases bile acid absorption at the distal ileum and increases colonic delivery of bile acids, resulting in bile acid diarrhea. In summary, the clinical course of the case presented in this report suggests that bile acid diarrhea is a possible mechanism of watery diarrhea observed in patients with coronavirus disease 2019.

Fenretinide inhibits vitamin A formation from ß-carotene and regulates carotenoid levels in mice.

N-[4-hydroxyphenyl]retinamide, commonly known as fenretinide, a synthetic retinoid with pleiotropic benefits for human health, is currently utilized in clinical trials for cancer, cystic fibrosis, and COVID-19. However, fenretinide reduces plasma vitamin A levels by interacting with retinol-binding protein 4 (RBP4), which often results in reversible night blindness in patients. Cell culture and in vitro studies show that fenretinide binds and inhibits the activity of ß-carotene oxygenase 1 (BCO1), the enzyme responsible for endogenous vitamin A formation. Whether fenretinide inhibits vitamin A synthesis in mammals, however, remains unknown. The goal of this study was to determine if the inhibition of BCO1 by fenretinide affects vitamin A formation in mice fed ß-carotene. Our results show that wild-type mice treated with fenretinide for ten days had a reduction in tissue vitamin A stores accompanied by a two-fold increase in ß-carotene in plasma (P < 0.01) and several tissues. These effects persisted in RBP4-deficient mice and were independent of changes in intestinal ß-carotene absorption, suggesting that fenretinide inhibits vitamin A synthesis in mice. Using Bco1-/- and Bco2-/- mice we also show that fenretinide regulates intestinal carotenoid and vitamin E uptake by activating vitamin A signaling during short-term vitamin A deficiency. This study provides a deeper understanding of the impact of fenretinide on vitamin A, carotenoid, and vitamin E homeostasis, which is crucial for the pharmacological utilization of this retinoid.

Computational Study of SARS-CoV-2 RNA Dependent RNA Polymerase Allosteric Site Inhibition.

The COVID-19 pandemic has caused millions of fatalities since 2019. Despite the availability of vaccines for this disease, new strains are causing rapid ailment and are a continuous threat to vaccine efficacy. Here, molecular docking and simulations identify strong inhibitors of the allosteric site of the SARS-CoV-2 virus RNA dependent RNA polymerase (RdRp). More than one hundred different flavonoids were docked with the SARS-CoV-2 RdRp allosteric site through computational screening. The three top hits were Naringoside, Myricetin and Aureusidin 4,6-diglucoside. Simulation analyses confirmed that they are in constant contact during the simulation time course and have strong association with the enzyme's allosteric site. Absorption, distribution, metabolism, excretion and toxicity (ADMET) data provided medicinal information of these top three hits. They had good human intestinal absorption (HIA) concentrations and were non-toxic. Due to high mutation rates in the active sites of the viral enzyme, these new allosteric site inhibitors offer opportunities to drug SARS-CoV-2 RdRp. These results provide new information for the design of novel allosteric inhibitors against SARS-CoV-2 RdRp.

Integration of advanced methods and models to study drug absorption and related processes: An UNGAP perspective.

This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.

ADMET profile and virtual screening of plant and microbial natural metabolites as SARS-CoV-2 S1 glycoprotein receptor binding domain and main protease inhibitors.

In an attempt to search for selective inhibitors against the SARS-CoV-2 which caused devastating of lives and livelihoods across the globe, 415 natural metabolites isolated from several plants, fungi and bacteria, belonging to different classes, were investigated. The drug metabolism and safety profiles were computed in silico and the results showed seven compounds namely fusaric acid, jasmonic acid, jasmonic acid methyl ester, putaminoxin, putaminoxin B and D, and stagonolide K were predicted to having considerable absorption, metabolism, distribution and excretion parameters (ADME) and safety indices. Molecular docking against the receptor binding domain (RBD) of spike glycoprotein (S1) and the main protease (Mpro) exposed the compounds having better binding affinity to main protease as compared to the S1 receptor binding domain. The docking results were compared to an antiviral drug penciclovir reportedly of clinical significance in treating the SARS-CoV-2 infected patients. The results demonstrated the test compounds jasmonic acid, putaminoxins B and D bound to the HIS-CYS catalytic dyad as well as to other residues within the MPro active site with much greater affinity than penciclovir. The findings of the study suggest that these compounds could be explored as potential SARS-CoV-2 inhibitors, and could further be combined with the experimental investigations to develop effective therapeutics to deal with the present pandemic.

An examination of gastrointestinal absorption using the acetaminophen absorption test in critically ill patients with COVID-19: A retrospective cohort study.

OBJECTIVE: Gastrointestinal (GI) dysfunction is prevalent in critically ill patients with coronavirus disease 2019 (COVID-19). The acetaminophen absorption test (AAT) has been previously described as a direct method for assessment of GI function. Our study determines whether the AAT can be used to assess GI function in critically ill COVID-19 patients, compared with traditional measures of GI function. DESIGN: Retrospective observational study of critically ill patients with COVID-19. SETTING: Three intensive care units at a tertiary care academic medical center. PATIENTS: Twenty critically ill patients with COVID-19. INTERVENTIONS: The results of AAT and traditional measures for assessing GI function were collected and compared. MEASUREMENTS AND MAIN RESULTS: Among the study cohort, 55% (11 of 20) of patients had evidence of malabsorption by AAT. Interestingly, all patients with evidence of malabsorption by AAT had clinical evidence of bowel function, as indicated by stool output and low gastric residuals during the prior 24 h. When comparing patients with a detectable acetaminophen level (positive AAT) with those who had undetectable acetaminophen levels (negative AAT), radiologic evidence of ileus was less frequent (20 vs 88%; P = .03), tolerated tube-feed rates were higher (40 vs 10 ml/h; P =.01), and there was a trend toward lower gastric residual volumes (45 vs 830 ml; P =.11). CONCLUSION: Malabsorption can occur in critically ill patients with COVID-19 despite commonly used clinical indicators of tube-feeding tolerance. The AAT provides a simple, rapid, and cost-effective mechanism by which enteral function can be efficiently assessed in COVID-19 patients.

Drug therapies for reducing gastric acidity in people with cystic fibrosis.

BACKGROUND: Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. This is an update of a previously published review. OBJECTIVES: To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic and non-electronic database searches, handsearches of relevant journals,  abstract books and conference proceedings. Both authors double checked the reference lists of the searches Most recent search of the Group's Trials Register: 26 April 2021. On the 26 April 2021 further searches were conducted on the clinicaltrials.gov register to identify any ongoing trials that may be of relevance. The WHO ICTRP database was last searched in 2020 and is not currently available for searching due to the Covid-19 pandemic. SELECTION CRITERIA: All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed trial quality and extracted data. MAIN RESULTS: The searches identified 40 trials; 17 of these, with 273 participants, were suitable for inclusion, but the number of trials assessing each of the different agents was small. Seven trials were limited to children and four trials enrolled only adults. Meta-analysis was not performed, 14 trials were of a cross-over design and we did not have the appropriate information to conduct comprehensive meta-analyses. All the trials were run in single centres and duration ranged from five days to six months. The included trials were generally not reported adequately enough to allow judgements on risk of bias. However, one trial found that drug therapies that reduce gastric acidity improved gastro-intestinal symptoms such as abdominal pain; seven trials reported significant improvement in measures of fat malabsorption; and two trials reported no significant improvement in nutritional status. Only one trial reported measures of respiratory function and one trial reported an adverse effect with prostaglandin E2 analogue misoprostol. No trials have been identified assessing the effectiveness of these agents in improving quality of life, the complications of increased gastric acidity, or survival. AUTHORS' CONCLUSIONS: Trials have shown limited evidence that agents that reduce gastric acidity are associated with improvement in gastro-intestinal symptoms and fat absorption. Currently, there is insufficient evidence to indicate whether there is an improvement in nutritional status, lung function, quality of life, or survival. Furthermore, due to the unclear risks of bias in the included trials, we are unable to make firm conclusions based on the evidence reported therein. We therefore recommend that large, multicentre, randomised controlled clinical trials are undertaken to evaluate these interventions.

Novel Case Report: A Previously Reported, but Pathophysiologically Unexplained, Association Between Collagenous Colitis and Protein-Losing Enteropathy May Be Explained by an Undetected Link with Collagenous Duodenitis.

Collagenous colitis (CC) is associated with non-bloody, watery diarrhea, which is pathophysiologically reasonable because normal colonic absorption (or excretion) of water and electrolytes can be blocked by the abnormally thick collagen layer in CC. However, CC has also been associated with six previous cases of protein-losing enteropathy (PLE), with no pathophysiologic explanation. The colon does not normally absorb (or excrete) amino acids/proteins, which is primarily the function of the small bowel. Collagenous duodenitis (CD) has not been associated with PLE. This work reports a novel case of CD (and CC) associated with PLE; a pathophysiologically reasonable mechanism for CD causing PLE (by the thick collagen layer of CD blocking normal intestinal amino acid absorption); and a novel association of PLE with severe COVID-19 infection (attributed to relative immunosuppression from hypoproteinemia, hypoalbuminemia, hypogammaglobulinemia, and malnutrition from PLE).

ACE2 and gut amino acid transport.

ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. These heterodimers can form quaternary structures able to function as binding sites for SARS-CoV-2 spike glycoproteins. The heterodimerization of the carboxypeptidase ACE2 with B0AT1 is suggested to favor the direct supply of substrate amino acids to the transporter, but whether this association impacts the ability of ACE2 to mediate viral infection is not known. B0AT1 mutations cause Hartnup disorder, a condition characterized by neutral aminoaciduria and, in some cases, pellagra-like symptoms, such as photosensitive rash, diarrhea, and cerebellar ataxia. Correspondingly, the lack of ACE2 and the concurrent absence of B0AT1 expression in small intestine causes a decrease in l-tryptophan absorption, niacin deficiency, decreased intestinal antimicrobial peptide production, and increased susceptibility to inflammatory bowel disease (IBD) in mice. Thus, the abundant expression of ACE2 in small intestine and its association with amino acid transporters appears to play a crucial role for the digestion of peptides and the absorption of amino acids and, thereby, for the maintenance of structural and functional gut integrity.