Application and mechanism of histamine receptor antagonists in treatment of coronavirus disease 2019: research progress.

The coronavirus disease 2019 (COVID-19) has become a global pandemic. It is urgent to find treatments to control the infection and improve symptoms. Homologous modeling and clinical analyses suggest that histamine receptor antagonists have broad prospects in the treatment of COVID-19. This article introduces the research progress of histamine H1 receptor antagonist combined with azithromycin, histamine H2 receptor antagonist famotidine alone or combined with aspirin, and histamine H1 and H2 receptor antagonists used in combination in the treatment of COVID-19. Finally, the possible mechanism of histamine receptor antagonists in the treatment of COVID-19 was introduced and the application prospect of histamine receptor antagonists in the treatment of COVID-19 was analyzed.Copyright © 2022, Second Military Medical University Press. All rights reserved.

METFORMIN USE IS ASSOCIATED WITH LESS FREQUENT SEVERE LIVER INJURY UPON HOSPITAL ADMISSIN WITH COVID-19

Introduction In a study involving > 10,000 patients hospitalized with COVID-19, we found that liver injury, which was present in ~70% of patients upon hospital admission, correlates with in-hospital mortality (Satapathy et al., Eur J Gastroenterol Hepatol 2021). Curiously, severe liver chemistry abnormalities (LCA) were seen less often in patients with diabetes or hypertension, although these diseases confer increased risk of severe disease. This raises the question whether home medications protect from COVID-19 associated liver injury. We now analyzed associations between LCA and twenty-six groups of antidiabetic, antihypertensive, and other common mediations. Results 9898 patients hospitalized with COVID-19 in 13 hospitals in New York between March 1 to August 31, 2020, who had an complete records on admission were retrospectively analyzed. LCA measured were alanine and aspartate aminotransferases, alkaline phosphatase, and bilirubin, and were defined as absent, mildmoderate (up to four times elevated), or severe. Diseases and socioeconomic factors were similar to the initial study. 67.2% had hypertension, and 40.8% had diabetes. The most common medications included insulin (12.2%), metformin (18.3%), sulfonylureas (6.8%), DDP4 inhibitors (6.3%), ACE inhibitors (14.8%), ARBs (18.6%), beta-blockers (33.2%), calcium-channel blockers (26.5%), diuretics (21.6%), statins (41.5%), PPIs (22.1%), H2- blockers (6.8%), antiplatelets (31.0%), anticoagulants (20.5%). Comparisons between groups were analyzed using Kruskal-Wallis test, chi-squared test, and Fisher's exact test. Univariate and multivariate regression analysis were performed. Univariate analysis showed a higher risk for severe LCA in men, Asian and Black race, non-Hispanic ethnicity. As in our prior analysis, hypertension and diabetes were associated with less frequent severe LCA. In addition, hyperlipidemia, CAD, CHF, atrial fibrillation, CKD, ESRD, GERD, asthma, COPD, cancer, and liver disease were inversely associated with severe LCA. Medications that were associated with less frequent severe LCA included statins, ACE, ARBs, calcium-channel blockers, betablockers, diuretics, antiplatelet medications, insulin, biguanide, sulfonylureas, PPIs, H2- blockers, and anticoagulants, but not oral steroids. In multivariate analysis, male gender, Asian and Black race were associated with increased risk of severe LCA. Hypertension, ESRD and asthma were associated with less frequent severe LCA, but not diabetes. Among medications, only metformin showed a statistically significant correlation with severe LCA on admission, with a hazard ratio 0.57 (p 0.0002). Conclusions Metformin use was inversely associated with severe liver chemistry abnormalities upon hospital admission with COVID- 19 in a large cohort of patients during the initial pandemic in New York.

COVID-19 PANDEMIC INCREASED HEALTHCARE UTILIZATION AMONG PATIENTS WITH FUNCTIONAL GASTROINTESTINAL DISORDERS

Introduction: SARS-CoV-2 is known to infect the gastrointestinal tract and COVID-19 may manifest with gastrointestinal symptoms. Studies regarding the risks factors for COVID-19 and the impact of the pandemic on healthcare utilization in patients with functional gastrointestinal disorders (FGID) are lacking. Methods: We performed a retrospective study of consecutive patients with FGID (irritable bowel syndrome, gastroparesis, functional dyspepsia) who tested positive for SARS-CoV-2 and compared to a randomly selected sample of FGID who tested negative. We used multivariate logistic regression to determine risk factors for SARS-CoV-2 infection. We also evaluated healthcare utilization by comparing health care visits (ED, inpatient, outpatient), medication prescriptions, abdominal CT scans, and endoscopy rate 6 month pre pandemic and 6 months after the start of the pandemic (using 3/15/20 as a cut-off point). Results: We identified and analyzed 2592 patients with FGID who underwent SARS-CoV-2 testing (83 positive COVID-19 cases). The total positivity rate was 3.9%. Inpatient admissions (0.36 vs 0.50, p<0.001), outpatient visits (4.78 vs 5.68, p<0.001), number of abdominal CT scans (0.18 vs 0.23, p=0.002), number of upper endoscopies (0.10 vs 0.19, p<0.001), and number of colonoscopies (0.04 vs 0.10, p<0.001) were higher during the 6 months after the start of the pandemic (compared to the 6 months before). Prescription rate for PPIs, H2 blockers, opioids, and anti-platelet agents were also higher during the pandemic (Table 1). Patients had higher rates of symptoms including abdominal pain, vomiting, diarrhea, constipation, and weight loss during the pandemic, as reported by ICD coding. Similar trends were seen when stratifying by FGID type, and by SARS-CoV-2 test positivity (but did not reach statistical significance in the SARS-CoV-2 positive group. Active smoking, cough, pneumonia, and diarrhea-predominant IBS were associated with increased risk of COVID-19 among patients with FGID, while alcohol use and functional dyspepsia decreased this risk (Table 2). Discussion: Health care utilization among patients with FGIDs increased significantly during the pandemic, independent of SARS-CoV-2 positivity. Increased psychosocial stress and increased utilization of telehealth visits may partially explain this trend. Our data suggest that smoking status, cough, pneumonia, and diarrhea-predominant IBS could independently determine the increased risk of COVID-19 among patients with FGID.(Table presented)(Table presented)

A Birds-Eye (Re)View of Acid-Suppression Drugs, COVID-19, and the Highly Variable Literature.

This Perspective examines a recent surge of information regarding the potential benefits of acid-suppression drugs in the context of COVID-19, with a particular eye on the great variability (and, thus, confusion) that has arisen across the reported findings, at least as regards the popular antacid famotidine. The degree of inconsistency and discordance reflects contradictory conclusions from independent, clinical-based studies that took roughly similar approaches, in terms of both experimental design (retrospective, observational, cohort-based, etc.) and statistical analysis workflows (propensity-score matching and stratification into sub-cohorts, etc.). The contradictions and potential confusion have ramifications for clinicians faced with choosing therapeutically optimal courses of intervention: e.g., do any potential benefits of famotidine suggest its use in a particular COVID-19 case? (If so, what administration route, dosage regimen, duration, etc. are likely optimal?) As succinctly put this March in Freedberg et al. (2021), "…several retrospective studies show relationships between famotidine and outcomes in COVID-19 and several do not." Beyond the pressing issue of possible therapeutic indications, the conflicting data and conclusions related to famotidine must be resolved before its inclusion/integration in ontological and knowledge graph (KG)-based frameworks, which in turn are useful for drug discovery and repurposing. As a broader methodological issue, note that reconciling inconsistencies would bolster the validity of meta-analyses which draw upon the relevant data-sources. And, perhaps most broadly, developing a system for treating inconsistencies would stand to improve the qualities of both 1) real world evidence-based studies (retrospective), on the one hand, and 2) placebo-controlled, randomized multi-center clinical trials (prospective), on the other hand. In other words, a systematic approach to reconciling the two types of studies would inherently improve the quality and utility of each type of study individually.

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms.

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease. Currently, there are no approved pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We have investigated several plausible hypotheses for famotidine activity including antiviral and host-mediated mechanisms of action. We propose that the principal mechanism of action of famotidine for relieving COVID-19 symptoms involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release. Based on these findings and associated hypothesis, new COVID-19 multi-drug treatment strategies based on repurposing well-characterized drugs are being developed and clinically tested, and many of these drugs are available worldwide in inexpensive generic oral forms suitable for both outpatient and inpatient treatment of COVID-19 disease.