Brett Sadowski - Academia.edu (original) (raw)

Papers by Brett Sadowski

Military medicine, Feb 12, 2024

Journal of xenobiotics, May 10, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

The American Journal of Gastroenterology, Jun 19, 2023

The American Journal of Gastroenterology, Oct 1, 2022

Medicinal Chemistry, Jun 1, 2023

Objective: A series of novel, substituted tetracyclic benzothiazepines were designed and prepared... more Objective: A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize potency of this chemical class against drug-resistant strains of the malaria parasite. Method: Tetracyclic benzothiazepines bearing structural modification at seven distinct positions within the structure were synthesized, in Knoevenagel condensation reactions followed by sequential intermolecular thio-Michael and then intramolecular imine formation reactions. Following purification and chemical characterization, the novel compounds were tested for in vitro efficacy against blood-stage P. falciparum and liver-stage P. berghei, and also for in vivo efficacy against P. berghei. Results: Benzothiazepines bearing structural modification at the sulfur atom and at the three carbocycles within the molecule were successfully synthesized. The majority of analogs inhibited blood-stage P. falciparum with submicromolar IC50 values. The potency of an 8-methoxy-substituted analog 12 exceeded that of chloroquine in all three P. falciparum strains tested. The parent benzothiazepine 1 possessed liver-stage activity, inhibiting P. berghei sporozoites infecting HepG2 cells with an IC50 of 106.4 nM and an IC90 of 408.9 nM, but failed to enhance the longevity of P. berghei infected mice compared to the controls. Compounds displayed modest toxicity toward HepG2 cells, and were tolerated by mice at the highest dose tested, 640 mg/kg/dose once daily for three days. Conclusion: The tetracyclic benzothiazepine described, which inhibits P. berghei infected hepatic cells with an IC50 of 106.4 nM, would appear to warrant further investigation. Optimization of ADME properties may be required, since the most active analogs are probably excessively lipophilic.

The American Journal of Gastroenterology, Jun 1, 2021

The American Journal of GASTROENTEROLOGY nature publishing group CLINICAL AND SYSTEMATIC REVIEWS ... more The American Journal of GASTROENTEROLOGY nature publishing group CLINICAL AND SYSTEMATIC REVIEWS 1075 REVIEW QUESTIONS: 1. Which one of the following statements is correct regarding the role of microbiota in irritable bowel syndrome (IBS)?

Current hepatology reports, Apr 1, 2022

Background and Purpose of Review The COVID-19 pandemic has resulted in over 800,000 deaths worldw... more Background and Purpose of Review The COVID-19 pandemic has resulted in over 800,000 deaths worldwide and resulted in fundamental changes in practice in nearly every aspect of medicine. The majority of symptomatic patients experience liver-associated enzyme (LAE) elevations which appear to be correlated to disease severity. Furthermore, there are unique considerations of COVID-19 on chronic liver disease. Background, including epidemiology, pathophysiologic mechanisms and therapeutics, as well as the impact of COVID-19 on specific chronic liver disease, is discussed. Findings Studies suggest that degree of LAE elevation correlates with illness severity, although it is unclear whether this represents true liver injury. Numerous proposed treatments for COVID-19 have been linked with drug induced liver injury and may have clinically significant drug-drug interactions. Others may have unintended consequences on chronic liver disease treatment including reactivation of hepatitis B. The risk of severe COVID-19 in patients with chronic liver disease is largely unknown; metabolic dysfunction-associated fatty liver disease may be linked to higher risk for severe illness. Implications for cirrhosis of other etiologies, autoimmune hepatitis, and viral hepatitis are less well defined. The treatment of chronic liver disease has been severely impacted by the pandemic. The societal factors created by the pandemic have led to decreased in person visits, evolving access to invasive screening modalities, food and financial insecurity, and likely increased alcohol use. Conclusions The impacts of COVID-19 on the liver range from a potential increased risk of severe infection in chronic liver disease patients, to hepatotoxic effects of proposed treatments, to second and third order impacts on the care of patients with chronic liver disease. Keywords Severe acute respiratory syndrome coronavirus 2/SARS-CoV-2 • COVID-19 • Chronic liver disease • Cirrhosis • Chemical and drug-induced liver injury This article is part of the Topical Collection on Drug-Induced Liver Injury

American Journal of Gastroenterology

Journal of Intensive Care Medicine

Objectives: To review ICU patients with elevated ammonia without a clear hepatic etiology, to com... more Objectives: To review ICU patients with elevated ammonia without a clear hepatic etiology, to compare outcomes between those who received lactulose and those who did not. Design: Retrospective observational study. Setting: Medical, surgical, and subspecialty intensive care units at Wake Forest Baptist Medical Center, Winston-Salem, North Carolina between December 2012 and August 2016. Patients: Adults with ammonia levels above 50 μmol/L, excluding those with known chronic liver disease, inborn error of metabolism, active use of valproic acid, total bilirubin ≥ 2 μmol/L, or alanine aminotransferase ≥ 100 units/L. Interventions: Comparison in ICU length of stay (LOS), hospital LOS, in-hospital mortality, and mortality at 30 and 90 days. Measurements and Main Results: Criteria for inclusion were met in 103 cases. Mean ammonia level was 75 μmol/L, with undetermined etiology in the majority of subjects. Lactulose was given in 48 cases (46.6%), with a median of 9.5 doses given. There were...

ACG Case Reports Journal, Apr 1, 2020

ABSTRACT Ectopic varices are a rare sequelae of portal hypertension and present in unique ways, w... more ABSTRACT Ectopic varices are a rare sequelae of portal hypertension and present in unique ways, which may not always prompt consideration. Furthermore, endoscopic interventions on venous collaterals in the setting of portal hypertension affect the portal system hemodynamics, which may further complicate the clinical picture. We report a man with decompensated hepatitis C cirrhosis who developed hemocholecyst complicated by perforation with hemoperitoneum soon after endoscopic variceal ligation of the esophageal varices in the setting of retrospectively discovered gallbladder varices.

Gastrointestinal Endoscopy, 2014

feeding tube presented with impairment of flow. Mobilization of the tube proved impossible. Endos... more feeding tube presented with impairment of flow. Mobilization of the tube proved impossible. Endoscopy confirmed the buried bumper syndrome, with the internal bumper being completely buried. Only the lumen of the internal tube could be suspected. We cut the external end of the tube at 3 cm from the abdominal wall and inserted a guide wire through the lumen into the stomach. An 18 mm esophageal balloon dilator was placed over the guide wire and through the endoscope (TTS) into the gastric tubular lumen of the PEG-tube. The balloon was inflated to the recommended maximum pressure so it remained solidly impacted in the PEG tube. Traction of the endoscope and balloon catheter permitted extraction of the bumper through the stomach and mouth. A new PEG tube was inserted during the same procedure using the guide wire, still in place. So only one endoscopy was needed. The patient's further course was uneventful.

American Journal of Gastroenterology, 2020

Institutions Institutions are listed at the end of article.

Clinical Liver Disease, 2021

Frailty, sarcopenia, and malnutrition are critical considerations in the evaluation of patients w... more Frailty, sarcopenia, and malnutrition are critical considerations in the evaluation of patients with cirrhosis who require liver transplantation (LT). The concept of frailty consists of functional decline, vulnerability to health stressors, and decreased physiological reserve. Sarcopenia, defined by a reduction in muscle mass and function, may occur as a result of aging or chronic diseases, including cirrhosis. Malnutrition can further lead to sarcopenia through decreased intake or altered uptake of nutrients, resulting in a change in body mass. Defining these elements in liver disease has not reached consensus, nor have measures of these elements been widely accepted.

Autoimmune hepatitis (AIH) is an inflammatory disorder of the liver with a wide spectrum of disea... more Autoimmune hepatitis (AIH) is an inflammatory disorder of the liver with a wide spectrum of disease presentation, from asymptomatic elevations in liver-associated enzymes to acute liver failure. AIH is classically associated with elevated immunoglobulins and autoantibodies, although approximately 20% of patients with features of AIH lack circulating antibodies. Recently, tumour necrosis factor alpha inhibitors have been implicated in several cases of drug-induced AIH which impact treatment regimens for patients with inflammatory bowel disease (IBD). We present a case of infliximab-induced seronegative AIH responding to budesonide therapy with successful alteration of IBD treatment regimen to vedolizumab.

Military Medicine

Objectives Drug-induced liver injury (DILI) is a significant cause of morbidity and mortality. Es... more Objectives Drug-induced liver injury (DILI) is a significant cause of morbidity and mortality. Establishing a diagnosis is challenging due to the broad differential diagnosis of liver injury. We retrospectively reviewed patients with severe idiosyncratic DILI at Walter Reed National Military Medical Center in order to define the scope and patterns of injury in the military population. Methods Using the military health database, we identified a total of 110 patients who had an International Classification of Disease (ICD)-10 code for toxic liver injury in the electronic medical record at Walter Reed National Military Medical Center between 2016 and 2019. Each patient record was reviewed, and all pertinent data for included patients were recorded into a database for analysis. Results Twenty-seven out of 110 patients with a diagnostic code for toxic liver injury met inclusion criteria for severe idiosyncratic DILI. Nine cases were caused by supplements, including 5 active duty service ...