ABSTRACT
One-compartment (1C) and permeability-limited models were used to evaluate the ability of microsomal and hepatocyte intrinsic clearances to predict hepatic clearance. Well-stirred (WSM), parallel tube (PTM), and dispersion (DM) models were evaluated within the liver as well as within whole-body physiologically based pharmacokinetic frameworks. It was shown that a linear combination of well-stirred and parallel-tube average liver blood concentrations accurately approximates dispersion model blood concentrations. Using a flow/permeability-limited model, a large systematic error was observed for acids and no systematic error for bases. A scaling factor that reduced interstitial fluid (ISF) plasma protein binding could greatly decrease the absolute average-fold error (AAFE) for acids. Using a 1C model, a scalar to reduce plasma protein binding decreased the microsomal clearance AAFE for both acids and bases. With a permeability-limited model, only acids required this scalar. The mechanism of the apparent increased cytosolic concentrations for acids remains unknown. We also show that for hepatocyte intrinsic clearance in vitro-in vivo correlations (IVIVCs), a 1C model is mechanistically appropriate since hepatocyte clearance should represent the net clearance from ISF to elimination. A relationship was derived that uses microsomal and hepatocyte intrinsic clearance to solve for an active hepatic uptake clearance, but the results were inconclusive. Finally, the PTM model generally performed better than the WSM or DM models, with no clear advantage between microsomes and hepatocytes. Significance Statement Prediction of drug clearance from microsomes or hepatocytes remains challenging. Various liver models (e.g. WSM, PTM, and DM) have been mathematically incorporated into liver as well as whole-body PBPK frameworks. Although the resulting models allow incorporation of pH partitioning, permeability, and active uptake for prediction of drug clearance, including these processes did not improve clearance predictions for both microsomes and hepatocytes.
ABSTRACT
Severe acute respiratory syndrome (SARS)-CoV-2 virus causes novel coronavirus disease 2019 (COVID-19), and there is a possible role for oxidative stress in the pathophysiology of neurological diseases associated with COVID-19. Excessive oxidative stress could be responsible for the thrombosis and other neuronal dysfunctions observed in COVID-19. This review discusses the role of oxidative stress associated with SARS-CoV-2 and the mechanisms involved. Furthermore, the various therapeutics implicated in treating COVID-19 and the oxidative stress that contributes to the etiology and pathogenesis of COVID-19-induced neuronal dysfunction are discussed. Further mechanistic and clinical research to combat COVID-19 is warranted to understand the exact mechanisms, and its true clinical effects need to be investigated to minimize neurological complications from COVID-19.
Subject(s)
COVID-19 , Nervous System Diseases , Humans , COVID-19/complications , SARS-CoV-2 , Oxidative Stress , Nervous System Diseases/etiology , Nervous System Diseases/therapyABSTRACT
The effect of laser pulse duration on the ablation of aqueous myoglobin is investigated using laser electrospray mass spectrometry (LEMS). Pulse durations of 55 femtoseconds (fs), 56 piscoseconds (ps), and 10 nanoseconds (ns) were used to ablate aqueous myoglobin from stainless-steel and quartz substrates. The integrated signal intensity of myoglobin increases with decreasing pulse duration for both substrates. Laser-induced thermal effects are assessed by the relative amount of solvent adduction and number of phosphate moieties adducted to myoglobin by each laser pulse duration. The mass spectra for 55 fs vaporization shows myoglobin with appreciable solvent and phosphate adduction and baseline elevation. The mass spectra for 10 ns ablation have minimal adduction and limited baseline elevation. Heat-induced conformation changes in myoglobin were used to measure the amount of thermal energy deposited by each laser pulse duration. Ablation using the 55 fs pulse revealed the highest ratio of unfolded to folded myoglobin in comparison to the 56 ps and 10 ns measurements due to increased droplet lifetime and consequent interaction with the acid in the electrospray solvent. Collisional activation and heated capillary temperature were employed to reduce the droplet lifetime and demonstrate that fs ablation preserves approximately 2 times more myoglobin folded conformation in comparison to ps and ns pulses.
Subject(s)
Myoglobin , Spectrometry, Mass, Electrospray Ionization , Myoglobin/chemistry , Spectrometry, Mass, Electrospray Ionization/methods , Muramidase/chemistry , Cytochromes c/chemistry , Lasers , Solvents , Water/chemistryABSTRACT
BACKGROUND: COVID-19 and tuberculosis (TB) are infectious diseases that predominantly affect the respiratory system with common symptoms, such as cough, fever, and shortness of breath, making them dual burdens. METHODS: This review will discuss the characteristics of the coexistence of TB and new infectious illnesses to provide a framework for addressing the current epidemic. Currently, there are no clear and significant data on COVID-19 infection in TB patients, they may not respond appropriately to drug therapy and may have worse treatment outcomes, especially if their TB treatment is interrupted. Due to emergence, measurements should be taken to minimize TB and COVID-19 transmission in communal settings and health care institutions were created. For both TB and COVID-19, accurate diagnostic testing and well-designed, and established therapeutic strategies are required for effective treatment. RESULTS: Several health care organizations and networks have specimen transit methods that can be utilized to diagnose and monitor the etiology and progression of COVID 19 and perform contact tracing in developed and underdeveloped nations. Furthermore, patients and health care programs could benefit from increased use of digital health technology, which could improve communication, counseling, treatment, and information management, along with other capabilities to improve health care. CONCLUSION: Patients with COVID-19 pulmonary/respiratory problems may seek treatment from respiratory physicians, pulmonologists, TB experts, and even primary health care workers. To have prophylactic and therapeutic strategies against COVID-19, TB patients should take the appropriate health care measures recommended by health care professionals/government officials and maintain their TB therapy as indicated.
Subject(s)
COVID-19 , Tuberculosis , Humans , Tuberculosis/diagnosis , Tuberculosis/drug therapy , Tuberculosis/epidemiology , Developing Countries , Health PersonnelABSTRACT
The novel coronavirus, namely, SARS-CoV-2 (COVID-19), broke out two years ago and has caused major global health issues. Adequate treatment options are still lacking for the management of COVID-19 viral infections. Many patients afflicted with COVID-19 may range from asymptomatic to severe symptomatic, triggering poor clinical outcomes, morbidity, and mortality. Cancer is one of the leading causes of death worldwide. It is pertinent to re-examine cancer prevalence during the COVID-19 pandemic to prevent mortality and complications. Understanding the impact of SARS-CoV-2 on cancer is key to appropriate healthcare measures for the treatment and prevention of this vulnerable population. Data was acquired from PubMed using key search terms. Additional databases were utilized, such as the Centers for Disease Prevention and Control, American Cancer Society (ACS), and National Cancer Institute (NCI). Cancer patients are more prone to SARS-CoV-2 infection and exhibit poor health outcomes, possibly due to a chronic immunosuppressive state and anticancer therapies. Male sex, older age, and active cancer disease or previous cancer are risk factors for COVID-19 infection, leading to possible severe complications, including morbidity or mortality. The speculated mechanism for potentially higher mortality or COVID-19 complications is through reduced immune system function and inflammatory processes through cancer disease, anticancer therapy, and active COVID-19 infection. This review includes prostate, breast, ovarian, hematologic, lung, colorectal, esophageal, bladder, pancreatic, cervical, and head and neck cancers. This review should help better maintain the health of cancer patients and direct clinicians for COVID-19 prevention to improve the overall health outcomes.
Subject(s)
COVID-19 , Neoplasms , United States , Humans , Male , COVID-19/complications , SARS-CoV-2 , Pandemics/prevention & control , Lung , Neoplasms/epidemiologyABSTRACT
The goal of this study was to analyze the effect of COVID-19 drugs and biologicals on hyperglycemia. A literature search with key terms, such as "COVID-19 drugs and hyperglycemia" and "COVID-19 vaccines and hyperglycemia," was conducted using PubMed through September 2021. The CDC data were referenced for current COVID-19 profile and statistics. The NIH COVID-19 guidelines were referenced for updated treatment recommendations. Micromedex and UpToDate were used for drug and disease information. Current results suggested that corticosteroids (dexamethasone), remdesivir and antivirals (lopinavir and ritonavir) all have the potential to significantly raise blood glucose levels putting patients at elevated risk for severe complications. In contrary, hydroxychloroquine is associated with hypoglycemia, and tocilizumab decreases inflammation which is associated with improving glucose levels. Other anti-cytokine bioactive molecules are correlated with lower blood glucose in patients with and without diabetes mellitus. Ivermectin, used for mild COVID-19 disease, possesses the potential for lowering blood glucose. Covishield, Pfizer-BioNTech, and Moderna have all been associated with hyperglycemia after the first dose. Individualized /personalized patient care is required for diabetic mellitus patients with COVID-19 infection. Improper drug therapy aggravates hyperglycemic conditions and other comorbid conditions, leading to increased morbidity and mortality.
Subject(s)
COVID-19 , Diabetes Mellitus , Hyperglycemia , Blood Glucose , COVID-19 Vaccines , ChAdOx1 nCoV-19 , Diabetes Mellitus/diagnosis , Diabetes Mellitus/drug therapy , Diabetes Mellitus/epidemiology , Humans , Hyperglycemia/chemically induced , Hyperglycemia/diagnosis , Hyperglycemia/drug therapy , SARS-CoV-2ABSTRACT
The widespread increase in multiple severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants is causing a significant health concern in the United States and worldwide. These variants exhibit increased transmissibility, cause more severe disease, exhibit evasive immune properties, impair neutralization by antibodies from vaccinated individuals or convalescence sera, and reinfection. The Centers for Disease Control and Prevention (CDC) has classified SARS-CoV-2 variants into variants of interest, variants of concern, and variants of high consequence. Currently, four variants of concern (B.1.1.7, B.1.351, P.1, and B.1.617.2) and several variants of interests (B.1.526, B.1.525, and P.2) are characterized and are essential for close monitoring. In this review, we discuss the different SARS-CoV-2 variants, emphasizing variants of concern circulating the world and highlight the various mutations and how these mutations affect the characteristics of the virus. In addition, we discuss the most common vaccines and the various studies concerning the efficacy of these vaccines against different variants of concern.
ABSTRACT
Viral infections persist globally, among all ages, gender, and ethnicity. Of particular importance is COVID-19, associated with asymptomatic to severe symptoms, including complications/mortality. Cardiovascular disease (CVD) involves heart and blood vessel disorders including coronary heart disease, cerebrovascular disease, peripheral artery disease, thrombosis, and more. CVD associated with severe COVID-19 includes heart failure, coronary artery disease, cardiomyopathy, hypertension, and cerebrovascular disease/stroke. Data were acquired from PubMed, Google Scholar, Centers for Disease Prevention and Control, and Lexi-Comp using the search terms "COVID-19 and cardiovascular pathology;" "COVID-19 induced CVD;" "Viral infection induced CVD;" and "Viral infection induced heart damage." COVID-19-induced CVD mechanisms include direct viral entry, inflammation, cytokine storm, hypoxia, interferon-mediated immune response, plaque destabilization, stress, and drug-induced causes. Other viral pathologies causing CVD include atherosclerosis, inflammation, cytokine storm, and plaque destabilization. Individual parameters, such as old age, males, and higher body mass index (BMI), are more likely to experience viral-associated complications, possibly explained by patient risk factors or comorbidities. Populations at higher risk include older males with an elevated BMI. Viral mechanisms associated with CVD are similar but differ in disease severity, potentially explained by diverse cytokine profiles where COVID-19 activates different types at higher quantities.