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1.
Front Pharmacol ; 12: 779135, 2021.
Article in English | MEDLINE | ID: covidwho-1649683

ABSTRACT

Remdesivir has displayed pharmacological activity against SARS-CoV-2. However, no pharmacometabolomics (PM) or correlation analysis with pharmacokinetics (PK) was revealed. Rats were intravenously administered remdesivir, and a series of blood samples were collected before and after treatment. Comprehensive metabolomics profile and PK were investigated and quantitated simultaneously using our previous reliable HPLC-MS/MS method. Both longitudinal and transversal metabolic analyses were conducted, and the correlation between PM and PK parameters was evaluated using Pearson's correlation analysis and the PLS model. Multivariate statistical analysis was employed for discovering candidate biomarkers which predicted drug exposure or toxicity of remdesivir. The prominent metabolic profile variation was observed between pre- and posttreatment, and significant changes were found in 65 metabolites. A total of 15 metabolites-12 carnitines, one N-acetyl-D-glucosamine, one allantoin, and one corticosterone-were significantly correlated with the concentration of Nuc (active metabolite of remdesivir). Adenosine, spermine, guanosine, sn-glycero-3-phosphocholine, and l-homoserine may be considered potential biomarkers for predicting drug exposure or toxicity. This study is the first attempt to apply PM and PK to study remdesivir response/toxicity, and the identified candidate biomarkers might be used to predict the AUC and Cmax, indicating capability of discriminating good or poor responders. Currently, this study originally offers considerable evidence to metabolite reprogramming of remdesivir and sheds light on precision therapy development in fighting COVID-19.

2.
Front Pharmacol ; 12: 747450, 2021.
Article in English | MEDLINE | ID: covidwho-1477852

ABSTRACT

Remdesivir, a nucleotide analog prodrug, has displayed pharmacological activity against SARS-CoV-2. Recently, eicosanoids are widely involved in regulating immunity and inflammation for COVID-19 patients. Rats were intravenously administered remdesivir at a dose of 5 mg/kg, and series of blood samples were collected before and after treatment. Targeted metabolomics regarding the eicosanoid profile were investigated and quantitated simultaneously using the previously reported reliable HPLC-MS/MS method. Additionally, interplay relationship between metabolomics and pharmacokinetic parameters was performed using the Pearson correlation analysis and PLS model. For the longitudinal metabolomics of remdesivir, metabolic profiles of the same rat were comparatively substantial at discrete sampling points. The metabolic fingerprints generated by individual discrepancy of rats were larger than metabolic disturbance caused by remdesivir. As for the transversal metabolomics, the prominent metabolic profile variation was observed between the baseline and treatment status. Except for TXB2, the inflammatory- and immunology-related eicosanoids of resolvin D2, 5-HEPE, 5-HETE, and DHA were significantly disturbed and reduced after single administration of remdesivir (p < 0.05, p < 0.001). Moreover, the metabolite of PGE2 correlated with GS-441524 (active metabolite of remdesivir) concentration and pharmacokinetic parameters of Cmax, AUC0-t, AUC0-infinity, and CL significantly. Eicosanoid metabolic profiles of remdesivir at both longitudinal and transversal levels were first revealed using the robust HPLC-MS/MS method. This initial observational eicosanoid metabolomics may lighten the therapy for fighting COVID-19 and further provide mechanistic insights of SARS-CoV-2 virus infection.

3.
Anal Bioanal Chem ; 413(23): 5811-5820, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1321733

ABSTRACT

Remdesivir is a nucleotide analog prodrug that has received much attention since the outbreak of the COVID-19 pandemic in December 2019. GS-441524 (Nuc) is the active metabolite of remdesivir and plays a pivotal role in the clinical treatment of COVID-19. Here, a robust HPLC-MS/MS method was developed to determine Nuc concentrations in rat plasma samples after a one-step protein precipitation process. Chromatographic separation was accomplished on Waters XBrige C18 column (50 × 2.1 mm, 3.5 µm) under gradient elution conditions. Multiple reaction monitoring transitions in electrospray positive ion mode were m/z 292.2 → 163.2 for Nuc and 237.1 → 194.1 for the internal standard (carbamazepine). The quantitative analysis method was fully validated in line with the United States Food and Drug Administration guidelines. The linearity, accuracy and precision, matrix effect, recovery, and stability results met the requirements of the guidelines. Uncertainty of measurement and incurred sample reanalysis were analyzed to further ensure the robustness and reproducibility of the method. This optimized method was successfully applied in a rat pharmacokinetics study of remdesivir (intravenously administration, 5 mg kg-1). The method can act as a basis for further pharmacokinetic and clinical efficacy investigations in patients with COVID-19. Graphical abstract.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adenosine/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/blood , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Adenosine/blood , Adenosine/pharmacokinetics , Adenosine/standards , Adenosine Monophosphate/blood , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/standards , Alanine/blood , Alanine/pharmacokinetics , Alanine/standards , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/standards , Limit of Detection , Male , Quality Control , Rats , Rats, Sprague-Dawley , Reference Standards , Reproducibility of Results
4.
Sci Rep ; 11(1): 6283, 2021 03 18.
Article in English | MEDLINE | ID: covidwho-1142455

ABSTRACT

Susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the risk of mortality among people living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (PLWHA) is largely unknown. PLWHA are unique due to their altered immune system from their history of chronic HIV infection and their use of antiretroviral therapy, some of which have been used experimentally to treat coronavirus disease 2019 (COVID-19). Therefore, we conducted a systematic review and meta-analysis to assess the epidemiology of SARS-COV-2/HIV coinfection and estimate associated mortality from COVID-19 (Prospero Registration ID: CRD42020187980). PubMed, SCOPUS, OVID and Cochrane Library databases, and medRxiv preprint repositories were searched from January 1, 2020, to December 12, 2020. Data were extracted from studies reporting COVID-19 attack and mortality rates in PLWHA compared to their HIV-negative counterparts. Pooled attack and mortality risks were quantified using random-effects models. We identified 22 studies that included 20,982,498 participants across North America, Africa, Europe, and Asia. The median age was 56 years, and 50% were male. HIV-positive persons had a significantly higher risk of SARS-CoV-2 infection [risk ratio (RR) 1.24, 95% CI 1.05-1.46)] and mortality from COVID-19 (RR 1.78, 95% CI 1.21-2.60) than HIV-negative individuals. The beneficial effects of tenofovir and protease-inhibitors in reducing the risk of SARS-CoV-2 infection and death from COVID-19 in PLWHA remain inconclusive. HIV remains a significant risk factor for acquiring SARS-CoV-2 infection and is associated with a higher risk of mortality from COVID-19. In support of the current Centers for Disease Control and Prevention (CDC) guidelines, persons with HIV need priority consideration for the SARS-CoV-2 vaccine.


Subject(s)
COVID-19/mortality , HIV Infections/complications , COVID-19/complications , Disease Susceptibility , Humans , SARS-CoV-2
5.
Ann Epidemiol ; 56: 26-33.e1, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1062223

ABSTRACT

PURPOSE: Contact tracing has proven successful at controlling coronavirus 2019 (COVID-19) globally, and the Center for Health Security has recommended that the United States add 100,000 contact tracers to the current workforce. METHODS: To address gaps in local contact tracing, health professional students partnered with their academic institution to conduct contact tracing for all COVID-19 cases diagnosed onsite, which included identifying and reaching their contacts, educating participants, and providing social resources to support effective quarantine and isolation. RESULTS: From March 24 to May 28, 536 laboratory-confirmed COVID-19 cases were contacted and reported an average of 2.6 contacts. Contacts were informed of their exposure, asked to quarantine, and monitored for the onset of symptoms. Callers reached 94% of cases and 84% of contacts. Seventy-four percent of cases reported at least one contact. Household members had higher rates of reporting symptoms (odds ratio, 1.65; 95% confidence interval, 1.19-2.28). The average test turnaround time decreased from 21.8 days for the first patients of this program to 2.3 days on the eleventh week. CONCLUSIONS: This provides evidence for the untapped potential of community contact tracing to respond to regional needs, confront barriers to effective quarantine, and mitigate the spread of COVID-19.


Subject(s)
COVID-19/diagnosis , Contact Tracing/methods , Pandemics , Students , Academic Medical Centers , COVID-19/prevention & control , Humans , Quarantine , United States
6.
Open Forum Infectious Diseases ; 7(Supplement_1):S266-S266, 2020.
Article in English | Oxford Academic | ID: covidwho-1010465
8.
Open Heart ; 7(2)2020 11.
Article in English | MEDLINE | ID: covidwho-913813

ABSTRACT

OBJECTIVE: The association between the use of renin-angiotensin-aldosterone (RAAS) inhibitors and the risk of mortality from COVID-19 is unclear. We aimed to estimate the association of RAAS inhibitors, including ACE inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) with COVID-19 mortality risk in patients with hypertension. METHODS: PubMed (MEDLINE) SCOPUS, OVID, Cochrane Library databases and medrxiv.org were searched from 1 January 2020 to 1 September 2020. Studies reporting the association of RAAS inhibitors (ACEi or ARBs) and mortality in patients with hypertension, hospitalised for COVID-19 were extracted. Two reviewers independently extracted appropriate data of interest and assessed the risk of bias. All analyses were performed using random-effects models on log-transformed risk ratio (RR) estimates, and heterogeneity was quantified. RESULTS: Fourteen studies were included in the systematic review (n=73,073 patients with COVID-19; mean age 61 years; 53% male). Overall, the between-study heterogeneity was high (I2=80%, p<0.01). Patients with hypertension with prior use of RAAS inhibitors were 35% less likely to die from COVID-19 compared with patients with hypertension not taking RAAS inhibitors (pooled RR 0.65, 95% CI 0.45 to 0.94). The quality of evidence by Grading of Recommendations, Assessment, Development and Evaluations was graded as 'moderate' quality. CONCLUSIONS: In this meta-analysis, with prior use of RAAS inhibitors was associated with lower risk mortality from COVID-19 in patients with hypertension. Our findings suggest a potential protective effect of RAAS-inhibitors in COVID-19 patients with hypertension. PROSPERO REGISTRATION NUMBER: The present study has been registered with PROSPERO (registration ID: CRD 42020187963).


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/therapeutic use , Coronavirus Infections/mortality , Hospitalization , Hypertension/drug therapy , Pneumonia, Viral/mortality , Renin-Angiotensin System/drug effects , Adult , Aged , Aged, 80 and over , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/therapy , Female , Humans , Hypertension/diagnosis , Hypertension/mortality , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/therapy , Protective Factors , Risk Assessment , Risk Factors , Treatment Outcome
9.
Am J Infect Control ; 48(12): 1451-1456, 2020 12.
Article in English | MEDLINE | ID: covidwho-712425

ABSTRACT

BACKGROUND: The Centers for Disease Control and Prevention recommends aggressive contact tracing to control the COVID-19 pandemic. In this work, we (1) describe the development of a COVID-19 contact tracing initiative that includes medical, nursing, and public health students, and is led by clinicians and infectious disease epidemiologists within our health system, and, (2) articulate process steps for contact tracing including workflows and telephone scripts, and, (3) highlight the key challenges and strategies to overcome these challenges. METHODS: A single academic institution-based contact tracing initiative was rapidly scaled to 110 health professional students, four physicians, two epidemiologists, and a research team. Following training, students called patients who were COVID-19 positive and the individuals they were in contact with to ensure proper isolation and quarantine measures. Students also assisted those who faced barriers to quarantine. IMPLICATIONS: In total, between March 24 and May 28 - this initiative completed contact tracing for 536 confirmed cases, which resulted in the identification of 953 contacts. We aim to disseminate this process, including telephone scripts and workflow, to other health systems for use in their initiatives to respond to the COVID-19 pandemic and future public health emergencies.


Subject(s)
COVID-19/prevention & control , Contact Tracing/methods , Emergency Responders/education , SARS-CoV-2 , Students, Health Occupations , Adult , Female , Health Plan Implementation , Health Workforce , Humans , Male , Process Assessment, Health Care , Quarantine/methods , Workflow , Young Adult
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