Project description:Many drugs are being administered to tackle coronavirus disease 2019 (COVID-19) pandemic situations without establishing clinical effectiveness or tailoring safety. A repurposing strategy might be more effective and successful if pharmacogenetic interventions are being considered in future clinical studies/trials. Although it is very unlikely that there are almost no pharmacogenetic data for COVID-19 drugs, however, from inferring the pharmacokinetic (PK)/pharmacodynamic(PD) properties and some pharmacogenetic evidence in other diseases/clinical conditions, it is highly likely that pharmacogenetic associations are also feasible in at least some COVID-19 drugs. We strongly mandate to undertake a pharmacogenetic assessment for at least these drug-gene pairs (atazanavir-UGT1A1, ABCB1, SLCO1B1, APOA5; efavirenz-CYP2B6; nevirapine-HLA, CYP2B6, ABCB1; lopinavir-SLCO1B3, ABCC2; ribavirin-SLC28A2; tocilizumab-FCGR3A; ivermectin-ABCB1; oseltamivir-CES1, ABCB1; clopidogrel-CYP2C19, ABCB1, warfarin-CYP2C9, VKORC1; non-steroidal anti-inflammatory drugs (NSAIDs)-CYP2C9) in COVID-19 patients for advancing precision medicine. Molecular docking and computational studies are promising to achieve new therapeutics against SARS-CoV-2 infection. The current situation in the discovery of anti-SARS-CoV-2 agents at four important targets from in silico studies has been described and summarized in this review. Although natural occurring compounds from different herbs against SARS-CoV-2 infection are favorable, however, accurate experimental investigation of these compounds is warranted to provide insightful information. Moreover, clinical considerations of drug-drug interactions (DDIs) and drug-herb interactions (DHIs) of the existing repurposed drugs along with pharmacogenetic (e.g., efavirenz and CYP2B6) and herbogenetic (e.g., andrographolide and CYP2C9) interventions, collectively called multifactorial drug-gene interactions (DGIs), may further accelerate the development of precision COVID-19 therapies in the real-world clinical settings.
Project description:To date, there is no licensed treatment or approved vaccine to combat the coronavirus disease of 2019 (COVID-19), and the number of new cases and mortality multiplies every day. Therefore, it is essential to develop an effective treatment strategy to control the virus spread and prevent the disease. Here, we summarized the therapeutic approaches that are used to treat this infection. Although it seems that antiviral drugs are effective in improving clinical manifestation, there is no definite treatment protocol. Lymphocytopenia, excessive inflammation, and cytokine storm followed by acute respiratory distress syndrome are still unsolved issues causing the severity of this disease. Therefore, immune response modulation and inflammation management can be considered as an essential step. There is no doubt that more studies are required to clarify immunopathogenesis and immune response; however, new therapeutic approaches including mesenchymal stromal cell and immune cell therapy showed inspiring results.
Project description:Germline inactivation of the Von Hippel-Lindau (VHL) tumor suppressor is the defining hallmark in hereditary VHL disease and VHL-associated renal cell carcinoma (RCC). However, somatic VHL mutations are also observed in patients with sporadic RCC. Loss of function VHL mutations result in constitutive activation of hypoxia-inducible factor-2 alpha (HIF-2α), which leads to increased expression of HIF target genes that promote angiogenesis and tumor growth. As of 2023, belzutifan is currently the only approved HIF-2α inhibitor for both VHL-associated and sporadic metastatic RCC (mRCC). However, there is potential for resistance with HIF-2α inhibitors which warrants novel HIF-2α-targeting strategies. In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC.
Project description:Coronaviruses disease 2019 (COVID-19) is the most crucial threat, the world has ever witnessed. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of this disease pandemic. The World Health Organization has confirmed the continuing epidemic as a worldwide public health crisis. Presently, the research on COVID-19 is even in the primitive stage. Studies on unveiling the natural route of COVID-19 infection and related pathophysiology, the biology of pulmonary airways pose a more rational restorative approach in the management of COVID-19. Thus, based on the existing facts, we methodically reviewed the efforts put forth by various research institutes, pharmaceutical companies and biotechnology firms in pulmonary delivery to prevent and control the COVID-19. This article would be valuable for the healthcare community, which is efficiently dealing with the SARS-CoV-2 crisis.
Project description:The urgent need for diagnostics and therapeutics against the COVID-19 pandemic has shown the great potential of antibodies, proteomics and metabolomics in this direction. Several clinical trials are underway using antibodies from COVID-19 patients that show very specific and strong binding to viral proteins leading to neutralization. On the other hand, proteomic and metabolomic profiles of COVID-19 patients present novel diagnostic biomarkers to predict patient outcomes and enable the development of personalized therapeutics to target the dysregulated pathways, as revealed by those profiles. Here, we discuss how studies based on antibodies, proteomics and metabolomics contribute to the development of diagnostics and therapeutics against COVID-19. The elegant technology can extend to high-throughput, rapid and reliable drug discovery strategies of the future. Lay abstract In order to prevent and treat the ongoing COVID-19 pandemic, several groups around the world are focused on a detailed understanding of the biology of SARS-CoV-2 infection, the biological events occurring inside the patients and the response of the patients to the infection. SARS-CoV-2 is the coronavirus that causes COVID-19. Some of the approaches to combat the pandemic have provided important results that can help toward therapeutic developments against COVID-19. This review discusses three such areas – antibody treatment to prevent COVID-19 infection, analysis of changes in protein profiles of COVID-19 patients, and analysis of metabolism or energy-related changes in COVID-19 patients. Antibodies are molecules produced in the host’s body as a defense response to infection. Antibodies extracted from patients who recovered from COVID-19 have been used to successfully manufacture large amounts of antibodies to treat COVID-19 patients. The analysis of protein and metabolism profiles of COVID-19 patients has shown that several proteins and metabolism-related entities in the body are either upregulated or downregulated in COVID-19. These abnormal levels can either be attenuated by medical intervention or can be monitored as indicators of COVID-19 diagnosis. Overall, antibodies, protein and metabolism profiles are three important tools, among several others, that are helpful in combating the COVID-19 pandemic.
Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive hematologic malignancy derived from precursors of plasmacytoid dendritic cells. There is no established standard therapy for BPDCN and the efficacy of conventional chemotherapy is limited, with an anticipated median overall survival ranging from 8 to 14 months. No randomized controlled trials have ever been performed to evaluate the benefit of frontline consolidation with an allogeneic hematopoietic cell transplant (allo-HCT) in BPDCN. Yet, offering an allograft has become the de facto option in BPDCN, and remains the only known long-term curative option for these patients, even in the modern era of targeted therapies. In our opinion, allo-HCT is recommended as part of frontline consolidation, especially in patients achieving first complete remission and who are deemed capable of tolerating the procedure, as published data show 3- to 4-year progression-free survival ranging from 69% to 74% in this population. Prompt referral to a transplant center, at the time of a diagnosis of BPDCN, is important to confirm allo-HCT candidacy and to initiate the process of identifying a suitable human leukocyte antigen (HLA)-compatible donor. Because disease relapse remains a major concern, additional strategies, such as post-allograft consolidation/maintenance therapy, are certainly needed to help further improve outcomes. Finally, patients deemed ineligible to receive an allo-HCT, due to lack of response and/or poor performance status, should be considered for enrollment in clinical trials.
Project description:The recent coronavirus disease 2019 outbreak around the world has had an enormous impact on the global health burden, threatening the lives of many individuals, and has had severe socio-economic consequences. Many pharmaceutical and biotechnology companies have commenced intensive research on different therapeutic strategies, from repurposed antiviral drugs to vaccines and monoclonal antibodies to prevent the spread of the disease and treat infected patients. Among the various strategies, advanced therapeutic approaches including cell- and gene-editing-based therapeutics are also being investigated, and initial results in in-vitro and early phase I studies have been promising. However, further assessments are required. This article reviews the underlying mechanisms for the pathogenesis of severe acute respiratory syndrome coronavirus-2, and discusses available therapeutic candidates and advanced modalities that are being evaluated in in-vitro/in-vivo models and are of note in clinical trials.
Project description:PurposeAs COVID-19 disease progresses, the host inflammatory response contributes to hypoxemia and severe and critical illness. In these latter stages of disease, patients may benefit from immunomodulatory therapies to control the aberrant host inflammatory response. In this review, we provide an overview of these therapies and provide summaries of the studies that led to issuance of FDA Emergency Use Authorization or recommendation by the Infectious Diseases Society of America (IDSA).Materials and methodsWe reviewed English-language studies, Emergency Use Authorizations (EUAs), and guidelines from March 2020 to present.Conclusion and relevanceThere are several therapies with proposed benefit in severe and critical COVID-19 disease. Few have been issued FDA EUA or recommendation by the Infectious Diseases Society of America (IDSA). Physicians should be familiar with the evidence supporting use of these therapies and the patient populations most likely to benefit from each.
Project description:A new global pandemic of coronavirus disease 2019 (COVID-19) has resulted in high mortality and morbidity. Currently numerous drugs are under expedited investigations without well-established safety or efficacy data. Pharmacogenomics may allow individualization of these drugs thereby improving efficacy and safety. In this review, we summarized the pharmacogenomic literature available for COVID-19 drug therapies including hydroxychloroquine, chloroquine, azithromycin, remdesivir, favipiravir, ribavirin, lopinavir/ritonavir, darunavir/cobicistat, interferon beta-1b, tocilizumab, ruxolitinib, baricitinib, and corticosteroids. We searched PubMed, reviewed the Pharmacogenomics Knowledgebase (PharmGKB®) website, Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the U.S. Food and Drug Administration (FDA) pharmacogenomics information in the product labeling, and the FDA pharmacogenomics association table. We found several drug-gene variant pairs that may alter the pharmacokinetics of hydroxychloroquine/chloroquine (CYP2C8, CYP2D6, SLCO1A2, and SLCO1B1); azithromycin (ABCB1); ribavirin (SLC29A1, SLC28A2, and SLC28A3); and lopinavir/ritonavir (SLCO1B1, ABCC2, CYP3A). We also identified other variants, that are associated with adverse effects, most notable in hydroxychloroquine/chloroquine (G6PD; hemolysis), ribavirin (ITPA; hemolysis), and interferon β -1b (IRF6; liver toxicity). We also describe the complexity of the risk for QT prolongation in this setting because of additive effects of combining more than one QT-prolonging drug (i.e., hydroxychloroquine/chloroquine and azithromycin), increased concentrations of the drugs due to genetic variants, along with the risk of also combining therapy with potent inhibitors. In conclusion, although direct evidence in COVID-19 patients is lacking, we identified potential actionable genetic markers in COVID-19 therapies. Clinical studies in COVID-19 patients are deemed warranted to assess potential roles of these markers.