作者: Nisar, Haseeb ; Anwar, Faria ; Sadaf, Saima ; Javaid, Anum ; Wajid, Bilal ; Saeed, Amir ; Attique, Syed Awais ; Nisar, Wardah ; Shahid, Samiah ; Ahmad, Ashfaq

The global health pandemic known as COVID-19, which stems from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a significant concern worldwide. Several treatment methods exist for COVID-19; however, there is an urgent demand for previously established drugs and vaccines to effectively combat the disease. Since, discovering new drugs poses a significant challenge, making the repurposing of existing drugs can potentially reduce time and costs compared to developing entirely new drugs from scratch. The objective of this study is to identify hub genes and associated repurposed drugs targeting them. We analyzed differentially expressed genes (DEGs) by analyzing RNA-seq transcriptomic datasets and integrated with genes associated with COVID-19 present in different databases. We detected 173 Covid-19 associated genes for the construction of a protein-protein interaction (PPI) network which resulted in the identification of the top 10 hub genes/proteins (STAT1, IRF7, MX1, IRF9, ISG15, OAS3, OAS2, OAS1, IRF3, and IRF1). Hub genes were subjected to GO functional and KEGG pathway enrichment analyses, which indicated some key roles and signaling pathways that were strongly related to SARS-CoV-2 infections. We conducted drug repurposing analysis using CMap, TTD, and DrugBank databases with these 10 hub genes, leading to the identification of Piceatannol, CKD-712, and PMID26394986-Compound-10 as top-ranked candidate drugs. Finally, drug-gene interactions analysis through molecular docking and validated via molecular dynamic simulation for 80 ns suggests PMID26394986-Compound-10 as the only potential drug. Our research demonstrates how in silico analysis might produce repurposing candidates to help respond faster to new disease outbreaks.Communicated by Ramaswamy H. Sarma.

2017-09-01·Journal of chromatography. B, Analytical technologies in the biomedical and life sciences3区 · 医学

Development of a LC–MS/MS method for the determination of CKD-712 in rat plasma: Application to a pharmacokinetic study in rats

3区 · 医学

Article

作者: Lee, Jong-Hwa ; Chae, Jung-Woo ; Jeong, Eun Ju ; Kwon, Kwang-Il ; Yun, Hwi-Yeol ; Eom, Han Young ; Koo, Tae-Sung

CKD-712 is a potential treatment for sepsis, as it exhibits protective effects against lipopolysaccharide-mediated platelet aggregation, inducible nitric oxide synthase expression, and cecum-ligation puncture-induced septic mortality in mice. In this study, we develop a rapid and sensitive LC-MS/MS method for determining CKD-712 in rat plasma. CKD-712 and papaverine hydrochloride (an internal standard) were analyzed using an LC-MS/MS system consisting of an Agilent HPLC system (HP-1100) equipped with an Atlantis HILIC Silica (2.1×50mm, 3μm) column and a API 4000 (Applied Biosystems/MDS Sciex, USA) in a positive ESI mode. We utilized multiple reaction monitoring (MRM) at m/z transitions of 306.2-164.0 to analyze CKD-712, and 340.3-202.1 m/z for IS, with a mobile phase of acetonitrile (0.025% trifluoroacetic acid):20mM ammonium acetate (94:6, v/v) at a flow rate of 0.25mL/min. The lower limit of quantification (LLOQ) was 5ng/mL, with a linearity ranging from 5 to 1000ng/mL (r>0.999). Validation parameters including specificity, precision, accuracy, matrix effect, recovery, dilution effect and stability results were well within acceptance criteria, and applied successfully on a pharmacokinetic study in rats.

2017-04-01·Clinical drug investigation4区 · 医学

Changes in Cardiac Function After a Single Intravenous Administration of CKD-712 in Healthy Male Volunteers

4区 · 医学

Article

作者: Lee, SeungHwan ; Kim, JaeWoo ; Yu, Kyung-Sang ; Jang, In-Jin ; Park, Sang-In

BACKGROUND AND OBJECTIVES:

CKD-712, a candidate treatment for septic shock, acts by increasing cardiac output. This study investigated changes in the pharmacodynamics, pharmacokinetics, and tolerability of CKD-712 after a single intravenous administration.

METHODS:

A dose-block-randomized, double-blind, placebo-controlled, single-dose escalation study was conducted in 44 healthy subjects receiving 20, 40, 80, 160, 240, or 320 μg/kg CKD-712 or placebo. Pharmacodynamics were evaluated using computerized impedance cardiography, vital signs, platelet aggregation, and bleeding time. Serial blood and urine samples for pharmacokinetic analysis were collected up to 12 and 24 h, respectively, after the initiation of intravenous drug infusion. Tolerability assessments were performed throughout the study.

RESULTS:

The area under the effect-time curve of the cardiac index (AUEC_CI) and systolic blood pressure (AUEC_SBP) changed significantly with the 160 and 320 µg/kg doses of CKD-712 compared with placebo. Furthermore, the AUEC_CI and AUEC_SBP tended to increase as the systemic exposure of CKD-712 increased from 20 to 240 µg/kg. The frequency of drug-related adverse events (AEs), including cardiovascular symptoms, was higher with the 320 µg/kg dose.

CONCLUSION:

The pharmacological effects and on-target AEs of CKD-712 increased relative to the dose increments. The results of this study suggest that potentially therapeutic doses of CKD-712 could range from 160 to 240 μg/kg.

100 项与 CKD-712 相关的药物交易

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