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We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL pro) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart.  With the 3CL pro molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache.  The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.

Green chemistry has a beneficial influence on the environment and the pharmaceutical enterprises’ economy. Research and quality control laboratories worldwide conduct millions of analyses daily, employing liquid chromatography as the primary analytical technique. Furthermore, advancements in stationary phase technologies aimed at achieving faster and more efficient separations have introduced a new objective for chromatographers. This objective is to supersede conventional methodologies that rely heavily on substantial quantities of organic solvents, pose environmental hazards and incur considerable economic costs. The aim of this work is to provide a brief comparison between monolithic, core-shell and traditional fully porous stationary phases. This could help analysts by offering options for high-speed versus high-resolution separation when choosing the best packing materials. The analytes used in the study are two essential drugs used in the treatment of hepatitis C virus: Sofosbuvir and Ledipasvir, which are co-formulated in tablet dosage forms. The monolithic column enabled the fastest analysis, whereas the core-shell provided the highest efficiency. Validation was conducted in accordance with ICH guidelines using the RP-C18 monolithic column, a mobile phase consisting of 0.1% acetic acid and ethanol (60:40), a flow rate of 1 mL.min − 1 , and detection at 210 nm. The total analysis time did not exceed 3 min, achieving high accuracy and sensitivity while minimizing the use of hazardous solvents. It achieved a very good score on different green analytical chemistry assessment metrics; 0.7 on AGREE, 76 on MoGAPI, 80 on BAGI, and 73 on CACI.

This study seeks to disseminate insights from Egypt’s management of COVID-19 patients by evaluating the effectiveness and safety of various treatment regimens using combined repurposed antivirals. A retrospective cohort study was conducted on 310 moderate hospitalized COVID-19 cases. Patients were divided into four treatment arms: standard care, sofosbuvir/daclatasvir (sovodak) plus ivermectin, sofosbuvir/ledipasvir (SOF/LED) plus hydroxychloroquine, and SOF/LED plus ivermectin. The study analyzed parameters such as hospitalization days, total clinical recovery percentage, and progressive CT chest changes. The median hospitalization days significantly differed in arm 1 versus arms 2 and 3 ( p  < 0.001 and p  = 0.025, respectively). There was a difference between arms 1 and 4 in the days till clinical improvement ( p  = 0.007). Complete normalization of vital signs occurred in 26% of arm 4 patients versus 43% in arm 1 ( p  = 0.023), and a statistically significant difference in the proportion of patients with total clinical recovery was found between arms 1 and 2 ( p  = 0.009). All arms displayed a statistically significant lower proportion of patients with progressive CT scans compared to arm 1. Our study reveals that most tested antiviral combinations effectively reduced hospitalization days and progressive CT scans. These regimens demonstrated efficacy in treating moderate COVID-19 to prevent disease progression and complications.

Chronic hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The introduction of direct acting antiviral agents (DAAs) for its treatment represents a major advance in terms of sustained virologic response (SVR) rates and adverse effect profiles. Mechanistically, DAAs inhibit specific HCV non-structural proteins (NS) that are vital for its replication. Boceprevir, telaprevir, simeprevir, asunaprevir, grazoprevir and paritaprevir are NS3/4A inhibitors. Ombitasvir, ledipasvir, daclatasvir, elbasvir and velpatasvir are NS5A inhibitors. Sofosbuvir and dasabuvir are NS5B inhibitors. Currently, a combination of two or more DAAs is the corner stone for the treatment of HCV infection. However, the success of DAA therapy is facing several challenges, including the potential of drug-drug interactions and resistant variance. Moreover, the shortage of relevant clinical pharmacological data and drug interaction regarding DAA is a clinical concern. The present review discusses the clinical pharmacology of DAAs with special emphasis on drug-drug interaction.

Background. Shortening the duration of treatment with HCV direct-acting antivirals (DAAs) leads to substantial cost reductions. According to the label, sofosbuvir and ledipasvir can be prescribed for 8 weeks (SL8) in noncirrhotic women or men with HCV genotype 1 and low viral loads. However, real-world data about the efficacy and safety of SL8 are largely missing. Methods. Interim results from an ongoing prospective, multicenter cohort of 9 treatment centers in Germany (GECCO). All patients started on treatment with HCV DAAs since January 2014 were included. This report describes safety and efficacy outcomes in 210 patients with HCV monoinfection and 35 with human immunodeficiency virus (HIV)–HCV coinfection given SL8 in a real-world setting. Results. Of 1353 patients included into the GECCO cohort until December 2015, a total of 1287 had complete data sets for this analysis; 337 (26.2%) fulfilled the criteria for SL8 according to the package insert, but only 193 (57.2%) were eventually treated for 8 weeks. Another 52 patients did not fulfill the criteria but were treated for 8 weeks. SL8 was generally well tolerated. The overall sustained virologic response rate 12 weeks after the end of treatment was 93.5% (186 of 199). The on-treatment response rate was 99.4% (159 of 160) in HCV-monoinfected and 96.4% (27 of 28) in HIV-HCV–coinfected patients. Ten patients were lost to follow-up. Conclusions. SL8 seems highly effective and safe in well-selected HCV-monoinfected and HIV-HCV–coinfected patients in a real-world setting.

This study aimed to design dual-responsive chitosan–polylactic acid nanosystems (PLA@CS NPs) for controlled and targeted ledipasvir (LED) delivery to HepG2 liver cancer cells, thereby reducing the systemic toxicity and improving the therapeutic selectivity. Two formulations were developed utilizing ionotropic gelation and w/o/w emulsion techniques: LED@CS NPs with a size of 143 nm, a zeta potential of +43.5 mV, and a loading capacity of 44.1%, and LED-PLA@CS NPs measuring 394 nm, with a zeta potential of +33.3 mV and a loading capacity of 89.3%, with the latter demonstrating significant drug payload capacity. Since most drugs work through interaction with DNA, the in vitro affinity of DNA to LED and its encapsulated forms was assessed using stopped-flow and other approaches. They bind through multi-modal electrostatic and intercalative modes via two reversible processes: a fast complexation followed by a slow isomerization. The overall binding activation parameters for LED (cordination affinity, Ka = 128.4 M−1, Kd = 7.8 × 10−3 M, ΔG = −12.02 kJ mol−1), LED@CS NPs (Ka = 2131 M−1, Kd = 0.47 × 10−3 M, ΔG = −18.98 kJ mol−1) and LED-PLA@CS NPs (Ka = 22026 M−1, Kd = 0.045 × 10−3 M, ΔG = −24.79 kJ mol−1) were obtained with a reactivity ratio of 1/16/170 (LED/LED@CS NPs/LED-PLA@CS NPs). This indicates that encapsulation enhanced the interaction between the DNA and the LED-loaded nanoparticle systems, without changing the mechanism, and formed thermodynamically stable complexes. The drug release kinetics were assessed under tumor-mimetic conditions (pH 5.5, 10 mM GSH) and physiological settings (pH 7.4, 2 μM GSH). The LED@CS NPs and LED-PLA@CS NPs exhibited drug release rates of 88.0% and 73%, respectively, under dual stimuli over 50 h, exceeding the release rates observed under physiological conditions, which were 58% and 54%, thereby indicating that the LED@CS NPs and LED-PLA@CS NPs systems specifically target malignant tissue. Release regulated by Fickian diffusion facilitates tumor-specific payload delivery. Although encapsulation did not enhance the immediate cytotoxicity compared to free LED, as demonstrated by an in vitro cytotoxicity in HepG2 cancer cell lines, it significantly enhanced the therapeutic index (2.1-fold for LED-PLA@CS NPs) by protecting non-cancerous cells. Additionally, the nanoparticles demonstrated broad-spectrum antibacterial effects, suggesting efficacy in the prevention of chemotherapy-related infections. The dual-responsive LED-PLA@CS NPs allowed controlled tumor-targeted LED delivery with better selectivity and lower off-target toxicity, making LED-PLA@CS NPs interesting candidates for repurposing HCV treatments into safer cancer nanomedicines. Furthermore, this thorough analysis offers useful reference information for comprehending the interaction between drugs and DNA.

Co-infection with hepatitis C virus (HCV) in human immunodeficiency virus (HIV) patients is common and has a poor prognosis leading to many complications. The anti-HIV drug emtricitabine (FTC) is co-administered with two direct acting anti-HCV drugs; daclatasvir (DAC) and ledipasvir (LDV). The three drugs are simultaneously determined in human urine for the first time by a validated, simple and sensitive RP-HPLC with programmed fluorescence detection. The column used is Exsil 100 ODS C18 column (250 × 4.6 mm, 5 μm). The used mobile phase is acetonitrile: methanol: 0.01 M ammonium acetate buffer, pH 4.5 in ratio (20: 60: 20) in isocratic mode pumped at flow rate 1 mL/min. The proposed method is successfully validated according to FDA bioanalytical validation guidelines. The calibration curves are linear over the ranges (500-15000, 1–50 and 10–100 ng/mL) with average recoveries (97.9-99.54%, 98.78-104.17% and 98.49–100.96%) for FTC, DAC and LDV, respectively. The intraday and inter-day accuracy and precision results are within the acceptable limits. Stability assays reveal that the three studied drugs were stable during preparation, injection and storage. The method can be applied for the quantification of the three drugs co-administered to HIV/HCV co-infected patients’ urine which aids in therapeutic drug monitoring and dosage adjustment for chronic patients.

Background/Aims: Direct-acting antiviral agents (DAAs) have increased the sustained viral response rate with minimal adverse effects and short treatment duration. In addition, recent data suggest the possibility that hepatitis C virus (HCV) clearance results in rapid improvement in metabolic pathways. The aim of the present study was to evaluate whether the DAA treatment without ribavirin lowers hemoglobin A1c (HbA1c) at 12 weeks after therapy completion. Methods: We performed an observational study to assess the effect of sofosbuvir and ledipasvir (SOF/LED) treatment on glycemic control. We compared HbA1c levels before and after treatment with SOF/LED, considering that anemia is not a side effect of these drugs. Results: In the 36 patients with HCV eradication, HbA1c levels decreased significantly after treatment (pre-treatment 5.85% vs. post-treatment 5.65%, p < 0.01). Conclusion: This pilot study shows the possibility that HCV eradication by SOF/LED was accompanied by an improvement of glucose metabolism in the population with or without diabetes, and suggests further investigation.

•Ledipasvir (LDV) and sofosbuvir (SOF) were best described using a 1-compartment model with zero-order absorption and lag time, while the 2-compartment model with first-order absorption and lag time was the best-fitting model for the SOF metabolite.•The patients’ weight explained the variability in the volume of distribution of LDV and the systemic clearance of SOF and LDV.•The final SOF model also included a statistically significant covariate of steatosis stage on its volume of distribution, while the final GS-331007 model included mean corpuscular volume values on GS-331007 central compartment volume, packed cell volume, and direct bilirubin values on metabolite intercompartmental clearance.•The presence of acute lymphoblastic leukemia did not explain any variability in the developed popPK models for SOF, LDV, and SOF major metabolite.•Despite weight being a significant covariate in the final pharmacokinetic models suggesting that body-weight-based dosing of LDV/SOF is better than less optimal fixed dosing, the fixed dosing (200/45 mg SOF/LDV) is more practical in terms of simplicity in dosing children at home with the currently available formulations. This study and previously published studies proved the efficacy and safety of the fixed dose through both the clinical outcomes and pharmacokinetic exposure results using non-compartmental analysis. Weight-based dosing is still hindered due to the absence of exposure-response analysis and the unavailability of dose-flexible formulas in the market. The pharmacokinetic (PK) profile of direct-acting antivirals, namely ledipasvir/sofosbuvir (LDV/SOF), might be altered in patients with acute lymphoblastic leukemia (ALL), affecting the optimum dose needed for hepatitis C virus treatment. Limited data are available evaluating the population PK of LDV/SOF and SOF metabolite GS-331007. We aimed to study whether ALL could affect population PK parameters of LDV, SOF, and the SOF major metabolite GS-331007 in hepatitis C virus-infected children, develop and validate a predictive PK model of LDV/SOF disposition in this special population, and identify their explained and unexplained sources of variability. Population PK modeling was performed using MonolixSuite software using the non-linear mixed effect modeling approach. Different compartmental models, absorption models, and lag times for absorption parameters were tested to find out the best-fitting base model. For final model development, data-driven systematic covariate analysis using conditional sampling for the stepwise approach based on the correlation tests method has been performed. The final models were then evaluated using internal validation approaches. The PK results of 22 fully compliant patients were included in the population PK analysis. LDV and SOF were best described by a 1-compartment model with zero-order absorption and lag time, while the 2-compartment model with first-order absorption and lag time was the best-fitting model for the SOF metabolite. The internal validation approach confirmed the good predictive power of the selected models. The patients’ weight explained the variability in the volume of distribution of LDV and the systemic clearance of SOF and LDV. The final SOF model also included a statistically significant covariate of steatosis stage on its volume of distribution, while the final GS-331007 model included mean corpuscular volume values on GS-331007 central compartment volume, packed cell volume, and direct bilirubin values on metabolite intercompartmental clearance. The presence of ALL did not explain any variability in the developed population PK models for SOF, LDV, and GS-331007. Despite weight being a significant covariate in the final models suggesting that weight-based dosing of LDV/SOF is better than fixed dosing, the fixed dosing (45/200 mg LDV/SOF) is more practical in terms of simplicity in dosing children at home besides the proved efficacy and safety through both the clinical outcomes and PK exposure results. Weight-based dosing is still hindered due to the absence of exposure-response analysis, and the unavailability of dose-flexible formulas in the market. Future studies are required to support these findings. NCT03903185.