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World Journal of Hepatology Jan 2016Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that... (Review)
Review
Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects.
PubMed: 26807205
DOI: 10.4254/wjh.v8.i2.92 -
Saudi Journal of Biological Sciences Apr 2021is a common enteric parasite, having a worldwide distribution. Many antimicrobial agents are effective against it, yet side effects and drug resistance have been...
INTRODUCTION AND AIM
is a common enteric parasite, having a worldwide distribution. Many antimicrobial agents are effective against it, yet side effects and drug resistance have been reported. Thus, ongoing trials are being conducted for exploring anti- alternatives. Proteases are attractive anti-protozoal drug targets, having documented roles in . Serine proteases are present in both hepatitis C virus and . Since drug repositioning is quite trendy, the efficacy of simeprevir (SMV), an anti-hepatitis serine protease inhibitor, against was investigated in the current study.
METHODS
Stool samples were collected from patients, Alexandria, Egypt. Concentrated stools were screened using direct smears, trichrome, and modified Ziehl-Neelsen stains to exclude parasitic co-infections. Positive stool isolates were cultivated, molecularly subtyped for assessing the efficacy of three SMV doses (100,150, and 200 μg/ml) along 72 hours (h), on the most common subtype, through monitoring parasite growth, viability, re-culture, and also via ultrastructure verification. The most efficient dose and duration were later tested on other subtypes.
RESULTS
Results revealed that was detected in 54.17% of examined samples. Molecularly, ST3 predominated (62%), followed by ST1 (8.6%) and ST2 (3.4%). Ascending concentrations of SMV progressively inhibited growth, viability, and re-culture of treated , with a non-statistically significant difference when compared to the therapeutic control metronidazole (MTZ). The most efficient dose and duration against ST3 was 150 µg/ml for 72 h. This dose inhibited the growth of ST3, ST1, and ST2 with percentages of 95.19%, 94.83%, and 94.74%, successively and viability with percentages of 98.30%, 98.09%, and 97.96%, successively. This dose abolished upon re-culturing. Ultra-structurally, SMV induced rupture of cell membrane leading to necrotic death, versus the reported apoptotic death caused by MTZ. In conclusion, 150 µg/ml SMV for 72 h proved its efficacy against ST1, ST2, and ST3 , thus sparing the need for pre-treatment molecular subtyping in developing countries.
PubMed: 33935570
DOI: 10.1016/j.sjbs.2021.01.050 -
Alimentary Pharmacology & Therapeutics Mar 2016Direct-acting anti-virals (DAAs) licensed to treat chronic HCV infection have revolutionised treatment algorithms by drastically mitigating side effects while enhancing... (Review)
Review
BACKGROUND
Direct-acting anti-virals (DAAs) licensed to treat chronic HCV infection have revolutionised treatment algorithms by drastically mitigating side effects while enhancing efficacy relative to interferon-based therapy.
AIM
To review adverse events (AEs) uniquely associated with DAA therapy across a broad spectrum of patient populations.
METHODS
Searches of PubMed and FDA surveillance studies were undertaken to complete an exhaustive review. Search terms included 'DAAs', 'safety', and 'tolerability'.
RESULTS
While DAAs are remarkably well tolerated, they are accompanied by unique AEs. Simeprevir, an NS3/4A protease inhibitor, has been known, albeit infrequently, to cause mild hyperbilirubinemia and photosensitivity reactions; and paritaprevir boosted with ritonavir causes bilirubin and ALT elevations. Asunaprevir, another protease inhibitor, infrequently causes elevated transaminase levels. NS5A and NS5B inhibitors are well tolerated, although sofosbuvir is contraindicated in patients with severe renal impairment. Ribavirin co-administered in certain treatment regimens has been associated with cough, rash and haemolytic anaemia.
CONCLUSIONS
With the impending reality of a more tolerable interferon-sparing regimen, the future of DAA therapy offers shorter treatment duration, simplified disease management, and a patient-centred regimen. With advantages come drawbacks, including development of resistance to therapy and accessibility to this expensive treatment. DAA therapy continues to advance at a brisk pace with a promising trend for higher tolerability, even in difficult-to-treat subgroups such as those with cirrhosis, nonresponders to prior therapy, and transplant recipients. Subgroup-specific contraindications and safety-related limitations are active areas of research. Concerted research efforts and continuing advances lend hope to the goal of rendering HCV a routinely curable disease.
Topics: Aged; Antiviral Agents; Cyclopropanes; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Isoquinolines; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Protease Inhibitors; Ritonavir; Simeprevir; Sofosbuvir; Sulfonamides
PubMed: 26787287
DOI: 10.1111/apt.13514 -
Digestive and Liver Disease : Official... Sep 2015The long awaited all-oral therapy for hepatitis C virus infection has officially been inaugurated by the registration of the hepatitis C nucleotide inhibitor sofosbuvir... (Review)
Review
The long awaited all-oral therapy for hepatitis C virus infection has officially been inaugurated by the registration of the hepatitis C nucleotide inhibitor sofosbuvir in a combination regimen with ribavirin. More recently, the oral array to treat hepatitis C has been enriched by the arrival of the NS5A inhibitors ledipasvir (also in a single formulation with sofosbuvir, Harvoni(®)) and daclatasvir; the protease inhibitor simeprevir, and the Viekirax(®)+Exviera™ regimen based on the ritonavir boosted protease inhibitor paritaprevir; the NS5A inhibitor ombitasvir, and the non-nucleoside inhibitor dasabuvir. Owing to the budget-breaking price of the newer oral medicines, the Italian National Health System elected to restrict reimbursement of oral anti-hepatitis C therapy to patients with advanced liver disease or transplanted organs, and those who are interferon unable, only. While this therapeutic strategy harmonizes with principles of distributive justice, at the same time it fuelled the argument of its doubtful cost-effectiveness, owing to the National Health System's reimbursement of the sole sofosbuvir+ribavirin regimen, which has suboptimal efficacy against the prevalent hepatitis C virus genotype 1b. As a consequence, we are left with a number of uncertainties regarding the optimal treatment modality for certain subgroups of hepatitis C patients, and the clinical benefits provided by hepatitis C virus clearance in patients with advanced liver disease.
Topics: 2-Naphthylamine; Antiviral Agents; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Cirrhosis; Ribavirin; Simeprevir; Sofosbuvir; Sulfonamides; Treatment Outcome; Uracil
PubMed: 25937625
DOI: 10.1016/j.dld.2015.04.003 -
Journal of Clinical and Experimental... Mar 2017Treatment of hepatitis C virus (HCV) with newer directly acting antivirals (DAAs) and lead to sustained viral response (SVR) in majority of patients and SVR has been... (Review)
Review
Treatment of hepatitis C virus (HCV) with newer directly acting antivirals (DAAs) and lead to sustained viral response (SVR) in majority of patients and SVR has been documented to be associated with reversal of liver cirrhosis. The improved SVR rates and safety profiles of DAAs have led to the treatment of patients with decompensated cirrhosis awaiting liver transplantation (LT). Several clinical trials of DAAs in decompensated HCV patients have recently demonstrated SVR rates above 80%, which have been associated with significant improvements, in the Child-Pugh-Turcotte scores/or model for end-stage liver disease scores in a proportion of patients. Moreover, it has been shown that HCV RNA becomes negative after 2-4 weeks of treatment, and those who are transplanted after becoming HCV RNA negative will be have very low the risk of HCV recurrence after transplantation. Some of the patients may have reached the "point of no return" and may proceed to worsening of decomposition over time. To avoid the risk of worsening, there is an additional option of treating these patients after LT should they develop recurrent HCV infection. Currently there are no guidelines as to select patients who would benefit from treatment prior to LT as opposed to those who will be better off being treated after the transplant surgery. The article discusses a possible approach for such selection.
PubMed: 28348470
DOI: 10.1016/j.jceh.2017.01.116 -
F1000Research 2016Chronic hepatitis C virus (HCV) infection still represents a major public health problem, as it is thought to be responsible for more than 350,000 deaths around the... (Review)
Review
Chronic hepatitis C virus (HCV) infection still represents a major public health problem, as it is thought to be responsible for more than 350,000 deaths around the globe on a yearly basis. Fortunately, successful eradication of the virus has been associated with improved clinical outcome and reduced mortality rates. In the past few years, treatment has improved considerably by the implementation of direct-acting antivirals (DAAs). From 2014 onwards, sofosbuvir, simeprevir, daclatasvir, ledipasvir, paritaprevir, ombitasvir, and dasabuvir have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Regimens with various combinations of these new drugs, without the use of interferon (IFN), proved to be very effective and well tolerated, even among patients with advanced liver disease. Moreover, treatment duration could be shortened to 12 weeks in the majority of patients. The high costs of these DAAs, however, limit the availability of IFN-free therapy worldwide. Even in wealthy countries, it is deemed necessary to prioritize DAA treatment in order to limit the immediate impact on the health budget. As patients with advanced liver disease are in most need of HCV clearance, many countries decided to treat those patients first. In the current review, we focus on the currently available IFN-free treatment options for patients with cirrhosis. We discuss the virological efficacy as well as the clinical relevance of these regimens among this specific patient population.
PubMed: 27006761
DOI: 10.12688/f1000research.7399.1 -
BMC Chemistry Jul 2023The present work was developed to create three rapid, simple, eco-friendly, cheap spectrophotometric methods for concurrent assay of Sofosbuvir (SOF) and Simeprevir...
Mathematical processing of absorption as green smart spectrophotometric methods for concurrent assay of hepatitis C antiviral drugs, Sofosbuvir and Simeprevir: application to combined pharmaceutical dosage forms and evaluation of the method greenness.
The present work was developed to create three rapid, simple, eco-friendly, cheap spectrophotometric methods for concurrent assay of Sofosbuvir (SOF) and Simeprevir (SMV) in their pure, laboratory prepared mixture and pharmaceutical dosage form with high degree of accuracy and precision. Three methods were developed including iso-absorptive point, ratio subtraction and dual wavelength. The linear range of the proposed methods was 3.0-50.0 and 2.0-50.0 µg mL for SMV and SOF, respectively. The proposed methods were validated according to ICH guidelines in terms of linearity, accuracy, precision, limit of detection and limit of quantitation. The proposed approach is highly simple and the procedure is environmentally green making it suitable for the drug analysis in routine works.
PubMed: 37452429
DOI: 10.1186/s13065-023-00984-5 -
Bioorganic Chemistry Jan 2021Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in finding a potential therapeutic agent for the...
BACKGROUND
Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in finding a potential therapeutic agent for the disease. Considering the matter of time, the computational methods of drug repurposing offer the best chance of selecting one drug from a list of approved drugs for the life-threatening condition of COVID-19. The present systematic review aims to provide an overview of studies that have used computational methods for drug repurposing in COVID-19.
METHODS
We undertook a systematic search in five databases and included original articles in English that applied computational methods for drug repurposing in COVID-19.
RESULTS
Twenty-one original articles utilizing computational drug methods for COVID-19 drug repurposing were included in the systematic review. Regarding the quality of eligible studies, high-quality items including the use of two or more approved drug databases, analysis of molecular dynamic simulation, multi-target assessment, the use of crystal structure for the generation of the target sequence, and the use of AutoDock Vina combined with other docking tools occurred in about 52%, 38%, 24%, 48%, and 19% of included studies. Studies included repurposed drugs mainly against non-structural proteins of SARS-CoV2: the main 3C-like protease (Lopinavir, Ritonavir, Indinavir, Atazanavir, Nelfinavir, and Clocortolone), RNA-dependent RNA polymerase (Remdesivir and Ribavirin), and the papain-like protease (Mycophenolic acid, Telaprevir, Boceprevir, Grazoprevir, Darunavir, Chloroquine, and Formoterol). The review revealed the best-documented multi-target drugs repurposed by computational methods for COVID-19 therapy as follows: antiviral drugs commonly used to treat AIDS/HIV (Atazanavir, Efavirenz, and Dolutegravir Ritonavir, Raltegravir, and Darunavir, Lopinavir, Saquinavir, Nelfinavir, and Indinavir), HCV (Grazoprevir, Lomibuvir, Asunaprevir, Ribavirin, and Simeprevir), HBV (Entecavir), HSV (Penciclovir), CMV (Ganciclovir), and Ebola (Remdesivir), anticoagulant drug (Dabigatran), and an antifungal drug (Itraconazole).
CONCLUSIONS
The present systematic review provides a list of existing drugs that have the potential to influence SARS-CoV2 through different mechanisms of action. For the majority of these drugs, direct clinical evidence on their efficacy for the treatment of COVID-19 is lacking. Future clinical studies examining these drugs might come to conclude, which can be more useful to inhibit COVID-19 progression.
Topics: Animals; Antiviral Agents; Cell Line, Tumor; Computational Chemistry; Drug Discovery; Drug Repositioning; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33261845
DOI: 10.1016/j.bioorg.2020.104490 -
Pharmacology Research & Perspectives Jun 2018This Phase I, open-label, two-group, fixed-sequence study evaluated the pharmacokinetics and safety of AL-335, odalasvir, and simeprevir in healthy subjects. Group 1... (Observational Study)
Observational Study
This Phase I, open-label, two-group, fixed-sequence study evaluated the pharmacokinetics and safety of AL-335, odalasvir, and simeprevir in healthy subjects. Group 1 (n=16) received AL-335 800 mg once daily (QD) (days 1-3, 11-13, and 21-23), simeprevir 150 mg QD (days 4-23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15-23). Group 2 (n=16) received the same AL-335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5-23) and simeprevir 150 mg QD (days 14-23). Blood samples were collected to determine plasma concentrations of AL-335 (prodrug) and its metabolites, ALS-022399 (monophosphate precursor) and ALS-022227 (parent nucleoside), odalasvir, and simeprevir. Thirty-two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL-335 area under plasma concentration-time curve over 24 hours (AUC ) 3-, 4-, and 7- to 8-fold, respectively; ALS-022399 AUC increased 2-, 2-, and 3-fold, respectively. Simeprevir had no effect on ALS-022227 AUC , whereas odalasvir with/without simeprevir increased ALS-022227 AUC 1.5-fold. AL-335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC increased 1.5- to 2-fold for both drugs when coadministered irrespective of AL-335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL-335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.
Topics: Administration, Oral; Adult; Alanine; Antiviral Agents; Area Under Curve; Benzimidazoles; Carbamates; Drug Administration Schedule; Drug Therapy, Combination; Female; Healthy Volunteers; Humans; Indoles; Male; Middle Aged; Phosphoramides; Prodrugs; Simeprevir; Uridine; Viral Nonstructural Proteins; Young Adult
PubMed: 29736243
DOI: 10.1002/prp2.395 -
Annals of Hepatology 2019Direct antiviral agents (DAAs) including sofosbuvir (SOF), daclatasvir (DCV), simeprevir (SIM) and ombitasvir, paritaprevir and dasabuvir were introduced 2015 in Brazil...
INTRODUCTION AND OBJECTIVES
Direct antiviral agents (DAAs) including sofosbuvir (SOF), daclatasvir (DCV), simeprevir (SIM) and ombitasvir, paritaprevir and dasabuvir were introduced 2015 in Brazil for treatment of hepatitis C virus (HCV) infection. The aims of this study were to assess effectiveness and safety of HCV treatment with DAA in real-life world in a highly admixed population from Brazil.
MATERIALS AND METHODS
All Brazilian reference centers for HCV treatment were invited to take part in a web-based registry, prospectively conducted by the Brazilian Society of Hepatology, to assess outcomes of HCV treatment in Brazil with DAAs. Data to be collected included demographics, disease severity and comorbidities, genotype (GT), viral load, DAA regimens, treatment side effects and sustained virological response (SVR).
RESULTS
3939 patients (60% males, mean age 58±10 years) throughout the country were evaluated. Most had advanced fibrosis or cirrhosis, GT1 and were treated with SOF/DCV or SOF/SIM. Overall SVR rates were higher than 95%. Subjects with decompensated cirrhosis, GT2 and GT3 have lower SVR rates of 85%, 90% and 91%, respectively. Cirrhosis and decompensated cirrhosis in GT1 and male sex and decompensated cirrhosis in GT3 were significantly associated with no SVR. Adverse events (AD) and serious AD occurred in 18% and 5% of those subjects, respectively, but less than 1% of patients required treatment discontinuation.
CONCLUSION
SOF-based DAA regimens are effective and safe in the heterogeneous highly admixed Brazilian population and could remain an option for HCV treatment at least in low-income countries.
Topics: Aged; Antiviral Agents; Brazil; Carbamates; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Prognosis; Prospective Studies; Pyrrolidines; Ribavirin; Sex Factors; Simeprevir; Sofosbuvir; Sustained Virologic Response; Valine
PubMed: 31537509
DOI: 10.1016/j.aohep.2019.08.001