benzofurans and Fatigue

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Combinations; Fatigue; Hepatitis C; Humans; Imidazoles; Nausea; Quinoxalines; Sulfonamides

The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.

Topics: Amides; Antiviral Agents; Benzimidazoles; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fatigue; Female; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Nausea; Quinoxalines; Sofosbuvir; Sulfonamides

Topics: Acetylation; Adult; Aged; Alanine Transaminase; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Benzofurans; Carcinoma, Renal Cell; Disease Progression; Disease-Free Survival; Drug Resistance; Drug Resistance, Neoplasm; Epigenesis, Genetic; Fatigue; Female; Gene Expression; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Indazoles; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neutropenia; Pyrimidines; Sulfonamides; Thrombocytopenia; Treatment Outcome; Vascular Endothelial Growth Factor A; Young Adult

Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection.. To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients.. Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467).. 60 centers in the United States, Europe, Australia, Scandinavia, and Asia.. Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection.. Oral, once-daily, fixed-dose grazoprevir 100 mg/elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy.. Proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups.. Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% CI, 92% to 97%]) achieved SVR12, including 144 of 157 (92% [CI, 86% to 96%]) with genotype 1a, 129 of 131 (99% [CI, 95% to 100%]) with genotype 1b, 18 of 18 (100% [CI, 82% to 100%]) with genotype 4, 8 of 10 (80% [CI, 44% to 98%]) with genotype 6, 68 of 70 (97% [CI, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [CI, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point [CI, -5.4 to 3.1 percentage points]); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%).. The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections.. Grazoprevir-elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection. This once-daily, all-oral, fixed-combination regimen represents a potent new therapeutic option for chronic HCV infection.. Merck & Co.

Topics: Administration, Oral; Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Fatigue; Female; Genotype; Headache; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Cirrhosis; Male; Middle Aged; Nausea; Quinoxalines; Sulfonamides; Treatment Outcome; Viral Load; Young Adult

Hepatitis C virus (HCV) infection is known to affect long-term patient survivals. Elbasvir/grazoprevir (EBR/GZR) has shown a high cure rate in hemodialysis patients with HCV infection. However, the combination is rarely used in peritoneal dialysis patients. Herein, we report a case of successful treatment with EBR/GZR in a peritoneal dialysis patient with HCV genotype 1 b infection. A 54-year-old woman on peritoneal dialysis（PD）with HCV genotype 1 b infection had been received EBR (100 mg) and GZR (50 mg) once daily for 12 weeks. Hepatitis C virus RNA was undetectable 4 weeks after the treatment. She achieved a sustained virological response at 12 weeks after the end of treatment. Only fatigue was reported as side effect during the treatment. Thus, elbasvir/grazoprevir was effective and safe in this PD patient with HCV genotype 1 b infection.

Topics: Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fatigue; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Middle Aged; Peritoneal Dialysis; Quinoxalines; Sulfonamides; Sustained Virologic Response

In the Republic of Korea, an estimated 231,000 individuals have chronic hepatitis C virus (HCV) infection. The aim of the present analysis was to evaluate the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) administered for 12 weeks in Korean patients who were enrolled in international clinical trial phase 3 studies.. This was a retrospective, integrated analysis of data from patients with HCV genotype (GT) 1b infection enrolled at Korean study sites in four EBR/GZR phase 3 clinical trials. Patients were treatment-naive or had previously failed interferon-based HCV therapy, and included those with human immunodeficiency virus coinfection or ChildPugh class A cirrhosis. All patients received EBR 50 mg/GZR 100 mg once daily for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after completion of therapy (SVR12, HCV RNA <15 IU/mL).. SVR12 was achieved by 73 of 74 (98.6%) patients. No patients had virologic failure and one discontinued from the study after withdrawing consent. SVR12 rates were uniformly high across all patient subgroups. A total of 16 patients had nonstructural protein 5A resistance-associated substitutions at baseline (16/73, 22%), all of whom achieved SVR12. Adverse events (AEs) reported in >5% of patients were fatigue (6.8%), upper respiratory tract infection (5.4%), headache (5.4%), and nausea (5.4%). Thirteen patients (17.6%) reported drug-related AEs, two serious AEs occurred, and two patients discontinued treatment owing to an AEs.. In this retrospective analysis, EBR/GZR administered for 12 weeks was well-tolerated and highly effective in Korean patients with HCV GT1b infection.

Topics: Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Clinical Trials, Phase III as Topic; Cyclopropanes; Drug Resistance, Viral; Fatigue; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Republic of Korea; Retrospective Studies; Sulfonamides; Sustained Virologic Response; Viral Nonstructural Proteins

Topics: Amides; Antiviral Agents; Asthenia; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Fatigue; Female; Genotype; Headache; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Nausea; Quinoxalines; Randomized Controlled Trials as Topic; Ribavirin; RNA, Viral; Sulfonamides; Sustained Virologic Response; Viral Load

In 1968, many people developed dioxin poisoning (Yusho) in Japan. Ingestion of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) was considered to be the cause of this poisoning. Although some patients had high concentrations of 2,3,4,7,8-PeCDF in their blood, individuals' half-lives of 2,3,4,7,8-PeCDF were long.. To evaluate the relationship between clinical and laboratory parameters and the individual half-life of 2,3,4,7,8-PeCDF in blood.. Clinical and laboratory data were collected during annual check-ups from 2001 to 2008. We enrolled 71 patients, who were measured more than 3 times, and who had 2,3,4,7,8-PeCDF concentrations in blood >50pgg(-1) lipid. The half-life of 2,3,4,7,8-PeCDF for each patient was estimated using linear regression. Moreover, relationships between clinical and laboratory parameters and individual half-life were investigated by linear regression.. A shortened individual half-life for 2,3,4,7,8-PeCDF was significantly correlated with an increased red blood cell count, increased viscous secretions from the meibomian glands, existing black comedones, and severe cedar pollen allergy.. Symptoms that accelerate excretion of lipids from the body, such as viscous secretions from the meibomian glands, may lead to a shorter half-life of 2,3,4,7,8-PeCDF. Red blood cells are related to the half-life of 2,3,4,7,8-PeCDF. However, further studies are required to investigate the excretory mechanism of 2,3,4,7,8-PeCDF.

Topics: Acne Vulgaris; Adult; Aged; Aged, 80 and over; Benzofurans; Erythrocyte Count; Fatigue; Female; Half-Life; Humans; Japan; Male; Middle Aged; Porphyrias; Rhinitis, Allergic, Seasonal

Kanemi Yusho is the name given to a 1968 food poisoning incident resulting from the ingestion of PCB contaminated rice bran oil that had been used as a heating medium. At the time, victims presented with mainly cutaneous manifestations and various other symptoms such as of the eyes and teeth, general fatigue, headaches, and paresthesia of the extremities. The characteristic symptoms then resolved with time. Yusho patients have been followed from immediately after the incident. Blood levels of dioxins such as PeCDF have been measured for those who wishing to since 2001.. The presence or absence of relationships between blood PeCDF level and various examination items/symptoms was investigated in 359 subjects whose blood levels of PCB-related chemical compounds such as PeCDF were measured in the Yusho related examinations between 2001 and 2003. Characteristic symptoms were also compared with the results of examinations done 15 years previously.. The average blood 2,3,4,7,8-PeCDF level in designated Yusho patients was 177.50 pg/g lipids; showing a markedly higher value than that of the normal control group (15.2 pg/g lipids). As well, the blood PeCDF level was related to PCB level, hexachlorobiphenyl level, urinary sugar, erythrocyte sedimetation rate (ESR) (2-hour), thymol and Na. There were also relationships with cutaneous findings (acneiform eruption and comedones), mucosal findings (oral pigmentation), constipation, numbness in the extremities, body weight loss, and abnormal abdominal ultrasonography. Symptoms seen in the skin and eyes in 2001 and 2003 had decreased compared with those in seen 1988. However, PCB and blood PeCDF levels remained high. Patients are continuing to present with mucosal and subjective symptoms as chronic conditions.

Topics: Benzofurans; Eye Diseases; Fatigue; Food Contamination; Headache; Humans; Japan; Oryza; Paresthesia; Plant Oils; Polychlorinated Biphenyls; Skin Diseases; Time Factors; Tooth Diseases