benzofurans and Drug-Related-Side-Effects-and-Adverse-Reactions

Napabucasin is a cancer stemness inhibitor that targets a number of oncogenic pathways, including signal transducer and activator of transcription 3 (STAT3). Phase 1/2 studies suggest tolerability and anti-tumor activity in various types of cancer; a Phase 3 study of napabucasin plus standard therapy in colorectal cancer is ongoing. This is a Phase 1 dose-escalation study in patients with advanced solid tumors, and the first study of napabucasin in Japanese patients.. Patients received napabucasin 480, 960, or 1440 mg daily in 28-day cycles until disease progression or intolerable toxicity. Primary objectives were to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and the pharmacokinetic (PK) profile of napabucasin. Blood samples were taken for PK analysis on Days 1, 2, 8, and 15 of Cycle 1, and Days 29 and 30 of Cycle 2. Secondary objectives were to assess napabucasin antitumor activity, and the relationship between biomarkers and antitumor activity. JapicCTI-No: JapicCTI-132152.. Enrolled were 14 patients (480 mg [n = 3], 960 mg [n = 4], 1440 mg [n = 7]). One patient experienced a DLT (Grade 3, anorexia). MTD was 1440 mg/day. Most common drug-related adverse events were diarrhea (n = 9), nausea (n = 4), vomiting (n = 3), and anorexia (n = 3). Napabucasin showed a similar PK profile to previous studies and no abnormal accumulation was observed. Following treatment, two patients had stable disease; the remaining 12 had progressive disease.. Napabucasin was well-tolerated at doses up to 1440 mg/day in Japanese patients with advanced solid tumors; the PK profile was comparable to that reported previously.

Topics: Adrenal Gland Neoplasms; Antineoplastic Agents; Benzofurans; Biological Availability; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Naphthoquinones; Progression-Free Survival; STAT3 Transcription Factor; Treatment Outcome

This is a phase I/II trial to assess the efficacy and safety of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC).. Phase I was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240 to 480 mg twice daily) with 200 mg pembrolizumab every 3 weeks. Phase II included cohort A (. A total of 55 patients were enrolled in this study. In phase I, no patients experienced dose-limiting toxicities, and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS < 1, 1≤ CPS <10, and CPS ≥ 10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3%, and 33.3% in CMS1, CMS2, CMS3, and CMS4, respectively. The common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B.. Napabucasin with pembrolizumab showed antitumor activity with acceptable toxicities for patients with MSS mCRC as well as MSI-H mCRC, although it did not meet the primary end point. The impact of related biomarkers on the efficacy warrants further investigations in the additional cohort.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Benzofurans; Colorectal Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Microsatellite Instability; Middle Aged; Naphthoquinones; Neoplasm Metastasis

People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group. The aim of the phase 2 C-SCAPE study was to evaluate elbasvir/grazoprevir (EBR/GZR), with or without ribavirin (RBV), in participants with HCV genotype 2, 4, 5 or 6 infection. This was a part randomised, open-label, parallel-group study (NCT01932762; PN047-03) of treatment-naive, noncirrhotic participants. Participants with HCV genotype 2 infection received GZR 100 mg + RBV ± EBR 50 mg for 12 weeks and those with genotype 4, 5 or 6 infection were randomized to receive EBR/GZR ± RBV for 12 weeks. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12; HCV RNA <25 IU/mL). Among participants with genotype 2 infection, SVR12 was achieved by 80% (24/30) of those receiving EBR/GZR + RBV and 73% (19/26) of those receiving GZR + RBV. SVR rates were high in participants with HCV genotype 4 infection receiving EBR/GZR with and without RBV (100% [10/10] and 90% [9/10]; respectively). In contrast, the addition of RBV to EBR/GZR appeared to increase SVR12 in participants with genotype 5 infection (EBR/GZR, 25%; EBR/GZR + RBV 100% [4/4]). In participants with genotype 6 infection, SVR12 was 75% (3/4) in both those receiving EBR/GZR and those receiving EBR/GZR + RBV. The safety profile was similar across treatment arms, with adverse events tending to occur more frequently among participants receiving RBV. In conclusion, these data support the inclusion of participants with genotype 4 or 6 infection in the EBR/GZR phase 3 studies. EBR/GZR ± RBV was unsatisfactory for participants with genotype 2 or 5 infection.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Ribavirin; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Young Adult

Additional targeted therapeutics are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models. We conducted a multicenter phase I/II study (N = 55) with single-agent abexinostat in relapsed/refractory lymphoma.. In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m(2) twice daily 5 days/week for 3 weeks or 7 days/week given every other week. Phase II evaluated abexinostat at the maximum tolerated dose in 30 patients with relapsed/refractory follicular lymphoma or mantle cell lymphoma.. The recommended phase II dose was 45 mg/m(2) twice daily (90 mg/m(2) total), 7 days/week given every other week. Of the 30 follicular lymphoma and mantle cell lymphoma patients enrolled in phase II, 25 (14 follicular lymphoma, 11 mantle cell lymphoma) were response-evaluable. Tumor size was reduced in 86% of follicular lymphoma patients with an investigator-assessed ORR of 64.3% for evaluable patients [intent-to-treat (ITT) ORR 56.3%]. Median duration of response was not reached, and median progression-free survival (PFS) was 20.5 months (1.2-22.3+). Of responding follicular lymphoma patients, 89% were on study/drug >8 months. In mantle cell lymphoma, the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and median PFS was 3.9 months (range, 0.1-11.5). Grade 3-4 treatment-related adverse events (phase II) with ≥ 10% incidence were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%) with rare QTc prolongation and no deaths.. The pan-HDACi, abexinostat, was overall well tolerated and had significant clinical activity in follicular lymphoma, including highly durable responses in this multiply relapsed patient population.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Disease-Free Survival; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Recurrence

AFN-1252 is a novel inhibitor of FabI, an essential enzyme in Staphylococcus spp. This study was undertaken to assess the safety, tolerability and pharmacokinetic properties of AFN-1252, following oral administration in an ascending dose trial.. This was a double-blind, randomized, placebo-controlled, two-part study. In Part I, single doses (QD) of 100, 200, 300, or 400 mg AFN-1252 were administered. In Part II, subjects received 200, 400, 600, or 800 mg (total daily dose) where 100, 200 and 400-mg doses were given twice in one day.. AFN-1252 was well-absorbed with Cmax at 3-4 h when given once per day and 2.5-9 h when dosed twice in a single dosing day. T½ ranged from 8 to 11 h. Total and peak exposures of AFN-1252 increased nonlinearly. Adverse events were primarily mild and resolved promptly.. Oral doses of AFN-1252 were safe and well tolerated. AFN-1252 has the potential for once or twice-a-day dosing for treatment of staphylococcal infections.

Topics: Administration, Oral; Adolescent; Adult; Anti-Bacterial Agents; Benzofurans; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Healthy Volunteers; Humans; Male; Middle Aged; Placebos; Pyrones; Tablets; Young Adult

The influence of direct-acting antivirals (DAAs) on the composition of gut microbiota in hepatitis C virus (HCV)-infected patients with or without human immunodeficiency virus (HIV) is unclear.. We enrolled 62 patients with HCV monoinfection and 24 patients with HCV/HIV coinfection receiving elbasvir-grazoprevir from a clinical trial. Fecal specimens collected before treatment and 12 weeks after treatment were analyzed using amplicon-based 16S ribosomal RNA sequencing.. Sustained virological response rates in the monoinfection and coinfection groups were similar (98.4% vs 95.8%). Pretreatment bacterial communities in the patient groups were less diverse and distinct from those of healthy controls. Compared with HCV-monoinfected patients, HCV/HIV-coinfected individuals showed comparable microbial alpha diversity but decreased Firmicutes-Bacteroidetes ratios. The improvement of microbial dysbiosis was observed in responders achieving sustained virological response across fibrosis stages but was not found in nonresponders. Responders with a low degree of fibrosis exhibited a recovery in alpha diversity to levels comparable to those in healthy controls. Reciprocal alterations of increased beneficial bacteria and reduced pathogenic bacteria were also observed in responders.. This study indicates a short-term effect of direct-acting antivirals in restoration of microbial dysbiosis. The favorable changes in gut microbiota profiles after viral eradication might contribute toward the reduction of HCV-related complications among infected individuals.

Topics: Adult; Aged; Antiviral Agents; Benzofurans; Coinfection; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Dysbiosis; Female; Gastrointestinal Microbiome; Hepacivirus; Hepatitis C; HIV Infections; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Treatment Outcome; Viral Load

This study was performed to investigate the efficacy and safety of grazoprevir-elbasvir guided by baseline resistance-associated substitutions (RASs) in the Swiss HCVree Trial.. We performed hepatitis C virus (HCV) RNA screening among all men who have sex with men (MSM) enrolled in the Swiss HIV Cohort Study. Individuals with replicating HCV genotype 1 or 4 infection were eligible for grazoprevir-elbasvir treatment. Genotype 1a-infected individuals with baseline RASs and genotype 4-infected individuals with prior failure of HCV treatment received 16 weeks of grazoprevir-elbasvir combined with ribavirin. All other individuals received 12 weeks of grazoprevir-elbasvir alone. Patients reporting unprotected sex with occasional partners were offered a HCV risk reduction-oriented behavioral intervention.. We screened 3722 MSM and identified 177 (4.8%) with replicating infection. A total of 122 individuals (3.3%) were eligible for study treatment. Six of 76 patients infected with genotype 1a (7.3%) harbored baseline RASs. Sustained virological response after 12 weeks of follow-up was achieved in 121 patients (99%), including all with genotype 1a infection. Overall, 8 serious adverse events occurred, none of which was related to the study drug. Seventy-five percent of eligible MSM participated in the risk counseling program.. Grazoprevir-elbasvir for 12 or 16 weeks, with or without ribavirin, achieved high cure rates and had an excellent safety profile. Unique to other studies, the treatment duration was guided by the presence of baseline RASs among genotype 1a-infected individuals, and the treatment phase was accompanied by an HCV risk reduction-oriented behavioral intervention. This successful population-wide treatment approach lays the groundwork to achieve HCV elimination in coinfected MSM.. NCT02785666.

Topics: Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Cyclopropanes; Drug Resistance, Viral; Drug-Related Side Effects and Adverse Reactions; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Homosexuality, Male; Humans; Imidazoles; Male; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Quinoxalines; Ribavirin; Sulfonamides; Sustained Virologic Response; Treatment Outcome

Topics: Amiodarone; Anti-Arrhythmia Agents; Benzofurans; Drug-Related Side Effects and Adverse Reactions; Humans; Hypothyroidism; Thyroid Gland

Topics: Amiodarone; Anti-Arrhythmia Agents; Benzofurans; Drug-Related Side Effects and Adverse Reactions; Humans; Hypothyroidism; Thyroid Gland

Usnic acid (UA) can be found in certain lichen species. Growing evidence suggests that UA possesses antitumoral, antioxidative and anti-inflammatory activities. Bleomycin (BLM) is widely used in the treatment of malignant ascites, however, it unexpectedly causes pulmonary fibrosis (PF). Researches show that excessive inflammatory response and oxidative stress in lung tissue is conspicuous causes of BLM-induced PF. Here we investigated mechanism underlying the effect-enhancing and toxicity-reducing activity of UA on H22-bearing mice treated with BLM. UA combined with BLM was significantly more effective than BLM alone in inhibiting the tumor growth, arresting the cell cycle at G0/G1 phase, and promoting the cleaved caspase-3 and cleaved caspase-8 activities to induce cancer cellular apoptosis. The mechanism may be associated with the transcriptional regulation of p53/p21/Cyclin pathway. Furthermore, UA effectively moderated the histopathological changes, reduced the content of MDA, HYP, TNF-α, IL-1β, IL-6 and TGF-β1, and increased the level of SOD when combined with BLM in lung tissues of H22-bearing mice, which was believed to be related to the inhibition on the protein level of p-Smad2/3 and enhancement of Smad7 expression. These findings suggested that UA might be a potential effect-enhancing and toxicity-reducing candidate for BLM in the treatment of malignant ascites.

Topics: Adjuvants, Pharmaceutic; Animals; Antineoplastic Agents; Apoptosis; Ascites; Benzofurans; Bleomycin; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Line, Tumor; Drug-Related Side Effects and Adverse Reactions; Humans; Lichens; Liver Neoplasms; Male; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Pulmonary Fibrosis; Smad Proteins

Human toxicity screening is an important stage in the development of safe drug candidates. Hepatotoxicity is one of the major reasons for the withdrawal of drugs from the market because the liver is the major organ involved in drug metabolism, and it can generate toxic metabolites. There is a need to screen molecules for drug-induced hepatotoxicity in humans at an earlier stage. Transcriptomics is a technique widely used to screen molecules for toxicity and to unravel toxicity mechanisms. To date, the majority of such studies were performed using animals or animal cells, with concomitant difficulty in interpretation due to species differences, or in human hepatoma cell lines or cultured hepatocytes, suffering from the lack of physiological expression of enzymes and transporters and lack of nonparenchymal cells. The aim of this study was to classify known hepatotoxicants on their phenotype of toxicity in humans using gene expression profiles ex vivo in human precision-cut liver slices (PCLS). Hepatotoxicants known to induce either necrosis (n = 5) or cholestasis (n = 5) were used at concentrations inducing low (<30%) and medium (30-50%) cytotoxicity, based on ATP content. Random forest and support vector machine algorithms were used to classify hepatotoxicants using a leave-one-compound-out cross-validation method. Optimized biomarker sets were compared to derive a consensus list of markers. Classification correctly predicted the toxicity phenotype with an accuracy of 70-80%. The classification is slightly better for the low than for the medium cytotoxicity. The consensus list of markers includes endoplasmic reticulum stress genes, such as C2ORF30, DNAJB9, DNAJC12, SRP72, TMED7, and UBA5, and a sodium/bile acid cotransporter (SLC10A7). This study shows that human PCLS are a useful model to predict the phenotype of drug-induced hepatotoxicity. Additional compounds should be included to confirm the consensus list of markers, which could then be used to develop a biomarker PCR-array for hepatotoxicity screening.

Topics: Acetaminophen; Aged; Benzofurans; Bile Acids and Salts; Chloramphenicol; Chlorpromazine; Cholestasis; Colchicine; Cyclosporine; Diethylnitrosamine; Drug-Related Side Effects and Adverse Reactions; Ethinyl Estradiol; Female; Gene Expression Profiling; Hepatocytes; Humans; Liver; Male; Methyltestosterone; Middle Aged; Necrosis; Phenotype; Toxicogenetics; Young Adult

Topics: Acamprosate; Adenine Nucleotides; Alcohol Deterrents; Amyloid; Analgesics, Non-Narcotic; Anti-HIV Agents; Antifungal Agents; Antineoplastic Agents; Aptamers, Nucleotide; Arabinonucleosides; Azabicyclo Compounds; Benzofurans; Clofarabine; Drug Approval; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Exenatide; Fibroblast Growth Factor 7; Guanine; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Lipopeptides; Lipoproteins; Macular Degeneration; Micafungin; omega-Conotoxins; Patient Education as Topic; Peptides; Peptides, Cyclic; Piperazines; Pyrrolidines; Quinuclidines; Solifenacin Succinate; Stomatitis; Taurine; Tetrahydroisoquinolines; Urinary Incontinence; Venoms

The depletion of lipids associated with pre-spawning migration of Pacific salmon has the potential to magnify concentrations of hydrophobic organic contaminants (HOCs), which elevates risk of toxic effects. We present data from a field study of sockeye salmon (Oncorhynchus nerka) migrating to spawn in Great Central Lake, BC, which demonstrate that pre-spawning migration causes a magnification of PCB, PCDD, and PCDF concentrations in female gonads (1.9-2.5-fold), female soma (3.4-5.6-fold), and male soma (5.6-9.7-fold). We further develop a model of prespawning migration chemical magnification for sockeye salmon stocks as a function of migration distance. This model is shown to be consistent with available empirical data on pre-spawning magnification and predicts magnification factors ranging between 1.4 and 7.9 in gonad and between 1.6 and 10.4 in soma in seven Pacific salmon stocks in British Columbia. Post-migration (prespawning) toxic equivalent dioxin concentrations in roe were measured to be approximately 3 pg/g lipid in salmon from the Great Central Lake sockeye stock and estimated to range between 1.5 pg/g lipid for the shortest-migrating stocks and 7 pg/g lipid for the longest-migrating stocks. Concentrations in certain stocks approach or exceed the concentration of 3 pg/g lipid associated with 30% egg mortality in Oncorhynchus mykiss. This indicates the potential for population-level effects of current contaminant levels. It also suggests that historic contaminant concentrations, which were greater than current concentrations, may have contributed significantly to the decline of certain Pacific salmon stocks in British Columbia.

Topics: Animal Migration; Animals; Benzofurans; British Columbia; Drug-Related Side Effects and Adverse Reactions; Female; Fresh Water; Lipid Metabolism; Oncorhynchus mykiss; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Population Dynamics; Reproduction; Water Pollutants, Chemical

Interaction between toxic compounds has long been known to researchers. Attempts to model this interaction have been based on two basic paradigms--termed additivity and independence (1, 2). Previous models based on these assumptions focused on measuring the interaction between the compounds and then classifying the type of interaction as synergism, antagonism, additivity or independence (3, 4). The aim of this work is to present a generalization of the independent action hypothesis that is quantitatively capable of describing deviations regardless of the underlying single component dose response models. The mathematical framework of copulas is employed. This approach is then tested against data sets with both human health and ecological risk applications.

Topics: Animals; Benzofurans; Cleft Palate; Data Interpretation, Statistical; Drug Antagonism; Drug Interactions; Drug Synergism; Drug-Related Side Effects and Adverse Reactions; Humans; Hydrocarbons, Chlorinated; Insecticides; Mice; Mice, Inbred C57BL; Models, Theoretical; Polychlorinated Dibenzodioxins

Topics: Antihypertensive Agents; Antimalarials; Arsenic; Benzofurans; Drug-Related Side Effects and Adverse Reactions; Gold; Humans; Metabolic Diseases; Pharmaceutical Preparations; Phenothiazines; Phosphates; Silver; Thorium Dioxide