The cost-effectiveness of iruplinalkib versus alectinib in anaplastic lymphoma kinase-positive crizotinib-resistant advanced non-small-cell lung cancer patients in China.

Background: Iruplinalkib is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC), which is independently developed by a Chinese pharmaceutical company. This study examined the cost-effectiveness of iruplinalkib versus alectinib in the Chinese healthcare setting. Methods: A partitioned survival model was developed to project the economic and health outcomes. Efficacy was derived using unanchored matching-adjusted indirect comparison (MAIC). Cost and utility values were obtained from the literature and experts' opinions. Deterministic and probabilistic sensitivity analyses (PSA) were carried out to evaluate the model's robustness. Results: Treatment with iruplinalkib versus alectinib resulted in a gain of 0.843 quality-adjusted life years (QALYs) with incremental costs of $20,493.27, resulting in an incremental cost-effectiveness ratio (ICER) of $24,313.95/QALY. Parameters related to relative efficacy and drug costs were the main drivers of the model outcomes. From the PSA, iruplinalkib had a 90% probability of being cost-effective at a willingness-to-pay threshold of $37,863.56/QALY. Conclusion: Compared to alectinib, iruplinalkib is a cost-effective therapy for patients with ALK-positive crizotinib-resistant advanced NSCLC.

Environmental persistence assessment of heterocyclic polyaromatic hydrocarbons - Ultimate and primary biodegradability using adapted and non-adapted microbial communities.

Heterocyclic polyaromatic hydrocarbons (heterocyclic PAHs) are of increasing concern and their environmental and human health impacts should be assessed due to their widespread presence and potential persistence in the environment. This study investigated the ultimate and primary biodegradability of ten heterocyclic PAHs, nine of which were found to be non-readily biodegradable. To generate a microbial community capable of degrading such compounds, a bacterial inoculum isolated from the effluent of a wastewater treatment plant (WWTP) was adapted to a mixture of heterocyclic PAHs for one year. Throughout the adaptation process, bacterial samples were collected at different stages to conduct primary biodegradation, ultimate biodegradation, and inoculum toxicity tests. Interestingly, after one year of adaptation, the community developed the ability to mineralize carbazole, but in the same time showed an increasing sensitivity to the toxic effects of benzo[c]carbazole. In two consecutive primary biodegradation experiments, degradation of four heterocycles was observed, while no biodegradation was detected for five compounds in any of the tests. Furthermore, the findings of this work were compared with predictions from in silico models regarding biodegradation timeframe and sorption, and it was found that the models were partially successful in describing these processes. The results of study provide valuable insights into the persistence of a representative group of heterocyclic PAHs in aquatic environments, which contributes to the hazard assessment of this particular class of substances.

Industrial source identification of polyhalogenated carbazoles and preliminary assessment of their global emissions.

Polyhalogenated carbazoles (PHCZs) are emerging global pollutants found in environmental matrices, e.g., 3000 tonnes of PHCZs have been detected in the sediments of the Great Lakes. Recognition of PHCZ emissions from ongoing industrial activities worldwide is still lacking. Here, we identify and quantify PHCZ emissions from 13 large-scale industries, 12 of which previously have no data. Congener profiles of PHCZs from investigated industrial sources are clarified, which enables apportioning of PHCZ sources. Annual PHCZ emissions from major industries are estimated on the basis of derived emission factors and then mapped globally. Coke production is a prime PHCZ emitter of 9229 g/yr, followed by iron ore sintering with a PHCZ emission of 3237 g/yr. China, Australia, Japan, India, USA, and Russia are found to be significant emitters through these industrial activities. PHCZ pollution is potentially a global human health and environmental issue.

Acute Toxicity Study of 5, 11-Dihydroindolo [3, 2-ß]carbazole as per OECD Regulatory Guidelines.

BACKGROUND: 5,11-Dihydroindolo [3, 2-ß]carbazole is one of the phytoconstituent of the Arisaema genus, which might have various important biological activities. Recently, we have predicted the antiviral potential of this phytoconstituent against the Japanese Encephalitis virus (JEV). METHODS: Thus, in the current study, the acute toxicity profile of 5, 11-dihydroindolo [3, 2-ß]carbazole as per OECD regulatory guidelines in female Wistar rats was evaluated. RESULTS: We did not find any adverse effects, mortality, and altered behaviour in animals after administration of 5, 11-dihydroindolo [3, 2-ß] carbazole at a dose of 300 and 2000 mg/Kg. Furthermore, no significant changes in physiological and haematological parameters were observed. The histopathological study of vital organs also showed no significant changes compared to the control. CONCLUSION: Based on the findings of the current investigation, 5, 11-dihydroindolo [3, 2-ß]carbazole is a safe phytoconstituent of the Arisaema genus, which can be explored for various biological activities.

Cost-effectiveness of ensartinib, crizotinib, ceritinib, alectinib, brigatinib and lorlatinib in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer in China.

Objective: Six anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), including one domestic (ensartinib) and five imported ALK-TKIs (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib), have been recommended as first-line treatments for advanced ALK-positive NSCLC in China. This study sought to examine the cost-effectiveness of these six novel therapies in Chinese patients. Material and methods: We constructed a Markov model to compare the cost-effectiveness of the six ALK-TKIs as a first-line treatment for patients with advanced ALK-positive NSCLC from the perspective of the Chinese healthcare system. Transition probabilities were estimated by synthesizing data from the PROFILE 1,029 trial and a network meta-analysis. Health state utilities and costs were sourced from published literature, publicly available national databases, and local general hospitals. The robustness of model was assessed via deterministic sensitivity analyses and probabilistic sensitivity analyses. Results: Compared with crizotinib, ensartinib achieved additional 0.12 quality-adjusted life-year (QALY) with marginal costs of $3,249, resulting in an incremental cost-effectiveness ratio (ICER) of $27,553/ QALY. When compared with ceritinib and brigatinib, ensartinib achieved additional 0.06 and 0.03 QALYs with substantially reduced costs. When compared with lorlatinib and alectinib, ensartinib was associated with a lower QALY and decreased total costs; the ICERs for lorlatinib and alectinib were $934,101/ QALY and $164,888/ QALY, respectively. Conclusion: For Chinese patients with advanced ALK-positive NSCLC, ensartinib was a cost-effective option compared with crizotinib, and was a dominant alternative to ceritinib and brigatinib. Although lorlatinib and alectinib were associated with prolonged survival compared with ensartinib, they were less cost-effective than ensartinib due to the overwhelming total costs.

A low-cost, flexible extruder for liposomes synthesis and application for Murrayafoline A delivery for cancer treatment.

Liposomal encapsulation is a drug delivery strategy with many advantages, such as improved bioavailability, ability to carry large drug loads, as well as controllability and specificity towards various targeted diseased tissues. Currently, most preparation techniques require an additional extrusion or filtering step to obtain monodisperse liposomes with the size of less than 100 nm. In this study, a compact liposome extruder was designed at a cost of $4.00 and used to synthesize liposome suspensions with defined particle size and high homogeneity for Murrayafoline A (Mu-A) loading and release. The synthesized MuA-loaded liposomes displayed a biphasic drug release and remained stable under the storage condition of 4°C. They also significantly reduced the viability of HepG2 cells in the cancer spheroids by 25%. The low-cost, flexible liposome extruder would allow the researchers to study liposomes and their applications in a cost-effective manner.

Ultrasonographic assessment of renal perfusion in bitches with mammary carcinoma treated with long-term carprofen.

The aim of this study was to evaluate renal hemodynamics, routine clinical and laboratory parameters used to estimate renal function, and clinical evolution during six months in bitches with mammary carcinomas that underwent mastectomy and were treated (TG) or not (CG) with carprofen for three months after surgery. Twenty-six bitches with mammary carcinoma were equally distributed into TG that received carprofen 4.4 mg/kg/day for 90 days and CG that did not receive anti-inflammatory medication. Renal artery Doppler flowmetry, contrast-enhanced ultrasound (CEUS) of renal parenchyma, haematological, biochemical and clinical analyses were obtained once a month. These data were compared between groups and time via analysis of variance (ANOVA) in a completely randomized design with repeated measures (P < 0.05). On B-mode ultrasound, the area of the renal artery was greater (P = 0.0003) in the TG. Regarding laboratory findings, haematocrit and haemoglobin were similar in both groups, showing a significant and gradual increase after three months of treatment; MCV, MHC, and MCHC were increased (P < 0.05) and lymphocyte and band counts decreased (P < 0.05) in the TG. Regarding biochemical tests, ALT was the only parameter with a significant difference, being higher (P = 0.0272) in the treated group. It can be concluded that the use of carprofen for 90 days causes minimal changes in renal perfusion, erythrocyte parameters and ALT activity, and reduces the proportion of blood inflammatory cells. Therefore, use of this medication can be carried out safely in patients who require auxiliary cancer treatment.

Assessment of Alectinib vs Ceritinib in ALK-Positive Non-Small Cell Lung Cancer in Phase 2 Trials and in Real-world Data.

Importance: Quantitative assessment of bias from unmeasured confounding and missing data can help evaluate uncertainty in findings from indirect comparisons using real-world data (RWD). Objective: To compare the effectiveness of alectinib vs ceritinib in terms of overall survival (OS) in patients with ALK-positive, crizotinib-refractory, non-small cell lung cancer (NSCLC) and to assess the sensitivity of these findings to unmeasured confounding and missing data assumptions. Design, Setting, and Participants: This comparative effectiveness research study compared patients from 2 phase 2 alectinib trials and real-world patients. Patients were monitored from June 2013 to March 2020. Comparisons of interest were between alectinib trial data vs ceritinib RWD and alectinib RWD vs ceritinib RWD. RWD treatment groups were selected from nationally representative cancer data from US cancer clinics, the majority from community centers. Participants were ALK-positive patients aged 18 years or older with advanced NSCLC, prior exposure to crizotinib, and Eastern Cooperative Oncology Group Performance Status (PS) of 0 to 2. Data analysis was performed from October 2020 to March 2021. Exposures: Initiation of alectinib or ceritinib therapy. Main Outcomes and Measures: The main outcome was OS. Results: In total, there were 355 patients: 183 (85 men [46.4%]) in the alectinib trial, 91 (43 men [47.3%]) in the ceritinib RWD group, and 81 (38 men [46.9%]) in the alectinib RWD group. Patients in the alectinib trial were younger (mean [SD] age, 52.53 [11.18] vs 57.97 [11.71] years), more heavily pretreated (mean [SD] number of prior therapy lines, 1.95 [0.72] vs 1.47 [0.81]), and had more favorable baseline ECOG PS (ECOG PS of 0 or 1, 165 patients [90.2%] vs 37 patients [77.1%]) than those in the ceritinib RWD group. The alectinib RWD group (mean [SD] age, 58.69 [11.26] years) had more patients with favorable ECOG PS (ECOG PS of 0 or 1, 49 patients [92.4%] vs 37 patients [77.1%]) and more White patients (56 patients [72.7%] vs 53 patients [62.4%]) compared with the ceritinib group. Compared with ceritinib RWD, alectinib-exposed patients had significantly longer OS in alectinib trials (adjusted hazard ratio [HR], 0.59; 95% CI, 0.44-0.75; P < .001) and alectinib RWD (HR, 0.46; 95% CI, 0.29-0.63; P < .001) after adjustment for baseline confounders. For the worst-case HR estimate of 0.59, residual confounding by a hypothetical confounder associated with mortality and treatment by a risk ratio greater than 2.24 was required to reverse the findings. Conclusions were robust to plausible deviations from random missingness for missing ECOG PS and underrecorded comorbidities and central nervous system metastases in RWD. Conclusions and Relevance: Alectinib exposure was associated with longer OS compared with ceritinib in patients with ALK-positive NSCLC, and only substantial levels of bias examined reversed the findings. These findings suggest that quantitative bias analysis can be a useful tool to address uncertainty of findings for decision-makers considering RWD.

Distribution characteristics and risk assessment of polyhalogenated carbazoles in sea water of the Yellow Sea.

Polyhalogenated carbazoles (PHCZs), a novel type of organic pollutants with dioxin-like toxicity, have gained increasing attention in the past several years. In this study detection and distribution of five PHCZ compounds found in the Yellow Sea region are studied. The range of ∑PHCZ in the detection area is 0.062-0.322 ng/L (median: 0.112 ng/L), with 3,6-dichlorocarbazole and 3,6-dibromocarbazole content being the greatest, ranging from 0.035-0.269 ng/L and 0.010-0.682 ng/L, respectively, followed by 3-CCZ (0.010-0.020 ng/L). The relative toxicity of PHCZs is evaluated by the toxicity equivalent (TEQ), in which a range of 0-0.19 pgTEQ/L (median: 0.006 pgTEQ/L) is determined. According to the results, PHCZs are widely distributed in Yellow Sea water with relatively lower toxicity, and the impact of natural factors, as well as their potential sources, are discussed in order to provide basic scientific data for the investigation of PHCZs in seawater.

Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity.

G-quadruplexes (G4) are considered new drug targets for human diseases such as cancer. More than 10,000 G4s have been discovered in human chromatin, posing challenges for assessing the selectivity of a G4-interactive ligand. 3,6-bis(1-Methyl-4-vinylpyridinium) carbazole diiodide (BMVC) is the first fluorescent small molecule for G4 detection in vivo. Our previous structural study shows that BMVC binds to the MYC promoter G4 (MycG4) with high specificity. Here, we utilize high-throughput, large-scale custom DNA G4 microarrays to analyze the G4-binding selectivity of BMVC. BMVC preferentially binds to the parallel MycG4 and selectively recognizes flanking sequences of parallel G4s, especially the 3'-flanking thymine. Importantly, the microarray results are confirmed by orthogonal NMR and fluorescence binding analyses. Our study demonstrates the potential of custom G4 microarrays as a platform to broadly and unbiasedly assess the binding selectivity of G4-interactive ligands, and to help understand the properties that govern molecular recognition.

Assessment of endocrine-disrupting effects of emerging polyhalogenated carbazoles (PHCZs): In vitro, in silico, and in vivo evidence.

Polyhalogenated carbazoles (PHCZs) are an emerging class of persistent, bioaccumulative compounds that are structurally and chemically related to dioxins. They have been detected widely in sediment, river, and soil samples, but their environmental risks are largely unknown. Therefore, seven common PHCZs were tested for their endocrine disrupting potential in silico, in vitro, and in vivo. A dual-luciferase reporter gene assay was used to detect receptor-mediated (agonist or antagonistic) activity (concentration range: 10-9-10-5 M) against the estrogen receptor α (ERα), glucocorticoid receptor α (GRα), and mineralocorticoid receptor (MR). The alterations in the steroidogenesis pathway were investigated in H295R cells. Antagonistic effects against GRα were observed with five PHCZs, along with an increase in the cortisol levels of H295R cells. The most common effect observed was that of the agonistic activity of ERα, with the molecular docking analysis further indicating that hydrogen bonding and hydrophobic interactions may stabilize the interaction between PHCZs and the estrogen receptor binding pocket. In addition, a seven-day exposure of young female rats to three PHCZs (27-BCZ, 3-BCZ, and 36-BCZ) resulted in changes in serum E2 levels, uterine epithelium cell heights, and relative uterus weights. In conclusion, endocrine-disrupting effects, especially the estrogenic effects, were observed for the tested PHCZs. Such adverse effects of PHCZs on humans and wildlife warrant further thorough investigation.

Economic burden in patients with ALK + non-small cell lung cancer, with or without brain metastases, receiving second-line anaplastic lymphoma kinase (ALK) inhibitors.

Aims: To describe the real-world economic burden of patients with anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) treated with post-crizotinib, second-line ALK inhibitor therapy.Materials and methods: Retrospective analysis using data from US Optum: Clinformatics Data Mart administrative claims database. Adult patients with ALK + NSCLC treated with ceritinib or alectinib as second-line ALK inhibitors between 1 January 2011 and 30 September 2017 were included. Healthcare costs and resource utilization for up to 1 year of therapy were calculated on a per-patient-per-month (PPPM) basis and stratified by presence or absence of brain metastases (BM). Multivariate regression analysis was performed to identify factors associated with costs. Top ten cost drivers of non-inpatient procedure costs were recorded.Results: One hundred and twelve patients received second-line ALK inhibitors. Total mean PPPM healthcare costs were $23,984 for all patients receiving up to 1 year of post-crizotinib, second-line ALK inhibitor therapy. Total mean PPPM costs for patients with BM on or prior to post-crizotinib, second-line ALK inhibitor therapy were 1.37-times as high as those for patients without BM (p = 0.0406). Mean PPPM outpatient visits and inpatient hospitalization stays were higher for patients with BM versus no BM. The main cost drivers for non-inpatient procedures were radiation therapy, medications, and diagnostic radiology.Limitations: Analyses did not include newer ALK-directed therapies. BM development after the index date (defined as the date of the first claim for a second-line ALK inhibitor) may have been misclassified as non-BM. Findings may not be generalizable to patients with no health insurance coverage.Conclusions: Treatment of patients with ALK + NSCLC with ceritinib or alectinib as post-crizotinib, second-line ALK inhibitor therapy represents a high economic burden. Healthcare costs and resource utilization were significantly higher for patients with ALK + NSCLC with BM versus no BM.

Assessment of anti-cancer effects of koenimbine on colon cancer cells.

BACKGROUND: Recent studies have highlighted the role of natural elements in reduction of cancer cell growth and apoptosis. Koenimbine, a natural product isolated from Murraya koenigii (L) Spreng is a substance with cytotoxic effects on cancer cells. AIM: The effects of koenimbine on HT-29 and SW48 colon cancer cells were evaluated by MTT and Annexin V assays. Expression levels of Wnt/ß-catenin pathway genes were quantified by real time PCR. RESULTS: The IC50 values of koenimbine in HT-29 and SW48 was calculated to be 50 µg/ml based on the results of MTT assay. This value was 75 µg/ml in IEC-18 cells which were used as normal control. Annexin V assays revealed induction of cell apoptosis and necrosis in HT-29 and SW48 cells but not IEG18 cells by koenimbine. Koenimbin treatment resulted in significant down-regulation of CYCLD1 expression in SW48 cell line, but up-regulation of this gene in HT29 cell line. Expression of TBLR1, DKK1, GSK3B and ß-catenin was significantly decreased after koenimbin treatment in HT-19 cell line. Moreover, expression of DKK1 and GSK3B was significantly decreased after koenimbin treatment in SW-40 cell line. TCF4 expression was not detected in any of cell lines either before or after treatment with koenimbin. CONCLUSION: The current in vitro study showed the cytotoxic effects of koenimbin on two colon cancer cell lines and the effects of this substance on expression of selected genes from Wnt-ß catenin pathway. Future in vivo studies are needed before suggestion of this substance as an anti-cancer drug.

Cost-effectiveness of alectinib compared to crizotinib for the treatment of first-line ALK+ advanced non-small-cell lung cancer in France.

The aim of the study is to evaluate the cost-effectiveness of alectinib for first-line treatment of ALK+ advanced non-small-cell lung cancer compared to crizotinib in the French setting. This study used a partitioned survival model, with three discrete health states (progression-free survival, post-progression survival and death). Survival probabilities were derived from a randomised Phase III clinical trial comparing alectinib to crizotinib (ALEX). Beyond the length of the trial (18 months), the efficacy of both treatments was considered equivalent. Occurrence of adverse events or brain metastases were considered as inter-current events. Utilities (and disutilities for intercurrent adverse events) derived from the EQ-5D were applied. Costs were attributed using standard French national public health tariffs. Projected mean overall survival was 4.62 years for alectinib and 4.18 years for crizotinib. Projected mean progression-free survival was 30.30 months for alectinib and 16.13 months for crizotinib. The total number of quality-adjusted life years projected was 3.40 for alectinib and 2.84 for crizotinib. The projected total cost of treatment over the lifetime of the model was € 246,022 for alectinib and € 195,486 for crizotinib. This extra cost was principally attributable to treatment acquisition costs and management before progression. Alectinib was associated with lower costs related to brain metastases and to management post-progression. The incremental cost per life year gained was 115,334 €/year and the incremental cost-effectiveness ratio was 90,232 €/QALY. First-line treatment of ALK+ NSCLC with alectinib provides superior clinical outcomes to crizotinib and is cost-effective in the French context.

Cost Effectiveness of Ceritinib and Alectinib Versus Crizotinib in First-Line Anaplastic Lymphoma Kinase-Positive Advanced Non-small-cell Lung Cancer.

BACKGROUND: Crizotinib, ceritinib, and alectinib improved survival in patients with anaplastic lymphoma kinase (ALK) arrangement non-small-cell lung cancer (NSCLC); however, the long-term economic outcomes of using ceritinib and alectinib versus crizotinib are still unclear. OBJECTIVE: This analysis aimed to evaluate the cost effectiveness of ceritinib and alectinib versus crizotinib in the Chinese healthcare setting. METHODS: A Markov model was developed to project the economic and health outcomes for the treatment of advanced NSCLC with ceritinib, alectinib or crizotinib. A network meta-analysis was performed to calculate the hazard ratios of ceritinib and alectinib versus crizotinib by pooling published trials. Cost and utility values were obtained from the literature, and one-way and probabilistic sensitivity analyses were carried out to determine the robustness of the model outcomes. The primary outputs included total cost, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). RESULTS: Treatment with alectinib and ceritinib yielded an additional 1.00 and 1.09 QALYs and incremental costs of $62,232 and $15,165, resulting in an ICER of $62,231 and $13,905 per QALY compared with crizotinib, respectively. Parameters related to drug costs and progression-free survival were the main drivers of the model outcomes. From the probabilistic sensitivity analysis, ceritinib and alectinib had a 99.9% and 0% probability of being cost effective, respectively, at a willingness-to-pay threshold of US$28,410/QALY. CONCLUSIONS: Our results indicate that compared with crizotinib and alectinib, ceritinib is a cost-effective option for treatment-naïve patients with ALK-positive advanced NSCLC.

A low-cost and high-efficiency carbazole-based porous organic polymer as a novel sorbent for solid-phase extraction of triazine herbicides in vegetables.

In this study, a porous organic polymer (denoted as Car-DMB) was fabricated by a simple one-step crosslinking polymerization of carbazole and p-dimethoxybenzene for the first time. Then the Car-DMB was served as adsorbent of solid phase extraction to enrich triazine herbicides from white gourd, tomato and soybean milk samples prior to their determination by high performance liquid chromatography. Under the optimal conditions, the response linearity was in the range of 0.3-100.0 ng g-1 for white gourds and tomato samples, and 0.5-100.0 ng mL-1 for soybean milk, with the coefficient of determination higher than 0.996. The detection limits were 0.1-0.2 ng g-1 for white gourd and tomato samples, and 0.15-0.3 ng mL-1 for soybean milk. The adsorption mechanism of the Car-DMB for the triazines was attributed to the strong H-bonding and weak π-π interactions. The efficient extraction for several other compounds demonstrated that Car-DMB holds great potential for diverse analysis applications.