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Alectinib, a potent ALK tyrosine kinase inhibitor, was more effective and somewhat less toxic than crizotinib when used as primary therapy in patients with ALK -positive non–small-cell lung cancer. Importantly, it reduced the risk of CNS relapse.

Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8–11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib. We enrolled patients with ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib. We administered various oral doses of alectinib (300–900 mg twice a day) during the dose-escalation portion of the study (phase 1), to ascertain the recommended dose for phase 2. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan (CT or MRI), with central radiological review of individuals with brain metastases. We assessed safety in all patients who received at least one dose of alectinib. Here, we present data for the phase 1 portion of the study, the primary objective of which was to establish the recommended phase 2 dose; phase 2 is ongoing. This trial is registered at ClinicalTrials.gov, number NCT01588028. 47 patients were enrolled. Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1–2), myalgia (eight [17%]; all grade 1–2), and peripheral oedema (seven [15%] grade 1–2, one [2%] grade 3). Dose-limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3–4 adverse events were increased levels of γ-glutamyl transpeptidase (two [4%]), a reduction in the number of neutrophils (two [4%]), and hypophosphataemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural effusion and pericardial effusion; and brain metastasis. At data cut-off (median follow-up 126 days [IQR 84–217]), 44 patients could be assessed for activity. Investigator-assessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. Pharmacokinetic data indicated that mean exposure (AUC0–10) after multiple doses of alectinib (300–600 mg twice a day) was dose-dependent. Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2. Chugai Pharmaceuticals, F Hoffmann La-Roche.

Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib. J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1:1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316). Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0·34 [99·7% CI 0·17–0·71], stratified log-rank p<0·0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20·3–not estimated) and was 10·2 months (8·2–12·0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group. These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study. Chugai Pharmaceutical Co, Ltd.

Commercial carbazole has been widely used to synthesize organic functional materials that have led to recent breakthroughs in ultralong organic phosphorescence 1 , thermally activated delayed fluorescence 2 , 3 , organic luminescent radicals 4 and organic semiconductor lasers 5 . However, the impact of low-concentration isomeric impurities present within commercial batches on the properties of the synthesized molecules requires further analysis. Here, we have synthesized highly pure carbazole and observed that its fluorescence is blueshifted by 54 nm with respect to commercial samples and its room-temperature ultralong phosphorescence almost disappears 6 . We discover that such differences are due to the presence of a carbazole isomeric impurity in commercial carbazole sources, with concentrations <0.5 mol%. Ten representative carbazole derivatives synthesized from the highly pure carbazole failed to show the ultralong phosphorescence reported in the literature 1 , 7 – 15 . However, the phosphorescence was recovered by adding 0.1 mol% isomers, which act as charge traps. Investigating the role of the isomers may therefore provide alternative insights into the mechanisms behind ultralong organic phosphorescence 1 , 6 – 18 . A carbazole isomer, typically present as an impurity in commercially produced carbazole batches, is shown to be responsible for the ultralong phosphorescence observed in these compounds and their derivatives.

The Aryl-hydrocarbon Receptor (AhR) is implicated in the regulation of several genes, including those encoding CYP1A1. Although it is an orphan receptor, the amount of data about its relationship with skin homeostasis and nosology is constantly increasing. Interestingly, 6-formylindolo[3,2-b]carbazole (6-FICZ), one of the most active AhR inducers and amongst the proposed receptor’s endogenous ligands, has been detected in Malassezia furfur isolates from lesional skin, as well as in skin scales from patients with seborrhoeic dermatitis. Aiming to study the structure–activity relationships of the indolo[3,2-b]carbazole (ICZ) scaffold and to clarify if the formyl group of 6-FICZ has any specific role in AhR induction, a series of analogues of ICZ (substituted at position 6 with methyl, formyl and hydroxymethyl groups) were synthesized and evaluated for their activity on AhR in cell lines of four different species. A new simple method for the synthesis of 6-FICZ was developed. 6-Methylindolo[3,2-b]carbazole (6-MICZ) showed higher activity than 6-FICZ in human, rat and guinea pig cell lines, and all synthesized derivatives showed comparable activity in the mouse cell line. Therefore, the formyl group does not seem to play a significantly specific role in the affinity for AhR, and 6-FICZ seems less likely to be an endogenous ligand.

We report pharmacokinetics, efficacy and safety data for a new 150‐mg alectinib capsule in ALK+ non‐small‐cell lung cancer in a multicenter, open‐label pharmacologic study (JP28927). Eligible patients (≥20 years, locally advanced/metastatic ALK+ disease, ALK inhibitor‐naïve and ‐pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300 mg twice daily (comprising different schedules of 20/40‐mg and 150‐mg capsules) until investigator‐determined lack of clinical benefit. Co‐primary endpoints were: bioequivalence of alectinib 20/40 mg vs 150 mg; food effect with 150 mg; and safety. Thirty‐five patients were enrolled; median treatment duration was 13.1 months (range 1.1−15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUClast ± standard deviation 3230 ± 914 h·ng/mL vs 3710 ± 1040 h·ng/mL, respectively, for 150‐mg vs 20/40‐mg capsules. Food effect with 150 mg alectinib was negligible. Treatment‐related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment‐related grade 4/5 events occurred. Median time to response was 1.2 months (95% CI 1.1−2.1). For the full analysis set (n = 35) and crizotinib‐failure subpopulations (n = 23), the overall response rate was 70.0% (95% CI 50.6−85.3) and 65.0% (95% CI 40.8−84.6), and median progression‐free survival was 13.9 months (95% CI 11.1−not reached) and 12.9 months (95% CI 3.9−not reached), respectively. The 150‐mg capsule had a similar exposure profile to 20/40‐mg capsules. Alectinib demonstrated promising efficacy and was well tolerated. We report pharmacokinetics, efficacy and safety data for a new 150‐mg alectinib capsule in ALK+ non‐small‐cell lung cancer in a multicenter, open‐label pharmacologic study (JP28927). Patients with locally advanced/metastatic ALK+ disease were randomized 1:1 to receive one of two sequences of alectinib 300 mg twice daily until investigator‐determined lack of clinical benefit. The 150‐mg alectinib capsule had a similar exposure profile to 20/40‐mg capsules and was well tolerated in ALK+ non‐small‐cell lung cancer.

Organic light-emitting diode (OLED) technology is promising for ultrahigh-definition displays and other applications, but further improvements in efficiency and colour purity are desired. Here, we designed and synthesized an ultrapure green emitter called DBTN-2, which is organoboron based and features a highly distorted fused π-conjugated molecular design. This design concept substantially reduces the relaxation energy between the geometries of the excited and ground states, leading to a full-width at half-maximum emission of only 20 nm. Furthermore, the different excitation characters of the singlet and triplet states enhance the spin–orbit couplings leading to highly efficient operation. The introduction of the multiple carbazole moieties gives rise to a charge-resonance-type excitation feature of the triplet states, thus resulting in a high density of the triplet states and a rate of reverse intersystem crossing (kRISC) as fast as 1.7 × 105 s−1. An ultrapure green OLED exploiting DBTN-2 as an emitter without optimized cavity effects and colour filters operated with Commission Internationale de l’Eclairage coordinates of (0.19, 0.74), satisfying the requirement for a commercial green OLED display. Moreover, in combination with a photoluminescence quantum yield of near 100% and a strong horizontal dipole orientation in the doped film, an excellent external quantum efficiency of 35.2% with suppressed efficiency roll-off is simultaneously obtained.An organoboron-emitter, DBTN-2, yields a green organic light-emitting diode with ultrapure colour and high efficiency.

In a trial of adjuvant treatment for patients with resected ALK -positive non–small-cell lung cancer, disease-free survival at 2 years was 93.6% with the ALK inhibitor alectinib and 63.7% with standard chemotherapy.

Abstract Despite COVID-19 vaccination, immune escape of new SARS-CoV-2 variants has created an urgent priority to identify additional antiviral drugs. Targeting main protease (Mpro) expressed by SARS-CoV-2 is a therapeutic strategy for drug development due to its prominent role in viral replication cycle. Leaves of Murraya koenigii are used in various traditional medicinal applications and this plant is known as a rich source of carbazole alkaloids. Thus, this computational study was designed to investigate the inhibitory potential of carbazole alkaloids from Murraya koenigii against Mpro. Molecular docking was initially used to determine the binding affinity and molecular interactions of carbazole alkaloids and the reference inhibitor (3WL) in the active site of SARS-CoV-2 Mpro (PDB ID: 6M2N).The top scoring compounds were further assessed for protein structure flexibility, physicochemical properties and drug-likeness, pharmacokinetic and toxicity (ADME/T) properties, antiviral activity, and pharmacophore modeling. Five carbazole alkaloids (koenigicine, mukonicine, o-methylmurrayamine A, koenine, and girinimbine) displayed a unique binding mechanism that shielded the catalytic dyad of Mpro with stronger binding affinities and molecular interactions than 3WL. Furthermore, the compounds with high affinity displayed favorable physicochemical and ADME/T properties that satisfied the criteria for oral bioavailability and druggability. The pharmacophore modeling study shows shared pharmacophoric features of those compounds for their biological interaction with Mpro. During the molecular dynamics simulation, the top docking complexes demonstrated precise stability except koenigicine. Therefore, mukonicine, o-methylmurrayamine A, koenine, and girinimbine may have the potential to restrict SARS-CoV-2 replication by inactivating the Mpro catalytic activity.

Background and aimsCarvedilol is effective in the primary prophylaxis for large oesophageal varices. We investigated its use in preventing progression of small to large oesophageal varices.MethodsConsecutive cirrhotics with small oesophageal varices were prospectively randomised to either carvedilol (n=70) or placebo (n=70) and followed up for a minimum of 24 months. Endoscopy was done at baseline and six monthly intervals. Hepatic vein pressure gradient (HVPG) was measured at baseline and at 12 months. The primary endpoint was development of large varices.ResultsBaseline characteristics in two groups were comparable. The predominant aetiology of cirrhosis was non-alcoholic fatty liver disease in both the groups. The mean dose of carvedilol administered was 12±1.67 mg/day and the target heart rate achieved was 58±3 bpm. A higher proportion of patients in carvedilol group had non-progression to large varices than placebo (79.4% vs 61.4%; p=0.04); the mean time of non-progression to large varices was 20.8 months (95% CI 19.4 to 22.4) in carvedilol group and 18.7 months (95% CI 17.1 to 20.4) in placebo group (p=0.04). There was a modest reduction of HVPG at 1 year in carvedilol group (−8.64%) compared with placebo (+0.33%) (p=0.22). None of the patients in either group died of variceal bleeding or liver-related causes. No major adverse events were observed in either group.ConclusionsCarvedilol is safe and effective in delaying the progression of small to large oesophageal varices in patients with cirrhosis.Trial registration numberNCT01196507; post-results.