A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)2(dppz)]+, Ir1-Ir4, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was p-CF3C6H4 or p-Me2NC6H4. These new Ir(III) complexes were assessed as photosensitizers to explore the structure-activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, the complexes exhibited high selective potency across several cancer cell lines predisposed to photodynamic therapy; the benzothiazole derivatives (Ir1 and Ir2) were the best performers, Ir2 being also activatable with green or red light. Notably, when irradiated, the complexes induced leakage of lysosomal content into the cytoplasm of HeLa cancer cells and induced oncosis-like cell death. The capability of the new Ir complexes to photoinduce cell death in 3D HeLa spheroids has also been demonstrated. The investigated Ir complexes can also catalytically photo-oxidate NADH and photogenerate 1O2 and/or •OH in cell-free media.
- MeSH
- benzothiazoly MeSH
- fotosenzibilizující látky farmakologie terapeutické užití MeSH
- fototoxická dermatitida * farmakoterapie MeSH
- iridium farmakologie MeSH
- komplexní sloučeniny * farmakologie MeSH
- lidé MeSH
- lyzozomy MeSH
- nádorové buněčné linie MeSH
- nádory * farmakoterapie MeSH
- protinádorové látky * farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Laccase-producing fungus (MY3) was successfully isolated from soil samples collected from Mansoura Governorate, Egypt. This fungal isolate has shown a high laccase production level over other isolated fungi. The identity of this isolate was determined by the molecular technique 18SrRNA as Curvularia lunata MY3. The enzyme purification was performed using ammonium sulfate precipitation followed by Sephacryl S-200 and DEAE-Sepharose column chromatography. The denatured enzyme using SDS-PAGE had a molar mass of 65 kDa. The purified laccase had an optimum temperature at 40 °C for enzyme activity with 57.3 kJ/mol activation energy for 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) oxidation. The enzyme had an optimum pH of 5.0, and it has shown a high stability at the acidic range (4.5 to 5.5). Mn2+ and Mg2+ ions enhanced the enzyme activity, while most of the enzyme activity was inhibited by Hg2+. Some compounds such as 2-mercaptoethanol, L-cysteine, and sodium azide at a concentration of 10 mmol/L had shown a high suppression effect on the enzyme activity. The enzyme strongly oxidized ABTS and syringaldazine and moderately oxidized DMP and guaiacol. The antimicrobial activity of the purified enzyme towards three pathogenic strains (Escherichia coli ATCC-25922, Staphylococcus aureus NRRLB-767, and Candida albicans ATCC-10231) was evaluated for the potential use as an antimicrobial therapeutic enzyme.
Amyotrofická laterální skleróza (ALS) je nevyléčitelné neurodegenerativní onemocnění s nejasnou patofyziologií a závažnou prognózou. Farmakoterapie v léčbě ALS cílí na zpomalení progrese a zmírnění symptomů onemocnění. První a aktuálně jediný lék zpomalující průběh onemocnění, který je určen pro celou populaci ALS pacientů, je riluzol. Pro geneticky predisponované pacienty s mutací v genu pro superoxiddismutázu (SOD1) je americkou a zcela recentně i evropskou lékovou agenturou schválen tofersen. Symptomatická farmakoterapie umožňuje zmírnit spasticitu, sialoreu, krampi, depresi, emoční nestabilitu a v terminálním stadiu onemocnění také dušnost.
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease with unclear pathophysiology and poor prognosis. Pharmacotherapy in the treatment of ALS is aimed at slowing disease progression and alleviating symptoms. The first and currently only drug that slows disease progression and is available to an unselected population is riluzole. For genetically predisposed patients with a mutation in the gene for superoxide dismutase (SOD1), tofersen is approved by the US Food and Drug Administration and more recently by the European Medicines Agency. European approval is expected soon. Symptomatic pharmacotherapy improves spasticity, sialorrhea, spasms, depression, emotional instability and, in palliative care at the end of life, dyspnea.
- Klíčová slova
- tofersen,
- MeSH
- amyotrofická laterální skleróza * diagnóza farmakoterapie MeSH
- farmakoterapie * klasifikace MeSH
- lidé MeSH
- management farmakoterapie MeSH
- příznaky a symptomy MeSH
- progrese nemoci MeSH
- riluzol farmakologie terapeutické užití MeSH
- superoxiddismutasa 1 genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Venetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient-derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status.
- MeSH
- apoptóza účinky léků MeSH
- benzothiazoly MeSH
- bicyklické sloučeniny heterocyklické * farmakologie terapeutické užití MeSH
- chemorezistence * MeSH
- isochinoliny MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- protein bcl-X * metabolismus antagonisté a inhibitory MeSH
- protein BCL2L11 * metabolismus genetika MeSH
- protinádorové látky farmakologie terapeutické užití MeSH
- protoonkogenní proteiny c-bcl-2 metabolismus antagonisté a inhibitory MeSH
- sulfonamidy * farmakologie terapeutické užití MeSH
- synergismus léků MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Benzotriazoles and benzothiazoles (BTs) are high-production volume chemicals as well as widely distributed emerging pollutants with potential health risk. However, information about human exposure to BTs and associated health outcomes is limited. OBJECTIVE: We aimed to characterise exposure to BTs among Czech men, including possible occupational exposure among firefighters, its predictors, and its associations with liver function, serum lipids and oxidative stress. METHODS: 165 participants (including 110 firefighters) provided urine and blood samples that were used to quantify the urinary levels of 8 BTs (high-performance liquid chromatography-tandem mass spectrometry), and 4 liver enzymes, cholesterol, low-density lipoprotein, and 8-hydroxy-2'-deoxyguanosine. Linear regression was used to assess associations with population characteristics and biomarkers of liver function, serum lipids and oxidative stress. Regression models were adjusted for potential confounding variables and false discovery rate procedure was applied to account for multiplicity. RESULTS: The BTs ranged from undetected up to 46.8 ng/mL. 2-hydroxy-benzothiazole was the most predominant compound (detection frequency 83%; median 1.95 ng/mL). 1-methyl-benzotriazole (1M-BTR) was measured in human samples for the first time, with a detection frequency 77% and median 1.75 ng/mL. Professional firefighters had lower urinary 1M-BTR compared to non-firefighters. Urinary 1M-BTR was associated with levels of γ-glutamyl transferase (β = - 17.54%; 95% CI: - 26.127, - 7.962). CONCLUSION: This is the first study to investigate BT exposure in Central Europe, including potentially exposed firefighters. The findings showed a high prevalence of BTs in the study population, the relevance of 1M-BTR as a new biomarker of exposure, and an urgent need for further research into associated adverse health outcomes.
- MeSH
- 8-hydroxy-2'-deoxyguanosin moč krev MeSH
- benzothiazoly * MeSH
- biologické markery * krev moč MeSH
- cholesterol krev MeSH
- deoxyguanosin analogy a deriváty moč krev MeSH
- dospělí MeSH
- hasiči MeSH
- játra účinky léků MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipidy krev MeSH
- oxidační stres * účinky léků MeSH
- pracovní expozice * analýza MeSH
- triazoly * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
The σ-1 receptor is a non-opioid transmembrane protein involved in various human pathologies including neurodegenerative diseases, inflammation, and cancer. The previously published ligand [18 F]FTC-146 is among the most promising tools for σ-1 molecular imaging by positron emission tomography (PET), with a potential for application in clinical diagnostics and research. However, the published six- or four-step synthesis of the tosyl ester precursor for its radiosynthesis is complicated and time-consuming. Herein, we present a simple one-step precursor synthesis followed by a one-step fluorine-18 labeling procedure that streamlines the preparation of [18 F]FTC-146. Instead of a tosyl-based precursor, we developed a one-step synthesis of the precursor analog AM-16 containing a chloride leaving group for the SN 2 reaction with 18 F-fluoride. 18 F-fluorination of AM-16 led to a moderate decay-corrected radiochemical yield (RCY = 7.5%) with molar activity (Am ) of 45.9 GBq/μmol. Further optimization of this procedure should enable routine radiopharmaceutical production of this promising PET tracer.
- MeSH
- azepiny MeSH
- benzothiazoly MeSH
- lidé MeSH
- pozitronová emisní tomografie * metody MeSH
- radiofarmaka MeSH
- radioizotopy fluoru chemie MeSH
- receptor sigma-1 * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Predložená práca sa zaoberá vývojom matricovej tablety s predĺženým uvoľňovaním ľahko rozpustného liečiva pramipexolu. Ako polymér riadiaci uvoľňovanie liečiva z vybraných prototypov bol použitý nový excipient Kollidon SR (zmes 80 % polyvinylacetátu a 20 % polyvinylpyrolidónu) a hypromelóza K15M. Testovali sa rôzne koncentrácie polymérov s cieľom dosiahnúť stabilné a pH nezávislé uvoľňovanie pramipexolu 0,26 mg po dobu 24 hodín, vzorky boli pripravené vlhkou granuláciou a lisovaním matricových tabliet. Uvoľňovanie liečiva bolo sledované v disolučných médiách s hodnotami pH od 1,2 až po 6,8 a porovnávané s referenčným prípravkom na báze hydrofilnej matrice s kombináciu troch rôznych polymérov. Požadovaný liberačný profil nízkodávkového liečiva bol dosiahnutý použitím 60,0 hm.% Kollidonu SR vo všetkých médiách a vybraná formulácia F2 vykazovala dostatočnú odolnosť aj voči pôsobeniu etanolu až do koncentrácie 40 obj.%.
The present work deals with the development of a prolonged release matrix tablet of the readily soluble drug pramipexole. The new excipient Kollidon SR (a mix-ture of 80% polyvinyl acetate and 20% polyvinylpyrroli-done) and hypromellose K15M were used as polymers to control drug release from selected prototypes. Various polymer concentrations were tested to achieve a stable and pH independent release of pramipexole of 0.26 mg over 24 hours; samples were prepared by wet granulation and compression of matrix tablets. Drug release was moni-tored in dissolution media with pH values from 1.2 to 6.8 and compared with a reference product based on a hydro-philic matrix with a combination of three different poly-mers. The required release profile of the low-dose drug formulation was achieved using 60.0% (w/w) of Kollidon SR in all dissolution media and the selected formulation F2 demonstrated a sufficient alcohol resistance up to the ethanol concentration of 40% (v/v).
Metabolic disorders caused by the imbalance of gut microbiota have been associated with the consumption of processed foods. Thus, this study aimed to evaluate the effects of antimicrobial food additives (benzoate, sorbate, nitrite, and bisulfite) and sweeteners (saccharin, stevia, sucralose, aspartame, and cyclamate) on the growth and metabolism of some gut and potentially probiotic bacterial species. The effects on the growth of Bifidobacterium longum, Enterococcus faecium, Lactobacillus acidophilus, and Lactococcus lactis subsp. lactis cultures were investigated using a turbidimetric test and by determining the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). To evaluate the metabolic activity, the cultures were exposed to compounds with the highest antimicrobial activity, subjected to cultivation with inulin (1.5%), and analyzed by liquid chromatography for the production of short-chain fatty acids (acetate, propionate, and butyrate). The results showed that potassium sorbate (25 mg/mL), sodium bisulfite (0.7 mg/mL), sodium benzoate, and saccharin (5 mg/mL) presented greater antimicrobial activity against the studied species. L. lactis and L. acidophilus bacteria had reduced short-chain fatty acid production after exposure to saccharin and sorbate, and B. longum after exposure to sorbate, in comparison to controls (acetic acid reduction 1387 μg/mL and propionic 23 μg/mL p < 0.05).
BACKGROUND: Patients with acute myeloid leukaemia (AML) positive for internal tandem duplication (ITD) mutations of FLT3 have poor outcomes. Quizartinib, an oral, highly potent, selective, type 2 FLT3 inhibitor, plus chemotherapy showed antitumour activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML. The aim of the study was to compare the effect of quizartinib versus placebo on overall survival in patients with FLT3-ITD-positive newly diagnosed AML aged 18-75 years. METHODS: We conducted a randomised, double-blind, placebo-controlled, phase 3 trial comparing quizartinib and placebo in combination with chemotherapy in induction and consolidation, followed by quizartinib or placebo single-agent continuation, in patients with FLT3-ITD-positive newly diagnosed AML at 193 hospitals and clinics in 26 countries in Europe; North America; and Asia, Australia, and South America. Patients aged 18-75 years were eligible. Patients were randomly assigned (1:1) to the quizartinib group or the placebo group by an independent biostatistician through an interactive web and voice response system, stratified by region, age, and white blood cell count at diagnosis. Patients, investigators, funders, and contract research organisations were masked to treatments assigned. Induction therapy comprised a standard 7 + 3 induction regimen of cytarabine 100 mg/m2 per day (or 200 mg/m2 per day allowed if institutional or local standard) by continuous intravenous infusion from day 1 to day 7 and anthracycline (daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day) by intravenous infusion on days 1, 2, and 3, then quizartinib 40 mg orally or placebo once per day, starting on day 8, for 14 days. Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose cytarabine plus quizartinib (40 mg per day orally) or placebo, allogeneic haematopoietic cell transplantation (allo-HCT), or both as consolidation therapy, followed by continuation of single-agent quizartinib or placebo for up to 3 years. The primary outcome was overall survival, defined as time from randomisation until death from any cause and assessed in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of quizartinib or placebo. This study is registered with ClinicalTrials.gov (NCT02668653). FINDINGS: Between Sept 27, 2016, and Aug 14, 2019, 3468 patients with AML were screened and 539 patients (294 [55%] male patients and 245 [45%] female patients) with FLT3-ITD-positive AML were included and randomly assigned to the quizartinib group (n=268) or placebo group (n=271). 148 (55%) of 268 patients in the quizartinib group and 168 (62%) of 271 patients in the placebo group discontinued the study, primarily because of death (133 [90%] of 148 in the quizartinib group vs 158 [94%] of 168 in the placebo group) or withdrawal of consent (13 [9%] of 148 in the quizartinib group vs 9 [5%] of 168 in the placebo group). Median age was 56 years (range 20-75, IQR 46·0-65·0). At a median follow-up of 39·2 months (IQR 31·9-45·8), median overall survival was 31·9 months (95% CI 21·0-not estimable) for quizartinib versus 15·1 months (13·2-26·2) for placebo (hazard ratio 0·78, 95% CI 0·62-0·98, p=0·032). Similar proportions of patients in the quizartinib and placebo groups had at least one adverse event (264 [100%] of 265 in the quizartinib group and 265 [99%] of 268 in the placebo group) and one grade 3 or higher adverse event (244 [92%] of 265 in the quizartinib group and 240 [90%] of 268 in the placebo group). The most common grade 3 or 4 adverse events were febrile neutropenia, hypokalaemia, and pneumonia in both groups and neutropenia in the quizartinib group. INTERPRETATION: The addition of quizartinib to standard chemotherapy with or without allo-HCT, followed by continuation monotherapy for up to 3 years, resulted in improved overall survival in adults aged 18-75 years with FLT3-ITD-positive newly diagnosed AML. Based on the results from the QuANTUM-First trial, quizartinib provides a new, effective, and generally well tolerated treatment option for adult patients with FLT3-ITD-positive newly diagnosed AML. FUNDING: Daiichi Sankyo.
- MeSH
- akutní myeloidní leukemie * farmakoterapie genetika MeSH
- benzothiazoly * terapeutické užití MeSH
- cytarabin MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- fenylmočovinové sloučeniny * terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- protokoly protinádorové kombinované chemoterapie terapeutické užití MeSH
- senioři MeSH
- tyrosinkinasa 3 podobná fms antagonisté a inhibitory genetika MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
OBJECTIVES: Quizartinib is an oral, potent, selective, type II FLT3 inhibitor with prolonged OS as a single-agent in relapsed/refractory FLT3-ITD+ AML. We report results from the global, randomized, double-blind, phase 3 QuANTUM-First trial (NCT02668653), evaluating quizartinib plus standard induction and post-remission consolidation (including allogeneic hematopoietic cell transplant [allo-HCT] in first complete remission [CR1]) followed by single-agent continuation (up to 3 years) vs placebo plus chemotherapy in newly diagnosed FLT3-ITD+ AML. METHODS: Patients 18-75 years with newly diagnosed FLT3-ITD+ AML received induction with cytarabine 100 or 200 mg/m2/day (days 1-7) and daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day (days 1-3). Patients were randomized to quizartinib (40 mg/day [days 8-21]) or placebo; stratified by region, age, and white blood cell count at diagnosis. Patients with CR or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus quizartinib (40 mg/day) or placebo and/or allo-HCT followed by continuation with quizartinib (30-60 mg/day) or placebo (up to 3 years). The primary endpoint was OS. RESULTS: Between September 2016 and August 2019, 539 patients were randomized (quizartinib [n=268], placebo [n=271]). Median age was 56 years (range, 20-75 years). As of August 2021 (median follow-up, 39.2 months), 58 patients remained on continuation. Median OS was significantly longer with quizartinib vs placebo (31.9 vs 15.1 months; HR, 0.776; 95% CI, 0.615-0.979; 2-sided P=.0324). CR+CRi rates were 71.6% and 64.9%, respectively. Allo-HCT in CR1 was performed in 157 patients (quizartinib, 31%; placebo, 27%). When censored for allo-HCT, OS trended longer with quizartinib vs placebo (HR, 0.752; 95% CI, 0.562-1.008; 2-sided P=.055). Relapse-free survival was longer with quizartinib vs placebo (HR, 0.733; 95% CI, 0.554-0.969). Grade ≥3 adverse events (AEs) were similar across arms. Discontinuations due to AEs occurred in 20.4% (quizartinib) and 8.6% (placebo). Fifty-six patients died from treatment-emergent AEs (quizartinib, 11.3%; placebo, 9.7%); mostly infections. Grade 3/4 electrocardiographic QT prolongation occurred in 3.0% (quizartinib) and 1.1% (placebo). CONCLUSIONS: Quizartinib plus standard therapy, followed by continuation, including after allo-HCT, for up to 3 years was tolerable with statistically significant and clinically meaningful OS improvements in adults ≤75 years with newly diagnosed FLT3-ITD+ AML.
- MeSH
- akutní myeloidní leukemie * farmakoterapie genetika MeSH
- benzothiazoly MeSH
- cytarabin terapeutické užití MeSH
- daunomycin terapeutické užití MeSH
- dospělí MeSH
- fenylmočovinové sloučeniny MeSH
- idarubicin terapeutické užití MeSH
- konsolidační chemoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- transplantace hematopoetických kmenových buněk * metody MeSH
- tyrosinkinasa 3 podobná fms genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
