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1.
J Colloid Interface Sci ; 605: 82-90, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34311315

RESUMO

A highly stable Pd-loaded N-doped carbon catalyst (ACNpd) for phenol hydrogenation was prepared from chitosan by hydrothermal carbonization. ACNpd does not require a reduction step before catalytic use due to the Pd in the as-prepared catalyst mainly exists in the form of Pd0 (80%). The carbon support involves N-containing groups such as pyridinic nitrogen and pyrrolic nitrogen, which could provide basic sites to adsorb phenol effectively. The as-fabricated ACNpd shows high catalytic performance with turnover frequency (TOF) of 29.34 h-1. Accordingly, a phenol conversion of 100% and a cyclohexanone selectivity of 99.1% are achieved in 5 h at 100 °C and 1 MPa H2. This outstanding performance is attributed to the synergetic effects of the Pd particles, the N-functional groups, and the Lewis acid sites on the support. The carbon support presents intrinsic Lewis acid sites due to its electrophilicity, and Pd doping further increases the strength of such acid sites as it causes electron-deficient structural features. Moreover, the Lewis acid sites inhibit the over-hydrogenation from cyclohexanone to cyclohexanol. This study provides new insights into the application of functional biomass-based carbon materials as catalyst supports.


Assuntos
Carbono , Quitosana , Cicloexanonas , Hidrogenação , Fenol , Fenóis
2.
Chemosphere ; 286(Pt 1): 131592, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34311397

RESUMO

Nitisinone (NTBC) is currently used for the treatment of tyrosinemia type 1, a rare disease. It also exhibits potential in the treatment of other orphan diseases as well as nervous system disorders - this is however limited by its side effects. In all living organisms, NTBC inhibits 4-hydroxyphenylpyruvate dioxygenase activity, thereby affecting l-tyrosine (L-TYR) catabolism, which results in the therapeutic effect. The NTBC metabolites formed in patient's body is one of the causes of its side effects. The influence of NTBC and its metabolites; 2-amino-4-(trifluoromethyl)benzoic acid, 2-nitro-4-(trifluoromethyl)benzoic acid, and cyclohexane-1,3-dione on L-TYR catabolism was investigated in Raphanus sativus var. longipinnatus. Based on targeted LC-MS/MS analysis the concentration of NTBC and its metabolites in exposed plant tissues was determined. Based on non-targeted LC-MS/MS analysis the concentrations of products of L-TYR catabolism: levodopa, epinephrine, norepinephrine, normetanephrine, dopamine, tyramine and vitamins C, B5 and B6, additionally leucine and valine were identified as influenced by the NTBC or its metabolites. NTBC and its metabolites influenced L-TYR catabolism differently. Particularly significant changes were found in the content of epinephrine and normetanephrine: in the plant tissues exposed to NTBC, an increase in the content of these neurotransmitters was found (+42%), whereas in the plant treated with 2-amino-4-(trifluoromethyl)benzoic acid or 2-nitro-4-(trifluoromethyl)benzoic acid a decrease in concentration (-39% and 55%, respectively) was observed. Cyclohexane-1,3-dione does not influence epinephrine and normetanephrine concentration. The conclusions of this study provide a platform for expanded research on the causes of side effects of NTBC treatment.


Assuntos
Nitrobenzoatos , Espectrometria de Massas em Tandem , Cromatografia Líquida , Cicloexanonas , Humanos , Tirosina
3.
Planta Med ; 87(12-13): 1008-1017, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34687029

RESUMO

Poupartia borbonica is an endemic tree from the Mascarene Islands that belongs to the Anacardiaceae family. The leaves of this plant were phytochemically studied previously, and isolated alkyl cyclohexenone derivatives, poupartones A - C, demonstrated antiplasmodial and antimalarial activities. In addition to their high potency against the Plasmodium sp., high toxicity on human cells was also displayed. The present study aims to investigate in more detail the cytotoxicity and pharmacological interest of poupartone B, one of the most abundant derivatives in the leaves of P. borbonica. For that purpose, real-time live-cell imaging of different human cancer cell lines and normal fibroblasts, treated or not treated with poupartone B, was performed. A potent inhibition of cell proliferation associated with the induction of cell death was observed. A detailed morphological analysis of different adherent cell lines exposed to high concentrations of poupartone B (1 - 2 µg/mL) demonstrated that this compound induced an array of cellular alterations, including a rapid retraction of cellular protrusions associated with cell rounding, massive cytoplasmic vacuolization, loss of plasma membrane integrity, and plasma membrane bubbling, ultimately leading to paraptosis-like cell death. The structure-activity relation of this class of compounds, their selective toxicity, and pharmacological potential are discussed.


Assuntos
Anacardiaceae , Cicloexanonas/farmacologia , Extratos Vegetais , Anacardiaceae/química , Linhagem Celular Tumoral , Humanos , Neoplasias , Extratos Vegetais/farmacologia , Plasmodium falciparum
4.
Molecules ; 26(20)2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34684885

RESUMO

A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins 3a-f (isatin, 3a, 6-chloroisatin, 3b, 5-fluoroisatin, 3c, 5-nitroisatin, 3d, 5-methoxyisatin, 3e, and 5-methylisatin, 3f, and (2S)-octahydro-1H-indole-2-carboxylic acid 2, in situ azomethine ylides reacted with the cyclohexanone based-chalcone 1a-f to afford the target di-spirooxindole compounds 4a-n. This one-pot method provided diverse structurally complex molecules, with biologically relevant spirocycles in a good yields. All synthesized di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were evaluated for their anticancer activity against four cancer cell lines, including prostate PC3, cervical HeLa, and breast (MCF-7, and MDA-MB231) cancer cell lines. The cytotoxicity of these di-spirooxindole analogs was also examined against human fibroblast BJ cell lines, and they appeared to be non-cytotoxic. Compound 4b was identified as the most active member of this series against prostate cancer cell line PC3 (IC50 = 3.7 ± 1.0 µM). The cyclohexanone engrafted di-spirooxindole analogs 4a and 4l (IC50 = 7.1 ± 0.2, and 7.2 ± 0.5 µM, respectively) were active against HeLa cancer cells, whereas NO2 substituted isatin ring and meta-fluoro-substituted (2E,6E)-2,6-dibenzylidenecyclohexanone containing 4i (IC50 = 7.63 ± 0.08 µM) appeared to be a promising agent against the triple negative breast cancer MDA-MB231 cell line. To explore the plausible mechanism of anticancer activity of di-spirooxindole analogs, molecular docking studies were investigated which suggested that spirooxindole analogs potentially inhibit the activity of MDM2.


Assuntos
Antineoplásicos/química , Antineoplásicos/síntese química , Cicloexanonas/química , Oxindóis/química , Compostos de Espiro/química , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Fibroblastos/efeitos dos fármacos , Células HeLa , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Células PC-3 , Relação Estrutura-Atividade
5.
Environ Monit Assess ; 193(10): 681, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34591205

RESUMO

A simple, accurate, sensitive, and selective spectrophotometric method has been developed for the determination of mesotrione. This method is based on the reaction of mesotrione with Fe(III) to form a charge transfer metal complex having λmax at 348 nm. Beer's law was obeyed in the concentration range of 0.2-10.0 µg mL-1 with limit of detection (LOD) and limit of quantification (LOQ) equal to 0.053 and 0.162 µg mL-1, respectively. The percent recovery of mesotrione from different environmental and agricultural samples was found to be 95.00-106.50% at various levels. Notably, the developed method was successfully employed for the determination of mesotrione in environmental (pond water, canal water, tap water, and soil) and agricultural (maize grains) samples.


Assuntos
Monitoramento Ambiental , Compostos Férricos , Cicloexanonas , Espectrofotometria
6.
Cells ; 10(9)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34571920

RESUMO

General inflammatory diseases include skin inflammation, rheumatoid arthritis, inflammatory bowel diseases, sepsis, arteriosclerosis, and asthma. Although these diseases have been extensively studied, most of them are still difficult to treat. Meanwhile, NF-κB is a transcription factor promoting the expression of many inflammatory mediators. NF-κB is likely to be involved in the mechanism of most inflammatory diseases. We discovered a specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), about 20 years ago by molecular design from a natural product. It directly binds to and inactivates NF-κB components. It has been widely used to suppress cellular and animal inflammatory disease models and was shown to be potent in vivo anti-inflammatory activity without any toxicity. We have prepared ointment of DHMEQ for the treatment of severe skin inflammation. It inhibited inflammatory cytokine expressions and lowered the clinical score in mouse models of atopic dermatitis. Intraperitoneal (IP) administration of DHMEQ ameliorated various disease models of inflammation, such as rheumatoid arthritis, sepsis, and also graft rejection. It has been suggested that inflammatory cells in the peritoneal cavity would be important for most peripheral inflammation. In the present review, we describe the synthesis, mechanism of action, and cellular and in vivo anti-inflammatory activities and discuss the clinical use of DHMEQ for inflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Benzamidas/farmacologia , Cicloexanonas/farmacologia , Modelos Animais de Doenças , Inflamação/prevenção & controle , NF-kappa B/antagonistas & inibidores , Animais , Humanos , Inflamação/metabolismo , Camundongos
7.
Ecotoxicol Environ Saf ; 225: 112766, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34509967

RESUMO

Natural adjuvants are novel options to reduce the doses of chemical herbicides. The aim of the current study was to examine the compositions and adjuvant effects of rosin and coconut oil on herbicides using a combination of indoor experiment and field trial. The GC-MS results showed that the main component of rosin was abietic acid (40.02%), and the main components of coconut oil were 2-pentanone, 4-hydroxy-4-methyl- (21.45%) and dodecanoic acid (14.59%). In greenhouse experiment, rosin showed a significant adjuvant effect on nicosulfuron against Digitaria sanguinalis and Amaranthus retroflexus, with the GR50 ratios of 1.47 and 1.69, respectively. The GR50 values of nicosulfuron in the present of coconut oil were 3.99 and 10.13 g a.i./hm2 against D. sanguinalis and A. retroflexus, lower than that of individual application. The adjuvant effect of rosin and coconut oil on mesotrione was also found. In field trial, the fresh weight control efficiency of nicosulfuron (45 g a.i./hm2) and mesotrione (112.5 g a.i./hm2) was significantly improved after the addition of rosin and coconut oil, similar with that of recommended dose. Rosin and coconut oil could reduce the contact angle of nicosulfuron, with the results of 56.68° and 53.90°, respectively, lower than that of individual application. Furthermore, rosin and coconut oil could decrease the surface tension, wetting and penetration time; and increase the spreading diameter and maximum retention. Both rosin and coconut oil have adjuvant effects on herbicides in the lab & field with multiple mechanisms. Thus, they have the potential to be developed into natural adjuvants for herbicide formulation to control weeds.


Assuntos
Adjuvantes Farmacêuticos , Óleo de Coco , Cicloexanonas , Piridinas , Resinas Vegetais , Compostos de Sulfonilureia
8.
Nutrients ; 13(9)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34579102

RESUMO

Tyrosinemia type I (HTI) is treated with nitisinone, a tyrosine (Tyr) and phenylalanine (Phe)-restricted diet, and supplemented with a Tyr/Phe-free protein substitute (PS). Casein glycomacropeptide (CGMP), a bioactive peptide, is an alternative protein source to traditional amino acids (L-AA). CGMP contains residual Tyr and Phe and requires supplementation with tryptophan, histidine, methionine, leucine, cysteine and arginine. AIMS: a 2-part study assessed: (1) the tolerance and acceptability of a low Tyr/Phe CGMP-based PS over 28 days, and (2) its long-term impact on metabolic control and growth over 12 months. METHODS: 11 children with HTI were recruited and given a low Tyr/Phe CGMP to supply all or part of their PS intake. At enrolment, weeks 1 and 4, caregivers completed a questionnaire on gastrointestinal symptoms, acceptability and ease of PS use. In study part 1, blood Tyr and Phe were assessed weekly; in part 2, weekly to fortnightly. In parts 1 and 2, weight and height were assessed at the study start and end. RESULTS: Nine of eleven children (82%), median age 15 years (range 8.6-17.7), took low Tyr/Phe CGMP PS over 28 days; it was continued for 12 months in n = 5 children. It was well accepted by 67% (n = 6/9), tolerated by 100% (n = 9/9) and improved gastrointestinal symptoms in 2 children. The median daily dose of protein equivalent from protein substitute was 60 g/day (range 45-60 g) with a median of 20 g/day (range 15 to 30 g) from natural protein. In part 2 (n = 5), a trend for improved blood Tyr was observed: 12 months pre-study, median Tyr was 490 µmol/L (range 200-600) and Phe 50 µmol/L (range 30-100); in the 12 months taking low Tyr/Phe CGMP PS, median Tyr was 430 µmol/L (range 270-940) and Phe 40 µmol/L (range 20-70). Normal height, weight and BMI z scores were maintained over 12 months. CONCLUSIONS: In HTI children, CGMP was well tolerated, with no deterioration in metabolic control or growth when studied over 12 months. The efficacy of CGMP in HTI needs further investigation to evaluate the longer-term impact on blood Phe concentrations and its potential influence on gut microflora.


Assuntos
Caseínas/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Tirosinemias/dietoterapia , Adolescente , Aminoácidos/administração & dosagem , Aminoácidos/sangue , Criança , Pré-Escolar , Cicloexanonas/administração & dosagem , Dieta/métodos , Proteínas na Dieta/administração & dosagem , Suplementos Nutricionais , Feminino , Humanos , Masculino , Nitrobenzoatos/administração & dosagem , Fenilalanina/administração & dosagem , Fenilalanina/sangue , Estudos Prospectivos , Tirosina/administração & dosagem , Tirosina/sangue
9.
ACS Sens ; 6(8): 3056-3062, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34357769

RESUMO

We report a chemiresistive cyclohexanone sensor on a flexible substrate based on single-walled carbon nanotubes (SWCNTs) functionalized with thiourea (TU) derivatives. A wrapper polymer containing both 4-vinylpyridine (4VP) groups and azide groups (P(4VP-VBAz)) was employed to obtain a homogeneous SWCNT dispersion via noncovalent functionalization of SWCNTs. The P(4VP-VBAz)-SWCNT composite dispersion was then spray-coated onto an organosilanized flexible poly(ethylene terephthalate) (PET) film to achieve immobilizing quaternization between the pyridyl groups from the polymer and the functional PET substrate, thereby surface anchoring SWCNTs. Subsequent surface functionalization was performed to incorporate a TU selector into the composites, resulting in P(Q4VP-VBTU)-SWCNT, for the detection of cyclohexanone via hydrogen bonding interactions. An increase in conductance was observed as a result of the hydrogen-bonded complex with cyclohexanone resulting in a higher hole density and/or mobility in SWCNTs. As a result, a sensor device fabricated with P(Q4VP-VBTU)-SWCNT composites exhibited chemiresistive responses (ΔG/G0) of 7.9 ± 0.6% in N2 (RH 0.1%) and 4.7 ± 0.4% in air (RH 5%), respectively, upon exposure to 200 ppm cyclohexanone. Selective cyclohexanone detection was achieved with minor responses (ΔG/G0 < 1.4% at 500 ppm) toward interfering volatile organic compounds (VOC). analytes. We demonstrate a robust sensing platform using the polymer-SWCNT composites on a flexible PET substrate for potential application in wearable sensors.


Assuntos
Nanotubos de Carbono , Compostos Orgânicos Voláteis , Cicloexanonas , Ligação de Hidrogênio , Polímeros
10.
Orphanet J Rare Dis ; 16(1): 343, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344451

RESUMO

Alkaptonuria (AKU, OMIM 203500) is a rare congenital disorder caused by a deficiency of the enzyme homogentisate-1,2,-dioxygenase. The long-term consequences of AKU are joint problems, cardiac valve abnormalities and renal problems. Landmark intervention studies with nitisinone 10 mg daily, suppressing an upstream enzyme activity, demonstrated its beneficial effects in AKU patients with established complications, which usually start to develop in the fourth decade. Lower dose of nitisinone in the range of 0.2-2 mg daily will already reduce urinary homogentisic acid (uHGA) excretion by > 90%, which may prevent AKU-related complications earlier in the course of the disease while limiting the possibility of side-effects related to the increase of plasma tyrosine levels caused by nitisinone. Future preventive studies should establish the lowest possible dose for an individual patient, the best age to start treatment and also collect evidence to which level uHGA excretion should be reduced to prevent complications.


Assuntos
Alcaptonúria , Alcaptonúria/tratamento farmacológico , Cicloexanonas/uso terapêutico , Humanos , Nitrobenzoatos/uso terapêutico , Tirosina
11.
J Photochem Photobiol B ; 223: 112296, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34450363

RESUMO

Mycosporine-like amino acids (MAAs) are promising natural antioxidative compounds with cosmetic applications for the prevention of skin aging. In this study, we evaluated the protective effects of natural resources-derived MAA-containing emulsions on mouse ear tissue exposed to UV irradiation. DBA/2CrSlc male mice were irradiated by UV light at 120 mJ/cm2/day for 9 days. MAA-containing emulsions were prepared using mycosporine-2-glycine (M2G), shinorine (SHI), or porphyra-334 (P334) and applied to mice ears at a dose of 50 mg/ear/day. After that, collected ear skin tissues were subjected to the observation of melanocytes, investigation for antioxidative stress markers, and measurement of advanced glycation-end products (AGEs). In addition, the antiglycative effects of MAAs were investigated in vitro. MAA-containing emulsions prepared in this study upregulated the activities of total superoxide dismutase (SOD) and catalase (CAT) in mouse ear tissue exposed to UV irradiation. Increased accumulation of copper/zinc (Cu/Zn) -SOD and/or CAT was also found in mouse ear tissue on which M2G- or P334-containing emulsion had been applied. Furthermore, P334 exhibited an antiglycative effect on elastin in vitro. Although MAA-containing emulsions have antioxidative effects as well as in vitro antiglycation, a protective effect by the accumulation of AGEs in mice ears exposed to UV was not observed. Thus, application of MAA-containing emulsions stimulated or protected the expression of antioxidant-associated proteins, thereby leading to upregulation of antioxidative activities in mouse ear skin samples tissues under UV irradiation. Additional optimization of MAA-containing emulsions, including composition, process, and dosage should be considered for further improvement of efficacy.


Assuntos
Antioxidantes/farmacologia , Emulsões/química , Pele/efeitos dos fármacos , Raios Ultravioleta , Animais , Antioxidantes/química , Catalase/metabolismo , Cicloexanóis/química , Cicloexanóis/farmacologia , Cicloexanonas/química , Cicloexanonas/farmacologia , Cicloexilaminas/química , Cicloexilaminas/farmacologia , Glicina/análogos & derivados , Glicina/química , Glicina/farmacologia , Glicosilação/efeitos dos fármacos , Glicosilação/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos DBA , Pele/efeitos da radiação , Superóxido Dismutase/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/efeitos da radiação
12.
Pain Res Manag ; 2021: 4919391, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239653

RESUMO

Objective: Inflammation and pain are involved in the pathophysiology of various clinical conditions. This investigation aims to probe the analgesic and anti-inflammatory activity of Maltoamide F. Methods: The possible toxicity of Maltoamide F was evaluated by an acute toxicity test. To assess the anti-inflammatory and antinociceptive effects of Maltoamide F on rats, the models of carrageenan-caused paw edema, xylene-induced ear edema, arachidonic-acid- (AA-) induced ear edema, formalin-caused plantar edema, and cotton-pellet-induced granuloma were established. Levels of TNF-α, PGE-2, and IL-6 were detected by enzyme-linked immunosorbent assay (ELISA). Results: Maltoamide F was safe at oral doses of 1-10 mg/kg for rats. Maltoamide F (1 mg/kg, 5 mg/kg, and 10 mg/kg) notably reduced carrageenan-induced edema percentage of paws in rats and decreased levels of PGE-2, IL-6, and TNF-α in homogenates of foot tissues. Maltoamide F (1 mg/kg, 5 mg/kg, and 10 mg/kg) reduced levels of PGE-2, IL-6, and TNF-α in foot tissues of formalin-induced rats. Maltoamide F (1 mg/kg, 5 mg/kg, and 10 mg/kg) repressed AA-induced increase of ear thickness in rats and reduced levels of PGE-2, IL-6, and TNF-α in homogenates of ear tissues. Maltoamide F (1 mg/kg, 5 mg/kg, and 10 mg/kg) reduced xylene-induced weight of ear edema in rats and reduced levels of PGE-2, IL-6, and TNF-α in homogenates of ear tissues. Maltoamide F (1 mg/kg, 5 mg/kg, and 10 mg/kg) reduced levels of PGE-2, IL-6, and TNF-α in homogenates of cotton ball granuloma of cotton-pellet-induced rats. Conclusions: Maltoamide F possessed anti-inflammatory and analgesic activity in inflammatory models of rats.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Cicloexanonas/farmacologia , Ácidos Graxos Monoinsaturados/farmacologia , Inflamação/tratamento farmacológico , Animais , Inflamação/induzido quimicamente , Masculino , Manejo da Dor/estatística & dados numéricos , Ratos , Ratos Sprague-Dawley
13.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208536

RESUMO

A ChCl: Gly (DESs) promoted environmentally benign method was developed for the first time using the reaction of aryl aldehydes and dimedone to give excellent yields of xanthene analogues. The major application of this present protocol is the use of green solvent, a wide range of substrate, short reaction times, ease of recovery, the recyclability of the catalyst, high reaction yield, and ChCl: Gly as an alternative catalyst and solvent. In addition to this, all the synthesized compounds were evaluated for their in vitro antimycobacterial activity against M. tuberculosis H37Ra (MTB) and M. bovis BCG strains. The compounds 3d, 3e, 3f, and 3j showed significant antitubercular activity against MTB and M. bovis strains with minimum inhibitory concentration (MIC) values of 2.5-15.10 µg/mL and 0.26-14.92 µg/mL, respectively. The compounds 3e, 3f, and 3j were found to be nontoxic against MCF-7, A549, HCT 116, and THP-1 cell lines. All the prepared compounds were confirmed by 1H NMR and 13C NMR analysis.


Assuntos
Cicloexanonas/química , Solventes/química , Xantenos/síntese química , Aldeídos/química , Antituberculosos/farmacologia , Linhagem Celular Tumoral , Glicerol/química , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade , Xantenos/química , Xantenos/isolamento & purificação
14.
Orphanet J Rare Dis ; 16(1): 256, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082789

RESUMO

BACKGROUND: While therapeutic advances have significantly improved the prognosis of patients with hereditary tyrosinemia type 1 (HT1), adherence to dietary and pharmacological treatments is essential for an optimal clinical outcome. Poor treatment adherence is well documented among patients with chronic diseases, but data from HT1 patients are scarce. This study evaluated pharmacological and dietary adherence in HT1 patients both directly, by quantifying blood levels nitisinone (NTBC) levels and metabolic biomarkers of HT1 [tyrosine (Tyr), phenylalanine (Phe), and succinylacetone]; and indirectly, by analyzing NTBC prescriptions from hospital pharmacies and via clinical interviews including the Haynes-Sackett (or self-compliance) test and the adapted Battle test of patient knowledge of the disease. RESULTS: This observational study analyzed data collected over 4 years from 69 HT1 patients (7 adults and 62 children; age range, 7 months-35 years) who were treated with NTBC and a low-Tyr, low-Phe diet. Adherence to both pharmacological and, in particular, dietary treatment was poor. Annual data showed that NTBC levels were lower than recommended in more than one third of patients, and that initial Tyr levels were high (> 400 µM) in 54.2-64.4% of patients and exceeded 750 µM in 25.8% of them. Remarkably, annual normalization of NTBC levels was observed in 29.4-57.9% of patients for whom serial NTBC determinations were performed. Poor adherence to dietary treatment was more refractory to positive reinforcement: 36.2% of patients in the group who underwent multiple analyses per year maintained high Tyr levels during the entire study period, and, when considering each of the years individually this percentage ranged from 75 to 100% of them. Indirect methods revealed percentages of non-adherent patients of 7.3 and 15.9% (adapted Battle and Haynes tests, respectively). CONCLUSIONS: Despite initially poor adherence to pharmacological and especially dietary treatment among HT1 patients, positive reinforcement at medical consultations resulted in a marked improvement in NTBC levels, indicating the importance of systematic positive reinforcement at medical visits.


Assuntos
Tirosinemias , Adolescente , Adulto , Criança , Pré-Escolar , Cicloexanonas/uso terapêutico , Humanos , Lactente , Nitrobenzoatos/uso terapêutico , Fenilalanina , Prognóstico , Cooperação e Adesão ao Tratamento , Tirosina , Tirosinemias/tratamento farmacológico , Adulto Jovem
15.
Chem Pharm Bull (Tokyo) ; 69(9): 886-891, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34148910

RESUMO

Functionalized nucleobases are utilized in a wide range of fields; therefore, the development of new synthesis methods is essential for their continued application. With respect to the C6-arylation of halopurines, which possess a substituent at the N7-position, only a small number of successful cases have been reported, which is predominately a result of large steric hinderance effects. Herein, we report efficient and metal-free C6-arylations and SNAr reactions of N7-substituted chloropurines in aromatic and heteroatom nucleophiles promoted by triflimide (Tf2NH) in fluoroalcohol.


Assuntos
Cicloexanonas/química , Purinas/química , Antivirais/síntese química , Antivirais/química , Purinas/síntese química , Estereoisomerismo
16.
Lancet Diabetes Endocrinol ; 9(7): 427-435, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34023005

RESUMO

BACKGROUND: Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1. METHODS: We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only). FINDINGS: 315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7-28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age <28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment. INTERPRETATION: Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy. FUNDING: Swedish Orphan Biovitrum (Sobi).


Assuntos
Cicloexanonas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Nitrobenzoatos/uso terapêutico , Tirosinemias/diagnóstico , Tirosinemias/tratamento farmacológico , Adolescente , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Criança , Pré-Escolar , Cicloexanonas/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Nefropatias/induzido quimicamente , Nefropatias/diagnóstico , Estudos Longitudinais , Masculino , Triagem Neonatal/métodos , Nitrobenzoatos/efeitos adversos , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
17.
ACS Appl Mater Interfaces ; 13(21): 24865-24876, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34009929

RESUMO

As the use of pesticides in agriculture is increasing at an alarming rate, food contamination by pesticide residues is becoming a huge global problem. It is essential to develop a sensitive and user-friendly sensor device to quantify trace levels of pesticide and herbicide residues in food samples. Herein, we report an electrocatalyst made up of yttrium iron garnet (Y3Fe5O12; YIG) and graphitic carbon nitride (GCN) to attain picomolar-level detection sensitivity for mesotrione (MTO), which is a widely used herbicide in agriculture. First, YIG was prepared by a hydrothermal route; then, it was loaded on GCN sheets via a calcination method. The surface structures, composition, crystallinity, and interfacial and electrocatalytic properties of the YIG and YIG/GCN were analyzed. As the YIG/GCN displayed better surface and catalytic properties than YIG, YIG/GCN was modified on a screen-printed carbon electrode to fabricate a sensor for MTO. The YIG/GCN-modified electrode displayed a detection limit of 950 pM for MTO. The method was demonstrated in (spiked) fruits and vegetables. Then, the modified electrode was integrated with a miniaturized potentiostat called KAUSTat, which can be operated wirelessly by a smartphone. A first smartphone-based portable sensor was demonstrated for MTO that is suitable for use in nonlaboratory settings.


Assuntos
Cicloexanonas/análise , Compostos Férricos/química , Contaminação de Alimentos/análise , Grafite/química , Compostos de Nitrogênio/química , Praguicidas/análise , Sistemas Automatizados de Assistência Junto ao Leito , Smartphone , Ítrio/química , Técnicas Eletroquímicas , Microscopia Eletrônica de Transmissão , Reprodutibilidade dos Testes , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
19.
Acta Chim Slov ; 68(1): 51-64, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34057520

RESUMO

In this work the multi-component reactions of either of the arylhydrazocyclohexan-1,3-dione derivatives 3a-c with either of benzaldehyde (4a), 4-chlorobenzaldehyde (4b) or 4-methoxybenzaldehyde (4c) and either malononitrile (5a) or ethyl cyanoacetate (5b) giving the 5,6,7,8-tetrahydro-4H-chromene derivatives 6a-r, respectively, are presented. The reaction of two equivalents of cyclohexan-1,3-dione with benzaldehyde gave the hexahydro-1H-xanthene-1,8(2H)-dione derivative 7. On the other hand, the multi-component reactions of compound 1 with dimedone and benzaldehyde gave 13. Both of 7 and 13 underwent heterocyclization reactions to produce fused thiophene, pyran and thiazole derivatives. Selected compounds among the synthesized compounds were tested against six cancer cell lines where most of them gave high inhibitions; especially compounds 3b, 3c, 6b, 6c, 6d, 6f, 6i, 6m, 6n, 8b, 14a, 15 and 16 being the most cytotoxic compounds. Further tests against the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR and Pim-1 kinase showed that compounds 3c, 6c, 6d, 6f, 6n, 14a and 15 were the most potent of the tested compounds toward the five tyrosine kinases and compounds 3c, 6c, 6d, 6n and 15 displayed the highest inhibitions toward Pim-1 kinase.


Assuntos
Antineoplásicos/farmacologia , Cicloexanonas/química , Inibidores de Proteínas Quinases/farmacologia , Xantenos/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazonas/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Xantenos/síntese química
20.
Acta Chim Slov ; 68(1): 72-87, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34057521

RESUMO

In the present work a series of heterocyclization reactions were adopted using cyclohexan-1,3-dione through its reaction with either furan-2-carbaldehyde or thiophene-2-carbaldehyde to give the corresponding ylidene derivatives 3a,b. The latter compounds underwent heterocyclization reactions to give thiophene and pyran derivatives 5a-d and 6a-d, respectively. Moreover, compounds 3a,b reacted with elemental sulfur and phenyl isothiocyanate to give the fused thiazole derivatives 8a,b. In addition, the reaction with either of hydrazine hydrate or phenylhydrazine has given the 4-hydrazono-4,5,6,7-tetrahydro-2H-indazole derivatives 10a-d, respectively. Similarly, the reaction of either 3a or 3b with hydroxylamine hydrochloride gave the 6,7-dihydrobenzo[c]isoxazol-4(5H)-one oxime derivatives 12a and 12b, respectively. Other fused heterocyclic compounds were produced and their structures were elucidated. Evaluation of the synthesized compounds against selected cancer cell lines was performed. The most active compounds were further evaluated against tyrosine kinases and Pim-1 kinase inhibitions.


Assuntos
Antineoplásicos/farmacologia , Cicloexanonas/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cicloexanonas/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Humanos , Estrutura Molecular , Proteínas Tirosina Quinases/síntese química , Proteínas Tirosina Quinases/farmacologia , Relação Estrutura-Atividade
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