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1.
Forensic Sci Int ; 325: 110888, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34186472

RESUMO

We present a case of fatal poisoning by 4-F-methcathinone (4-FMC; also called flephedrone), 4-methoxy-α-pyrrolidinopentiophenone (4-MeO-α-PVP), 4-fluoro-α-pyrrolidinopentiophenone (4-F-α-PVP), and α-pyrrolidinohepatanophenone (PV8). In this study, we compared the mass spectra of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, PV8, and α-pyrrolidinohexanophenone between LC-ESI-LIT-MS and GC-EI-MS analyses. Subsequently, we applied LC-ESI-LIT-MS for detection and quantification analyses of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8 in human authentic whole blood samples. More specific mass spectra for the target compounds were obtained with the LC-ESI-LIT-MS qualitative analyses than with the GC-EI-MS analyses, indicating that LC-ESI-LIT-MS was more suitable for the qualitative analysis of cathinones. The LC-ESI-LIT-MS validation data showed moderately good linearity and reproducibility for the compounds in the quantitative analyses at the range of 1-500 ng/mL. The detection limits of four cathinones ranged from 0.1 to 1 ng/mL. The concentrations of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8 in heart whole blood samples were 365, 449, 145, and 218 ng/mL, respectively. Those of the 4 cathinones in femoral vein whole blood samples were 397, 383, 127, and 167 ng/mL, respectively. We can then assume that the cause of death was acute poisoning by a combination of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8. In this article, we present a detailed LC-ESI-LIT-MS procedure for detection and quantification analyses of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8 in authentic human whole blood samples.


Assuntos
Alcaloides/sangue , Butirofenonas/sangue , Pentanonas/sangue , Propiofenonas/sangue , Psicotrópicos/sangue , Pirrolidinas/sangue , Adulto , Cromatografia Líquida , Toxicologia Forense , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Espectrometria de Massas por Ionização por Electrospray
2.
Arch Toxicol ; 95(4): 1443-1462, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33550444

RESUMO

Synthetic cathinones are among the most popular new psychoactive substances, being abused for their stimulant properties, which are similar to those of amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Considering that the liver is a likely target for cathinones-induced toxicity, and for their metabolic activation/detoxification, we aimed to determine the hepatotoxicity of three commonly abused synthetic cathinones: butylone, α-methylamino-butyrophenone (buphedrone) and 3,4-dimethylmethcathinone (3,4-DMMC). We characterized their cytotoxic profile in primary rat hepatocytes (PRH) and in the HepaRG and HepG2 cell lines. PRH was the most sensitive cell model, showing the lowest EC50 values for all three substances (0.158 mM for 3,4-DMMC; 1.21 mM for butylone; 1.57 mM for buphedrone). Co-exposure of PRH to the synthetic cathinones and CYP450 inhibitors (selective and non-selective) proved that hepatic metabolism reduced the toxicity of buphedrone but increased that of butylone and 3,4-DMMC. All compounds were able to increase oxidative stress, disrupting mitochondrial homeostasis and inducing apoptotic and necrotic features, while also increasing the occurrence of acidic vesicular organelles in PRH, compatible with autophagic activation. In conclusion, butylone, buphedrone and 3,4-DMMC have hepatotoxic potential, and their toxicity lies in the interference with a number of homeostatic processes, while being influenced by their metabolic fate.


Assuntos
3,4-Metilenodioxianfetamina/análogos & derivados , Butirofenonas/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Metilaminas/toxicidade , Propiofenonas/toxicidade , 3,4-Metilenodioxianfetamina/administração & dosagem , 3,4-Metilenodioxianfetamina/toxicidade , Animais , Autofagia/efeitos dos fármacos , Butirofenonas/administração & dosagem , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/patologia , Drogas Desenhadas/administração & dosagem , Drogas Desenhadas/toxicidade , Relação Dose-Resposta a Droga , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Masculino , Metilaminas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Propiofenonas/administração & dosagem , Ratos , Ratos Wistar
3.
Toxicol In Vitro ; 72: 105103, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33516932

RESUMO

Photoinitiators (PIs) are widely used for photopolymerization in industrial area and recently paid close attention to in biomedical field. However, there are few reports on their toxicity to human health. Here we explored cytotoxicity and cytocompatibilty of seven commercial and industrial-used PIs for developing their potential clinical application. Phenylbis(acyl) phosphine oxides (BAPO), 2-Benzyl-2-(dimethylamino)-4'-morpholinobutyrophenone (369), 4,4'-Bis(diethylamino) benzophenone (EMK), Diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide (TPO), and 2-Isopropylthioxanthone (ITX) caused different extent cytotoxicities to four tissue types of cells at the concentrations of 1 to 50 µM under a non-irradiation condition, of which the BAPO cytotoxicity was the highest, whereas Ethyl (2,4,6-trimethylbenzoyl) phenylphosphinate (TPOL) and Methyl benzoylformate (MBF) displayed the lowest cellular toxicity. The cell lines and primary cells appeared highly sensitive to BAPO toxicity, the primary lymphocytes relatively to photoinitiator 369 (369) and EMK toxicities, LO2 cells to EMK and TPO toxicities, the primary lymphocytes and HUVEC-12 cells to MBF toxicity, but only HEK293T cells not to 369 toxicity. Furthermore, these PIs led to increasing cytotoxicity to different extents after exposure to 455 nm blue light, which is consistent with non-irradiation tendency. All the cells presented low sensitivity to TPOL and MBF, of which TPOL-triggered polymer is dramatically superior in its cytocompatibility to MBF, and in its transparency to clinically exclusively-used camphorquinone (CQ). The novel findings indicate that BAPO is the most toxic among the seven PIs, but TPOL and MBF are the least toxic, directing their development and application. Combined their triggered polymer cytocompatibility and color with reported deep curing efficiency, TPOL is more promising to be applied especially to clinical practice.


Assuntos
Benzofenonas/toxicidade , Butirofenonas/toxicidade , Óxidos N-Cíclicos/toxicidade , Luz , Fosfinas/toxicidade , Fotoiniciadores Dentários/toxicidade , Polímeros/toxicidade , Tioxantenos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/efeitos da radiação , Masculino , Camundongos Endogâmicos C57BL , Polimerização
4.
Sci Rep ; 10(1): 22267, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33335233

RESUMO

Cytochrome P450 2J2 (CYP2J2) is responsible for the epoxidation of endogenous arachidonic acid, and is involved in the metabolism of exogenous drugs. To date, no crystal structure of CYP2J2 is available, and the proposed structural basis for the substrate recognition and specificity in CYP2J2 varies with the structural models developed using different computational protocols. In this study, we developed a new structural model of CYP2J2, and explored its sensitivity to substrate binding by molecular dynamics simulations of the interactions with chemically similar fluorescent probes. Our results showed that the induced-fit binding of these probes led to the preferred active poses ready for the catalysis by CYP2J2. Divergent conformational dynamics of CYP2J2 due to the binding of each probe were observed. However, a stable hydrophobic clamp composed of residues I127, F310, A311, V380, and I487 was identified to restrict any substrate access to the active site of CYP2J2. Molecular docking of a series of compounds including amiodarone, astemizole, danazol, ebastine, ketoconazole, terfenadine, terfenadone, and arachidonic acid to CYP2J2 confirmed the role of those residues in determining substrate binding and specificity of CYP2J2. In addition to the flexibility of CYP2J2, the present work also identified other factors such as electrostatic potential in the vicinity of the active site, and substrate strain energy and property that have implications for the interpretation of CYP2J2 metabolism.


Assuntos
Astemizol/química , Butirofenonas/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Piperidinas/química , Ácido Araquidônico/genética , Ácido Araquidônico/metabolismo , Astemizol/farmacologia , Butirofenonas/farmacologia , Domínio Catalítico/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Simulação de Acoplamento Molecular , Oxirredução/efeitos dos fármacos , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Especificidade por Substrato
5.
Artigo em Inglês | MEDLINE | ID: mdl-32905991

RESUMO

N-ethylhexedrone (NEH) and buphedrone (BUPH) are synthetic drugs structurally related to natural cathinone. These synthetic cathinones (SC) are members of the heterogenous family of new psychoactive substances (NPS), which have caused major concern in scientific and forensic communities over the past years, due to their widespread consume. Thus, there is a constant need for monitoring the use of these new substances and gather knowledge on their metabolism and excretion profiles, in order to try to identify markers of NPS consumption. This study aimed at the identification and quantification of NEH, BUPH and selected phase I metabolites using HPLC-MS/MS. NEH, BUPH and some related metabolites were synthesized in-house and quantified in 24 h mice urine, following single dose administration of each drug (64 mg kg-1, i.p.). NEH and BUPH were quantified in mice urine at 58.3 ± 14.4 and 146.2 ± 14.9 µg mL-1, respectively. Similar metabolic pathways were observed for both drugs. Among the metabolites studied, the most excreted ones derived from N-dealkylation of either NEH or BUPH (at around 80 µg mL-1 of urine). Other metabolites resulting from ketone reduction and ketone reduction combined with N-dealkylation or 4-aryl hydroxylation (detected for the first time in non-ring substituted SC) were also identified and quantified. Urine samples were screened using liquid chromatography-high resolution mass spectrometry and various phase II metabolites, including N-acetylated, glucuronides and dicarboxylic acid conjugates were tentatively identified, some of them for the first time. This work is a contribution to the identification of metabolites from SC that can become potential markers to estimate drug consumption.


Assuntos
Butirofenonas , Cromatografia Líquida de Alta Pressão/métodos , Metilaminas , Medicamentos Sintéticos , Espectrometria de Massas em Tandem/métodos , Alcaloides , Animais , Butirofenonas/química , Butirofenonas/farmacocinética , Butirofenonas/urina , Limite de Detecção , Modelos Lineares , Masculino , Metilaminas/química , Metilaminas/farmacocinética , Metilaminas/urina , Camundongos , Reprodutibilidade dos Testes , Medicamentos Sintéticos/análise , Medicamentos Sintéticos/química , Medicamentos Sintéticos/farmacocinética
6.
Front Immunol ; 11: 2094, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973818

RESUMO

The spread of the novel human respiratory coronavirus (SARS-CoV-2) is a global public health emergency. There is no known successful treatment as of this time, and there is a need for medical options to mitigate this current epidemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and is primarily trophic for the lower and upper respiratory tract. A number of current studies on COVID-19 have demonstrated the substantial increase in pro-inflammatory factors in the lungs during infection. The virus is also documented in the central nervous system and, particularly in the brainstem, which plays a key role in respiratory and cardiovascular function. Currently, there are few antiviral approaches, and several alternative drugs are under investigation. Two of these are Idelalisib and Ebastine, already proposed as preventive strategies in airways and allergic diseases. The interesting and evolving potential of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, together with Ebastine, lies in their ability to suppress the release of pro-inflammatory cytokines, such as IL-1ß, IL-8, IL-6, and TNF-α, by T cells. This may represent an optional therapeutic choice for COVID-19 to reduce inflammatory reactions and mortality, enabling patients to recover faster. This concise communication aims to provide new potential therapeutic targets capable of mitigating and alleviating SARS-CoV-2 pandemic infection.


Assuntos
Betacoronavirus , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Terapia de Alvo Molecular/métodos , Pneumonia Viral/tratamento farmacológico , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Antivirais/uso terapêutico , Butirofenonas/farmacologia , Butirofenonas/uso terapêutico , COVID-19 , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Infecções por Coronavirus/virologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Pandemias , Peptidil Dipeptidase A/metabolismo , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pneumonia Viral/virologia , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , SARS-CoV-2
7.
Mol Cancer Ther ; 19(10): 2023-2033, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32855270

RESUMO

Enhancer of zester homolog 2 (EZH2), a histone lysine methyltransferase and the catalytic component of polycomb repressive complex 2, has been extensively investigated as a chromatin regulator and a transcriptional suppressor by methylating H3 at lysine 27 (H3K27). EZH2 is upregulated or mutated in most cancers, and its expression levels are negatively associated with clinical outcomes. However, the current developed small-molecule inhibitors targeting EZH2 enzymatic activities could not inhibit the growth and progression of solid tumors. Here, we discovered an antihistamine drug, ebastine, as a novel EZH2 inhibitor by targeting EZH2 transcription and subsequently downregulating EZH2 protein level and H3K27 trimethylation in multiple cancer cell lines at concentrations below 10 µmol/L. The inhibition of EZH2 by ebastine further impaired the progression, migration, and invasiveness of these cancer cells. Overexpression of Ezh2 wild-type and its mutant, H689A (lacking methyltransferase activity), rescued the neoplastic properties of these cancer cells after ebastine treatment, suggesting that EZH2 targeted by ebastine is independent of its enzymatic function. Next-generation RNA-sequencing analysis also revealed that C4-2 cells treated with 8 µmol/L ebastine showed a gene profiling pattern similar to EZH2-knockdown C4-2 cells, which was distinctively different from cells treated with GSK126, an EZH2 enzyme inhibitor. In addition, ebastine treatment effectively reduced tumor growth and progression, and enhanced progression-free survival in triple-negative breast cancer and drug-resistant castration-resistant prostate cancer patient-derived xenograft mice. Our data demonstrated that ebastine is a novel, safe, and potent anticancer agent for patients with advanced cancer by targeting the oncoprotein EZH2.


Assuntos
Butirofenonas/uso terapêutico , Proteína Potenciadora do Homólogo 2 de Zeste/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Piperidinas/uso terapêutico , Butirofenonas/farmacologia , Feminino , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Masculino , Piperidinas/farmacologia
8.
Neurotox Res ; 38(2): 536-551, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32506339

RESUMO

Two chloromethcathinones, 3-chloromethcathinone (3-CMC) and 4-chloromethcathinone (4-CMC), and two para-substituted α-pyrrolidinophenones, 4-methoxy-α-pyrrolidinopentiophenone (4-MeO-PVP) and 4-fluoro-α-pyrrolidinopentiophenone (4-F-PVP), represent synthetic cathinones, the second most frequently abused group of new psychoactive substances (NPSs), which has aroused a worldwide health concern in the last decade. Synthetic cathinones act as psychostimulants by elevating extracellular levels of monoaminergic neurotransmitters. This study investigates effects of 3-CMC, 4-CMC, 4-MeO-PVP, and 4-F-PVP on the spontaneous locomotor activity and motor performance of mice. Additionally, neurotoxicity of substituted methcathinones against SH-SY5Y neuroblastoma cells was evaluated. All test cathinones stimulate in a dose-dependent manner horizontal locomotor activity of mice. Consistently to our prior findings, pyrrovalerones, but not methcathinone derivatives, produce dose-dependent elevation of vertical locomotor activity (rearing behavior). None of the tested compounds decreases the time spent on the accelerating rotarod, pointing to the lack of considerable motor disability in mice after acute exposition. Only 4-MeO-PVP at the high tested dose (20 mg/kg) increases motor performance of mice. Considering that α-pyrrolidinophenones are highly potent and selective DA uptake inhibitors, while chloromethcathinones enhance non-selective DA/5-HT release, we suggest that the increase of vertical locomotor activity and performance on rotarod in mice may serve as a behavioral indicator of the monoaminergic profile of synthetic cathinones. Finally, this study gives first insights into cytotoxicity of both 3-CMC and 4-CMC displayed against SH-SY5Y cells, which emerges and intensifies after prolonged incubation, suggesting the indirect mechanism of action, unrelated to interactions with monoamine transporters.


Assuntos
Butirofenonas/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Locomoção/efeitos dos fármacos , Metilaminas/farmacologia , Pentanonas/farmacologia , Propiofenonas/farmacologia , Pirrolidinas/farmacologia , Pirrolidinonas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Drogas Desenhadas , Humanos , Camundongos , Neurônios/efeitos dos fármacos , Teste de Desempenho do Rota-Rod
9.
Int J Pharm ; 586: 119504, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32505576

RESUMO

Generally, since at least 6 months are usually needed for accelerated testing of tablet at 40 °C/75% relative humidity (RH), it would be crucial important to predict the dissolution profiles during long-term storage period by using samples stored with shorter periods such as 3 months. In this study, we developed a new method for predicting changes in dissolution from tablets during long-term storage-based changes in the available surface area [S (t)]. In addition, we discussed the dissolution behavior and mechanisms using S (t). The results revealed drastic delays in dissolution in samples stored at 40 °C/75% RH for 7 weeks. Considering changes of S (t) patterns, this delay was derived from changes of the tablet surface. New parameters, namely T22.1 and T63.2, calculated from the S (t) profile tended to increase with an increased duration of testing. Concerning the long-term prediction model using short-term data, a nonlinear model was deemed appropriate because good agreement was observed between the value predicted using the model and the measured value for samples stored at 40 °C/75% RH for 6 months. Therefore, using the new evaluation method based on S (t), we can predict changes in dissolution during long-term storage using short-term methods.


Assuntos
Butirofenonas/administração & dosagem , Química Farmacêutica , Piperidinas/administração & dosagem , Butirofenonas/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Umidade , Dinâmica não Linear , Piperidinas/química , Solubilidade , Comprimidos , Temperatura , Fatores de Tempo
10.
Clin Pharmacokinet ; 59(11): 1393-1405, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32394297

RESUMO

BACKGROUND: Pipamperone is a frequently prescribed antipsychotic in children and adolescents in the Netherlands, Belgium, and Germany. However, pediatric pharmacokinetics and the relationship with side effects and efficacy are unknown. Currently, divergent pediatric dosing recommendations exist. OBJECTIVES: The objective of this study was to describe the population pharmacokinetics of pipamperone in children and adolescents; to correlate measured and predicted pipamperone trough concentrations and predicted 24-h area under the curves with effectiveness, extrapyramidal symptoms, and sedation; and to propose dose recommendations based on simulations. METHODS: Pipamperone concentrations were collected from Dutch pediatric patients in a prospective naturalistic trial (n = 8), and German pediatric patients in a therapeutic drug monitoring service (n = 22). A total of 70 pipamperone concentrations were used to develop a population pharmacokinetic model with non-linear mixed-effects modeling (NONMEM®). Additionally, an additional random sample of 21 German patients with 33 pipamperone concentrations from the same therapeutic drug monitoring service was used for external validation. Pharmacokinetic parameters were related to clinical improvement, sedation, and extrapyramidal symptoms. Simulations were performed to determine optimal dosages. RESULTS: In a one-compartment model, the apparent volume of distribution was 416 L/70 kg and the apparent clearance was 22.1 L/h/70 kg. Allometric scaling was used to correct for differences in bodyweight. The model was successfully externally validated. The median [25th-75th percentile] measured pipamperone trough concentrations were numerically higher in responders (98.0 µg/L [56.0-180.5 µg/L]) than in non-responders (58.0 µg/L [14.9-105.5 µg/L]), although non-significant (p = 0.14). A twice-daily 0.6-mg/kg dosage was better than a fixed dosage to attain the concentration range observed in responders. CONCLUSIONS: Our findings suggest that pipamperone therapeutic reference ranges may be lower for children with behavioral problems than recommended for adults with psychotic symptoms (100-400 µg/L). When dosing pipamperone in children and adolescents, bodyweight should be taken into account.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Espectro Autista , Butirofenonas/farmacocinética , Adolescente , Transtorno do Espectro Autista/tratamento farmacológico , Butirofenonas/efeitos adversos , Criança , Pré-Escolar , Feminino , Alemanha , Humanos , Masculino , Países Baixos , Estudos Prospectivos
11.
Biomed Chromatogr ; 34(10): e4904, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32449558

RESUMO

A simple LC-tandem mass spectrometry (MS/MS) method to determine ebastine and carebastine (active metabolite) in human plasma was developed and validated. Analytes and internal standards were precipitated by protein precipitation and separated on Synergi Hydro-RP 80A column (4 µm, 50 mm × 2.0 mm; Phenomenex) by gradient elution with mobile phase A comprising 0.1% formic acid in 5 mm ammonium acetate (NH4 Ac) and B comprising 100% methanol at a flow rate 0.4 mL/min. Ions were detected in positive multiple reaction monitoring mode, and they exhibited linearity over concentration range 0.01-8.0 and 1.00-300 ng/mL for ebastine and carebastine, respectively. A clinical pharmacokinetic study was conducted in healthy Chinese volunteers under fasting and fed conditions after a single oral administration of 10 mg ebastine. The maximum plasma concentration (Cmax ), time to Cmax (Tmax ) and elimination half-life for ebastine were 0.679 ± 0.762 ng/mL, 1.67 ± 1.43 h and 7.86 ± 6.18 h, respectively, whereas these for carebastine were 143 ± 68.4 ng/mL, 5.00 ± 2.00 h and 17.4 ± 4.97 h, respectively under fasting conditions; the corresponding values under fed conditions were 4.13 ± 2.53 ng/mL, 3.18 ± 1.09 h and 21.6 ± 7.77 h for ebastine and 176 ± 68.4 ng/mL, 6.14 ± 2.0 h and 20.0 ± 4.97 h for carebastine.


Assuntos
Butirofenonas/sangue , Cromatografia Líquida/métodos , Piperidinas/sangue , Espectrometria de Massas em Tandem/métodos , Administração Oral , Butirofenonas/administração & dosagem , Butirofenonas/isolamento & purificação , Butirofenonas/farmacocinética , Precipitação Química , Humanos , Piperidinas/administração & dosagem , Piperidinas/isolamento & purificação , Piperidinas/farmacocinética
13.
Forensic Sci Int ; 306: 110043, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31743834

RESUMO

3',4'-methylenedioxy-2,2-dibromobutyrophenone has been identified and fully characterized in a sample obtained from an anonymous consumer acquired as ketamine through the Internet market. The substance has been deeply characterized by using standard and high performance analytical techniques such as: attenuated total reflectance-infrared spectroscopy, gas chromatography-mass spectrometry, high-resolution mass spectrometry, elemental analysis, and nuclear magnetic resonance, including 1H, 13C, distortionless enhancement by polarization transfer, two dimensional homonuclear 1H-1H correlation spectroscopy, and 1H-13C heteronuclear single-quantum correlation spectra. 3',4'-methylenedioxy-2,2-dibromobutyrophenone is a precursor or intermediate in the synthesis of several synthetic cathinone derivatives, such as pentylone and methylenedioxy pyrovalerone. It is expected that 3',4'-methylenedioxy-2,2-dibromobutyrophenone does not act as psychoactive substance through disruption nor dysregulation of central and peripheral nervous systems, due to the absence of the characteristic amine group of cathinone derivatives. Although it cannot be considered a trend in new psychoactive substances consumption, the presence in the market and the unknown toxicity of this substance makes it a relevant fact.


Assuntos
Alcaloides/química , Butirofenonas/química , Medicamentos Falsificados , Drogas Desenhadas/química , Psicotrópicos/química , Cromatografia Líquida , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Drogas Ilícitas/química , Internet , Ketamina , Espectroscopia de Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier
14.
J Investig Allergol Clin Immunol ; 30(3): 156-168, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30977465

RESUMO

Histamine, acting predominantly via the H1-receptor, is an important mediator of the symptoms of allergy. H1-antihistamines, which stabilize the receptor in its inactive form, are the treatment of choice for some chronic allergic conditions. Ebastine is a well-established secondgeneration oral H1-antihistamine that is administered once daily at a dose of 10-20 mg and is available both as a standard tablet and as a fast-dissolving tablet that disintegrates in the mouth. Ebastine has been shown to relieve symptoms in patients with allergic rhinitis or urticaria in multiple clinical trials. In addition to its antihistamine effects, the drug has modulating effects on the allergic inflammatory process, thus potentially explaining its beneficial effect on nasal obstruction in some patients. Ebastine is generally well tolerated at recommended doses and is one of the lowest-risk antihistamines with respect to adverse cognitive/psychomotor effects, as confirmed by decades of pharmacovigilance. New long-term data confirm its efficacy and tolerability during up to 1 year of treatment in patients with chronic urticaria.


Assuntos
Butirofenonas/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Histamina/metabolismo , Piperidinas/uso terapêutico , Rinite Alérgica/tratamento farmacológico , Urticária/tratamento farmacológico , Administração Oral , Humanos , Resultado do Tratamento
15.
Pak J Pharm Sci ; 33(5(Supplementary)): 2301-2306, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33832904

RESUMO

Although ebastine (EBT) can impede histamine-induced skin allergic reaction and persuade long acting selective H1 receptor antagonistic effects but its poor water solubility circumscribed its clinical application. The main objective of this research work was to improve the aqueous solubility and oral bioavailability of EBT by preparing EBT-loaded bilosomes (EBT-PC-SDC-BS). A thin film hydration method was used to prepare ebastine loaded bilosomes. The prepared-formulations were optimized considering size, morphology and entrapment efficiency. The SEM images revealed regular and spherical shape of bilosomes. Average size of the prepared EBT-PC-SDC-BS was 665.8 nm and zeta potential was around-32.9 mV with 89.05 % average entrapment efficiency (EE).Importantly, the solubility of EBT in water was amplified up to 17.9 µg/ml compared to pure drug (2 µg/mL) reflecting a highest solubility increase of 751 %. In vitro drug release results of prepared EBT-PC-SDC-BS exhibited improved release behavior. Finally, it is established from the results that the EBT-PC-SDC-BS could function as a favorable nano-carrier system to improve the solubility as well as dissolution of EBT.


Assuntos
Ácidos e Sais Biliares/química , Butirofenonas/química , Antagonistas dos Receptores Histamínicos H1/química , Fosfatidilcolinas/química , Piperidinas/química , Administração Oral , Disponibilidade Biológica , Butirofenonas/administração & dosagem , Butirofenonas/farmacocinética , Composição de Medicamentos , Liberação Controlada de Fármacos , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Lipossomos , Nanopartículas , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Solubilidade
16.
Molecules ; 26(1)2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33383880

RESUMO

Dryopteris crassirhizoma rhizomes are used as a traditional medicine in Asia. The EtOAc extract of these roots has shown potent xanthine oxidase (XO) inhibitory activity. However, the main phloroglucinols in D. crassirhizoma rhizomes have not been analyzed. Thus, we investigated the major constituents responsible for this effect. Bioassay-guided purification isolated four compounds: flavaspidic acid AP (1), flavaspidic acid AB (2), flavaspidic acid PB (3), and flavaspidic acid BB (4). Among these, 1 showed the most potent inhibitory activity with a half-maximal inhibitory concentration (IC50) value of 6.3 µM, similar to that of allopurinol (IC50 = 5.7 µM) and better than that of oxypurinol (IC50 = 43.1 µM), which are XO inhibitors. A comparative activity screen indicated that the acetyl group at C3 and C3' is crucial for XO inhibition. For example, 1 showed nearly 4-fold higher efficacy than 4 (IC50 = 20.9 µM). Representative inhibitors (1-4) in the rhizomes of D. crassirhizoma showed reversible and noncompetitive inhibition toward XO. Furthermore, the potent inhibitors were shown to be present in high quantities in the rhizomes by a UPLC-QTOF-MS analysis. Therefore, the rhizomes of D. crassirhizoma could be used to develop nutraceuticals and medicines for the treatment of gout.


Assuntos
Dryopteris/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Floroglucinol/análogos & derivados , Floroglucinol/farmacologia , Xantina Oxidase/antagonistas & inibidores , Butirofenonas/química , Butirofenonas/farmacologia , Humanos , Hiperuricemia/tratamento farmacológico , Hiperuricemia/enzimologia , Rizoma/química , Xantina Oxidase/metabolismo
17.
Emerg Med Pract ; 21(11): 1-24, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31647862

RESUMO

Pain is a common factor in many emergency department visits. While opioids remain a mainstay of treatment for many patients, prescription-opioid overuse and misuse have become epidemic in the United States. A lack of clear understanding of the pain management options available contributes to this problem, resulting in opioid overuse and over-prescription. National guidelines and consensus statements emphasize the importance of knowing nonopioid pharmacological and nonpharmacological options for treating patients with acute pain. This evidence-based review summarizes the pathophysiology of pain and pain syndromes and provides recommendations for a variety of nonopioid treatment options.


Assuntos
Manejo da Dor/métodos , Manejo da Dor/tendências , Analgésicos/uso terapêutico , Anestésicos Locais/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Butirofenonas/uso terapêutico , Serviço Hospitalar de Emergência/organização & administração , Serviço Hospitalar de Emergência/estatística & dados numéricos , Humanos , Dor/tratamento farmacológico , Dor/fisiopatologia
18.
J Nutr Health Aging ; 23(4): 381-385, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30932138

RESUMO

OBJECTIVE: To investigated the effects of antipsychotics on rehabilitation outcomes for geriatric hip fracture inpatients. DESIGN: Retrospective cohort study. SETTING: The registry data from the Japan Rehabilitation Nutrition Database for analysis. PARTICIPANTS: Of the 234 patients in the Japan Rehabilitation Nutrition Database admitted between November 2015 and March 2018, 214 met the eligibility criteria. MEASUREMENTS: The antipsychotics were phenothiazine, butyrophenone, benzamide, and atypical antipsychotics. For hip fracture patients, the following information was registered: (a) admission data: age, sex, Charlson Comorbidity Index, Functional Independence Measure (FIM) at admission, medications, height, body weight, and Mini Nutritional Assessment-Short Form score (MNA-SF) and (b) discharge data: discharge destination, FIM at discharge, MNA-SF, and total units of provided rehabilitation therapy (one unit = 20 minutes based on the national healthcare insurance policy). RESULTS: Thirteen patients (6.1%) were prescribed antipsychotics. According to the multiple linear regression analysis, antipsychotics negatively affected FIM efficiency (ß=-0.190, 95% confidence interval, -0.652 to -0.104, p=0.007). Furthermore, on logistic regression analysis, fall during hospitalization was correlated with the use of antipsychotics (odds ratio=4.376, 95% confidence interval: 1.153 to 16.612, p=0.030). CONCLUSION: The use of antipsychotics impaired the improvement of the activities of daily living (ADL) and increased the incidence of fall during hospitalization. Reviewing medication therapies at admission may further improve ADL.


Assuntos
Acidentes por Quedas/estatística & dados numéricos , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Fraturas do Quadril/reabilitação , Recuperação de Função Fisiológica/efeitos dos fármacos , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Benzamidas/uso terapêutico , Butirofenonas/uso terapêutico , Feminino , Fraturas do Quadril/fisiopatologia , Humanos , Pacientes Internados , Japão , Masculino , Avaliação Nutricional , Estado Nutricional , Alta do Paciente , Fenotiazinas/uso terapêutico , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
19.
Biomed Res Int ; 2019: 6360503, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30886861

RESUMO

Ebastine is a second-generation histamine H1 receptor antagonist that is used to attenuate allergic inflammation. Ebastine has also shown to affect hair loss; however, the immunoregulatory effect of ebastine cannot completely exclude the possibility of spontaneous hair regrowth in ebastine-treated mice. In this study, we examined the effects of ebastine on the growth of human follicle dermal papilla cells (HFDPC) using a WST-1 cell proliferation assay and a bromodeoxyuridine incorporation assay. Ebastine was shown to significantly increase the proliferation of HFDPC. The expression levels of cell-cycle regulatory proteins and an antiapoptotic protein were increased in ebastine-treated HFDPC. Furthermore, elevated expression levels of phospho-AKT and phospho-p44/42 extracellular signal-regulated kinase (ERK) were observed in ebastine-treated HFDPC. Ebastine-mediated HFDPC growth was completely reversed by blocking ERK kinase. The results from our present study suggest that the regulation of HFDPC proliferation by ebastine might be directly involved in hair regrowth through the ERK signaling pathway.


Assuntos
Alopecia/genética , Butirofenonas/farmacologia , Folículo Piloso/crescimento & desenvolvimento , Proteína Quinase 3 Ativada por Mitógeno/genética , Piperidinas/farmacologia , Alopecia/tratamento farmacológico , Alopecia/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Derme/efeitos dos fármacos , Derme/crescimento & desenvolvimento , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Folículo Piloso/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-akt/genética
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