Development and validation of a UHPLC-MS/MS bioanalytical method to quantify in plasma the analgesic candidate PT-31 following a preliminary pharmacokinetic study in rats.

A selective and sensitive UHPLC-MS/MS bioanalytical method to determine PT-31, an analgesic drug candidate, in rat plasma was developed and validated. Analyses were performed using a UHPLC-MS/MS system equipped with an electrospray ionization interface operating in the positive ionization mode using a C18 reversed-phase column with a mobile phase of water:acetonitrile (68:31, v/v) containing 0.1% acetic acid eluting in a gradient mode with a flow rate of 0.3 mL/min. Plasma samples were deproteinized with cold acetonitrile containing 0.01% TFA (1:2, v/v) and 50 µL of the supernatant were injected into the system. PT-31 and phenytoin (internal standard) retention times were roughly 1.0 and 1.5 min, respectively. Linear standard curves were plotted for the 0.01-10 µg/mL concentration range, with a coefficient of determination > 0.99. The method's precision was over 88%. Maximum intra- and inter-day relative standard deviations were 14.6% and 11.6%, respectively. Interfering substances were not detected in the chromatogram, indicating that the method was specific. PT-31 stability was assessed under different temperature and storage settings. The method was used to characterize PT-31 plasma pharmacokinetics following administration of 5 mg/kg i.v. to Wistar rats. Therefore, the method described is sensitive, linear, precise and specific enough to determine PT-31 in preclinical pharmacokinetic investigations. Copyright © 2015 John Wiley & Sons, Ltd.

Perfil de pacientes com artrite reumatoide em uso de inibidores do Fator de Necrose Tumoral alfa (TNF-alfa), cadastrados no Componente Especializado da Assistência Farmacêutica de Pernambuco, Brasil / Profile of patients with rheumatoid arthritis under treatment with inhibitors of tumor necrosis factor alpha (TNF-alfa) enrolled in the Specialized Program for Pharmaceutical Services of Pernambuco State (Brazil)

In Pernambuco, with federal funding from the Brazilian Ministry of Health, the State Department of Health provides the anti-TNF-α drugs (adalimumab, etanerceptand infliximab) for the treatment of rheumatoid arthritis (RA), as set out in a Clinical Protocol of Therapeutic Guidelines. The aim of the study was to describe the demographic and clinical profile of RA patients treated with anti-TNF-α drugs enrolled in the Specialized Programfor Pharmaceutical Services (CEAF) in Pernambuco. A cross-sectional study was performed by collecting patient data recorded in the Computerized System for Management and Monitoring of Drugs of the CEAF, for the base month and year, September 2012. The data analyzed were age, gender, International Classification of Diagnosed Disease, anti-TNF-α dispensed and city of residence. Out of 525 RA patients taking anti-TNF-α, 384 (73%) were women. Etanercept (57%) was in the highest number of prescriptions, followed by adalimumab (37%) and infliximab (11%). According to their home addresses, Health Management Region I had the highest prevalence of patients with RA in Pernambuco. The study enabled the profile of patients treated for RA with anti-TNF-α to be described. This information may help decision making and contribute to improving the management of Pharmaceutical Services and public health policies...

Em Pernambuco, por meio de financiamento federal do Ministério da Saúde, a Secretaria Estadual de Saúde, provê, ao tratamento da Artrite Reumatóide (AR), os medicamentos anti-TNF-α (adalimumabe, etanercepte e infliximabe), cujas linhas de cuidados estão definidas em Protocolos Clínicos de Diretrizes Terapêuticas. O estudo objetivou descrever o perfil demográfico e clínico dos pacientes com AR em uso de anti-TNF-α cadastrados no Componente Especializado da Assistência Farmacêutica (CEAF) em Pernambuco. Realizou-se um estudo transversal com a coleta de dados de pacientes cadastrados no Sistema Informatizado de Gerenciamento e Acompanhamento de Medicamentos do CEAF. Com mês e ano base em setembro de 2012, foram consideradas para análise a idade, gênero, Classificação Internacional da Doença diagnosticada, anti-TNF-α dispensado e município de residência. Considerando 525 pacientes com AR que utilizam anti-TNF-α, 384 (73%) eram mulheres. O Etanercepte (57%) apresentou maior número de prescrições, seguido do Adalimumabe (37%) e Infliximabe (11%). Segundo o local de residência, a I Gerência Regional de Saúde apresentou maior prevalência de pacientes com AR. O estudo possibilitou descrever o perfil dos pacientes que utilizam anti-TNF-α no tratamento da AR. Essas informações podem subsidiar tomadas de decisões, contribuir na melhoria da gestão da Assistência Farmacêutica e de políticas públicas em saúde...

Anti-inflammatory and antioxidant properties of a new arylidene-thiazolidinedione in macrophages.

Thiazolidinediones (TZDs) are a class of drugs used for treatment of type 2 diabetes. However, the therapy with currently available TDZs (e.g. rosiglitazone) is associated with important side effects, such as edema and weight gain, suggesting that the investigation of alternative TZDs with better pharmacological properties is warranted. In this study, we investigated both anti-inflammatory and antioxidant properties of a new chemically modified TZD, the arylidene-thiazolidinedione 5-(4-methanesulfonyl-benzylidene)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione (SF23), and compared the results to those obtained with rosiglitazone. We found that our SF23 displays a weaker affinity for PPARγ, up-regulating in a lower magnitude the expression of both PPARγ and CD36 compared to rosiglitazone. In lipopolysaccharide (LPS)-stimulated macrophages, SF23 decreased nitrite production and attenuated the mRNA expression of both iNOS and COX-2. These anti-inflammatory effects were comparable to those obtained with rosiglitazone. Interestingly, SF23, but not rosiglitazone, prevented LPS-induced mitochondrial membrane hyperpolarization, apoptosis, reactive oxygen species (ROS) generation, and the expression of NADPH oxidase subunits, Nox1 and Nox2. In addition, in macrophages from Nrf2⁻/⁻ mice, SF23 protected against LPSinduced cellular death and ROS production, whereas rosiglitazone was only able to protect normal Nrf2⁺/⁺ cells against oxidative injury, suggesting that, unlike rosiglitazone, the antioxidant activity of SF23 might be Nrf2-independent. Finally, in macrophages exposed to high concentrations of glucose, SF23 induced significant increases in the mRNA expression of glucose transporters, insulin receptor substrate and mitoNEET. Altogether, our data indicate that our new chemically modified TDZ displays similar anti-inflammatory properties, but superior antioxidant effects on the LPS-stimulated macrophages compared to rosiglitazone.

Immunological studies and in vitro schistosomicide action of new imidazolidine derivatives

Schistosomiasis is a major public health problem with 207 million people infected and more than 779 million at risk. The drug of choice for treating schistosomiasis is praziquantel (PZQ); however, it is inefficient against immature forms of schistosomes. The aim of this study was to test new imidazolidine derivatives LPSF/PT09 and LPSF/PT10 against adult Schistosoma mansoni worms. IC50, cytotoxicity, immune response and cell viability assays were also available for these imidazolidines. Different concentrations of imidazolidine, from 32 to 320 »M, promoted motor abnormalities in breeding and unpaired worms, and death in 24 hours at higher concentrations. Although LPSF/PT09 and LPSF/PT10 did not affect IFN-³ and IL-10 production, they induced nitric oxide production and showed a similar behavior to praziquantel on cell death test. Thus, these new imidazolidine derivatives should undergo further study to develop schistosomiasis drugs.

Synthesis and biological activity of novel acridinylidene and benzylidene thiazolidinediones.

A novel set of acridinylidene thiazolidinediones and benzylidene thiazolidinediones was synthesized by nucleophilic addition of cyanoacrylates. Some of these compounds were evaluated for their glucose lowering capability and their effects on the triglyceride level in alloxan diabetic mice.

Synthesis and schistosomicidal activity of new substituted thioxo-imidazolidine compounds.

Synthesis and physico-chemical properties of 3-benzyl-5-(4-fluoro-benzylidene)-1-methyl-2-thioxo-imidazolidin-4-ones, 5-benzylidene-3-(4-nitro-benzyl)-2-thioxo-imidazolidin-4-ones and 4-acridin-9-ylmethylene-1-benzyl-5-thioxo-imidazolidin-2-ones compounds are described. These thioxo-imidazolidine derivatives were prepared by alkylation and condensation with 4-fluoro-benzaldehyde or nucleophilic Michael addition with cyanoacrylates. The schistosomicidal activity of 3-benzyl-5-(4-fluoro-benzylidene)-1-methyl-2-thioxo-imidazolidin-4-one compounds was evaluated.

Synthesis and structural study of substituted thioxothiazolidinones and thioxoimidazolidinones.

A new set of derivative thioxothiazolidinones and thioxoimidazolidinones 3,5-dissubstituted has been synthesized with satisfactory yield from the condensation Knoevenagel type between benzaldéhydes and 4-thioxothiazolidin-2-one, 2-thioxothiazolidin-4-one and 1-méthyl-2-thioxoimidazolidin-4-one compounds following by N-alkylation with aryl or acyl halides. The physico-chemical properties of the 5-benzylidene-3-[2-(4-chlorophenyl)-2-oxoethyl]-2 (or 4)-thioxothiazolidin-4 (or 2)-ones and 5-benzylidene-1-methyl-2-thioxoimidazolidin-4-ones synthesized have been described.

[New substituted 4-thioxothiazolidin-2-one derivatives: synthesis and structural study]. / Synthèse et étude structurale de nouvelles 4-thioxothiazolidin-2-ones substituées.

Synthesis and physico-chemical properties of some 3-benzyl- and 3-phenacyl-4-thioxo-5-benzylidenethiazolidin-2-one derivatives are described. Fifteen new compounds were synthesized from thiazolidin-2-one by thionation of the 4-carbonyle, alkylation of the 3-N and aldolisation-crotonisation of 5-CH(2) with aromatic aldehydes. Soon, these new compounds will be tested for their bacteriostatic activity.

Synthesis and microbiological activity of some 4-butyl-2H-benzo[1,4]thiazin-3-one derivatives.

The synthesis and physicochemical properties of 4-butyl-2H-benzo[1,4]thiazin-3-one derivatives are described. These new compounds were synthesised by alkylation in 4-N position and acylation and/or alkylation of 6-NH2 by phase transfer catalysis. Acid hydrolysis of 6-alkylacylamino group yielded 6-alkylamino-4-butyl-2H-benzo[1,4]thiazin-3-ones. The antimicrobial in vitro activity was determined on five compounds.

[Synthesis and structural study of substituted arylideneimidazolidines and arylidenebenzothiazines]. / Synthesis and structural study of substituted arylideneimidazolidines and arylidenebenzothiazines.

Synthesis and physico-chemical properties of six 5-arylidène-3-benzyl-1-methyl-2-thioxoimidazolidin-4-ones and three 2-arylidene-6-nitro-2H-1,4-benzothiazin-3(4H)-ones have been described. These new compounds were synthetised by Knoevenagel condensation reaction from aromatic aldehydes. The N-alkylation reaction of arylidenebenzothiazines by methyl iodide give the N-methylarylidenebenzothiazines.

[Substituted thiazolidinediones and thioxothiazolidinones: synthesis and structure]. / Thiazolidinediones et thioxothiazolidinones substituées: synthèse et étude structurale.

Synthesis and physico-chemical properties of 3-(4-bromobenzyl)-, 3-(4-chlorobenzyl)-5-arylidene-thiazolidine-2,4-diones and 3-(4-chlorobenzyl)-4-thioxo-5-arylidene-thiazolidin-2- ones are described. Twelve new products were synthesized by the aldolisation-crotonisation reaction from aromatic aldehydes and N-alkylated thiazolidinediones or thioxothiazolidinones. Seven compounds were preliminary tested for their bacteriostatic activity.

Synthesis and antimicrobial activity of substituted imidazolidinediones and thioxoimidazolidinones.

Synthesis and physico-chemical properties of new 3-benzyl-4-thioxo-5-arylideneimidazolidine-2-ones and 3-benzyl-5-arylideneimidazolidine-2,4-dione are described. These compounds were synthesized by condensation reaction from aromatic aldehydes and 3-substituted imidazolidine-2,4-diones or 4-thioxoimidazolidine-2-ones. The N-alkylation of 5-benzylideneimidazolidine-2,4-dione led simultaneously to mono- and dialkylated derivatives. The nucleophilic addition of 1-methyl-3-benzylimidazolidine-2,4-dione with 2-cyano-3-(3,4-dichlorophenyl) acrylate also yielded the 3-substituted 5-arylideneimidazolidine-2,4-dione derivative. Antimicrobial in vitro activity was determined on some compounds.

[Substituted thio-arylidene thiazolidinones: synthesis and structural study]. / Thio-arylidène thiazolidinones substituées: synthèse et étude structurale.

The synthesis and physico-chemical properties of fourteen 4-thio-5-arylidene-thiazolidine-2-ones and eight 3-(4-bromophenacyl)-4-thio-5-arylidene-thiazolidine-2-ones are described. These products were synthetized by the aldolisation-crotonisation reaction between aromatic aldehydes and 4-thio-thiazolidine-2-one followed by N-alkylation of this substituted compounds.

[Synthesis and structure of substituted arylazo-imidazolidines and arylidenethiazolidines]. / Synthèse et structure des arylazo-imidazolidines et arylidènethiazolidines substituées.

Synthesis and physico-chemical properties of four 3-benzyl or 3-(4-chlorobenzyl)-4-thioxo-5-arylazo-imidazolidin-2-ones, five 3-(4-nitrobenzyl)-5-arylidenethiazolidine-2,4-diones and three 3-(4-phenyl-phenacyl)-4-thioxo-5-arylidenethiazolidin-2-ones have been described. These new products were synthesized by an aldolisation-crotonisation reaction from aromatic aldehydes and 3-substituted thioxothiazolidin-2-ones or thiazolidine-2,4-diones. The arylazo-imidazolidine compounds were synthesized by copulation of diazonium ions with imidazolidines. Antimicrobial activity was determined for some compounds.

[Synthesis and structural study of 5-arylidene thiazolidine-2,4-diones and 3-substituted-4-thio-imidazolidine-2-ones]. / Synthèse et étude structurale des 5-arylidène thiazolidine-2, 4-diones et 4-thio-imidazolidine-2-ones-3-substituées.

The synthesis and the physico-chemical properties of four 3-(4-bromophenacyl)-5-arylidene-thiazolidine-2,4-diones, two 3-(4-bromobenzyl)-5-arylidene-thiazolidine-2,4-diones and seven 3-(4-chlorobenzyl)-5-arylidene-4-thio-imidazolidine-2-ones were described. These products were synthetized by the aldolisation-crotonisation reaction between aromatic aldehydes and substituted thiazolidinediones or thio-imidazolidinones.

[Substituted imidazolidinediones and thiazolidinediones: synthesis, structure and cytotoxic activity]. / Imidazolidinediones et thiazolidinediones substituées: synthèse, étude structurale et activité cytotoxique.

Synthesis and physico-chemical properties of nine 3-(4-fluoro or chlorobenzyl)-5-arylidène-imidazolidine-2,4-diones, four 3-(4-fluoro or bromobenzyl)-5-arylidène-thiazolidine-2,4-diones and three 3-)4-bromophénacyl)-5-arylidène-thiazolidine-2,4- diones has been described. These compounds were synthesized by aldolisation-crotonisation reaction from aromatic aldehydes and 3-substituted imidazolidine-2,4-diones or thiazolidine-2,4-diones. In vitro cytotoxic activity was determined for compounds 8, 17, 18, 21 and 22.

[Quantitative structure-hypoglycemic activity relationships of some thiazolidine and imidazolidine-2,4-diones]. / Relations quantitatives structure-activité hypoglycémiante de quelques thiazolidine- et imidazolidine-2,4-diones.

Quantitative structure-activity relationships are described for twenty six title compounds. Five compounds exhibit a significant hypoglycemic activity like insulin used as standard. The aim of the present paper is to investigate the contribution of the different substituents in the biological activity. The application of Fujita-Ban and Hansch models has shown that lipophilic and electronic parameters seem to be the best explanation of variance of biological data.

[Synthesis and antimicrobial activity of chlorobenzyl benzylidene imidazolidinedione derivatives and substituted thiazolidinediones]. / Synthèse et activité antimicrobienne de dérivès chlorobenzyl benzylidène imidazolidinediones et thiazolidinediones substituées.

The synthesis of five chlorobenzyl benzylidene imidazolidinediones and four fluorobenzyl benzylidene thiazolidinediones is described. In order to investigate their antimicrobial activity they are evaluated against microorganism such as Candida albicans, Neurospora crassa, Staphylococcus aureus, Mycobacterium smegmatis and Escherichia coli.

[Synthesis and structure of substituted bromo and nitrobenzyl benzylidene imidazolidinediones and thiazolidinediones]. / Synthèse et structure des bromo et nitrobenzyl benzylidène imidazolidinediones et thiazolidinediones substituées.

Synthesis and physico-chemical properties of five bromobenzyl-benzylidene-imidazolidinediones and five nitrobenzyl- or benzyl-benzylidene-thiazolidinediones are described. The microbiological activity of bromobenzyl-benzylidene-imidazolidinediones against microorganisms such as Candida albicans, Neurospora crassa and Mycobacterium smegmatis are evaluated.

[Synthesis and antimicrobial activity of substituted fluorobenzyl benzylidenethiazolidinediones and imidazolidinediones]. / Synthèse et activité antimicrobienne des fluorobenzyl benzylidène thiazolidinediones et imidazolidinediones substituées.

The synthesis of six benzylidene thiazolidine-diones and three benzylidene imidazolidine-diones is described. In order to investigate their antimicrobial activity, they are evaluated against micro-organism such as Staphylococcus aureus, Streptococcus feacalis, Mycobacterium smegmatis and Neurospora crassa.