Relative bioavailability/bioequivalence between two oral formulations of rivaroxaban (20 mg) in healthy brazilian subjects, under fasting and fed conditions: Biodisponibilidade relativa/bioequivalência entre duas formulações orais de rivaroxabana (20 mg) em participantes brasileiros saudáveis, em condições de jejum e alimentação

O estudo teve como objetivo avaliar a bioequivalência entre dois comprimidos revestidos de rivaroxabana em participantes brasileiros saudáveis após administração em dose única em condições de jejum e alimentação. Dois estudos foram conduzidos com um desenho aberto, randomizado, cruzado com duas sequências, quatro períodos e washout de sete dias entre os períodos. Foram realizadas coletas seriadas de sangue para quantificar a concentração plasmática de rivaroxabana e realizar a análise farmacocinética. A bioequivalência é confirmada se os intervalos de confiança de 90% (IC de 90%) para a razão entre as médias geométricas das duas formulações estiverem dentro dos limites de bioequivalência de 80-125% para a área sob a curva do tempo 0 à última concentração mensurável (AUC0-t) e concentração máxima (Cmax). Além disso, o limite superior do IC de 90% para a razão da variabilidade intra-sujeito (σWT/σWR) entre ambas as formulações deve ser ≤ 2,5. Os pontos estimados e o IC de 90% para AUC0-t (102,4; 97,3-107,9), Cmax (97,5; 91,6-103,7), σWT/σWR para AUC0-t (0,70; 0,51-0,95) e σWT/σWR para Cmax (0,94; 0,69-1,28) demonstraram que ambas as formulações foram bioequivalentes no estudo jejum. Resultados semelhantes foram obtidos para AUC0-t (99,5; 96,1-103,1), Cmax (98,9; 95,1-102,9), σWT/σWR para AUC0-t (0,94; 0,70-1,25) e σWT/σWR para Cmax (0,97; 0,73-1,30) no estudo alimentado. Assim, as formulações têm biodisponibilidade sistêmica equivalente sob condições de jejum e alimentação, e um desempenho clínico semelhante pode ser esperado

Biodisponibilidade Relativa/Bioequivalência entre duas formulações orais de rivaroxabana (20mg) em participantes brasileiros saudáveis, em condições de jejum e alimentação: Relative Bioavailability/Bioequivalence between two oral formulations of rivaroxaban (20 mg) in healthy Brazilian subjects, under fasting and fed conditions

O estudo teve como objetivo avaliar a bioequivalência entre dois comprimidos revestidos de rivaroxabana em participantes brasileiros saudáveis após administração em dose única em condições de jejum e alimentação. Dois estudos foram conduzidos com um desenho aberto, randomizado, cruzado com duas sequências, quatro períodos e washout de sete dias entre os períodos. Foram realizadas coletas seriadas de sangue para quantificar a concentração plasmática de rivaroxabana e realizar a análise farmacocinética. A bioequivalência é confirmada se os intervalos de confiança de 90% (IC de 90%) para a razão entre as médias geométricas das duas formulações estiverem dentro dos limites de bioequivalência de 80-125% para a área sob a curva do tempo 0 à última concentração mensurável (AUC0-t) e concentração máxima (Cmax). Além disso, o limite superior do IC de 90% para a razão da variabilidade intra-sujeito (σWT/σWR) entre ambas as formulações deve ser ≤ 2,5. Os pontos estimados e o IC de 90% para AUC0-t (102,4; 97,3-107,9), Cmax (97,5; 91,6-103,7), σWT/σWR para AUC0-t (0,70; 0,51-0,95) e σWT/σWR para Cmax (0,94; 0,69-1,28) demonstraram que ambas as formulações foram bioequivalentes no estudo jejum. Resultados semelhantes foram obtidos para AUC0-t (99,5; 96,1-103,1), Cmax (98,9; 95,1-102,9), σWT/σWR para AUC0-t (0,94; 0,70-1,25) e σWT/σWR para Cmax (0,97; 0,73-1,30) no estudo alimentado. Assim, as formulações têm biodisponibilidade sistêmica equivalente sob condições de jejum e alimentação, e um desempenho clínico semelhante pode ser esperado

Pharmacokinetics and Pharmacodynamics Evaluation of Tramadol in Thermoreversible Gels

We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) induced by new formulations of tramadol (TR) in thermoreversible gels. The poloxamer- (PL-) tramadol systems were prepared by direct dispersion of the drug in solutions with PL 407 and PL 188. The evaluated formulations were as follows: F1: TR 2% in aqueous solution and F2: PL 407 (20%) + PL 188 (10%) + TR 2%; F3: PL 407 (25%) + PL 188 (5%) + TR 2%; F4: PL 407 (20%) + TR 2%. New Zealand White rabbits were divided into four groups (n=6) and treated by subcutaneous route with F1, F2, F3, or F4 (10 μg·kg−1). PK evaluation used TR and M1 plasma levels. PD evaluation was performed with the measurement of both pupils’ diameters. F2 showed higher TR plasma concentration after 180 minutes and presented lower M1 concentrations at almost all evaluated periods. Areas under the curve (ASC0–480 and ASC0–∞) and clearance of F2 presented differences compared to F1. F2 presented significant correlation (Pearson correlation) between the enhancement of TR and M1 concentrations and the decrease of pupil size (miosis). Thus, F2 was effective in altering pharmacokinetics and pharmacodynamics effects of TR

Preclinical evaluation of ropivacaine in 2 liposomal modified systems

Our research group has recently developed liposomes with ionic gradient and in a combined manner as donor and acceptor vesicles containing ropivacaine (RVC; at 2% or 0.75%). Looking for applications of such novel formulations for postoperative pain control, we evaluated the duration of anesthesia, pharmacokinetics, and tissue reaction evoked by these new RVC formulations. The formulations used in this study were large multivesicular vesicle (LMVV) containing sodium acetate buffer at pH 5.5 or in a combined manner with LMVV as donor and large unilamellar vesicles (LUVs) as acceptor vesicles with an external pH of 7.4. Wistar rats were divided into 6 groups (n = 6) and received sciatic nerve block (0.4 mL) with 6 formulations of RVC (LMVVRVC0.75%, LMVV/LUVRVC0.75%, LMVVRVC2%, LMVV/LUVRVC2%, RVC 0.75%, and RVC 2%). To verify the anesthetic effect, the animals were submitted to the pain pressure test and the motor block was also monitored. Histopathology of the tissues surrounding the sciatic nerve region was also assessed 2 and 7 days after treatment. Rats (n = 6) were submitted to a hind paw incision, and mechanical hypersensitivity was measured via the withdrawal response using von Frey filaments after injection of the 6 formulations. Finally, New Zealand white rabbits (n = 6) received sciatic nerve block (3 mL) with 1 of the 6 formulations of RVC. Blood samples were collected predose (0 minutes) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, and 540 minutes after injection. RVC plasma levels were determined using a triple-stage quadrupole mass spectrometer. Duration and intensity of the sensory block were longer with all liposomal formulations, when compared to the plain RVC solution (P < .05). Histopathological evaluation showed greater toxicity for the positive control (lidocaine 10%), when compared to all formulations (P < .05). After the hind paw incision, all animals presented postincisional hypersensitivity and liposomal formulations showed longer analgesia (P < .05). LMVVRVC0.75% presented higher time to reach maximum concentration and mean residence time than the remaining formulations with RVC 0.75% (P < .05), so LMVV was able to reduce systemic exposure of RVC due to slow release from this liposomal system. All new liposomal formulations containing 0.75% RVC were able to change the pharmacokinetics and enhance anesthesia duration due to slow release of RVC from liposomes without inducing significant toxic effects to local tissues1292387396FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2014/14457-5The authors are grateful to Cristália Produtos Químicos Farmacêuticos Ltda (SP, Brazil) for the donation of ropivacaine (RVC) and Fundação de Amparo á Pesquisa do Estado de São Paulo (No. 2014/14457-5) for the financial support. The authors thank Dr Marcelo Sperandio for his kind contribution to this manuscript. The authors also thank Mr Fabio Saia Cereda for his contribution in the statistical analysi

Determination of nimodipine in plasma by HPLC-MS/MS and pharmacokinetic application

To develop and validate a rapid, specific and highly sensitive method to quantify nimodipine in human plasma using dibucaine as the internal standard (IS). The analyte and IS were extracted from plasma samples by liquid-liquid extraction using hexane-ethyl acetate (1:1 v/v). The chromatographic separation was performed on a Varian® Polaris C18 analytical column (3 &#956;m, 50 x 2.0 mm) and pre-column SecurityguardTM C18 (4.0 x 3.0 mm) with a mobile phase of Acetonitrile-Ammonium acetate 0.02 ml/L (80:20v/v). The method had a chromatographic run time of 4.5 min and linear calibration curve over the range of 0.1- 40 ng/mL (r > 0.9938). The limit of quantification was 100 pg/mL. Acceptable precision and accuracy were obtained for concentrations over the standard curve ranges. This validated method was successfully applied in determining the pharmacokinetic profile of nimodipine tablets of 30 mg administered to 24 healthy volunteers. The proposed method of analysis provided a sensitive and specific assay for nimodipine determination in human plasma. The time for the determination of one plasma sample was 4.5 min. This method is suitable for the analysis of nimodipine in human plasma samples collected for pharmacokinetic, bioavailability or bioequivalence studies in humans.<br>Um método rápido, específico e sensível para quantificar nimodipino em plasma humano usando dibucaína como padrão interno (IS) é descrito. O analito e o IS foram extraídos das amostras de plasma por extração líquido-líquido usando hexano-acetato de etila (1:1 v/v). A separação cromatográfica foi realizada utilizando-se uma coluna analítica C18 Varian® Polaris (3 &#956;m, 50 x 2,0 mm) e uma pré-coluna SecurityguardTM C18 (4,0 x 3,0 mm) e acetonitrila-acetato de amônia 0,02 mol/L (80:20 v/v) como fase móvel. O método apresentou tempo total de corrida de 4,5 min e curva de calibração linear com concentrações entre 0,1-40 ng/mL (r > 0,9938). O limite de quantificação foi de 100 pg/mL. Os valores de precisão e exatidão foram obtidos por meio da análise das amostras de controle de qualidade. A análise de uma única amostra de plasma foi realizada em 4,5 minutos. A metodologia validada foi aplicada na determinação do perfil farmacocinético do nimodipino, comprimido de 30 mg administrado em 24 voluntários saudáveis. O método para quantificar nimodipino em plasma é adequado para aplicação em estudos farmacocinéticos, biodisponibilidade e bioequivalência em humanos

IVTH BRAZILIAN CONSENSUS CONFERENCE ON HELICOBACTER PYLORI INFECTION

ABSTRACT Significant progress has been obtained since the III Brazilian Consensus Conference on H. pylori infection held in 2012, in Bento Gonçalves, Brazil, and justify a fourth meeting to establish updated guidelines on the current management of H. pylori infection. Therefore, the Núcleo Brasileiro para Estudo do Helicobacter pylori e Microbiota (NBEHPM), association linked to Brazilian Federation of Gastroenterology (FBG) held its fourth meeting again in Bento Gonçalves, RS, Brazil, on August 25-27, 2017. Twenty-six delegates, including gastroenterologists, endoscopists, and pathologists from the five regions of Brazil as well as one international guest from the United States, participated in the meeting. The participants were invited based on their knowledge and contribution to the study of H. pylori infection. The meeting sought to review different aspects of treatment for infection; establish a correlation between infection, dyspepsia, intestinal microbiota changes, and other disorders with a special emphasis on gastric cancer; and reassess the epidemiological and diagnostic aspects of H. pylori infection. Participants were allocated into four groups as follows: 1) Epidemiology and Diagnosis, 2) Dyspepsia, intestinal microbiota and other afections, 3) Gastric Cancer, and, 4) Treatment. Before the consensus meeting, participants received a topic to be discussed and prepared a document containing a recent literature review and statements that should be discussed and eventually modified during the face-to-face meeting. All statements were evaluated in two rounds of voting. Initially, each participant discussed the document and statements with his group for possible modifications and voting. Subsequently, during a second voting in a plenary session in the presence of all participants, the statements were voted upon and eventually modified. The participants could vote using five alternatives: 1) strongly agree; 2) partially agree; 3) undecided; 4) disagree; and 5) strongly disagree. The adopted consensus index was that 80% of the participants responded that they strongly or partially agreed with each statement. The recommendations reported are intended to provide the most current and relevant evidences to management of H. pylori infection in adult population in Brazil

IV Consenso Brasileiro sobre a infecção por Helicobacter pylori

Significant progress has been obtained since the III Brazilian Consensus Conference on H. pylori infection held in 2012, in Bento Gonçalves, Brazil, and justify a fourth meeting to establish updated guidelines on the current management of H. pylori infection. Therefore, the Núcleo Brasileiro para Estudo do Helicobacter pylori e Microbiota (NBEHPM), association linked to Brazilian Federation of Gastroenterology (FBG) held its fourth meeting again in Bento Gonçalves, RS, Brazil, on August 25-27, 2017. Twenty-six delegates, including gastroenterologists, endoscopists, and pathologists from the five regions of Brazil as well as one international guest from the United States, participated in the meeting. The participants were invited based on their knowledge and contribution to the study of H. pylori infection. The meeting sought to review different aspects of treatment for infection; establish a correlation between infection, dyspepsia, intestinal microbiota changes, and other disorders with a special emphasis on gastric cancer; and reassess the epidemiological and diagnostic aspects of H. pylori infection. Participants were allocated into four groups as follows: 1) Epidemiology and Diagnosis, 2) Dyspepsia, intestinal microbiota and other afections, 3) Gastric Cancer, and, 4) Treatment. Before the consensus meeting, participants received a topic to be discussed and prepared a document containing a recent literature review and statements that should be discussed and eventually modified during the face-to-face meeting. All statements were evaluated in two rounds of voting. Initially, each participant discussed the document and statements with his group for possible modifications and voting. Subsequently, during a second voting in a plenary session in the presence of all participants, the statements were voted upon and eventually modified. The participants could vote using five alternatives: 1) strongly agree; 2) partially agree; 3) undecided; 4) disagree; and 5) strongly disagree. The adopted consensus index was that 80% of the participants responded that they strongly or partially agreed with each statement. The recommendations reported are intended to provide the most current and relevant evidences to management of H. pylori infection in adult population in Brazil.Os avanços significativos ocorridos desde o III Consenso Brasileiro sobre H. pylori realizado em 2012, em Bento Gonçalves, justificam este quarto consenso. O evento foi organizado pelo Núcleo Brasileiro para Estudo do Helicobacter e Microbiota, associação vinculada à Federação Brasileira de Gastroenterologia, tendo sido realizado novamente em Bento Gonçalves, RS, nos dias 25 a 27 de agosto de 2017. Participaram 26 delegados provenientes das cinco regiões brasileiras incluindo gastroenterologistas, endoscopistas e patologistas, além de um convidado internacional (EUA). Os participantes foram convidados pelo conhecimento e contribuição ao estudo da infecção por H. pylori. O encontro buscou rever diferentes aspectos relacionados ao tratamento da infecção, suas inter-relações com a dispepsia, microbiota e outras afecções, com ênfase especial ao câncer gástrico, além de promover uma reavaliação dos aspectos epidemiológicos e diagnósticos desta infecção. Os participantes foram alocados em quatro grupos, a saber: 1) Epidemiologia e diagnóstico, 2) Dispepsia, microbiota e outras afecções, 3) Neoplasias gástricas, e 4) Tratamento. Previamente à reunião do Consenso, os participantes receberam um tema a ser discutido e elaboraram texto com uma revisão recente da literatura, contendo uma assertiva de sua revisão. Todas as assertivas foram avaliadas em dois turnos de votação. Inicialmente, cada participante apresentava sua compilação e assertiva ao seu grupo, para eventuais modificações e votação. Posteriormente, em uma segunda votação, agora em sessão plenária, as assertivas eram novamente votadas e eventualmente modificadas. As votações obedeceram a cinco alternativas: 1) concorda fortemente; 2) concorda com reservas; 3) indeciso; 4) discorda e; 5) discorda fortemente. O índice de consenso adotado para cada afirmativa foi de 80% dos votantes respondendo que concorda fortemente ou concorda com reservas. As recomendações aqui apresentadas foram baseadas nas evidências científicas mais relevantes para o manuseio da infecção por H. pylori na população adulta no Brasil.ASSUMPÇÃO, P. P. Universidade Federal do Par