Anticonvulsant effects of desvenlafaxine on modulating brain monoamine and oxidative stress in mice / Efeitos anticonvulsivantes da desvenlafaxina na modulação da monoamina cerebral e do estresse oxidativo em camundongos

Desvenlafaxine succinate (DVS) inhibits serotonin reuptake selectively and is approved for major depressive disorders. This research investigated influence of DVS on modulating brain monoamine and oxidative stress in mice. The antiepileptic potential of DVS (10, 20, or 30 mg/kg/i.p.) in pentylenetetrazole (PTZ; 85 mg/kg) with i.p. route of administration, strychnine (STR; 75 mg/kg) with i.p. route, pilocarpine (400 mg/kg) with s.c. route and maximal electroshock MES-induced convulsion in mouse models. The activities of oxidative stress, i.e. superoxide dismutase (SOD), glutathione (GSH) and lipid peroxidation (LPO) as well as gamma-aminobutyric acid (GABA) in the brains of PTZ-induced convulsive mice. Treatment with DVS increased the latency to develop siezures and declined mortalities in rodents against PTZ, STR and pilocarpine-induced convulsions. Results of MES-leaded siezures revealed that DVS reduced tonic hind limb extension duration and mortalities significantly. Brain, SOD, GSH and GABA level were significantly (P<0.01) increased and LPO reduced significantly (P<0.01) after DVS treatment. Furthermore, the DVS did not show any motor coordination signs in the rotarod test. We demonstrated that the role of DVS in convulsion genesis in mice under control condition and attenuate the PTZ-induced oxidative damage.

O succinato de desvenlafaxina (DVS) inibe seletivamente a recaptação da serotonina e é aprovado para transtornos depressivos maiores. Esta pesquisa investigou a influência do DVS na modulação da monoamina cerebral e do estresse oxidativo em camundongos. O potencial antiepiléptico de DVS (10, 20 ou 30 mg / kg / i.p.) Em pentilenotetrazole (PTZ; 85 mg / kg) com i.p. via de administração, estricnina (STR; 75 mg / kg) com i.p. via, pilocarpina (400 mg / kg) com s.c. rota e convulsão induzida por MES de eletrochoque máximo em modelos de camundongos. As atividades de estresse oxidativo, ou seja, superóxido dismutase (SOD), glutationa (GSH) e peroxidação lipídica (LPO), bem como ácido gama-aminobutírico (GABA) nos cérebros de camundongos convulsivos induzidos por PTZ. O tratamento com DVS aumentou a latência para desenvolver crises e diminuiu a mortalidade em roedores contra convulsões induzidas por PTZ, STR e pilocarpina. Os resultados de siezures conduzidos por MES revelaram que o DVS reduziu significativamente a duração e a mortalidade da extensão tônica dos membros posteriores. Os níveis de cérebro, SOD, GSH e GABA aumentaram significativamente (P < 0,01) e o LPO reduziu significativamente (P < 0,01) após o tratamento com DVS. Além disso, o DVS não apresentou sinais de coordenação motora no teste do rotarod. Demonstramos o papel do DVS na gênese da convulsão em camundongos sob condição de controle e atenua o dano oxidativo induzido por PTZ.

Anticonvulsant effects of desvenlafaxine on modulating brain monoamine and oxidative stress in mice

Abstract Desvenlafaxine succinate (DVS) inhibits serotonin reuptake selectively and is approved for major depressive disorders. This research investigated influence of DVS on modulating brain monoamine and oxidative stress in mice. The antiepileptic potential of DVS (10, 20, or 30 mg/kg/i.p.) in pentylenetetrazole (PTZ; 85 mg/kg) with i.p. route of administration, strychnine (STR; 75 mg/kg) with i.p. route, pilocarpine (400 mg/kg) with s.c. route and maximal electroshock MES-induced convulsion in mouse models. The activities of oxidative stress, i.e. superoxide dismutase (SOD), glutathione (GSH) and lipid peroxidation (LPO) as well as gamma-aminobutyric acid (GABA) in the brains of PTZ-induced convulsive mice. Treatment with DVS increased the latency to develop siezures and declined mortalities in rodents against PTZ, STR and pilocarpine-induced convulsions. Results of MES-leaded siezures revealed that DVS reduced tonic hind limb extension duration and mortalities significantly. Brain, SOD, GSH and GABA level were significantly (P 0.01) increased and LPO reduced significantly (P 0.01) after DVS treatment. Furthermore, the DVS did not show any motor coordination signs in the rotarod test. We demonstrated that the role of DVS in convulsion genesis in mice under control condition and attenuate the PTZ-induced oxidative damage.

Resumo O succinato de desvenlafaxina (DVS) inibe seletivamente a recaptação da serotonina e é aprovado para transtornos depressivos maiores. Esta pesquisa investigou a influência do DVS na modulação da monoamina cerebral e do estresse oxidativo em camundongos. O potencial antiepiléptico de DVS (10, 20 ou 30 mg / kg / i.p.) Em pentilenotetrazole (PTZ; 85 mg / kg) com i.p. via de administração, estricnina (STR; 75 mg / kg) com i.p. via, pilocarpina (400 mg / kg) com s.c. rota e convulsão induzida por MES de eletrochoque máximo em modelos de camundongos. As atividades de estresse oxidativo, ou seja, superóxido dismutase (SOD), glutationa (GSH) e peroxidação lipídica (LPO), bem como ácido gama-aminobutírico (GABA) nos cérebros de camundongos convulsivos induzidos por PTZ. O tratamento com DVS aumentou a latência para desenvolver crises e diminuiu a mortalidade em roedores contra convulsões induzidas por PTZ, STR e pilocarpina. Os resultados de siezures conduzidos por MES revelaram que o DVS reduziu significativamente a duração e a mortalidade da extensão tônica dos membros posteriores. Os níveis de cérebro, SOD, GSH e GABA aumentaram significativamente (P 0,01) e o LPO reduziu significativamente (P 0,01) após o tratamento com DVS. Além disso, o DVS não apresentou sinais de coordenação motora no teste do rotarod. Demonstramos o papel do DVS na gênese da convulsão em camundongos sob condição de controle e atenua o dano oxidativo induzido por PTZ.

Avaliação da bioequivalência entre duas formulações de succinato de desvenlafaxina monoidratado ­ 50 mg comprimido revestido de liberação prolongada ­ administradas em jejum e pós-prandial em voluntários sadios de ambos os sexos / Bioequivalence evaluation of two desvenlafaxine succinate monohydrate formulations 50-mg extendedrelease coated tablet administered in fasted and fed conditions in healthy male and female volunteers

Objetivo: O objetivo deste trabalho foi avaliar a bioequivalência entre duas formulações de succinato de desvenlafaxina monoidratado 50 mg comprimido revestido de liberação prolongada, sendo a formulação teste produzida por Medley Farmacêutica Ltda. e a formulação referência (Pristiq™) comercializada por Wyeth Indústria Farmacêutica Ltda. Métodos: Os estudos foram conduzidos em voluntários sadios e as formulações administradas em dose única, sob o estado jejum e pós-prandial. Cada estudo foi conduzido de maneira independente, sendo ambos do tipo aberto, dois períodos, utilizando um delineamento do tipo crossover 2x2, envolvendo 48 voluntários, com intervalo de sete dias entre os períodos (washout). Resultados: Na administração em jejum, a razão entre a média geométrica da formulação teste e referência (T/R) de Cmáx foi 107,49%, com intervalo de confiança (IC) 90% de 100,81 a 114,60%. Para ASC0-t, a razão T/R foi de 104,90%, com IC 90% de 97,53 a 112,82%. Na administração pós-prandial, a razão T/R de Cmáx foi 103,17%, com IC 90% de 95,08 a 111,94%. Para ASC0-t, a razão T/R foi 103,40%, com IC 90% de 94,97 a 112,58%. Conclusões: As formulações teste e referência foram consideradas estatisticamente bioequivalentes em ambas as condições de administração, jejum e pós-prandial, de acordo com os critérios exigidos pela Agência Nacional de Vigilância Sanitária (Anvisa). A formulação teste foi o primeiro medicamento similar (Zodel®, 50 e 100 mg) registrado pela Anvisa nessa categoria e disponibilizado para comercialização, contribuindo assim com a ampliação da disponibilidade do tratamento para o transtorno depressivo maior e a redução de custos ao paciente.

Objective: The objective of this work was to evaluate the bioequivalence between two desvenlafaxine succinate monohydrate formulations 50-mg extended-release tablet, the test product manufactured by Medley Farmacêutica Ltd. and reference product (Pristiq™) commercialized by Wyeth Indústria Farmacêutica Ltda. Methods: The studies were performed in healthy volunteers and the formulations were administered in single-dose under fasted and fed conditions. Each study was conducted independently and performed of type open, two periods, using a 2x2 crossover design, involving 48 volunteers, with seven days of minimum interval between periods (washout). Results: In the fasted administration, the ratio between the geometrical mean of test formulation and reference (T/R) of Cmax was 107.49%, with confidence interval 90% (CI 90%) of 100.81 to 114.60%. For AUC0-t, the ratio T/R was of 104.90%, with CI 90% from 97.53% to 112.82%. In the fed administration, the ratio T/R of Cmax was 103.17% with CI 90% of 95.08 to 111.94%. For AUC0-t, the ratio T/R was 103.40%, with CI 90% of 94.97 to 112.58%. Conclusions: The test and reference formulations were considered statistically bioequivalent in the two administration conditions, fasted and fed, according to the requirements of Brazilian National Health Surveillance Agency (Anvisa). The test formulation was the first similar medicine (Zodel®, 50 e 100 mg) to be registered by Anvisa in this category and available to commercialization, thus contributing to increase the availability of treatment for major depressive disorder and the reduction of costs to the patient.

Quality control of desvenlafaxine succinate extended-release tablets / 国际药学研究杂志

Objective To establish and validate the assay methods of release,content,content uniformity and related sub?stances of desvenlafaxine succinate (DVS) in extended-release tablets. Methods The ultraviolet spectrophotometric method was used to determine the DVS release from DVS extended-release tablets. The content uniformity,content and related substance were deter?mined by high-performance liquid chromatography(HPLC). To validate all the method,we respectively examined specificity,linearity, recovery rate,precision and stability,etc. Results The results showed that the analysis method for release was specific,the calibra?tion curve was linear in the range of 10-200μg/ml,and all the recovery,repeatability and intermediate precision met requirements. The method for detection of content and content uniformity was specific and linear in the range of 5-400μg/ml,the recovery,repeat?ability and intermediate precision met requirements. The method for related substances was specific and sensitive ,the linear and recovery rate met the requirements. All of the solutions were stable during 24 h at room temperature. Conclusion The analysis meth?od for release is simple,sensitive,specific and accurate,the method for content and content uniformity is accurate and reliable,and the method for related substances is specific,sensitive and accurate. These methods are suitable for quality control of DVS extended-release tablets.

Quality control of desvenlafaxine succinate extended-release tablets / 国际药学研究杂志

Objective To establish and validate the assay methods of release, content, content uniformity and related substances of desvenlafaxine succinate (DVS) in extended- release tablets. Methods The ultraviolet spectrophotometric method was used to determine the DVS release from DVS extended-release tablets. The content uniformity, content and related substance were determined by high-performance liquid chromatography (HPLC). To validate all the method, we respectively examined specificity, linearity, recovery rate, precision and stability, etc. Results The results showed that the analysis method for release was specific, the calibration curve was linear in the range of 10-200 µg/ml, and all the recovery, repeatability and intermediate precision met requirements. The method for detection of content and content uniformity was specific and linear in the range of 5-400 µg/ml, the recovery, repeatability and intermediate precision met requirements. The method for related substances was specific and sensitive, the linear and recovery rate met the requirements. All of the solutions were stable during 24 h at room temperature. Conclusion The analysis method for release is simple, sensitive, specific and accurate, the method for content and content uniformity is accurate and reliable, and the method for related substances is specific, sensitive and accurate. These methods are suitable for quality control of DVS extendedrelease tablets.

LC-UV and LC-MS evaluation of stress degradation behavior of desvenlafaxine / 药物分析学报

The objective of current study was to develop a validated specific stability indicating reversed-phase liquid chromatographic method for the quantitative determination of desvenlafaxine in bulk sample and pharmaceutical dosage form in the presence of degradation products.Forced degradation studies were performed on bulk sample of desvenlafaxine as per ICH prescribed stress conditions using acid,base,oxidative and photolytic degradation to show the stability indicating power of the method.Significant degradation was observed under acidic stress condition and the degradation product formed was identified by LC-MS and a degradation pathway for drug has been proposed.Successful separation of drug from degradation products formed under stress conditions was achieved on a SymmetryShield column C18 (5 μm,250 mm × 4.6 mm,i.d.) using the mobile phase consisting of a mixture of 0.2％ (v/v) triethylamine in ammonium acetate (0.05 M; pH 6.5) and methanol using isocratic gradient.