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.

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.

Randomized controlled trials of serotonin-norepinephrine reuptake inhibitor in treating major depressive disorder in children and adolescents: a meta-analysis of efficacy and acceptability

New generation antidepressant therapies, including serotonin-norepinephrine reuptake inhibitor (SNRIs), were introduced in the late 1980s; however, few comprehensive studies have compared the benefits and risks of various contemporary treatments for major depressive disorder (MDD) in young patients. A comprehensive literature search of PubMed, Cochrane, Embase, Web of Science, and PsycINFO databases was conducted from 1970 to January 2015. Only clinical trials that randomly assigned one SNRI or placebo to patients aged 7 to 18 years who met the diagnostic criteria for major depressive disorder were included. Treatment success, dropout rate, and suicidal ideation/attempt outcomes were measured. Primary efficacy was determined by pooling the risk ratios (RRs) of treatment response and remission. Acceptability was determined by pooling the RRs of dropouts for all reasons and for adverse effects as well as suicide-risk outcomes. Five trials with a total of 973 patients were included. SNRIs were not significantly more effective than placebo for treatment response but were for remission. The comparison of patients taking SNRIs that dropped out for all reasons and those taking placebo did not reach statistical significance. Significantly more patients taking SNRIs dropped out for adverse effects than those taking placebo. No significant difference was found in suicide-related risk outcomes. SNRI therapy does not display a superior efficacy and is not better tolerated compared to placebo in these young patients. However, duloxetine has a potential beneficial effect for depression in young populations, showing a need for further research.

The enantioselective pharmacokinetic study of desvenlafaxine sustained release tablet in Chinese healthy male volunteers after oral administration / 药学学报

A chiral LC-MS/MS method for the simultaneous analysis of desvenlafaxine (DVS) enantiomers in human plasma was developed and applied to a pharmacokinetic study on 12 Chinese healthy volunteers. d6-Desvenlafaxine was used as internal standard (IS). Chromatographic separation was performed on the Astec Chirobiotic V chiral column (150 mm x 4.6 mm, 5 μm). The assay was linear over the concentration range of 0.500-150 ng x mL(-1) for both enantiomers (r2 > 0.99). The method was successfully applied to a stereoselective pharmacokinetic study of 100 mg desvenlafaxine sustained release tablets on 12 Chinese healthy volunteers under fasting conditions. The results showed that the pharmacokinetic parameters were similar to both enantiomers in Chinese healthy volunteers. The AUC(0-t), and C(max) of the two enantiomers were about 1.5 times higher than those of blacks and whites reported in the literature.

Venlafaxine-Induced Acute Toxic Hepatitis

Venlafaxine is among the most widely prescribed antidepressants. It is extensively metabolized to O-desmethylvenlafaxine via cytochrome P450 (CYP) 2D6. We report a case of acute toxic hepatitis resulting from venlafaxine in a 54-year-old woman with pain disorder. During venlafaxine treatment, laboratory tests revealed elevated liver enzymes with a maximum of 169 IU/L for aspartate transaminase (AST) and 166 IU/L for alanine transaminase (ALT). AST and ALT levels returned to normal after 6 days of discontinuation of venlafaxine. The patient was finally diagnosed with acute toxic hepatitis through liver biopsy. This case indicates the importance that clinicians should be aware of the hepatotoxicity of venlafaxine in practice.

SSRIs and SNRIs for Management of Hot Flushing / 대한폐경학회지

For postmenopausal women who fear hormone therapy, women 60 years of age with continuous, severe hot flushing or women with a history of breast cancer, we should consider selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) as therapeutic agents. Base on the results from a meta-analysis and clinical trials regarding hot flushing, paroxetine and the conetrolled-release formultation of paroxetine have been shown to effectively reduce hot flushing by 30~40% and 60~70%, respectively, and 13~41% more reductions as compared to placebo. Venlafaxine reduced hot flushes by 30~60% (133% reductions compared to placebo), and desvenlafaxine reduced hot flushes by 30~70%. Fluoxetine and citalopram were shown to be less effective than paroxetine and venlafaxine, by 20% (113% reductions compared to placebo) and 40~50%, respectively. Sertraline reduced hot flushes 3~18% compared to the placebo group, but was considered ineffective. Citalopram (20 mg), paroxetine (10 mg), venlafaxine (37.5~150 mg), and desvenlafaxine (100~200 mg) not only reduced vasomotor symptoms, but demonstrated additional beneficial outcomes with respect to sleep disturbances, mood, the vigor index, and improved quality of life. Citalopram (20 mg), fluoxetine (20 mg), paroxetine (10 mg), venlafaxine (75~150 mg), and desvenlafaxine (150 mg) are recommended at the corresponding doses after weighing the risks and benefits of these medications. SSRIs and SNRIs were shown to interrupt the conversion of tamoxifen into the active metabolite, endoxifen, and thus SSRIs and SNRIs must not be used in breast cancer patients who are taking tamoxifen. Paroxetine suppressed vasomotor symptoms most potently, followed by fluoxetine, sertraline, citalopram, and venlafaxine.