Depressive disorders impose a significant mental health burden on individuals and our society. Among smokers there is a high comorbidity of depression/depressive symptoms (e.g., Glassman et al., 1998). Here the parietal EEG alpha asymmetry was used as a dimensional neuropsychological marker of depressive symptoms (i.e., the more depressed, the higher alpha power in the right vs. left parietal lobe during visuospatial tasks [Henriques & Davidson, 1997; Rabe et al, 2005]). Participants, all of whom were smokers and none of whom were clinically depressed, were randomly assigned to the Bupropion group (n = 30) or Placebo group (n = 80) in this double blind study. EEG data during the performance of a visuospatial task were collected prior to and after 14 days on bupropion or placebo capsules. It was found that bupropion significantly reduced the right parietal alpha power and parietal asymmetry whereas placebo did not. Self-reports on depressive symptoms with the Beck Depression Inventory (BDI) were also collected but they did not change after bupropion treatment, suggesting that EEG measures are more sensitive to subtle/early bupropion’s antidepressant effects. Finally the close investigation of individual differences showed that positive (vs. negative) parietal asymmetry during pretreatment predicted greater benefits from bupropion treatment. The present study sheds light on the antidepressant mechanisms of bupropion and represents a valuable addition to the paucity of research on the effects of bupropion on brain activity with EEG measures in general.

Orientador: Wilma De Grava Kempinas / Resumo: A obesidade é um problema mundial de saúde pública associada ao aumento do risco de síndrome metabólica, dislipidemia, entre outras comorbidades. Entre os fármacos utilizados no tratamento de pacientes obesos estão as estatinas, como a rosuvastatina e sinvastatina, as quais reduzem os níveis séricos de colesterol, precursor de testosterona, e os agentes inibidores de recaptura de neurotransmissores, como a sibutramina e a bupropiona, utilizados na redução do peso corpóreo. Estudos anteriores relataram efeitos adversos da exposição isolada a estes fármacos sobre parâmetros reprodutivos masculinos. Considerando a exposição de pacientes obesos a estatinas e inibidores da recaptura de neurotransmissores, o presente estudo objetivou investigar os efeitos da co-exposição à rosuvastatina e sibutramina, bem como a co-exposição à sinvastatina e bupropiona, sobre os parâmetros reprodutivos em ratos adultos. Para isso, foram realizados dois experimentos. No primeiro experimento, ratos adultos (90 dias) alocados nos grupos controle (salina e dimetilsulfóxido), rosuvastatina (5 mg/kg de rosuvastatina), sibutramina (10 mg/kg de sibutramina) e rosuvastatina associada à sibutramina (n = 26-28/grupo) foram tratados via oral por 70 dias. No segundo experimento, ratos adultos (70 dias) alocados nos grupos controle (água destilada), sinvastatina (50 mg/kg de sinvastatina), bupropiona (30 mg/kg de bupropiona) e sinvastatina associada à bupropiona (n = 20/grupo) foram tratados via oral por 52 dias... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Obesity is a global public health problem associated with an increased risk of metabolic syndrome, dyslipidemia, and other comorbidities. The drugs used to treat obese patients include statins, as rosuvastatin and simvastatin, which reduce serum levels of cholesterol, a precursor of testosterone, and neurotransmitter reuptake inhibitors, such as sibutramine and bupropion, used to reduce body weight. Previous studies reported adverse effects of the isolated exposure to these drugs on male reproductive parameters. Considering the exposure of obese patients to statins and neurotransmitter reuptake inhibitors, the present study aimed to investigate the effects of the co-exposure to rosuvastatin and sibutramine, as well as the co-exposure to simvastatin and bupropion, on reproductive parameters in adult male rats. For this, two experiments were conducted. In the first experiment, adult male rats (90 days) allocated into control (saline and dimethylsulfoxide), rosuvastatin (5 mg/kg rosuvastatin), sibutramine (10 mg/kg sibutramine) and rosuvastatin combined with sibutramine (n = 26-28 / group) were treated orally for 70 days. In the second experiment, adult male rats (70 days) allocated into control (distilled water), simvastatin (50 mg/kg simvastatin), bupropion (30 mg/kg bupropion) and simvastatin combined with bupropion (n = 20 / group) were treated for 52 days. In the first experiment, treatment with rosuvastatin, alone or in combination with sibutramine, resulted in hyperplasia... (Complete abstract click electronic access below) / Doutor

Rökning är ett stort problem i hela världen. 5 000 000 dödsfall varje år kan vara tobaksrelaterade. Nikotin ärden viktigaste farmakologiskt aktiva substansen i cigaretter. Den verkar på nikotinerga receptorer (nAChRs),som är en typ av acetylkolin-receptorer. När man röker riskerar man att utveckla cancersjukdom, hjärtkärlsjukdomeller KOL. Rökning skadar även foster.Syftet med denna litteraturstudie var att studera effektiviteten av bupropion, vareniklin och cytisine vidrökavvänjning. Nio artiklar granskades för att utreda läkemedlens effektivitet.Fyra granskade artiklar handlar om vareniklin. Alla visar att det är ett effektivt och säkert läkemedel som medframgång kan användas för rökavvänjning. NNT-tal för nikotinabstinens under vecka 9 och 12 av behandlingenmed vareniklin beräknades till mellan 3,8 och 5 i tre av studierna. I en fjärde studie var 837 av 1177 deltagarerökfria mellan veckorna 11 och 12. Två granskade studier handlar om bupropion. Båda visar att bupropion är ettsäkert och effektivt läkemedel för rökavvänjning. I en studie visas att bupropion i styrkorna 150 och 300 mg gerbäst effekt. Abstinensnivån var 10,5 respektive 10,7 procentenheter högre än för placebo vid 12 månader efterrökavslutningsdag. I en studie beräknades NNT-tal för bupropion till 5,03 vid månad 12. Två granskade artiklarhandlar om cytisine, en var en randomiserad studie och en var en meta-analys. Studierna visar att cytisine ocksåär ett säker och effektivt läkemedel vid rökavvänjning. I en studie beräknades NNT-tal för 12 månadersnikotinabstinens för cytisine till 16,6. Sex av åtta granskade i meta-analysen studier visade att cytisine är etteffektivt läkemedel. En studie visade att det är viktigt med motiverande stöd förutom läkemedelsbehandling vidrökavvänjning. För läkemedelsbehandling (bupropion eller vareniklin eller nikotin innehållande produkter) medspecialiststöd beräknades NNT-tal till 23,3 vid undersökningsdagen.Vareniklin och bupropion är läkemedel som är registrerade i Sverige under namn Champix® och Zyban®. NärNNT-tal jämförs är vareniklin det effektivaste läkemedlet, men skillnaden mellan bupropion och vareniklin ärliten (2-3) vilket gör att det kan vara svårt att avgöra vilket läkemedel är effektivare. Cytisine finns interegistrerat i Sverige och har högst NNT-tal, 16,6, men ändå lågt vilket visar att det är ett effektivt läkemedel.Detta gör att registrering i andra europeiska länder skulle kunna ske. Det är också det billigaste läkemedel.

Bupropion (BUP) is an efficacious pharmacologic aid for individuals attempting to quit tobacco smoking (Wilkes., 2008), yet little is known about the effects of BUP on neural responses to either smoking cues (SC) or affective cues (AC), stimuli that are known to promote smoking and relapse to smoking for those attempting to quit. In fact, only one published study has assessed BUP’s effects on neuroelectrical event-related responses (ERPs) to SC or AC (Versace, Stevens, Robinson, Cui, Deweese, Engelmann, et al., 2019), and this study did not detect any neural effects of BUP, relative to placebo. It is important to note that Versace et al. (2019) study’s smokers were instructed to focus their attention solely on large color pictures of SC or AC that were presented for several seconds, something that may differ from conditions in which BUP might alter brain responses to SC. In contrast, several studies have assessed the effects of BUP on functional magnetic resonance imaging (fMRI)-assessed brain activity, with several finding that BUP enhanced activation of the nucleus accumbens during the anticipation of a brief (140-460ms) monetary target (Ikeda et al., 2019) and in the right middle and inferior frontal gyri, right caudate, and bilateral precuneus during AC presentation (Robertson et al 2007), while several others found reductions in activation in the left ventral striatum, right medial orbitofrontal cortex, and bilateral anterior cingulate cortex during presentation of SC (Culbertson et al., 2011), and reductions in the activation of right orbitofrontal cortex, left dorsomedial prefrontal cortex, right ventromedial prefrontal cortex, right anterior cingulate cortex, right inferior frontal cortex, right amygdala/parahippocampal area, right caudate, right fusiform gyrus, and left posterior cingulate during AC presentation (Robertson et al 2007). The inconsistencies across these studies may reflect underlying effects of the task used to assess the participant (i.e., context of the task). Thus, it is reasonable to hypothesize that the effects of BUP SC and AC on brain reactivity depend on assessment context and task demands. Few studies have assessed the effects of BUP on brain responses to SC and AC when they are briefly presented distractors, as opposed to the primary focus of sustained attention. This study demonstrates the importance of task context for SC and AC presentation to detect the effects of BUP. By neglecting context-specific effect, the field is missing measurable targets for drug efficacy. This is the 1st study to find an BUP induced LPP reduction. The data is obtained from smokers who were randomly assigned to a BUP (n=24) group or a placebo group (n=66) and assessed prior to and after 14 days on BUP or PLA capsules while still smoking at their typical rate.

Abstract Metabolism is a major determinant of the pharmacokinetic properties of most drugs and is often behind bioavailability problems, drug-drug interactions, and metabolic idiosyncrasies. Cytochrome P450 (CYP) enzymes are a superfamily of microsomal hemoproteins catalysing the metabolic reactions of several exogenous compounds. The majority of crucial steps within drug metabolism are in connection with CYP enzymes. In the present study, in vivo, in vitro, and in silico approaches were applied and characterised to evaluate the effects of chemical entities on CYP-mediated metabolism. CYP2B6 was used as a target enzyme for these studies. For evaluation of the CYP inhibition potential of new chemical entities, a novel in vitro test system utilising the n-in-one approach was developed. This method proved to be robust and applicable to screening purposes. Validation of the n-in-one assay was done by comparing its performance to commonly used in vitro techniques using six structurally diverse drugs. All assay types yield remarkably similar results with the majority of the CYP forms tested. Several chemicals were screened in vitro and in silico in order to find potent and selective chemical inhibitors for CYP2B6. Ticlopidine, thioTEPA and 4-(4-chlorobenzylpyridine) were found to be highly effective inhibitors of CYP2B6. The selectivity of thioTEPA proved to be very high, whereas ticlopidine and 4-(4-chlorobenzylpyridine) also inhibited other CYPs. At a concentration level of 1 μM for ticlopidine and 0.1 μM for 4-(4-chlorobenzylpyridine), the inhibitory effect towards other CYPs was negligible. Due to wide clinical use and relevance, clopidogrel and ticlopidine were selected for further in vivo interaction studies. Both clopidogrel and ticlopidine significantly inhibited the CYP2B6-catalysed bupropion hydroxylation and patients receiving either clopidogrel or ticlopidine are likely to need dose adjustments when treated with drugs primarily metabolised by CYP2B6. The effect of impaired kidney function on CYP2B6 activity and on bupropion pharmacokinetics was also explored. In patients with kidney disease, the bupropion AUC and Cmax were significantly higher and the apparent oral clearance of bupropion was notably lower compared to healthy controls. The present results indicate that the in silico and in vitro methods used are helpful in predicting in vivo drug-drug interactions. The effective utilisation of these models in the early phases of drug discovery could therefore help to target the in vivo studies and to eliminate metabolically unfavourable drug candidates.

<div><b>Background:</b> Bupropion, an atypical antidepressant and smoking cessation aid, is associated with wide inter-subject variability in its efficacy and safety. Variability in response to bupropion therapy is thought to be driven by variability in metabolism. Bupropion undergoes complex phase 1 and 2 stereoselective metabolism. Though bupropion`s pharmacology is not fully understood, much of it is thought to be due to its metabolites, specially, S, S-hydroxybupropion. In vitro studies (functional assays measuring IC50 at dopamine transporter-DAT, norepinephrine transporter-NET, various subtypes of nicotinic receptors-nAChR) and mouse models (forced swim test to assess antidepressant effect, antinociceptive models to assess antagonism of nicotine effects) indicate S, S-hydroxybupropion to contribute more towards efficacy as an antidepressant and smoking cessation aid than racemic bupropion and R, R-hydroxybupropion, respectively. Both pharmacokinetics (PK) and pharmacodynamics (PD) of bupropion and its metabolites are complex and reported to be stereoselective. As bupropion is known to act on multiple central nervous system (CNS) targets (DAT, NET nAChR), understanding CNS disposition (target site) is critical to explain variability in bupropion`s therapeutic and toxic effects. </div><div><b>Objective: </b>The objective of our study was to characterize the exposure of bupropion enantiomers and corresponding phase 1 metabolite diastereomers in plasma and brain in a surrogate non-clinical species, and to subsequently develop animal-to-human-translational population-PK and Physiologically Based PK (PBPK) models to predict human brain concentrations of bupropion and its active metabolite S, S-hydroxybupropion. Application of these PK modeling approaches to map the time course of unbound brain concentration can then be compared to in vitro potency measures at DAT, NET and nAChRs to predict target engagement over time (PD). Establishing relationships between plasma PK, target site PK along with PD would elucidate possible cause(s) of inter-patient variability to bupropion therapy. </div><div><b>Methods: </b>The first step towards development of a CNS model was to identify a nonclinical species with phase 1 metabolism closest to humans. To accomplish this, hepatic microsomal incubations of four species-rat, mouse, non-human primates (NHPs) and humans were conducted separately for the R- and S-bupropion enantiomers, and the formation of enantiomer-specific metabolites was determined using LC-MS/MS. Intrinsic formation clearance (CLint) of metabolites across the four species (rats, mice, NHPs, humans) was determined from the formation rate versus substrate concentration relationship. </div><div>Racemic bupropion (10 mg/kg) and preformed S, S-hydroxybupropion (2 mg/kg) were administered subcutaneously to adult male Sprague Dawley rats (n = 24/compound). Brain and plasma were collected from rats (n = 3) at eight time points for 6 hours and analyzed using a chiral LC-MS/MS method. Rat plasma protein and brain homogenate binding studies were conducted for all analytes to correct for unbound fraction using equilibrium dialysis method.</div><div>A plasma-brain compartmental pharmacokinetic approach was used to describe the blood–brain-barrier transport of both bupropion and S, S-hydroxybupropion. Also, a 2-compartment permeability-limited brain model consisting of brain blood, brain mass compartments was developed and incorporated into a whole body physiologically-based pharmacokinetic (PBPK) parent-metabolite model for bupropion and S, S-hydroxybupropion. Both population PK and PBPK modeling approaches were subsequently translated to humans to predict human plasma and brain site exposure and its relationship to DAT and NET IC50 potencies.</div><div><b>Results: </b>The total clearance of S-bupropion was higher than that of R-bupropion in monkey and human liver microsomes. The contribution of hydroxybupropion to the total racemic bupropion clearance was 38%, 62%, 17%, and 96% in human, monkey, rat, and mouse, respectively. In the same species order, threohydrobupropion contributed 53%, 23%, 17%, and 3%, and erythrohydrobupropion contributed 9%, 14%, 66%, and 1.3%, respectively, to racemic bupropion clearance. Hepatic microsomal incubation studies indicated non-human primates to be the appropriate species to model CNS disposition. However, the cost and limited pharmacokinetic and pharmacodynamic data in NHPs were insurmountable barriers to conducting in vivo studies in NHPs. After considering multiple factors, such as the formation of reductive metabolites (higher in rats than mice), which are also thought to contribute to bupropion`s therapeutic efficacy, availability of microdialysis data measuring bupropion and dopamine, norepinephrine levels in brain extracellular fluid (ECF) and other in vitro potency evaluations in rats, rat was chosen as the surrogate species to model bupropion`s disposition.</div><div>In rats, unbound plasma and brain exposures and plasma clearances of both R and S-bupropion were similar. The exposure to parent was higher (50 to 100-fold) than to metabolites. The exposure of oxidative metabolites (R, R- and S, S-hydroxybupropion) was 2 to 3-fold higher in brain and plasma than reductive metabolites (R, R- and S, S-threohydrobupropion, S, R- and R, S-erythrohydrobupropion). Hepatic clearances of R- and S-bupropion scaled from in vitro rat hepatic microsomal incubation studies were 3-fold and 25-fold lower than their respective in vivo unbound apparent clearances. This could possibly be due to substantial contribution of metabolic pathways not characterized in this in vivo study and/or possible extrahepatic disposition in the rat. The unbound brain to unbound plasma AUC0-6h ratio (Kp,uu) of R- and S-bupropion were 0.43 and 0.38 respectively. Kp,uu of oxidative metabolites (R, R- and S, S-hydroxybupropion) and reductive metabolites (R, R- and S, S-threohydrobupropion) were close to 1. Kp,uu of S, R-erythrohydrobupropion was 0.43 and that of pre-formed S, S-hydroxybupropion was 5.</div><div>With respect to population PK modeling of both bupropion and S, S-hydroxybupropion, a plasma-brain compartmental model structure with time dependent change in brain influx clearance was required to adequately characterize the BBB transport of parent and this active metabolite. Using a physiologically-based pharmacokinetic model (PBPK) approach too, incorporation of active efflux and carrier mediated uptake terms in addition to passive permeability was necessary to adequately characterize brain disposition of bupropion and S, S-hydroxybupropion. Both modeling approaches (population-PK and PBPK) when translated to humans indicated that the predicted human brain exposures fall below the reported DAT and NET IC50 measures of bupropion and S, S-hydroxybupropion. </div><div><b>Conclusion: </b>Specific to our work in the rat, the discrepancy between in vitro scaled hepatic clearance and in vivo plasma clearance of R and S-bupropion suggests alternative non-CYP mediated clearance pathways and/or extra hepatic disposition of bupropion. Both translational PK models indicate active process such as efflux transporter or carrier mediated uptake could be involved in bupropion`s disposition in the brain. Variability in expression of these speculated active/carrier mediated transporters could possibly cause variability in response. Also, other CNS targets could contribute to bupropion`s therapeutic efficacy, elucidation of which would require further investigation.</div><div><br></div>

Indiana University-Purdue University Indianapolis (IUPUI) / A version of this thesis was published as: Masters AR, McCoy M, Jones DR, and Desta Z. Stereoselective method to quantify bupropion and its three major metabolites, hydroxybupropion, erythro-dihydrobupropion, and threo-dihydrobupropion using HPLC-MS/MS. J Chromatography B Analyt Technol Biomed Life Sci 1015-1016:201-208, 2016. / Bupropion is a dual dopamine-norepinephrine uptake inhibitor and a nicotine receptor antagonist. Clinically, bupropion is given as a racemate for the management of depression, smoking cessation aid, and for the management of weight. Bupropion has also been targeted as a phenotypic probe of CYP2B6 activity. Bupropion metabolites are formed via oxidation (4-hydroxybupropion) through CYP2B6, and reduction (erythro- and threo-dihydrobupropion) through carbonyl reductases. These metabolites exhibit pharmacological activity, but little is known regarding their stereoselective disposition due to the lack of a chiral assay. A novel reversed phase chiral-HPLC-MS/MS method involving a simple liquid-liquid extraction procedure and a small plasma sample volume (50µL) was developed that allowed simultaneous separation and quantification of enantiomers of bupropion, 4-hydroxybupropion, and those of threo- and erythro-dihydrobupropion in human plasma. This method was successfully implemented to determine the unique stereoselective disposition of bupropion and its metabolites in 15 human volunteers administered a single 100 mg oral dose of racemic bupropion. Significant differences (p<0.05) in the stereoselective metabolism were observed for all of the enantiomers. The highest plasma exposure (AUC0-∞) was (2R, 3R)-4-hydoxybupropion, almost 65 fold higher, than (2S, 3S)-4-hydoxybupropion, and over 32 fold greater than the parent R-bupropion. The second highest plasma exposure was threo-dihydrobupropion A, which was almost 5 fold higher than threo-dihydrobupropion B. (Nomenclature of the enantiomers for erythro- and threo-dihydrobupropion was based on the chromatography of the first eluting peak as “A” and the second eluting peak as “B”.) Threo-dihydrobupropion A and B showed the most significant difference between the racemic and enantiomer profiles. Although the AUC was greater for threo-dihydrobupropion B, threo-dihydrobupropion A had a significantly (p<0.05) higher Cmax. The half-life for threo-dihydrobupropion A and erythro-dihydrobupropion A were the longest for all analytes, which could indicate accumulation in multiple dosing. The importance of this study was, for the first time, to be able to characterize the stereoselective metabolism of bupropion and its three major metabolites. This new method and subsequent pharmacokinetic data should enhance further research into bupropion stereoselective metabolism, drug interactions, and effect. / A version of this thesis was published as: Masters AR, McCoy M, Jones DR, and Desta Z. Stereoselective method to quantify bupropion and its three major metabolites, hydroxybupropion, erythro-dihydrobupropion, and threo-dihydrobupropion using HPLC-MS/MS. J Chromatography B Analyt Technol Biomed Life Sci 1015-1016:201-208, 2016.

Made available in DSpace on 2016-08-10T10:29:46Z (GMT). No. of bitstreams: 1 VALQUIRIA LUZIA DE CASTRO.pdf: 16657284 bytes, checksum: 1a01a269f0ffa3172c86e8ea2baba363 (MD5) Previous issue date: 2010-06-30 / The bupropion hydrochloride is an antidepressant pharmacological used in treatment of smoking cessation; the drug increases the interstitial concentrations of dopamine, reducing the smoking habit. The objective was the achievement of physical and chemical tests of the tablets of bupropion hydrochloride, of a laboratory acquired in similar ethical and commercial pharmacies in Imperatriz city, the drug being used in the Smoking Cessation Program of the Ministry of Health, Brazil. Were evaluated twelve lots of tablets of bupropion hydrochloride and observed the conditions of air conditioning in commercial pharmacies using a digital thermometer of Sper Scient brand. The raw materials of bupropion hydrochloride was used as a reference standard, purchased at a masterful pharmacy and subjected to laboratory tests in Quality Control of Faculdade de Imperatriz. The temperature verification at pharmacies where the tablets were purchased ranged from 37 ° C to 40 ° C, which is above the specification of boxes of medicine, whose guidelines: keep the temperature between 15°C to 30°C, which can cause instability pharmaceuticals. When weighing values were observed within the variation limits allowed. The friability showed no variations. The disintegration occurred at the scheduled time of 45 minutes. The twelve lots subject to durometer to resistance verification were higher than 3 Kgf, it is possible to change the nature of the excipients. There was no significant dissolution of the samples showing a concentration of 0.95 &#956;g / ml, less than 80% of predicted value. The content of the active principle, analyzed by non aqueous titration, samples were taken by present concentration of between 90% and 110% as stated in the American Pharmacopoeia. Pharmaceutical equivalence between the similar medicine and the ethical medicine becomes related that both possess the same fármaco, and similar results evaluated in vitro. One concludes that the process of dissolution and hardness can have been affected significantly for the peculiar characteristics to the proper fármaco, as well as for the presence of excipientes that had made it difficult the same dissolution or for the employed techniques of manufacture. Also suggesting an analysis in the process of production inside of the quality control in the Pharmaceutical Industry verifying the processes of validation for attainment of planned results. / O Cloridrato de bupropiona é um fármaco antidepressivo utilizado no tratamento na cessação do tabagismo, o fármaco aumenta as concentrações intersticiais de dopamina, diminuindo a saciedade do fumo. O objetivo deste trabalho foi a realização dos ensaios físicos e químicos dos comprimidos do Cloridrato de Bupropiona, de um laboratório ético e similar adquiridos nas farmácias comerciais na cidade de Imperatriz, sendo o fármaco empregado no Programa da Cessação do Tabagismo pelo Ministério da Saúde, Brasil. Foram avaliados doze lotes dos comprimidos do Cloridrato de Bupropiona e observadas as condições de climatização nas farmácias comerciais utilizando um termômetro digital da marca Sper Scient. Utilizou-se como padrão de referência a matéria prima, adquirida em uma farmácia magistral e submetida aos testes realizados no laboratório de Controle de Qualidade da Faculdade de Imperatriz. A verificação da temperatura nas farmácias onde os comprimidos foram adquiridos variava de 37°C a 40°C, estando acima das especificações das caixas do medicamento, cujas orientações: manter a temperatura entre 15°C a 30°C, o que pode causar instabilidade nos fármacos. Na pesagem foram observados valores dentro dos limites de variações permitidos. A friabilidade não apresentou variações. A desintegração ocorreu no tempo previsto de 45 minutos. Os doze lotes submetidos ao durômetro para verificação da resistência foram superiores a 3 Kgf, sendo possível a variação pela natureza dos excipientes. Não houve dissolução significativa das amostras analisadas apresentando uma concentração de 0,95 &#956;g/ml, inferior a 80% do valor previsto. O teor do princípio ativo, analisado por titulação em meio não aquoso, as amostras foram aprovadas por apresentarem concentração situada entre 90% e 110% como consta a Farmacopéia Americana. A equivalência farmacêutica entre o medicamento similar e o medicamento ético relaciona-se que ambos possuem o mesmo fármaco, e resultados semelhantes avaliados in vitro. Conclui-se que o processo de dissolução e dureza pode ter sido afetado significativamente pelas características peculiares ao próprio fármaco, bem como pela presença de excipientes que dificultaram a dissolução ou mesmo pelas técnicas de fabricação empregadas. Sugerindo também uma análise no processo de produção dentro do controle de qualidade na Indústria Farmacêutica verificando os processos de validação para obtenção de resultados planejados.

O uso de fármacos durante a lactação é uma prática comum; porém, os tratamentos farmacológicos impõem grandes dúvidas tanto aos profissionais quanto às nutrizes sobre a segurança do uso destes durante este período. A amamentação é uma forma de vínculo entre mãe e bebê e está associada a diversos benefícios nutricionais, imunológicos, cognitivos, psicoafetivos, econômicos e sociais. A depressão é um problema clínico importante durante o período pós-parto, e a vulnerabilidade para o início ou recorrência de sintomas depressivos aumenta a possibilidade de uso de psicofármacos enquanto ocorre a lactação. Os antidepressivos inibidores seletivos da recaptação da serotonina são comumente prescritos para o tratamento destes quadros depressivos, entre eles fluoxetina, sertralina, citalopram e paroxetina, sendo que a maioria destes é excretada no leite materno e há grande variabilidade na quantidade de analitos que pode ser recebida pelo lactente. Bupropiona é um fármaco antidepressivo utilizado para o tratamento do tabagismo e quadros depressivos e tem sua excreção ao leite materno relatada em literatura. Métodos bioanalíticos para determinação da excreção de fármacos antidepressivos foram desenvolvidos e validados por cromatografia líquida acoplada a espectrômetro de massas e cromatografia líquida com detecção ultravioleta. Estes métodos demonstraram serem seletivos, lineares, precisos e exatos, com limites de quantificação de 5 ng/mL (fluoxetina, citalopram e bupropiona) e 20 ng/mL (sertralina e paroxetina) para método por LC-MS e de 200 ng/mL para todos os analitos no método por CLAE-UV. As amostras de leite materno foram coletadas em Banco de Leite de mães que declararam utilizar fluoxetina ou sertralina ou paroxetina e analisados. Os dados de concentração encontrados para os fármacos referidos estão dentro da faixa encontrada em literatura confirmando sua excreção no leite materno. Paroxetina apresentou valores abaixo do limite de quantificação. Das concentrações encontradas no leite materno, foram estimadas as doses absolutas e relativas no lactante, sendo que os resultados demonstraram baixos valores em relação a estas estimativas, podendo os fármacos analisados ser considerados seguros para manutenção do uso durante a lactação. Foi também detectada nas análises por LC-MS a presença de norfluoxetina, metabólito da fluoxetina, confirmando sua excreção nesta matriz. / The use of medications during lactation is a common practice; however pharmacological treatments impose serious doubts to both, professionals and nursing mothers, about the safety of drugs use during this period. Breastfeeding is a natural form of bonding between mother and baby and it is associated with many nutritional, immunological, cognitive, psychoemotional, social and economic benefits. Depression is a major clinical problem during the postpartum period and the vulnerability to onset or recurrence of depressive symptoms increases the possibility of psychotropic drug use during lactation. Selective inhibitors of serotonin reuptake are commonly prescribed for the treatment of depressive disorders, including fluoxetine, sertraline, citalopram and paroxetine. Most of these drugs are excreted in breast milk and there is great variability in the amount of analytes that can be received by the infant. Bupropion is an antidepressant used for tabagism treatment and for depression symptoms; it is also described in literature its excretion into breast milk. Bioanalytical methods for determining the excretion of antidepressants were developed and validated by liquid chromatography coupled to mass spectrometry and liquid chromatography with ultraviolet detection. These methods proved to be selective, linear, precise and accurate with quantification limits of 5 ng/mL (fluoxetine, citalopram e bupropion) and 20 ng/mL (sertraline e paroxetine) for LC-MS method and 200 ng/mL for all analytes in the CLAE-UV method. Human milk samples were collected in milk banks from mothers to which the antidepressants fluoxetine or sertraline or paroxetine were administered, and the concentrations in this matrix were verified. Found concentrations were within the range described in the literature confirming their excretion in the breast milk. Paroxetine presented values less than limit of quantification. From the found concentrations, the absolute and relative doses in nursing were estimated. The results showed low values for these estimates and so the analyzed drugs can be considered safe to continue use during lactation. The presence of norfluoxetine, a metabolite of fluoxetine, was also detected by LC-MS, confirming its excretion in this matrix.

O uso de fármacos durante a lactação é uma prática comum; porém, os tratamentos farmacológicos impõem grandes dúvidas tanto aos profissionais quanto às nutrizes sobre a segurança do uso destes durante este período. A amamentação é uma forma de vínculo entre mãe e bebê e está associada a diversos benefícios nutricionais, imunológicos, cognitivos, psicoafetivos, econômicos e sociais. A depressão é um problema clínico importante durante o período pós-parto, e a vulnerabilidade para o início ou recorrência de sintomas depressivos aumenta a possibilidade de uso de psicofármacos enquanto ocorre a lactação. Os antidepressivos inibidores seletivos da recaptação da serotonina são comumente prescritos para o tratamento destes quadros depressivos, entre eles fluoxetina, sertralina, citalopram e paroxetina, sendo que a maioria destes é excretada no leite materno e há grande variabilidade na quantidade de analitos que pode ser recebida pelo lactente. Bupropiona é um fármaco antidepressivo utilizado para o tratamento do tabagismo e quadros depressivos e tem sua excreção ao leite materno relatada em literatura. Métodos bioanalíticos para determinação da excreção de fármacos antidepressivos foram desenvolvidos e validados por cromatografia líquida acoplada a espectrômetro de massas e cromatografia líquida com detecção ultravioleta. Estes métodos demonstraram serem seletivos, lineares, precisos e exatos, com limites de quantificação de 5 ng/mL (fluoxetina, citalopram e bupropiona) e 20 ng/mL (sertralina e paroxetina) para método por LC-MS e de 200 ng/mL para todos os analitos no método por CLAE-UV. As amostras de leite materno foram coletadas em Banco de Leite de mães que declararam utilizar fluoxetina ou sertralina ou paroxetina e analisados. Os dados de concentração encontrados para os fármacos referidos estão dentro da faixa encontrada em literatura confirmando sua excreção no leite materno. Paroxetina apresentou valores abaixo do limite de quantificação. Das concentrações encontradas no leite materno, foram estimadas as doses absolutas e relativas no lactante, sendo que os resultados demonstraram baixos valores em relação a estas estimativas, podendo os fármacos analisados ser considerados seguros para manutenção do uso durante a lactação. Foi também detectada nas análises por LC-MS a presença de norfluoxetina, metabólito da fluoxetina, confirmando sua excreção nesta matriz. / The use of medications during lactation is a common practice; however pharmacological treatments impose serious doubts to both, professionals and nursing mothers, about the safety of drugs use during this period. Breastfeeding is a natural form of bonding between mother and baby and it is associated with many nutritional, immunological, cognitive, psychoemotional, social and economic benefits. Depression is a major clinical problem during the postpartum period and the vulnerability to onset or recurrence of depressive symptoms increases the possibility of psychotropic drug use during lactation. Selective inhibitors of serotonin reuptake are commonly prescribed for the treatment of depressive disorders, including fluoxetine, sertraline, citalopram and paroxetine. Most of these drugs are excreted in breast milk and there is great variability in the amount of analytes that can be received by the infant. Bupropion is an antidepressant used for tabagism treatment and for depression symptoms; it is also described in literature its excretion into breast milk. Bioanalytical methods for determining the excretion of antidepressants were developed and validated by liquid chromatography coupled to mass spectrometry and liquid chromatography with ultraviolet detection. These methods proved to be selective, linear, precise and accurate with quantification limits of 5 ng/mL (fluoxetine, citalopram e bupropion) and 20 ng/mL (sertraline e paroxetine) for LC-MS method and 200 ng/mL for all analytes in the CLAE-UV method. Human milk samples were collected in milk banks from mothers to which the antidepressants fluoxetine or sertraline or paroxetine were administered, and the concentrations in this matrix were verified. Found concentrations were within the range described in the literature confirming their excretion in the breast milk. Paroxetine presented values less than limit of quantification. From the found concentrations, the absolute and relative doses in nursing were estimated. The results showed low values for these estimates and so the analyzed drugs can be considered safe to continue use during lactation. The presence of norfluoxetine, a metabolite of fluoxetine, was also detected by LC-MS, confirming its excretion in this matrix.