http://dx.doi.org/10.1016/j.jad.2015.03.021 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19618号 / 医博第4125号 / 新制||医||1015(附属図書館) / 32654 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川上 浩司, 教授 清水 章, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

A case is presented of a fatal drug interaction caused by ingestion of clozapine (Clozaril(TM)) and fluoxetine (Prozac(TM)). Clozapine is a tricyclic dibenzodiazepine derivative used as an 'atypical antipsychotic' in the treatment of severe paranoid schizophrenia. Fluoxetine is a selective serotonin reuptake inhibitor used for the treatment of major depression. Clinical studies have proven that concomitant administration of fluoxetine and clozapine produces increased plasma concentrations of clozapine and enhances clozapine's pharmacological effects due to suspected inhibition of clozapine metabolism by fluoxetine. Blood, gastric, and urine specimens were analyzed for fluoxetine by gas chromatography/mass spectrometry (GC/MS) and for clozapine by gas-liquid chromatography (GLC). Clozapine concentrations were: plasma, 4.9 μg/mL; gastric contents, 265 mg; and urine, 51.5 μg/mL. Fluoxetine concentrations were: blood, 0.7 μg/mL; gastric contents, 3.7 mg; and urine 1.6 μg/mL. Norfluoxetine concentrations were: blood, 0.6 μg/mL, and none detected in the gastric contents or urine. Analysis of the biological specimens for other drugs revealed the presence of ethanol (blood, 35 mg/dL; vitreous, 56 mg/dL; and urine 153 mg/dL) and caffeine (present in all specimens). The combination of these drugs produced lethal concentrations of clozapine and high therapeutic to toxic concentrations of fluoxetine. The deceased had pulmonary edema, visceral vascular congestion, paralytic ileus, gastroenteritis and eosinophilia. These conditions are associated with clozapine toxicity. The combined central nervous system, respiratory and cardiovascular depression of these drugs was sufficient to cause death. The death was determined to be a clozapine overdose due to a fatal drug interaction.

No / The effect of the selective serotonin reuptake inhibitor fluoxetine was examined on the 5-HT4 receptor-mediated relaxation in the rat isolated ileum. Fluoxetine unsurmountably antagonized the relaxation to exogenous 5-HT with abolition of the response at 10 ¿M. Fluoxetine (10 ¿M) also caused a gradual loss of the resting tension. These effects of fluoxetine were prevented by a prior addition of the 5-HT4 receptor selective antagonist GR113808 (100 nM), which itself caused a contraction of the tissues when administered alone. Fluoxetine (10 ¿M) also failed to prevent the relaxation due to exogenous 5-HT and the 5-HT4 receptor agonist 5-methoxytryptamine in tissues taken from the rats treated with para-chlorophenylalanine (300 mg kg¿1) for 3 and 6 days, which reduced the 5-HT level in the mucosa by 88 and 97.5% respectively. The contraction of the tissues with GR113808 indicates the presence of an endogenous 5-HT tone at the 5-HT4 receptor in the rat ileum. It is hypothesized that in the presence of fluoxetine, the concentration of endogenous 5-HT at the receptor was increased sufficiently to reduce or abolish the relaxation to 5-HT added exogenously. The inability of fluoxetine to prevent the relaxation to 5-HT in the presence of GR113808 or after the p-CPA treatment supports this hypothesis. The effect of the selective serotonin reuptake inhibitor fluoxetine was examined on the 5-HT4 receptor-mediated relaxation in the rat isolated ileum. Fluoxetine unsurmountably antagonized the relaxation to exogenous 5-HT with abolition of the response at 10 ¿M. Fluoxetine (10 ¿M) also caused a gradual loss of the resting tension. These effects of fluoxetine were prevented by a prior addition of the 5-HT4 receptor selective antagonist GR113808 (100 nM), which itself caused a contraction of the tissues when administered alone. Fluoxetine (10 ¿M) also failed to prevent the relaxation due to exogenous 5-HT and the 5-HT4 receptor agonist 5-methoxytryptamine in tissues taken from the rats treated with para-chlorophenylalanine (300 mg kg¿1) for 3 and 6 days, which reduced the 5-HT level in the mucosa by 88 and 97.5% respectively. The contraction of the tissues with GR113808 indicates the presence of an endogenous 5-HT tone at the 5-HT4 receptor in the rat ileum. It is hypothesized that in the presence of fluoxetine, the concentration of endogenous 5-HT at the receptor was increased sufficiently to reduce or abolish the relaxation to 5-HT added exogenously. The inability of fluoxetine to prevent the relaxation to 5-HT in the presence of GR113808 or after the p-CPA treatment supports this hypothesis. The effect of the selective serotonin reuptake inhibitor fluoxetine was examined on the 5-HT4 receptor-mediated relaxation in the rat isolated ileum. Fluoxetine unsurmountably antagonized the relaxation to exogenous 5-HT with abolition of the response at 10 ¿M. Fluoxetine (10 ¿M) also caused a gradual loss of the resting tension. These effects of fluoxetine were prevented by a prior addition of the 5-HT4 receptor selective antagonist GR113808 (100 nM), which itself caused a contraction of the tissues when administered alone. Fluoxetine (10 ¿M) also failed to prevent the relaxation due to exogenous 5-HT and the 5-HT4 receptor agonist 5-methoxytryptamine in tissues taken from the rats treated with para-chlorophenylalanine (300 mg kg¿1) for 3 and 6 days, which reduced the 5-HT level in the mucosa by 88 and 97.5% respectively. The contraction of the tissues with GR113808 indicates the presence of an endogenous 5-HT tone at the 5-HT4 receptor in the rat ileum. It is hypothesized that in the presence of fluoxetine, the concentration of endogenous 5-HT at the receptor was increased sufficiently to reduce or abolish the relaxation to 5-HT added exogenously. The inability of fluoxetine to prevent the relaxation to 5-HT in the presence of GR113808 or after the p-CPA treatment supports this hypothesis.

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Seventeen years have passed since Smith and Glass’s paper "Meta-analysis of Psychotherapy Outcome Studies" (1977) influenced how researchers integrated cumulative knowledge. The problem is that no meta-analyses have been found which compare psychotherapeutic methods to the use of Prozac in the treatment of unipolar major depression. Prozac was chosen, specifically, due to its reputation as a new, very effective anti-depressant. This study used a meta-analysis to compare three psychotherapies with medication: 1) cognitive therapy, 2) behavioral therapy, 3) cognitive-behavioral therapy, and 4) the prescription of Prozac. New methods of meta-analysis advocated by Rosenthal (1984) and Wolf (1986) were integrated with Smith and Glass’s (1977) Original approach to analyze the outcome research. The results indicate that Prozac is more effective than psychotherapy in the treatment of unipolar major depression. Psychotherapy results were statistically significant (p=.05) for the subjects as own control condition, but not for the control condition. In the subjects as own control group, cognitive and cognitive-behavior therapy were statistically significant (p < .05). The effectiveness of Prozac may have been caused in part by a selection bias of subjects or other factors outlined in the discussion. / Ph. D.

Serotonin (5-Hydroxytryptamin, 5-HT) ist ein wichtiger Neurotransmitter im Zentralnervensystem (ZNS). Seine Biosynthese erfolgt unter Beteiligung des Enzyms Tryptophanhydroxylase 2 (TPH2). Polymorphismen im TPH2 Gen beim Menschen sind Risikofaktoren bei der Entstehung von Depressionen und Angstverhalten. Die gängigsten Antidepressiva und Anxiolytika wirken auf das Serotonin System. Unklar ist, ob das komplette oder teilweise Fehlen von Serotonin im Gehirn zu Entwicklungsstörungen und neurochemischen oder psychologischen Veränderungen führt. In dieser Arbeit werden Mauslinien mit unterschiedlichen TPH2 Aktivitäten im ZNS verglichen und der Einfluss verringerter 5-HT Konzentrationen auf Entwicklung und Verhalten der Tiere untersucht. Zentrales Serotonin ist nur für die postnatale Entwicklung notwendig. Das verzögerte Wachstum von Tph2-/- Tieren ist nicht auf eine Störung der Hypothalamus-Hypophysen-Nebennieren-Achse oder auf metabolische Veränderungen zurückzuführen, sondern kann aus verringerter Vokalisation im Ultraschallbereich resultieren. Tph2-/- Mäuse wurden mit generierten Mausmodellen mit niedriger TPH2 Aktivität vergleichen. Die Ergebnisse zeigen, dass 20% weniger zentrales Serotonin nicht ausreichen, um Depression oder Angst-Verhalten herbeizuführen. Möglicherweise greifen kompensatorische Mechanismen wie ein verringerter Serotoninmetabolismus oder eine gesteigerte 5-HT1A-Rezeptorsensitivität. Der komplette Verlust von Serotonin im Gehirn führt zu einem starken depressiven und weniger ängstlich Verhalten, mit erhöhter Aggression - ohne Veränderung in Aktivität, Geruchsinn, Gedächnis und adulter Neurogenese. Fluoxetine Behandlung von Tph2-defizienten Mäusen zeigte einen Serotonin-unabhängigen Effekt dieses Antodepressivums auf Angst-Verhalten und Depression. Fluoxeine reduzieren den Serotoningehalt im Gehirn von Mäusen mit geringen TPH2-Aktivität, was zeigt, dass TPH-Aktivität die Effizienz von Serotonin beeinflussenAntidepressiva bestimmen, / Serotonin (5-HT) is a major neurotransmitter in the brain biosynthesis of which is initiated by tryptophan hydroxylase 2 (TPH2). Polymorphisms in the TPH2 gene are suggested as risk factors associated with depression and anxiety in humans. Furthermore, the most frequently prescribed antidepressants and anxiolytics target the serotonergic system. However, the question whether a complete ablation or partial reduction in brain serotonin leads to the developmental, neurochemical, or psychological abnormalities remains unresolved. In this study, I took advantage of mouse lines with various degree of decrease in TPH2 activity in order to dissect the impact of 5-HT loss on development, brain neurochemistry and behavior. Using Tph2-deficient mice I showed that central serotonin is essential for normal postnatal, but not prenatal development. Growth retardation of Tph2-/- mice was not a result of a disruption of the hypothalamo-pituitary-adrenal axis, metabolic abnormalities, or impaired thermoregulation, but could result from reduced ultrasonic vocalization. I tested Tph2-/- mice along with other newly generated mouse models with partial TPH2 reduction, and showed that 20% reduction in central serotonin is not enough to cause changes in anxiety- and depression-like behaviors most likely due to compensatory mechanisms including reduced serotonin metabolism and increased 5-HT1A receptor sensitivity. However, complete loss of central serotonin leads to a depression-like phenotype, reduced anxiety-like behavior, and exaggerated aggression, but no differences in activity, olfaction, memory, and adult neurogenesis. Fluoxetine treatment of Tph2-/- mice revealed serotonin-independent action of this antidepressant on anxiety- and depression-like behavior. Furthermore, fluoxetine drastically reduced the brain 5-HT content in mice with low TPH2 activity indicating that TPH2 activity may determine the efficiency of antidepressants targeting the serotonergic system.

Les antidépresseurs de type Inhibiteur Sélectif de la Recapture de la Sérotonine (SSRI pour Selective Serotonin Reuptake Inhibitor), dont fait partie la fluoxétine (Prozac), ont été décrits comme capables de déclencher l'apoptose de cellules tumorales in vitro et in vivo, suggérant une potentielle utilisation de ces molécules pour le traitement des cancers. Cependant, leur mécanisme apoptotique n’a pas été élucidé à ce jour. Nous avons donc entrepris de déterminer les étapes de l'apoptose induite par la fluoxétine et les SSRI, en choisissant comme modèle d'étude des lignées cellulaires de lymphomes non-Hodgkiniens agressifs. Nous avons identifié plusieurs étapes de la signalisation apoptotique de la fluoxétine et des SSRI. Ainsi, via une inhibition de la chaîne respiratoire, la fluoxétine induit la production d'espèces réactives de l'oxygène conduisant à la surexpression des récepteurs de mort DR4 et DR5 ; la fluoxétine induit également l'activation de la caspase-8. DR4 et DR5 sont très probablement la cause de l'apoptose induite par la fluoxétine, de façon indépendante de leur ligand, TRAIL (TNF-Related Apoptosis-Inducing Ligand). Partant du constat que l'utilisation de TRAIL comme antitumoral pour le traitement des lymphomes présente des résultats prometteurs mais encore insuffisants, nous avons envisagé que la fluoxétine puisse augmenter l’apoptose induite par TRAIL dans ce type de tumeurs. Nous montrons en effet qu'une association de la fluoxétine avec TRAIL conduit à une augmentation de l'action apoptotique de TRAIL dans les lignées de lymphomes non-Hodgkiniens agressifs. De plus, nos résultats montrent que la fluoxétine induit la mort cellulaire d'une façon indépendante de la caspase-8. Cet effet semble trouver son origine dans une surcharge en calcium de la mitochondrie, alimentée par une stimulation maintenue de l'entrée de calcium par les canaux CRAC (Calcium Release Activated Calcium). En conclusion, les éléments de la signalisation calcique et apoptotique de la fluoxétine et des SSRI que nous avons identifiés encouragent leur utilisation en thérapie, et notamment dans le cadre d'associations avec TRAIL et d'autres molécules pour permettre une augmentation de l'apoptose des cellules tumorales, voire des cellules résistantes à l'apoptose induite par TRAIL. / Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants, such as fluoxetine (Prozac), have been shown to induce apoptosis in cancer cells in vitro and in vivo, suggesting a potential use for cancer treatment. However, their apoptotic mechanism has remained undetermined until now. Therefore, we have undertaken the determination of fluoxetine- and SSRIs-induced apoptotic signalling, our study model being aggressive Non-Hodgkin's Lymphoma (NHL) cell lines. We have identified several steps of the apoptotic signalling of fluoxetine and the SSRIs. Thus, via an inhibition of the respiratory chain, fluoxetine induces a reactive oxygen species production leading to the overexpression of the death receptors DR4 and DR5; fluoxetine also induces caspase-8 activation. DR4 and DR5 are probably the cause of fluoxetine-induced apoptosis, independently of their ligand TRAIL (TNF-Related Apoptosis-Inducing Ligand). Knowing that TRAIL as an antitumoral agent for lymphoma treatment has shown promising but insufficient results, we have hypothesized that fluoxetine could increase TRAIL-induced apoptosis in these tumors. Indeed, we show that fluoxetine in association with TRAIL leads to an increase in TRAIL-induced apoptosis in aggressive NHL cell lines. Furthermore, our results show that fluoxetine induces cell death in a caspase-8–independent manner. This effect seems to originate from a mitochondrial calcium overload fueled by a sustained calcium entry from the CRAC (Calcium Release Activated Calcium) channels. In conclusion, the calcium pathway and the apoptotic steps of the fluoxetine's and the SSRIs' signalling that we have delineated encourage their use in therapy, especially in association with TRAIL and other molecules in order to enable an increase in cancer cells' apoptosis, or even in cancer cells which are resistant to TRAIL-induced apoptosis.

A obesidade é uma doença crônica que vêm alcançando proporções epidêmicas em todo o mundo. É um fator de risco para inúmeras desordens médicas, morbidade e mortalidade, além de estar também associada a um aumento dos custos socioeconômicos e com saúde. O tratamento a longo prazo, incluindo a farmacoterapia, mostra-se necessário para muitos pacientes obesos. Neste contexto, este trabalho teve a finalidade de avaliar a tolerabilidade e eficácia clínica da Fluoxetina, adjunta a uma dieta de 1.500 Kcal/dia, na redução de parâmetros antropométricos e metabólicos em mulheres obesas. Cloridrato de Fluoxetina (60 mg/dia), foi comparado ao placebo em 19 mulheres obesas, durante 90 dias de tratamento. O grupo Fluoxetina (n=9) apresentou uma redução estatisticamente significativa do peso (-9,24 vs -1,05 kg), IMC (-3,64 vs -0,45 Kg/m²) e circunferência abdominal (-12,3 vs -2,9 cm), em relação ao placebo (n=10). Observou-se ainda uma elevação estatisticamente significativa dos níveis séricos de HDL-colesterol (p< 0,01) no grupo tratado com o fármaco, e uma redução significativa dos níveis plasmáticos de triglicérides (-39,5 vs +18,7 mg/dL) quando comparado ao grupo placebo. As reações adversas mais comumente reportadas pelos pacientes foram insônia, náuseas e sonolência. Concluímos que a Fluoxetina demonstrou ser um fármaco bem tolerado e eficaz na redução de parâmetros antropométricos e metabólicos, prevenindo o desenvolvimento de fatores de risco cardiovasculares e diminuindo morbidade em mulheres obesas. / Obesity is a chronic condition that has been reaching epidemic proportions worldwide. It is a risk factor for numerous medical disorders and excessive mortality. Long-term treatment, including pharmacotherapy, may be necessary for many obese patients. This study aimed to assess the tolerability and clinical effectiveness of Fluoxetine, as an adjunct therapy to a 1.500 Kcal/day diet, in reducing anthropometric and metabolic parameters in obese women. Fluoxetine (60 mg/day), was compared to placebo in 19 obese females in a 90-day trial. Fluoxetine therapy (n=9) resulted in a statistically significant greater mean reduction in weight (-9,24 vs -1,05 kg), BMI (-3,64 vs -0,45 Kg/m²) and waist circumference (-12,3 vs -2,9 cm), than placebo group (n=10). There was also an elevation of HDL-cholesterol (p< 0,01) in Fluoxetine group and mean triglycerides levels was reduced (-39,5 vs +18,7 mg/dL) when compared to placebo. Side effects most commonly reported by the patients were insomnia, nausea and somnolence. We concluded that Fluoxetine may provide an effective and well tolerated possibility in reducing anthropometric and metabolic parameters, preventing the development of cardiovascular risk factors and reducing morbidity in obese women.

A ampla utilização de medicamentos, a falta de gerenciamento na produção e no descarte desses produtos, bem como a dificuldade na remoção de resíduos de fármacos das águas residuais durante as fases do tratamento de efluentes tem causado a liberação destes micropoluentes nos recursos hídricos. O cloridrato de fluoxetina, conhecido comercialmente como Prozac®, tem sido muito utilizado em diversos países. Estudos demonstram sua presença no meio ambiente e o potencial de danos que este fármaco pode causar à biota. Desta forma, este trabalho estudou uma tecnologia de tratamento (POA - Processo Oxidativo Avançado) utilizando-se radiação ionizante, proveniente de um acelerador de elétrons, para a degradação do fármaco cloridrato de fluoxetina em solução aquosa e na mistura com esgoto doméstico. Após a irradiação foram feitas análises químicas na solução aquosa do fármaco com Espectrofotometria UV/VIS, Cromatografia Líquida Ultra Rápida (detectores UV/VIS e fluorescência) e quantificação do Carbono Orgânico Total (COT). Também foram empregados ensaios de toxicidade aguda (Daphnia similis e Vibrio fischeri) e crônica (Ceriodaphnia dubia). A eficiência na degradação do fármaco foi superior a 98,00% na menor dose de radiação (0,5 kGy), porém houve baixa taxa de mineralização para as doses aplicadas neste estudo. Para a Daphnia similis na dose de 0,5 kGy houve eficiência de 83,75% na redução da toxicidade do cloridrato de fluoxetina e 87,24% para 5,0 kGy, houve eficiência de 100,00% na redução da toxicidade para o esgoto doméstico e para a mistura (CF + esgoto) 79,32% na dose de 5,0 kGy. A eficiência para a Vibrio fischeri foi de 17,26% (melhor eficiência na dose de 5,0 kGy) e após a correção do pH das amostras a melhor eficiência foi para 20,0 kGy (26,78%), para o esgoto e para a mistura as eficiências ficaram em torno dos 20,00% para todas as doses de radiação aplicadas. Em relação a toxicidade crônica para Ceriodaphnia dubia a eficiência foi de 97,50% para 5,0 kGy. Verificou-se que a Ceriodaphnia dubia possui maior sensibilidade ao fármaco, seguido da bactéria Vibrio fischeri e por fim a Daphnia similis. / Extensive use of drugs, lack of management in the production and disposal of these products as well as the difficulty in removing residues of pharmaceuticals during wastewater treatment phases imply the release of these micropollutants in water resources. Fluoxetine hydrochloride, known commercially as Prozac®, have been often used in many countries. Studies demonstrate their presence in the environment and potential damage that this drug may cause the biota. Therefore, this paper studied a treatment technology (AOP - Advanced Oxidative Process) using ionizing radiation from an electron accelerator, for the degradation of the drug fluoxetine hydrochloride in aqueous solution and mixed with domestic sewage. After irradiation at aqueous solution chemical analyzes at the drug were done using spectrophotometry UV/VIS, Ultra Fast Liquid Chromatography (detectors UV/ VIS and fluorescence) and quantification of Total Organic Carbon (TOC). Acute toxicity tests (Daphnia similis and Vibrio fischeri) and chronic (Ceriodaphnia dubia) were employed. The efficiency for the degradation of the drug was greater than 98.00% at the lowest absorbed dose of radiation (0.5 kGy), however there was low rate of mineralization to the doses applied in this study. The efficiency reduction of toxicity was 83.75% using Daphnia similis at 0.5 kGy of absorbed dose and 87.24% at 5.0 kGy to fluoxetine hydrochloride, efficiency was 100.00% in reducing toxicity to domestic sewage and the mixture (CF + sewage) was 79.32% at a dose of 5.0 kGy. The efficiency to Vibrio fischeri was 17.26% (better efficiency at the dose of 5.0 kGy) and after correction of pH to a better performance was 20.0 kGy (26.78%), for sewage and mixture efficiencies were about 20,00% for all doses of radiation applied. In relation to chronic toxicity effects to Ceriodaphnia dubia efficiency was 97.50% at 5.0 kGy. It was verified that Ceriodaphnia dubia is more sensitive to the drug, followed by the bacterium Vibrio fischeri and finally Daphnia similis.