Phenotypical Screening of an MMV Open Box Library and Identification of Compounds with Antiviral Activity against St. Louis Encephalitis Virus.

St. Louis encephalitis virus (SLEV) is a neglected mosquito-borne Flavivirus that may cause severe neurological disease in humans and other animals. There are no specific treatments against SLEV infection or disease approved for human use, and drug repurposing may represent an opportunity to accelerate the development of treatments against SLEV. Here we present a scalable, medium-throughput phenotypic cell culture-based screening assay on Vero CCL81 cells to identify bioactive compounds that could be repurposed against SLEV infection. We screened eighty compounds from the Medicines for Malaria Venture (MMV) COVID Box library to identify nine (11%) compounds that protected cell cultures from SLEV-induced cytopathic effects, with low- to mid-micromolar potencies. We validated six hit compounds using viral plaque-forming assays to find that the compounds ABT-239, Amiodarone, Fluphenazine, Posaconazole, Triparanol, and Vidofludimus presented varied levels of antiviral activity and selectivity depending on the mammalian cell type used for testing. Importantly, we identified and validated the antiviral activity of the anti-flavivirus nucleoside analog 7DMA against SLEV. Triparanol and Fluphenazine reduced infectious viral loads in both Vero CCL81 and HBEC-5i cell cultures and, similar to the other validated compounds, are likely to exert antiviral activity through a molecular target in the host.

Eficácia, segurança e efetividade comparada de palmitato de paliperidona e outros antipsicóticos injetáveis de efeito prolongado para tratamento de esquizofrenia: revisão rápida de evidências / Efficacy, safety and effectiveness in the real world for paliperidone palmitate compared to the others long acting injectable antipsychotics for schizophrenia treatment: rapid review of evidence

Tecnologia: Palmitato de Paliperidona (PP) é um antipsicótico injetáveis de efeito prolongado (AIEP). Indicação: Tratamento sintomático da esquizofrenia. Objetivo: Comparar a eficácia, segurança e efetividade terapêutica entre PP e outros AIEP para o tratamento de esquizofrenia em adultos. Pergunta: O PP é mais eficaz e seguro que os outros AIEP (Decanoato de Haloperidol, Enantato de Flufenazina, Decanoato de Zuclopentixol, Risperidona-IEP) para o tratamento sintomático de esquizofrenia em adultos? Métodos: Levantamento bibliográfico, com estratégias estruturadas de busca, na base de dados PUBMED. Foi feita avaliação da qualidade metodológica das revisões sistemáticas (RS), ensaios clínicos randomizados (ECR) e dos estudos observacionais de efetividade no mundo real (EOEMR) com as ferramentas Assessing the Methodological Quality of Systematic Reviews (AMSTAR), Delphi List e Newcastle-Ottawa Scale (NOS), respectivamente. Resultados: Foram selecionadas 3 RS, 1 ECR e 3 EOEMR. Conclusão: PP (de aplicação mensal) tem similar eficácia e segurança com a Risperidona-IEP para o tratamento de esquizofrenia, exceto que provoca menor incidência de sintomas extrapiramidais. PP e Decanoato de Haloperidol são similares na eficácia e segurança para o tratamento de esquizofrenia, inclusive no risco de sintomas extrapiramidais (discinesias tardias e parkinsonismo), exceto que PP tem menor incidência de acatisia. PP é similar aos outros AIEP nos vários desfechos de eficácia e segurança terapêutica, inclusive mortalidade

Technology: Paliperidone palmitate (PP) is a long-acting injectable (LAI) antipsychotics. Indication: Symptomatic treatment of schizophrenia. Objective: To compare the therapeutic efficacy, safety and effectiveness in the real world between PP and other LAI antipsychotics for the treatment of schizophrenia in adults. Question: Is PP more effective and safer than other LAI antipsychotics (Haloperidol Decanoate, Fluphenazine Enanthate, Zuclopentixol Decanoate, Risperidone-LAI), for the symptomatic treatment of schizophrenia? Methods: Bibliographic survey, with structured search strategies, in the PUBMED database. Na evaluation was made of the methodological quality of systematic reviews (SR), randomized clinical trials (RCT) and observational studies (OS) of effectiveness in the real world with Assessing the Methodological Quality of Systematic Reviews (AMSTAR), Delphi List and Newcastle-Ottawa Scale (NOS) tools, respectively. Results: 3 SR, 1 RCT and 3 OE were included. Conclusion: PP (monthly dose presentation) has similar efficacy and safety with Risperidone-LAI for the treatment of schizophrenia, except that it causes a lower incidence of extrapyramidal symptoms. PP and Haloperidol Decanoate are similar in efficacy and safety for the treatment of schizophrenia, including the risk of extra-pyramidal symptoms (tardive dyskinesias and parkinsonism), except that PP has a lower incidence of akathisia. PP has similar outcomes of efficacy and safety to the other LAI antipsychotics, including mortality risk

La intoxicación con cobre disminuye la sobrevida e induce alteraciones neurológicas en Drosophila melanogaster / Copper intoxication decreases lifespan and induces neurologic alterations in Drosophila melanogaster

La enfermedad de Wilson, es un trastorno hereditario autosómico recesivo causado por mutaciones del gen de la trifosfatasa de adenosina (ATP7B). Dicha mutación ocasiona intoxicación con cobre, generando manifestaciones clínicas por los efectos tóxicos del metal, principalmente a nivel del hígado y el encéfalo. Recientemente se han desarrollado modelos genéticos de la enfermedad para su estudio clínico. Sin embargo, la utilidad de los mismos es limitada por el hecho de que en tales modelos no se observan manifestaciones neurológicas. El presente estudio tuvo como objetivo desarrollar un modelo de la enfermedad de Wilson en Drosophila melanogaster. Inicialmente se evaluó el efecto de la suplementación con concentraciones de 31 µM y 47 µM de cobre en la sobrevida. Posteriormente se realizaron estudios de conducta para determinar si existían alteraciones en el desempeño motor asociadas al tratamiento con la dosis de 47 µM de cobre. Los resultados obtenidos sugieren que el tratamiento con cobre disminuye la viabilidad de la Drosophila. La disminución de la sobrevida estuvo asociada a un aumento y una disminución de los registros de actividad motora en las etapas tempranas y tardías de la intoxicación respectivamente. Por último, se evaluó el papel del sistema de neurotransmisión dopaminérgico sobre las alteraciones conductuales inducidas por el cobre. El tratamiento con el precursor de la dopamina, L-dopa, indujo un aumento de la actividad motora similar al inducido por el cobre. Por el contrario, el tratamiento con Flufenazina, un antagonista de los receptores dopaminérgicos D2, fue capaz de impedir las alteraciones conductuales en todas las edades evaluadas. Estos resultados sugieren que la Drosophila melanogaster podría ser empleada como modelo para el estudio de posibles intervenciones con potencial terapéutico en la enfermedad de Wilson.

Wilson disease is a hereditary disorder caused by mutations of the ATP7B gene, which leads to intoxication with copper as a result of an unbalance of copper homeostasis. The clinical manifestations resulting from this intoxication are related to the affectation of liver and the encephalon in most cases. Several animal models are currently available for the study of the malady. However, in such models no neurological symptoms are observed, which limits their use for the study of pathogenic effects of this disease on the central nervous system. The aim of the present study was to evaluate if copper feeding could induce a disease state in Drosophila melanogaster to model Wilson disease. The effect of the feeding of copper at the doses of 31 µM and 47 µM on the survival was initially evaluated. Next, behavioral experiments were conducted to determine whether the motor performance was altered by the 47 µM concentration. The results suggest that copper treatment decreases the viability of the flies. In addition, the decrease of viability was associated to an increase and decrease of spontaneous motor activity at early and late stages of the intoxication, respectively. Finally, the role of the dopaminergic neurotransmission system on the observed motor alterations was evaluated. The dopamine precursor L-dopa increased motor activity. In contrast, D2 receptor antagonist, Fluphenazine, was able to block both the increase and decrease of motor activity scores induced by copper. These results suggest that Drosophila melanogaster could be used as a model organism for the study of possible interventions with potential neuroprotective effects in Wilson disease.

Chronic effect of antidopaminergic drugs or estrogen on male Wistar rat lactotrophs and somatotrophs

The aim of the present study was to evaluate the effect of antidopaminergic agents on the somatotrophs in the presence of hyperprolactinemia. Adult male Wistar rats were divided into 6 groups: a control group and five groups chronically treated (60 days) with haloperidol, fluphenazine, sulpiride, metoclopramide or estrogen. Somatotrophs and lactotrophs were identified by immunohistochemistry and the data are reported as percent of total anterior pituitary cells counted. The drugs significantly increased the percentage of lactotrophs: control (mean + or - SD) 21.3 + or - 4.4, haloperidol 27.8 + or - 2.2, fluphenazine 34.5 + or - 3.6, sulpiride 32.7 + or - 3.5, metoclopramide 33.4 + or - 5.5 and estrogen 42.4 + or - 2.8. A significant reduction in somatotrophs was observed in animals treated with haloperidol (23.1 + or - 3.0), fluphenazine (22.1 + or - 1.1) and metoclopramide (24.2 + or - 3.0) compared to control (27.3 + or - 3.8), whereas no difference was observed in the groups treated with sulpiride (25.0 + or - 2.2) and estrogen (27.1 + or - 2.8). In the groups in which a reduction occurred, this may have simply been due to dilution, secondary to lactotroph hyperplasia. In view of the duplication of the percentage of prolactin-secreting cells, when estrogen was applied, the absence of a reduction in the percent of somatotrophs suggests a replication effect on this cell population. These data provide additional information about the direct or indirect effect of drugs which, in addition to interfering with the dopaminergic system, may act on other pituitary cells as well as on the lactotrophs.

Photo-oxidative damage to isolated rat liver mitochondria induced by phenothiazines

Photosensitization is a well-known side-effect of phenothiazines that could involve photochemically promoted oxidative damage to mitochondria, leading to the impairment of metabolic functions and apoptosis. In this work, for the first time, we investigated the effects of photoexcited thioridazine (TR), trifluoperazine (TFP) and fluphenazine (FP) on isolated rat liver mitochondria. Under UV irradiation, the presence of these phenothiazines led to a dose-dependent lack of the respiratory control ratio. These effects were not accompanied by significant swelling and oxidation of protein thiol groups but were accompanied by lipid peroxidation. Lycopene and sorbate, well-known quenchers of singlet oxygen and triplet species, respectively, were ineffective at protecting mitochondrial lipids against the damage promoted by the excited phenothiazines, suggesting that photochemically-produced cation radicals were the pro-oxidant species. Corroborating this proposal, butylated hydroxytoluene (BHT) completely inhibited the lipid peroxidation induced by UV irradiation in the presence of phenothiazines. These novel results make a significant contribution to the understanding of the photochemical properties of phenothiazines in biological systems

Embarazo en usuarias de decanoato de flufenazina: descripción de 22 casos / Pregnancy and flufenazine decanoate

Generalmente en las pacientes usuarias de neurolépticos de depósito se mantiene un estricto control de la fertilidad, en caso de ocurrencia de embarazo se recomienda la suspensión del fármaco de depósito puesto que nose ha establecido su inocuidad durante la gestación. Se presentan 22 pacientes usuarias de decanoato de flufenazina que presentaron 25 gestaciones. Se trata de pacientes en control en la Clínica de Psicofármacos del Servicio de Psiquiatría del Hospital de Valdivia entre 1979 y 1989. Se analizan la historia psiquiátrica, indicaciones farmacológicas, antecedentes, evolución de la gestación y parto, condición del recién nacido, reagudizaciones y evolución posterior de las pacientes. De acuerdo a las experiencias analizadas se sugieren medidas terapéuticas en caso de ocurrencia de gestación en pacientes usuarias de neuroléptico de depósito

Decanoato de flufenazina en el tratamiento de mantención de pacientes esquizofrénicos ambulatorios / Maintenance treatment of schizophrenic outpatients with fluphenazine decanoate

Se describen resultados de un estudio prospectivo acerca de los efectos del Decanoato de Flufenazina como tratamiento de mantención de 71 pacientes esquizofrénicos ambulatorios, realizado en el Servicio "A" del Hospital psiquiátrico "Dr. José Horwitz B.", entre los años 1976 y 1979. El 69,1% de los pacientes tuvo evolución satisfactoria. Los síntomas que más claramente mejoran fueron los desajustes conductuales, delirios y alucinaciones. Se modificaron menos los trastornos de la afectividad y el desgano. La evolución más favorable fue en esquizofrenias de tipo catatónico y paranoide. Las dosis terapéuticas oscilaron entre 12,5 y 52,5 mg. al mes. El efecto adverso más frecuente fue el temblor extrapiramidal. El 25,4% de pacientes abandonó el tratamiento y un 14% recayó a pesar de recibir tratamiento en forma regular

Neurolépticos: os legítimos e verdadeiros antimanicomiais / Neuroleptic: the real antimanicomial drug

O autor analisa o advento dos neurolépticos e suas conseqüências. Faz ampla revisão do tema abordando a farmacologia destas substâncias, os aspectos clínicos, principais indicações e efeitos colaterais. Conclui mostrando o verdadeiro alcance antimanicomial dos neurolépticos

Tardive dyskinesia in outpatients on depot phenothiazine

Two hundred and thirty-two psychiatric Outpatients on depor fluphenazine decanoate for more than six months were examined for Tardive Dyskinesia (TD), using the AIMS rating scale, and the prevalence rates of TD at different criteria of severity were asssessed. The prevalence rates ranged from 7% for patients with asevere TD to 45% for patients with any degree of TD. The sex distribution of patients with TD showed no bias but the female patients were significantly older than the male patients. Increases in prevalence rats of TD were associated with the combination of an anticholinergic anti-Parkinsonian drug with the depot neuroleptic, and with the concomitant use of an oral neuroleptic with the depot preparation. Implications of these finding for the long-term management of schizopherinia are discussed

Effect of estrogen and neuroleptics on prolactin secretion and immunoreactive prolactin cells

The use of estrogen and dopamine receptor antagonists is associated with elevated prolactin levels and, in rats, chronic estrogen treatment is also associated with lactotroph proliferation. In this study, haloperidol, fluphenazine, sulpiride and metoclopramide, alone or combined with estradiol, were administered to Wistar rats. Pituitary weight, serum prolactin levels and percent of immunoreactive prolactin cells in the anterior pituitary glands were determined at the end of 60 days of treatment. The pituitary weight of rats treated with estrogen alone or in combination with other drugs was significantly higher than the control group. The serum prolactin level was higher than the upper confidence limit in all but three of the 90 treated rats. While in the control group the percent of immunoreactive prolactin cells was 20 per cent, administration of the neuroleptic drugs and metoclopramide increased this percent to approximately 30 per cent, and estrogen alone or in combination with one of the neuroleptic drugs increased it to approximately 40 per cent. The results presented here demonstrate the elationship between prolactin secretion and prolactin cell number when different neuroleptics and related drugs are used.

Tensäo pré-menstrual: resultados clínicos com 5 tipos de tratamento / Premenstrual syndrome: clinical results with 5 types of treatment

A tensao pré-menstrual (TPM) é uma patologia muito comum em ginecologia, acometendo, em menor ou maior grau, uma em cada duas mulheres. Caracteriza-se por um conjunto de sintomas e sinais durante a fase lútea. Há várias etiologias propostas para explicar a síndrome, assim como várias opçoes terapêuticas. Neste trabalho foram tratadas 50 mulheres com cinco drogas diferentes, escolhidas aleatoriamente. Os sintomas mais freqüentes foram irritabilidade, mastalgia, cefaléia e depressao. O melhor efeito terapêutica foi obtido com cloridrato de piridoxina. Destaca-se que a utilizaçao do placebo reduziu a sintomatologia em 30 por cento, aproximadamente. Os autores enfatizaram que, muito possivelmente, a TPM é provocada pela associaçao de mais de um fator e evidenciaram a influência de aspectos emocionais na etiologia da sindrome.

Síndrome maligna induzida por neuroléptico / Malignant syndrome induced by neuroleptics

A síndrome maligna (SM) é uma reaçäo idiossincrásica e potencialmente fatal ao uso de neurolépticos, caracterizada por febre, rigidez muscular, alteraçöes da consciência e disfunçöes autonômicas. No presente trabalho, apresentamos uma revisäo da literatura sobre a SM nos últimos oito anos, a luz da qual discutimos um possível novo caso que ilustra as dificuldades e a importância de um diagnóstico precoce, condiçäo fundamental para um tratamento efetivo e uma evoluçäo bem-sucedida da SM. Fazemos ainda sugestöes quanto a procedimentos necessários ao pronto diagnóstico, bem como ressaltamos aspectos importantes para futuros estudos

Niveles sanguíneos de los neurolépticos / Serum levels of neuroleptics

La determinación de los niveles sanguíneos de la drogas antipsicóticas podría, eventualmente, proporcionar: una guía para determinar las dosis terapéuticas óptimas y un margen de seguridad dentro de un rango de dosis, una manera de discriminar a los pacientes refractarios, la información farmacocinética necesaria para ajustar adecuadamente las dosificaciones, la posibilidad de predecir los efectos terapéuticos y una ayuda en la selección de la droga para cada caso en particular. Evidentemente, estos puntos son de una gran trascendencia para la clínica, lo que ha dado lugar a un creciente interés en la investigación de las relaciones entre los niveles sanguíneos de los neurolépticos y diversas respuestas: la antipsicótica, la extrapiramidal y la endócrina. En el presente documento se revisan, en primer término, las técnicas de laboratorio que se han utilizado con mayor frecuencia para la cuantificación de las concentraciones de los neurolépticos en las muestras biológicas: cromatografía, radio-inmunoanálisis y ensayo de radio-receptor. En segundo lugar se analiza la información disponible acerca de los antipsicóticos de uso más frecuente en nuestro medio, abordándose aspectos farmacocinéticos, estudios referentes a las relaciones entre los niveles sanguíneos de la droga y los tres tipos de respuestas mencionadas, así como la influencia de otras drogas en las concentraciones sanguíneas de los antipsicóticos. Finalmente, se comenta la información presentada y se señala su relevancia para la práctica clínica

Participaçäo colinérgica nos efeitos das drogas antipsicóticas na febre devida a um pirogênio bacteriano / Cholinergic participation in effects of antipsichotics drugs in the fever elicited by one bacterial pyrogen

Os resultados mostraram que a associaçäo de atropina às drogas antipsicóticas produziu reduçäo da resposta febril, quando clorpromazina e flufenazina foram os antipsicóticos utilizados. A associaçäo de atropina ao haloperidol e ao pimozide potencializou a resposta febril

Herpes zoster, estudio de 96 pacientes: neuralgia postherpética y corticoides / Herpes zoster, study of 96 patients: postherpetic neuralgia and corticoids

96 pacientes con herpes zoster (HZ) registrados entre agosto de 1987 y febrero de 1989 fueron seguidos durante un año. En todos los casos fueron tratados con Aciclovir 1gr/día. 48 pacientes fueron además, tratados con prednisona oral 60 mg/día 1 semana, 40 mg/día la segunda semana y 20 mg diarios la tercera semana, a fin de evaluar la incidencia de neuralgia postherpética (NP). No se observó diferencia estadísticamente significativa entre el grupo tratado con corticoides y el grupo no tratado con corticoides (p=o.45). El promedio de edad de los pacientes con NP fue de 73 años y el de pacientes con HZ que no padecieron NP fue de 63 años (P=0.003). Los resultados sugieren la inutilidad de los corticoides para prevenir la NP y que la edad avanzada es un factor de riesgo de padecer NP. Se discute además la fisiopatología de la NP y sus distintas alternativas terapéuticas

Seguimiento de pacientes tratados con fenotiazinas de deposito, en Valparaiso, Chile. / Follow-up study of patient treated with depot phenothiazines in Valparaiso, Chile

En este trabajo se consideran los resultados del tratamiento con decanoato de flufenazina en un grupo de 112 pacientes psiquiatricos, controlados por personal profesional de enfermeria. De acuerdo con la evaluacion de dicho tratamiento, podria indicarse su efecto positivo, como tambien una marcada ventaja, al permitir que se reduzcan los dias de hospitalizacion y consultas medicas, en la mayor parte de los pacientes considerados

Possível envolvimento dopaminérgico na resposta febril induzida pelo lipopolissacarídeo de E. coli, no coelho / Dopaminergic involvement in the fever response induced in rabbits by lipopolysaccharide from E. coli

Drogas neurolépticas como a clorpromazina (CLOR), flufenazina (Flu), haloperidol (HAL) e pinozide (Pim), conhecidas por atuarem como antipsicóticas e bloqueadoras de receptores dopaminérgicos centrais, inibiram parcialmente a resposta febril induzida pelo lipopolissacarídeo de E. coli (LPS), um pirogênio bacteriano, em coelhos. Os presentes resultados sugerem que os receptores dopaminérgicos centrais podem estar envolvidos nessa resposta febril, muito embora essa mobilizaçäo näo represente o principal mecanismo

Nortriptyline-fluphenazine vs. carbamazepine in the symptomatic treatment of diabetic neuropathy

We compared the efficacy and tolerance of the combination of nortriptyline-fluphenazine (NF) vs. carbamazepine (CNZ) in the symptomatic therapy of patients with severe, distal, symmetrical, predominantly sensitive diabetic polyneuropathy (DPN). We followed a double blind, crossover, randomized and double placebo design. Sixteen patients with severe DPN participated in the study. Patients received either NF (1 tablet three times a day (tid)), for 2 weeks. After this, patients received placebos of both drugs (wash-out period), until symptoms returned to baseline levels (100 percent), then they were crossed over to receive the other comparing drug schedule. A visual analoque scale was used to evaluate the percent changes in pain and paresthesia. HBA1, fasting serum glucose, and safety tests were performed at 2- and 4-week intervals, respectively. Both therapies produced significant improvement of both pain and paresthesis. No statistically significant differences were observed between both therapies for either pain or paresthesia. No significant biochemical changes were observed with any of the two therapies. Side effects were mild and more frequent in the NF period. In this study no superiority of either drug schedule was demonstrated; therefore, the decision to use any of them should be made according to the associated pathology and potential side effects of each drug