RESUMO
Background: In the absence of antiviral alternatives, interventions under research for COVID-19 might be offered following guidelines from WHO for monitored emergency use of unregistered and experimental interventions (MEURI). Ivermectin is among several drugs explored for its role against SARS-CoV-2, with a well-known safety profile but conflicting data regarding clinical utility for COVID-19. The aim of this report is to inform on the results of a MEURI Program of high-dose ivermectin in COVID-19 carried out by the Ministry of Health of the Province of La Pampa, Argentina. Methods: COVID-19 subjects, within 5 days of symptoms onset were invited to participate in the program, which consisted in the administration of ivermectin 0.6 mg/kg/day for 5 days plus standard of care. Active pharmacosurveillance was performed for 21 days, and hepatic laboratory assessments were performed in a subset of patients. Frequency of Intensive Care Unit (ICU) admission and COVID-19-related mortality of subjects in the ivermectin intention to treat group were compared with that observed in inhabitants of the same province during the same period not participating in the program. Results: From 21,232 subjects with COVID-19, 3,266 were offered and agreed to participate in the ivermectin program and 17,966 did not and were considered as controls. A total of 567 participants reported 819 adverse events (AEs); 3.13% discontinued ivermectin due to adverse events. ICU admission was significantly lower in the ivermectin group compared to controls among participants ≥40 year-old (1.2 vs. 2.0%, odds ratio 0.608; p = 0.024). Similarly, mortality was lower in the ivermectin group in the full group analysis (1.5 vs. 2.1%, odds ratio 0.720; p = 0.029), as well as in subjects ≥ 40 year- old (2.7 vs. 4.1%, odds ratio 0.655; p = 0.005). Conclusions: This report highlights the safety and possible efficacy of high dose ivermectin as a potentially useful intervention deserving public health-based consideration for COVID-19 patients.
Assuntos
Tratamento Farmacológico da COVID-19 , Ivermectina , Adulto , Humanos , Ivermectina/uso terapêutico , SARS-CoV-2RESUMO
INTRODUCTION: Different studies have assessed the influence of chewing gum to aid control of appetite and reduce food intake. PURPOSE: The aims of the present study were to evaluate the effects of chewing gum on satiety, food hedonics and snack intake and to explore the potential effects of the combination of Garcinia c ambogia, green coffee extract and L-carnitine on satiety, when administered in a gum format. METHODS: This was a prospective study in which 57 subjects randomly received three kinds of treatments, in a crossover design: (1) active gum; (2) placebo gum; and (3) no gum. Food preferences and appetite sensations were evaluated by means of the Leeds Food Preference Questionnaire and visual analog scales. RESULTS: There was a significant reduction in low-fat sweet snack intake with placebo gum and the active gum compared to no gum and a reduction in high-fat sweet snack intake with the active gum compared to placebo gum and no gum. Total caloric intake was only reduced in the active gum condition. Both the active and placebo gum conditions significantly reduced hunger and prospective food consumption and increased fullness compared to no gum and were associated with a reduced wanting for sweet food in the LFPQ, consistent in a reduction in the relative preference for sweet snacks versus savoury snacks. CONCLUSION: This study supports the notion that chewing gum containing nutraceutical products might aid in the control over snack intake and reduce hunger sensations.
Assuntos
Regulação do Apetite , Carnitina/uso terapêutico , Goma de Mascar , Coffea/química , Garcinia/química , Sobrepeso/dietoterapia , Extratos Vegetais/uso terapêutico , Adulto , Depressores do Apetite/administração & dosagem , Depressores do Apetite/uso terapêutico , Argentina , Índice de Massa Corporal , Carnitina/administração & dosagem , Estudos Cross-Over , Dieta Redutora , Método Duplo-Cego , Feminino , Preferências Alimentares , Humanos , Masculino , Sobrepeso/prevenção & controle , Cooperação do Paciente , Extratos Vegetais/administração & dosagem , Resposta de Saciedade , Sementes/química , LanchesRESUMO
Research in psychopharmacology began around 1950 with the description of antipsychotic effect of chlorpromazine followed shortly later with the mechanism of action of antidepressants. In these initial phases, pharmacy industry was open to knowledge and made efforts tending to the development to new drugs that showed efficacy and good safety profiles. In parallel development of theories attempting to find the etiology of psychiatric disorders acquired impulse. This review summarizes the new drugs for the treatment of psychiatric disorders currently under development and also presents a short list of the main biomarkers proposed for the diagnosis or the comprehension of the etiopathogeny in Psychiatry. Several questions arose when brain structures, biochemical pathways, proteins and genes began to be identified in the search for a better comprehension of etiopathogeny of mental disorders. Pharmaceutical industry virtually moved away from this field of research. Epistemological and methodological obstacles in psychopharmacological investigation together with the lack of priority given by industry to this field allow us to predict few advances for the treatment in Psychiatry in the short term.
Assuntos
Pesquisa Biomédica , Psicofarmacologia , Previsões , Humanos , Psiquiatria , Psicofarmacologia/tendênciasRESUMO
A nutraceutical product composed of a combination of Garcinia cambogia, l-carnitine and a seaweed extract of Ascophyllum nodosum has been recently developed. The aim of the present study was to characterize its effects on subjective satiety sensations and food preferences in healthy volunteers. In a crossover design, 28 subjects (21 females and 7 males, aged 31 ± 5, BMI 22.6 ± 1.7) were randomly assigned to receive the active treatment (LIS) or placebo (PL) over one week. At the end of each treatment period, subjects were instructed to consume ad libitum a test meal. Food preferences and appetite sensations were evaluated by means of the Leeds Food Preferences Questionnaire and visual analog scales, before and after meal, over three hours. There were no differences in energy intake between study groups. LIS was associated with a reduction in subjective hunger sensations (p = 0.018) and to an increase in satiety (p = 0.02) and fullness (p = 0.01) ratings. The preference for high fat foods was reduced after consuming the test meal in both study groups. There was a significant effect of LIS treatment on food explicit liking and implicit wanting, as evidenced by an increase in preference for sweet foods (relative to savory foods; p = 0.03 and p = 0.004, respectively), but no differences were observed regarding the preference for low or high fat foods (NS). These results provide proof of principle for the satiating properties of a nutraceutical containing Garcinia cambogia, Ascophyllum nodosum extract and l-carnitine and suggest that it might be useful as an appetite modulator.
Assuntos
Ascophyllum/química , Suplementos Nutricionais/análise , Garcinia cambogia/química , Extratos Vegetais/química , Saciação/efeitos dos fármacos , Adulto , Apetite , Ingestão de Energia/efeitos dos fármacos , Feminino , Preferências Alimentares/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Masculino , Extratos Vegetais/farmacologia , Adulto JovemRESUMO
Dysfunction of hippocampal plasticity has been proposed to play a critical role in the pathophysiology of depression. However, antidepressant drug effects on synaptic plasticity and cytoskeletal remodeling remain controversial. The aim of the present study was to evaluate in animals exposed to the learned helplessness (LH) paradigm, an accepted experimental model of depression, the effect of chronic treatment with fluoxetine (FLX) on synaptic and cytoskeletal proteins known to undergo plastic changes. Synaptophysin (SYN), postsynaptic density 95 (PSD-95), axon growth-associated protein 43 (GAP-43), and cytoskeletal proteins (intermediate neurofilaments and MAP-2) were studied in the hippocampus by immunohistochemistry. Whereas LH animals treated 21 days with saline (LH-S group) displayed diminished SYN and PSD-95 immunostainings in the CA3 but not in the DG, chronic treatment with FLX not only reversed the despaired behavior induced by exposure to LH paradigm, but also fully recovered SYN and PSD-95 labeling to control values. Similar results were obtained for the axonal remodeling marker GAP-43. FLX treatment did not modify either the decreased light neurofilament subunit (NFL) observed in the hippocampus of LH animals or any other cytoskeletal protein studied. When FLX treatment was withdrawn for 90 days in those LH-FLX animals in which reversion of despair had been observed at day 25, recurrence of despaired behavior was found accompanied by decreased SYN, PSD-95, and NFL labelings. Results indicate that the synapse remodeling induced by FLX in the CA3 region could underlie its behavioral efficacy despite the absence of cytoskeletal remodeling and that the stability of synaptic changes would depend on the continuous administration of the drug.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/psicologia , Fluoxetina/uso terapêutico , Desamparo Aprendido , Sinapses/metabolismo , Animais , Antidepressivos de Segunda Geração/administração & dosagem , Axônios/fisiologia , Biomarcadores , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/patologia , Interpretação Estatística de Dados , Transtorno Depressivo/metabolismo , Fluoxetina/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Wistar , Recidiva , Sinapses/efeitos dos fármacos , Fixação de TecidosRESUMO
BACKGROUND: Atrophy of pyramidal hippocampal neurons and of the entire hippocampus has been reported in experimental models of depression and in depressive patients respectively. We investigated the efficacy of valproic acid (VPA) for reversing a depressive-like behaviour and a cytoskeletal alteration in the hippocampus, the loss of the light neurofilament subunit (NF-L). METHODS: Depressive-like behaviour was induced by inescapable stress. Animals were divided into four groups: two to assess the response to 21 days of treatment with 200 mg/kg (I.P.) of valproic acid, and two in which the treatment was interrupted and the effects of VPA were evaluated 90 days later. Depressive-like behaviour was evaluated by the quantification of escape movements in a swimming test. NF-L was quantified by immunohistochemistry in dentate gyrus and CA3 of hippocampus. RESULTS: VPA corrected the depressive-like behaviour and reversed the diminution of NF-L in the hippocampus. Ninety days after the end of the treatment, and in contrast to the results previously obtained with fluoxetine, no recurrence of the depressive-like behaviour was observed. CONCLUSIONS: Despite interruption of the treatment, a long-lasting effect of VPA was observed. A possible relationship between the effect on NF-L and the prevention of depressive-like behaviour recurrence could be suggested.
Assuntos
Antidepressivos , Citoesqueleto/efeitos dos fármacos , Depressão/tratamento farmacológico , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ácido Valproico/farmacologia , Animais , Atrofia , Comportamento Animal/efeitos dos fármacos , Depressão/psicologia , Imuno-Histoquímica , Masculino , Proteínas de Neurofilamentos/metabolismo , Ratos , Ratos Wistar , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Natação/psicologia , Fixação de TecidosRESUMO
It has been demonstrated that the neuronal plasticity and resilience could participate in the pathophysiology of neurodegenerative diseases such as Alzheimer and others like depression and schizophrenia. Recently, it has been proposed a new intracellular pathway, known as Wnt pathway, which could be related to the induction of the plastic changes mentioned above. The glycogen synthase kinase-3beta (GSK-3beta), one of the main enzymes of the Wnt signaling, has been associated to Alzheimer;s and schizophrenia diseases etiology. Furthermore, the mood stabilizing agents;s action mechanism, like lithium and valproic acid, implies the inhibition of this protein. The issue of this work is to describe the proteins that are recruited when this pathway is activated and the GSK-3beta role in the pathologies mentioned.
Assuntos
Doença de Alzheimer/fisiopatologia , Depressão/fisiopatologia , Esquizofrenia/fisiopatologia , Transdução de Sinais/fisiologia , Proteínas Wnt/fisiologia , Doença de Alzheimer/enzimologia , Depressão/enzimologia , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Plasticidade Neuronal/fisiologia , Esquizofrenia/enzimologia , Fatores de Transcrição , beta Catenina/fisiologiaRESUMO
The expiration date of medicines is an application and direct interpretation of the knowledge obtained from stability studies, which are conducted under rigorous conditions, employing appropriate statistical and conceptual procedures. Instability of an active compound may result on one hand in efficacy decrease and on other in the possible presence of toxic degradation products. In this review, we analyze the reasons underlying the definition of the expiration date of medicines and their relationship with the stability, we mention the essays that must be performed to support this definition and finally give examples of degradation products and of their possible adverse effects.
Assuntos
Estabilidade de Medicamentos , Psicotrópicos/química , Disponibilidade Biológica , Humanos , Psicotrópicos/análise , Fatores de TempoRESUMO
Hypercortisolism is a common trait of Cushing's disease and depression. These two disorders also share hippocampal volume decrease and cognitive deficits. However, experimentally induced hypercortisolism induces neuronal atrophy, which has been proposed to be the phenomenon underlying the hippocampal shrinkage. We hypothesized that the above-mentioned atrophy is due to a deleterious effect of high concentrations of glucocorticoids on cytoskeletal proteins. One or two pellets (100 mg each) of corticosterone were subcutaneously implanted in adult rats. Twenty-one days later, light, medium and heavy subunits of intermediate neurofilaments (NFL, NFM and NFH) and the microtubule-associated protein 2 (MAP2) were quantified by immunohistochemistry in Ammon's horn and dentate gyrus. We also evaluated the in vitro glutamate release in hippocampal slices. Both doses of corticosterone induced a decrement of NFL, NFM and NFH in both hippocampal areas but only 200 mg decreased MAP2. This dose also diminished the potassium-stimulated glutamate release. All of these changes seemed not to be due to neuron loss, as no decrement in neuron-specific nuclear protein-positive cells was found. With the exception of NFL, the above-mentioned diminution was not observed in the globus pallidus, one of the brain regions with the lowest glucocorticoid receptor density. These results provide a subcellular insight into the trophic changes found in experimental models of hypercortisolism. The coincidence between decrements in MAP2 and glutamate release suggests possible links between high glucocorticoid levels, dendritic atrophy and the cognitive impairment reported in patients suffering from Cushing's disease and depression.
Assuntos
Anti-Inflamatórios/administração & dosagem , Corticosterona/administração & dosagem , Proteínas do Citoesqueleto/metabolismo , Regulação da Expressão Gênica/genética , Hipocampo/efeitos dos fármacos , Animais , Anti-Inflamatórios/sangue , Contagem de Células/métodos , Corticosterona/sangue , Relação Dose-Resposta a Droga , Ácido Glutâmico/metabolismo , Hipocampo/anatomia & histologia , Imuno-Histoquímica/métodos , Técnicas In Vitro , Masculino , Fosfopiruvato Hidratase/metabolismo , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
The proconvulsive effect of the new generation of antidepressants remains controversial. The authors investigated in naïve rats the effect of chronic treatment with fluoxetine (FLX) on the convulsive threshold and on two parameters of the hippocampal glutamatergic neurotransmission: the in vitro glutamate release and the binding of [3H] MK801 to NMDA receptors. While the acute treatment with FLX provoked no change either in seizure susceptibility or in the glutamate release, the chronic treatment decreased the convulsive threshold in coincidence with an increment in the in vitro glutamate release. No significant effects on the binding of [3H] MK801 to NMDA receptors were found to be attributable to the FLX treatment. We also assessed the effect of the chronic treatment with FLX on the seizure threshold in rats exposed to an experimental model of depression, the learned helplessness paradigm (LH). While a decrease in the K+-stimulated glutamate release was observed in non treated LH animals, when they were chronically injected with FLX, no changes in the epileptic susceptibility and no increments in the glutamate release were found. Our results indicate that chronic treatment with FLX decreases the epileptic threshold in naïve but not in LH rats and that this effect correlates with the levels of the hippocampal glutamate release.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Fluoxetina/farmacologia , Ácido Glutâmico/metabolismo , Desamparo Aprendido , Hipocampo/metabolismo , Convulsões/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Convulsivantes , Maleato de Dizocilpina/metabolismo , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Pentilenotetrazol , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/efeitos dos fármacosRESUMO
Excitotoxic cell death is a direct consequence of the glutamate interaction with its receptors, through which the neuronal excitatory impulses are transmitted. Despite some well characterized aspects of this process--such as a subsequent increase in intracellular calcium concentrations and the activation of some enzymatic mechanisms--the specific intracellular pathways which mediate this cell death mechanism are still unknown. In this article, we summarize the different theories which try to explain how the neurotoxic effect development goes on beyond the glutamate receptor interaction. Apart from that, since there is a lot of evidence for the role of excitotoxicity in the aetiology and the progression of many human neurodegenerative diseases, we mention some of the experimental evidence relating certain pathologies to this form of cell death. Finally, and due the increasing necessity of more effective treatments for such diseases, we describe some anti-excitotoxic agents and its mechanisms of action.
Assuntos
Cálcio/metabolismo , Radicais Livres/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurotoxinas/metabolismo , Receptores de Glutamato/fisiologia , Membrana Celular/metabolismo , Humanos , Potenciais da MembranaRESUMO
Excitotoxic cell death is a direct consequence of the glutamate interaction with its receptors, through which the neuronal excitatory impulses are transmitted. Despite some well characterized aspects of this process--such as a subsequent increase in intracellular calcium concentrations and the activation of some enzymatic mechanisms--the specific intracellular pathways which mediate this cell death mechanism are still unknown. In this article, we summarize the different theories which try to explain how the neurotoxic effect development goes on beyond the glutamate receptor interaction. Apart from that, since there is a lot of evidence for the role of excitotoxicity in the aetiology and the progression of many human neurodegenerative diseases, we mention some of the experimental evidence relating certain pathologies to this form of cell death. Finally, and due the increasing necessity of more effective treatments for such diseases, we describe some anti-excitotoxic agents and its mechanisms of action.
RESUMO
Excitotoxic cell death is a direct consequence of the glutamate interaction with its receptors, through which the neuronal excitatory impulses are transmitted. Despite some well characterized aspects of this process--such as a subsequent increase in intracellular calcium concentrations and the activation of some enzymatic mechanisms--the specific intracellular pathways which mediate this cell death mechanism are still unknown. In this article, we summarize the different theories which try to explain how the neurotoxic effect development goes on beyond the glutamate receptor interaction. Apart from that, since there is a lot of evidence for the role of excitotoxicity in the aetiology and the progression of many human neurodegenerative diseases, we mention some of the experimental evidence relating certain pathologies to this form of cell death. Finally, and due the increasing necessity of more effective treatments for such diseases, we describe some anti-excitotoxic agents and its mechanisms of action.