RESUMO
OBJECTIVE: To evaluate the role of dextromethorphan/quinidine (DM/Q; Nuedexta™) in the treatment of pseudobulbar affect (PBA). DATA SOURCES: A literature search of MEDLINE/PubMed (January 1966-June 2013) was conducted using search terms pseudobulbar affect, pathological laughing and/or crying, emotional lability, dextromethorphan, and quinidine. STUDY SELECTION AND DATA EXTRACTION: English language clinical trials and case reports evaluating the safety and efficacy of DM/Q in PBA were included for review. Bibliographies of all relevant articles were reviewed for additional citations. DATA SYNTHESIS: PBA, a poorly understood disorder, is characterized by involuntary crying and/or laughing. In the past, antidepressants and antiepileptics have been used off-label with mixed results. Four clinical trials have evaluated the use of DM/Q for the treatment of PBA. Although the therapeutic outcomes with DM/Q have been positive, interpretation of the published evidence is limited by small sample size and short treatment duration. CONCLUSIONS: Based on the data available, DM/Q may be a viable, short-term treatment alternative for PBA. Long-term safety and efficacy data are lacking.
Assuntos
Dextrometorfano/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Paralisia Pseudobulbar/tratamento farmacológico , Quinidina/uso terapêutico , Receptores sigma/agonistas , Ensaios Clínicos como Assunto , Choro/psicologia , Dextrometorfano/administração & dosagem , Dextrometorfano/efeitos adversos , Dextrometorfano/farmacologia , Combinação de Medicamentos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Humanos , Riso/psicologia , Paralisia Pseudobulbar/metabolismo , Paralisia Pseudobulbar/psicologia , Quinidina/administração & dosagem , Quinidina/efeitos adversos , Quinidina/farmacologia , Resultado do Tratamento , Receptor Sigma-1RESUMO
Ibogaine, an alkaloid derived from the African shrub Tabernanthe iboga, has shown promising anti-addictive properties in animals. Anecdotal evidence suggests that ibogaine is also anti-addictive in humans. Thus, it alleviates drug craving and impedes relapse of drug use. Although not licensed as therapeutic drug, and despite evidence that ibogaine may disturb the rhythm of the heart, this alkaloid is currently used as an anti-addiction drug in alternative medicine. Here, we report that therapeutic concentrations of ibogaine reduce currents through human ether-a-go-go-related gene potassium channels. Thereby, we provide a mechanism by which ibogaine may generate life-threatening cardiac arrhythmias.
Assuntos
Arritmias Cardíacas/induzido quimicamente , Comportamento Aditivo/tratamento farmacológico , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ibogaína/farmacologia , Adulto , Animais , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Ibogaína/efeitos adversos , Prevenção SecundáriaRESUMO
Ibogaine is a naturally occurring alkaloid derived from the roots of the rain forest shrub Tabernanthe iboga. Deaths have occurred temporarily related to the use of ibogaine. However, although not licensed as therapeutic drug, and despite evidence that ibogaine may disturb the rhythm of the heart, this alkaloid is currently used as an anti-addiction drug in alternative medicine for detoxification purposes. We report the case of a man who died suddenly 12-24 h after ibogaine use for alcohol detoxification treatment. In the autopsy liver cirrhosis and heavy fatty infiltration was found. The concentration of ibogaine was 2 mg/l. The potential risks of ibogaine use, especially for persons with pathological medical background, are discussed.
Assuntos
Alcoolismo/tratamento farmacológico , Morte Súbita Cardíaca/etiologia , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Ibogaína/efeitos adversos , Doença da Artéria Coronariana/patologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Fígado Gorduroso Alcoólico/patologia , Humanos , Ibogaína/administração & dosagem , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Síndrome de Abstinência a Substâncias/tratamento farmacológicoRESUMO
Damage to the medial temporal lobe impairs the encoding of new memories and the retrieval of memories acquired immediately before the damage in human. In this study, we demonstrated that artificial visuoauditory memory traces can be established in the rat auditory cortex and that their encoding and retrieval depend on the entorhinal cortex of the medial temporal lobe in the rat. We trained rats to associate a visual stimulus with electrical stimulation of the auditory cortex using a classical conditioning protocol. After conditioning, we examined the associative memory traces electrophysiologically (i.e., visual stimulus-evoked responses of auditory cortical neurons) and behaviorally (i.e., visual stimulus-induced freezing and visual stimulus-guided reward retrieval). The establishment of a visuoauditory memory trace in the auditory cortex, which was detectable by electrophysiological recordings, was achieved over 20-30 conditioning trials and was blocked by unilateral, temporary inactivation of the entorhinal cortex. Retrieval of a previously established visuoauditory memory was also affected by unilateral entorhinal cortex inactivation. These findings suggest that the entorhinal cortex is necessary for the encoding and involved in the retrieval of artificial visuoauditory memory in the auditory cortex, at least during the early stages of memory consolidation.
Assuntos
Córtex Auditivo/fisiologia , Mapeamento Encefálico , Córtex Entorrinal/fisiologia , Rememoração Mental/fisiologia , Percepção Visual/fisiologia , Estimulação Acústica , Potenciais de Ação/fisiologia , Análise de Variância , Animais , Córtex Auditivo/citologia , Córtex Auditivo/lesões , Condicionamento Clássico/fisiologia , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Extinção Psicológica , Feminino , Lateralidade Funcional , Masculino , Vias Neurais/fisiologia , Neurônios/fisiologia , Estimulação Luminosa , Quinoxalinas/efeitos adversos , Ratos , Ratos Sprague-Dawley , Recompensa , Fatores de TempoRESUMO
Evidence suggests that 30-50% of patients suffering from major depressive disorder (MDD) are classified as suffering from treatment resistant depression (TRD) as they have an inadequate response to standard antidepressants. A key feature of this patient population is the increased incidence of co-morbid symptoms like anxiety and pain. Recognizing that current standards of care are largely focused on monoaminergic mechanisms of action (MOAs), innovative approaches to drug discovery for TRD are targeting glutamate hyperfunction. Here we describe the in vitro and in vivo profile of GRN-529, a novel negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). In cell based pharmacology assays, GRN-529 is a high affinity (Ki 5.4 nM), potent (IC50 3.1 nM) and selective (>1000-fold selective vs mGluR1) mGluR5 NAM. Acute administration of GRN-529 (0.1-30 mg/kg p.o.) had dose-dependent efficacy across a therapeutically relevant battery of animal models, comprising depression (decreased immobility time in tail suspension and forced swim tests) and 2 of the co-morbid symptoms overrepresented in TRD, namely anxiety (attenuation of stress-induced hyperthermia, and increased punished crossings in the four plate test) and pain (reversal of hyperalgesia due to sciatic nerve ligation or inflammation). The potential side effect liability of GRN-529 was also assessed using preclinical models: GRN-529 had no effect on rat sexual behavior or motor co-ordination (rotarod), however it impaired cognition in mice (social odor recognition). Efficacy and side effects of GRN-529 were compared to standard of care agents (antidepressant, anxiolytic or analgesics) and the tool mGluR5 NAM, MTEP. To assess the relationship between target occupancy and efficacy, ex vivo receptor occupancy was measured in parallel with efficacy testing. This revealed a strong correlation between target engagement, exposure and efficacy across behavioral endpoints, which supports the potential translational value of PET imaging to dose selection in patients. Collectively this broad spectrum profile of efficacy of GRN-529 supports our hypothesis that negative allosteric modulation of mGluR5 could represent an innovative therapeutic approach to the treatment of TRD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Regulação Alostérica/fisiologia , Analgésicos/farmacologia , Animais , Ansiolíticos/farmacologia , Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Cálcio/metabolismo , Transtorno Depressivo Resistente a Tratamento/metabolismo , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/psicologia , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/farmacologia , Células HEK293 , Humanos , Camundongos , Piridinas/efeitos adversos , Piridinas/farmacologia , Piridinas/uso terapêutico , Ensaio Radioligante/métodos , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/fisiologiaRESUMO
Memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease with a good safety profile, is increasingly being studied in a variety of non-dementia psychiatric disorders. We aimed to critically review relevant literature on the use of the drug in such disorders. We performed a PubMed search of the effects of memantine in animal models of psychiatric disorders and its effects in human studies of specific psychiatric disorders. The bulk of the data relates to the effects of memantine in major depressive disorder and schizophrenia, although more recent studies have provided data on the use of the drug in bipolar disorder as an add-on. Despite interesting preclinical data, results in major depression are not encouraging. Animal studies investigating the possible usefulness of memantine in schizophrenia are controversial; however, interesting findings were obtained in open studies of schizophrenia, but negative placebo-controlled, double-blind studies cast doubt on their validity. The effects of memantine in anxiety disorders have been poorly investigated, but data indicate that the use of the drug in obsessive-compulsive disorder and post-traumatic stress disorder holds promise, while findings relating to generalized anxiety disorder are rather disappointing. Results in eating disorders, catatonia, impulse control disorders (pathological gambling), substance and alcohol abuse/dependence, and attention-deficit hyperactivity disorder are inconclusive. In most psychiatric non-Alzheimer's disease conditions, the clinical data fail to support the usefulness of memantine as monotherapy or add-on treatment However, recent preclinical and clinical findings suggest that add-on memantine may show antimanic and mood-stabilizing effects in treatment-resistant bipolar disorder.
Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Memantina/efeitos adversos , Memantina/química , Memantina/farmacologia , Resultado do TratamentoRESUMO
N-methyl-D-aspartate (NMDA) receptor is a glutamate receptor which has an important role on mammalian brain development. We have reported that prenatal treatment with phencyclidine (PCP), a NMDA receptor antagonist, induces long-lasting behavioral deficits and neurochemical changes. However, the mechanism by which the prenatal antagonism of NMDA receptor affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that prenatal NMDA receptor antagonism impaired the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and the subventricular zone. Furthermore, using a PCR array focused on neurogenesis and neuronal stem cells, we evaluated changes in gene expression causing the impairment of neuronal progenitor proliferation and found aberrant gene expression, such as Notch2 and Ntn1, in prenatal PCP-treated mice. Consequently, the density of glutamatergic neurons in the prefrontal cortex was decreased, probably resulting in glutamatergic hypofunction. Prenatal PCP-treated mice displayed behavioral deficits in cognitive memory and sensorimotor gating until adulthood. These findings suggest that NMDA receptors regulate the proliferation and maturation of progenitor cells for glutamatergic neuron during neurodevelopment, probably via the regulation of gene expression.
Assuntos
Proliferação de Células/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Ácido Glutâmico/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Neurônios/patologia , Fenciclidina/efeitos adversos , Córtex Pré-Frontal/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Estimulação Acústica , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Sintomas Comportamentais/induzido quimicamente , Peso Corporal/efeitos dos fármacos , Bromodesoxiuridina/metabolismo , Embrião de Mamíferos , Comportamento Exploratório/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microdissecção , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Inibição Neural/efeitos dos fármacos , Neurônios/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Natação/psicologiaRESUMO
Alzheimer disease is the most common form of dementia, affecting nearly one-half [corrected] of Americans older than 85 years. It is characterized by progressive memory loss and cognitive decline. Amyloid plaque accumulation, neurofibrillary tau tangles, and depletion of acetylcholine are among the pathologic manifestations of Alzheimer disease. Although there are no proven modalities for preventing Alzheimer disease, hypertension treatment, omega-3 fatty acid supplementation, physical activity, and cognitive engagement demonstrate modest potential. Acetylcholinesterase inhibitors are first-line medications for the treatment of Alzheimer disease, and are associated with mild improvements in cognitive function, behavior, and activities of daily living; however, the clinical relevance of these effects is unclear. The most common adverse effects of acetylcholinesterase inhibitors are nausea, vomiting, diarrhea, dizziness, confusion, and cardiac arrhythmias. Short-term use of the N-methyl-D-aspartate receptor antagonist memantine can modestly improve measures of cognition, behavior, and activities of daily living in patients with moderate to severe Alzheimer disease. Memantine can also be used in combination with acetylcholinesterase inhibitors. Memantine is generally well tolerated, but whether its benefits produce clinically meaningful improvement is controversial. Although N-methyl-D-aspartate receptor antagonists and acetylcholinesterase inhibitors can slow the progression of Alzheimer disease, no pharmacologic agents can reverse the progression. Atypical antipsychotics can improve some behavioral symptoms, but have been associated with increased mortality rates in older patients with dementia. There is conflicting evidence about the benefit of selegiline, testosterone, and ginkgo for the treatment of Alzheimer disease. There is no evidence supporting the beneficial effects of vitamin E, estrogen, or nonsteroidal anti-inflammatory drug therapy.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , Nootrópicos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/economia , Medicina Baseada em Evidências , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/economia , Feminino , Humanos , Masculino , Anamnese/métodos , Memantina/efeitos adversos , Memantina/economia , Nootrópicos/efeitos adversos , Nootrópicos/economia , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Estados UnidosRESUMO
Drugs currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease include acetylcholinesterase inhibitor (i.e., tacrine, donepezil, rivastigmine, and galantamine) and glutamate-modulating (i.e., memantine) drugs. Because these drugs have modest benefits, various alternative drug therapies have been of interest. Drugs with vasodilator activity were originally tried in dementia when it was hypothesized that the condition was due to cerebrovascular insufficiency. Isoxsuprine and ergoloid mesylates are FDA approved for the treatment of dementia, although they have limited evidence of benefit and are rarely used. The hypothesis that free radicals may initiate and maintain mechanisms responsible for neurodegeneration in dementia has stimulated interest in investigating various antioxidant and anti-inflammatory drugs. There is no evidence that other drug therapies, including vitamin E, selegiline, nonsteroidal anti-inflammatory drugs, statin drugs, omega-3 fatty acids, estrogen or combined estrogen plus progestin therapy, or B vitamins, are sufficiently effective and safe to justify their clinical use for the treatment of dementing disorders.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enfermagem , Nootrópicos/uso terapêutico , Idoso , Doença de Alzheimer/etiologia , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Antioxidantes/efeitos adversos , Antioxidantes/uso terapêutico , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/uso terapêutico , Terapia de Reposição de Estrogênios , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ácidos Graxos Ômega-3/efeitos adversos , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Memantina/efeitos adversos , Memantina/uso terapêutico , Nootrópicos/efeitos adversos , Vasodilatadores/efeitos adversos , Vasodilatadores/uso terapêuticoRESUMO
INTRODUCTION: Glaucoma is a slowly progressive optic neuropathy that is one of the leading causes of legal blindness throughout the world. Currently there is a limited group of topical drugs for the medical treatment of glaucoma is currently limited, and research needs to be focused on new therapeutic horizons, such as the potential usefulness of the cannabinoid agonists for the treatment of glaucoma. AIM: To review the current scientific literature related to the beneficial effects derived from the different ways of administration of cannabinoids indicated for the glaucomatous optic neuropathy. DEVELOPMENT: Cannabinoid receptors have shown an intense expression in ocular tissues implicated in the regulation of the intraocular pressure, as well as inner layers of the retina. Through activation of CB1 and CB1 specific receptors and through other still unknown pathways, the cannabinoid agonists have shown both a clear hypotensive, as well as an experimentally proved neuroprotective effect on retinal ganglion cells. CONCLUSIONS: Some cannabinoid agonists (WIN 55212-2, anandamide) have demonstrated, in experimental studies, to act as «ideal drugs¼ in the management of glaucoma, as they have been shown to have good tolerability after topical application, efficiently reduce intraocular pressure, and behave as neuroprotectors on retinal ganglion cells. Further studies as regards the safety and clinical assays must be carried out in order to examine the effectiveness of these drugs for the treatment of glaucoma in our daily clinical practice.
Assuntos
Canabinoides/uso terapêutico , Glaucoma/tratamento farmacológico , Animais , Ácidos Araquidônicos/administração & dosagem , Ácidos Araquidônicos/efeitos adversos , Ácidos Araquidônicos/farmacologia , Ácidos Araquidônicos/uso terapêutico , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Benzoxazinas/farmacologia , Benzoxazinas/uso terapêutico , Agonistas de Receptores de Canabinoides , Moduladores de Receptores de Canabinoides/agonistas , Moduladores de Receptores de Canabinoides/fisiologia , Canabinoides/administração & dosagem , Canabinoides/efeitos adversos , Canabinoides/farmacologia , Vias de Administração de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Endocanabinoides , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Proteínas do Olho/agonistas , Proteínas do Olho/fisiologia , Ácido Glutâmico/fisiologia , Humanos , Pressão Intraocular/efeitos dos fármacos , Mamíferos , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/patologia , Alcamidas Poli-Insaturadas/administração & dosagem , Alcamidas Poli-Insaturadas/efeitos adversos , Alcamidas Poli-Insaturadas/farmacologia , Alcamidas Poli-Insaturadas/uso terapêutico , Receptores de Canabinoides/fisiologia , Células Ganglionares da Retina/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversosRESUMO
We have previously reported that lurasidone, a novel atypical antipsychotic with potent serotonin 5-HT(7) antagonist and 5-HT(1A) partial agonist activities, is superior to other antipsychotics in improving the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801-induced learning and memory impairment in the passive avoidance (PA) and Morris water maze (MWM) tests in rats. In this study, we investigated the effects of selective antagonists of 5-HT(7) and 5-HT(1A) receptors (SB-656104-A and WAY-100635, respectively) on MK-801-induced learning and memory impairment in the same tests. In the PA test, either pre-training (3 and 10mg/kg, p.o.) or post-training (0.3mg/kg, i.v.) administration of lurasidone significantly reversed the test response impaired by MK-801, consistent with our previous reports. Pre-training administration of either SB-656104-A (10 and 30 mg/kg, i.p.) or WAY-100635 (1mg/kg, s.c.) also significantly reversed MK-801-induced memory impairment. Furthermore, post-training administration of either SB-656104-A (0.3mg/kg, i.v.) or WAY-100635 (0.01 mg/kg, i.v.) counteracted the effect of MK-801, which suggested that both 5-HT receptor subtype-selective antagonists could restore the memory consolidation process. In the MWM test, SB-656104-A (3mg/kg, i.p.) reversed learning impairment induced by MK-801. On the other hand, WAY-100635 (0.3 and 1mg/kg, i.p.) did not have any effect on the MK-801-induced learning impairment. Taken together, our results showed that 5-HT(7) and 5-HT(1A) receptor antagonists mimic the effect of lurasidone in whole or in part, respectively, to reverse MK-801-induced learning and memory impairment, which warrants further investigation of the interaction of lurasidone with these serotonin receptors as a possible mechanism underlying its procognitive effects in these animal models.
Assuntos
Aprendizagem da Esquiva/fisiologia , Isoindóis/uso terapêutico , Aprendizagem em Labirinto/fisiologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Tiazóis/uso terapêutico , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Modelos Animais de Doenças , Maleato de Dizocilpina/efeitos adversos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/tratamento farmacológico , Cloridrato de Lurasidona , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Serotoninérgicos/farmacologia , Fatores de TempoRESUMO
BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem. METHODS: Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. RESULTS: Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory (p = 0.053) and motor subscales (p = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity. CONCLUSION: Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.
Assuntos
Amitriptilina/uso terapêutico , Baclofeno/uso terapêutico , Ketamina/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Administração Cutânea , Inibidores da Captação Adrenérgica/administração & dosagem , Inibidores da Captação Adrenérgica/efeitos adversos , Inibidores da Captação Adrenérgica/uso terapêutico , Idoso , Amitriptilina/administração & dosagem , Amitriptilina/efeitos adversos , Antineoplásicos/efeitos adversos , Baclofeno/administração & dosagem , Baclofeno/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Agonistas dos Receptores de GABA-B/administração & dosagem , Agonistas dos Receptores de GABA-B/efeitos adversos , Agonistas dos Receptores de GABA-B/uso terapêutico , Géis , Humanos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Lecitinas/química , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Poloxâmero/química , Resultado do TratamentoRESUMO
BACKGROUND: Severe, intractable, chronic pain is a significant management problem for those involved in the long-term care of spinal cord injury (SCI) patients . Gabapentin, an anticonvulsant, is widely used for treating chronic pain. Ketamine, an NMDA receptor antagonist, has been available in clinical practice for 35 years. Its usefulness in pathological pain states is known. Despite this, no formal research on its effectiveness in treating neuropathic SCI pain exists. OBJECTIVES: This double-blind study sought to determine the safety and efficacy of adding a multi-day low dose ketamine infusion to oral gabapentin for treating chronic pain related to post spinal cord injury. STUDY DESIGN: Randomized, controlled, double blind trial. SETTING: Hospital, in-patient setting. METHODS: Forty patients diagnosed with neuropathic pain secondary to spinal cord injury were randomized into 2 equal groups. Group I received an 80 mg intravenous ketamine infusion diluted in 500 cc normal saline over a 5 hour period daily for one week and 300 mg of gabapentin 3 times daily. Group II received a placebo infusion and 300 mg of gabapentin 3 times daily (continued) after 300 mg of gabapentin 3 times daily. Using the visual analogue scale, pain was assessed prior to treatment, daily following ketamine or placebo infusions for 7 days, and then weekly for one month after infusion termination. Side effects, specifically those related to ketamine or gabapentin, were reported. RESULTS: Both groups demonstrated significantly reduced pain scores compared with pre-treatment values (P < 0.05). Group I showed significant pain score improvements over Group II at all measurements (P < 0.0001) during infusion and 2 weeks after infusion termination. There was no statistical difference between the groups at 3 weeks and 4 weeks after infusion termination (P = 0.54 and P = 0.25 respectively). Both drugs were tolerated by all patients; no side effects required intervention. CONCLUSION: Multi-day low dose ketamine infusion as adjuvant to gabapentin in post-spinal cord injury related chronic pain is safe and efficacious in reducing pain, but the effect compared to placebo ceased 2 weeks after infusion termination. LIMITATIONS: Study size limited to 40 patients.
Assuntos
Adjuvantes Farmacêuticos/administração & dosagem , Aminas/administração & dosagem , Analgésicos/administração & dosagem , Ácidos Cicloexanocarboxílicos/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ketamina/administração & dosagem , Dor/tratamento farmacológico , Traumatismos da Medula Espinal/complicações , Ácido gama-Aminobutírico/administração & dosagem , Adjuvantes Farmacêuticos/efeitos adversos , Adulto , Doença Crônica , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Feminino , Gabapentina , Humanos , Infusões Intravenosas , Pacientes Internados , Ketamina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Resultado do TratamentoRESUMO
INTRODUCTION: Some anticonvulsants ameliorate signs and symptoms of alcohol withdrawal, but have an unacceptable side effect burden. Among the advantages of using anticonvulsant agents in this capacity is their purported lack of interaction with alcohol that could increase psychomotor deficits, increase cognitive impairment, or increase intoxication. The aim of this study was to evaluate alcohol use and symptom reduction of gabapentin when compared with lorazepam in the treatment of alcohol withdrawal in a double-blinded randomized clinical trial. METHODS: One hundred individuals seeking outpatient treatment of alcohol withdrawal with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) ratings > or =10 were randomized to double-blind treatment with 2 doses of gabapentin (900 mg tapering to 600 mg or 1200 tapering to 800 mg) or lorazepam (6 mg tapering to 4 mg) for 4 days. Severity of alcohol withdrawal was measured by the CIWA-Ar on days 1 to 4 of treatment and on days 5, 7, and 12 post-treatment and alcohol use monitored by verbal report and breath alcohol levels. RESULTS: CIWA-Ar scores decreased over time in all groups; high-dose gabapentin was statistically superior but clinically similar to lorazepam (p = 0.009). During treatment, lorazepam-treated participants had higher probabilities of drinking on the first day of dose decrease (day 2) and the second day off medication (day 6) compared to gabapentin-treated participants (p = 0.0002). Post-treatment, gabapentin-treated participants had less probability of drinking during the follow-up post-treatment period (p = 0.2 for 900 mg and p = 0.3 for 1200 mg) compared to the lorazepam-treated participants (p = 0.55). The gabapentin groups also had less craving, anxiety, and sedation compared to lorazepam. CONCLUSIONS: Gabapentin was well tolerated and effectively diminished the symptoms of alcohol withdrawal in our population especially at the higher target dose (1200 mg) used in this study. Gabapentin reduced the probability of drinking during alcohol withdrawal and in the immediate postwithdrawal week compared to lorazepam.
Assuntos
Aminas/uso terapêutico , Ácidos Cicloexanocarboxílicos/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Lorazepam/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêutico , Adulto , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/psicologia , Aminas/efeitos adversos , Ácidos Cicloexanocarboxílicos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Feminino , Gabapentina , Humanos , Hipnóticos e Sedativos/efeitos adversos , Lorazepam/efeitos adversos , Masculino , Escalas de Graduação Psiquiátrica , Recidiva , Síndrome de Abstinência a Substâncias/psicologia , Síndrome de Abstinência a Substâncias/reabilitação , Resultado do Tratamento , Ácido gama-Aminobutírico/efeitos adversosRESUMO
INTRODUCTION: Electrophysiological responses to auditory stimuli have provided a useful means of elucidating mechanisms and evaluating treatments in psychiatric disorders. Deficits in gating during paired-click tasks and lack of mismatch negativity following deviant stimuli have been well characterized in patients with schizophrenia. Recently, analyses of basal, induced, and evoked frequency oscillations have gained support as additional measures of cognitive processing in patients and animal models. The purpose of this study is to examine frequency oscillations in mice across the theta (4-7.5 Hz) and gamma (31-61 Hz) bands in the context of N-methyl-d-aspartic acid receptor (NMDAR) hypofunction and dopaminergic hyperactivity, both of which are thought to serve as pharmacological models of schizophrenia. EXPERIMENTAL PROCEDURES: Electroencephalograms (EEG) were recorded from mice in five treatment groups that consisted of haloperidol, risperidone, amphetamine, ketamine, or ketamine plus haloperidol during an auditory task. Basal, induced and evoked powers in both frequencies were calculated. RESULTS: Ketamine increased basal power in the gamma band and decreased the evoked power in the theta band. The increase in basal gamma was not blocked by treatment with a conventional antipsychotic. No other treatment group was able to fully reproduce this pattern in the mice. CONCLUSIONS: Ketamine-induced alterations in EEG power spectra are consistent with abnormalities in the theta and gamma frequency ranges reported in patients with schizophrenia. Our findings support the hypothesis that NMDAR hypofunction contributes to the deficits in schizophrenia and that the dopaminergic pathways alone may not account for these changes.
Assuntos
Relógios Biológicos/efeitos dos fármacos , Eletroencefalografia , Potenciais Evocados Auditivos/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Ketamina/efeitos adversos , Esquizofrenia/induzido quimicamente , Estimulação Acústica/métodos , Anfetamina/administração & dosagem , Animais , Antipsicóticos/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Interações Medicamentosas , Haloperidol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tempo de Reação/efeitos dos fármacos , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologiaRESUMO
Sudden outbursts of laughing, crying, or other emotional expression without an apparent triggering stimulus have been recorded in the literature for decades. Confusing nomenclature and a paucity of clinical research, however, have had clinicians wondering whether this syndrome may be both under-recognized and undertreated. Treatment options, including antidepressants, levodopa, and dextromethorphan/quinidine, may show promise in ameliorating symptoms for patients plagued with disorders of emotional expression.
Assuntos
Sintomas Afetivos/diagnóstico , Emoções Manifestas , Volição , Sintomas Afetivos/tratamento farmacológico , Sintomas Afetivos/psicologia , Antidepressivos/uso terapêutico , Choro , Dextrometorfano/efeitos adversos , Dextrometorfano/uso terapêutico , Diagnóstico Diferencial , Dopaminérgicos/uso terapêutico , Combinação de Medicamentos , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Riso , Levodopa/uso terapêutico , Quinidina/efeitos adversos , Quinidina/uso terapêutico , Resultado do TratamentoRESUMO
UNLABELLED: CHF3381 is a new low-affinity, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor. The analgesic activity of CHF3381 was investigated in the heat-capsaicin human pain model and compared with those of gabapentin. Twenty-seven young, healthy male volunteers received a single oral dose of CHF3381 (500 mg), gabapentin (1,200 mg), or placebo in a randomized, double-blind, crossover study design. Measurements were done before and 135 to 145 minutes after treatment administration and included area of secondary hyperalgesia around the sensitized skin of the forearm (45 degrees C for 5 minutes followed by topical capsaicin for 30 minutes), area of secondary hyperalgesia after thermal sensitization of the thigh (45 degrees C for 3 minutes), heat pain detection thresholds (degrees C), and pain on a visual analogue scale after long thermal stimulation (45 degrees C for 1 minute). Compared with placebo, both gabapentin and CHF3381 significantly reduced the area of secondary hyperalgesia on the dominant forearm. Median (and interquartile range) percent values over baseline were 86% after placebo (69% to 100%), 56% (41% to 76%) after gabapentin (P < .001), and 67% (49% to 88%) after CHF3381 (P < .009). Both drugs also significantly decreased the area of secondary hyperalgesia on the dominant thigh. The other pain variables were not significantly affected. Adverse events, mainly fatigue and dizziness, were mild to moderate. PERSPECTIVE: This article presents the antihyperalgesic effect of CHF3381, a new NMDA receptor antagonist and reversible MAO-A inhibitor, in a human pain model and might guide the proper selection of CHF3381 doses to be used in Phase 2 studies in patients with neuropathic pain.
Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Glicina/análogos & derivados , Hiperalgesia/tratamento farmacológico , Indanos/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/metabolismo , Dor/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Adulto , Aminas/uso terapêutico , Analgésicos/uso terapêutico , Capsaicina , Estudos Cross-Over , Ácidos Cicloexanocarboxílicos/uso terapêutico , Método Duplo-Cego , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/sangue , Gabapentina , Glicina/efeitos adversos , Glicina/sangue , Glicina/farmacologia , Humanos , Hiperalgesia/etiologia , Indanos/efeitos adversos , Indanos/sangue , Masculino , Inibidores da Monoaminoxidase/efeitos adversos , Inibidores da Monoaminoxidase/sangue , Dor/etiologia , Medição da Dor/efeitos dos fármacos , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
OBJECTIVE: To evaluate the efficacy and safety of DM/Q (capsules containing dextromethorphan [DM] and quinidine [Q]) compared with placebo, taken twice daily, for the treatment of pseudobulbar affect over a 12-week period in multiple sclerosis patients. METHODS: A total of 150 patients were randomized in a double-blind, placebo-controlled study to assess pseudobulbar affect with the validated Center for Neurologic Study-Lability Scale. Each patient also recorded the number of episodes experienced between visits, estimated quality of life and quality of relationships on visual analog scales, and completed a pain rating scale. RESULTS: Patients receiving DM/Q had greater reductions in Center for Neurologic Study-Lability Scale scores than those receiving placebo (p < 0.0001) at all clinic visits (days 15, 29, 57, and 85). All secondary end points also favored DM/Q, including the number of crying or laughing episodes (p Assuntos
Afeto/efeitos dos fármacos
, Dextrometorfano/uso terapêutico
, Antagonistas de Aminoácidos Excitatórios/uso terapêutico
, Esclerose Múltipla/tratamento farmacológico
, Esclerose Múltipla/psicologia
, Quinidina/uso terapêutico
, Idoso
, Choro
, Dextrometorfano/efeitos adversos
, Dextrometorfano/farmacocinética
, Método Duplo-Cego
, Combinação de Medicamentos
, Antagonistas de Aminoácidos Excitatórios/efeitos adversos
, Antagonistas de Aminoácidos Excitatórios/farmacocinética
, Feminino
, Humanos
, Riso
, Masculino
, Pessoa de Meia-Idade
, Medição da Dor/efeitos dos fármacos
, Qualidade de Vida
, Quinidina/efeitos adversos
, Quinidina/farmacocinética
RESUMO
A 44-year-old man with treated neurosyphilis presented with subclinical status epilepticus (SE) refractory to intravenous high-dose lorazepam, phenytoin, and valproic acid over 4 days. Ketamine infusion was instituted after low-dose propofol sedation with gradual control of electrographic seizures over 72h. Reevaluation 3 months later revealed diffuse cerebellar and worsened cerebral atrophy, consistent with animal models of N-methyl-D-aspartate antagonist-mediated neurotoxicity. Animal studies of prolonged ketamine therapy are required before widespread human use in SE.
Assuntos
Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Ketamina/efeitos adversos , Síndromes Neurotóxicas/etiologia , Estado Epiléptico/tratamento farmacológico , Adulto , Anticonvulsivantes/uso terapêutico , Atrofia/patologia , Encéfalo/patologia , Eletroencefalografia , Humanos , Lorazepam/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Fenitoína/uso terapêutico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Índice de Gravidade de Doença , Estado Epiléptico/diagnóstico , Ácido Valproico/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: Proton MR spectroscopy has revealed impaired neuronal integrity in the motor cortex of patients with amyotrophic lateral sclerosis (ALS). We hypothesized that the N-acetylaspartate (NAA)-creatine (Cr) ratios in the motor cortex and adjacent brain could reflect the therapeutic effectiveness of gabapentin (GBP) treatment in ALS. METHODS: Eight patients with ALS underwent MR spectroscopy before and 26.5 days +/- 8.8 after starting GBP. In 10 patients with ALS who were not treated with GBP, paired spectra were obtained 21.4 days +/- 7.2 apart. Fourteen healthy subjects underwent a single MR spectroscopic examination. The NAA/Cr ratio was measured in the precentral gyrus, the postcentral gyrus, the superior parietal lobule, the supplementary motor area, and the premotor cortex. RESULTS: The NAA/Cr ratio was decreased in the precentral and postcentral gyri of patients with ALS compared with healthy controls. In those with ALS, the change in the NAA/Cr ratio was not different between treated patients and untreated patients in any of the regions studied. CONCLUSION: No improvement in neuronal integrity was detected in motor and nonmotor cerebral regions after GBP treatment. This result agrees with that of prior investigations showing the equivocal clinical effectiveness of GBP for ALS and supports the validity of the NAA/Cr ratio as a surrogate of therapeutic effectiveness.