RESUMO
BACKGROUND: Fampridine is a broad-spectrum voltage-dependent potassium channel blocker that enhances synaptic transmission. The drug has been shown to be able to ameliorate conduction in demyelinated axons, thereby leading to improved gait in patients with multiple sclerosis (MS). OBJECTIVE: To assess the "real-life" efficacy and safety of fampridine prescribed for gait disorders in MS. This was an observational and prospective study carried out at MS Units participating in the Brazilian Multiple Sclerosis Study Group. METHODS: Patients with MS and gait disorders were prescribed fampridine (10âmg twice a day), irrespectively of the degree of disability determined by MS. Neurological disability determined by MS was assessed with the expanded disability scale score (EDSS). Outcomes for efficacy and safety of the drug were evaluated by the 25 foot-walk test and by the adverse events of fampridine. RESULTS: The time taken to walk 25 feet decreased by 20% or more in 62 patients (70%). Twenty-five patients were considered to be non-responders to this treatment. Improvement in walking speed was independent of improvement of disability. Mild or moderate adverse events were reported in 8% of patients. CONCLUSION: Fampridine is an efficient and safe therapeutic option for patients with MS and gait disorders.
Assuntos
4-Aminopiridina/uso terapêutico , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/tratamento farmacológico , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , 4-Aminopiridina/farmacologia , Adulto , Idoso , Feminino , Transtornos Neurológicos da Marcha/epidemiologia , Humanos , Acontecimentos que Mudam a Vida , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Bloqueadores dos Canais de Potássio/farmacologia , Estudos ProspectivosRESUMO
We evaluated the effects of K+ channel blockers in the vascular reactivity of in vitro perfused kidneys, as well as on the influence of vasoactive agents in the renal blood flow of rats subjected to the cecal ligation and puncture (CLP) model of sepsis. Both norepinephrine and phenylephrine had the ability to increase the vascular perfusion pressure reduced in kidneys of rats subjected to CLP at 18 h and 36 h before the experiments. The non-selective K+ channel blocker tetraethylammonium, but not the Kir6.1 blocker glibenclamide, normalized the effects of phenylephrine in kidneys from the CLP 18 h group. Systemic administration of tetraethylammonium, glibenclamide, or the KCa1.1 blocker iberiotoxin, did not change the renal blood flow in control or septic rats. Norepinephrine or phenylephrine also had no influence on the renal blood flow of septic animals, but its injection in rats from the CLP 18 h group previously treated with either glibenclamide or iberiotoxin resulted in an exacerbated reduction in the renal blood flow. These results suggest an abnormal functionality of K+ channels in the renal vascular bed in sepsis, and that the blockage of different subtypes of K+ channels may be deleterious for blood perfusion in kidneys, mainly when associated with vasoactive drugs.
Assuntos
Canais KATP/antagonistas & inibidores , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/antagonistas & inibidores , Norepinefrina/farmacologia , Fenilefrina/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Circulação Renal/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/fisiologia , Canais KATP/fisiologia , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/fisiologia , Masculino , Bloqueadores dos Canais de Potássio/uso terapêutico , Ratos , Ratos Wistar , Circulação Renal/fisiologia , Sepse/fisiopatologiaRESUMO
The administration of hesperidin elicits an antidepressant-like effect in mice by a mechanism dependent on an interaction with the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, whose stimulation is associated with the activation of potassium (K(+)) channels. Thus, this study investigated the involvement of different types of K(+) channels in the antidepressant-like effect of hesperidin in the mice tail suspension test (TST). The intracerebroventricular administration of tetraethylammonium (TEA, a nonspecific blocker of K(+) channels), glibenclamide (an ATP-sensitive K(+) channel blocker), charybdotoxin (a large- and intermediate-conductance calcium-activated K(+) channel blocker) or apamin (a small-conductance calcium-activated K(+) channel blocker) combined with a subeffective dose of hesperidin (0.01 mg/kg, intraperitoneally [i.p.]) was able to produce a synergistic antidepressant-like effect in the mice TST. Moreover, the antidepressant-like effect elicited by an effective dose of hesperidin (0.3 mg/kg, i.p.) in TST was abolished by the treatment of mice with pharmacological compounds K(+) channel openers (cromakalim and minoxidil). Results showed that the antidepressant-like effect of hesperidin in TST may involve, at least in part, the modulation of neuronal excitability through inhibition of K(+) channels and may act through a mechanism dependent on the inhibition of L-arginine-NO pathway.
Assuntos
Antidepressivos/farmacologia , Hesperidina/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/fisiologia , Animais , Apamina/administração & dosagem , Arginina/farmacologia , Charibdotoxina/administração & dosagem , Sinergismo Farmacológico , Glibureto/administração & dosagem , Hesperidina/administração & dosagem , Elevação dos Membros Posteriores , Masculino , Camundongos , Bloqueadores dos Canais de Potássio/administração & dosagem , Bloqueadores dos Canais de Potássio/uso terapêutico , Canais de Potássio/efeitos dos fármacos , Tetraetilamônio/administração & dosagemRESUMO
Geraniol is a monoterpene present in several essential oils, and it is known to have a plethora of pharmacological activities. In this study, we explored the contractile and electrophysiological properties of geraniol and its antiarrhythmic effects in the heart. The geraniol effects on atrial contractility, L-type Ca(2+) current, K(+) currents, action potential (AP) parameters, ECG profile and on the arrhythmia induced by ouabain were evaluated. In the atrium, geraniol reduced the contractile force (~98%, EC = 1,510 ± 160 µM) and diminished the positive inotropism of CaCl2 and BAY K8644. In cardiomyocytes, the IC a,L was reduced by 50.7% (n = 5) after perfusion with 300 µM geraniol. Moreover, geraniol prolonged the AP duration (APD) measured at 50% (n = 5) after repolarization, without changing the resting potential. The increased APD could be attributed to the blockade of the transient outward K(+) current (Ito ) (59.7%, n = 4), the non-inactivation K(+) current (Iss ) (39.2%, n = 4) and the inward rectifier K(+) current (IK 1 ) (33.7%, n = 4). In isolated hearts, geraniol increased PRi and QTi without affecting the QRS complex (n = 6), and it reduced both the left ventricular pressure (83%) and heart rate (16.5%). Geraniol delayed the time to onset of ouabain-induced arrhythmias by 128%, preventing 30% of the increase in resting tension (n = 6). Geraniol exerts its negative inotropic and chronotropic responses in the heart by decreasing both L-type Ca(2+) and voltage-gated K(+) currents, ultimately acting against ouabain-induced arrhythmias.
Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacologia , Coração/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Terpenos/farmacologia , Monoterpenos Acíclicos , Animais , Antiarrítmicos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio , Eletrocardiografia/efeitos dos fármacos , Cobaias , Átrios do Coração/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Contração Miocárdica/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/uso terapêutico , Terpenos/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: There is increasing evidence that potassium channels are involved in the cardiovascular dysfunction of sepsis. This evidence was obtained after the systemic inflammation, cardiovascular dysfunction and organ damage had developed. Here we have studied the consequences of early interference with potassium channels on development of sepsis. EXPERIMENTAL APPROACH: Sepsis was induced by caecal ligation and puncture (CLP) or sham surgery in Wistar rats. Four hours after surgery, animals received tetraethylammonium (TEA; a non-selective potassium channel blocker) or glibenclamide (a selective ATP-sensitive potassium channel blocker). Twenty-four hours after surgery, inflammatory, biochemical, haemodynamic parameters and survival were evaluated. KEY RESULTS: Sepsis significantly increased plasma NO(x) levels, expression of inducible nitric oxide synthase (NOS-2) protein in lung and thigh skeletal muscle, lung myeloperoxidase, urea, creatinine and lactate levels, TNF-α and IL-1ß, hypotension and hyporesponsiveness to phenylephrine and hyperglycemia followed by hypoglycemia. TEA injected 4 h after surgery attenuated the increased NOS-2 expression, reduced plasma NO(x) , lung myeloperoxidase activity, levels of TNF-α and IL-1ß, urea, creatinine and lactate levels, prevented development of hypotension and hyporesponsiveness to phenylephrine, the alterations in plasma glucose and reduced late mortality by 50%. Glibenclamide did not improve any of the measured parameters and increased mortality rate, probably due to worsening the hypoglycemic phase of sepsis. CONCLUSIONS AND IMPLICATIONS: Early blockade of TEA-sensitive (but not the ATP-sensitive subtype) potassium channels reduced organ damage and mortality in experimental sepsis. This beneficial effect seems to be, at least in part, due to reduction in NOS-2 expression.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Glibureto/uso terapêutico , Bloqueadores dos Canais de Potássio/uso terapêutico , Sepse/complicações , Tetraetilamônio/uso terapêutico , Animais , Pressão Sanguínea , Feminino , Regulação Enzimológica da Expressão Gênica , Frequência Cardíaca , Longevidade , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Wistar , Vasoconstritores/farmacologiaRESUMO
BACKGROUND AND AIMS: Many patients with complete spinal cord injury (SCI) exhibit demyelinated and poorly myelinated nerve fibers traversing the lesion site. Conventional doses of 4-aminopyridine (4-AP, 30 mg/day) have shown to provide no or minor functional improvement in these patients. We undertook this study to test the functional effect of high doses of 4-AP on patients with chronic complete SCI with cord continuity at the site of injury demonstrated by magnetic resonance imaging. METHODS: Fourteen patients were included in a double-blind, randomized, placebo-controlled trial followed by an open label long-term follow-up. Initially, patients received 4-AP or placebo orally, with 4-AP being increased gradually (5 mg/week) to reach 30 mg/day. For long-term treatment, 4-AP was increased 10 mg periodically according to negative electroencephalogram and blood test abnormalities and minor adverse reactions. Pre-treatment, 12 and 24 weeks of the controlled trial, and 6 and 12 months of open trial evaluations, or with the highest doses reached were obtained. RESULTS: Three of 12 patients were able to walk with the assistance of orthopedic devices, 1/12 became incomplete (AIS B), 7/12 improved their somatosensory evoked potentials, 5/12 had sensation and control of bladder and anal sphincters, and 4/9 male patients had psychogenic erection. CONCLUSIONS: Positive changes were seen mainly in patients with cyst (4/5) or atrophy (3/5) of the injury site. Two patients withdrew from the study: one had seizures and one had intolerant adverse reactions. We conclude that high doses of 4-AP in the studied population produced several functional benefits not observed using lower doses.
Assuntos
4-Aminopiridina/uso terapêutico , Bloqueadores dos Canais de Potássio/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Medula Espinal/anatomia & histologia , Medula Espinal/patologia , 4-Aminopiridina/farmacologia , Adulto , Método Duplo-Cego , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Placebos/uso terapêutico , Bloqueadores dos Canais de Potássio/farmacologia , Recuperação de Função Fisiológica , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Adulto JovemRESUMO
OBJECTIVES: This study investigated the involvement of different types of K(+) channels and PPARgamma receptors in the antidepressant-like effect of diphenyl diselenide in mice. METHODS: Mice were pretreated with subeffective doses of K(+) channel inhibitors (tetraethylammonium, glibenclamide, charybdotoxin and apamin), openers (cromakalim, minoxidil), GW 9662 (a PPARgamma antagonist) or vehicle. Thirty minutes later the mice received diphenyl diselenide in either an effective or a subeffective dose, 30 min before a tail-suspension test. KEY FINDINGS: Pre-treatment with tetraethylammonium, charybdotoxin or apamin combined with a subeffective dose of diphenyl diselenide was effective in decreasing the immobility time in the mouse tail-suspension test. The reduction in the immobility time elicited by an effective dose of diphenyl diselenide in this test was prevented by the pretreatment of mice with minoxidil and GW 9662. CONCLUSIONS: Diphenyl diselenide elicited an antidepressant-like effect and this action was mediated, at least in part, by modulation of K(+) channels and PPARgamma receptors.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Derivados de Benzeno/farmacologia , Depressão/tratamento farmacológico , Compostos Organosselênicos/farmacologia , PPAR gama/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Anilidas/farmacologia , Animais , Antidepressivos/uso terapêutico , Derivados de Benzeno/uso terapêutico , Cromakalim/farmacologia , Elevação dos Membros Posteriores , Masculino , Camundongos , Minoxidil/farmacologia , Compostos Organosselênicos/uso terapêutico , Bloqueadores dos Canais de Potássio/uso terapêutico , Vasodilatadores/farmacologiaRESUMO
AIMS: Studies have shown that the acute administration of venlafaxine elicits an antidepressant-like effect in the mouse forced swim test (FST) by a mechanism dependent on the l-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Because it has been reported that NO activates different types of potassium (K(+)) channels in the brain, this study investigated the involvement of K(+) channels in the antidepressant-like effect of venlafaxine in the mouse FST. MAIN METHODS: Male adult Swiss mice were pretreated with different K(+) channel inhibitors or openers 15 min before venlafaxine administration. After 30 min, the open-field test (OFT) and FST were carried out. KEY FINDINGS: Intracerebroventricular (i.c.v.) pretreatment of mice with subeffective doses of tetraethylammonium (TEA, a non-specific inhibitor of K(+) channels, 25 pg/site), glibenclamide (an ATP-sensitive K(+) channel inhibitor, 0.5 pg/site), charybdotoxin (a large- and intermediate-conductance calcium-activated K(+) channel inhibitor, 25 pg/site) or apamin (a small-conductance calcium-activated K(+) channel inhibitor, 10 pg/site) was able to potentiate the action of a subeffective dose of venlafaxine (2mg/kg, i.p.). Moreover, the reduction in the immobility time elicited by an effective dose of venlafaxine (8 mg/kg, i.p.) in the FST was prevented by the pretreatment of mice with the K(+) channel openers cromakalim (10 microg/site, i.c.v.) and minoxidil (10 microg/site, i.c.v.). The drugs used in this study did not produce any change in locomotor activity. SIGNIFICANCE: The results demonstrate that the neuromodulatory effects of venlafaxine, via the inhibition of K(+) channels, are possibly involved in its anti-immobility activity in the mouse FST.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Cicloexanóis/farmacologia , Canais de Potássio/fisiologia , Animais , Cicloexanóis/uso terapêutico , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Depressão/psicologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/uso terapêutico , Canais de Potássio/metabolismo , Cloridrato de VenlafaxinaRESUMO
The convenience to count with a safe and effective pharmacological wealth for atrial fibrillation treatment had conduced, in a way, to a deep depuration of the vast array of antiarrhythmic drugs, keeping only a very restricted number of compounds with a widely proved anti-atrial activity. On the other hand, it had lead to the discovery of the pathophysiological concepts that point to novel therapeutic targets. Within these objectives is that new antiarrhythmic drugs with preferential, even selective, activity on myocardial atrium ion channels had been developed. Among these new antiarrhythmics, dofetilide, and AVE0118, are taken into account. In addition, new possibilities are opened based on the knowledge of the cardioprotective-antiarrhythmic qualities of the opioidergic system.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Compostos de Bifenilo/uso terapêutico , Fenetilaminas/uso terapêutico , Bloqueadores dos Canais de Potássio/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Antiarrítmicos/farmacologia , Fibrilação Atrial/fisiopatologia , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacologia , Eletrofisiologia , Átrios do Coração/efeitos dos fármacos , Humanos , Canais Iônicos/efeitos dos fármacos , Fenetilaminas/administração & dosagem , Fenetilaminas/farmacologia , Bloqueadores dos Canais de Potássio/administração & dosagem , Bloqueadores dos Canais de Potássio/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Opioides/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Fatores de TempoRESUMO
BACKGROUND: Cisplatin-induced renal damage was associated with an inflammatory process. ATP-sensitive potassium channels can be involved in neutrophil migration. This study evaluated the effects of glibenclamide, an ATP-sensitive potassium channel blocker, on cisplatin-induced renal damage. METHODS: A total of 48 Wistar rats received glibenclamide (20 mg/kg/day, s.c.) and 24 h later, these animals, and an additional group of 45 rats, were injected with cisplatin (5 mg/kg, i.p.). In addition, 38 control rats were injected with saline, i.p. Twenty-four hours and 5 days after saline or cisplatin injections blood and urine samples were collected to evaluate renal function and the kidneys were removed for analysis of neutrophil accumulation, tumor necrosis factor-alpha and interleukin-1beta and histological and immunohistochemical studies. RESULTS: Cisplatin injection induced neutrophil recruitment and increased tumor necrosis factor-alpha and interleukin-1beta contents in renal cortices and outer medullae tissues. Cisplatin-treated rats also presented reduction in the glomerular filtration rate, as well as greater immunostaining for ED1 (macrophages/monocytes) and acute tubular necrosis. All of these alterations were reduced by treatment with glibenclamide. These effects seem to be related, at least in part, to the restriction of neutrophil recruitment and inflammatory process observed in the kidneys from glibenclamide+cisplatin-treated rats.