RESUMEN
INTRODUCTION: The Drosophila dorsal vessel (DV) is comprised of two opposing rows of cardioblasts (CBs) that migrate toward the dorsal midline during development. While approaching the midline, CBs change shape, enabling dorsal and ventral attachments with their contralateral partners to create a linear tube with a central lumen. We previously demonstrated DV closure occurs via a "buttoning" mechanism where specific CBs advance ahead of their lateral neighbors, and attach creating transient holes, which eventually seal. RESULTS: Here, we investigate the role of the actin-regulatory protein enabled (Ena) in DV closure. Loss of Ena results in DV cell shape and alignment defects. Live analysis of DV formation in ena mutants shows a reduction in CB leading edge protrusion length and gaps in the DV between contralateral CB pairs. These gaps occur primarily between a specific genetic subtype of CBs, which express the transcription factor seven-up (Svp) and form the ostia inflow tracts of the heart. In WT embryos these gaps between Svp+ CBs are observed transiently during the final stages of DV closure. CONCLUSIONS: Our data suggest that Ena modulates the actin cytoskeleton in order to facilitate the complete sealing of the DV during the final stages of cardiac tube formation.
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Vasos Sanguíneos/embriología , Proteínas de Unión al ADN/metabolismo , Regulación del Desarrollo de la Expresión Génica , Morfogénesis/fisiología , Animales , Vasos Sanguíneos/metabolismo , Movimiento Celular/fisiología , Proteínas de Unión al ADN/genética , Drosophila melanogasterRESUMEN
The embryonic heart tube is formed by the migration and subsequent midline convergence of two bilateral heart fields. In Drosophila the heart fields are organized into two rows of cardioblasts (CBs). While morphogenesis of the dorsal ectoderm, which lies directly above the Drosophila dorsal vessel (DV), has been extensively characterized, the migration and concomitant fundamental factors facilitating DV formation remain poorly understood. Here we provide evidence that DV closure occurs at multiple independent points along the A-P axis of the embryo in a "buttoning" pattern, divergent from the zippering mechanism observed in the overlying epidermis during dorsal closure. Moreover, we demonstrate that a genetically distinct subset of CBs is programmed to make initial contact with the opposing row. To elucidate the cellular mechanisms underlying this process, we examined the role of Rho GTPases during cardiac migration using inhibitory and overexpression approaches. We found that Cdc42 shows striking cell-type specificity during DV formation. Disruption of Cdc42 function specifically prevents CBs that express the homeobox gene tinman from completing their dorsal migration, resulting in a failure to make connections with their partnering CBs. Conversely, neighboring CBs that express the orphan nuclear receptor, seven-up, are not sensitive to Cdc42 inhibition. Furthermore, this phenotype was specific to Cdc42 and was not observed upon perturbation of Rac or Rho function. Together with the observation that DV closure occurs through the initial contralateral pairing of tinman-expressing CBs, our studies suggest that the distinct buttoning mechanism we propose for DV closure is elaborated through signaling pathways regulating Cdc42 activity in this cell type.
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Movimiento Celular/fisiología , Proteínas de Drosophila/metabolismo , Drosophila/embriología , Proteínas de Unión al GTP/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Corazón/embriología , Miocardio/metabolismo , Transducción de Señal/fisiología , Animales , Inmunohistoquímica , Microscopía Confocal , Modelos Biológicos , Miocardio/citología , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Deep brain stimulation (DBS) is effective in treating the segmental symptoms of Parkinson's disease (PD) as well as axial symptoms that are levodopa responsive. PD patients on chronic DBS who develop axial symptoms and gait disturbances several years later oftentimes are refractory to high frequency stimulation (HFS). Several studies report benefit produced by low frequency subthalamic nucleus (STN) stimulation in such patients, though the sustainability of the effects has been mixed. OBJECTIVE: To report the clinical outcomes of a series of patients with Parkinson's disease and levodopa responsive axial and gait disturbances who were switched to 60 Hz stimulation within one year of their DBS surgery. METHODS: A retrospective review of 5 patients, whose severe pre-DBS, levodopa responsive gait disorders worsened on HFS STN-DBS and were subsequently switched to 60 Hz stimulation within 1 year of their surgery. RESULTS: The median age of this cohort was 66 years with median disease duration of 14 years. Four of 5 patients' experienced acute worsening of their axial and gait UPDRS III scores on HFS. All patients' gait disorder improved with 60 Hz along with amelioration of their segmental symptoms and reduction of their levodopa induced dyskinesia. The median time on HFS prior to switching to 60 Hz was two months. Stimulation through the ventral contacts was utilized in all patients with relatively modest changes achieved in levodopa equivalent daily dose. CONCLUSION: This case series demonstrates the clinical efficacy of utilizing low frequency (60 Hz) STN stimulation early in the DBS programming course in more advanced PD patients with levodopa responsive gait disturbance and freezing of gait. Activation of a broader stimulation field likely contributed to both axial and segmental symptom improvement while possibly aiding in the reduction of dyskinesia.
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Estimulación Encefálica Profunda , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiología , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Background: Glutamic acid decarboxylase antibody-spectrum disorders (GAD-SDs) include a group of autoimmune neurological diseases associated with neuronal excitability, most noticeably stiff person syndrome. Immune modulators are the mainstay of treatment, but a significant number of patients remain refractory. Methods: We present our single-center experience of eight cases of GAD-SD, two of which were refractory to immune modulatory treatments. Results: Of the two cases that were refractory to immunomodulation, one showed significant improvement with bilateral globus pallidus interna deep brain stimulation (GPi DBS) placement, and the other showed significant improvement with autologous hematopoietic stem cell transplant (aHSCT). Discussion: To our knowledge, this is the first instance of GPi DBS placement being noted to improve GAD-SD movements.
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Enfermedades Autoinmunes del Sistema Nervioso , Glutamato Descarboxilasa , Humanos , Anticuerpos , InmunomodulaciónRESUMEN
Mutations in the human Jup gene cause arrhythmogenic right ventricular cardiomyopathy (ARVC), a heart muscle disease that often leads to sudden cardiac death. Inactivation of the murine Jup gene (also known as plakoglobin) results in embryonic lethality due to cardiac rupture. In an effort to generate a conditional knockout allele, a neomycin cassette was introduced into the murine plakoglobin (PG) gene. This allele (PG F(N)) functions as a hypomorph when combined with a null allele (PG Δ). About half of the PG F(N)/Δ animals were smaller than their littermates and died before weaning age, whereas the remaining PG F(N)/Δ animals survived. Despite the reduced levels of PG in the heart, there were no signs of cardiomyopathy or cardiac dysfunction as determined by echocardiography. Importantly, the PG homolog, ß-catenin (CTNNB1), was increased in the PG F(N)/Δ hearts. In addition to its structural role as part of the N-cadherin/catenin adhesion complex, ß-catenin is a downstream effector of Wnt signaling. However, no change in ß-catenin/TCF reporter activity was observed in PG F(N)/Δ embryos suggesting that excess ß-catenin was not likely causing increased transcription of Wnt/ß-catenin target genes. These data suggest novel function(s) for PG beyond the heart and define a critical threshold of PG expression that is necessary for postnatal survival.
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Alelos , Miocardio/metabolismo , gamma Catenina/genética , Animales , Displasia Ventricular Derecha Arritmogénica/genética , Cadherinas/genética , Cadherinas/metabolismo , Eliminación de Gen , Regulación del Desarrollo de la Expresión Génica , Genes Letales , Corazón/anatomía & histología , Corazón/crecimiento & desarrollo , Corazón/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Transcripción Genética , Vía de Señalización Wnt , beta Catenina/genética , beta Catenina/metabolismo , gamma Catenina/metabolismoRESUMEN
Activation of the A(2A) adenosine receptor (A(2A)R) has been shown to be cardioprotective. We hypothesized that A(2A)R overexpression could protect the heart from adriamycin-induced cardiomyopathy. Transgenic (TG) mice overexpressing the A(2A)R and wild-type mice (WT) were injected with adriamycin (5 mg.kg(-1).wk(-1) ip, 4 wk). All WT mice survived adriamycin treatment while A(2A)R TG mice suffered 100% mortality at 4 wk. Telemetry showed progressive prolongation of the QT interval, bradyarrhythmias, heart block, and sudden death in adriamycin-treated A(2A)R TG but not WT mice. Both WT and A(2A)R TG demonstrated similar decreases in heart function at 3 wk after treatment. Adriamycin significantly increased end-diastolic intracellular Ca(2+) concentration in A(2A)R TG but not in WT myocytes (P < 0.05). Compared with WT myocytes, action potential duration increased dramatically in A(2A)R TG myocytes (P < 0.05) after adriamycin treatment. Expression of connexin 43 was decreased in adriamycin treated A(2A)R TG but not WT mice. In sharp contrast, A(2A)R overexpression induced after the completion of adriamycin treatment resulted in no deaths and enhanced cardiac performance compared with WT adriamycin-treated mice. Our results indicate that the timing of A(2A)R activation is critical in terms of exacerbating or protecting adriamycin-induced cardiotoxicity. Our data have direct relevance on the clinical use of adenosine agonists or antagonists in the treatment of patients undergoing adriamycin therapy.
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Cardiomiopatías/inducido químicamente , Cardiomiopatías/metabolismo , Doxorrubicina/efectos adversos , Miocardio/metabolismo , Receptor de Adenosina A2A/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/efectos adversos , Cadherinas/metabolismo , Calcio/metabolismo , Cardiomiopatías/mortalidad , Células Cultivadas , Conexina 43/metabolismo , Modelos Animales de Enfermedad , Doxorrubicina/farmacología , Humanos , Potenciales de la Membrana/efectos de los fármacos , Ratones , Ratones Transgénicos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/ultraestructura , Receptor de Adenosina A2A/genéticaRESUMEN
CD is a complex disorder that can have significant impact on a patient's quality of life and physical well-being. BoNTs are a very effective and well-tolerated first-line therapy in relieving CD symptoms over long-term treatment. BoNT treatment should be administered at the lowest effective dose with a minimum of 3 months between treatments. As the incidence of immunoresistance is low, a reassessment of muscle selection, dosing, and diagnosis should take place in the event of suboptimal patient response. Optimal treatment may involve a combination of oral pharmacologic treatment with BoNTs to maintain the use of lowest possible dosing and to extend effectiveness to the recommended 3-month dosing interval. Physical therapy in conjunction with BoNT treatment can also extend treatment efficacy as well. Comorbidities such as insomnia, depression, and anxiety can interfere with successful CD treatment and should be actively managed along with the symptoms of CD. Although our understanding of CD is incomplete, it is ever expanding. As a deeper understanding of disease pathophysiology and disease progression is gained, treatment efforts will be refined for optimal outcome and patient satisfaction.
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Antidiscinéticos/uso terapéutico , Toxinas Botulínicas/uso terapéutico , Guías de Práctica Clínica como Asunto , Tortícolis/tratamiento farmacológico , HumanosRESUMEN
BACKGROUND: Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B (MAO-B) prolong the duration of action of both endogenously and exogenously derived dopamine. Rasagiline [N-propargyl-l(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits brain MAO-B and is specifically designed for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to review the pharmacology, tolerability, and clinical efficacy of rasagiline in the treatment of PD. METHODS: MEDLINE (1966-April 2007), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-April 2007) were searched for original research and review articles published in English. The search terms were monoamine oxidase, neuroprotection, Parkinson disease, propargylamine, rasagiline, and selegiline. The reference lists of articles were also consulted, as was information provided by the manufacturer of rasagiline. RESULTS: Data from 63 clinical and laboratory studies were analyzed. Based on the results from those studies, we concluded that rasagiline PO QD, at the therapeutic dosage range of 0.5 to 1 rag/d, is effective and well tolerated and completely, selectively, and specifically inhibited MAO-B. Pharmacologically, rasagiline was found to be < or =10-fold more potent than selegiline and was not metabolized to amphetamine derivatives. Rasagiline was effective both as monotherapy in early PD and as adjunctive treatment in patients with advancing PD and motor fluctuations. As monotherapy, rasagiline provided modest yet clinically meaningful benefit. A randomized, double-blind, placebo-controlled study found that, after 26 weeks of treatment, the adjusted effect size for total Unified Parkinson's Disease Rating Scale score was -4.20 (95% CI, -5.66 to -2.73) for rasagiline 1 mg/d versus placebo (P < 0.001). Preliminary long-term data from an open-label study suggest a sustained therapeutic advantage when rasagiline is initiated early (before the need for dopaminergic agents) rather than later. In patients with more advanced disease who received treatment with dopaminergic agents, rasagiline and entacapone were associated with reductions of "off" time significantly greater than placebo (-1.18 and -1.2 vs 0.4 hour; both, P < or = 0.001). Rasagiline was well tolerated in younger (aged <;70 years) and older (aged > or =70 years) patients with early or advanced PD. Pharmacologically, rasagiline has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the "cheese reaction"). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, rasagiline has been found to have neuroprotective properties that may be independent of MAO-B inhibition. CONCLUSIONS: Based on this review, rasagiline has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations. Whether rasagiline is associated with clinically significant neuroprotection (ie, disease modification) in PD is the subject of ongoing clinical trials.
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Antiparkinsonianos/uso terapéutico , Indanos/uso terapéutico , Inhibidores de la Monoaminooxidasa/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/farmacología , Interacciones Farmacológicas , Quimioterapia Combinada , Interacciones Alimento-Droga , Humanos , Indanos/administración & dosificación , Indanos/efectos adversos , Indanos/farmacología , Inhibidores de la Monoaminooxidasa/administración & dosificación , Inhibidores de la Monoaminooxidasa/efectos adversos , Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacología , Selegilina/administración & dosificación , Selegilina/efectos adversos , Selegilina/farmacología , Selegilina/uso terapéuticoRESUMEN
The available pharmacotherapies for Parkinson's disease address symptomatology because no agent has been demonstrated to provide definite neuroprotection against the disease. Choice of pharmacotherapy must include consideration of short-term benefits as well as long-term consequences. Patients with mild Parkinson's disease often function adequately without symptomatic treatment. However, recent data suggest that initiation of treatment with a well-tolerated agent (e.g., the monoamine oxidase [MAO]-B inhibitor rasagiline) in the absence of functional impairment is associated with improved long-term outcomes. Consideration should also be given to many patient-specific factors, including patient expectations, level of disability, employment status, functional as well as chronologic age, expected efficacy and tolerability of drugs, and response to previous Parkinson's disease therapies. Increasingly, initial monotherapy begins with a nondopaminergic agent or, if the patient is considered functionally young, a dopamine agonist. Since Parkinson's disease is a progressive disorder, adjustments to pharmacotherapy must be expected over time. When greater symptomatic relief is desired, or in the more frail elderly patient, levodopa therapy should be considered. If motor fluctuations develop, addition of a catechol-O-methyltransferase inhibitor or MAO-B inhibitor should be considered. For management of levodopa-induced dyskinesias, addition of amantadine is an option. Surgery may be considered when patients need additional symptomatic control or are experiencing severe motor complications despite pharmacologically optimized therapy.
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Antiparkinsonianos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Amantadina/uso terapéutico , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/economía , Inhibidores de Catecol O-Metiltransferasa , Antagonistas Colinérgicos/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Humanos , Levodopa/efectos adversos , Levodopa/uso terapéutico , Inhibidores de la Monoaminooxidasa/uso terapéutico , Enfermedad de Parkinson/economía , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapiaRESUMEN
As Parkinson's disease progresses, fluctuations between akinesia, or hypomobility ("off" times), and mobility ("on" times) increase in frequency despite optimized pharmacotherapy. Motor fluctuations include predictable shortening of therapeutic effects, nocturnal or early morning akinesia, random hypomobility, and delayed mobility (variable responses to individual doses of drugs). Current oral antiparkinson drugs are inadequate for rapid and consistent relief of symptoms during hypomobility. Apomorphine, an injectable dopamine agonist recently introduced in the United States, is indicated for the management of hypomobility associated with advanced Parkinson's disease. Subcutaneous apomorphine is effective for rapid and consistent rescue from hypomobility, with a magnitude of motor improvement similar to that of levodopa. The effect begins within 20 minutes after dosing and lasts approximately 100 minutes. Therapeutic rescue doses are 2-6 mg, and patients typically require approximately three rescue doses/day. Apomorphine is associated with a clinically significant potential to cause nausea and orthostatic hypotension. These potential effects can be managed with antiemetic prophylaxis and appropriate determination of the therapeutic rescue dose.
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Apomorfina/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos/uso terapéutico , Dopamina/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Discinesia Inducida por Medicamentos/fisiopatología , Humanos , Modelos Biológicos , Estructura Molecular , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatologíaRESUMEN
Rasagiline is a novel second-generation propargylamine that irreversibly and selectively inhibits monoamine oxidase type B (MAO-B). For the management of Parkinson disease (PD), rasagiline is efficacious across the span of PD stages ranging from monotherapy in early disease to adjunctive treatment in patients with advancing disease and motor fluctuations. Rasagiline completely and selectively inhibits MAO-B with a potency 5 to 10 times greater than selegiline. Unlike the prototype propargylamine selegiline, which is metabolized to amphetamine derivatives, rasagiline is biotransformed to aminoindan, a non-amphetamine compound. Rasagiline is well tolerated with infrequent cardiovascular or psychiatric side effects, and at the recommended therapeutic dose of up to 1 mg once daily, tyramine restriction is unnecessary. In addition to MAO-B inhibition, the propargylamine chain also confers dose-related antioxidant and antiapoptotic effects, which have been associated with neuroprotection in multiple experimental models. Thus, in addition to symptomatic benefits, rasagiline offers the promise of clinically relevant neuroprotection.
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Indanos/uso terapéutico , Inhibidores de la Monoaminooxidasa/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Ensayos Clínicos como Asunto , Interacciones Farmacológicas , Humanos , Indanos/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/farmacología , Selegilina/farmacología , Selegilina/uso terapéuticoRESUMEN
Essential tremor is a common movement disorder in adults that interferes with the performance of functional and social activities. Differentiation of essential tremor from other tremor syndromes is important in order to provide appropriate patient education and therapy. The mainstays of pharmacotherapy are propranolol and primidone; however, in selected patients, agents such as alcohol, benzodiazepines, botulinum toxin, and gabapentin may provide symptomatic benefits. Advances in surgical interventions, such as stereotactic thalamotomy and thalamic deep brain stimulation, offer patients an alternative treatment modality when pharmacotherapy is inadequate. A treatment algorithm is provided to guide clinicians in the management of patients with essential tremor.
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Aminas , Ácidos Ciclohexanocarboxílicos , Temblor Esencial/diagnóstico , Temblor Esencial/terapia , Ácido gamma-Aminobutírico , Acetatos/uso terapéutico , Diagnóstico Diferencial , Temblor Esencial/clasificación , Gabapentina , Humanos , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Primidona/uso terapéutico , Propranolol/uso terapéuticoRESUMEN
Plakoglobin (PG, γ-Catenin, JUP), a member of the armadillo protein family and close homolog of ß-catenin, functions to link cell surface cadherin molecules with the cytoskeleton. PG is the only junctional component found in both desmosomes and adherens junctions and thus plays a critical role in the regulation of cell-cell adhesion. Similar to ß-catenin, PG is able to interact with components of the Wnt signaling pathway and directly affect gene expression by binding with LEF/TCF transcription factors. In addition, it has been proposed that PG functions primarily as a competitive inhibitor of ß-catenin transcriptional activity by sequestering LEF/TCF. Compared to ß-catenin, the contribution of PG as a transcriptional regulator in either physiological or pathological conditions is poorly understood. There is increasing clinical interest in PG as both a structural protein as well as a signaling molecule as mutations have been identified in the human PG gene that cause Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and cutaneous syndromes. This review will discuss the connection between altered cell adhesion and gene expression and its contribution to disease pathogenesis.
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Proteínas del Dominio Armadillo/metabolismo , Adhesión Celular , Miocardio/metabolismo , Animales , Proteínas del Dominio Armadillo/química , Proteínas del Dominio Armadillo/genética , Displasia Ventricular Derecha Arritmogénica/metabolismo , Displasia Ventricular Derecha Arritmogénica/patología , Regulación de la Expresión Génica , Humanos , Transducción de Señal , beta Catenina/química , beta Catenina/metabolismo , gamma Catenina/química , gamma Catenina/genética , gamma Catenina/metabolismoAsunto(s)
Ceruloplasmina/deficiencia , Trastornos del Metabolismo del Hierro/diagnóstico , Enfermedades Neurodegenerativas/diagnóstico , Putamen/patología , Negro o Afroamericano , Ceruloplasmina/genética , Femenino , Humanos , Trastornos del Metabolismo del Hierro/diagnóstico por imagen , Trastornos del Metabolismo del Hierro/genética , Trastornos del Metabolismo del Hierro/patología , Persona de Mediana Edad , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Putamen/diagnóstico por imagenRESUMEN
BACKGROUND: It is generally agreed that diffusion of botulinum toxin occurs, but the extent of the spread and its clinical importance are disputed. Many factors have been suggested to play a role but which have the most clinical relevance is a subject of much discussion. METHODS: This review discusses the variables affecting diffusion, including protein composition and molecular size as well as injection factors (e.g., volume, dose, injection method). It also discusses data on diffusion from comparative studies in animal models and human clinical trials that illustrate differences between the available botulinum toxin products (onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB). RESULTS: Neither molecular weight nor the presence of complexing proteins appears to affect diffusion; however, injection volume, concentration, and dose all play roles and are modifiable. Both animal and human studies show that botulinum toxin products are not interchangeable, and that some products are associated with greater diffusion and higher rates of diffusion-related adverse events than others. DISCUSSION: Each of the botulinum toxins is a unique pharmacologic entity. A working knowledge of the different serotypes is essential to avoid unwanted diffusion-related adverse events. In addition, clinicians should be aware that the factors influencing diffusion may range from properties intrinsic to the drug to accurate muscle selection as well as dilution, volume, and dose injected.
RESUMEN
BACKGROUND: Tetrabenazine (TBZ) is a monoamine storage inhibitor that was first introduced in the 1970s for the management of hyperkinetic movement disorders. Despite acceptance and usage worldwide, TBZ was only recently approved in the United States for the treatment of Huntington chorea. This review focuses on the use of TBZ in various hyperkinetic movement disorders, which are considered "rare" or "orphan" diseases, to help practitioners better understand its clinical role and use. OBJECTIVE: This review describes the clinical efficacy and tolerability of TBZ in the management of dystonia, Huntington chorea, tardive dyskinesia (TDk), and tic disorders. METHODS: A Cochrane Library, EMBASE, MedlinePlus, PubMed, and clinical trials database search (up to May 2012) was conducted to identify articles and studies using the subject terms tetrabenazine, Huntington disease, dystonia, tardive dyskinesia, Tourette, tics, and hyperkinetic movement. Only English-language articles were reviewed. RESULTS: TBZ variably undergoes extensive first-pass metabolism to active metabolites, some of which are metabolized by the cytochrome P450 2D6 isozyme. Pharmacology studies demonstrate that TBZ reversibly inhibits the activity of vesicular monoamine transporter 2, resulting in depletion of central dopamine. For management of dystonias, 1 of 3 small prospective blinded studies and 4 of 5 retrospective studies reported clinical benefit with TBZ use in pediatrics and adults. For Huntington chorea, 2 randomized, double-blind, placebo-controlled studies along with open-label studies demonstrate the effectiveness of TBZ in adults. For TDk, 9 of 11 studies (prospective controlled and retrospective) reported positive benefit. For Gilles de la Tourette syndrome, 9 of 11 studies (prospective controlled and retrospective) reported positive benefit on motor and phonic tics in pediatric and adult patients. Overall, adverse effects are dose and age related and include depression, fatigue, parkinsonism, and somnolence. CONCLUSIONS: TBZ is an effective oral therapy for chorea of Huntington disease and may be considered as an alternative agent for the management of dystonia, TDk, and tic disorders (these latter 3 conditions are off-label uses in the United States). The drug possesses an acceptable tolerability profile and has been used in pediatric and adult populations.
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Inhibidores de Captación Adrenérgica/uso terapéutico , Hipercinesia/tratamiento farmacológico , Tetrabenazina/uso terapéutico , Inhibidores de Captación Adrenérgica/efectos adversos , Inhibidores de Captación Adrenérgica/farmacología , Animales , Corea/tratamiento farmacológico , Corea/fisiopatología , Distonía/tratamiento farmacológico , Distonía/fisiopatología , Humanos , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/fisiopatología , Hipercinesia/fisiopatología , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/fisiopatología , Enfermedades Raras/tratamiento farmacológico , Enfermedades Raras/fisiopatología , Tetrabenazina/efectos adversos , Tetrabenazina/farmacología , Trastornos de Tic/tratamiento farmacológico , Trastornos de Tic/fisiopatologíaRESUMEN
Arrhythmic right ventricular cardiomyopathy (ARVC) is a hereditary heart muscle disease that causes sudden cardiac death (SCD) in young people. Almost half of ARVC patients have a mutation in genes encoding cell adhesion proteins of the desmosome, including plakoglobin (JUP). We previously reported that cardiac tissue-specific plakoglobin (PG) knockout (PG CKO) mice have no apparent conduction abnormality and survive longer than expected. Importantly, the PG homolog, ß-catenin (CTNNB1), showed increased association with the gap junction protein connexin43 (Cx43) in PG CKO hearts. To determine whether ß-catenin is required to maintain cardiac conduction in the absence of PG, we generated mice lacking both PG and ß-catenin specifically in the heart (i.e., double knockout [DKO]). The DKO mice exhibited cardiomyopathy, fibrous tissue replacement, and conduction abnormalities resulting in SCD. Loss of the cadherin linker proteins resulted in dissolution of the intercalated disc (ICD) structure. Moreover, Cx43-containing gap junction plaques were reduced at the ICD, consistent with the arrhythmogenicity of the DKO hearts. Finally, ambulatory electrocardiogram monitoring captured the abrupt onset of spontaneous lethal ventricular arrhythmia in the DKO mice. In conclusion, these studies demonstrate that the N-cadherin-binding partners, PG and ß-catenin, are indispensable for maintaining mechanoelectrical coupling in the heart.
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Arritmias Cardíacas/fisiopatología , Cadherinas/metabolismo , Uniones Comunicantes/patología , Corazón/fisiopatología , beta Catenina/genética , gamma Catenina/genética , Animales , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patología , Conexina 43/metabolismo , Uniones Comunicantes/genética , Uniones Comunicantes/metabolismo , Eliminación de Gen , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocardio/metabolismo , Miocardio/patología , Unión Proteica , beta Catenina/metabolismo , gamma Catenina/metabolismoRESUMEN
Mutations in the plakoglobin (JUP) gene have been identified in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. However, the mechanisms underlying plakoglobin dysfunction involved in the pathogenesis of ARVC remain poorly understood. Plakoglobin is a component of both desmosomes and adherens junctions located at the intercalated disc (ICD) of cardiomyocytes, where it functions to link cadherins to the cytoskeleton. In addition, plakoglobin functions as a signaling protein via its ability to modulate the Wnt/ß-catenin signaling pathway. To investigate the role of plakoglobin in ARVC, we generated an inducible cardiorestricted knockout (CKO) of the plakoglobin gene in mice. Plakoglobin CKO mice exhibited progressive loss of cardiac myocytes, extensive inflammatory infiltration, fibrous tissue replacement, and cardiac dysfunction similar to those of ARVC patients. Desmosomal proteins from the ICD were decreased, consistent with altered desmosome ultrastructure in plakoglobin CKO hearts. Despite gap junction remodeling, plakoglobin CKO hearts were refractory to induced arrhythmias. Ablation of plakoglobin caused increase ß-catenin stabilization associated with activated AKT and inhibition of glycogen synthase kinase 3ß. Finally, ß-catenin/TCF transcriptional activity may contribute to the cardiac hypertrophy response in plakoglobin CKO mice. This novel model of ARVC demonstrates for the first time how plakoglobin affects ß-catenin activity in the heart and its implications for disease pathogenesis.
Asunto(s)
Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/patología , Técnicas de Inactivación de Genes , beta Catenina/metabolismo , gamma Catenina/genética , Uniones Adherentes/genética , Uniones Adherentes/metabolismo , Uniones Adherentes/patología , Animales , Displasia Ventricular Derecha Arritmogénica/metabolismo , Citocinas/inmunología , Desmosomas/genética , Desmosomas/metabolismo , Desmosomas/patología , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Noqueados , Miocardio/patología , beta Catenina/genética , gamma Catenina/metabolismoAsunto(s)
Toxinas Botulínicas Tipo A/uso terapéutico , Trastornos Distónicos/inducido químicamente , Trastornos Distónicos/tratamiento farmacológico , Fluoxetina/efectos adversos , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/etiología , Fármacos Neuromusculares/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Anciano , Antidiscinéticos/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/etiología , Fluoxetina/uso terapéutico , Humanos , Masculino , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
Rotigotine is a highly lipophilic dopamine-receptor agonist and the first transdermally delivered agent to demonstrate efficacy and safety as monotherapy in early Parkinson's disease and to reduce "off" hours in levodopa-treated patients with advanced Parkinson's disease. The rotigotine pharmacophore is nonergolinic and demonstrates high affinity for dopamine D(2) and D(3) receptors. With once-daily application, the patch matrix provides continuous, nonfluctuating plasma drug levels at steady state, resulting in continuous and steady plasma and brain levels and striatal dopamine-receptor stimulation. In early Parkinson's disease, doses of rotigotine up to 8 mg/24 hours demonstrate comparable efficacy to ropinirole (at doses up to 12 mg/day); in advanced Parkinson's disease, doses of rotigotine up to 16 mg/24 hours demonstrate comparable efficacy and tolerability to pramipexole (at doses up to 4.5 mg/day). In the registration trials for early and advanced Parkinson's disease, the adverse effects most commonly observed with rotigotine were minor application site reactions, dizziness, nausea, and somnolence. Doses of transdermal rotigotine can be titrated to a maintenance dose within 2-3 weeks, and the once-daily regimen minimizes complexity of therapy. The transdermal delivery system is also an advantage when nonoral administration is desired, and the 24-hour, continuous, nonfluctuating drug levels can improve early morning and nocturnal symptoms of Parkinson's disease. Thus, transdermally delivered rotigotine is a clinically innovative and useful addition to the dopamine-receptor agonist class. This review summarizes the key pharmacologic and clinical data for rotigotine and provides a focused clinical context for its use in early-to-advanced Parkinson's disease, as well as a brief summary for its role in restless legs syndrome.