RESUMEN
BACKGROUND: Calcitonin gene-related peptide (CGRP) therapeutics introduce new excitement and possibly yet to be determined distressing discords in the field of Headache Medicine. Growth in knowledge of CGRP in the pathophysiology of migraine introduced CGRP antagonism to headache treatment. Potential adverse effects on the other circulatory and neurovascular diseases have been foremost concerns. Failures in development of gepants and growth in knowledge of monoclonal antibody therapeutics combined to deliver the anti-CGRP monoclonal antibodies (mAbs). CURRENT SITUATION AS OF JULY 2018: Erenumab, eptinezumab, fremanezumab, and galcanezumab are approved, submitted to, or preparing for submission at both the European Medicines Agency and the US Food and Drug Administration (FDA). METHODS: This Headache Currents update emanates from a symposium on CGRP and immunology in Headache Medicine, and reviews both. RESULTS AND CONCLUSION: Understanding CGRP in Headache Medicine requires information on aspects of the CGRP ligand, cell surface G protein receptor, CGRP receptor specifics, and antagonism by CGRP small and large molecules. Recent reports of CGRP's high affinity for amylin receptors dictate some attention to this family-related peptide. To better understand potential immunogenic risks and off-target toxicities of the anti-CGRP monoclonal antibodies, this review discusses immunology and CGRP and reviews IgG structure and function, monoclonal antibody production, ligand-antigen-antibody relationships, and clinical CGRP mAb specifics. Upon completion, the reader should better summarize CGRP antagonist fundamentals, recall antibody structure and function, restate therapeutic mAbs attributes, and appraise immunogenic risks.
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Anticuerpos Monoclonales/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Cefalea/tratamiento farmacológico , Péptido Relacionado con Gen de Calcitonina/metabolismo , Cefalea/inmunología , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Receptores de Polipéptido Amiloide de Islotes Pancreáticos/metabolismoRESUMEN
Growth in knowledge about calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine brought CGRP antagonism to headache medicine. Failures in development of small molecule CGRP receptor antagonists and increasing knowledge and use of monoclonal antibodies (mAbs) in medicine led to the breakthrough development of large molecule anti-CGRP mAbs: eptinezumab, erenumab, fremanezumab, and galcanezumab. This specifics about CGRP immunology aims to outline: (1) knowledge needed for CGRP antagonism and (2) developmental issues of specific CGRP antagonists for provider use. This clinically oriented review documents IgG structure and function; state of the art of monoclonal IgG production and ligand-antigen-antibodies in migraine therapeutics contributing to immunogenic risks and off-target toxicities. Specifics to CGRP ligand, receptor, antagonism, and molecules, small and large, complete this review. Completion will facilitate assessment of the similarities, differences, and application of the forthcoming anti-CGRP receptor and ligand antagonists for patients.
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Anticuerpos Monoclonales/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/inmunología , Péptido Relacionado con Gen de Calcitonina/inmunología , Trastornos Migrañosos/inmunología , Receptores de Péptido Relacionado con el Gen de Calcitonina/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Complejo Antígeno-Anticuerpo/metabolismo , Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Péptido Relacionado con Gen de Calcitonina/metabolismo , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Unión Proteica , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismoRESUMEN
A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in two different models of neuropathic pain in addition to downregulating glial activation markers in the spinal cord. We aimed to determine whether a single intrathecal administration of an A2AR agonist was able to attenuate motor symptoms induced by experimental autoimmune encephalopathy. Two A2AR agonists (CGS21680 and ATL313) significantly attenuated progression of motor symptoms following a single intrathecal administration at the onset of motor symptoms. OX-42, a marker of microglial activation, was significantly attenuated in the lumbar spinal cord following A2AR administration compared to vehicle. Therefore, A2AR agonists attenuate motor symptoms of EAE by acting on A2AR in the spinal cord.
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Agonistas del Receptor de Adenosina A2/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Parálisis/tratamiento farmacológico , Médula Espinal/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina/uso terapéutico , Agonistas del Receptor de Adenosina A2/farmacología , Animales , Masculino , Microglía/efectos de los fármacos , Fenetilaminas/farmacología , Fenetilaminas/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , RatasRESUMEN
Drugs containing the benzimidazole carbamate scaffold include anthelmintic and antifungal agents, and they are now also recognized as having potential applications in the treatment of colorectal and other cancers. These agents act by binding to ß-tubulin, and in doing so they disrupt microtubules, arrest cell division, and promote apoptotic cell death in malignant cells. We have evaluated several commercially available benzimidazole carbamates for cytotoxic activity in colorectal cancer cells. In addition to cytotoxicity, we also observe activation of the transcription factor, heat shock factor-1 (HSF1). HSF1 is well known to mediate a cytoprotective response that promotes tumor cell survival and drug resistance. Here, we show that biochemical inhibition with the HSF1 inhibitor KRIBB11 or siRNA-based silencing of HSF1 results in a significant enhancement of drug potency, causing an approximately two-fold decrease in IC50 values of parbendazole and nocodazole. We also define a mechanism for drug-induced HSF1 activation, which results from a phosphorylation event at Ser326 that is dependent on the activation of the extracellular regulated protein kinase-1/2 (ERK-1/2) mitogen-activated protein kinase pathway. Inhibition of the upstream kinase MEK-1/2 with U0126 attenuates the phosphorylation of both ERK-1/2 and HSF1, and significantly enhances drug cytotoxicity. From these data we propose a unique model whereby the ERK-1/2-dependent activation of HSF1 promotes chemotherapeutic resistance to benzimidazole carbamates. Therefore, targeting the ERK-1/2 signaling cascade is a potential strategy for HSF1 inhibition and a means of enhancing the cytotoxicity of these agents.
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Antineoplásicos/farmacología , Bencimidazoles/farmacología , Carbamatos/farmacología , Neoplasias Colorrectales/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Factores de Transcripción/metabolismo , Línea Celular Tumoral/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Factores de Transcripción del Choque Térmico , Humanos , Sistema de Señalización de MAP Quinasas , Nocodazol/farmacología , FosforilaciónRESUMEN
BACKGROUND: Migraineurs variably attribute the cause of their headache to tobacco exposure, whereas tobacco is often stated to cause headache-related disability worldwide. Given tobacco's physiological and emotional addictiveness and migraine's substantial economic impact, improved functionality can be difficult for those with migraine exposed to tobacco products. Environmental tobacco exposure in indoor spaces and workplaces is associated with exacerbation of headache. Avoidance of headache triggers is included in most comprehensive migraine treatment programs, yet tobacco awareness, avoidance, or coping is rarely emphasized as part of that regimen. OBJECTIVE: The aims of this study were to examine the various types of tobacco products to which headache sufferers are exposed and the known basic mechanisms by which tobacco (nicotine) exposure promotes headache pain, and to review the extensive literature on tobacco related to headache with a detailed descriptive narrative providing the basis for conclusions regarding association of noncluster headache-related tobacco exposure. Tobacco-related recommendations are offered. METHODS: MEDLINE, EMBASE, and Google Scholar databases were searched without yearly restriction through the date of submission (May 2015), using the MeSH terms "tobacco," "tobacco products," "smoking," "tobacco use," "headache," and "headache disorders." The selection of articles was not limited to English studies or to humans. Articles were excluded when "headache" and "tobacco" were not both mentioned with data provided. Case series were included. Bibliographies of all articles were screened for additional relevant articles. RESULTS: Although migraineurs worldwide report tobacco smoke among triggers, it is rarely among the highest in frequency, and biases abound with predominantly noncontrolled retrospective data. Prospective population-based diary data are extremely limited, and no controlled trials exist to confirm a cause and effect for headache of any type. Although some studies are nonsupportive and even conflicting, headache, pain, and tobacco exposure currently remain associated. CONCLUSION: Conflicting data support the validity of patient-reported environmental tobacco exposure as a headache trigger. Prospective controlled studies are needed, but unlikely to be performed, to determine the extent that tobacco influences the headache process, in addition to other under-recognized factors. Meanwhile, because of numerous other negative health effects, decreased tobacco exposure should be recommended to headache patients of all ages in hopes of decreasing disability and improving functionality.
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Exposición a Riesgos Ambientales/efectos adversos , Trastornos Migrañosos/inducido químicamente , Nicotiana/química , Nicotina/efectos adversos , Fumar/efectos adversos , Productos de Tabaco/efectos adversos , Contaminación por Humo de Tabaco/efectos adversos , Enfermedades de los Trabajadores Agrícolas/inducido químicamente , Sesgo , Cefalalgia Histamínica/inducido químicamente , Sistemas Electrónicos de Liberación de Nicotina/efectos adversos , Humanos , Trastornos Migrañosos/epidemiología , Trastornos Migrañosos/fisiopatología , Nicotina/farmacología , Estudios Prospectivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVES: Systematic review of preventive pharmacologic treatments for community-dwelling adults with episodic migraine. DATA SOURCES: Electronic databases through May 20, 2012. ELIGIBILITY CRITERIA: English-language randomized controlled trials (RCTs) of preventive drugs compared to placebo or active treatments examining rates of ≥50 % reduction in monthly migraine frequency or improvement in quality of life. STUDY APPRAISAL AND SYNTHESIS METHODS: We assessed risk of bias and strength of evidence and conducted random effects meta-analyses of absolute risk differences and Bayesian network meta-analysis. RESULTS: Of 5,244 retrieved references, 215 publications of RCTs provided mostly low-strength evidence because of the risk of bias and imprecision. RCTs examined 59 drugs from 14 drug classes. All approved drugs, including topiramate (9 RCTs), divalproex (3 RCTs), timolol (3 RCTs), and propranolol (4 RCTs); off-label beta blockers metoprolol (4 RCTs), atenolol (1 RCT), nadolol (1 RCT), and acebutolol (1 RCT); angiotensin-converting enzyme inhibitors captopril (1 RCT) and lisinopril (1 RCT); and angiotensin II receptor blocker candesartan (1 RCT), outperformed placebo in reducing monthly migraine frequency by ≥50 % in 200-400 patients per 1,000 treated. Adverse effects leading to treatment discontinuation (68 RCTs) were greater with topiramate, off-label antiepileptics, and antidepressants than with placebo. Limited direct evidence as well as frequentist and exploratory network Bayesian meta-analysis showed no statistically significant differences in benefits between approved drugs. Off-label angiotensin-inhibiting drugs and beta-blockers were most effective and tolerable for episodic migraine prevention. LIMITATIONS: We did not quantify reporting bias or contact principal investigators regarding unpublished trials. CONCLUSIONS: Approved drugs prevented episodic migraine frequency by ≥50 % with no statistically significant difference between them. Exploratory network meta-analysis suggested that off-label angiotensin-inhibiting drugs and beta-blockers had favorable benefit-to-harm ratios. Evidence is lacking for long-term effects of drug treatments (i.e., trials of more than 3 months duration), especially for quality of life.
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Anticonvulsivantes/uso terapéutico , Trastornos Migrañosos/prevención & control , Adulto , Anticonvulsivantes/efectos adversos , Medicina Basada en la Evidencia/métodos , Humanos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in a chronic constriction injury (CCI) model of neuropathic pain. We aimed to determine if this long-term reversal was induced by A2AR agonism versus more generalized across adenosine receptor subtypes, and begin to explore the intracellular signaling cascades involved. In addition, we sought to identify whether the enduring effect could be extended to other models of neuropathic pain. We tested an A1R and A2BR agonist in CCI and found the same long duration effect with A2BR but not A1R agonism. An A2AR agonist (ATL313) produced a significant long-duration reversal of mechanical allodynia induced by long established CCI (administered 6 weeks after surgery), spinal nerve ligation and sciatic inflammatory neuropathy. To determine if ATL313 had a direct effect on glia, ATL313 was coadministered with lipopolysaccharide to neonatal microglia and astrocytes in vitro. ATL313 significantly attenuated TNFα production in both microglia and astrocytes but had no effect on LPS induced IL-10. Protein kinase C significantly reversed the ATL313 effects on TNFα in vitro in microglia and astrocytes, while a protein kinase A inhibitor only effected microglia. Both intrathecal PKA and PKC inhibitors significantly reversed the effect of the A2AR agonist on neuropathic allodynia. Therefore, A2AR agonists administered IT remain an exciting novel target for the treatment of neuropathic pain.
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Agonistas del Receptor de Adenosina A2/uso terapéutico , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Hiperalgesia/metabolismo , Proteína Quinasa C/fisiología , Neuropatía Ciática/tratamiento farmacológico , Neuropatía Ciática/enzimología , Transducción de Señal/inmunología , Agonistas del Receptor de Adenosina A2/administración & dosificación , Animales , Células Cultivadas , Enfermedad Crónica , Constricción Patológica/tratamiento farmacológico , Constricción Patológica/enzimología , Constricción Patológica/patología , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Hiperalgesia/enzimología , Hiperalgesia/patología , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Inflamación/patología , Inyecciones Espinales , Ligadura , Masculino , Piperidinas/administración & dosificación , Piperidinas/uso terapéutico , Proteína Quinasa C/antagonistas & inhibidores , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Neuropatía Ciática/patología , Transducción de Señal/efectos de los fármacosRESUMEN
Opioids, such as morphine, induce potent analgesia and are the gold standard for the treatment of acute pain. However, opioids also activate glia, inducing pro-inflammatory cytokine and chemokine production, which counter-regulates the analgesic properties of classical opioid receptor activation. It is not known how long these adverse pro-inflammatory effects last or whether prior morphine could sensitize the central nervous system (CNS) such that responses to a subsequent injury/inflammation would be exacerbated. Here, multiple models of inflammation or injury were induced two days after morphine (5mg/kg b.i.d., five days , s.c.) to test the generality of morphine sensitization of later pain. Prior repeated morphine potentiated the duration of allodynia from peripheral inflammatory challenges (complete Freund's adjuvant (CFA) into either hind paw skin or masseter muscle) and from peripheral neuropathy (mild chronic constriction injury (CCI) of the sciatic nerve). Spinal cord and trigeminal nucleus caudalis mRNAs were analyzed to identify whether repeated morphine was sufficient to alter CNS expression of pro-inflammatory response genes, measured two days after cessation of treatment. Prior morphine elevated IL-1ß mRNA at both sites, MHC-II and TLR4 in the trigeminal nucleus caudalis but not spinal cord, but not glial activation markers at either site. Finally, in order to identify whether morphine sensitized pro-inflammatory cytokine release, spinal cord was isolated two days after morphine dosing for five days , and slices stimulated ex vivo with lipopolysaccharide. The morphine significantly induced TNFα protein release. Therefore, repeated morphine is able to sensitize subsequent CNS responses to immune challenges.
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Hiperalgesia/metabolismo , Morfina/toxicidad , Dolor/metabolismo , Enfermedades del Sistema Nervioso Periférico/metabolismo , Analgésicos Opioides/efectos adversos , Animales , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hiperalgesia/inmunología , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Enfermedades del Sistema Nervioso Periférico/inmunología , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE OF REVIEW: Recent descriptions of the group of clinical disorders collectively defined as IgG4-related systemic disease (IgG4-RSD) have prompted this review of the unique biology of the IgG4 antibody. This article will discuss IgG4 structure and function, the unique phenomenon of half-antibody exchange, and the implications of IgG4 biology for its proposed role in immunologic diseases. RECENT FINDINGS: IgG4 antibodies have unique structural and functional properties and undergo 'half-antibody exchange' in vivo, resulting in recombined antibodies composed of two different binding specificities. The production of IgG4 antibodies appears to be driven in part by T helper 2 (Th2) cytokines that mediate allergic responses and IgE production. Although serum IgG4 levels in healthy individuals vary significantly, data from multiple sclerosis (MS) patients suggest tight regulation of individual IgG4 levels over time. IgG4-RSD represents a diverse group of clinical disorders unified by elevated IgG4 levels and specific histopathologic findings. A key unanswered question is whether IgG4, a relatively weak activator of effector cells, is pathogenic in these disorders. SUMMARY: IgG4 is a unique antibody biologically and structurally. Increased understanding of its precise role in the clinical syndromes that comprise IgG4-RSD may ultimately elucidate the underlying pathogenesis.
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Inmunoglobulina G/química , Inmunoglobulina G/inmunología , Anticuerpos Biespecíficos/biosíntesis , Anticuerpos Biespecíficos/química , Anticuerpos Biespecíficos/inmunología , Especificidad de Anticuerpos , Autoanticuerpos/biosíntesis , Autoanticuerpos/química , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/uso terapéutico , Estructura Molecular , Estructura Terciaria de Proteína , Células Th2/inmunologíaRESUMEN
While stress and stress-induced glucocorticoids are classically considered immunosuppressive, they can also enhance proinflammatory responses to subsequent challenges. Corticosterone (CORT) primes rat immune cells, exacerbating pro-inflammatory responses to subsequent immune challenges. Stress can also sensitize pain. One possibility is that stress primes spinal immune cells, predominantly glia, which are key mediators in pain enhancement through their release of proinflammatory cytokines. Therefore, we aimed to identify whether prior CORT sensitizes spinal cord glia such that a potentiated pro-inflammatory response occurs to later intrathecal (IT) lipopolysaccharide (LPS), thereby enhancing pain. Rats received subcutaneous CORT/vehicle 24 h before IT LPS/vehicle. Hind paw pain thresholds were measured before CORT/vehicle, before and up to 48 h after IT LPS/vehicle. In separate rats treated as above, lumbar spinal cord tissue was collected and processed for proinflammatory mediators. CORT alone had no effect on pain responses, nor on any pro-inflammatory cytokines measured. LPS induced allodynia (decreased pain threshold) lasting <4 h and elevated spinal IL-1ß and IL-6 protein. Prior CORT potentiated allodynia, lasting >24 h following LPS and potentiated spinal IL-1 and IL-6 protein. Coadministration of IL-1 receptor antagonist with LPS IT completely blocked the allodynia irrespective of whether the system was primed by CORT or not. At 24 h, TLR2, TLR4, MD2, and CD14 mRNAs were significantly elevated within the spinal cord in the CORT+LPS group compared to all other groups. Prior CORT before a direct spinal immune challenge is able to potentiate pain responses and pro-inflammatory cytokine production.
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Corticosterona/farmacología , Glucocorticoides/farmacología , Hiperalgesia/fisiopatología , Inflamación/fisiopatología , Lipopolisacáridos/farmacología , Médula Espinal/fisiopatología , Animales , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Dimensión del Dolor , Estimulación Física , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismoRESUMEN
OBJECTIVE: The study was carried out to assess the efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treating acute migraine in patients who are non-responders to sumatriptan. BACKGROUND: Many migraineurs report dissatisfaction with sumatriptan efficacy. It is unclear whether sumatriptan 100 mg non-responders will respond to other triptans. METHODS: This was a randomized, placebo-controlled, double-blind study in adults with >1-year history of ICHD-II (International Classification of Headache Disorders, second edition) migraine who reported that they generally do not respond to sumatriptan (≥50% unsatisfactory response). In the baseline phase, participants treated a single moderate/severe migraine attack with open-label generic sumatriptan 100 mg. Those who continued to experience moderate/severe pain at two hours post-dose were eligible to enter the double-blind treatment phase, during which participants treated three migraine attacks in crossover fashion (two with rizatriptan 10-mg ODT, one with placebo) after being randomly assigned to one of three treatment sequences (1 : 1 : 1 ratio). The primary endpoint was two-hour pain relief. RESULTS: A total of 102 (94%) participants treated at least one study migraine. Pain relief at two hours was significantly greater with rizatriptan compared with placebo (51% vs. 20%, p < .001). Response rates also favored rizatriptan on two-hour pain freedom (22% vs. 12%, p = .013) as well as 24-hour sustained pain relief (38% vs. 14%, p < .001) and sustained pain freedom (20% vs. 11%, p = .036). Treatment was generally well tolerated. CONCLUSION: Rizatriptan 10-mg ODT was superior to placebo at providing two-hour pain relief and two-hour pain freedom in the treatment of acute migraine in those who do not respond to sumatriptan 100 mg. Rizatriptan was generally well tolerated in this population.
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Trastornos Migrañosos/tratamiento farmacológico , Agonistas de Receptores de Serotonina/uso terapéutico , Triazoles/uso terapéutico , Triptaminas/uso terapéutico , Adulto , Anciano , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sumatriptán/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
Nutrition must affect the structure and functioning of the brain. Since the brain has very high metabolic activity, what we consume throughout the day is likely to dramatically influence both its structure and moment to moment function. It follows that nutritional approaches to all neurological disorders are being researched and entering medical practice, while nutraceutical use is a mainstay of public habits. This review discusses the biological basis for non-conventional or non-mainstream approaches to the treatment of migraine. This requires at least limited discussion of current migraine pathophysiologic theory. How nutrients and other chemicals and approaches are mechanistically involved within migraine pathways is the focus of this article. The nutraceuticals reviewed in detail are: magnesium, riboflavin, coenzyme Q10, petasites, and feverfew with additional comments on marijuana and oxygen/hyperbaric oxygen. This article reviews the science when known related to the potential genetic susceptibility and sensitivity to these treatments. As we know, the basic science in this field is very preliminary, so whether to combine approaches and presumably mechanisms or use them alone or with or without conventional therapies is far from clear. Nonetheless, as more patients and providers participate in patient-centered approaches to care, knowledge of the science underpinning nutritional, nutraceutical, and complementary approaches to treatment for migraine will certainly benefit this interaction.
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Suplementos Dietéticos , Cefalea/fisiopatología , Cefalea/terapia , Predisposición Genética a la Enfermedad/genética , Cefalea/genética , Humanos , Oxigenoterapia Hiperbárica , Trastornos Migrañosos/fisiopatología , Farmacogenética , Resultado del TratamientoRESUMEN
OPINION STATEMENT: Migraine is a biologic disorder of the brain characterized by a heterogeneous array of symptoms and episodes of disabling headache. By definition, such attacks last between 4 and 72 h without treatment, with the disability arising from a variety of factors including severe pain, gastrointestinal symptoms such as nausea or vomiting, and sensory sensitivities to light, noise, or odor. All these features may be exacerbated by stimulation, motion, or activity, often rendering the patient completely immobile. Although retreat and rest, coupled with local application of ice, may provide some measure of comfort, most of those with migraine hunt for therapeutic solutions. In designing acute headache treatment strategies, it is imperative for clinicians to recognize the variability between individuals in the frequency, intensity, and duration of attacks. Certain patients require more aggressive options. It is also crucial to identify the significant intra-individual variability of migraine; most patients describe an assortment of headaches of different intensities and time to disability. Less intense episodes, which patients often term sinus, tension, or regular headaches, usually represent milder versions of migraine, simplifying both diagnostic and therapeutic approaches. Evidence-based guidelines and clinical experience support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the management of mild to moderate migraine attacks. Recommend migraine-specific agents (triptans and dihydroergotamine) when the attacks are more severe or have consistently failed to respond to the use of NSAIDs in the past. Encourage those with less frequent episodic migraine to use their acute agents at the earliest signs of headache. Advise those with frequent headache (>10 days per month) to limit acute treatments to only the most disabling episodes in order to avoid the "medication overuse" phenomenon. Consider rescue or back-up therapy. Do not use compounds containing butalbital or opiates (or place extreme limits on them), out of concern for progression to chronic migraine.
RESUMEN
Previous studies of peripheral immune cells have documented that activation of adenosine 2A receptors (A(2A)Rs) decrease proinflammatory cytokine release and increase release of the potent anti-inflammatory cytokine, interleukin-10 (IL-10). Given the growing literature supporting that glial proinflammatory cytokines importantly contribute to neuropathic pain and that IL-10 can suppress such pain, we evaluated the effects of intrathecally administered A(2A)R agonists on neuropathic pain using the chronic constriction injury (CCI) model. A single intrathecal injection of the A(2A)R agonists 4-(3-(6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-ynyl)piperidine-1-carboxylic acid methyl ester (ATL313) or 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine HCl (CGS21680), 10-14 d after CCI versus sham surgery, produced a long-duration reversal of mechanical allodynia and thermal hyperalgesia for at least 4 weeks. Neither drug altered the nociceptive responses of sham-operated controls. An A(2A)R antagonist [ZM241385 (4-(2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin-5-ylamino]ethyl)phenol)] coadministered intrathecally with ATL313 abolished the action of ATL313 in rats with neuropathy-induced allodynia but had no effect on allodynia in the absence of the A(2A)R agonist. ATL313 attenuated CCI-induced upregulation of spinal cord activation markers for microglia and astrocytes in the L4-L6 spinal cord segments both 1 and 4 weeks after a single intrathecal ATL313 administration. Neutralizing IL-10 antibodies administered intrathecally transiently abolished the effect of ATL313 on neuropathic pain. In addition, IL-10 mRNA was significantly elevated in the CSF cells collected from the lumbar region. Activation of A(2A)Rs after intrathecal administration may be a novel, therapeutic approach for the treatment of neuropathic pain by increasing IL-10 in the immunocompetent cells of the CNS.
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Agonistas del Receptor de Adenosina A2 , Neuralgia/tratamiento farmacológico , Piperidinas/administración & dosificación , Receptor de Adenosina A2A/fisiología , Animales , Inyecciones Espinales , Masculino , Neuralgia/fisiopatología , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-DawleyRESUMEN
Nicotinic acetylcholine receptors (nAchRs) are not only key receptors in the autonomic nervous system, but also are present on immune cells. The alpha seven subunit of nAchR (alpha7nAchR) suppresses pro-inflammation in peripheral monocytes by decreasing pro-inflammatory cytokine production. In spinal cord, alpha7nAchRs are found on microglia, which are known to induce and maintain pain. We predicted that alpha7nAchR agonists might attenuate intrathecal HIV-1 gp120-induced, pro-inflammatory cytokine- and microglia-dependent mechanical allodynia. Choline, a precursor for acetylcholine and selective agonist for alpha7nAchR, was administered intrathecally either with, or 30 min after, intrathecal gp120. Choline significantly blocked and reversed gp120-induced mechanical allodynia for at least 4 h after drug administration. In addition, intrathecal choline, delivered either with or 30 min after gp120, reduced gp120-induced IL-1beta protein and pro-inflammatory cytokine mRNAs within the lumbar spinal cord. A second alpha7nAchR agonist, GTS-21, also significantly reversed gp120-induced mechanical allodynia and lumbar spinal cord levels of pro-inflammatory cytokine mRNAs and IL-1beta protein. A role of microglia is suggested by the observation that intrathecal choline suppressed the gp120-induced expression of, cd11b, a macrophage/microglial activation marker. Taken together, the data support that alpha7nAchR may be a novel target for treating pain where microglia maintain the pro-inflammatory state within the spinal cord.
Asunto(s)
Citocinas/biosíntesis , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Agonistas Nicotínicos/farmacología , Dolor/prevención & control , Receptores Nicotínicos/efectos de los fármacos , Médula Espinal/metabolismo , Animales , Compuestos de Bencilideno/farmacología , Cartilla de ADN , ADN Complementario/biosíntesis , ADN Complementario/genética , Inyecciones Espinales , Interleucina-1beta/biosíntesis , Masculino , Proteínas del Tejido Nervioso/biosíntesis , Agonistas Nicotínicos/administración & dosificación , Dolor/inducido químicamente , Estimulación Física , Piridinas/farmacología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Médula Espinal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesis , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Optimum acute treatment of migraine requires prevention of headache as a top priority. Recognition of the multitude of migraine presentations, the frequency of total headache attacks, and number of days of headache disability are critical. Successful treatment requires excellent patient-clinician communication enhancing confidence and mutual trust based on patient needs and preferences. Optimum management of acute migraine nearly always requires pharmacologic treatment for rapid resolution. Migraine-specific triptans, dihydroergotamine, and several antiinflammatories have substantial empirical clinical efficacy. Older nonspecific drugs, particularly butalbital and opioids, contribute to medication overuse headache and are to be avoided. Clinicians should utilize evidence-based acute migraine-specific therapy stressing the imperative acute treatment goal of early intervention, but not too often with the correct drug, formulation, and dose. This therapy needs to provide cost-effective fast results, meaningful to the patient while minimizing the need for additional drugs. Migraine-ACT evaluates 2-hour pain freedom with return to normal function, comfort with treatment, and consistency of response. Employ a thoroughly educated patient, formulary, testimonials, stratification, and rational cotherapy against the race to central sensitization for optimum outcomes.
Asunto(s)
Analgesia/métodos , Trastornos Migrañosos/tratamiento farmacológico , Neurofarmacología/métodos , Enfermedad Aguda , Analgesia/normas , Antiinflamatorios/uso terapéutico , Dihidroergotamina/uso terapéutico , Femenino , Humanos , Masculino , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/fisiopatología , Evaluación de Resultado en la Atención de Salud , Educación del Paciente como Asunto , Relaciones Médico-Paciente , Triptaminas/uso terapéuticoRESUMEN
Menstrual migraine (MM) is either pure, if attacks are limited solely during the perimenstrual window (PMW), or menstrually related (MRM), if two of three PMWs are associated with attacks with additional migraine events outside the PMW. Acute migraine specific therapy is equally effective in MM and non-MM. Although the International Classification of Headache Disorders-II classifies MM without aura, data suggest this needs revision. The studies on extended-cycle oral contraceptives suggest benefits for headache-prone individuals. Triptan mini-prophylaxis outcomes are positive, but a conclusion of "minimal net benefit compared to placebo" is not entirely unwarranted. In a 2008 evidence-based review, grade B recommendations exist for sumatriptan (50 and 100 mg), mefenamic acid (500 mg), and riza-triptan (10 mg) for the acute treatment of MRM. For the preventive mini-prophylactic treatment of MRM, grade B recommendations are provided for transcutaneous estrogen (1.5 mg), frovatriptan (2.5 mg twice daily), and naratriptan (1 mg twice daily).
Asunto(s)
Cefalea/etiología , Cefalea/terapia , Síndrome Premenstrual/complicaciones , Síndrome Premenstrual/terapia , Femenino , Cefalea/diagnóstico , Humanos , Migraña sin Aura/diagnóstico , Migraña sin Aura/etiología , Migraña sin Aura/terapia , Síndrome Premenstrual/diagnóstico , Ensayos Clínicos Controlados Aleatorios como Asunto/métodosRESUMEN
Patent foramen ovale (PFO) appears to be associated with migraine with aura (MA), probably through cardiac shunting. PFOs may also be comorbid with cryptogenic strokes. Although multiple open-label, retrospective, and case-controlled studies have noted sometimes dramatic reductions of MA after PFO closure, the only prospective sham-controlled study of PFO closure for MA, MIST, was negative for all primary and secondary measures of migraine improvement. MIST did demonstrate an association between MA and severe PFO shunts prospectively. Difficulty with recruitment closed the MIST II and ESCAPE trials; the PREMIUM and PRIMA randomized controlled trials are ongoing at the time of this writing.