In vivo neuroprotective capacity of a Dunaliella salina extract - comprehensive transcriptomics and metabolomics study.

In this study, an exhaustive chemical characterization of a Dunaliella salina (DS) microalga extract obtained using supercritical fluids has been performed, and its neuroprotective capacity has been evaluated in vivo using an Alzheimer's disease (AD) transgenic model of Caenorhabditis elegans (strain CL4176). More than 350 compounds were annotated in the studied DS extract, with triacylglycerols, free fatty acids (FAs), carotenoids, apocarotenoids and glycerol being the most abundant. DS extract significantly protects C. elegans in a dose-dependent manner against Aß-peptide paralysis toxicity, after 32 h, 53% of treated worms at 50 µg/mL were not paralyzed. This concentration was selected to further evaluate the transcriptomics and metabolomics changes after 26 h by using advanced analytical methodologies. The RNA-Seq data showed an alteration of 150 genes, mainly related to the stress and detoxification responses, and the retinol and lipid metabolism. The comprehensive metabolomics and lipidomics analyses allowed the identification of 793 intracellular metabolites, of which 69 were significantly altered compared to non-treated control animals. Among them, different unsaturated FAs, lysophosphatidylethanolamines, nucleosides, dipeptides and modified amino acids that have been previously reported as beneficial during AD progression, were assigned. These compounds could explain the neuroprotective capacity observed, thus, providing with new evidences of the protection mechanisms of this promising extract.

Omics approaches to investigate the neuroprotective capacity of a Citrus sinensis (sweet orange) extract in a Caenorhabditis elegans Alzheimer's model.

Citrus sinensis by-products are a promising source of neuroprotective molecules. In this study, a pressurized liquid extract of Citrus by-products (PLE100) has been extensively characterized, and its neuroprotective capacity tested in the Caenorhabditis elegans strain CL4176, a validated in vivo model of Alzheimer's disease (AD). More than 450 compounds have been annotated in the extract, being triacylglycerols (TGs), stigmastanes, fatty acids (FAs) and carbohydrates the most abundant. The results demonstrate that worms PLE100-treated are significantly protected in a dose-dependent manner against the Aß-peptide paralysis toxicity. The RNA-Seq data showed an alteration of 294 genes mainly related to the stress response defense along with genes involved in the lipid transport and metabolism. Moreover, the comprehensive metabolomics study allowed the identification of 818 intracellular metabolites, of which 54 were significantly altered (mainly lipids). The integration of these and previous results provides with new evidences of the protection mechanisms of this promising extract.

Medicamentos bioterapéuticos: uso de toxinas botulínicas en la era de biosimilares / Biotherapeutic medicines: use of botulinum toxins in the era of biosimilars

Introducción: Las toxinas botulínicas son medicamentos bioterapéuticos con grandes aplicaciones en el campo de la neurología, como la cefalea y los movimientos anormales. Debido a la importancia médica y al incremento de las indicaciones terapéuticas de la toxina botulínica, este artículo pretende hacer claridad acerca de la terminología básica con respecto a la naturaleza de este medicamento, a las diferencias estructurales con medicamentos convencionales y aspectos importantes en relación con su potencia biológica e inmunogenicidad, para así comprender las potenciales diferencias entre las toxinas disponibles y conceptuar en torno a la no intercambiabilidad o sustitución de una toxina por otra. Materiales y métodos: Revisión no sistemática, según lo recomendado en la Escala para la Verificación de los Artículos Revisiones Narrativas (Sanra). Conclusiones: Los medicamentos biológicos no son intercambiables entre sí, aunque demuestren bioequivalencia. No se pueden evaluar como medicamentos genéricos intercambiables porque son biológicos; no existen estudios comparativos cabeza a cabeza; son diferentes, debido al proceso individual de manufactura.

Introduction: Botulinum toxins are biotherapeutic drugs with great applications in the field of neurology such as headache and abnormal movements. Due to the medical importance and the increase in therapeutic indications of botulinum toxin, this article aims to clarify the basic terminology regarding the nature of this drug, the structural differences with conventional drugs and important aspects in relation to its biological potency and immunogenicity in order to understand the potential differences between the available toxins and conceptualize regarding the non-interchangeability or substitution of one toxin for another. Materials and methods: Non-systematic review as recommended in the Scale for the Verification of Narrative Review Articles (SANRA). Conclusions: Biological drugs are not interchangeable with each other, even if they demonstrate bioequi-valence. They cannot be evaluated as interchangeable generic drugs because they are biologics. There are no head-to-head comparative studies. They are different due to the individual manufacturing process.

Neuroprotective Potential of Thinned Peaches Extracts Obtained by Pressurized Liquid Extraction after Different Drying Processes.

Genetic, environmental and nutritional factors are suggested as primary factors of Alzheimer's disease (AD), and secondary metabolites such as polyphenols present in thinned peaches are considered as good candidates for AD prevention. Thinned peaches are usually dried to avoid putrefaction, but the effects of the drying method and the extraction process on the polyphenol composition and the neuroprotective potential have never been addressed. In this work, a pressurized liquid extraction (PLE) method was optimized and applied to thinned peaches dried under different conditions, and their neuroprotective potential was evaluated in vitro. In addition, the PLE extracts were characterized via HPLC-Q-TOF-MS/MS, and a permeability assay was performed to evaluate the ability of the identified metabolites to cross the blood-brain barrier (BBB). The PLE extracts obtained from freeze-dried (FD) samples with 50% ethanol in water at 180 °C showed the best neuroprotective potential. Finally, among the 81 metabolites identified, isoferulic acid, 4-methyldaphnetin, coniferyl aldehyde and 3,4-dihydroxyacetophenone were found at higher concentrations in FD extracts. These metabolites are able to cross the BBB and are positively correlated with the neuroprotective potential, suggesting FD together with PLE extraction as the best combination to exploit the neuroprotective capacity of thinned peaches.

Blood-Brain Barrier Permeability Study of Potential Neuroprotective Compounds Recovered From Plants and Agri-Food by-Products.

Plants and agri-food by-products represent a wide and renewable source of bioactive compounds with neuroprotective properties. In this research, various green extraction techniques were employed to recover bioactive molecules from Kalanchoe daigremontiana (kalanchoe), epicarp of Cyphomandra betacea (tamarillo), and cooperage woods from Robinia pseudoacacia (acacia) and Nothofagus pumilio (lenga), as well as a reference extract (positive control) from Rosmarinus officinalis L. (rosemary). The neuroprotective capacity of these plant extracts was evaluated in a set of in vitro assays, including enzymatic [acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and lipoxygenase (LOX)] and antioxidant [ABTS, and reactive oxygen and nitrogen species (ROS and RNS)] bioactivity tests. Extracts were also submitted to a parallel artificial membrane permeability assay mimicking the blood-brain barrier (PAMPA-BBB) and to two cell viability assays in HK-2 and SH-SY5Y cell lines. Comprehensive phytochemical profiling based on liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (LC-Q-TOF-MS) analysis showed enriched content of phenolic and terpenoid compounds in the target extracts. Moreover, in vitro bioactivity tests showed promising neuroprotective capacity, particularly for supercritical-fluid extraction (SFE) extract from acacia (ABTS IC50 = 0.11 µg ml-1; ROS IC50 = 1.56 µg ml-1; AChE IC50 = 4.23 µg ml-1; BChE IC50 = 1.20 µg ml-1; and LOX IC50 = 4.37 µg ml-1), whereas PAMPA-BBB assays revealed high perfusion capacity of some representative compounds, such as phenolic acids or flavonoids. Regarding cytotoxic assays, tamarillo and rosemary SFE extracts can be considered as non-toxic, acacia SFE extract and lenga pressurized liquid extraction (PLE) extract as mild-cytotoxic, and kalanchoe as highly toxic extracts. The obtained results demonstrate the great potential of the studied biomass extracts to be transformed into valuable food additives, food supplements, or nutraceuticals with promising neuroprotective properties.

Neuroprotective potential of terpenoid-rich extracts from orange juice by-products obtained by pressurized liquid extraction.

Pressurized liquid extraction (PLE) conditions were optimized to improve the recovery of orange (Citrus sinensis) by-products terpenoids. The neuroprotective potential of the PLE extracts were tested against a set of in-vitro assay (antioxidant (ABTS), reactive oxygen/nitrogen species (ROS/RNS)) as well as enzymatic tests (acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and lipoxygenase (LOX)). Gas chromatography coupled to high-resolution mass spectrometry (GC-q-TOF-MS) analysis revealed a higher enrichment in mono- and sesquiterpenoids of the PLE extracts with the highest neuroprotection capacity. In-silico molecular docking analysis showed the specific interaction of representative terpenoids with enzymes active sites. The results demonstrate that the selected extract at 100 °C and 30 minutes possesses high antioxidant (ABTSIC50 = 13.5 µg mL-1; ROSIC50 = 4.4 µg mL-1), anti-cholinesterase (AChEIC50 = 137.1 vg  L-1; BChEIC50 = 147.0 µg mL-1) and anti-inflammatory properties (against IL-6 and LOXIC50 = 76.1 µg mL-1), with low cytotoxicity and protection against L-glutamic acid in cell models.

Recomendaciones de la Asociación Colombiana de Neurología para el uso de anticuerpos monoclonales antiCGRP en la profilaxis de migraña / Recommendations on the use of the antiCGRP monoclonal antibodies for migraine prophylaxis on behalf of the Colombian Association of Neurology

RESUMEN INTRODUCCIÓN: El desarrollo de anticuerpos monoclonales (mAbs) contra el péptido relacionado con el gen de la calcitonina (CGRP) ha determinado una nueva era terapéutica en la profilaxis de migraña, demostrando su efectividad en pacientes con migraña episódica (ME) y migraña crónica (MC), con respuesta desde pacientes naïve hasta refractarios a múltiples medicamentos. La disminución del 50% de los ataques de migraña al mes (DMM) durante los primeros 3 meses de uso es el desenlace aproximado en el 50% de los pacientes que reciben esta terapia. OBJETIVO: Este consenso de la Asociación Colombiana de Neurología (ACN) tiene el objetivo de guiar la selección y uso racional de los mAbs antiCGRP en pacientes con ME y MC. MATERIALES Y MÉTODOS: El comité de cefalea de la ACN mediante la aplicación de la metodología Delphi y discusiones en reuniones posteriores desarrolló un documento en formato de consenso soportado en literatura y recomendaciones de expertos. RESULTADOS: Se obtuvieron respuestas de 14 expertos en cefalea sobre moléculas utilizadas en profilaxis de migraña, analizando su aplicabilidad en situaciones clínicas frecuentes. DISCUSIÓN: Los mAbs antiCGRP han demostrado efectividad con adecuado soporte fisiopatológico, considerando que son moléculas de alto precio en una enfermedad de alta prevalencia, existe la necesidad de guíar la selección del paciente que mejor puede beneficiarse de su administración CONCLUSIONES: Los mAbs antiCGRP están recomendados en pacientes con ME y MC que presentan falla terapéutica a otras moléculas profilácticas.

ABSTRACT INTRODUCTION: The development of monoclonal antibodies (mAbs) against Calcitonin Gene Related Peptide (CGRP) has determined a new therapeutic era in migraine prophylaxis, demonstrating its effectiveness in patients with episodic migraine (EM) and chronic migraine (CM), obtaining a response in naive patients and in those who are refractory to multiple medications. A 50% decrease in migraine attacks per month during the first 3 months of use is the approximate outcome in 50% of patients receiving this therapy. OBJECTIVE: This consensus from the Colombian Association of Neurology (ACN) has the objective of serving as a guide for the rational use of antiCGRP mAbs in patients with EM and CM. METHODS AND MATERIALS: The headache committee through the application of the Delphi methodology and discussions in subsequent meetings, develops this consensus, supported in the published literature and expert recommendations. RESULTS: Fourteen answers from headache experts were received regarding the use of drugs for migraine prophylaxis, analyzing their applicability in frequent clinical situations. DISCUSSION: AntiCGRP mAbs have proved their effectiveness with adequate pathophysiological support, but with a high price in a highly prevalent disease, there is then a need to select the patient who best benefits from this therapy. CONCLUSIONS: AntiCGRP mAbs are recommended in patients with EM and CM that have previously failed to other prophylactic drugs.

In Vitro Study of the Blood-Brain Barrier Transport of Natural Compounds Recovered from Agrifood By-Products and Microalgae.

Agrifood by-products and microalgae represent a low-cost and valuable source of bioactive compounds with neuroprotective properties. However, the neuroprotective effectiveness of therapeutic molecules can be limited by their capacity to cross the blood-brain barrier (BBB) and reach the brain. In this research, various green extracts from Robinia pseudoacacia (ASFE), Cyphomandra betacea (T33), Coffea arabica (PPC1), Olea europaea L., (OL-SS), Citrus sinensis (PLE100) by-products and from the microalgae Dunaliella salina (DS) that have demonstrated in vitro neuroprotective potential were submitted to an in vitro BBB permeability and transport assay based on an immortalized human brain microvascular endothelial cells (HBMEC) model. Toxicity and BBB integrity tests were performed, and the transport of target bioactive molecules across the BBB were evaluated after 2 and 4 h of incubation using gas and liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (GC/LC-Q-TOF-MS). The HBMEC-BBB transport assay revealed a high permeability of representative neuroprotective compounds, such as mono- and sesquiterpenoids, phytosterols and some phenolic compounds. The obtained results from the proposed in vitro BBB cellular model provide further evidence of the neuroprotective potential of the target natural extracts, which represent a promising source of functional ingredients to be transferred into food supplements, food additives, or nutraceuticals with scientifically supported neuroprotective claims.

Study of the potential neuroprotective effect of Dunaliella salina extract in SH-SY5Y cell model.

Alzheimer's disease (AD) is the most common form of dementia caused by a progressive loss of neurons from different regions of the brain. This multifactorial pathophysiology has been widely characterized by neuroinflammation, extensive oxidative damage, synaptic loss, and neuronal cell death. In this sense, the design of multi-target strategies to prevent or delay its progression is a challenging goal. In the present work, different in vitro assays including antioxidant, anti-inflammatory, and anti-cholinergic activities of a carotenoid-enriched extract from Dunaliella salina microalgae obtained by supercritical fluid extraction are studied. Moreover, its potential neuroprotective effect in the human neuron-like SH-SY5Y cell model against remarkable hallmarks of AD was also evaluated. In parallel, a comprehensive metabolomics study based on the use of charged-surface hybrid chromatography (CSH) and hydrophilic interaction liquid chromatography (HILIC) coupled to high-resolution tandem mass spectrometry (Q-TOF MS/MS) was applied to evaluate the effects of the extract on the metabolism of the treated cells. The use of advanced bioinformatics and statistical tools allowed the identification of more than 314 metabolites in SH-SY5Y cells, of which a great number of phosphatidylcholines, triacylglycerols, and fatty acids were significantly increased, while several phosphatidylglycerols were decreased, compared to controls. These lipidomic changes in cells along with the possible role exerted by carotenoids and other minor compounds on the cell membrane might explain the observed neuroprotective effect of the D. salina extract. However, future experiments using in vivo models to corroborate this hypothesis must be carried out.

Neuroprotective Potential of Tamarillo (Cyphomandra betacea) Epicarp Extracts Obtained by Sustainable Extraction Process.

Tamarillo (Cyphomandra betacea (Cav.) Sendt.), or tree tomato, is a tropical fruit from the Andean region of South America; it is highly rich in vitamins, minerals, and polyphenolic compounds. In this study, extracts from tamarillo epicarp (TE) were obtained by pressurized liquid extraction (PLE), and their in-vitro neuroprotective potential was assessed. A central composite design with response surface methodology was performed to optimize PLE as a function of solvent composition and temperature. Selected response variables were extraction yield, total phenolic content (TPC), total flavonoid content (TFC), total carotenoid content (TCC), antioxidant (ABTS), and anti-inflammatory (LOX) activities, and anti-acetylcholinesterase (AChE) inhibitory capacity. According to the desirability function, the optimal conditions were 100% ethanol and 180°C with a 0.87 desirability value. Next, the anti-butyrylcholinesterase enzyme (BChE), reactive oxygen species (ROS), and reactive nitrogen species (RNS) inhibition as well as cytotoxicity in HK-2, THP-1 monocytes, and SH-5YSY neuroblastoma cell lines were studied for the TE extract obtained under optimized conditions. The optimum TE extract provided the following results: extraction yield (36.25%), TPC (92.09 mg GAE/g extract), TFC (4.4 mg QE/g extract), TCC (107.15 mg CE/g extract), antioxidant capacity (ABTS, IC50 = 6.33 mg/ml extract), LOX (IC50 = 48.3 mg/ml extract), and AChE (IC50 = 97.46 mg/ml extract), and showed no toxicity at concentration up to 120 µg/ml extract for all the tested cell lines. Finally, chemical characterization by liquid chromatography-tandem mass spectrometry (UHPLC-q-TOF-MS/MS) of the optimum TE extract exhibited an important presence of hydroxycinnamic acid derivatives and other phenolic acids as well as quercetin hexoside and rutin, as main metabolites responsible for the observed biological properties. All these results suggested that TE, which represents between 8 and 15% of the total fruit, could become a promising natural by-product with a potential "multitarget" activity against Alzheimer's disease.

Comparison of different extraction methods of Brazilian "pacová" (Renealmia petasites Gagnep.) oilseeds for the determination of lipid and terpene composition, antioxidant capacity, and inhibitory effect on neurodegenerative enzymes.

Pacová (Renealmia petasites Gagnep.) is a Brazilian native plant, usually cultivated in south regions of the country. Pacová was previously reported concerning their possible health benefits, mostly from folk medicine. However, only few works relates the health benefits with the composition of the fruit parts. In this context, this work aimed to bring, for the first time in literature, the chemical characterization in respect to lipid and terpene composition of R. petasites oilseed, performed by three different extraction methods (supercritical fluid extraction (SFE) with CO2, Soxhlet with petroleum ether (SOX), and maceration with hexane (MAC)). SFE was most selective for MUFAs, PUFAs, sesqui- and diterpenes. The main terpene identified in all extracts was 2-carene. The extracts presented poor AChE inhibition, and SOX presented potential inhibitory effect against lipoxygenase activity. Overall, R. petasites oilseed is a natural source of terpenes and their potential health benefits are highly encouraged to be investigated.

Optimization of Pressurized Liquid Extraction and In Vitro Neuroprotective Evaluation of Ammodaucus leucotrichus. Untargeted Metabolomics Analysis by UHPLC-MS/MS.

Ammodaucus leucotrichus is a spontaneous plant endemic of the North African region. An efficient selective pressurized liquid extraction (PLE) method was optimized to concentrate neuroprotective extracts from A. leucotrichus fruits. Green solvents were tested, namely ethanol and water, within a range of temperatures between 40 to 180 °C. Total carbohydrates and total phenolics were measured in extracts, as well as in vitro antioxidant capacity (DPPH radical scavenging), anticholinesterase (AChE) and anti-inflammatory (LOX) activities. Metabolite profiling was carried out by ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-q-TOF-MS/MS), identifying 94 compounds. Multivariate analysis was performed to correlate composition with bioactivity. A remarkable effect of the temperature using water was observed: the higher temperature, the higher extraction yield, the higher total phenolic content, as well as the higher total carbohydrates content. The water extract obtained at 180 °C, 10.34 MPa and 10 min showed meaningful anti-inflammatory (IC50LOX = 39.4 µg/mL) and neuroprotective activities (IC50AChE = 55.6 µg/mL). The Principal Components Analysis (PCA) and the cluster analysis correlated these activities with the presence of carbohydrates and phenolic compounds.

Neuroprotective Effect of Terpenoids Recovered from Olive Oil By-Products.

The neuroprotective potential of 32 natural extracts obtained from olive oil by-products was investigated. The online coupling of supercritical fluid extraction (SFE) and dynamic adsorption/desorption allowed the selective enrichment of olive leaves extracts in different terpenoids' families. Seven commercial adsorbents based on silica gel, zeolite, aluminum oxide, and sea sand were used with SFE at three different extraction times to evaluate their selectivity towards different terpene families. Collected fractions were analyzed by gas chromatography coupled to quadrupole-time-of-flight mass spectrometry (GC-QTOF-MS) to quantify the recoveries of monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), and triterpenes (C30). A systematic analysis of the neuroprotective activity of the natural extracts was then carried out. Thus, a set of in vitro bioactivity assays including enzymatic (acetylcholinesterase (AChE), butyrylcholinesterase (BChE)), and anti-inflammatory (lipoxidase (LOX)), as well as antioxidant (ABTS), and reactive oxygen and nitrogen species (ROS and RNS, respectively) activity tests were applied to screen for the neuroprotective potential of these extracts. Statistical analysis showed that olive leaves adsorbates from SS exhibited the highest biological activity potential in terms of neuroprotective effect. Blood-brain barrier permeation and cytotoxicity in HK-2 cells and human THP-1 monocytes were studied for the selected olive leaves fraction corroborating its potential.

In vitro neuroprotective potential of terpenes from industrial orange juice by-products.

Citrus sinensis (orange) by-products represent one of the most abundant citric residues from orange juice industrial production, and are a promising source of health-promoting compounds like terpenes. In this work, different extraction solvents have been employed to increase terpene extraction yield and selectivity from this orange juice by-product. A set of bioactivity assays including enzymatic (acetylcholinesterase (AChE), butylcholinesterase (BChE) and lipoxygenase (LOX)) as well as antioxidant (ABTS, reactive oxygen species (ROS) and reactive nitrogen species (RNS)) activity tests have been applied to investigate the neuroprotective potential of these compounds. New fluorescence-based methodologies were developed for AChE and BChE assays to overcome the drawbacks of these tests when used in vitro to determine the anticholinergic activity of colored extracts. Comprehensive phytochemical profiling based on gas chromatography coupled to quadrupole time of flight mass spectrometry (GC-qTOF-MS) analysis showed ahigh content of mono- and sesquiterpenes in the extracts obtained with ethyl acetate, whereas n-heptane extracts exhibited a large amount of triterpenes and carotenoids. From a neuroprotective activity point of view, ethyl acetate extract is the most promising due to its anticholinergic activity and antioxidant capacity. Finally, a multivariate data analysis revealed a good correlation between some monoterpenes (e.g. nerol or limonene) and the antioxidant capacity of the natural extract, while a group of sesquiterpenes (e.g.δ-Cadinene or nootkatone) showed correlation with the observed AChE, BChE and LOX inhibition capacity. Hydrocarbons mono- and sesquiterpenoids reveal high capacity in vitro to cross the blood-brain barrier (BBB).

El paciente con cefalea por uso excesivo de medicamentos en urgencias / Patient with medication-overuse headache in the emergency department

RESUMEN La cefalea por abuso de medicamentos es una condición neurológica endémica y discapacitante que afecta a entre el 1 y el 2 % de la población general y ayuda a la cronificación de una cefalea previa de base, generalmente la migraña. Se define como una cefalea que aparece 15 o más días al mes en pacientes con cefalea primaria preexistente, como consecuencia del abuso habitual de medicación aguda o sintomática contra la cefalea (durante 10 o más o 15 o más días al mes, según el fármaco) en un periodo superior a tres meses. Suele, aunque no siempre, remitir al detener el abuso de la medicación. El tratamiento requiere varios pasos: educación, retiro del medicamento usado en exceso, desintoxiación e inicio de manejo profiláctico.

SUMMARY Medication-overuse headache (MOH) is an endemic and disabling neurological condition that affects between 1-2 % of the general population, which helps chronify a previous underlying headache, usually migraine. It is defined as a headache that appears 15 or more days a month in a patient with pre-existing primary headache as a consequence of habitual abuse of acute or symptomatic headache medication (for 10 or more, or 15 or more days a month, depending on the drug) in a period of more than three months. Usually, but not always, remit when stopping medication abuse. Treatment requires several steps: education, withdrawal of excess medication, detoxification, and initiation of prophylactic management.

Guideline on the preventive treatment of chronic migraine, chronic tension type headache, hemicrania continua and new daily persistent headache on behalf of the Colombian Association of Neurology / Guía de la Asociación Colombiana de Neurología para el tratamiento preventivo de la migraña crónica, cefalea tipo tensión crónica, hemicránea continua y cefalea diaria persistente de novo

SUMMARY INTRODUCTION: Chronic daily headache is a high impact entity in the general population. Although chronic migraine and tension-type headache are the most frequent conditions, it is necessary to consider hemicrania continua and new daily persistent headache as part of the differential diagnoses to perform a correct therapeutic approach. OBJECTIVE: To make recommendations for the treatment of chronic daily headache of primary origin METHODOLOGY: The Colombian Association of Neurology, by consensus and Grade methodology (Grading of recommendations, assessment, development and evaluation), presents the recommendations for the preventive treatment of each of the entities of the daily chronic headache of primary origin group. RESULTS: For the treatment of chronic migraine, the Colombian Association of Neurology recommends onabotulinum toxin A, erenumab, topiramate, flunarizine, amitriptyline, and naratriptan. In chronic tension-type headache the recommended therapeutic options are amitriptyline, imipramine, venlafaxine and mirtazapine. Topiramate, melatonin, and celecoxib for the treatment of hemicrania continua. Options for new daily persistent headache include gabapentin and doxycycline. The recommendations for inpatient treatment of patients with chronic daily headache and the justifications for performing neural blockades as a therapeutic complement are also presented. CONCLUSION: The therapeutic recommendations for the treatment of chronic daily headache based on consensus methodology and Grade System are presented.

RESUMEN INTRODUCCIÓN: La cefalea crónica diaria es una entidad de alto impacto en la población general. Aunque la migraña crónica y la cefalea tipo tensión son las condiciones más frecuentes, es necesario considerar la hemicránea continua y la cefalea diaria persistente de novo como parte de los diagnósticos diferenciales para realizar un enfoque terapéutico correcto. OBJETIVO: Hacer recomendaciones para el tratamiento de la cefalea crónica diaria de origen primario METODOLOGÍA: La Asociación Colombiana de Neurología, mediante consenso y metodología GRADE (Grading of Reccomendations, Assesment, Development and Evaluation), presenta las recomendaciones para el tratamiento preventivo de cada una de las entidades del grupo de la cefalea crónica diaria de origen primario. RESULTADOS: Para el tratamiento de la migraña crónica, la Asociación Colombiana de Neurología recomienda onabotulinum toxina A, erenumab, galcanezumab, fremanezumab, topiramato, flunarizina, amitriptilina y naratriptan. En cefalea tipo tensional crónica las opciones terapéuticas recomendadas son amitriptilina, imipramina, venlafaxina y mirtazapina. Para el tratamiento de la hemicránea continua topiramato, melatonina y celecoxib. Las opciones para cefalea diaria persistente de novo incluyen gabapentin y doxiciclina. Se presentan adicionalmente las recomendaciones para el tratamiento intrahospitalario de los pacientes con cefalea crónica diaria y las justificaciones para la realización de bloqueos neurales como complemento terapéutico. CONCLUSIÓN: se presentan las recomendaciones terapéuticas para el tratamiento de la cefalea crónica diaria basado en metodología de consenso y sistema GRADE.