Antimigraine Research Articles

Genetic and Epigenetic Regulation of Organic Cation Transporters.

Organic cation transporters (OCTs) of the solute carrier family (SLC) 22 are the subject of intensive research because they mediate the transport of many clinically-relevant drugs such as the antidiabetic agent metformin, the opioid tramadol, and the antimigraine agent sumatriptan. OCT1 (SLC22A1) and OCT2 (SLC22A2) are highly expressed in human liver and kidney, respectively, while OCT3 (SLC22A3) shows a broader tissue distribution. As suggested from studies using knockout mice, particularly OCT2 and OCT3 appear to be of relevance for brain physiological function and drug response. The knowledge of genetic factors and epigenetic modifications affecting function and expression of OCTs is important for a better understanding of disease mechanisms and for personalized treatment of patients. This review briefly summarizes the impact of genetic variants and epigenetic regulation of OCTs in general. A comprehensive overview is given on the consequences of OCT2 and OCT3 knockout in mice and the implications of genetic OCT2 and OCT3 variants on central nervous system function in humans.

Effect of BIBN4096 in Neurobehavioural Changes of Nitroglycerin-induced Migraineous Rat Model

: Background: The pathogenesis of migraine pain has not yet been adequately explained. The incidence of cognitive dysfunction and psychological symptoms, as well as their reciprocal relationships in migraine patients, is still under consideration. The study aims to characterise the neurobehavioral and molecular changes that occur during a migraine condition. Methods: For the present study, nitro-glycerine (NTG)- induced rats were treated with antimigraine drugs such as ergotamine, sumatriptan, as well as BIBN4096. The pain was measured by the hot plate method, and the motor activity was assessed using actophotometer. The neurobehavioural activities were tested by using open field, elevated plusmaze and forced swim test. Vasoactive substances such as NO and CGRP were detected in the plasma and CGRP was detected in the isolated parts of the rat’s brain. Analysis of the proinflammatory marker such as TNF-α was carried out in the serum. Histopathological changes of the animal brain were identified using Cresyl violet (Nissl body) staining. Results: A significant analgesic activity was observed with BIBN4096 (p<0.01). Significant (p<0.05) regaining of motor and neurobehavioural changes was observed in the NTG-induced migraneous animal after treatment with BIBN4096 as compared to the NTG-treated animal. But there was a non-significant difference observed in the forced swim test. Vasoactive and inflammatory markers such as NO, CGRP and TNF-α were significantly reduced on treatment with BIBN4096 (p<0.05) when compared to the model group. On Cresyl violet staining, less damage of neurons was observed with BIBN4096 treatment and a near-normal morphology of the rat’s cerebral cortex was observed. Conclusion: Thus, the present study exhibited a remarkable antimigraine effect with a CGRP antagonistic agent, BIBN4096 than the other tested drugs such as ergotamine and sumatriptan.Key words: Migraine, Nitroglycerin, CGRP, BIBN4096, Open field task, Elevated plus-maze.

Pharmacokinetics, Pharmacodynamics and Drug-Drug Interactions of New Anti-Migraine Drugs-Lasmiditan, Gepants, and Calcitonin-Gene-Related Peptide (CGRP) Receptor Monoclonal Antibodies.

In the last few years, there have been significant advances in migraine management and prevention. Lasmiditan, ubrogepant, rimegepant and monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) are new drugs that were launched on the US pharmaceutical market; some of them also in Europe. This publication reviews the available worldwide references on the safety of these anti-migraine drugs with a focus on the possible drug–drug (DDI) or drug–food interactions. As is known, bioavailability of a drug and, hence, its pharmacological efficacy depend on its pharmacokinetics and pharmacodynamics, which may be altered by drug interactions. This paper discusses the interactions of gepants and lasmiditan with, i.a., serotonergic drugs, CYP3A4 inhibitors, and inducers or breast cancer resistant protein (BCRP) and P-glycoprotein (P-gp) inhibitors. In the case of monoclonal antibodies, the issue of pharmacodynamic interactions related to the modulation of the immune system functions was addressed. It also focuses on the effect of monoclonal antibodies on expression of class Fc gamma receptors (FcγR).

Development and validation of spectrophotometric methods for estimation of antimigraine drug eletriptan hydrobromide in pure form and pharmaceutical formulations

The present study aims to develop and validate four simple, sensitive, reproducible, and low-cost spectrophotometric methods for the determination of antimigraine drug (eletriptan hydrobromide) in pure form and pharmaceutical formulations. The methods are based on the formation of yellow colored ion-pair complex between eletriptan hydrobromide and four acid dyes, namely, bromocresol purple (BCP), bromocresol green (BCG), bromophenol blue (BPB), and bromothymol blue (BTB) with absorption maxima at 410, 420, 414 and 416nm, respectively. Several parameters such as pH, buffer type and volume, reagent volume, sequence of addition and effect of extracting solvent were optimized. Under the optimum experimental conditions, beer's law is obeyed over the concentration ranges of 1.0-20 and 1.0-16μgmL-1 for (BCP or BCG) and (BPB or BTB), respectively with good correlation coefficients (0.9995-0.9999). The apparent molar absorptivity and Sandell's sensitivity values are reported for all methods. The limit of detection (LOD) and the limit of quantification (LOQ) values are found to be 0.27, 0.28, 0.25, and 0.30μgmL-1 and 0.90, 0.93, 0.83, and 1.0μgmL-1 for BCP, BCG, BPB and BTB, respectively. The stoichiometric ratio of the formed ion-pair complexes was found to be 1:1 (drug: reagent) for all methods. The developed methods were successfully applied for the determination of eletriptan hydrobromide in pharmaceutical formulations with good accuracy and precision. Statistical comparison of the results was performed using Student's t-test and variance ratio F-test at the 95% confidence level and there was no significant difference between the reported and proposed methods regarding accuracy and precision. Further, the validity of the proposed methods was confirmed by recovery studies via standard addition method.

Procalcitonin Exerts a Mediator Role in Septic Shock Through the Calcitonin Gene-Related Peptide Receptor.

Clinically, procalcitonin represents the most widely used biomarker of sepsis worldwide with unclear pathophysiologic significance to date. Pharmacologically, procalcitonin was shown to signal through both calcitonin receptor and calcitonin gene-related peptide receptor in vitro, yet the identity of its biologically relevant receptor remains unknown. Prospective randomized animal investigations and in vitro human blood studies. Research laboratory of a university hospital. C57BL/6J mice and patients with post-traumatic sepsis. Procalcitonin-deficient mice were used to decipher a potential mediator role in experimental septic shock and identify the relevant receptor for procalcitonin. Cecal ligation and puncture and endotoxemia models were employed to investigate septic shock. Disease progression was evaluated through survival analysis, histology, proteome profiling, gene expression, and flow cytometry. Mechanistic studies were performed with cultured macrophages, dendritic cells, and gamma delta T cells. Main findings were confirmed in serum samples of patients with post-traumatic sepsis. Procalcitonin-deficient mice are protected from septic shock and show decreased pulmonary inflammation. Mechanistically, procalcitonin potentiates proinflammatory cytokine expression in innate immune cells, required for interleukin-17A expression in gamma delta T cells. In patients with post-traumatic sepsis, procalcitonin positively correlates with systemic interleukin-17A levels. In mice with endotoxemia, immunoneutralization of interleukin-17A inhibits the deleterious effect of procalcitonin on disease outcome. Although calcitonin receptor expression is irrelevant for disease progression, the nonpeptide calcitonin gene-related peptide receptor antagonist olcegepant, a prototype of currently introduced antimigraine drugs, inhibits procalcitonin signaling and increases survival time in septic shock. Our experimental data suggest that procalcitonin exerts a moderate but harmful effect on disease progression in experimental septic shock. In addition, the study points towards the calcitonin gene-related peptide receptor as relevant for procalcitonin signaling and suggests a potential therapeutic application for calcitonin gene-related peptide receptor inhibitors in sepsis, which warrants further clinical investigation.

Supramolecular Structure of Temperature‐Dependent Polymeric Hydrogels Modulated by Drug Incorporation

AbstractPoloxamers or Pluronics® (PL) have been described as promising pharmaceutical and cosmetics matrices. Herein, we have explored the structural organization of hydrogel formulations composed of PL F‐127 and PL L‐81, considering their different hydrophilic‐lipophilic balances and interactions with an antimigraine drug, sumatriptan succinate (SMT). Hydrogels phase organizations were investigated by X‐ray diffraction (XRD) and Small Angle Neutron Scattering (SANS) to establish the relationship between structural features and drug release modulation. XRD analysis revealed very low intensity peaks for hydrogels containing SMT due to the presence of small amounts of SMT as crystalline form, which is an evidence of drug incorporation into hydrogels. At physiological temperature, a structural transition from lamellar to hexagonal was observed after SMT incorporation. In addition, SANS patterns displayed a distorted hexagonal structure, (calculated &gt;experimental ), indicating the presence of a comprised structure compared to a perfect hexagonal assembly. This structural shift however have no influence on the drug release mechanism, allowing the SMT molecules to access the micellar and intermicellar hydrophilic spaces, with release mechanism dependent on the drug diffusion (R2=0.998 ≥ 0.986) from the hydrogel to the medium and release constant (Krel) values from 9.8 to 14.7 %.h−1; 31.5 to 39.1 %.h−1/2; 0.84 to 1.2 %.h−n for Zero‐order, Higuchi and Korsmeyer‐Peppas models, respectively. Using SMT as a drug model, it could be concluded that the drug access to the micellar/intermicellar hydrophilic spaces can be modulated by interplaying the polarity of binary PL‐based hydrogels. Therefore, drug release constants and mechanisms will be then dependent on the hydrogels physico‐chemical and structural properties, which determine the drug diffusion from the hydrogel to the release medium.

Mibefradil and Flunarizine, Two T-Type Calcium Channel Inhibitors, Protect Mice against Lipopolysaccharide-Induced Acute Lung Injury.

Recent studies have illuminated that blocking Ca2+ influx into effector cells is an attractive therapeutic strategy for lung injury. We hypothesize that T-type calcium channel may be a potential therapeutic target for acute lung injury (ALI). In this study, the pharmacological activity of mibefradil (a classical T-type calcium channel inhibitor) was assessed in a mouse model of lipopolysaccharide- (LPS-) induced ALI. In LPS challenged mice, mibefradil (20 and 40 mg/kg) dramatically decreased the total cell number, as well as the productions of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF). Mibefradil also suppressed total protein concentration in BALF, attenuated Evans blue extravasation, MPO activity, and NF-κB activation in lung tissue. Furthermore, flunarizine, a widely prescripted antimigraine agent with potent inhibition on T-type channel, was also found to protect mice against lung injury. These data demonstrated that T-type calcium channel inhibitors may be beneficial for treating acute lung injury. The important role of T-type calcium channel in the acute lung injury is encouraged to be further investigated.

TOXICITY AND HAZARD OF ZOLMITRIPTAN (EXPERIMENTAL STUDY)

Zolmitriptan is a widely used antimigraine drug, belongs to the group of second-generation tryptans, has a pronounced central mechanism of action and high selectivity to serotonin receptors of 5HT1D- and 5HT1B-types. Zolmitriptan belongs to hazard class 3 according to GOST 12.1.007-76: DL50 are 660 (495 - 881) mg/kg for male mice and 1045 (749 - 1292) mg/kg for female mice when administered into the stomach. When injected into the abdominal cavity, DL50 is 172 (131 - 225) mg/kg for male mice. The drug has a weak irritating effect on the mucous membranes of the eyes, does not irritate the skin, there are no signs of skin-resorptive action, and has a low ability to accumulate. The threshold of acute inhalation action is set at 0,9 mg/m3 for the effect on the functional state of the nervous system and liver. For the zolmitriptan aerosol, it is recommended to approve the tentative safe exposure level in the air of the working area at 0,01 mg/m3 and the tentative safe exposure level in the atmospheric air of urban and rural settlements at 0,0001 mg/m3.

α6GABAA Receptor Positive Modulators Alleviate Migraine-like Grimaces in Mice via Compensating GABAergic Deficits in Trigeminal Ganglia.

Migraine is caused by hyperactivity of the trigeminovascular system, where trigeminal ganglia (TG) play an important role. This hyperactivity might originate from an underfunctional GABAergic system in TG. To investigate this possibility, we adapted a mouse model of migraine by inducing migraine-like grimaces in male mice via repeated injections of nitroglycerin (NTG, 10mg/kg, i.p.), once every 2days, for up to 5 sessions. Migraine-like facial pain scores were measured using the mouse grimace scale. Repeated NTG treatments in mice caused significant increases in migraine-like grimaces that were aborted and prevented by two anti-migraine agents sumatriptan and topiramate, respectively. After 5 sessions of NTG injections, the GABA-synthesizing enzyme, 65-kDa glutamate decarboxylase (GAD65), but not the GABA transporter 1 (GAT1) or the α6 subunit-containing GABAA receptors (α6GABAARs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG α6GABAAR expression in NTG-treated mice, we demonstrated that an α6GABAAR-selective positive allosteric modulator (PAM), DK-I-56-1, exhibited both abortive and prophylactic effects, comparable to those of sumatriptan and topiramate, respectively, in this migraine-mimicking mouse model. The brain-impermeable furosemide significantly prevented the effects of DK-I-56-1, suggesting its peripheral site of action, likely via preventing α6GABAAR modulation in TG. Results suggest that a decreased GABA synthesis caused by the reduced GAD65 expression in TG contributes to the trigeminovascular activation in this repeated NTG-induced migraine-mimicking model and that the unaltered α6GABAARs in TG are potential targets for migraine treatment. Thus, α6GABAAR-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies.

Recognition and clinical implications of high prevalence of migraine in patients with Brugada syndrome and drug-induced type 1 Brugada pattern.

We have previously reported high 1-year prevalence of migraine in patients with atrial arrhythmias associated with DI-type 1 BrP. The present study was designed to determine the lifetime prevalence of migraine in patients with Brugada syndrome (BrS) or drug-induced type 1 Brugada pattern (DI-type 1 BrP) and control group, to investigate the demographic and clinical characteristics, and to identify clinical variables to predict underlying BrS/DI-type 1 BrP among migraineurs. Lifetime prevalence of migraine and migraine characteristics were compared between probands with BrS/DI-type 1 BrP (n = 257) and control group (n = 370). Lifetime prevalence of migraine was 60.7% in patients with BrS/DI-type 1 BrP and 30.3% in control group (p = 3.6 × 10-14 ). On stepwise regression analysis, familial migraine (odds ratio [OR] of 4.4; 95% confidence interval [CI]: 2.0-9.8; p = 1.3 × 10-4 ), vestibular migraine (OR of 5.4; 95% CI: 1.4-21.0); p = .013), migraine with visual aura (OR of 1.8; 95% CI: 1.0-3.4); p = .04) and younger age-at-onset of migraine (OR of 0.95; 95% CI: 0.93-0.98); p = .004) were predictors of underlying BrS/DI-type 1 BrP among migraineurs. Use of anti-migraine drugs classified as "to be avoided" or "preferably avoided" in patients with BrS and several other anti-migraine drugs with potential cardiac INa /ICa channel blocking properties was present in 25.6% and 26.9% of migraineurs with BrS/DI-type 1 BrP, respectively. Migraine comorbidity is common in patients with BrS/DI-type 1 BrP. We identify several clinical variables that point to an underlying type-1 BrP among migraineurs, necessitating cautious use of certain anti-migraine drugs.

Neonatal abstinence syndrome and intra‐uterine growth restriction secondary to maternal antimigraine drug abuse

Substance use and abuse among pregnant women is a major public health issue. Headache during pregnancy is a frequent event due to hormonal imbalance. Combination products containing butalbital with caffeine and an analgesic, acetaminophen, aspirin, or codeine are prescribed for the treatment of migraine and tension-type headaches. We report here a case of barbiturate Neonatal Abstinence Syndrome (NAS) and caffeine-related Intra Uterine Growth Restriction (IUGR) due to maternal abuse of a combination drug made from butalbital, caffeine and propyphenazone (Optalidon®), diagnosed after suggestive clinical features.

Topiramate Decelerates Bicarbonate-Driven Acid-Elimination of Human Neocortical Neurons: Strategic Significance for its Antiepileptic, Antimigraine and Neuroprotective Properties

Mammalian central neurons regulate their intracellular pH (pHi) strongly and even slight pHi-fluctuations can influence inter-/intracellular signaling, synaptic plasticity and excitability. For the first time, we investigated topiramate´s (TPM) influence on pHi-behavior of human central neurons representing a promising target for anticonvulsants and antimigraine drugs. In slice-preparations of tissue resected from the middle temporal gyrus of five adults with intractable temporal lobe epilepsy, BCECF-AM-loaded neocortical pyramidal-cells were investigated by fluorometry. The pHi-regulation was estimated by using the recovery-slope from intracellular acidification after an Ammonium-Prepulse (APP). Among 17 pyramidal neurons exposed to 50 μM TPM, seven (41.24%) responded with an altered resting-pHi (7.02±0.12), i.e., acidification of 0.01-0.03 pH-units. The more alkaline the neurons, the greater the TPM-related acidifications (r=0.7, p=0.001, n=17). The recovery from APPacidification was significantly slowed under TPM (p<0.001, n=5). Further experiments using nominal bicarbonate-free (n=2) and chloride-free (n=2) conditions pointed to a modulation of the HCO3 -- driven pHi-regulation by TPM, favoring a stimulation of the passive Cl-/HCO3 --antiporter (CBT) - an acid-loader predominantly in more alkaline neurons. TPM modulated the bicarbonate-driven pHi-regulation, just as previously described in adult guinea-pig hippocampal neurons. We discussed the significance of the resulting subtle acidifications for beneficial antiepileptic, antimigraine and neuroprotective effects as well as for unwanted cognitive deficits.

A Review of the Potential Receptors of Migraine with a Special Emphasis on CGRP to Develop an Ideal Antimigraine Drug.

Migraine is a neurovascular syndrome associated with a unilateral, throbbing headache accompanied by nausea, vomiting and photo/phonophobia. Several proteins are involved in the etiopathogenesis of migraine headaches. The aim of the present review is to provide an insight into the various target proteins involved in migraine headaches pertaining to the development of a potential anti-migraine drug molecule. Proteins/receptors, such as serotonin (5-HT), Calcitonin Gene-Related Peptide (CGRP), Transient Receptor Potential Vanilloid 1 (TRPV1), cannabinoid, glutamate, opioid, and histamine receptors play various roles in migraine. The nature of the proteins, their types, binding partner membrane proteins and the consequences of the reactions produced have been discussed. The studies conducted on animals and humans with the above-mentioned target proteins/receptors and the results obtained have also been reviewed. Calcitonin Gene-Related Peptide (CGRP), a G protein-coupled receptor (GPCR), significantly contributes to the progression of migraine. CGRP antagonist inhibits the release of CGRP from trigeminal neurons of the trigeminal ganglion. Based on the study results, the present review suggests that the inhibition of the CGRP receptor might be a successful way to treat migraine headaches. Currently, researchers across the world are focusing their attention towards the development of novel molecules to treat migraine headaches by targeting the CGRP receptor, which can be attributed to its specificity among the several proteins involved in migraine.

The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing.

BackgroundImpaired fracture healing represents an ongoing clinical challenge, as treatment options remain limited. Calcitonin gene-related peptide (CGRP), a neuropeptide targeted by emerging anti-migraine drugs, is also expressed in sensory nerve fibres innervating bone tissue.MethodBone healing following a femoral osteotomy stabilized with an external fixator was analysed over 21 days in αCGRP-deficient and WT mice. Bone regeneration was evaluated by serum analysis, µCT analysis, histomorphometry and genome-wide expression analysis. Bone-marrow-derived osteoblasts and osteoclasts, as well as the CGRP antagonist olcegepant were employed for mechanistic studies.FindingsWT mice with a femoral fracture display increased CGRP serum levels. αCGRP mRNA expression after skeletal injury is exclusively induced in callus tissue, but not in other organs. On protein level, CGRP and its receptor, calcitonin receptor-like receptor (CRLR) complexing with RAMP1, are differentially expressed in the callus during bone regeneration. On the other hand, αCGRP-deficient mice display profoundly impaired bone regeneration characterised by a striking reduction in the number of bone-forming osteoblasts and a high rate of incomplete callus bridging and non-union. As assessed by genome-wide expression analysis, CGRP induces the expression of specific genes linked to ossification, bone remodeling and adipogenesis. This suggests that CGRP receptor-dependent PPARγ signaling plays a central role in fracture healing.InterpretationThis study demonstrates an essential role of αCGRP in orchestrating callus formation and identifies CGRP receptor agonism as a potential approach to stimulate bone regeneration. Moreover, as novel agents blocking CGRP or its receptor CRLR are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone regeneration warrants clinical investigation.FundingThis work was funded by grants from the Else-Kröner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH).

Sumatriptan reduces severity of status epilepticus induced by lithium-pilocarpine through nitrergic transmission and 5-HT1B/D receptors in rats: A pharmacological-based evidence.

Status epilepticus (SE) is a life-threatening neurologic disorder that can be as both cause and consequence of neuroinflammation. In addition to previous reports on anti-inflammatory property of the anti-migraine medication sumatriptan, we have recently shown its anticonvulsive effects on pentylenetetrazole-induced seizure in mice. In the present study, we investigated further (i) the effects of sumatriptan in the lithium-pilocarpine SE model in rats, and (ii) the possible involvement of nitric oxide (NO), 5-hydroxytryptamin 1B/1D (5-HT1B/1D ) receptor, and inflammatory pathways in such effects of sumatriptan. Status epilepticus was induced by lithium chloride (127mg/kg, i.p) and pilocarpine (60mg/kg, i.p.) in Wistar rats. While SE induction increased SE scores and mortality rate, sumatriptan (0.001-1mg/kg, i.p.) improved it (P<0.001). Administration of the selective 5-HT1B/1D antagonist GR-127935 (0.01mg/kg, i.p.) reversed the anticonvulsive effects of sumatriptan (0.01mg/kg, i.p.). Although both tumor necrosis factor-α (TNF-α) and NO levels were markedly elevated in the rats' brain tissues post-SE induction, pre-treatment with sumatriptan significantly reduced both TNF-α (P<0.05) and NO (P<0.001) levels. Combined GR-127935 and sumatriptan treatment inhibited these anti-inflammatory effects of sumatriptan, whereas combined non-specific NOS (L-NAME) or selective neuronal NOS (7-nitroindazole) inhibitors and sumatriptan further reduced NO levels. In conclusion, sumatriptan exerted a protective effect against the clinical manifestations and mortality rate of SE in rats which is possibly through targeting 5-HT1B/1D receptors, neuroinflammation, and nitrergic transmission.

A Head-to-Head Comparison of Percutaneous Mastoid Electrical Stimulator and Supraorbital Transcutaneous Stimulator in the Prevention of Migraine: A Prospective, Randomized Controlled Study

This prospective, randomized, multicenter head-to-head outcome study was performed to compare the efficacy and safety of Percutaneous Mastoid Electrical Stimulator (PMES) and Supraorbital Transcutaneous Stimulator (STS) in migraine prevention. This was a prospective, randomized, head-to-head outcome study that involved three medical centers. After a one-month run-in, episodic patients with at least two migraine attacks/month were randomized to receive PMES daily for 45 min or STS daily for 20 min for three months. The primary outcomes were change in monthly migraine days and the 50% response rate. A total of 90 patients were included in this study. We observed statistically significant reduction of migraine days in the third month treatment both in the PMES group and STS group. The difference between the two groups was not significant (60.5% vs. 53.8%, p = 0.88). Of note, 77.8% patients in the PMES group and 62.2% patients in the STS group had a ≥50% reduction of migraine days in the third month (p = 0.070). The change in monthly migraine days, monthly migraine attacks, severity of migraine days, accompanying symptoms during migraine and monthly acute anti-migraine drug intake were not significantly different between the two groups. The change of Headache Impact Test-6 (HIT-6) from run-in to the third-month treatment in the STS group was more remarkable than that in the PMES group (36.5% vs. 25.6%, p = 0.041). The occurrence of discomfort paresthesia was higher in the STS group (13.3% vs. 0%, p = 0.026). PMES and STS treatment were both effective in migraine prevention. The safety and efficacy of PMES and STS were comparable.

Neurological Manifestations of the Celiac Disease in Children

Gluten-related disorders (GRDs) represent a spectrum of diverse clinical manifestations triggered by the ingestion of gluten in genetically susceptible individuals. The most common and widely recognized diseases within this spectrum are celiac disease and non-celiac gluten sensitivity. The clinical manifestations are intestinal, but extraintestinal manifestations may also appear, such as neurological or psychiatric. This work will specifically review the neurological or psychiatric manifestations that are more frequently associated with GRD in children. Gluten ataxia, celiac disease, neuropathy, and celiac disease-epilepsy-brain calcifications syndrome are key entities that appear silently or oligosymptomatically on many occasions. However, they are more typical disorders in adult patients. The treatment with a gluten-free diet can usually alleviate the symptoms and, in some cases, even the neurological condition is cured. Other conditions, such as headache, behavioral disorders, or generalized developmental disorders, are more typical in children. The pathophysiological basis of these conditions is not completely well-defined, although it is probably triggered by autoimmune mechanisms. The effective treatment approach is a gluten-free diet, although drugs such as antiepileptics, anti-migraine, immunomodulators, analgesics, or psychotropic drugs can control the clinical symptoms. The diagnosis of GRD should be made in the presence of neurological and psychiatric signs and symptoms, especially if they are of an unclear etiology. Also, the diagnosis should be made early, since their early correction can substantially improve the prognosis in some of these disorders.

Effect of Lomerizine Hydrochloride on Preventing Strokes in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an orphan disease clinically characterized by migraine, recurrent strokes, and dementia. Currently, there are no disease-modifying therapies, and it is difficult to prevent cerebral ischemic events in CADASIL patients by conventional antithrombotic medication. We hypothesized that an antimigraine agent, lomerizine hydrochloride, may prevent strokes in CADASIL patients, based on its effect on increasing cerebral blood flow. This was an open-labeled clinical trial in which 30 adult CADASIL patients received lomerizine at 10 mg/d. Numbers of symptomatic strokes during the 2 years after the start of lomerizine administration were compared with those in the 2 years before its initiation. The effect of lomerizine on preventing strokes was evaluated based on the incidence rate ratio (IR) calculated with the Mantel-Haenszel method. When including all 30 patients (analysis 1), the IR was less than 1 (0.46; 95% confidence interval [CI], 0.19-1.12) but did not reach significance. To evaluate the effect of lomerizine on secondary prevention, subgroups of 15 patients with stroke episodes occurring any time before lomerizine administration (analysis 2) and 10 patients with stroke episodes during the 2 years before lomerizine administration (analysis 3) were analyzed. The IR values were 0.33 (95% CI, 0.12-0.94) in analysis 2 and 0.17 (95% CI, 0.04-0.67) in analysis 3. Our results suggest the effect of lomerizine on preventing secondary stroke in CADASIL patients.

Migraine And Pregnancy: What Should We Know

Migraine is a common headache characterized by unilateral throbbing-like headache and pulsating in nature and sometimes associated with aura. Migraine is a disabling disorder that among adults is more prevalent among women than men. It is primary headache that is often found in pregnancy. Migraine is a common disorder in women of childbearing age, and usually requires pharmacological treatment. Migraine can be considered an important risk factor for hypertensive and vascular diseases during pregnancy. Migraine therapy in pregnancy is very challenging, it must taken into a consideration about the health of the mother and fetus. Several effective antimigraine medications are reasonably safe for use by pregnant and breastfeeding women. Prophylactic theraphy should be given to patient with recurrent migraine attacks in pregnancy. Nonpharmacological strategies are always first-line treatment options for mild migraine, and should also be used complementarily whenever pharmacological treatment is required. Women with migraine should be offered periconceptional counselling to promote a safe and healthy pregnancy. Keywords: migraine; pregnancy; therapy

Migraine And Pregnancy: What Should We Know

Migraine is a common headache characterized by unilateral throbbing-like headache and pulsating in nature and sometimes associated with aura. Migraine is a disabling disorder that among adults is more prevalent among women than men. It is primary headache that is often found in pregnancy. Migraine is a common disorder in women of childbearing age, and usually requires pharmacological treatment. Migraine can be considered an important risk factor for hypertensive and vascular diseases during pregnancy. Migraine therapy in pregnancy is very challenging, it must taken into a consideration about the health of the mother and fetus. Several effective antimigraine medications are reasonably safe for use by pregnant and breastfeeding women. Prophylactic theraphy should be given to patient with recurrent migraine attacks in pregnancy. Nonpharmacological strategies are always first-line treatment options for mild migraine, and should also be used complementarily whenever pharmacological treatment is required. Women with migraine should be offered periconceptional counselling to promote a safe and healthy pregnancy. Keywords: migraine; pregnancy; therapy