Migréna je časté invalidizující onemocnění. Celosvětová prevalence migrény se odhaduje mezi 10-15 %. Migréna často propuká již v dětském věku, kdy je poměr dívek a chlapců kloněn k vyššímu počtu u chlapců, během puberty se pak počty vyrovnávají. S pokračujícím věkem se poměr kloní více k ženskému pohlaví. Nejvíce však postihuje dospělé v produktivním věku, kde již výrazně převažují ženy nad muži. V České republice je více než milion migreniků. Většina z nich trpí migrénou epizodickou, nejméně dvacet procent z nich pak trpí formou chronickou, která se významně odráží na kvalitě života nemocného i jeho rodiny. V léčbě migrény zažíváme v posledních letech revoluci. Máme k dispozici specifickou medikaci akutní i profylaktickou v různých formách podání.
Migraine is a frequent disabling disease. The worldwide prevalence of migraine is estimated to be between 10-15 %. Migraines often start already in childhood, when the ratio of girls to boys tends to be higher in boys, and during puberty the numbers even out. As age continues, the ratio leans more towards the female sex. However, it mostly affects adults of working age, where women already significantly outnumber men. There are more than a million migrainers in the Czech Republic. Most of them suffer from episodic migraine, while at least twenty percent of them suffer from the chronic form, which significantly affects the quality of life of the patient and her/his family. In recent years, we have experienced a revolution in the treatment of migraine. We have available specific acute and prophylactic medication in various forms of administration.
- Klíčová slova
- atogepant, rimegepant,
- MeSH
- antagonisté CGRP receptorů * farmakologie klasifikace terapeutické užití MeSH
- antiflogistika nesteroidní farmakologie terapeutické užití MeSH
- lidé MeSH
- migréna * diagnóza farmakoterapie patofyziologie MeSH
- tryptaminy farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Monoamine oxidase (MAO) inhibitors can interact with selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs). There is clinical interest surrounding use of ozanimod with SSRIs/SNRIs because the major metabolites of ozanimod are weak inhibitors of MAO-B in vitro. OBJECTIVE: To evaluate the incidence of treatment-emergent adverse events (TEAEs) potentially related to serotonin accumulation (SA) during concomitant ozanimod and SSRI/SNRI use by performing analyses of data from an open-label, oral ozanimod 0.92 mg trial (DAYBREAK; NCT02576717). METHODS: SA narrow (serotonin syndrome, neuroleptic malignant syndrome, and hyperthermia malignant) and broad (terms potentially associated with SA) MedDRA v24.0 searches were performed using TEAE data from participants with relapsing multiple sclerosis who entered DAYBREAK from phase 3 studies (cutoff February 1, 2022). Incidences of TEAEs matching terms from each search were stratified by SSRI/SNRI use. RESULTS: Of 2257 DAYBREAK participants, 274 (12.1%) used an SSRI/SNRI. No participants had TEAEs matching the SA narrow search terms. There was no significant difference in the percentage of participants with ⩾1 TEAE matching the SA broad search for those on versus off SSRIs/SNRIs (on: 12.4%, n = 34/274; off: 15.6%, n = 310/1982, nominal p = 0.1630). CONCLUSION: MedDRA searches showed no increase in TEAEs potentially associated with SA with concomitant SSRI/SNRI and ozanimod use.
- MeSH
- antidepresiva škodlivé účinky MeSH
- indany * MeSH
- inhibitory zpětného vychytávání serotoninu a noradrenalinu * škodlivé účinky MeSH
- lidé MeSH
- oxadiazoly * MeSH
- roztroušená skleróza * chemicky indukované MeSH
- selektivní inhibitory zpětného vychytávání serotoninu škodlivé účinky MeSH
- serotonin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Patients with alcohol use disorder (AUD) who seek treatment show highly variable outcomes. A precision medicine approach with biomarkers responsive to new treatments is warranted to overcome this limitation. Promising biomarkers relate to prefrontal control mechanisms that are severely disturbed in AUD. This results in reduced inhibitory control of compulsive behavior and, eventually, relapse. We reasoned here that prefrontal dysfunction, which underlies vulnerability to relapse, is evidenced by altered neuroelectric signatures and should be restored by pharmacological interventions that specifically target prefrontal dysfunction. To test this, we applied our recently developed biocompatible neuroprosthesis to measure prefrontal neural function in a well-established rat model of alcohol addiction and relapse. We monitored neural oscillations and event-related potentials in awake alcohol-dependent rats during abstinence and following treatment with psilocybin or LY379268, agonists of the serotonin 2A receptor (5-HT2AR), and the metabotropic glutamate receptor 2 (mGluR2), that are known to reduce prefrontal dysfunction and relapse. Electrophysiological impairments in alcohol-dependent rats are reduced amplitudes of P1N1 and N1P2 components and attenuated event-related oscillatory activity. Psilocybin and LY379268 were able to restore these impairments. Furthermore, alcohol-dependent animals displayed a dominance in higher beta frequencies indicative of a state of hyperarousal that is prone to relapse, which particularly psilocybin was able to counteract. In summary, we provide prefrontal markers indicative of relapse and treatment response, especially for psychedelic drugs.
- MeSH
- alkoholismus * farmakoterapie patofyziologie MeSH
- aminokyseliny MeSH
- bicyklické sloučeniny heterocyklické * farmakologie MeSH
- biologické markery MeSH
- evokované potenciály účinky léků MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech * MeSH
- prefrontální mozková kůra * účinky léků patofyziologie metabolismus MeSH
- psilocybin * farmakologie MeSH
- receptory metabotropního glutamátu MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Executive function deficits, common in psychiatric disorders, hinder daily activities and may be linked to diminished neural plasticity, affecting treatment and training responsiveness. In this pioneering study, we evaluated the feasibility and preliminary efficacy of psilocybin-assisted frontal-midline theta neurofeedback (NF), a neuromodulation technique leveraging neuroplasticity, to improve executive functions (EFs). Thirty-seven eligible participants were randomized into an experimental group (n = 18) and a passive control group (n = 19). The experimental group underwent three microdose sessions and then three psilocybin-assisted NF sessions, without requiring psychological support, demonstrating the approach's feasibility. NF learning showed a statistical trend for increases in frontal-midline theta from session to session with a large effect size and non-significant but medium effect size dynamical changes within sessions. Placebo effects were consistent across groups, with no tasks-based EF improvements, but significant self-reported gains in daily EFs-working memory, shifting, monitoring and inhibition-showing medium and high effect sizes. The experimental group's significant gains in their key training goals underscored the approach's external relevance. A thorough study with regular sessions and an active control group is crucial to evaluate EFs improvement and their specificity in future. Psilocybin-enhanced NF could offer significant, lasting benefits across diagnoses, improving daily functioning. This article is part of the theme issue 'Neurofeedback: new territories and neurocognitive mechanisms of endogenous neuromodulation'.
- MeSH
- dospělí MeSH
- exekutivní funkce * účinky léků MeSH
- lidé MeSH
- mladý dospělý MeSH
- neurofeedback * metody MeSH
- psilocybin * farmakologie MeSH
- studie proveditelnosti * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
Proper fetal development requires tight regulation of serotonin concentrations within the fetoplacental unit. This homeostasis is partly maintained by the placental transporter OCT3/SLC22A3, which takes up serotonin from the fetal circulation. Metformin, an antidiabetic drug commonly used to treat gestational diabetes mellitus, was shown to inhibit OCT3. We, therefore, hypothesized that its use during pregnancy could disrupt placental serotonin homeostasis. This hypothesis was tested using three experimental model systems: primary trophoblast cells isolated from the human term placenta, fresh villous human term placenta fragments, and rat term placenta perfusions. Inhibition of serotonin transport by metformin at three concentrations (1 μM, 10 μM, and 100 μM) was assessed in all three models. The OCT3 inhibitor decynium-22 (100 μM) and paroxetine (100 μM), a dual inhibitor of SERT and OCT3, were used as controls. In primary trophoblasts, paroxetine exhibited the strongest inhibition of serotonin uptake, followed by decynium-22. Metformin showed a concentration-dependent effect, reducing serotonin uptake by up to 57 % at the highest concentration. Its inhibitory effect was less pronounced in fresh villous fragments but remained statistically significant at all concentrations. In the perfused rat placenta, metformin demonstrated a concentration-dependent effect, reducing placental serotonin uptake by 44 % at the highest concentration tested. Our findings across all experimental models show inhibition of placental OCT3 by metformin, resulting in reduced serotonin uptake by the trophoblast. This sheds light on mechanisms that may underpin metformin-mediated effects on fetal development.
- MeSH
- biologický transport účinky léků MeSH
- hypoglykemika farmakologie MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- lidé MeSH
- metformin * farmakologie MeSH
- oktamerní transkripční faktor 3 metabolismus MeSH
- placenta * metabolismus účinky léků MeSH
- potkani Wistar MeSH
- proteiny přenášející organické kationty MeSH
- serotonin * metabolismus MeSH
- těhotenství MeSH
- trofoblasty * metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
There are currently no pharmacological treatments for cocaine use disorder. Recently there has been a great deal of interest in the potential of psychedelic drugs such as psilocybin to treat psychiatric disorders. Human studies have indicated that a single administration of psilocybin can have long-lasting effects. Few preclinical studies have examined a role for psilocybin in addiction models. The goal of the current study was to determine whether psilocybin would enhance extinction following cocaine self-administration in male and female mice and rats and thus result in an attenuation of cue-induced drug-seeking. In experiments in mice, 16 female and 19 male mice underwent 8d of cocaine self-administration (0.5 mg/kg/infusion) and extinction training. Immediately following extinction trials, mice were injected with vehicle or 1.0 mg/kg psilocybin. Following the conclusion of extinction training, mice were tested for cue-induced reinstatement. In experiments in rats, 24 female and 23 male rats underwent 15d of cocaine self-administration (0.8 mg/kg/infusion) and extinction training. Immediately following extinction trials, rats were injected with vehicle, 1.0 mg/kg psilocybin, or 2.5 mg/kg psilocybin. Following the conclusion of extinction training, rats were tested for cue-induced reinstatement. Psilocybin administered following extinction trials had no effect, as both female and male mice and rats demonstrated significant cue-induced reinstatement. These data suggest that psilocybin is ineffective at altering cocaine-seeking behavior in the paradigm and doses used in the current study. It remains to be seen whether treatment with psilocybin under different conditions may be useful in the long-standing goal of finding pharmacotherapies to treat CUD.
- MeSH
- autoaplikace * MeSH
- chování při shánění drogy * účinky léků MeSH
- extinkce (psychologie) * účinky léků MeSH
- halucinogeny * farmakologie aplikace a dávkování MeSH
- inhibitory vychytávání dopaminu farmakologie aplikace a dávkování MeSH
- kokain * farmakologie aplikace a dávkování MeSH
- krysa rodu rattus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- operantní podmiňování účinky léků MeSH
- podněty * MeSH
- pohlavní dimorfismus MeSH
- poruchy spojené s užíváním kokainu farmakoterapie psychologie MeSH
- potkani Sprague-Dawley MeSH
- psilocybin * farmakologie aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Migréna je neurologické onemocnění s opakujícími se záchvaty bolesti hlavy a významným dopadem na pacienty i společnost. Cílem tohoto souhrnu je poskytnout základní informace o této diagnóze a aktuální doporučení pro léčbu migrény. Úvodní přehled zahrnuje údaje o epidemiologii, diagnostice, klinickém obrazu, klasifikaci, etiologii a patofyziologii migrény. Novinkami ve farmakologické léčbě migrény je kontraindikace topiramátu u žen ve fertilním věku (riziko neurovývojových poruch v případě otěhotnění) a také valproátu u mužů (potenciální riziko u jejich dětí). Nově je pacientům hrazen atogepant (antagonista CGRP receptoru) za stejných podmínek jako monoklonální protilátky s anti-CGRP účinkem. Zvláštní pozornost je věnována léčebným doporučením pro ženy ve fertilním věku, v těhotenství a při kojení. Doplněny jsou také informace o nefarmakologické léčbě migrény a naznačeny jsou očekávané směry vývoje nových léčiv.
Migraine is a neurological disorder characterized by recurrent episodes of headache with significant impact on patients and society. The aim of this summary is to provide basic information about this diagnosis and current recommendations for migraine treatment. The introductory overview includes data on epidemiology, diagnosis, clinical presentation, classification, etiology and pathophysiology of migraine. Recent advancements in pharmacological treatment include contraindications of topiramate in women of childbearing age (risk of neurodevelopmental disorders in pregnancy) and also valproate in men (potential risk for their children). Atogepant (CGRP receptor antagonist) is now reimbursed to patients under the same conditions as monoclonal antibodies with anti-CGRP effect. Special attention is given to treatment recommendations for women of childbearing age, during pregnancy and breastfeeding. Additionally, information on non-pharmacological treatment of migraine is also provided and anticipated directions for the development of new drugs are indicated.
- MeSH
- analgetika MeSH
- antagonisté CGRP receptorů MeSH
- antiemetika MeSH
- antikonvulziva MeSH
- beta blokátory MeSH
- centra terciární péče MeSH
- lidé MeSH
- migréna * diagnóza farmakoterapie klasifikace patofyziologie MeSH
- monoklonální protilátky MeSH
- tryptaminy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- směrnice pro lékařskou praxi MeSH
The increasing use of cannabis during pregnancy raises concerns about its impact on fetal development. While cannabidiol (CBD) shows therapeutic promise, its effects during pregnancy remain uncertain. We investigated CBD's influence on tryptophan (TRP) metabolism in the human placenta. TRP is an essential amino acid that is metabolized via the serotonin and kynurenine (KYN) pathways, which are critical for fetal neurodevelopment. We used human term villous placental explants, an advanced ex vivo model, to study CBD's impact on key TRP metabolic enzymes. In addition, vesicles isolated from the microvillous membrane (MVM) of the human placenta were used to assess CBD's effect on placental serotonin uptake. Explants were exposed to CBD at therapeutic (0.1, 1, 2.5 μg/ml) and non-therapeutic (20 and 40 μg/ml) concentrations to determine its effects on the gene and protein expression of key enzymes in TRP metabolism and metabolite release. CBD upregulated TRP hydroxylase (TPH) and downregulated monoamine oxidase (MAO-A), resulting in reduced levels of 5-hydroxyindoleacetic acid (HIAA). It also downregulated serotonin transporter expression and inhibited serotonin transport across the MVM by up to 60% while simultaneously enhancing TRP metabolism via the kynurenine pathway by upregulating indoleamine-pyrrole 2,3-dioxygenase (IDO-1). Among kynurenine pathway enzymes, kynurenine 3 monooxygenase (KMO) was upregulated while kynurenine aminotransferase 1 (KAT-1) was downregulated; the former is associated with neurotoxic metabolite production, while the latter is linked to reduced neuroprotective metabolite levels. Overall, these results indicate that CBD modulates TRP catabolism in the human placenta, potentially disrupting the tightly regulated homeostasis of the serotonin and KYN pathways.
Maternal immune activation during pregnancy is a risk factor for offspring neuropsychiatric disorders. Among the mechanistic pathways by which maternal inflammation can affect fetal brain development and programming, those involving tryptophan (TRP) metabolism have drawn attention because various TRP metabolites have neuroactive properties. This study evaluates the effect of bacterial (lipopolysaccharides/LPS) and viral (polyinosinic:polycytidylic acid/poly I:C) placental infection on TRP metabolism using an ex vivo model. Human placenta explants were exposed to LPS or poly I:C, and the release of TRP metabolites was analyzed together with the expression of related genes and proteins and the functional activity of key enzymes in TRP metabolism. The rate-limiting enzyme in the serotonin pathway, tryptophan hydroxylase, showed reduced expression and functional activity in explants exposed to LPS or poly I:C. Conversely, the rate-limiting enzyme in the kynurenine pathway, indoleamine dioxygenase, exhibited increased activity, gene, and protein expression, suggesting that placental infection mainly promotes TRP metabolism via the kynurenine (KYN) pathway. Furthermore, we observed that treatment with LPS or poly I:C increased activity in the kynurenine monooxygenase branch of the KYN pathway. We conclude that placental infection impairs TRP homeostasis, resulting in decreased production of serotonin and an imbalance in the ratio between quinolinic acid and kynurenic acid. This disrupted homeostasis may eventually expose the fetus to suboptimal/toxic levels of neuroactive molecules and impair fetal brain development.
- MeSH
- indolamin-2,3,-dioxygenasa metabolismus MeSH
- kynurenin * metabolismus MeSH
- lidé MeSH
- lipopolysacharidy toxicita MeSH
- placenta * metabolismus MeSH
- poly I metabolismus MeSH
- serotonin metabolismus MeSH
- těhotenství MeSH
- tryptofan metabolismus MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- halucinogeny ekonomika terapeutické užití MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- nádory komplikace psychologie MeSH
- psilocybin * ekonomika terapeutické užití MeSH
- vyvíjení léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- rozhovory MeSH
