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1.
J Sex Med ; 16(12): 1885-1894, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31678098

RESUMO

INTRODUCTION: Prior medication treatment for hypoactive sexual desire disorder (HSDD) in women has left about half the subjects without benefit. Lorexys (LOR), a proprietary combination of the stimulating/excitatory dopamine-norepinephrine reuptake inhibitor bupropion (BUP) and the sedating/inhibitory serotonergic agonist-antagonist trazodone (TRZ), was developed as a multifunctional solution for this problem. AIM: Test efficacy, safety, and tolerability of LOR in a range of doses in a combined phase IB/IIA study in premenopausal outpatients with HSDD. METHODS: Otherwise healthy premenopausal women from 25-50 years of age with HSDD were tested in an open-label, active-control, one-way crossover study, with three 4-week treatments of extended-release TRZ and/or sustained-release BUP. Evaluations were made before and after each treatment. A washout of at least a week followed each treatment. The order of treatments was a standard dose of BUP; a subtherapeutic dose of BUP and TRZ (LOR-low); and a threshold-therapeutic dose of BUP and TRZ (LOR-mod). A midpoint interim analysis was planned to consider adapting doses for efficacy or safety. MAIN OUTCOME MEASURE: The primary efficacy measure was the Female Sexual Function Index, Desire domain; the main secondary efficacy measures included the Female Sexual Distress Scale-Revised 13th item, on bother about low desire, and a Patient's Global Impression of Change. The main outcome comparison was the proportions of responders. Safety measures were elicited adverse events, Epworth Sleepiness Scale, Columbia Suicide Severity Rating Scale 6-item SCREEN version, vital signs, electrocardiograms, and standard laboratory tests. RESULTS: Interim analysis did not require altering doses. Most evaluable subjects responded to LOR-mod (at the standard thresholds for response based on minimum clinically relevant difference from baseline, 79% on Female Sexual Function Index, Desire domain, 87% on Female Sexual Distress Scale-Revised Item 13, and 79% on Patient's Global Impression of Change; each P < .05 vs BUP). As expected, close to half responded to BUP (38%, 45%, and 52%, respectively). Response to LOR-low was intermediate (not significant vs BUP). Sensitivity analyses to compensate for carryover effects supported the efficacy of LOR-mod. Elicited adverse events showed the expected profile of TRZ, but led to no sedative-type dropouts or worsening on the Epworth Sleepiness Scale. CLINICAL IMPLICATIONS: The open-label 1-way crossover design of this phase IB/IIA study limits conclusions, but the consistency of responder analyses showing superiority of LOR-mod dose over control, and the lack of central depressant dropouts, favor further development in double-blind placebo-control trials. STRENGTH & LIMITATIONS: Strengths include large margins of efficacy over control agent, rapid onset of action, and rigorous safety assessment. Limitations are open-label, cross-over design/lack of placebo control and 1-month duration of exposure. CONCLUSION: Moderate-dose LOR was generally well-tolerated and was significantly more effective than BUP (active control). The results seem highly favorable compared to previously tested agents. Pyke RE, Clayton AH. Dose-Finding Study of Lorexys for Hypoactive Sexual Desire Disorder in Premenopausal Women. J Sex Med 2019;16:1885-1894.


Assuntos
Bupropiona/uso terapêutico , Libido , Serotoninérgicos/uso terapêutico , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Trazodona/uso terapêutico , Adulto , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Libido/efeitos dos fármacos , Pessoa de Meia-Idade , Pré-Menopausa , Comportamento Sexual/efeitos dos fármacos , Resultado do Tratamento
2.
Biochim Biophys Acta Mol Basis Dis ; 1865(11): 165528, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398464

RESUMO

Chronic kidney disease (CKD) is a pathological condition associated with renal osteodystrophy for which there are limited treatment options. Gut-derived serotonin (GDS) is one of the key signaling factors controlling the osteoblast proliferation. Previously, we shown that inhibition of GDS synthesis by LP533401 improved bone mineral status of rats with 5/6 nephrectomy-induced CKD model. Here, we investigated whether the use of LP533401 can modify GDS-dependent molecular pathway involved in osteoblast formation and bone mineralization in CKD rats. The 8-weeks of pharmacological manipulation after a complete CKD development reduced GDS and lead to the advantage of endogenous vitamin D [25(OH)D] over serotonin and parathyroid hormone (PTH) in rats treated with LP533401. The imbalance between GDS - 25(OH)D - PTH resulted in the intensified expression of cAMP- responsive element-binding protein (Creb), whereas the expression of myelocytomatosis oncogene (c-Myc) was simultaneously reduced. This lead to disruption of Foxo1- activating transcription factor 4 (Atf4) complex, and decrease in the expression of the major osteogenic markers. The weakening of excessive osteoblastogenesis was associated with better bone mineral status in all rats with CKD, and especially in LP533401-treated animals. In conclusion, the inhibition of GDS synthesis resulted in the mitigation of osteoblastogenesis observed in CKD, which translated into improvement of bone mineral status. This study provides key mechanistic insights into how modification of GDS-dependent molecular pathway affects bone mineral status in CKD and lays the groundwork for translating the role of functional serotonin signaling in the origin of impaired bone mineral status in patients with CKD.


Assuntos
Calcificação Fisiológica/efeitos dos fármacos , Pirimidinas/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Serotoninérgicos/uso terapêutico , Serotonina/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteogênese/efeitos dos fármacos , Hormônio Paratireóideo/metabolismo , Ratos , Ratos Wistar , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia
4.
Curr Neuropharmacol ; 17(12): 1098-1108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31418663

RESUMO

The association of chronic pain with depression is becoming increasingly recognized. Treating both the conditions together is essential for an effective treatment outcome. In this regard, it is important to identify a shared mechanism involved in the association of chronic pain with depression. Central serotonin (5-hydroxytryptamine; 5-HT) neurotransmission has long been known to participate in the processing of signals related to pain. It also plays a key role in the pathogenesis and treatment of depression. Although functional responses to serotonin are mediated via the activation of multiple receptor types and subtypes, the 5-HT1A subtype is involved in the processing of nociception as well as the pathogenesis and treatment of depression. This receptor is located presynaptically, as an autoreceptor, on the perikaryon and dendritic spines of serotonin-containing neurons. It is also expressed as a heteroreceptor on neurons receiving input from serotonergic neurons. This article targets the 5-HT1A receptors to show that indiscriminate activation of pre and postsynaptic 5-HT1A receptors is likely to produce no therapeutic benefits; biased activation of the 5-HT heteroreceptors may be a useful strategy for treating chronic pain and depression individually as well as in a comorbid condition.


Assuntos
Analgésicos não Entorpecentes/farmacologia , Antidepressivos/farmacologia , Dor Crônica/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Receptor 5-HT1A de Serotonina , Serotoninérgicos/farmacologia , Analgésicos não Entorpecentes/uso terapêutico , Animais , Antidepressivos/uso terapêutico , Dor Crônica/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Transtorno Depressivo/metabolismo , Humanos , Receptor 5-HT1A de Serotonina/metabolismo , Serotoninérgicos/uso terapêutico
5.
Artigo em Inglês | MEDLINE | ID: mdl-31330215

RESUMO

Anxiety disorders are serious and common mental diseases, yet there is still a need for the development of more effective anxiolytics with better safety profiles than benzodiazepines and serotonin reuptake inhibitors. The serotonergic and noradrenergic systems have reciprocal interactions and are intricately related to the pathogenesis of anxiety. In this study, the anxiolytic-like effect of the novel compound ACH-000029, 3-(2-(4-(2-methoxyphenyl) piperazine-1-yl) ethyl) quinazoline-4(3H)-one, is reported. This compound acts at selected serotonergic (5-HT1A and 5-HT1D partial agonism and 5-HT2A antagonism) and α-adrenergic (α-1A, 1B and 1D antagonism) receptors, with good selectivity over other G-protein-coupled receptors. ACH-000029 exhibited high blood-brain barrier permeation and acute anxiolytic effects in the marble burying (MB) and light-dark box (LDB) models of anxiety over the dose ranges of 8-32 mg/kg i.p. and 16-30 mg/kg p.o. The anxiolytic activity was comparable to that observed for serotonin reuptake inhibitors (paroxetine and fluoxetine) and benzodiazepines (alprazolam, diazepam and clobazam). The analysis of the whole-brain c-fos expression following oral dosing showed that ACH-000029 regulated regions highly associated with the processing of environmental stimuli and anxiety behavior, such as the amygdala, paraventricular nucleus of the thalamus, retrosplenial dorsal, pallidum, bed nuclei of the stria terminalis, and locus ceruleus. No safety concerns were identified for ACH-000029 in the functional observational battery up to 50 mg/kg i.p. and in the nonprecipitated withdrawal test up to 30 mg/kg p.o. twice daily for 20 days. This work supports the further development of ACH-000029 as a drug candidate for the treatment of anxiety disorders. The analysis of the in vitro pharmacology and brain regions regulated by this compound may also lead to the exploration of other indications within the psychiatry field.


Assuntos
Adrenérgicos/farmacologia , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Serotoninérgicos/farmacologia , Adrenérgicos/uso terapêutico , Animais , Ansiolíticos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Serotoninérgicos/uso terapêutico
6.
Lancet Psychiatry ; 6(7): 601-609, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31178367

RESUMO

BACKGROUND: Depression is the single largest contributor to non-fatal health loss worldwide. Second-generation antidepressants are the first-line option for pharmacological management of depression. Optimising their use is crucial in reducing the burden of depression; however, debate about their dose dependency and their optimal target dose is ongoing. We have aimed to summarise the currently available best evidence to inform this clinical question. METHODS: We did a systematic review and dose-response meta-analysis of double-blind, randomised controlled trials that examined fixed doses of five selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, paroxetine, and sertraline), venlafaxine, or mirtazapine in the acute treatment of adults (aged 18 years or older) with major depression, identified from the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS, MEDLINE, PsycINFO, AMED, PSYNDEX, websites of drug licensing agencies and pharmaceutical companies, and trial registries. We imposed no language restrictions, and the search was updated until Jan 8, 2016. Doses of SSRIs were converted to fluoxetine equivalents. Trials of antidepressants for patients with depression and a serious concomitant physical illness were excluded. The main outcomes were efficacy (treatment response defined as 50% or greater reduction in depression severity), tolerability (dropouts due to adverse effects), and acceptability (dropouts for any reasons), all after a median of 8 weeks of treatment (range 4-12 weeks). We used a random-effects, dose-response meta-analysis model with flexible splines for SSRIs, venlafaxine, and mirtazapine. FINDINGS: 28 554 records were identified through our search (24 524 published and 4030 unpublished records). 561 published and 121 unpublished full-text records were assessed for eligibility, and 77 studies were included (19 364 participants; mean age 42·5 years, SD 11·0; 7156 [60·9%] of 11 749 reported were women). For SSRIs (99 treatment groups), the dose-efficacy curve showed a gradual increase up to doses between 20 mg and 40 mg fluoxetine equivalents, and a flat to decreasing trend through the higher licensed doses up to 80 mg fluoxetine equivalents. Dropouts due to adverse effects increased steeply through the examined range. The relationship between the dose and dropouts for any reason indicated optimal acceptability for the SSRIs in the lower licensed range between 20 mg and 40 mg fluoxetine equivalents. Venlafaxine (16 treatment groups) had an initially increasing dose-efficacy relationship up to around 75-150 mg, followed by a more modest increase, whereas for mirtazapine (11 treatment groups) efficacy increased up to a dose of about 30 mg and then decreased. Both venlafaxine and mirtazapine showed optimal acceptability in the lower range of their licensed dose. These results were robust to several sensitivity analyses. INTERPRETATION: For the most commonly used second-generation antidepressants, the lower range of the licensed dose achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression. FUNDING: Japan Society for the Promotion of Science, Swiss National Science Foundation, and National Institute for Health Research.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Mirtazapina/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Serotoninérgicos/uso terapêutico
8.
Am J Manag Care ; 25(4 Suppl): S55-S62, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31002489

RESUMO

Chronic idiopathic constipation is a functional bowel disorder characterized by difficult, infrequent, and/or incomplete defecation, affecting 35 million adult Americans, resulting in more than millions of physician visits annually. Symptoms of constipation vary from patient to patient and impact all age groups and patient populations in the United States. The definition of constipation was previously not well specified, beyond stool frequency, and has been revised to incorporate the patient perspective and experience in addition to specific criteria created by the Rome Foundation. In the absence of red-flag (alarm) symptoms, and with a normal physical (including rectal) examination, patients can initially be empirically treated for their symptoms of chronic constipation assuming adequate follow-up is arranged. Unfortunately, both patients and healthcare providers have documented unmet needs with currently available therapeutic options, thus prompting research for new agents with novel mechanisms of action that are both efficacious and safe.


Assuntos
Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/fisiopatologia , Fatores Etários , Ácidos e Sais Biliares/antagonistas & inibidores , Doença Crônica , Colo/fisiopatologia , Constipação Intestinal/epidemiologia , Humanos , Laxantes/farmacologia , Laxantes/uso terapêutico , Guias de Prática Clínica como Assunto , Secretagogos/farmacologia , Secretagogos/uso terapêutico , Serotoninérgicos/uso terapêutico , Estados Unidos/epidemiologia
9.
Sex Med Rev ; 7(3): 380-392, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30803922

RESUMO

INTRODUCTION: Flibanserin, a multifunctional serotonin agonist and antagonist, is approved by the U.S. Food and Drug Administration (FDA) for treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women. During the FDA's review of flibanserin, concerns were raised about the risks of hypotension, syncope, and sedation-related adverse events, which increase with alcohol use. Based on the results of an alcohol challenge study, the FDA required a boxed warning and alcohol contraindication in the flibanserin prescribing information, as part of a risk evaluation and mitigation strategy program. AIM: To evaluate the adverse event profile of flibanserin in the context of that seen with other medications that affect serotonin in the brain and are commonly prescribed for women. METHODS: This was a review of data provided in the product prescribing information for flibanserin, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, other serotonergic antidepressants, and triptans. MAIN OUTCOME MEASURES: The incidence of adverse events was assessed. RESULTS: The incidences of hypotension, syncope, and sedation-related adverse events (eg, dizziness, somnolence, fatigue) in studies of flibanserin were within the ranges observed for serotonergic antidepressants; the rates of these adverse events were generally lower with triptan medications. Other flibanserin-associated adverse events (eg, nausea, insomnia, dry mouth) occurred more commonly in patients taking antidepressant medications. CONCLUSION: Although medications that affect the serotonin system have varying adverse event profiles (likely mediated by differences in serotonin-related mechanisms of action, specific brain structures affected, and effects on other neurotransmitter systems), the occurrence of central nervous system-related adverse events was not dissimilar between flibanserin and serotonergic antidepressants. Kingsberg SA, McElroy SL, Clayton AH. Evaluation of Flibanserin Safety: Comparison with Other Serotonergic Medications. Sex Med Rev 2019;7:380-392.


Assuntos
Benzimidazóis/uso terapêutico , Libido/efeitos dos fármacos , Pré-Menopausa , Serotoninérgicos/uso terapêutico , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Feminino , Humanos , Disfunções Sexuais Psicogênicas/fisiopatologia
10.
Epilepsia ; 60(3): 485-494, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30719703

RESUMO

OBJECTIVE: Prevention of sudden unexpected death in epilepsy (SUDEP) is a critical goal for epilepsy therapy. The DBA/1 mouse model of SUDEP exhibits an elevated susceptibility to seizure-induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. The serotonin hypothesis of SUDEP is based on findings that treatments which modify serotonergic function significantly alter susceptibility to seizure-induced sudden death in several epilepsy models, including DBA/1 mice. Serotonergic abnormalities have also recently been observed in human SUDEP. Fenfluramine is a drug that enhances serotonin release in the brain. Recent studies have found that the addition of fenfluramine improved seizure control in patients with Dravet syndrome, which has a high incidence of SUDEP. Therefore, we investigated the effects of fenfluramine on seizures and seizure-induced respiratory arrest (S-IRA) in DBA/1 mice. METHODS: The dose and time course of the effects of fenfluramine (i.p.) on audiogenic seizures (Sz) induced by an electric bell in DBA/1 mice were determined. Videos of Sz-induced behaviors were recorded for analysis. Statistical significance (P < 0.05) was evaluated using the chi-square test. RESULTS: Sixteen hours after administration of 15 mg/kg of fenfluramine, a high incidence of selective block of S-IRA susceptibility (P < 0.001) occurred in DBA/1 mice without blocking any convulsive behavior. Thirty minutes after 20-40 mg/kg of fenfluramine, significant reductions of seizure incidence and severity, as well as S-IRA susceptibility occurred, which were long-lasting (≥48 hours). The median effective dose (ED50 ) of fenfluramine for significantly reducing Sz at 30 minutes was 21 mg/kg. SIGNIFICANCE: This study presents the first evidence for the effectiveness of fenfluramine in reducing seizure incidence, severity, and S-IRA susceptibility in a mammalian SUDEP model. The ability of fenfluramine to block S-IRA selectively suggests the potential usefulness of fenfluramine in prophylaxis of SUDEP. These results further confirm and extend the serotonin hypothesis of SUDEP.


Assuntos
Anticonvulsivantes/uso terapêutico , Fenfluramina/uso terapêutico , Convulsões/tratamento farmacológico , Serotoninérgicos/uso terapêutico , Morte Súbita Inesperada na Epilepsia/prevenção & controle , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos DBA , Respiração/efeitos dos fármacos , Convulsões/complicações
13.
Expert Opin Emerg Drugs ; 23(4): 261-269, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30482063

RESUMO

Introduction: Dravet syndrome (DS) is an early-onset genetic developmental epileptic encephalopathy characterized by multiple seizure types which are refractory to antiseizure medication. There is an unmet need for effective and tolerable drugs to control different seizure types in DS types, with the aim of improving quality of life and preventing neurological impairment. Areas covered: Narrative review of efficacy and tolerability of fenfluramine, cannabidiol (CBD), verapamil, and modulators of serotonin signaling pathways (lorcaserin or trazodone) in the treatment of DS. Expert opinion/commentary: A recent large randomized controlled trial has shown that CBD is effective in the treatment of DS; preliminary data from the placebo-controlled trial on fenfluramine are also promising. Further studies are definitely required to evaluate the role of verapamil and modulators of serotonin signaling in DS. At present, drugs used to treat seizures in DS treat the symptoms of epilepsy rather than its cause(s). Future research should focus on elucidating the natural history of DS and whether appropriate treatment can have a beneficial impact on its disease course. A multidisciplinary, individualized approach to care of DS patients is required.


Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Animais , Canabidiol/uso terapêutico , Fenfluramina/uso terapêutico , Humanos , Serotoninérgicos/uso terapêutico , Verapamil/uso terapêutico
14.
Expert Opin Pharmacother ; 19(16): 1817-1819, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30244613

RESUMO

INTRODUCTION: Resistant depression is still a common and burdensome issue and there is an urgent need for new and effective adjunctive treatments. Areas covered: In this paper, the author discusses the background, trial design, results and implications of a recent study (NCT02196506, Sirius study) which confirmed the possible benefit of brexpiprazole as adjunctive treatment in depressed subjects with inadequate benefit from first line treatments. As secondary aims, the study confirmed the effects in subjects with minimal benefit from standard treatments and in subjects with anxious distress. Despite some reported side effects such as akathisia, restlessness, and increased weight, the treatment was well tolerated. Expert opinion: The unique pharmacodynamic profile of brexpiprazole, in terms of reduced dopamine intrinsic stimulation and a range of other more anxiolytic receptor effects, suggests that brexpiprazole should be preferred in specific subpopulations, particularly where a more sedative profile is needed. Indeed, this study suggests another step in the direction of precision medicine.


Assuntos
Depressão/tratamento farmacológico , Medicina de Precisão/métodos , Quinolonas/uso terapêutico , Serotoninérgicos/uso terapêutico , Tiofenos/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/patologia , Humanos , Quinolonas/farmacologia , Serotoninérgicos/farmacologia , Tiofenos/farmacologia
15.
Expert Rev Clin Pharmacol ; 11(9): 889-902, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30102078

RESUMO

INTRODUCTION: Mood, anxiety, and substance-use disorders are among the most prevalent psychiatric disorders in the population. Although several pharmacological treatments are available, they are not effective for a significant proportion of patients and are associated with several adverse reactions. Therefore, new treatments should be explored. Recent studies suggest that serotonergic hallucinogens/psychedelics including ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) have anxiolytic, antidepressive, and antiaddictive effects. Areas Covered: A systematic review of systematic reviews assessing the efficacy, safety, and tolerability of serotonergic hallucinogens/psychedelic was performed using the PubMed data base until 11 April 2018. Systematic reviews with or without meta-analysis were analyzed, but only reviews that described at least one randomized controlled trial (RCT) were included. Expert Commentary: Psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression symptoms in treatment-resistant depression. Although the results are promising, several studies were open label, and only few were RCTs, and most had small sample sizes and a short duration. Single or few doses of these drugs seem to be well tolerated, but long-term studies are lacking. New RCTs with bigger samples and longer duration are needed to replicate these findings.


Assuntos
Alucinógenos/uso terapêutico , Serotoninérgicos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/fisiopatologia , Banisteriopsis/química , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/fisiopatologia , Alucinógenos/efeitos adversos , Alucinógenos/farmacologia , Humanos , Dietilamida do Ácido Lisérgico/efeitos adversos , Dietilamida do Ácido Lisérgico/farmacologia , Dietilamida do Ácido Lisérgico/uso terapêutico , Psilocibina/efeitos adversos , Psilocibina/farmacologia , Psilocibina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Serotoninérgicos/efeitos adversos , Serotoninérgicos/farmacologia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia
16.
Continuum (Minneap Minn) ; 24(4, Headache): 1032-1051, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30074548

RESUMO

PURPOSE OF REVIEW: This article provides a framework to help providers formulate a plan for the acute treatment of migraine. Topics covered include the cost-effective patient-centered approach known as stratified care and a summary of evidence-based treatment options that are currently available. Strategies for improving treatment response, troubleshooting suboptimal results, and addressing the needs of special populations are also reviewed. RECENT FINDINGS: Both the American Headache Society and the Canadian Headache Society have released evidence-based assessments and reviews of acute treatments for migraine that can be used to help guide treatment decisions. Although several older medications have been re-released with new formulations or new delivery systems, several new medications have also become available or are in the final phases of study, further increasing the number of options available for patients. SUMMARY: The acute management of migraine should incorporate a stratified care model in concert with evidence-based treatment options. The response to treatment should be monitored regularly, and measures should be taken to identify suboptimal tolerability or efficacy.


Assuntos
Medicina Baseada em Evidências , Transtornos de Enxaqueca/terapia , Acetaminofen/uso terapêutico , Analgésicos não Entorpecentes/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Terapia por Estimulação Elétrica , Humanos , Masculino , Pessoa de Meia-Idade , Serotoninérgicos/uso terapêutico , Triptaminas/farmacologia
17.
Am J Case Rep ; 19: 604-607, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29795058

RESUMO

BACKGROUND Serotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone. Treatment is focused on withdrawal of serotonergic agents, which leads to resolution in the majority of cases. In the setting of serotonergic overdose, the onset of serotonin syndrome is usually within 4 to 13 h. Here, we report a case of delayed-onset serotonin syndrome in a patient who ingested a mixture of longer-acting serotonin agonists with serotonin antagonists. CASE REPORT A 24-year-old male was transferred to our medical intensive care unit with hypotension and altered mental status after an overdose of fluoxetine, cyproheptadine, trazodone, olanzapine, risperidone, and bupropion. After approximately 72 h, the patient developed symptoms of fever, lower leg clonus, hyperreflexia, and agitation. He was diagnosed with delayed-onset serotonin syndrome, which responded well to re-administration of cyproheptadine, leading to resolution of symptoms by day 5 of his stay. CONCLUSIONS In this present case, our patient presented with the longest reported delay in the onset of serotonin syndrome after intentional ingestion. This was likely secondary to co-ingestion of long-acting serotonin agonists with protective shorter-acting serotonin antagonists (cyproheptadine and olanzapine). Clinicians should consider delayed-onset serotonin syndrome when patients ingest longer-acting serotonergic agents with serotonin antagonists.


Assuntos
Overdose de Drogas/tratamento farmacológico , Fluoxetina/efeitos adversos , Serotoninérgicos/efeitos adversos , Serotoninérgicos/uso terapêutico , Síndrome da Serotonina/induzido quimicamente , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Bupropiona/administração & dosagem , Bupropiona/efeitos adversos , Ciproeptadina/administração & dosagem , Ciproeptadina/efeitos adversos , Ciproeptadina/uso terapêutico , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/efeitos adversos , Overdose de Drogas/complicações , Fluoxetina/administração & dosagem , Humanos , Masculino , Olanzapina , Risperidona/administração & dosagem , Risperidona/efeitos adversos , Serotoninérgicos/administração & dosagem , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/efeitos adversos , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/efeitos adversos , Síndrome da Serotonina/tratamento farmacológico , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/efeitos adversos , Fatores de Tempo , Trazodona/administração & dosagem , Trazodona/efeitos adversos , Adulto Jovem
18.
Mayo Clin Proc ; 93(5): 639-645, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29728203

RESUMO

By the end of their reproductive life cycle, roughly 40% of women have experienced migraine. Women have certain times of vulnerability for migraine that relate to abrupt declines in estrogen levels. Specifically, the prevalence of migraine is higher after menarche, during menstruation, during the postpartum period, and during perimenopause, but it is commonly lower during the second and third trimesters of pregnancy and the postmenopausal years. Therapeutic strategies for migraine management include hormonal manipulation aimed at eliminating or minimizing the decreases in estrogen that trigger the especially severe menstrual-related attacks. This article reviews special considerations for triptan use in pregnant and lactating women and in women with high risk for cardiovascular disease. Health care professionals caring for women throughout their life span should be aware of these important sex-based differences in migraine and migraine management.


Assuntos
Menopausa , Ciclo Menstrual , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Saúde da Mulher , Feminino , Humanos , Serotoninérgicos/uso terapêutico , Triptaminas/uso terapêutico
20.
Phytother Res ; 32(6): 1014-1022, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29468757

RESUMO

The anxiolytic and antidepressant activities of the Reunion Geranium (Pelargonium roseum Willd) essential oil (EO) were evaluated in male Swiss albino mice by intraperitoneal administration of 10, 20, and 50 mg/kg bw using elevated plus maze (EPM), open-field test (OFT), and forced swimming test (FST). Moreover, we evaluated whether the 5-HT1A and GABAA -benzodiazepine receptor systems are involved in the anxiolytic effects through the coadministration of WAY-100635 (a selective 5-HT1A receptor antagonist) and flumazenil (an antagonist of benzodiazepine). GC-MS revealed the monoterpene alcohols citronellol (35.9%) and geraniol (18.5%) as the main components of the P. roseum EO. EO was effective in increasing the total number of entries and time spent in the open arms of EPM whereas number of rearing in OFT was significantly decreased in comparison with the control. In the FST, immobility time decreased in EO treated mice. Pretreatment with WAY-100635, but not Flumazenil, was able to reverse the effects of the EO in the EPM and FST, indicating that the EO activity occurs via the serotonergic but not GABAergic transmission. Overall, results of this work showed significant anxiolytic and antidepressant activity of P. roseum EO and confirmed the traditional uses of Pelargonium species as calming agents.


Assuntos
Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Óleos Voláteis/uso terapêutico , Pelargonium/química , Serotoninérgicos/uso terapêutico , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos , Óleos Voláteis/farmacologia , Serotoninérgicos/farmacologia
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