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1.
Nursing ; 50(5): 48-53, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32332506

RESUMO

The FDA has approved brexanolone specifically for treatment of adults with postpartum depression (PPD). Administered I.V., it can relieve severe signs and symptoms of PPD within days rather than weeks. This article discusses the benefits and risks of brexanolone as a treatment for PPD, including nursing considerations and patient teaching.


Assuntos
Depressão Pós-Parto/tratamento farmacológico , Depressão Pós-Parto/enfermagem , Pregnanolona/uso terapêutico , beta-Ciclodextrinas/uso terapêutico , Adulto , Aprovação de Drogas , Combinação de Medicamentos , Feminino , Humanos , Educação de Pacientes como Assunto , Pregnanolona/efeitos adversos , Medição de Risco , Estados Unidos , United States Food and Drug Administration , beta-Ciclodextrinas/efeitos adversos
2.
JAMA Netw Open ; 3(3): e200287, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32119096

RESUMO

Importance: In response to the national opioid public health crisis, there is an urgent need to develop nonopioid solutions for effective pain management. Neurosteroids are endogenous molecules with pleotropic actions that show promise for safe and effective treatment of chronic low back pain. Objective: To determine whether adjunctive pregnenolone has therapeutic utility for the treatment of chronic low back pain in Iraq- and Afghanistan-era US military veterans. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled clinical trial that enrolled for 42 months, from September 2013 to April 2017. Participants were Iraq- and Afghanistan-era veterans aged 18 to 65 years with chronic low back pain who received treatment in the Durham VA Health Care System in Durham, North Carolina, over 6 weeks. Data analysis began in 2018 and was finalized in March, 2019. Interventions: Following a 1-week placebo lead-in, participants were randomized to pregnenolone or placebo for 4 weeks. Pregnenolone and placebo were administered at fixed, escalating doses of 100 mg for 1 week, 300 mg for 1 week, and 500 mg for 2 weeks. Main Outcomes and Measures: The primary outcome measure was the change in mean pain intensity ratings from a daily pain diary (numerical rating scale, 0-10) between visit 3 (baseline) and visit 6. Secondary outcomes included pain interference scores (Brief Pain Inventory, Short Form). Preintervention and postintervention neurosteroid levels were quantified by gas chromatography with tandem mass spectrometry. Hypotheses tested were formulated prior to data collection. Results: A total of 94 participants (84 [89.4%] male; mean [SD] age, 37.5 [9.8] years; 53 [56.4%] of self-reported Caucasian race and 31 [33.0%] of self-reported African American race) were included. Forty-eight participants were randomized to pregnenolone and 52 to placebo, of whom 45 and 49, respectively, were included in baseline demographic characteristics secondary to noncompliance with medications as per protocol. Veterans randomized to pregnenolone reported significant reductions in low back pain relative to those randomized to placebo. Baseline unadjusted mean (SE) pain diary ratings were 4.83 (0.23) and 5.24 (0.22) for the placebo- and pregnenolone-treated groups, respectively (baseline unadjusted mean [SE] ratings for pain recall were 4.78 [0.24] and 5.15 [0.23], respectively). Unadjusted mean (SE) ratings following treatment (visit 6) were 4.74 (0.26) in the placebo group and 4.19 (0.30) in the pregnenolone-treated group. Unadjusted mean (SE) ratings for pain recall following treatment were 4.86 (0.27) for placebo and 4.18 (0.29) for pregnenolone. Least-square mean (LSM) analysis showed that pain scores significantly improved in the pregnenolone-treated group compared with placebo (LSM [SE] change in pain diary rating, -0.56 [0.25]; P = .02; LSM [SE] change in pain recall, -0.70 [0.27]; P = .01). Pain interference scores for work (LSM [SE] change, 0.71 [0.12]; P = .04) and activity (LSM [SE] change, 0.71 [0.11]; P = .03) were also improved in veterans randomized to pregnenolone compared with placebo. Pregnenolone was well tolerated. Conclusions and Relevance: Participants receiving pregnenolone reported a clinically meaningful reduction in low back pain and 2 pain interference domains compared with those receiving placebo. Pregnenolone may represent a novel, safe, and potentially efficacious treatment for the alleviation of chronic low back pain in Iraq- and Afghanistan-era veterans. Trial Registration: ClinicalTrials.gov Identifier: NCT01898013.


Assuntos
Dor Crônica/tratamento farmacológico , Dor Lombar/tratamento farmacológico , Pregnenolona/uso terapêutico , Veteranos , Adulto , Campanha Afegã de 2001- , Método Duplo-Cego , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Guerra do Iraque 2003-2011 , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Medição da Dor , Pregnanolona/sangue , Pregnenolona/sangue , Autorrelato , Espectrometria de Massas em Tandem , Estados Unidos
5.
J Endocrinol ; 244(1): 201-211, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600724

RESUMO

The verified hypothesis assumed that centrally administered neurosteroid, allopregnanolone (AL), could affect basal and/or stress-induced activity of the hypothalamic-pituitary-adrenal (HPA) axis in sheep. Four groups (n = 6 each) of luteal-phase sheep were intracerebroventricularly infused for 3 days with a vehicle without stress (control); a vehicle treated with stressful stimuli (isolation and partial movement restriction) on the third day; AL (4 × 15 µg/60 µL/30 min, at 30-min intervals) treated with stressful stimuli, and AL alone. Simultaneously, the push-pull perfusion of the infundibular nucleus/median eminence and plasma sample collection were performed. After the experiment, the sheep were killed to collect the hypothalamic and anterior pituitary (AP) tissues. Stressful stimuli evoked an increase in the expression of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) mRNA in the hypothalamic paraventricular nucleus (PVN), and AVP receptor (V1b) and proopiomelanocortin (POMC) mRNA in the AP; the concentrations of perfusate CRH, and plasma adrenocorticotropic hormone (ACTH) and cortisol compared to controls. Conversely, the expression of the CRH receptor (CRHR1) mRNA in the AP was downregulated. AL decreased the expression of CRH and AVP mRNA in the PVN, and AVPRV1b and POMC mRNA in the AP in stressed sheep, compared to only stressed ones. There was also a reduction in perfusate CRH, and plasma ACTH and cortisol concentrations. AL alone decreased the expression of CRHR1 mRNA in the AP, and plasma cortisol concentration at the beginning of the collection period compared to controls. In conclusion, AL may function centrally as a suppressor of HPA axis activity in stressed sheep.


Assuntos
Adaptação Fisiológica/fisiologia , Sistema Hipotálamo-Hipofisário/metabolismo , Pregnanolona/metabolismo , Estresse Fisiológico/fisiologia , Hormônio Adrenocorticotrópico/sangue , Animais , Arginina Vasopressina/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Feminino , Hidrocortisona/sangue , Adeno-Hipófise/metabolismo , Pró-Opiomelanocortina/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores de Vasopressinas/metabolismo , Ovinos
6.
J Pharmacol Exp Ther ; 372(3): 285-298, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31843812

RESUMO

Epilepsy is often treated with a combination of antiepileptic drugs. Although neurosteroids are potent anticonvulsants, little is known about their combination potential for the treatment of refractory epilepsy. Here, we investigated the combination efficacy of neurosteroids allopregnanolone (AP, brexanolone) and ganaxolone (GX) with the GABA-reuptake inhibitor tiagabine (TG) or the benzodiazepine midazolam (MDZ) on tonic inhibition in dentate gyrus granule cells and seizure protection in the hippocampus kindling and 6-Hz seizure models. Isobolographic analysis indicated that combinations of GX and TG or AP and TG at three standard ratios (1:1, 3:1, and 1:3) displayed significant synergism in augmenting tonic inhibition. In pharmacological studies, GX, AP, and TG produced dose-dependent antiseizure effects in mice (ED50 = 1.46, 4.20, and 0.20 mg/kg, respectively). The combination of GX and TG at the fixed ratio of 1:1 exerted the greatest combination index (CI = 0.53), indicating strong synergistic interaction in seizure protection. In addition, combination regimens of AP and TG showed robust synergism for seizure protection (CI = 0.4). Finally, combination regimens of GX and MDZ elicited synergistic (CI = 0.6) responses for seizure protection. These results demonstrate striking synergism of neurosteroids and TG combination for seizure protection, likely because of their effects at extrasynaptic GABA type A (GABA-A) receptors from TG-induced elevation in GABA levels. Superadditive antiseizure activity of neurosteroid-MDZ combinations may stem from their actions at both synaptic and extrasynaptic GABA-A receptors. Together, these findings provide a potential mechanistic basis for combination potential of neurosteroids with TG or benzodiazepines for the management of refractory epilepsy, status epilepticus, and seizure disorders. SIGNIFICANCE STATEMENT: This paper investigates for the first time the potential synergistic interactions between two neurosteroids with anticonvulsant properties, allopregnanolone (brexanolone) and the very similar synthetic analog, ganaxolone, and two conventional antiepileptic drugs active at GABA type A receptors: the GABA-reuptake inhibitor tiagabine and a benzodiazepine, midazolam. The results demonstrate a synergistic protective effect of neurosteroid-tiagabine combinations, as well as neurosteroid-midazolam regimens in seizure models.


Assuntos
Anticonvulsivantes/administração & dosagem , Hipocampo/efeitos dos fármacos , Neuroesteroides/administração & dosagem , Receptores de GABA-A/metabolismo , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Hipocampo/metabolismo , Hipocampo/fisiologia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Midazolam/administração & dosagem , Midazolam/uso terapêutico , Neuroesteroides/uso terapêutico , Técnicas de Patch-Clamp , Pregnanolona/administração & dosagem , Pregnanolona/análogos & derivados , Pregnanolona/uso terapêutico , Convulsões/metabolismo , Convulsões/fisiopatologia , Tiagabina/administração & dosagem , Tiagabina/uso terapêutico , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/uso terapêutico
7.
Biol Aujourdhui ; 213(3-4): 131-140, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31829933

RESUMO

Discovered in the eighties by Pr Baulieu and colleagues, neurosteroids are a class of neuroactive brain-born steroids, which comprises the steroid hormones, their biosynthesis precursors and their metabolites. They can act through genomic as well as non-genomic pathways. Genomic pathways, only triggered by the neurosteroid hormones, are, in the brain, the same as those largely described in the periphery: the binding of these steroid hormones to nuclear receptors leads to transcription regulations. On the other hand, their precursors and metabolites, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), their respective sulfate esters, pregnenolone sulfate (PREG-S) and DHEA sulfate (DHEA-S) and allopregnanolone (ALLOP), are defined as neurosteroids, but no corresponding nuclear receptors have been identified so far. In fact, they trigger non-genomic pathways which consist in (i) inhibitory ionotropic receptors, (ii) excitatory ionotropic receptors and (iii) the microtubular system. Hence, inhibitory neurosteroids, whose mostly studied representative is ALLOP, positively modulate, or directly activate, the ionotropic GABA-A receptors. In contrast, excitatory neurosteroids, represented by PREG-S, DHEA-S and DHEA, inhibit the GABA-A receptors, and activate, directly or indirectly, through the sigma-1 receptors, the NMDA glutamate receptors. Neurosteroids of the third group, the microtubular neurosteroids, are able to bind microtubule associated proteins, in particular MAP2, to promote microtubule assembly, neurite outgrowth and in fine structural neuroplasticity. So far, PREG, DHEA and progesterone are the three identified microtubular neurosteroids. The pharmacological properties of neurosteroids have led to specific investigations for assessing their therapeutic potentialities in psychiatric diseases, using validated animal models. In some cases, clinical trials were also performed. These studies showed that ALLOP, the main inhibitory neurosteroid, displayed clear-cut anxiolytic-like and antidepressant-like efficacy in animals. It has been subsequently developed as Brexanolone and tested with success in phase III of clinical trials for the treatment of post-partum depression. Although showing pro-cognitive properties in animals, the sulfated neurosteroids, PREG-S and DHEA-S, were, in contrast, never tested in clinical trials, probably due to their poor stability and proconvulsivant side effects. Their respective non-sulfated forms, PREG and DHEA, showed antidepressant and antipsychotic efficacies in clinical trials, but these drugs never reached the phase III of clinical development because their therapeutic uses would have led to an overproduction of active metabolites responsible for intolerable side effects. The alternative strategy which has been selected consists of the development of non-metabolizable synthetic derivatives of these natural steroids, which keep the same neuroactive properties as their parent molecules, but are devoid of any hormonal side effects. An example of such innovative drugs is MAP4343, a synthetic derivative of PREG, which exhibits potent antidepressant-like efficacy in validated animal models. It is currently tested in depressed patients.


Assuntos
Transtornos Mentais/tratamento farmacológico , Neuroesteroides/uso terapêutico , Psiquiatria/tendências , Animais , Desidroepiandrosterona/farmacologia , Sulfato de Desidroepiandrosterona/farmacologia , Depressão/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Humanos , Plasticidade Neuronal/efeitos dos fármacos , Pregnanolona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Terapias em Estudo/métodos , Terapias em Estudo/tendências
10.
Front Neuroendocrinol ; 55: 100799, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31614151

RESUMO

Hormonal contraceptives are frequently prescribed drugs among women, mainly for their reversible contraceptive purposes but also for beneficial effects in some gynecological pathologies. Despite extensive studies aimed at elucidating the physical effects of hormonal contraceptives and ameliorating some unwanted outcomes, little is known yet about the effects of these drugs on brain function and related behavior, which are known to be modulated by endogenous steroid hormones. We describe the current literature on preclinical studies in animals undertaken to investigate effects of hormonal contraceptives on brain function and behavior. These studies suggest that hormonal contraceptives influence neurohormones, neurotransmitters, neuropeptides, and emotional, cognitive, social and sexual behaviors. Animals allow examination of the basic biological mechanisms of these drugs, devoid of the psychological aspect often associated to hormonal contraceptives' use in women. Understanding the neurobiological effects of these drugs may improve women's health and may help women making informed choices on hormonal contraception.


Assuntos
Ansiedade , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Contraceptivos Hormonais/farmacologia , Depressão , Aprendizagem/efeitos dos fármacos , Neuropeptídeos/efeitos dos fármacos , Neuroesteroides , Pregnanolona/farmacologia , Comportamento Sexual/efeitos dos fármacos , Comportamento Social , Estresse Psicológico , Transmissão Sináptica/efeitos dos fármacos , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Depressão/induzido quimicamente , Depressão/metabolismo , Depressão/fisiopatologia , Feminino , Humanos , Estresse Psicológico/induzido quimicamente , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo
12.
Nurse Pract ; 44(12): 21-32, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31658218

RESUMO

In 2019, the FDA approved several new drugs for use in primary care. This article highlights the following new drugs: risankizumab-rzaa (Skyrizi); halobetasol and tazarotene (Duobrii); dolutegravir and lamivudine (Dovato); romosozumab-aqqg (Evenity); brexanolone (Zulresso); solriamfetol (Sunosi); aclidinium and formoterol (Duaklir Pressair); and siponimod (Mayzent).


Assuntos
Aprovação de Drogas , Anticorpos Monoclonais/uso terapêutico , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Carbamatos/uso terapêutico , Clobetasol/análogos & derivados , Clobetasol/uso terapêutico , Combinação de Medicamentos , Fumarato de Formoterol/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Lamivudina/uso terapêutico , Ácidos Nicotínicos/uso terapêutico , Fenilalanina/análogos & derivados , Fenilalanina/uso terapêutico , Pregnanolona/uso terapêutico , Tropanos/uso terapêutico , Estados Unidos , United States Food and Drug Administration , beta-Ciclodextrinas/uso terapêutico
13.
Drugs Today (Barc) ; 55(9): 537-544, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584571

RESUMO

On March 19, 2019, the United States Food and Drug Administration (FDA) approved Zulresso (brexanolone) for intravenous use for the treatment of postpartum depression (PPD) in adult women. The decision was based on three recent clinical trials following an FDA priority review and breakthrough therapy designation. Brexanolone is now available through a restricted process called the Zulresso Risk Evaluation and Mitigation Strategy Program that requires the drug to be administered by a healthcare provider in a certified healthcare facility. Brexanolone represents an important new treatment option to address treatment-resistant depressive symptoms. In this article, we discuss the current critical need for PPD treatments, the mechanisms of brexanolone action, and the efficacy and drug safety studies that led to FDA approval. Additionally, we discuss some limitations of the current formulation, specific populations of women that might benefit from this treatment, and how new drugs on the horizon may increase the ability to treat PPD in a variety of patient populations.


Assuntos
Depressão Pós-Parto/tratamento farmacológico , Pregnanolona/uso terapêutico , beta-Ciclodextrinas/uso terapêutico , Aprovação de Drogas , Combinação de Medicamentos , Feminino , Humanos , Estados Unidos , United States Food and Drug Administration
14.
Elife ; 82019 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566568

RESUMO

The molecular mechanisms by which environmental light conditions affect cerebellar development are incompletely understood. We showed that circadian disruption by light-at-night induced Purkinje cell death through pineal allopregnanolone (ALLO) activity during early life in chicks. Light-at-night caused the loss of diurnal variation of pineal ALLO synthesis during early life and led to cerebellar Purkinje cell death, which was suppressed by a daily injection of ALLO. The loss of diurnal variation of pineal ALLO synthesis induced not only reduction in pituitary adenylate cyclase-activating polypeptide (PACAP), a neuroprotective hormone, but also transcriptional repression of the cerebellar Adcyap1 gene that produces PACAP, with subsequent Purkinje cell death. Taken together, pineal ALLO mediated the effect of light on early cerebellar development in chicks.


Assuntos
Encéfalo/crescimento & desenvolvimento , Ritmo Circadiano , Luz , Glândula Pineal/fisiologia , Pregnanolona/metabolismo , Animais , Encéfalo/citologia , Células COS , Morte Celular , Galinhas , Chlorocebus aethiops , Masculino , Estimulação Luminosa , Células de Purkinje/citologia
15.
Front Neuroendocrinol ; 55: 100789, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31525393

RESUMO

The pregnenolone-progesterone-allopregnanolone pathway is receiving increasing attention in research on the role of neurosteroids in pathophysiology, particularly in stress-related and drug use disorders. These disorders involve an allostatic change that may result from deficiencies in allostasis or adaptive responses, and may be downregulated by adjustments in neurotransmission by neurosteroids. The following is an overview of findings that assess how pregnenolone and/or allopregnanolone concentrations are altered in animal models of stress and after consumption of alcohol or cannabis-type drugs, as well as in patients with depression, anxiety, post-traumatic stress disorder or psychosis and/or in those diagnosed with alcohol or cannabis use disorders. Preclinical and clinical evidence shows that pregnenolone and allopregnanolone, operating according to a different or common pharmacological profile involving GABAergic and/or endocannabinoid system, may be relevant biomarkers of psychiatric disorders for therapeutic purposes. Hence, ongoing clinical trials implicate synthetic analogs of pregnenolone or allopregnanolone, and also modulators of neurosteroidogenesis.


Assuntos
Alcoolismo/metabolismo , Uso da Maconha/metabolismo , Neuroesteroides/metabolismo , Pregnanolona/metabolismo , Pregnenolona/metabolismo , Progesterona/metabolismo , Transdução de Sinais/fisiologia , Estresse Psicológico/metabolismo , Alcoolismo/tratamento farmacológico , Animais , Uso da Maconha/tratamento farmacológico
16.
Nurs Womens Health ; 23(5): 450-454, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31445988

RESUMO

Postpartum depression is a mood disorder that affects up to 20% of women in the first year after childbirth. Symptoms can range from mild depression and anxiety to severe mood alterations and psychosis. A mainstay of treatment has included selective serotonin reuptake inhibitors. However, it can take 2 to 6 weeks for clinical improvement with this approach. In March 2019, the U.S. Food and Drug Administration approved brexanolone, the first medication specifically indicated for the treatment of postpartum depression. Given as an intravenous infusion over the course of 60 hr, brexanolone has the potential to fill an unmet need for women with postpartum depression. In this column, I will provide an overview of brexanolone and discuss administration, adverse effects, and practice implications for nurses who work with childbearing women.


Assuntos
Depressão Pós-Parto/tratamento farmacológico , Mães/psicologia , Pregnanolona/uso terapêutico , beta-Ciclodextrinas/uso terapêutico , Administração Intravenosa/métodos , Adulto , Depressão Pós-Parto/psicologia , Combinação de Medicamentos , Feminino , Humanos , Mães/estatística & dados numéricos , Período Pós-Parto/efeitos dos fármacos , Inibidores de Captação de Serotonina/uso terapêutico
17.
Mol Pharmacol ; 96(3): 320-329, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31263018

RESUMO

The two-state coagonist model has been successfully used to analyze and predict peak current responses of the γ-aminobutyric acid type A (GABAA) receptor. The goal of the present study was to provide a model-based description of GABAA receptor activity under steady-state conditions after desensitization has occurred. We describe the derivation and properties of the cyclic three-state resting-active-desensitized (RAD) model. The relationship of the model to receptor behavior was tested using concatemeric α1ß2γ2 GABAA receptors expressed in Xenopus oocytes. The receptors were activated by the orthosteric agonists GABA or ß-alanine, the allosteric agonist propofol, or combinations of GABA, propofol, pentobarbital, and the steroid allopregnanolone, and the observed steady-state responses were compared with those predicted by the model. A modified RAD model was employed to analyze and describe the actions on steady-state current of the inhibitory steroid pregnenolone sulfate. The findings indicate that the steady-state activity in the presence of multiple active agents that interact with distinct binding sites follows standard energetic additivity. The derived equations enable prediction of peak and steady-state activity in the presence of orthosteric and allosteric agonists, and the inhibitory steroid pregnenolone sulfate. SIGNIFICANCE STATEMENT: The study describes derivation and properties of a three-state resting-active-desensitized model. The model and associated equations can be used to analyze and predict peak and steady-state activity in the presence of one or more active agents.


Assuntos
Agonistas de Receptores de GABA-A/farmacologia , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Xenopus laevis/genética , Regulação Alostérica , Animais , Complexos Multiproteicos/metabolismo , Pentobarbital/farmacologia , Pregnanolona/farmacologia , Propofol/farmacologia , Receptores de GABA-A/genética , Xenopus laevis/metabolismo , beta-Alanina/farmacologia
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