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1.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505754

RESUMO

Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%-93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress.


Assuntos
Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Lorazepam/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Acrilatos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/química , Carragenina/farmacologia , Cromanos/química , Cromanos/farmacologia , Humanos , Hiperlipidemias/patologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/farmacologia , Lorazepam/análogos & derivados , Ratos , Ácido Tióctico/análogos & derivados , Ácido Tióctico/farmacologia
2.
Paediatr Drugs ; 21(5): 379-387, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31418168

RESUMO

BACKGROUND: Digestive endoscopies must be performed within a safe and comfortable environment. We have previously shown that the quality of intravenous sedation is influenced by preoperative stress. AIM: Our primary objective was to compare the effects of oral lorazepam and placebo on the salivary cortisol response of children undergoing a digestive endoscopy. Secondary objectives were the assessment of procedural pain and comfort as well as the occurrence of adverse events. METHODS: Participants were randomized and received either lorazepam, placebo, or no premedication. Saliva was collected upon arrival at the hospital and 1 h following randomization. The sedation protocol included midazolam and fentanyl ± ketamine. Procedural pain was evaluated with the Nurse Assessed Patient Comfort Score (NAPCOMS). Patients completed a postoperative questionnaire. The primary outcome was defined as the proportion of children having a cortisol decrease ≥ 15 nmol/L. RESULTS: 101 participants (54 females) were included. The rate of children having a cortisol decrease ≥ 15 nmol/L was 27.3%, 35.3%, and 19.4% for lorazepam, placebo, and no premedication, respectively (p = 0.356). The median (IQR) NAPCOMS pain score was 3.0 (0-6) for lorazepam, 4.4 (0-6) for placebo, and 3.4 (3-4) for no premedication (p = 0.428). With lorazepam, 75.9% of children reported experiencing a comfortable procedure, compared with 41.9% taking placebo and 34.5% with no premedication (p = 0.013). Transient tachycardia was the most frequent intraoperative adverse event, particularly with lorazepam (62.5%, p = 0.029). CONCLUSIONS: Oral lorazepam had no effect on patients' preoperative stress, as measured by salivary cortisol, but was associated with a higher rate of comfortable procedures. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, Identifier NCT03180632.


Assuntos
Endoscopia/métodos , Hipnóticos e Sedativos/uso terapêutico , Lorazepam/uso terapêutico , Adolescente , Criança , Método Duplo-Cego , Feminino , Humanos , Hipnóticos e Sedativos/farmacologia , Lorazepam/farmacologia , Masculino
3.
Transl Psychiatry ; 9(1): 185, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383851

RESUMO

Depressive symptoms are often accompanied by cognitive impairments and recurrent depressive episodes are discussed as a potential risk for dementia. Especially, stressful life events are considered a potent risk factor for depression. Here, we induced recurrent stress-induced depressive episodes over the life span of rats, followed by cognitive assessment in the symptom-free period. Rats exposed to stress-induced depressive episodes learned faster than control rats. A high degree of stress-induced depressive-like behavior early in the paradigm was a predictor of improved cognitive performance, suggesting induction of resilience. Subsequently, exposure to lorazepam prior to stress-induced depressive episodes and cognitive testing in a nonaversive environment prevented the positive effect. This indicates a beneficial effect of the stress-associated situation, with the existence of individual coping abilities. Altogether, stress may in some have a beneficial effect, yet for those individuals unable to tackle these aversive events, consecutive unpleasant episodes may lead to worse cognitive performance later in life.


Assuntos
Comportamento Animal/fisiologia , Cognição/fisiologia , Depressão/psicologia , Resiliência Psicológica , Estresse Psicológico/psicologia , Animais , Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Lorazepam/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Recidiva
4.
Am J Physiol Lung Cell Mol Physiol ; 316(5): L894-L902, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30724097

RESUMO

Ovarian cancer G protein-coupled receptor 1 (OGR1) is a recently deorphanized G protein-coupled receptor shown to signal in response to low extracellular pH (↓pHo) or certain benzodiazepines. The pleiotropic nature of OGR1 signaling in human airway smooth muscle (HASM) cells suggests that OGR1 is a potential therapeutic target for the management of obstructive lung diseases. However, the basic pharmacological and regulatory features of OGR1 remain poorly understood. We employed model systems of heterologously expressed [human embryonic kidney 293 (HEK293) cells] or endogenous (HASM) OGR1 to assess changes in expression, subcellular localization, and signaling capabilities following acute or chronic treatment with ↓pHo or the benzodiazepines lorazepam and sulazepam. In HEK293 cells expressing OGR1, treatment with ↓pHo and/or lorazepam, but not sulazepam, caused rapid OGR1 internalization. In HASM cells, acute treatment with ↓pHo or benzodiazepines did not alter abundance of OGR1 mRNA; however, significant downregulation was observed following chronic treatment. Acute and chronic pretreatment of HASM cells with sulazepam or lorazepam resulted in receptor desensitization as demonstrated by reduced phosphorylation of vasodilator-stimulated phosphoprotein (VASP) or p42/p44 upon rechallenge. Acid (acute but not chronic) pretreatment of HASM cells induced desensitization of OGR1-mediated VASP (but not p42/p44) phosphorylation. In contrast to a recent study reporting OGR1 upregulation and sensitization in cardiac tissue subject to ischemic/acidic insult, chronic OGR1 activation in multiple model systems did not increase OGR1 expression or signaling capacity. The ability to induce OGR1 internalization and desensitization was activator dependent, reflecting the ability of different activators to induce specific receptor confirmations and engagement of specific heterotrimeric G proteins.


Assuntos
Sistema de Sinalização das MAP Quinases , Miócitos de Músculo Liso/metabolismo , Receptores Acoplados a Proteínas-G/biossíntese , Sistema Respiratório/metabolismo , Regulação para Cima , Animais , Moléculas de Adesão Celular/metabolismo , Feminino , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Lorazepam/farmacologia , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Miócitos de Músculo Liso/patologia , Fosfoproteínas/metabolismo , Sistema Respiratório/patologia
5.
Bosn J Basic Med Sci ; 19(2): 125-129, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30501608

RESUMO

Phenibut is a glutamic acid derivative with activity on the γ-aminobutyric acid (GABA)B, A, and B-phenethylamine receptors. It is prescribed in former Communist Bloc countries for anxiolysis and related psychiatric disorders. It can be easily obtained in Western countries and is thought to have abuse potential. Abrupt discontinuation has been reported to precipitate an abstinence syndrome. A review of the literature identified 22 reported cases, many of which were notable for severe psychomotor agitation and requirements for aggressive pharmacologic treatment. Neurologic and autonomic signs and symptoms may mimic serotonin or neuroleptic malignant syndrome. Patients were typically younger and had coexisting substance abuse disorders to other drugs. Also presented is a case of a 23-year-old male with an acute phenibut abstinence syndrome. This patient exhibited severe psychomotor agitation requiring physical restraints, dexmedetomidine, lorazepam, haloperidol, diphenhydramine, cyproheptadine, melatonin, olanzapine, and baclofen for symptom control.


Assuntos
Acatisia Induzida por Medicamentos/diagnóstico , Síndrome de Abstinência a Substâncias , Ácido gama-Aminobutírico/análogos & derivados , Baclofeno/farmacologia , Ciproeptadina/farmacologia , Dexmedetomidina/farmacologia , Difenidramina/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Agonistas dos Receptores de GABA-B/farmacologia , Haloperidol/farmacologia , Humanos , Lorazepam/farmacologia , Masculino , Melatonina/farmacologia , Síndrome Maligna Neuroléptica/diagnóstico , Olanzapina/farmacologia , Receptores de GABA/metabolismo , Transtornos Relacionados ao Uso de Substâncias , Adulto Jovem , Ácido gama-Aminobutírico/efeitos adversos , Ácido gama-Aminobutírico/farmacologia
6.
J Physiol ; 596(21): 5267-5280, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30192388

RESUMO

KEY POINTS: Short-latency afferent inhibition (SAI) is modulated by GABAA receptor activity, whereas the pharmacological origin of long-latency afferent inhibition remains unknown. This is the first study to report that long-latency afferent inhibition (LAI) is reduced by the GABAA positive allosteric modulator lorazepam, and that both SAI and LAI are not modulated by the GABAB agonist baclofen. These findings advance our understanding of the neural mechanisms underlying afferent inhibition. ABSTRACT: The afferent volley evoked by peripheral nerve stimulation has an inhibitory influence on transcranial magnetic stimulation induced motor evoked potentials. This phenomenon, known as afferent inhibition, occurs in two phases: short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI). SAI exerts its inhibitory influence via cholinergic and GABAergic activity. The neurotransmitter receptors that mediate LAI remain unclear. The present study aimed to determine whether LAI is contributed by GABAA and/or GABAB receptor activity. In a double-blinded, placebo-controlled study, 2.5 mg of lorazepam (GABAA agonist), 20 mg of baclofen (GABAB agonist) and placebo were administered to 14 males (mean age 22.7 ± 1.9 years) in three separate sessions. SAI and LAI, evoked by stimulation of the median nerve and recorded from the first dorsal interosseous muscle, were quantified before and at the peak plasma concentration following drug ingestion. Results indicate that lorazepam reduced LAI by ∼40% and, in support of previous work, reduced SAI by ∼19%. However, neither SAI, nor LAI were altered by baclofen. In a follow-up double-blinded, placebo-controlled study, 10 returning participants received placebo or 40 mg of baclofen (double the dosage used in Experiment 1). The results obtained indicate that SAI and LAI were unchanged by baclofen. This is the first study to show that LAI is modulated by GABAA receptor activity, similar to SAI, and that afferent inhibition does not appear to be a GABAB mediated process.


Assuntos
Baclofeno/farmacologia , Agonistas GABAérgicos/farmacologia , Lorazepam/farmacologia , Inibição Neural , Neurônios Aferentes/efeitos dos fármacos , Humanos , Masculino , Nervo Mediano/efeitos dos fármacos , Nervo Mediano/fisiologia , Neurônios Aferentes/fisiologia , Tempo de Reação , Adulto Jovem
7.
Eur Neuropsychopharmacol ; 28(8): 925-932, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30135030

RESUMO

Etifoxine hydrochloride (Stresam®), a treatment indicated for psychosomatic manifestations of anxiety, could be an alternative to benzodiazepines. While no impact on alertness and cognitive functions has been proven among youth, data on elderly are lacking. The primary objective of this study was to measure the impact of etifoxine, lorazepam or placebo on alertness in the elderly. The secondary objectives were to evaluate cognitive performances and adverse effects. In this randomized, placebo-controlled, double-blind, 3-way crossover design, 30 healthy volunteers aged 65 to 75 years underwent three one-day sessions. After treatment intake, standardized cognitive tests were conducted using the Cambridge Neuropsychological Test Automated Batteries and other psychological tests (Stroop, Rey Auditory Verbal Learning Test, Digit Span). The reaction time (RTI) as primary endpoint was analysed using a 3 × 3 latin square variance analysis. A 100-mg dose of etifoxine has no deleterious impact on alertness and causes no cognitive disorders as compared to placebo (RTI: 744 ±â€¯146 ms versus 770 ±â€¯153 ms; p = 1.00). As expected, a 2-mg dose of lorazepam impairs alertness (RTI: 957 ±â€¯251 ms versus placebo; p < 0.0001) and cognitive functions. A similar frequency of adverse events was observed with etifoxine and placebo while their incidence was 3-fold higher with lorazepam, drowsiness being the most frequent adverse event. No serious adverse events were observed. This study demonstrates in the elderly that a single dose of etifoxine does neither impair alertness nor any of the cognitive parameters evaluated. Etifoxine may be a good option when anxiolytic treatment is required, especially in elderly people.


Assuntos
Ansiolíticos/farmacologia , Atenção/efeitos dos fármacos , Cognição/efeitos dos fármacos , Oxazinas/farmacologia , Idoso , Ansiolíticos/efeitos adversos , Atenção/fisiologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Lorazepam/efeitos adversos , Lorazepam/farmacologia , Masculino , Testes Neuropsicológicos , Oxazinas/efeitos adversos , Tempo de Reação/efeitos dos fármacos
8.
Pharmacol Biochem Behav ; 172: 59-67, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30030126

RESUMO

Benzodiazepine (BZD) is a commonly prescribed anxiolytic and sedation aid medication, especially in elderly women. However, long-term use of BZD provokes adverse nontherapeutic effects that include movement deficit. Here, we investigated motoric deficit and molecular changes in cerebellum associated with the chronic use of BZD (cBZD) in female mice. We measured neuroprotective translocator protein (TSPO), neurotoxic amyloid ß (Aß), Aß-producing presenilin-1 (PS1), and Aß-degrading neprilysin. We also tested whether cBZD treatment damages mitochondrial membranes by measuring mitochondrial membrane swelling and mitochondrial respiration. Young and old mice received BZD (lorazepam) for 20 days, were tested for motoric function using Rotarod, and then euthanized to collect cerebellum. The major methods were immunoblot and RT-PCR for TSPO, PS1, and neprilysin expressions; ELISA for Aß level; spectrometry for mitochondrial membrane swelling; XF-respirometry for mitochondrial respiration. cBZD-treated old mice showed poorer motoric function than old control or young cBZD-treated mice. Old mice treated with cBZD showed a decrease in TSPO and neprilysin and an increase in Aß and PS1 production compared to old control mice. Old cBZD-mice also showed an increase in mitochondrial membrane swelling and a decrease in mitochondrial respiration. These data suggest that cBZD exacerbates motoric aging in a manner that involves diminished TSPO, elevated Aß, and mitochondrial damage.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Lorazepam/administração & dosagem , Receptores de GABA/metabolismo , Fatores Etários , Peptídeos beta-Amiloides/biossíntese , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Feminino , Lorazepam/farmacologia , Camundongos Endogâmicos C57BL , Membranas Mitocondriais/efeitos dos fármacos , Dilatação Mitocondrial , Modelos Animais , Atividade Motora/efeitos dos fármacos , Neprilisina/biossíntese , Neprilisina/metabolismo , Respiração/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
J Psychopharmacol ; 32(6): 678-690, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29783905

RESUMO

BACKGROUND: Saccadic eye movements are controlled by a network of parietal, frontal, striatal, cerebellar and brainstem regions. The saccadic peak velocity is an established biomarker of benzodiazepine effects, with benzodiazepines reliably reducing the peak velocity. AIMS: In this study, we aimed to replicate the effects of benzodiazepines on peak velocity and we investigated effects on previously less studied measures of saccades. We also explored the roles of sex, task characteristics and the baseline variables age, intelligence and trait anxiety in these effects. METHOD: Healthy adults ( N = 34) performed a horizontal step prosaccade task under 1 mg lorazepam, 2 mg lorazepam and placebo in a double-blind, within-subjects design. RESULTS: We replicated the dose-dependent reduction in peak velocity with lorazepam and showed that this effect is stronger for saccades to targets at smaller eccentricities. We also demonstrated that this effect is independent of sex and other baseline variables. Lorazepam effects were widespread, however, occurring on mean and variability measures of most saccadic variables. Additionally, there were sex-dependent lorazepam effects on spatial consistency of saccades, indicating more adverse effects in females. CONCLUSIONS: We conclude that saccadic peak velocity is a sensitive and robust biomarker of benzodiazepine effects. However, lorazepam has pronounced effects also on other parameters of horizontal saccades. Sex-dependent drug effects on spatial consistency may reflect cerebellar mechanisms, given the role of the cerebellum in saccadic spatial accuracy.


Assuntos
Ansiolíticos/administração & dosagem , Benzodiazepinas/administração & dosagem , Lorazepam/administração & dosagem , Movimentos Sacádicos/efeitos dos fármacos , Adulto , Ansiolíticos/efeitos adversos , Ansiolíticos/farmacologia , Benzodiazepinas/efeitos adversos , Benzodiazepinas/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Lorazepam/efeitos adversos , Lorazepam/farmacologia , Masculino , Fatores Sexuais , Adulto Jovem
11.
Methods Enzymol ; 603: 279-303, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29673531

RESUMO

Functional neuroimaging with positron emission tomography (PET) is one of the cornerstones for studying the central nervous system effects of general anesthetics and anesthesia mechanisms. General anesthesia offers a unique and safe way to directly manipulate consciousness, and can thus be used as a powerful research tool to study the neurobiology of human consciousness. In this chapter, we will address the possibilities of PET imaging in revealing the mysteries of general anesthesia and anesthetic induced unconsciousness and summarize some of the recent advancements in the field. Importantly, we will discuss possible ways to separate brain activity changes associated with the changing level of consciousness from the concentration or dose-dependent direct or indirect drug effects on the brain. We will try to demonstrate how state-of-the-art clinical pharmacology, use of specific anesthetic drugs, and innovative study design solutions could be utilized.


Assuntos
Anestesia Geral/métodos , Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/farmacologia , Encéfalo/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/anatomia & histologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Estado de Consciência/efeitos dos fármacos , Estado de Consciência/fisiologia , Relação Dose-Resposta a Droga , Neuroimagem Funcional/instrumentação , Neuroimagem Funcional/métodos , Glucose/metabolismo , Halotano/farmacologia , Humanos , Lorazepam/farmacologia , Imagem por Ressonância Magnética/métodos , Propofol/farmacologia , Projetos de Pesquisa , Vigília/efeitos dos fármacos , Vigília/fisiologia
12.
Behav Brain Res ; 339: 215-221, 2018 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-29203336

RESUMO

Agitation and aggression are common sequelae of traumatic brain injury (TBI) and pose a challenge to physicians and other health providers during acute patient care and subsequent neurorehabilitation. Antipsychotic drugs (APDs) are routinely administered to manage TBI patients displaying such maladaptive behaviors despite several clinical and preclinical studies demonstrating that they hinder recovery. A potentially viable alternative to APDs may be the benzodiazepines, which have differing mechanisms of action. Hence, the aim of the study was to test the hypothesis that lorazepam (LOR) would not impede recovery after TBI. Anesthetized adult male rats received a cortical impact or sham injury and then were intraperitoneally administered LOR (0.1mg/kg, 1.0mg/kg, or 2.0mg/kg) or vehicle (VEH; 1mL/kg) commencing 24-h after surgery and once daily for 19days. Motor and cognitive outcomes were assessed on post-operative days 1-5 and 14-19, respectively. No differences were revealed among the four sham control groups and thus they were pooled into one inclusive SHAM group. The SHAMs performed better than all TBI groups on all assessments (p<0.05). Regarding TBI, the 2.0mg/kg LOR group performed better than the VEH and 0.1mg/kg or 1.0mg/kg LOR groups on every task (p<0.05); no differences were observed among the latter three groups on any endpoint (p>0.05). Overall, these preclinical behavioral data support the hypothesis and reveal a therapeutic benefit with the higher dose of LOR. The findings suggest that LOR may be an alternative, to APDs, for controlling agitation without compromising spontaneous recovery and perhaps could afford a dual benefit by also promoting therapeutic efficacy.


Assuntos
Antipsicóticos/farmacologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Cognição/efeitos dos fármacos , Lorazepam/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Antipsicóticos/administração & dosagem , Modelos Animais de Doenças , Haloperidol/farmacologia , Lorazepam/administração & dosagem , Masculino , Atividade Motora/efeitos dos fármacos , Ratos Sprague-Dawley
13.
Alzheimer Dis Assoc Disord ; 31(4): 271-277, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28582280

RESUMO

INTRODUCTION: This study set out to clarify the differential acute cognitive impact of lorazepam based on varying genetic risk for Alzheimer disease. METHODS: Fifty-seven cognitively unimpaired individuals aged 51 to 88, genotyped according to apolipoprotein E (APOE) and translocase of outer mitochondrial membrane (40 homolog) poly-T lengths, completed cognitive testing before, 2.5 and 5 hours after receiving a 1 mg dose of lorazepam. RESULTS: Post-lorazepam, there were significant (P<0.05) declines from baseline in memory, psychomotor processing speed, and executive function. At 2.5 hours, the magnitude of this lorazepam-induced cognitive change was significantly greater in the APOE3/4 group than in the APOE3/3 group for tests of working memory and visuospatial memory/executive function. At 5 hours postchallenge, verbal memory and working memory deficits persisted in the APOE3/4 group compared with the APOE3/3 group. At 5 hours after lorazepam challenge, as compared with the very long/very long group, the short/short group performed slightly worse on a test of working memory (P<0.05), but no other differences were observed among translocase of the outer mitochondrial membrane 40 homolog poly-T variant groups. DISCUSSION: The lorazepam challenge may be unmasking presymptomatic cognitive dysfunction associated with APOE4 carriage.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Cognição/efeitos dos fármacos , Moduladores GABAérgicos/farmacologia , Lorazepam/farmacologia , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
14.
Gen Hosp Psychiatry ; 45: 40-43, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28274337

RESUMO

OBJECTIVE: The aims of the present study were to determine the prevalence of catatonia in women with postpartum psychosis, describe its socio demographic, clinical and obstetric correlates and identify predictors of treatment response. METHODS: Data was extracted from clinical charts of 200 women with postpartum psychosis admitted to an inpatient mother baby unit (MBU) in India over a 3year period. RESULTS: Of the 200 patients, 20% (n=40) had symptoms of catatonia. Mean catatonia score on the Bush Francis Catatonia Rating Scale (BFCRS) was 14.97±3.2. The most frequent catatonic feature was mutism (n=40, 100%). Adequate response to lorazepam trial in catatonia was seen in half the women (n=18/36), with longer duration of untreated catatonia being associated with poorer response. An adequate response to Electroconvulsive therapy (ECT) was seen in 19 women who did not respond to the lorazepam trial. Women with catatonia had significantly higher rates of onset within the first four weeks of postpartum period (50% vs 31.5%, P=0.022) and a longer duration of untreated psychosis at presentation (79.46±159.88 vs 56.12±47.26, P=0.002) compared to mothers without catatonia. CONCLUSION: Catatonic symptoms were identified in one-fifth (20%) of women with postpartum psychosis. Early identification and treatment of catatonia are essential for rapid control of symptoms in this vulnerable population.


Assuntos
Catatonia/epidemiologia , Catatonia/terapia , Transtornos Psicóticos/epidemiologia , Transtornos Puerperais/epidemiologia , Adulto , Catatonia/etiologia , Terapia Combinada , Eletroconvulsoterapia/métodos , Feminino , Departamentos Hospitalares/estatística & dados numéricos , Hospitais Especializados/estatística & dados numéricos , Humanos , Hipnóticos e Sedativos/farmacologia , Índia/epidemiologia , Lorazepam/farmacologia , Transtornos Psicóticos/complicações , Adulto Jovem
16.
Clin Pharmacokinet ; 56(8): 941-951, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-27943220

RESUMO

BACKGROUND: Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE. METHODS: We developed a population pharmacokinetic model for lorazepam using the NONMEM software. We then assessed exploratory exposure-response relationships using the overall efficacy and safety study endpoints, and performed dosing simulations. RESULTS: A total of 145 patients contributed 439 pharmacokinetic samples. The median (range) age and dose were 5.4 years (0.3-17.8) and 0.10 mg/kg (0.02-0.18), respectively. A two-compartment pharmacokinetic model with allometric scaling described the data well. In addition to total body weight (WT), younger age was associated with slightly higher weight-normalized clearance (CL). The following relationships characterized the typical values for the central compartment volume (V1), CL, peripheral compartment volume (V2), and intercompartmental CL (Q), using individual subject WT (kg) and age (years): V1 (L) = 0.879*WT; CL (L/h) = 0.115*(Age/4.7)0.133*WT0.75; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT0.75. No pharmacokinetic parameters were associated with clinical outcomes. Simulations suggest uniform pediatric dosing (0.1 mg/kg, to a maximum of 4 mg) can be used to achieve concentrations of 50-100 ng/mL in children with SE, which have been previously associated with effective seizure control. CONCLUSIONS: The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE.


Assuntos
Anticonvulsivantes/farmacocinética , Lorazepam/farmacocinética , Estado Epiléptico/tratamento farmacológico , Adolescente , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacologia , Peso Corporal , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Infusões Intravenosas , Lorazepam/administração & dosagem , Lorazepam/sangue , Lorazepam/farmacologia , Masculino , Modelos Biológicos , Estudos Prospectivos , Software/estatística & dados numéricos
17.
Am J Ther ; 24(4): e381-e385, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-26270797

RESUMO

Benzodiazepines are the first-line treatment of catatonia, but a substantial number of patients do not respond to them. Amisulpride is one of the atypical antipsychotic that has been effective for negative symptoms of schizophrenia. We examined the effect of augmentation of oral low doses of amisulpride with lorazepam on resolution of catatonic symptoms. Fifteen patients with catatonia were treated with a combination of oral lorazepam (2-4 mg) with amisulpride (100 mg). Catatonic symptoms were rated using the Bush Francis Catatonia Rating Scale at the baseline and daily thereafter. There was complete resolution of catatonic symptoms on the third day in all patients. There was significant reduction of the total Bush Francis Catatonia Rating Scale score over time (F = 181.38, P < 0.001) with a strong effect size (partial η = 0.96). Augmentation of lorazepam with low-dose amisulpride can be a reliable strategy for management of catatonia.


Assuntos
Antipsicóticos/farmacologia , Benzodiazepinas/farmacologia , Catatonia/tratamento farmacológico , Moduladores GABAérgicos/farmacologia , Lorazepam/farmacologia , Sulpirida/análogos & derivados , Administração Oral , Adolescente , Adulto , Amissulprida , Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Moduladores GABAérgicos/uso terapêutico , Humanos , Lorazepam/uso terapêutico , Masculino , Escalas de Graduação Psiquiátrica , Sulpirida/farmacologia , Sulpirida/uso terapêutico , Adulto Jovem
18.
Brain Imaging Behav ; 11(6): 1885-1900, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27928709

RESUMO

Context-related extinction learning and renewal in humans is mediated by hippocampal and prefrontal regions. Renewal is defined as the reoccurrence of an extinguished response if the contexts present during extinction learning and recall differ. Animal studies implicate hippocampal γ-aminobutyric acid (GABA) A receptors in extinction and renewal. However, human studies on GABAergic mechanisms in extinction learning are lacking. In this fMRI study, we therefore investigated the role of the GABAergic system in context-related extinction learning and renewal. Participants treated with the GABA A agonist lorazepam prior to extinction learning were impaired in encoding changed associations during extinction learning, regardless of context, and in retrieving extinction associations during recall. In contrast, retrieval of associations learned during acquisition was largely unaffected, which led to reduced genuine renewal, since acquisition associations were retrieved context-independently. These deficits, which were presumably due to weak encoding of extinction associations, were related to altered BOLD activation in regions relevant for context processing and retrieval, as well as response selection: reduced activation in bilateral PFC and hippocampus during extinction learning and recall, and increased ventromedial/orbitofrontal cortex activation during recall. Our findings indicate that the GABergic system is involved in context-related extinction learning and recall in humans, by modulating hippocampus-based context processing and PFC-based processing of changed associations and subsequent response selection.


Assuntos
Extinção Psicológica/fisiologia , Hipocampo/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores de GABA-A/metabolismo , Adulto , Mapeamento Encefálico , Extinção Psicológica/efeitos dos fármacos , Feminino , Agonistas de Receptores de GABA-A/farmacologia , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Humanos , Lorazepam/farmacologia , Imagem por Ressonância Magnética , Masculino , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Testes Neuropsicológicos , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Tempo de Reação , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologia , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
19.
J Emerg Med ; 52(5): 680-683, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27979642

RESUMO

BACKGROUND: Carisoprodol, a centrally acting muscle relaxant with a high abuse potential, has barbiturate-like properties at the GABA-A receptor, leading to central nervous system depression and desired effects. Its tolerance and dependence has been previously demonstrated in an animal model, and withdrawal has been described in several recent case reports. Many cases can be effectively managed with a short course of benzodiazepines or antipsychotic agents. However, abrupt cessation in a patient with a history of long-term and high-dose carisoprodol abuse may result in symptoms that are more difficult for providers to treat. CASE REPORT: We present a case of a 34-year-old man with a long history of carisoprodol abuse who was found unresponsive after having ingested 7.5 grams of carisoprodol. He was intubated and admitted to the intensive care unit. He was given propofol, dexmedetomidine, fentanyl, ketamine, lorazepam, midazolam, quetiapine, and haloperidol, some at high-dose infusions, before his agitation and ventilator asynchrony could be controlled. His improvement coincided with the addition of carisoprodol and phenobarbital to his treatment regimen. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Trends show increasing emergency department presentations for drug-related disorders and treatment. This case highlights an uncommon case of carisoprodol withdrawal that may be encountered by emergency physicians, and demonstrates that benzodiazepines may not be sufficient to suppress severe withdrawal symptoms. Treatment with carisoprodol and phenobarbital provided additional benefit and can be considered in cases of severe carisoprodol withdrawal.


Assuntos
Carisoprodol/efeitos adversos , Síndrome de Abstinência a Substâncias/complicações , Síndrome de Abstinência a Substâncias/diagnóstico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Adulto , Dexmedetomidina/farmacologia , Dexmedetomidina/uso terapêutico , Overdose de Drogas/complicações , Overdose de Drogas/diagnóstico , Overdose de Drogas/tratamento farmacológico , Fentanila/farmacologia , Fentanila/uso terapêutico , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Humanos , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Unidades de Terapia Intensiva/organização & administração , Ketamina/farmacologia , Ketamina/uso terapêutico , Lorazepam/farmacologia , Lorazepam/uso terapêutico , Masculino , Midazolam/farmacologia , Midazolam/uso terapêutico , Propofol/farmacologia , Propofol/uso terapêutico , Fumarato de Quetiapina/farmacologia , Fumarato de Quetiapina/uso terapêutico , Respiração Artificial/métodos , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
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