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1.
Obesity (Silver Spring) ; 31(2): 454-465, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36617436

RESUMO

OBJECTIVE: In contrast to what is seen clinically, male mice are resistant to antipsychotic-induced obesity. This is problematic as preclinical studies examining mechanisms of antipsychotic-induced metabolic dysfunction might be relevant to only half the population. This study sought to determine whether housing mice at thermoneutrality and under conditions of preexisting obesity, steps that have not been previously considered, would uncover a greater obesogenic effect of the antipsychotic olanzapine (OLZ). METHODS: C57BL6/J mice were fed a low- or high-fat diet (HFD) for 4 weeks and then switched to a control HFD or an HFD supplemented with OLZ for 6 weeks. RESULTS: Irrespective of obesity, OLZ treatment attenuated weight gain and increased energy expenditure in male mice. In females, OLZ increased food intake and potentiated weight gain in mice with preexisting obesity. CONCLUSIONS: Despite taking steps to increase clinical translatability, this study did not unmask an obesogenic effect of OLZ in male mice. Interestingly, prior studies in female mice could have been underestimating the metabolic consequences of OLZ by not considering the importance of preexisting obesity. Uncovering the mechanisms conferring resistance to weight gain in males may provide clues for approaches to counter the metabolic side effects of antipsychotics clinically.


Assuntos
Antipsicóticos , Masculino , Feminino , Camundongos , Animais , Olanzapina , Antipsicóticos/efeitos adversos , Habitação , Benzodiazepinas/efeitos adversos , Obesidade/metabolismo , Aumento de Peso
2.
Iran J Med Sci ; 48(1): 70-76, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36688194

RESUMO

Background: Genetic diversity in human leukocyte antigen (HLA) alleles across populations is a significant risk factor for drug-induced severe cutaneous adverse reactions (SCARs), e.g., carbamazepine (CBZ)- and lamotrigine (LTG)-induced Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). The present study aimed to investigate the frequency of different HLA alleles in Iranian patients with CBZ- and LTG-induced SJS/TEN. Methods: A case-control study was conducted from 2011 to 2018 at various hospitals affiliated with Shiraz University of Medical Sciences (Shiraz, Iran). A total of 31 patients receiving anticonvulsant drugs (CZB or LTG) were recruited and divided into two groups. The drug-induced group (n=14) included hospitalized patients due to CBZ- or LTG-induced SJS/TEN. The drug-tolerant group (n=17) included individuals receiving CBZ or LTG for at least three months with no adverse effects. In addition, 46 healthy individuals (control group) were recruited. The frequency of HLA-A, -B, and -DRB1 alleles in patients with CZB- or LTG-induced SJS/TEN was investigated. HLA typing was performed using the allele-specific polymerase chain reaction method. The Chi square test and Fisher's exact test were used to determine a potential association between SJS/TEN and HLA alleles. P<0.05 was considered statistically significant. Results: CBZ- or LTG-induced SJS/TEN was not significantly associated with HLA alleles. However, HLA-DRB1*01 showed a significantly higher frequency in patients with CBZ-induced SJS/TEN than the CBZ-tolerant patients (30% vs. 9%, P=0.07). Conclusion: Overall, no significant association was found between CBZ- or LTG-induced SJS/TEN and HLA alleles. Further large-scale studies are required to substantiate our findings.


Assuntos
Anticonvulsivantes , Síndrome de Stevens-Johnson , Humanos , Anticonvulsivantes/efeitos adversos , Lamotrigina/efeitos adversos , Irã (Geográfico) , Síndrome de Stevens-Johnson/genética , Alelos , Estudos de Casos e Controles , Antígenos HLA-B/genética , Carbamazepina/efeitos adversos , Benzodiazepinas
3.
Chemosphere ; 315: 137741, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36610515

RESUMO

Carbamazepine (CBZ) as an extensively distributed emerging pollutant has menaced ecological security. The degradation performance of CBZ by UV driven bisulfite process was investigated in this work. The kinetics results indicated that CBZ was high-efficiently degraded by UV/bisulfite following a pseudo first-order kinetic model (Kobs = 0.0925 min-1). SO4•- and •OH were verified as the reactive oxidants by EPR test and the radicals scavenging experiment using MeOH and TBA. SO4•- played a dominant role for CBZ degradation. The Density functional theory (DFT) and LC-qTOF-MS/MS clarified that hydroxylation, ketonation, ring opening reaction, and ring contraction were main transformation patterns of CBZ. As to influence factors, CBZ degradation was significantly hindered in presence of CO32-, HPO42- and NOM. Toxicological analysis derived from metabonomics suggested that the remarkable alteration of metabolic profile was triggered by exposure to intermediates mixture. CBZ intermediates interfered in several key metabolic pathways, including pentose phosphate, amino acids, lysine degradation, glycerophospholipid, glutathione, nucleotides and carbohydrate, which was alleviated after UV/bisulfite treatment. This work provided a meaningful support to potential risk of CBZ intermediates products, which shed light on the future application in eliminating drugs using UV /bisulfite.


Assuntos
Poluentes Químicos da Água , Purificação da Água , Espectrometria de Massas em Tandem , Poluentes Químicos da Água/análise , Purificação da Água/métodos , Carbamazepina/química , Benzodiazepinas , Cinética , Oxirredução , Raios Ultravioleta
4.
J Prim Care Community Health ; 14: 21501319221147378, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36625271

RESUMO

OBJECTIVE: When prescribed with opioids, sedative-hypnotics substantially increase the risk of overdose. The objective of this paper was to describe characteristics and trends in opioid sedative-hypnotic co-prescribing in a network of safety-net clinics serving low-income, publicly insured, and uninsured individuals. METHODS: This retrospective longitudinal analysis of prescription orders examined opioid sedative-hypnotic co-prescribing rates between 2009 and 2018 in the OCHIN network of safety-net community health centers. Sedative-hypnotics included benzodiazepine and non-benzodiazepine sedatives (eg, zolpidem). Co-prescribing patterns were assessed overall and across patient demographic and co-morbidity characteristics. RESULTS: From 2009 to 2018, 240 587 patients had ≥1 opioid prescriptions. Most were White (65%), female (59%), and had Medicaid insurance (43%). One in 4 were chronic opioid users (25%). During this period, 55 332 (23%) were co-prescribed a sedative-hypnotic. The prevalence of co-prescribing was highest for females (26% vs 19% for males), non-Hispanic Whites (28% vs 13% for Hispanic to 20% for unknown), those over 44 years of age (25% vs 20% for <44 years), Medicare insurance (30% vs 21% for uninsured to 22% for other/unknown), and among those on chronic opioid therapy (40%). Co-prescribing peaked in 2010 (32%) and declined steadily through 2018 (20%). Trends were similar across demographic subgroups. Co-prescribed sedative-hypnotics remained elevated for those with chronic opioid use (27%), non-Hispanic Whites (24%), females (23%), and those with Medicare (23%) or commercial insurance (22%). CONCLUSIONS: Co-prescribed sedative-hypnotic use has declined steadily since 2010 across all demographic subgroups in the OCHIN population. Concurrent use remains elevated in several population subgroups.


Assuntos
Analgésicos Opioides , Medicare , Masculino , Humanos , Feminino , Idoso , Estados Unidos , Adulto , Analgésicos Opioides/uso terapêutico , Estudos Retrospectivos , Hipnóticos e Sedativos/uso terapêutico , Benzodiazepinas
5.
Crit Care ; 27(1): 8, 2023 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624526

RESUMO

BACKGROUND: Generalised convulsive status epilepticus (GCSE) is a medical emergency. Guidelines recommend a stepwise strategy of benzodiazepines followed by a second-line anti-seizure medicine (ASM). However, GCSE is uncontrolled in 20-40% patients and is associated with protracted hospitalisation, disability, and mortality. The objective was to determine whether valproic acid (VPA) as complementary treatment to the stepwise strategy improves the outcomes of patients with de novo established GCSE. METHODS: This was a multicentre, double-blind, randomised controlled trial in 244 adults admitted to intensive care units for GCSE in 16 French hospitals between 2013 and 2018. Patients received standard care of benzodiazepine and a second-line ASM (except VPA). Intervention patients received a 30 mg/kg VPA loading dose, then a 1 mg/kg/h 12 h infusion, whilst the placebo group received an identical intravenous administration of 0.9% saline as a bolus and continuous infusion. Primary outcome was proportion of patients discharged from hospital by day 15. The secondary outcomes were seizure control, adverse events, and cognition at day 90. RESULTS: A total of 126 (52%) and 118 (48%) patients were included in the VPA and placebo groups. 224 (93%) and 227 (93%) received a first-line and a second-line ASM before VPA or placebo infusion. There was no between-group difference for patients hospital-discharged at day 15 [VPA, 77 (61%) versus placebo, 72 (61%), adjusted relative risk 1.04; 95% confidence interval (0.89-1.19); p = 0.58]. There were no between-group differences for secondary outcomes. CONCLUSIONS: VPA added to the recommended strategy for adult GCSE is well tolerated but did not increase the proportion of patients hospital-discharged by day 15. TRIAL REGISTRATION NO: NCT01791868 (ClinicalTrials.gov registry), registered: 15 February 2012.


Assuntos
Benzodiazepinas , Ácido Valproico , Adulto , Humanos , Ácido Valproico/uso terapêutico , Hospitalização , Alta do Paciente , Administração Intravenosa
6.
Sci Rep ; 13(1): 510, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627363

RESUMO

Anxiety is one of the most prevalent forms of psychopathology that affects millions worldwide. It gained more importance under the pandemic status that resulted in higher anxiety prevalence. Anxiolytic drugs such as benzodiazepines have an unfavorable risk/benefit ratio resulting in a shift toward active ingredients with better safety profile such as the naturally occurring quercetin (QRC). The delivery of QRC is hampered by its low water solubility and low bioavailability. The potential to enhance QRC delivery to the brain utilizing polymeric nanocapsules administered intranasally is investigated in the current study. Polymeric nanocapsules were prepared utilizing the nanoprecipitation technique. The best formula displayed a particle size of 227.8 ± 11.9 nm, polydispersity index of 0.466 ± 0.023, zeta potential of - 17.5 ± 0.01 mV, and encapsulation efficiency % of 92.5 ± 1.9%. In vitro release of QRC loaded polymeric nanocapsules exhibited a biphasic release with an initial burst release followed by a sustained release pattern. Behavioral testing demonstrated the superiority of QRC loaded polymeric nanocapsules administered intranasally compared to QRC dispersion administered both orally and intranasally. The prepared QRC loaded polymeric nanocapsules also demonstrated good safety profile with high tolerability.


Assuntos
Nanocápsulas , Quercetina , Polímeros , Benzodiazepinas , Ansiedade/tratamento farmacológico , Tamanho da Partícula
7.
BMC Public Health ; 23(1): 85, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631810

RESUMO

BACKGROUND: Population-based research examining geographic variability in psychotropic medication dispensing to children and youth and the sociodemographic correlates of such variation is lacking. Variation in psychotropic use could reflect disparities in access to non-pharmacologic interventions and identify potentially concerning use patterns. METHODS: We conducted a population-based study of all Ontario residents aged 0 to 24 years who were dispensed a benzodiazepine, stimulant, antipsychotic or antidepressant between January 1, 2018, and December 31, 2018. We conducted small-area variation analyses and identified determinants of dispensing using negative binomial generalized estimating equation models. RESULTS: The age- and sex-standardized rate of psychotropic dispensing to children and youth was 76.8 (range 41.7 to 144.4) prescriptions per 1000 population, with large variation in psychotropic dispensing across Ontario's census divisions. Males had higher antipsychotic [rate ratio (RR) 1.40; 95% confidence interval (CI) 1.36 to 1.44) and stimulant (RR 1.75; 95% CI 1.70 to 1.80) dispensing rates relative to females, with less use of benzodiazepines (RR 0.85; 95% CI 0.83 to 0.88) and antidepressants (RR 0.81; 95% CI 0.80 to 0.82). Lower antipsychotic dispensing was observed in the highest income neighbourhoods (RR 0.72; 95% CI 0.70 to 0.75) relative to the lowest. Benzodiazepine (RR 1.12; 95% CI 1.01 to 1.24) and stimulant (RR 1.11; 95% CI 1.01 to 1.23) dispensing increased with the density of mental health services in census divisions, whereas antipsychotic use decreased (RR 0.82; 95% CI 0.73 to 0.91). The regional density of child and adolescent psychiatrists and developmental pediatricians (RR 1.00; 95% CI 0.99 to 1.01) was not associated with psychotropic dispensing. CONCLUSION: We found significant variation in psychotropic dispensing among young Ontarians. Targeted investment in regions with long wait times for publicly-funded non-pharmacological interventions and novel collaborative service models may minimize variability and promote best practices in using psychotropics among children and youth.


Assuntos
Antipsicóticos , Masculino , Feminino , Humanos , Criança , Adolescente , Antipsicóticos/uso terapêutico , Ontário , Psicotrópicos/uso terapêutico , Antidepressivos/uso terapêutico , Prescrições de Medicamentos , Benzodiazepinas/uso terapêutico , Projetos de Pesquisa
8.
Drug Alcohol Depend ; 243: 109759, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36621199

RESUMO

BACKGROUND: In response to the opioid epidemic, many states implemented mandates requiring providers to check prescription drug monitoring programs (PDMPs) before prescribing opioids. We examine how overlapping benzodiazepine and opioid prescriptions changed after Kentucky implemented a PDMP mandate in July 2012. METHODS: We conducted an interrupted time series analysis using monthly data from Kentucky's PDMP from 2010 to 2016. Separate analyses were conducted for overlapping prescriptions from a single provider or multiple providers, and by sex and age group. We also conducted an individual-level longitudinal analysis that compared changes in utilization patterns after the mandate went into effect to changes in earlier periods during which the mandate was not in effect. RESULTS: Kentucky's PDMP mandate was associated with an immediate 7.5 % decline in the rate of overlapping benzodiazepine and opioid prescriptions and a significant change in the trend from increasing to decreasing. Approximately half of the immediate effect in level terms was explained by decreases in overlapping prescriptions written by a single provider. Our longitudinal analysis suggests that over one year the mandate reduced initiation of overlapping prescriptions by 29.3 % and reduced continuation of overlapping prescriptions by 9.4 %. The effects of the policy were largest for women and men aged 36-50. CONCLUSIONS: Though not the main rationale for the policy, Kentucky's PDMP mandate reduced overlapping prescriptions of benzodiazepines and opioids. Further efforts to reduce overlapping prescriptions should consider the effects on populations such as women over 50, who have high rates of overlapping prescriptions.


Assuntos
Programas de Monitoramento de Prescrição de Medicamentos , Masculino , Humanos , Feminino , Analgésicos Opioides/uso terapêutico , Kentucky/epidemiologia , Benzodiazepinas/uso terapêutico , Prescrições , Padrões de Prática Médica , Prescrições de Medicamentos
9.
Curr Opin Psychiatry ; 36(2): 96-103, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36705008

RESUMO

PURPOSE OF REVIEW: Down syndrome regression disorder (DSRD) is a symptom cluster consisting of neuropsychiatric regression without cause. Although knowledge of this condition has accelerated over the last decade, prior studies have been limited by heterogenous nomenclature, diagnostic approaches and therapeutic interventions. This review highlights recent advances in the diagnosis and clinical approach to DSRD and reviews the most up-to-date literature on therapeutic interventions for this condition. RECENT FINDINGS: Several multicentre studies have reported exciting findings on the presence of neurodiagnostic study abnormalities and responses to a variety of therapeutics, including psychotropics (including benzodiazepines), electroconvulsive therapy and immunotherapy. Differential response rates have been observed in the presence and absence of a variety of clinical and diagnostic factors. SUMMARY: Individuals with DSRD are responsive to a variety of psychiatric pharmacotherapy and immunotherapy underscoring this phenotype may have multiple causes. Multidisciplinary care is helpful in the evaluation and management of individuals with this condition.


Assuntos
Síndrome de Down , Eletroconvulsoterapia , Humanos , Síndrome de Down/terapia , Psicotrópicos , Benzodiazepinas/uso terapêutico
11.
Br Dent J ; 234(2): 73, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36707554
12.
Drug Des Devel Ther ; 17: 143-153, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36712948

RESUMO

Background: Postoperative delirium is common in older adult patients and associated with a poor prognosis. The use of benzodiazepine was identified as an independent risk factor for delirium, but there is no randomized controlled trial regarding the relationship between remimazolam, a new ultra-short acting benzodiazepine, and postoperative delirium. We designed a randomized controlled trial to evaluate if remimazolam increases the incidence of postoperative delirium compared with propofol in older adult patients undergoing orthopedic surgery with general anesthesia. Patients and Methods: We enrolled 320 patients aged more than 60 with American Society of Anesthesiologists physical status I-III who underwent orthopedic surgery. Patients were randomized to two groups to receive intraoperative remimazolam or propofol, respectively. Our primary outcome was the incidence of delirium within 3 days after surgery. Secondary outcome was emergence quality including the incidence of emergence agitation, extubation time, and length of post-anesthesia care unit (PACU) stay. Adverse events were also recorded. Results: The incidence of postoperative delirium was 15.6% in the remimazolam group and 12.4% in the propofol group (Risk ratio, 1.26; 95% CI, 0.72 to 2.21; Risk difference, 3.2%; 95% CI, -4.7% to 11.2%; P = 0.42). No significant differences were observed for time of delirium onset, duration of delirium, and delirium subtype between the two groups. Patients in remimazolam group had a lower incidence of hypotension after induction and consumed less vasoactive drugs intraoperatively, but had a longer postoperative extubation time and PACU stay. Conclusion: General anesthesia with remimazolam was not associated with an increased incidence of postoperative delirium compared with propofol in older adult patients undergoing orthopedic surgery.


Assuntos
Delírio , Delírio do Despertar , Procedimentos Ortopédicos , Propofol , Humanos , Idoso , Delírio do Despertar/epidemiologia , Propofol/efeitos adversos , Delírio/epidemiologia , Delírio/etiologia , Procedimentos Ortopédicos/efeitos adversos , Benzodiazepinas/efeitos adversos
13.
Sci Total Environ ; 857(Pt 2): 159351, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36243065

RESUMO

Z-drugs, benzodiazepines and ketamine are classes of psychotropic drugs prescribed for treating anxiety, sleep disorders and depression with known side effects including an elevated risk of addiction and substance misuse. These drugs have a strong potential for misuse, which has escalated over the years and was hypothesized here to have been exacerbated during the COVID-19 pandemic. Wastewater-based epidemiology (WBE) constitutes a fast, easy, and relatively inexpensive approach to epidemiological surveys for understanding the incidence and frequency of uses of these drugs. In this study, we analyzed wastewater (n = 376) from 50 cities across the United States and Mexico from July to October 2020 to estimate drug use rates during a pandemic event. Both time and flow proportional composite and grab samples of untreated municipal wastewater were analyzed using solid-phase extraction followed by liquid chromatography-tandem mass spectrometry to determine loadings of alprazolam, clonazepam, diazepam, ketamine, lorazepam, nordiazepam, temazepam, zolpidem, and zaleplon in raw wastewater. Simultaneously, prescription data of the aforementioned drugs were extracted from the Medicaid database from 2019 to 2021. Results showed high detection frequencies of ketamine (90 %), lorazepam (87 %), clonazepam (76 %) and temazepam (73 %) across both Mexico and United States and comparatively lower detection frequencies for zaleplon (22 %), zolpidem (9 %), nordiazepam (<1 %), diazepam (<1 %), and alprazolam (<1 %) during the pandemic. Average mass consumption rates, estimated using WBE and reported in units of mg/day/1000 persons, ranged between 62 (temazepam) and 1100 (clonazepam) in the United States. Results obtained from the Medicaid database also showed a significant change (p < 0.05) in the prescription volume between the first quarter of 2019 (before the pandemic) and the first quarter of 2021 (pandemic event) for alprazolam, clonazepam and lorazepam. Study results include the first detections of zaleplon and zolpidem in wastewater from North America.


Assuntos
COVID-19 , Ketamina , Humanos , Estados Unidos/epidemiologia , Benzodiazepinas , Alprazolam/análise , Pandemias , Nordazepam/análise , Zolpidem/análise , Clonazepam/análise , Lorazepam/análise , Espectrometria de Massas em Tandem/métodos , COVID-19/epidemiologia , Temazepam/análise , México/epidemiologia , Diazepam
14.
Addiction ; 118(1): 7-16, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35815384

RESUMO

BACKGROUND AND AIMS: A total of 2.4 million adults in England were dispensed a benzodiazepine or Z-drug (BZRA) in 2017/18, and more than 250 000 patients in the UK take BZRAs beyond the recommended duration. Deprescribing is a clinician-guided process of withdrawing inappropriate drugs. This review aimed to evaluate the evidence base supporting the feasibility and clinical effectiveness of all forms of deprescribing initiatives used to discontinue long-term (≥ 4 weeks) BZRAs. METHOD: Systematic review of randomized controlled trials evaluating BZRAs deprescribing among adults in community, primary or outpatient settings. MEDLINE, Embase and PsycINFO were searched from inception to February 2021. Primary outcomes were successful discontinuation in the short (< 4 weeks) or long term (≥ 4 weeks) and the occurrence of withdrawal symptoms, behavioural or psychological symptoms. Studies were categorized as pharmacological or non-pharmacological supported interventions. Study quality was assessed using the Cochrane risk-of-bias tool. Where appropriate, risk ratios (RRs), mean differences and 95% confidence intervals (CIs) were calculated, and Mantel-Haenszel methods using the random-effect meta-analysis was undertaken to calculate summary effect estimates. RESULTS: Ten studies were included (n = 1431 participants). Heterogeneity in study design and effect was observed. Benzodiazepines were successfully deprescribed when gradually tapered with non-pharmacological support compared with gradual tapering alone in the short term (n = 124; RR = 2.02; 95% CI = 1.41, 2.89) and long term (n = 123; RR = 2.45; 95% CI = 1.56, 3.85). Benzodiazepine deprescribing was more successful when supported by non-pharmacological methods versus routine care (n = 189; RR = 3.26; 95% CI = 2.36, 4.51). Quality of evidence reporting effectiveness was very low to low. CONCLUSIONS: It may be feasible to deprescribe benzodiazepines depending on the process and support mechanisms employed.


Assuntos
Desprescrições , Síndrome de Abstinência a Substâncias , Adulto , Humanos , Benzodiazepinas/uso terapêutico , Estudos de Viabilidade , Resultado do Tratamento
15.
Am J Geriatr Psychiatry ; 31(1): 67-74, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36266201

RESUMO

Phenibut is a misused substance which has shown an increase in use over the past decade. Marketed as a "dietary supplement," it is not approved in the United States for use and is not regulated by the Food and Drug Administration. The substance, however, is readily available for purchase through online markets. It has a similar drug profile as alcohol, gabapentin and benzodiazepines. Clinical effects of this drug include physiologic dependence, euphoria, anxiolysis, antispasticity, sedation, and possible nootropic properties. While there are emerging new cases of managing phenibut withdrawal, no cases currently feature phenibut addiction and withdrawal management in the geriatric population. Here we discuss such a case of phenibut addiction and withdrawal in a 68-year-old male who initially began misusing phenibut to alleviate anxiety and insomnia precipitated by worsening affective disorder, sedative, hypnotic, or anxiolytic use disorder, and alcohol use disorder.


Assuntos
Transtornos Relacionados ao Uso de Substâncias , Ácido gama-Aminobutírico , Idoso , Masculino , Humanos , Ácido gama-Aminobutírico/uso terapêutico , Hipnóticos e Sedativos/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Benzodiazepinas/efeitos adversos
16.
Int J Geriatr Psychiatry ; 38(1): e5861, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36514248

RESUMO

BACKGROUND: The adverse cardiovascular effects of benzodiazepines and Z-drugs (jointly referred as BZDRs) have been of concern. Yet, little is known about the use of BZDRs in relation to mortality risk among older adults with myocardial infarction history (post-MI). METHODS: This study is a secondary analysis of the Alpha Omega Cohort study, comprising post-MI patients aged 40-60 years. Self-reported information on the use of BZDRs, including types and dose, was collected at baseline. Four categories of mortality were examined, namely all-cause mortality, cardiovascular (CVD) mortality, cancer mortality, and non-CVD/non-cancer mortality. Associations between BZDRs use, by types and doses, and mortality were estimated with Cox regression models, adjusted for demographic and classic cardiovascular risk factors. RESULTS: A total of 433 (8.9%) out of 4837 (21.8% females) patients reported BZDRs use at baseline. During a median follow-up of 12.4 years, 2287 deaths were documented, of which 825 (36.1%) were due to CVD. BZDRs use was related to a statistically significantly higher risk of all-cause and CVD mortality; adjusted hazard ratios [95% CI] were (1.31 [1.41, 1.52]) and (1.43 [1.14, 1.81]), respectively. These relationships were dose-dependent-patients using BZDRs on an as-needed basis had similar risks compared to the non-uses, whereas patients with a daily use schedule and increasing doses had higher risks (p-value for trend: <0.001). CONCLUSION: BZDRs use was independently associated with a higher risk of all-cause and cardiovascular mortality in older post-MI patients, and there was evidence for a dose-dependent relationship. CLINICAL TRIAL REGISTRATION: NCT00127452 (www. CLINICALTRIALS: gov).


Assuntos
Doenças Cardiovasculares , Infarto do Miocárdio , Feminino , Humanos , Idoso , Masculino , Estudos de Coortes , Doenças Cardiovasculares/complicações , Fatores de Risco , Benzodiazepinas/efeitos adversos , Infarto do Miocárdio/tratamento farmacológico , Modelos de Riscos Proporcionais
17.
Neurosci Lett ; 795: 137014, 2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36521643

RESUMO

Benzodiazepines, such as diazepam (DZP), are used to treat anxiety disorders, and are prescribed to pregnant woman for therapeutic purposes. Concerns regarding their consequences on postnatal development rise as they cross the placenta and interact with the embryo. Occurrence of malformation and behavioral syndromes have been reported for different ages, but little is known about their effects on the brain after exposure during intrauterine life. Thus, we sought to evaluate the effects of intrauterine exposure to DZP on the number of brainstem's catecholaminergic and serotonergic neurons, implicated in respiratory control, in male and female rats on postnatal (P) day 12-13, using immunofluorescence labeling for tyrosine-hydroxylase (TH) and serotonin (5-HT). We observed a reduction in the number of catecholaminergic neurons for males and females. Special attention is given to the reduction in the density of neurons in the A6 region, involved in ventilatory responses to CO2. Interestingly, only males showed a reduction in the number of serotonergic neurons, while females were not affected. These findings suggest that in utero exposure to DZP results in deleterious neuroanatomical effects on P12-13 rats and raises a note of concern for women clinicians to make more informed choices about the use of anxiolytic treatments during gestation.


Assuntos
Ansiolíticos , Diazepam , Gravidez , Ratos , Animais , Feminino , Masculino , Diazepam/farmacologia , Neurônios Serotoninérgicos , Benzodiazepinas/farmacologia , Ansiolíticos/farmacologia , Encéfalo , Serotonina/farmacologia
18.
Exp Neurol ; 360: 114294, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36493860

RESUMO

Epilepsy is a serious neurological disorder associated with recurrent and unpredictable seizures and extensive neuropsychiatric comorbidities. There is no cure for epilepsy, and over one third of epileptic patients have been diagnosed with drug-refractory epilepsy, indicating the critical need for novel antiseizure medications (ASMs). Cannabidiol (CBD) has been shown to decrease seizures in pediatric epilepsies, such as Dravet and Lennox-Gastaut syndromes; however, it has not been rigorously tested for adult seizures or in models of refractory focal epilepsy. Although the exact mechanism is unknown, it is likely to act in a way that is unique to certain GABA-A receptor-modulating drugs, such as neurosteroids and benzodiazepines. In this study, we sought to determine the adjunct antiseizure activity of a clinical CBD product in an adult 6-Hz model of focal refractory epilepsy. CBD was evaluated alone in both a dose-response and time-course manner and in an adjunct combination with two ASMs ganaxolone (neurosteroid) and midazolam (benzodiazepine) against 6-Hz-induced refractory focal onset, generalized seizures. In pharmacological studies, CBD produced dose-dependent protection against seizures (ED50, 53 mg/kg, i.p.) without any side effects. CBD significantly reduced both electrographic activity and behavioral ictal responses with no apparent sex differences. CBD was evaluated in an isobologram design in conjunction with ganaxolone or midazolam at three standard ratios (1:1, 1:3, 3:1). Isobolographic analysis shows the combination regimens of CBD + ganaxolone and CBD + midazolam exerted combination index of 0.313 and 0.164, indicating strong synergism for seizure protection, with little to no toxicity. Together, these results demonstrate the therapeutic potential of CBD monotherapy and as an adjunct therapy for adult focal refractory epilepsy in combination with GABAergic ASMs.


Assuntos
Canabidiol , Epilepsia Resistente a Medicamentos , Epilepsias Parciais , Epilepsia , Neuroesteroides , Humanos , Adulto , Feminino , Masculino , Criança , Canabidiol/uso terapêutico , Neuroesteroides/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Benzodiazepinas/uso terapêutico , Anticonvulsivantes/uso terapêutico , Midazolam/uso terapêutico , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Epilepsias Parciais/tratamento farmacológico
20.
J Am Pharm Assoc (2003) ; 63(1): 409-415, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36564330

RESUMO

BACKGROUND: Benzodiazepines are commonly used among older adults, despite well-known risks. Clinical pharmacists can lead tapering efforts, leveraging their clinical expertise and relieving time-pressured primary care providers. OBJECTIVES: The objective of this study is to describe the design, implementation, and evaluation of an outpatient pharmacist-led benzodiazepine-tapering clinic. PRACTICE DESCRIPTION: The clinic is based within a community medical group associated with a large academic health system in Los Angeles, California. PRACTICE INNOVATION: The clinic is staffed by clinical pharmacists and supervised by a psychiatrist. The initial visit consists of patient education, design of patient-driven tapering schedule, and medical history review. Follow-up phone/video visits are used to monitor withdrawal symptoms and provide support. EVALUATION METHODS: We used chart review to assess tapering status among those enrolled in the tapering clinic versus those who did not enroll. We compared outcomes across the 2 groups using bivariate statistics. RESULTS: From March 2017 to May 2019, 176 patients were referred to the clinic; 17 were deemed ineligible. Of the 159 patients contacted, 62 patients enrolled in the clinic; 97 patients did not enroll. Among patients in the clinic, 13 (27%) of patients were tapered down, 29 (60%) completely tapered off, 6 (13%) were unable to taper, and 14 (23%) were in the process of tapering. In contrast, among patients who did not enroll, 3 (4%) of patients were tapered down, 15 (20%) completely tapered off, 57 (76%) were unable to taper, and 22 (22%) were in the process of tapering. Ninety percent of patients had at least some benzodiazepine tapering when enrolled in the clinic compared to 41% among not enrolled in the clinic (P<0.001). CONCLUSION: A pharmacist-led benzodiazepine-tapering clinic can be an effective way to engage patients motivated to taper down. Lessons learned include the importance of ensuring referring providers adequately counsel patients prior to referral.


Assuntos
Distúrbios do Início e da Manutenção do Sono , Síndrome de Abstinência a Substâncias , Humanos , Idoso , Benzodiazepinas , Farmacêuticos , Pacientes Ambulatoriais
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