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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
Int J Drug Policy ; 111: 103933, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36529033

RESUMO

The overdose crisis in Canada has continuously evolved and is increasingly challenging to contain, while efforts from governments and policymakers to address it have often fallen short and resulted in unintended consequences. One of the main repercussions has been an unprecedented rise in adulterants in the illegal drug supply, including a wide array of pharmacological and psychoactive compounds and chemicals, which has resulted in a progressively toxic drug supply. Most recently, there has been a stark increase in synthetic benzodiazepine-laced opioids (i.e., 'benzodope') in some Canadian jurisdictions. This unique combination carries distinct and amplified risks for people who use drugs including fatal and non-fatal overdoses, increased dependence and withdrawal symptoms, and places them in extremely vulnerable positions. The emergence of benzodiazepines within the illicit drug supply has substantially contributed to drug-related morbidity and mortality in Canada, and has further complicated current public health initiatives and overdose prevention efforts. This reality underscores the need for effective and sustainable policy solutions to address the evolving overdose epidemic including increased knowledge and education on the specific harms of opioid and benzodiazepine co-use (especially in regards to the complexity of opioid/benzodiazepine overdoses), scaling-up harm reduction measures, and eliminating the toxic drug supply altogether.


Assuntos
Overdose de Drogas , Drogas Ilícitas , Humanos , Analgésicos Opioides , Canadá/epidemiologia , Benzodiazepinas/efeitos adversos , Overdose de Drogas/epidemiologia , Overdose de Drogas/prevenção & controle , Risco
10.
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
12.
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
14.
Addict Behav ; 136: 107492, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36156454

RESUMO

BACKGROUND: Prior research indicates rising methamphetamine use and harms in the U.S., potentially related to increases in methamphetamine injection. To date, research on trends and correlates of methamphetamine injection is limited. METHODS: Analysis of trends and correlates of methamphetamine injection among treatment admissions among persons aged ≥ 12 whose primary substance of use at admission is methamphetamine. Data are from the Treatment Episode Data Set. Analyses includes descriptive statistics, trend analyses, and multilevel multivariable logistic regression. RESULTS: Primary methamphetamine treatment admissions increased from 138,379 in 2010 to 201,021 in 2019. Among primary methamphetamine admissions, injection as the usual route of use increased from 24,821 (18.0 % of admissions) in 2010 to 55,951 (28.2 % of admissions) in 2019. Characteristics associated with increased adjusted odds of reporting methamphetamine injection included: males (aOR = 1.13, 95 % CI = 1.10-1.15); admission age 25-34 years (aOR = 1.23, 95 % CI = 1.19-1.28) and 35-44 years (aOR = 1.12, 95 % CI = 1.08-1.17) compared to age 18-24; dependent living (aOR = 1.33, 95 % CI = 1.29-1.37) and homelessness (aOR = 1.58, 95 % CI = 1.54-1.63) compared to independent living; part-time employment (aOR = 1.08, 95 % CI = 1.02-1.14), unemployment (aOR = 1.39, 95 % CI = 1.34-1.44) and not in labor force (aOR = 1.43, 95 % CI = 1.37-1.49) compared to full-time employment; one to ≥ four prior treatment admissions (aORs ranging from 1.19 to 1.94) compared to no prior admissions; also reporting use of cocaine (aOR = 1.10, 95 % CI = 1.05-1.16), heroin (aOR = 3.52, 95 % CI = 3.40-3.66), prescription opioids (aOR = 1.61, 95 % CI = 1.54-1.67), or benzodiazepines (aOR = 1.42, 95 % CI = 1.32-1.52) at treatment admission. CONCLUSIONS: Findings lend further evidence to a resurgence of methamphetamine use that is intertwined with the ongoing opioid crisis in the U.S. Efforts to expand evidence-based prevention, treatment, and response efforts, particularly to populations at highest risk, are urgently needed.


Assuntos
Cocaína , Metanfetamina , Transtornos Relacionados ao Uso de Substâncias , Analgésicos Opioides , Benzodiazepinas , Heroína , Humanos , Masculino
15.
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
16.
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
17.
Neurosci Lett ; 795: 137014, 2023 Jan 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
19.
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
20.
J Anal Toxicol ; 46(9): e285-e290, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36516236

RESUMO

Toxicologists are often confronted with the abuse of multiple drugs and are obliged to decide which compound may have been the cause of death. We report on a 21-year-old man (182 cm, 84 kg), who was found unconscious in his bed. Beside him, the police found several controlled substances, among them were dried opium poppy pods containing thebaine, codeine and morphine, a clear liquid with the designer benzodiazepines flualprazolam and clonazolam and a white powder with the imprint SGT-25, instead of SGT-78 (CUMYL-4CN-BINACA). These compounds were also found in the urine sample following a non-targeted gas chromatography-mass spectrometry and a targeted liquid chromatography-tandem mass spectrometry (LC-MS-MS) screening approach. Subsequently, these compounds were quantified in whole femoral blood and scalp hair. Based on the concentrations measured in femoral blood in particular, we assume that the deceased had taken a lethal dose of the designer benzodiazepines-flualprazolam (0.74 mg/L) and clonazolam (2.08 mg/L), an extremely high dose of the opiates-thebaine (0.81 mg/L), codeine (0.23 mg/L) and morphine (0.13 mg/L ) and a high dose of the synthetic cannabinoid-CUMYL-4CN-BINACA (0.01 mg/L). Besides postmortem concentrations, we also present electron impact and electrospray ionization mass spectra of compounds found in the vicinity of the decedent, namely the tryptamines-4-hydroxy-N-isopropyl-N-methyltryptamine (4-HO-MIPT), 4-hydroxy-N-ethyl-N-methyltryptamine (4-HO-MET) and 4-acetoxy-N,N-diethyltryptamine (4-ACO-DET), the amphetamines-3-fluoroethamphetamine (3-FEA) and 2-fluoromethamphetamine (2-FMA) and the arylcyclohexylamines-N-ethyldeschloroketamine (O-PCE), 3-methoxyphencyclidine (3-MeO-PCP) and 3-methoxyeticyclidine (3-MeO-PCE).


Assuntos
Papaver , Humanos , Masculino , Adulto Jovem , Adulto , Tebaína/análise , Benzodiazepinas , Codeína , Morfina , Detecção do Abuso de Substâncias/métodos
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