Cannabis Laws and Utilization of Medications for the Treatment of Mental Health Disorders.

Importance: Mental health disorders are prevalent yet undertreated health conditions in the US. Given perceptions about the potential effect of cannabis on individuals with mental health disorders, there is a need to understand the association of cannabis laws with psychotropic use. Objective: To investigate the association of medical and recreational cannabis laws and dispensary openings with the dispensing of psychotropic medications used to treat mental health disorders in the US. Design, Setting, and Participants: This cross-sectional study of 10 013 948 commercially insured patients used a synthetic control method to examine the association of cannabis policies with prescribing. Data on all patients dispensed prescriptions for each of the 5 classes of psychotropic medications from January 1, 2007, to December 31, 2020, were extracted from Optum's deidentified Clinformatics Data Mart Database. Statistical analysis was performed from September 2022 to November 2023. Exposures: The 4 exposure variables measured were whether medical or recreational cannabis laws were in effect and whether medical or recreational cannabis dispensaries were open in each state and calendar quarter. Main Outcome and Measures: One measure of the extensive margins of dispensing and 2 measures of the intensive margins of dispensing were constructed for 5 medication classes (benzodiazepines, antidepressants, antipsychotics, barbiturates, and sleep medications). Results: The primary sample (the benzodiazepine sample) included 3 848 721 patients (mean [SD] age, 46.1 [11.4] years; 65.4% women; 53.7% aged 35-54 years). Medical cannabis laws were associated with a 12.4% reduction in the benzodiazepine fill rate (average treatment effect on the treated [ATT], -27.4; 95% CI, -14.7 to 12.0; P = .001), recreational cannabis laws were associated with a 15.2% reduction in the fill rate (ATT, -32.5; 95% CI, -24.4 to 20.1; P = .02), and medical cannabis laws were associated with a 1.3% reduction in the mean number of benzodiazepine fills per patient (ATT, -0.02; 95% CI, -0.02 to 0.02; P = .04). Medical dispensaries were associated with a 3.9% reduction in mean days' supply per benzodiazepine fill (ATT, -1.7; 95% CI, -0.8 to 0.6; P = .001), while recreational dispensaries were associated with a 6.2% reduction (ATT, -2.4; 95% CI, -1.0 to 0.9; P < .001). Medical cannabis laws were associated with a 3.8% increase in antidepressant fills (ATT, 27.2; 95% CI, -33.5 to 26.9; P = .048), and medical dispensaries were associated with an 8.8% increase (ATT, 50.7; 95% CI, -32.3 to 28.4; P = .004). The mean number of antipsychotic medication fills per patient increased by 2.5% (ATT, 0.06; 95% CI, -0.04 to 0.05; P = .02) after medical cannabis laws and by 2.5% (ATT, 0.06; 95% CI, -0.04 to 0.04; P = .02) after medical dispensary openings. Findings for the other drug classes showed substantial heterogeneity by state and direction of association. Conclusions and Relevance: This cross-sectional study of commercially insured patients suggests that there may have been meaningful heterogeneous associations between cannabis policy and state and between cannabis policy and drug class (eg, decreases in dispensing of benzodiazepines but increases in dispensing of antidepressants and antipsychotics). This finding suggests additional clinical research is needed to understand the association between cannabis use and mental health. The results have implications for patient substance use and mental health-related outcomes.

[An analysis of 4695 acute poisoning cases in Tianjin-Heibei from 2020-2022].

Objective: To study and analyze the epidemiological regularity of acute poisoning in Tianjin-Hebei region from 2020 to 2022, and to provide reference for the treatment and prevention of related patients. Methods: In December 2023, the analysis results and clinical data of 4695 patients with drug poisoning from January 2020 to December 2022 in multiple centers of Tianjin-Hebei region were collected as research objects. Gender, age, type of drug poisoning, season and poisoning route of the research objects were analyzed, and statistical analysis was conducted as well. Results: The sex ratio of men and women was 1∶1.16 (2173/2522). The poisoning of antidepressants and benzodiazepines were the most common drug poisonings, accounting for 1550 and 1274 cases respectively (33%, 27.1%). Paraquat poisoning has decreased year by year, while the poisonings of herbicides with low toxicity such as diquat, glyphosate and cremart have increased. The number of cases reached a peak during May to August which was the poisoning season, while was relatively fewer during October to December. Conclusion: Effective intervention measures should be taken according to the age of high incidence of poisoning, different seasons and populations. Essential drug poisoning prevention measures should be established and improved. The systems of sedative drug management and use should be established, and pesticide management and storage need to be strengthened.

Unraveling the Role of Bromodomain and Extra-Terminal Proteins in Human Uterine Leiomyosarcoma.

Uterine leiomyosarcoma (uLMS) is the most common type of uterine sarcoma, associated with poor prognosis, high rates of recurrence, and metastasis. Currently, the molecular mechanism of the origin and development of uLMS is limited. Bromodomain and extra-terminal (BET) proteins are involved in both physiological and pathological events. However, the role of BET proteins in the pathogenesis of uLMS is unknown. Here, we show for the first time that BET protein family members, BRD2, BRD3, and BRD4, are aberrantly overexpressed in uLMS tissues compared to the myometrium, with a significant change by histochemical scoring assessment. Furthermore, inhibiting BET proteins with their small, potent inhibitors (JQ1 and I-BET 762) significantly inhibited the uLMS proliferation dose-dependently via cell cycle arrest. Notably, RNA-sequencing analysis revealed that the inhibition of BET proteins with JQ1 and I-BET 762 altered several critical pathways, including the hedgehog pathway, EMT, and transcription factor-driven pathways in uLMS. In addition, the targeted inhibition of BET proteins altered several other epigenetic regulators, including DNA methylases, histone modification, and m6A regulators. The connections between BET proteins and crucial biological pathways provide a fundamental structure to better understand uterine diseases, particularly uLMS pathogenesis. Accordingly, targeting the vulnerable epigenome may provide an additional regulatory mechanism for uterine cancer treatment.

Consumption patterns and factors associated with inappropriate prescribing of benzodiazepines in Primary Health Care settings.

BACKGROUND: Benzodiazepines are frequently prescribed to treat anxiety and insomnia, but long-term use has been associated with the development of dependence, tolerance, and cognitive decline, especially among older adults. This study aimed to investigate the pattern of consumption and factors associated with inappropriate prescribing of benzodiazepines in primary health care. METHODS: This is a cross-sectional analytical study, using dispensing records of diazepam, clonazepam, and nitrazepam from public pharmacies in a Brazilian municipality between 2018 and 2022. Metrics for benzodiazepine consumption were DDD (Defined Daily Dose) and DDD/1000PD (per 1000 population per day). Long-term/prolonged benzodiazepine use was defined as consuming at least 90 DDD and at least 2 dispensations per year. To ascertain associations between long-term use and predictor variables, a multivariate logistic regression model was utilized. FINDINGS: A total of 40402 participants were included, with an average age of 55 years (SD = 0.30), 38.5% were older aged. Diazepam and nitrazepam exceeded the daily dose recommended. There was a reduction in diazepam consumption during the study period, as calculated by DDD/1.000PD, while the consumption of other benzodiazepines remained stable. However, a significant increase in diazepam consumption is noted when considering the last decade. Prolonged use was observed in 29.1% of participants, with a significant prevalence among the older people (34.8% of them were long-term users) and advancing age was identified as a risk factor for long-term use. Higher PDDs were also associated with long-term use and aging. Participants who used different benzodiazepines during the period had a higher risk of prolonged use. CONCLUSIONS: These results provide insights into the prevalence of problematic utilization of benzodiazepines in primary health care. Authorities and health care providers must take steps to encourage gradual cessation of prolonged benzodiazepine prescriptions and the embrace of suitable strategies for addressing anxiety and insomnia within primary health care settings.

Association of reductions in rescue medication requirements with vagus nerve stimulation: Results of long-term community collected data from a seizure diary app.

OBJECTIVE: To assess the impact of vagus nerve stimulation (VNS) on quality of life contributors such as rescue medications. METHODS: Using the seizure diary application SeizureTracker™ database, we examined trends in rescue administration frequency before and after the first recorded VNS magnet swipe in patients with drug-resistant epilepsy who had 1) At least one VNS magnet swipe recorded in the diary, and 2) Recorded usage of a benzodiazepine rescue medication (RM) within 90 days prior to the first swipe. A paired Wilcoxon rank-sum test was used to assess changes in RM usage frequency between 30-, 60-, 90-, 180- and 360-day intervals beginning 30 days after first magnet swipe. Longitudinal changes in RM usage frequency were assessed with a generalized estimating equation model. RESULTS: We analyzed data of 95 patients who met the inclusion criteria. Median baseline seizure frequency was 8.3 seizures per month, with median baseline rescue medication usage frequency of 2.1 administrations per month (SD 3.3). Significant reductions in rescue medication usage were observed in the 91 to 180 day interval after first VNS magnet swipe, and at 181 to 360 days and at 361 to 720 days, with the magnitude of reduction increasing over time. Decreases in rescue medication usage were sustained when controlling for patients who did not record rescue medication use after the first VNS magnet swipe (N=91). Significant predictors of reductions in rescue medication included baseline frequency of rescue medication usage and time after first VNS magnet swipe. SIGNIFICANCE: This retrospective analysis suggests that usage of rescue medications is reduced following the start of VNS treatment in patients with epilepsy, and that the magnitude of reduction may progressively increase over time.

A Retrospective Observational Study to Understand Medication Utilization and Lines of Treatment in Patients With Insomnia Disorder.

Background: Insomnia is a common sleep disorder, associated with multiple health concerns. Current medications for insomnia are associated with higher safety risks if clinical practice guidelines or monograph recommendations are not followed. This study aims to understand real-world prescribing practices among patients with insomnia in Canada, including medication utilization, potentially inappropriate medication use, cost incurred, and lines of treatment.Methods: This retrospective observational study utilized longitudinal drug claims data from 2018 to 2020 from the Canadian IQVIA National Private Drug Plan and Ontario Drug Benefit databases. Patients with any claims for medications approved for insomnia in Canada were identified. Four types of inappropriate medication usage were defined: (1) elevated daily dose; (2) extended duration of use for benzodiazepines (BZD) and/or Z-drugs; (3) combination use; and (4) opioid overlap with BZD and/or Z-drugs.Results: In 2019, 597,222 patients with insomnia were identified; 64% were female, with an average age of 55 years. Inappropriate medication use was noted in 52.5% of adult patients (aged 18-65 years) and 69.5% of senior patients (aged >65 years). Extended duration was the most common inappropriate medication usage category. The annual cost of medications for insomnia was $54.8 million, and $30.3 million (55.2%) met inappropriate medication use criteria.Conclusion: High prevalence of inappropriate medications usage in insomnia raises serious safety concerns for patients suffering from insomnia, particularly seniors, while also placing a substantial burden on the Canadian public and private health systems. This highlights an unmet need for better education regarding current guidelines and more effective and safer treatment options.

Spherical cellulose/chitosan aerogel-supported MOF-199 for the magnetic solid-phase extraction of benzodiazepines from urine.

Metal-organic frameworks (MOFs) are promising materials for sample pretreatment. The performance improvement of powdered MOFs is hindered by their aggregation and difficult recovery. To overcome these issues, a biodegradable lightweight spherical aerogel was used as a support for the in situ growth of copper-based MOFs (MOF-199). Furthermore, Fe3O4 nanoparticles were incorporated into the aerogel to achieve magnetic properties. Thus, hybrid aerogel spheres containing MOF-199 supported on magnetic oxidized cellulose nanofiber/carboxymethyl chitosan (MOF-199@mag-CNF/CMC) were fabricated. The effects of Fe3O4 loading amount and organic-ligand concentration on the properties (spherical geometry and mechanical strength) of the hybrid aerogel spheres were studied. Their potential application in the extraction of benzodiazepines (BZPs) from urine samples prior to liquid chromatography-mass spectrometry was evaluated. The highly dispersed MOF-199 crystals on the spherical aerogel effectively overcame the inherent structural shrinkage of the bare aerogel spheres; thus, the MOF-199@mag-CNF/CMC aerogel spheres were robust and could withstand repeated use for at least eight consecutive extraction cycles. Further, MOF-199@mag-CNF/CMC exhibited improved BZP extraction efficiency, which was 2.5-11.6 times higher than that of bare Cu2+@mag-CNF/CMC aerogel spheres, primarily due to additional π-π interaction and H-bonding as well as improved specific surface area. Parameters influencing the extraction and desorption processes were also comprehensively investigated. Under optimal conditions, this method provided a wide linear range of 0.1-10 µg/L (R2 > 0.995) and good precision (2.8-6.7% for intra-day; 1.9-7.8 % for inter-day). The limits of detection and quantification ranged from 0.02 to 0.11 µg/L and from 0.06 to 0.33 µg/L, respectively. The recoveries for the urine samples spiked with three concentrations of BZPs ranged from 73.9 % to 114.1 %. The proposed method is simple, sensitive and eco-friendly and can be used for the determination of BZPs from urine for clinical and forensic examinations.

The relationship between clinical impairment and blood drug concentration: Comparison between the most prevalent traffic relevant drug groups.

AIM: The aim of the present study was to investigate the relationship between blood concentrations of four different drug classes; ethanol, benzodiazepines, amphetamines and tetrahydrocannabinol (THC) and driver impairment as assessed by a clinical test of impairment (CTI). METHODS: Data was retrieved from a national database on CTI assessments and accompanying blood drug concentrations from apprehended drivers. All drug concentrations in blood were quantified using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS), and compared to the results of the CTI which were categorized as either "not impaired", "mildly impaired", "moderately impaired", or "considerably impaired". RESULTS: A total number of 15 514 individual mono drug-cases collected over 9 years was included. 89 % were men and the median age was 34 years. In addition, 3 684 individual cases with similar age and gender distribution where no drugs were detected, were included as a reference group. For ethanol and benzodiazepines the percentage of clinically impaired cases increased markedly from lower to higher concentration windows, from 60 % to 97 % for ethanol and from 38 % to 76 % for benzodiazepines. The corresponding increase for amphetamines and THC was modest, from 43 % to 58 % for amphetamines and from 41 % to 55 % for THC. The correlation between drug concentration and degree of impairment was high for ethanol (Spearman´s rho=0.548, p<0.001) and relatively high for benzodiazepines (Spearman´s rho=0.377, p<0.001), but low for amphetamines (Spearman´s rho=0.078, p<0.001) and THC (Spearman´s rho=0.100, p<0.001). CONCLUSION: The percentage of impaired drivers increased with increasing blood drug concentration for all four drug classes, most pronounced for ethanol and benzodiazepines and much less for amphetamines and THC. The median blood drug concentration increased with increasing magnitude of impairment for ethanol and benzodiazepines, while this was much less pronounced for amphetamines and THC. The ranges of drug concentrations, however, were wide for all four drug classes in all impairment categories as assessed by individual clinical examination.

Factors associated with the long-term use of benzodiazepine receptor agonists as hypnotics among patients with major depressive disorder and comorbid insomnia.

BACKGROUND: Patients with major depressive disorder (MDD) and comorbid insomnia are often co-prescribed benzodiazepines (BZDs) or Z-drugs as hypnotics with antidepressants to manage persistent insomnia. However, factors associated with their long-term use remain unclear among MDD patients. METHODS: We retrospectively analyzed data from 351 MDD patients who started antidepressants with co-prescribed hypnotics (BZDs/Z-drugs) and investigated the prevalence of and factors associated with their long-term use at 12 months. We conducted logistic regression analyses of their long-term use, and compared insomnia severities between the continued and discontinued groups of hypnotics in 32 patients whose insomnia severities had been longitudinally assessed. RESULTS: 66.1% of patients had continued hypnotics for 12 months. Multiple logistic regression analysis revealed that the diazepam-equivalent dose of hypnotics at the start of the combined treatment (>5 mg), the presence of chronic insomnia prior to MDD, and hospitalization correlated with their long-term use (all p < 0.01). We also found the relationship between the insufficient amelioration of insomnia severities and their long-term use. However, confidence in these results is tempered by various factors, including the dependence on hypnotics, the patient's attitude about hypnotic treatment, and the exclusion of subjects treated with other drugs such as sedative antidepressants or antipsychotics. CONCLUSIONS: These clinical indicators may facilitate the selection of treatment strategies for MDD with comorbid insomnia. To avoid the long-term use of hypnotics, their dose at the start of the combined treatment needs to be adequate (≤5 mg) and alternative treatments to BZDs/Z-drugs are required for refractory insomnia.

Incident Benzodiazepine and Z-Drug Use and Subsequent Risk of Serious Infections.

BACKGROUND AND OBJECTIVES: Animal studies have suggested a link between benzodiazepine and related Z-drug (BZDR) use and immune dysfunction. Corresponding evidence in humans is limited and focuses mainly on pneumonia. This study aimed to assess the association of incident BZDR use with subsequent development of serious infections. METHODS: This Swedish register-based study included a population-based demographically matched cohort, a co-twin control cohort, and an active comparator cohort. Out of 7,362,979 individuals aged below 65 years who were BZDR naïve by 2007, 713,896 BZDR recipients with incident dispensation of any BZDRs between 2007 and 2019 were 1:1 matched to 713,896 nonrecipients from the general population; 9197 BZDR recipients were compared with their 9298 unexposed co-twins/co-multiples; and 434,900 BZDR recipients were compared with 428,074 incident selective serotonin reuptake inhibitor (SSRI) recipients. The outcomes were identified by the first inpatient or specialist outpatient diagnosis of serious infections in the National Patient Register, or death from any infections recorded as the underlying cause in the Cause of Death Register. Cox proportional hazards regression models were fitted and controlled for multiple confounders, including familial confounding and confounding by indication. To study a possible dose-response association, the cumulative dosage of BZDRs dispensed during the follow-up was estimated for each BZDR recipient and modeled as a time-varying exposure with dose categories in tertiles [≤ 20 defined daily doses (DDDs), > 20 DDDs ≤ 65, and > 65 DDDs). The risk of infections was assessed in BZDR recipients within each category of the cumulative BZDR dosage compared to their demographically matched nonrecipients. RESULTS: In the demographically matched cohort (average age at incident BZDR use 42.8 years, 56.9% female), the crude incidence rate of any serious infections in BZDR recipients and matched nonrecipients during 1-year follow-up was 4.18 [95% confidence intervals (CI) 4.13-4.23] and 1.86 (95% CI 1.83-1.89) per 100 person-years, respectively. After controlling for demographic, socioeconomic, clinical, and pharmacological confounders, BZDR use was associated with 83% relative increase in risk of any infections [hazard ratio (HR) 1.83, 95% CI 1.79-1.89]. The risk remained increased, although attenuated, in the co-twin cohort (HR 1.55, 95% CI 1.23-1.97) and active comparator cohort (HR 1.33, 95% CI 1.30-1.35). The observed risks were similar across different types of initial BZDRs and across individual BZDRs, and the risks increased with age at BZDR initiation. We also observed a dose-response association between cumulative BZDR dosage and risk of serious infections. CONCLUSIONS: BZDR initiation was associated with increased risks of serious infections, even when considering unmeasured familial confounding and confounding by indication. The exact pathways through which BZDRs may affect immune function, however, remain unclear. Further studies are needed to explore the neurobiological mechanisms underlying the association between BZDR use and serious infections, as it can lead to safer therapeutic strategies for patients requiring BZDR.

Comparison of the recovery quality between remimazolam and propofol after general anesthesia: systematic review and a meta-analysis of randomized controlled trials.

Introduction: To evaluate the recovery quality between remimazolam and propofol after general anesthesia surgery. Methods: We included eligible randomized controlled trials (RCTs) in EMBASE, PubMed, Cochrane Central, Scopus, and Web of Science up to June 26, 2024 for comparison the recovery quality of remimazolam and propofol after general anaesthesia. The primary outcomes were the total Quality of Recovery-15 (QoR-15) and five dimensions of QoR-15 on postoperative day 1 (POD1). Secondary outcomes were adverse events, the Quality of Recovery-40 (QoR-40) on POD1, and the intraoperative and postoperative time characteristics. Results: Thirteen RCTs with a total of 1,305 patients were included in this meta-analysis. Our statistical analysis showed that remimazolam group had higher QoR-15 score on POD1, with no significant difference (Mean Difference (MD) = 1.24; 95% confidence interval (CI), [-1.67-4.15]; I2 = 75%; P = 0.41). In the five dimensions of QoR-15, remimazolam group was superior to propofol group in terms of physical independence (MD = 0.79; 95% CI [0.31-1.27]; I2 = 0%; P = 0.001). Remimazolam group was lower than propofol group in incidence of hypotension (Risk Ratio (RR) = 0.48; 95% CI [0.40-0.59]; I2 = 14%; P < 0.00001), bradycardia (RR = 0.18; 95% CI [0.08-0.38]; I2 = 0%; P < 0.0001) and injection pain (RR = 0.03; 95% CI [0.01-0.12]; I2 = 48%; P < 0.00001), respectively. The intraoperative and postoperative time characteristics and the QoR-40 were similar in the two groups. Conclusions: Our analysis showed that the recovery quality of the remimazolam group after general anaesthesia was similar to propofol group, while the incidence of adverse events was low in remimazolam group. As a potential anesthetic, remimazolam can be used in place of propofol for surgical general anesthesia.

Trends in toxicological findings in unintentional opioid or stimulant toxicity deaths in Québec, Canada, 2012-2021: Has Québec entered a new era of drug-related deaths?

INTRODUCTION: We aimed to describe rates and toxicological findings of unintentional opioid and stimulant toxicity deaths, 2012-2021. METHODS: The dataset included accidental deaths determined by the Coroner to be due to opioids or stimulants. We calculated annual crude mortality rates and described combinations of drugs identified in toxicological examinations of these deaths. We described temporal trends in the detection of specific opioids, stimulants, benzodiazepines (including novel benzodiazepines), gabapentinoids and z-drugs in deaths due to opioids and stimulants. RESULTS: Mortality rates increased over time, reaching their peak in 2020 and remaining high in 2021. In deaths due to opioids, there was a decline in the proportion of deaths involving pharmaceutical opioids after 2019, and a corresponding increase in the proportion of deaths with fentanyl detected. Benzodiazepines were often present in deaths due to opioids, with novel benzodiazepines increasing rapidly from 2019 onwards. Cocaine was the most frequently detected drug in deaths due to stimulants, but amphetamine/methamphetamine was detected in around half of all stimulant deaths from 2016 onwards. DISCUSSION AND CONCLUSIONS: Despite availability of a multitude of overdose prevention interventions, mortality rates due to drug toxicity have increased in Québec. Toxicological findings of these deaths suggest concerning shifts in the illicit drug market, with Québec potentially having entered a new era of elevated overdose mortality. Intervention scale-up is essential, but unlikely to be sufficient, to reduce drug-related mortality. Policy reform to address the root causes of drug toxicity deaths, including an unpredictable drug supply, strained health systems and socio-economic precarity, is essential.

[Remimazolam-Update on basic pharmacologic principles and clinical potential]. / Remimazolam ­ Update zu Grundlagen und klinischem Potenzial.

In recent years the still relatively new short-acting benzodiazepine remimazolam has been approved and clinically implemented in several countries and regions. Remimazolam is also now approved in the EU and the market launch in Germany is expected in the not too distant future. This is therefore a good point in time to summarize the current evidence for various areas of application, including general anesthesia, sedation and intensive care medicine as well as different dosing schemes.

The Impact of Fentanyl on the Effective Dose of Remimazolam-Induced Sedation in Elderly Female Patients: An Up-and-Down Sequential Allocation Trial.

Purpose: This study aimed to investigate the influence of fentanyl on the effective dose of remimazolam-induced sedation in elderly female patients undergoing general anesthesia. Patients and Methods: Sixty female patients aged 65-80 years undergoing selective general anesthesia were randomized into two groups: Group R+F received an initial dose of remimazolam (7.5 mg) with fentanyl (1 µg/kg), while Group R received remimazolam alone. Dosing adjustments (±2.5 mg) were made based on the response of the preceding patient using the up-and-down allocation technique. The ED50 and ED95 were calculated using a sequential formula and probit regression. Probit regression was also used to assess the relative potency of remimazolam between groups. Sedation levels were evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. Results: The ED50 for remimazolam was significantly lower in Group R+F compared to Group R (p= 0.007). Probit regression estimated the ED50 and ED95 values for Group R+F at 4.878 mg (95% CI, 3.845-5.859) and 8.184 mg (95% CI, 6.636-13.546), respectively. In contrast, Group R demonstrated ED50 and ED95 values of 6.733 mg (95% CI, 5.533-8.068) and 11.298 mg (95% CI, 9.101-19.617), respectively. Conclusion: This study provides compelling evidence that the administration of 1 µg/kg of fentanyl significantly reduces the required sedative dose of remimazolam by approximately 30% during induction in elderly patients. Importantly, the concomitant use of 1 µg/kg of fentanyl does not increase the risk of adverse effects such as hypotension, respiratory depression.

Therapeutic Effects, Side Effects, and Adverse Effects of Neuropsychiatric Drugs in the Context of Treating Cancer-Related Anorexia With Olanzapine and Mirtazapine.

Drugs have actions that may be classified as therapeutic effects and side effects; side effects are actions that do not contribute to therapeutic benefit. Some side effects are neutral; others, experienced as undesirable or unpleasant, are recorded as adverse effects. Some drug actions are therapeutic for some disorders and adverse for others; or therapeutic during acute illness and adverse during maintenance treatment. As an example, anticholinergic action may be adverse when a tricyclic antidepressant is used to treat depression but therapeutic when the drug is used to treat irritable bowel syndrome with diarrhea. In clinical practice, side or adverse effects of a drug may be leveraged to manage troublesome symptoms. As an example, the sedative effect of a low dose of trazodone may be useful for some patients with insomnia. With this background, studies have examined whether the increase in appetite and weight associated with olanzapine and mirtazapine may be effective against anorexia and cachexia associated with cancer and cancer chemotherapy. The subject is important because cachexia may be present in 30%-50% of patients with cancer (with higher prevalence in patients with more advanced cancer) and because the presence of cachexia is associated with a higher risk of disease progression and mortality. Many randomized controlled trials (RCTs) have examined pharmacologic interventions such as progestins, corticosteroids, anamorelin, and medical cannabis for cancer related cachexia; most results have been disappointing. A recent RCT found that olanzapine (2.5 mg/d for 12 weeks) improved appetite, weight, other nutritional parameters, and quality of life in patients with locally advanced or metastatic cancer treated with chemotherapy. Another RCT, however, found that mirtazapine (30 mg/d for 8 weeks) brought no nutritional or anthropometric gain in patients with cancer and anorexia. It is concluded that olanzapine but not mirtazapine merits further investigation in patients with cancer who have anorexia and cachexia.

The effects of remimazolam in combination with estazolam on postoperative hemodynamics and pain intensity in patients undergoing laparoscopic gastrointestinal surgery.

OBJECTIVE: This study aimed to investigate the effects of combining remimazolam with estazolam on hemodynamics and pain levels after laparoscopic gastrointestinal surgery. METHODS: A total of 184 patients who underwent laparoscopic gastrointestinal surgery were enrolled in this double-blind randomized controlled trial. The patients were divided into four groups: Study Group 1(Remimazolam), Study Group 2(Estazolam), Study Group 3(Remimazolam + Estazolam), and Control Group. Anesthesia induction included intravenous injection of remimazolam and estazolam in the study groups, while the control group received normal saline. Hemodynamic parameters, stress responses, anxiety levels, and pain intensity were assessed at various time points. RESULTS: The results showed that the combination of remimazolam and estazolam significantly improved hemodynamic parameters compared to the control group. Study Group 3 exhibited the lowest anxiety levels and stress responses among all groups. Furthermore, Study Group 3 had the lowest pain intensity scores at different postoperative time points. CONCLUSION: The combination of remimazolam and estazolam effectively stabilized hemodynamics, reduced anxiety levels, and alleviated pain intensity after laparoscopic gastrointestinal surgery. These findings suggest that this combination therapy has the potential to improve surgical outcomes and patient comfort.

[Comparison of the efficacy of remimazolam and propofol on hemodynamics and quality of early postoperative recovery in elderly patients with frailty undergoing endoscopic retrograde cholangiopancreatography].

Objective: To compare the efficacy of remimazolam and propofol on hemodynamics and quality of early postoperative recovery in elderly patients with frailty undergoing endoscopic retrograde cholangiopancreatography (ERCP). Methods: A total of 108 elderly patients with frailty (aged≥75 years) undergoing elective ERCP in the General Hospital of Northern Theater Command were prospectively enrolled from November 2022 to May 2023. According to the different anesthetic drugs used, the patients were divided into two groups by random number table method: remimazolam group (group R) and propofol group (group P). The group R was given remimazolam 0.15-0.20 mg/kg and alfentanil 5.0 µg/kg for anesthesia onset, and then was pumped remimazolam 0.4-0.8 mg·kg-1·h-1 and alfentanil 0.5 µg·kg-1·min-1 to maintain sedation. The group P was given propofol 1.0-1.5 mg/kg and alfentanil 5.0 µg/kg, and was pumped propofol 2.0-6.0 mg·kg-1·h-1 and alfentanil 0.5 µg·kg-1·min-1. The primary outcome was the incidence of intraoperative hypotension [mean arterial pressure (MAP)<65 mmHg (1 mmHg=0.133 kPa) or MAP>20% decrease from baseline value] and severe hypotension (MAP<55 mmHg) in both groups, and other outcomes included: MAP, heart rate, pulse oxygen saturation (SpO2) and bispectral index (BIS) values of patients at each time of before anesthesia induction (T0), 1 min after anesthesia induction (T1), endoscope through the oropharynx (T2), immediate lithotomy (T3), endoscope withdrawal from the oropharynx (T4), and patients awake (T5); the use of vasoactive drug during operation; the incidence of bradycardia, hypoxemia and injection pain; and the postoperative 15-item Quality of Recovery (QoR-15) score. Results: Group R included 33 males and 20 females, aged (81.5±4.9) years. Group P included 26 males and 29 females, aged (82.3±6.0) years. The incidence of intraoperative hypotension in group R was 24.5% (13/53), which was lower than 43.6% (24/55) in group P (P=0.036), there was no significant difference of the incidence of severe hypotension which was 0 (0/53) and 5.5% (3/55) (P=0.225). Compared with T0, MAP and BIS decreased at T1-T4 (both P<0.05); heart rate and SpO2 decreased at T1-T2 in both groups (both P<0.05). Compared with group P, MAP increased at T1-T4; heart rate, SpO2 and BIS increased in group R (all P<0.05). The use of intraoperative vasoactive drug in group R was (93.9±21.4) µg, lower than (123.3±29.7) µg in group P (P<0.001), and the incidence of bradycardia, hypoxemia and injection pain in group R was 5.7% (3/53), 13.2% (7/53), and 3.8% (2/53), lower than 18.2% (10/55), 30.9% (17/55), and 16.4% (9/55) in group P (all P<0.05). There was no significant difference in the incidence of bucking or involuntary body movement and hiccuping in both groups (both P>0.05). The awakening time in group R was (11.8±3.0) min, longer than (10.3±3.3) min in group P (P=0.016), and the incidence of emergence agitation was 3.8% (2/53), lower than 16.4% (9/55) (P=0.031). There was no significant difference in postanesthesia care unit (PACU) stay duration and the incidence of postoperative nausea and vomiting in both groups (all P>0.05). The postoperative QoR-15 scores at 1 d were (131.9±4.7) and (129.3±5.7) with statistically significant difference (P=0.010), and QoR-15 scores at 3 d were (134.8±3.3) and (133.6±5.0) with no significant difference (P=0.205). Conclusions: Compared with propofol, remimazolam reduces the incidence of intraoperative hypotension, bradycardia, injection pain and the use of intraoperative vasoactive drug on elderly patients with frailty undergoing ERCP. Remimazolam has relatively stable hemodynamics, it prolongs the recovery time but does not significantly affect the quality of early postoperative recovery.

Potentially inappropriate medication on communitydwelling older adults: Longitudinal analysis using the International Mobility in Aging Study. / Medicación potencialmente inapropiada en adultos mayores de la comunidad: análisis longitudinal del estudio IMIAS

Introduction: Medications are a fundamental part of the treatment of multiple pathologies. However, despite their benefits, some are considered potentially inappropriate medications for older people given their safety profile. Epidemiological data differences related to potentially inappropriate medications make it difficult to determine their effects on elderly people. Objective: To estimate the prevalence and types of potentially inappropriate medications using the 2019 Beers Criteria® in a cohort of adults older than 65 years. Materials and methods: We performed an observational, multicenter, retrospective, longitudinal study of a four-year follow-up of potentially inappropriate medications in community-dwelling older adults. Results: We followed 820 participants from five cities for four years (2012-2016) and evaluated them in three different moments (m1 = 2012, m2 = 2014, and m3 = 2016). The average age was 69.07 years, and 50.9% were women. The potentially inappropriate medication prevalence in the participants was 40.24%. The potentially inappropriate medications' mean among the studied subjects in the first moment was 1.65 (SD = 0.963), in the second was 1.73 (SD = 1.032), and in the third was 1.62 (SD = 0.915). There were no statistical differences between measurements (Friedman test, value = 0.204). The most frequent potentially inappropriate medications categories were gastrointestinal (39.4%), analgesics (18.8%), delirium-related drugs (15.4%), benzodiazepines (15.2%), and cardiovascular (14.2%). Conclusions: About half of the population of the community-dwelling older adults had prescriptions of potentially inappropriate medications in a sustained manner and without significant variability over time. Mainly potentially inappropriate medications were gastrointestinal and cardiovascular drugs, analgesics, delirium-related drugs, and benzodiazepines.

Introducción. Los fármacos son parte fundamental del tratamiento de múltiples enfermedades. Sin embargo, a pesar de sus beneficios, algunos se consideran medicamentos potencialmente inapropiados en adultos mayores, dado su perfil de seguridad. Las diferencias en los datos epidemiológicos relacionados con los medicamentos potencialmente inapropiados dificultan el establecimiento de sus efectos en adultos mayores. Objetivo. Estimar la prevalencia longitudinal y los tipos de medicamentos potencialmente inapropiados, utilizando los criterios Beers® del 2019 en una cohorte de adultos mayores de 65 años. Materiales y métodos. Se realizó un estudio observacional, multicéntrico, retrospectivo y longitudinal, de cuatro años de seguimiento de los medicamentos potencialmente inapropiados en adultos mayores de la comunidad. Resultados. Se evaluaron 820 participantes de cinco ciudades durante cuatro años (2012 a 2016) en tres momentos (m1: 2012, m2: 2014 y m3; 2016). La edad promedio fue de 69,07 años y el 50,9 % eran mujeres. La prevalencia de medicamentos potencialmente inapropiados en los participantes fue del 40,24 %. El promedio de estos medicamentos entre los sujetos estudiados en el primer momento fue de 1,65 (DE = 0,963), en el segundo fue de 1,73 (DE = 1,032) y en el tercero fue de 1,62 (DE = 0,915). No hubo diferencias estadísticas entre las mediciones (prueba de Friedman, p = 0,204). Las categorías de los medicamentos potencialmente inapropiados más frecuentes fueron: gastrointestinales (39,4 %), analgésicos (18,8 %), relacionados con delirium (15,4 %), benzodiacepinas (15,2 %) y cardiovasculares (14,2 %). Conclusiones. En cerca de la mitad de la población de adultos mayores de la comunidad, se prescribieron medicamentos potencialmente inapropiados de manera sostenida y sin variabilidad importante en el tiempo. Los más recetados fueron aquellos para tratar malestares gastrointestinales y cardiovasculares, analgésicos, para el delirium y benzodiacepinas.

Opioid and benzodiazepine requirements in critically ill post-surgical children with down syndrome: a systematic review and meta-analysis.

BACKGROUND: Down syndrome (DS), or Trisomy 21, is defined by the existence of an additional chromosome 21. Various physiological considerations in DS patients might lead to challenges in adequate pain management and sedation after surgery. The aim of this systematic review and meta-analysis is to evaluate the variations of the requirement needed for pain management and sedation in patients with DS who have undergone surgery compared to patients without DS. METHODS: A systematic review and meta-analysis of studies were conducted, focusing on critically ill patients with DS who were admitted to Intensive care units (ICUs) post-surgery and received opioids and/or benzodiazepines. Searches were conducted in four databases from their inception to November 18, 2023 (Pubmed, Scopus, Cochrane Library, and Web of Science). The primary outcome measured was the dosage of Oral Morphine Equivalent (OME) administered in the days following surgery. Fixed-effect models were used, an approach advisable when only a limited number of studies are available. RESULTS: Out of the 992 studies initially screened, the systematic review included ten studies, encompassing 730 patients, while the meta-analysis consisted of seven studies, encompassing 533 patients. Of the seven studies included in the analysis, 298 patients were identified to have DS, and 235 patients served as controls. Patients with DS showed a slight increase in OME needs on the first day, but this increase was not statistically significant (mean difference [MD] = 0.09; 95% Confidence Interval [CI]: [-0.02, 0.20]; P = 0.11). There was also no significant difference in the requirement for Midazolam on the first day among DS patients (MD = 0.01; CI [-0.16, 0.19]; P = 0.88). In addition, the duration of mechanical ventilation was not statistically significant in patients with DS compared with the control group (MD = -1.46 hours; 95% CI [-9.74, 6.82]; P = 0.73). CONCLUSION: Patients with Down syndrome did not require more sedation or analgesia in the first three days after surgery than patients without Down syndrome. Additionally, the two groups showed no significant difference in the duration of mechanical ventilation.