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Atomistic Model for Simulations of the Sedative Hypnotic Drug 2,2,2-Trichloroethanol.

ABSTRACT: 2,2,2-Trichloroethanol (TCE) is the active form of the sedative hypnotic drug chloral hydrate, one of the oldest sleep medications in the market. Understanding of TCE's action mechanisms to its many targets, particularly within the ion channel family, could benefit from the state-of-the-art computational molecular studies. In this direction, we employed de novo modeling aided by the force field toolkit to develop CHARMM36-compatible TCE parameters. The classical potential energy function was calibrated targeting molecular conformations, local interactions with water molecules, and liquid bulk properties. Reference data comes from both tabulated thermodynamic properties and ab initio calculations at the MP2 level. TCE solvation free energy calculations in water and oil reproduce a lipophilic, yet nonhydrophobic, behavior. Indeed, the potential mean force profile for TCE partition through the phospholipid bilayer reveals the sedative's preference for the interfacial region. The calculated partition coefficient also matches experimental measures. Further validation of the proposed parameters is supported by the model's ability to recapitulate quenching experiments demonstrating TCE binding to bovine serum albumin.

SUBMITTER: Kiametis AS

PROVIDER: S-EPMC6288786 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Atomistic Model for Simulations of the Sedative Hypnotic Drug 2,2,2-Trichloroethanol.

Kiametis Alessandra S AS Stock Letícia L Cirqueira Leonardo L Treptow Werner W

ACS omega 20181126 11

2,2,2-Trichloroethanol (TCE) is the active form of the sedative hypnotic drug chloral hydrate, one of the oldest sleep medications in the market. Understanding of TCE's action mechanisms to its many targets, particularly within the ion channel family, could benefit from the state-of-the-art computational molecular studies. In this direction, we employed de novo modeling aided by the force field toolkit to develop CHARMM36-compatible TCE parameters. The classical potential energy function was cal ...[more]

PMID: 30556017

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Project description:IntroductionOpioid and sedative/hypnotic drug overdoses are major causes of morbidity in the U.S. This study compares 12-month incidence of fatal unintentional drug overdose, suicide, and other mortality among emergency department patients presenting with nonfatal opioid or sedative/hypnotic overdose.MethodsThis is a retrospective cohort study using statewide, longitudinally linked emergency department patient record and mortality data from California. Participants comprised all residents presenting to a licensed emergency department at least once in 2009-2011 with nonfatal unintentional opioid overdose, sedative/hypnotic overdose, or neither (a 5% random sample). Participants were followed for 1 year after index emergency department presentation to assess death from unintentional overdose, suicide, or other causes, ascertained using ICD-10 codes. Absolute death rates per 100,000 person years and standardized mortality ratios relative to the general population were calculated. Data were analyzed February-August 2019.ResultsFollowing the index emergency department visit, unintentional overdose death rates per 100,000 person years were 1,863 following opioid overdose, 342 following sedative/hypnotic overdose, and 31 for reference patients without an index overdose (respective standardized mortality ratios of 106.1, 95% CI=95.2, 116.9; 24.5, 95% CI=21.3, 27.6; and 2.6, 95% CI=2.2, 3.0). Suicide mortality rates per 100,000 were 319, 174, and 32 following opioid overdose, sedative/hypnotic overdose, and reference visits, respectively. Natural causes mortality rates per 100,000 were 8,058 (opioid overdose patients), 17,301 (sedative/hypnotic overdose patients), and 3,097 (reference patients).ConclusionsEmergency department patients with nonfatal opioid or sedative/hypnotic drug overdose have exceptionally high risks of death from unintentional overdose, suicide, and other causes. Emergency department-based interventions offer potential for reducing these patients' overdose and other mortality risks.

Project description:BackgroundBenzodiazepines and sedative-hypnotic drugs (BZD/SHDs), such as zopiclone and the antidepressant trazodone, pose risks such as falls, fractures, and confusion, especially for older adults. Use of these drugs in the acute care setting is poorly understood.ObjectivesTo determine the point prevalence and characteristics of use of BZD/SHDs in hospitals in Nova Scotia, Canada.MethodsA point prevalence survey was conducted for adults admitted to all hospitals with at least 30 acute care beds between May and August 2016. Drugs administered intravenously, patients in long-term care, and patients receiving mental health services, addiction treatment, or critical care were excluded. The proportion of included patients who had received a BZD/SHD within the 24 h before the start of the survey was determined. A descriptive statistical analysis was performed.ResultsOverall BZD/SHD prevalence was 34.6% (487/1409) across the 16 eligible hospitals. The average age was 70.3 years, and 150 (30.8%) of the patients were 80 years or older. Among the 585 prescriptions for these patients, commonly used drugs were zopiclone (32.0%), lorazepam (21.9%), and trazodone (21.9%). The most common indications for use were bedtime/daytime sedation (60.0%) and anxiety (12.5%). More than half of the prescriptions (55.7%) had been initiated at home, 37.6% were started in hospital, and the place of initiation was unknown for 6.7%. Benzodiazepines were prescribed more frequently to patients under 65 years than those 80 years or older (41.3% versus 22.2%, p < 0.001) whereas trazodone was more frequently prescribed to the older of these 2 age groups (52.7% versus 14.3%, p < 0.001).ConclusionsBZD/SHDs were frequently used by hospitalized adult patients in Nova Scotia. Trazodone appears to have been substituted for benzodiazepines in the oldest age group. Pharmacists should direct their efforts toward preventing inappropriate initiation of BZD/SHDs in hospital, particularly for elderly patients.

Dataset Information

Atomistic Model for Simulations of the Sedative Hypnotic Drug 2,2,2-Trichloroethanol.

Publications

Atomistic Model for Simulations of the Sedative Hypnotic Drug 2,2,2-Trichloroethanol.

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