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- Application of unbound liver-to-plasma concentration ratio to quantitative projection of cytochrome P450-mediated drug-drug interactions using physiologically-based pharmacokinetic modelling approach. [Journal Article]
- XXenobiotica 2018 Dec 05; :1-47
- 1. This study evaluated the prediction accuracy of cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) using minimal physiologically-based pharmacokinetic (PBPK) modelling incorporating the he...
1. This study evaluated the prediction accuracy of cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) using minimal physiologically-based pharmacokinetic (PBPK) modelling incorporating the hepatic accumulation factor of an inhibitor (i.e. unbound liver/unbound plasma concentration ratio [Kp,uu,liver]) based on 22 clinical DDI studies. 2. Kp,uu,liver values were estimated using three methods: (1) ratio of cell-to-medium ratio in human cryopreserved hepatocytes (C/M,u) at 37 °C to that on ice (Kp,uu,C/M), (2) multiplication of total liver/unbound plasma concentration ratio (Kp,u,liver) estimated from C/M,u at 37 °C with unbound fraction in human liver homogenate (Kp,uu,cell), and (3) observed Kp,uu,liver in rats after intravenous infusion (Kp,uu,rat). 3. PBPK model using each Kp,uu,liver projected the area under the curve (AUC) increase of substrates more accurately than the model assuming a Kp,uu,liver of 1 for the average fold error and root mean square error did. Particularly, the model with a Kp,uu,liver of 1 underestimated the AUC increase of triazolam following co-administration with CYP3A4 inhibitor itraconazole by 5-fold, whereas the AUC increase projected using the model incorporating the Kp,uu,C/M, Kp,uu,cell, or Kp,uu,rat of itraconazole and hydroxyitraconazole was within approximately 2-fold of the actual value. 4. The results indicated that incorporating Kp,uu,liver into the PBPK model improved the accuracy of DDI projection.
- Progress in the Consideration of Possible Sex Differences in Drug Interaction Studies. [Journal Article]
- CDCurr Drug Metab 2018 Nov 28
- CONCLUSIONS: This review has shown that only limited progress had been made with the inclusion of both sexes in DDI studies.
- Outdoor Artificial Nighttime Light and Use of Hypnotic Medications in Older Adults: A Population-Based Cohort Study. [Journal Article]
- JCJ Clin Sleep Med 2018 Nov 15; 14(11):1903-1910
- CONCLUSIONS: Outdoor artificial nighttime light exposure was significantly associated with prescription of hypnotic drugs in older adults. These findings are consistent with the hypothesis that outdoor artificial nighttime light may cause sleep disturbances.
- Effects of hypnotics on prefrontal cortex activity during a verbal fluency task in healthy male subjects: A near-infrared spectroscopy study. [Journal Article]
- HPHum Psychopharmacol 2018; 33(6):e2678
- CONCLUSIONS: The differential effects of two types of hypnotics on oxy-Hb change measured by NIRS were observed in acute dosing, suggesting that when assessing brain activity of patients with psychiatric disorders, researchers should consider how certain types of hypnotics can influence brain function. This would also provide useful information to clinicians when prescribing hypnotics suitable for their patients' conditions.
- Benzodiazepines and risk of pneumonia in schizophrenia: a nationwide case-control study. [Journal Article]
- PPsychopharmacology (Berl) 2018; 235(11):3329-3338
- CONCLUSIONS: Benzodiazepines had a dose-dependent relationship with pneumonia in patients with schizophrenia. The differences in risk and mechanism of action of the individual drugs require further investigation. Clinicians should be aware of the early signs of pneumonia in patients with schizophrenia receiving benzodiazepines.
- Analysis of the effect of oral midazolam and triazolam premedication before general anesthesia in patients with disabilities with difficulty in cooperation. [Journal Article]
- JDJ Dent Anesth Pain Med 2018; 18(4):245-254
- CONCLUSIONS: With administration of oral midazolam or triazolam, general anesthesia induction without any physical restraint was possible in approximately 50% of patients, with no difference between the drugs.
- Effects of zolpidem/triazolam on cognitive performance 12 hours after acute administration. [Journal Article]
- SMSleep Med 2018; 52:213-218
- CONCLUSIONS: The administration of hypnotics significantly increased total sleep time, sleep efficiency, and sleep stages 2 and 4, and significantly decreased wake after sleep onset and sleep stage 1. PVT parameters were not affected by the administration of hypnotics, but DSST score was significantly lower, and "subjective alertness," "vigor," and "sadness" significantly deteriorated, after administration. In conclusion, while objective sleepiness disappeared 12 h after the administration of ultra-short acting hypnotics, their effects to decrease cognitive function persisted even after 12 h post-administration.
- Insomnia in Elderly Patients: Recommendations for Pharmacological Management. [Review]
- DADrugs Aging 2018; 35(9):791-817
- Chronic insomnia affects 57% of the elderly in the United States, with impairment of quality of life, function, and health. Chronic insomnia burdens society with billions of dollars in direct and ind...
Chronic insomnia affects 57% of the elderly in the United States, with impairment of quality of life, function, and health. Chronic insomnia burdens society with billions of dollars in direct and indirect costs of care. The main modalities in the treatment of insomnia in the elderly are psychological/behavioral therapies, pharmacological treatment, or a combination of both. Various specialty societies view psychological/behavioral therapies as the initial treatment intervention. Pharmacotherapy plays an adjunctive role when insomnia symptoms persist or when patients are unable to pursue cognitive behavioral therapies. Current drugs for insomnia fall into different classes: orexin agonists, histamine receptor antagonists, non-benzodiazepine gamma aminobutyric acid receptor agonists, and benzodiazepines. This review focuses on Food and Drug Administration (FDA)-approved drugs for insomnia, including suvorexant, low-dose doxepin, Z-drugs (eszopiclone, zolpidem, zaleplon), benzodiazepines (triazolam, temazepam), and ramelteon. We review the indications, dosing, efficacy, benefits, and harms of these drugs in the elderly, and discuss data on drugs that are commonly used off-label to treat insomnia, and those that are in clinical development. The choice of a hypnotic agent in the elderly is symptom-based. Ramelteon or short-acting Z-drugs can treat sleep-onset insomnia. Suvorexant or low-dose doxepin can improve sleep maintenance. Eszopiclone or zolpidem extended release can be utilized for both sleep onset and sleep maintenance. Low-dose zolpidem sublingual tablets or zaleplon can alleviate middle-of-the-night awakenings. Benzodiazepines should not be used routinely. Trazodone, a commonly used off-label drug for insomnia, improves sleep quality and sleep continuity but carries significant risks. Tiagabine, sometimes used off-label for insomnia, is not effective and should not be utilized. Non-FDA-approved hypnotic agents that are commonly used include melatonin, diphenhydramine, tryptophan, and valerian, despite limited data on benefits and harms. Melatonin slightly improves sleep onset and sleep duration, but product quality and efficacy may vary. Tryptophan decreases sleep onset in adults, but data in the elderly are not available. Valerian is relatively safe but has equivocal benefits on sleep quality. Phase II studies of dual orexin receptor antagonists (almorexant, lemborexant, and filorexant) have shown some improvement in sleep maintenance and sleep continuity. Piromelatine may improve sleep maintenance. Histamine receptor inverse agonists (APD-125, eplivanserin, and LY2624803) improve slow-wave sleep but, for various reasons, the drug companies withdrew their products.
- Drugs and Lactation Database (LactMed) [BOOK]
- BOOKNational Library of Medicine (US): Bethesda (MD)
- Because little information is available on the use of triazolam during breastfeeding, an alternate hypnotic may be preferred, especially while nursing a newborn or preterm infant. Triazolam has a rel...
Because little information is available on the use of triazolam during breastfeeding, an alternate hypnotic may be preferred, especially while nursing a newborn or preterm infant. Triazolam has a relatively short half-life, so occasional use while breastfeeding an older infant should pose little risk to the infant, but monitor the infant for excessive drowsiness.
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- LC-MS-MS Method Development and Analysis of Stimulants, Opiates, Synthetic Opiates, PCP, and Benzodiazepines in Wastewater. Preponderance of these Drugs During Football Games. [Journal Article]
- MMMethods Mol Biol 2018; 1810:149-182
- A method was developed for the analysis of stimulant drugs, opiates, synthetic opiates, PCP, and benzodiazepines in wastewater samples using liquid chromatography coupled with tandem mass spectrometr...
A method was developed for the analysis of stimulant drugs, opiates, synthetic opiates, PCP, and benzodiazepines in wastewater samples using liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). A total of 33 compounds (stimulant-type drugs and metabolites of opiates, synthetic opiates, PCP, and benzodiazepines) were analyzed. These drugs included amphetamine (Amp) (1), methamphetamine (Meth) (2), methylenedioxyamphetamine (MDA) (3), methylenedioxymethamphetamine (MDMA) (4), methylenedioxyethylamphetamine (MDEA) (5), benzoylecgonine (BE, the major metabolite of Coc) (6), cocaine (Coc) (7), 6-monoacetylmorphine (6-MAM, the primary urinary metabolite of heroin) (8), codeine (9), hydrocodone (10), hydromorphone (11), morphine (12), norhydrocodone (the primary urinary metabolite of hydrocodone) (13), oxycodone (14), oxymorphone (15), 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrolidine (EDDP, the primary urinary metabolite of methadone) (16), fentanyl (17), meperidine (18), methadone (19), norfentanyl (the primary urinary metabolite of fentanyl) (20), normeperidine (the primary urinary metabolite of meperidine) (21), phencyclidine (PCP) (22), tramadol (23), alprazolam (24), temazepam (25), nordiazepam (26), chlordiazepoxide (27), flurazepam (28), oxazepam (29), α-OH-alprazolam (the primary urinary metabolite of alprazolam) (30), α-OH-triazolam (the primary urinary metabolite of triazolam) (31), 2-OH-ethylflurazepam (the primary urinary metabolite of flurazepam) (32), and 7-NH2-flunitrazepam (the primary urinary metabolite of flunitrazepam) (33). These drugs were chosen because of their widespread abuse. Wastewater samples were collected at both the Oxford Wastewater Treatment Plant in Oxford, Mississippi (MS), and the University Wastewater Treatment Plant in University, MS. Samples were collected on weekends on which the Ole Miss Rebel football team held home games (Vaught-Hemingway Stadium, University, MS 38677). The collected samples were analyzed using a validated method and found to contain Amp, Meth, MDMA, MDA, Coc, BE, codeine, hydrocodone, hydromorphone, morphine, norhydrocodone, oxycodone, oxymorphone, tramadol, EDDP, meperidine, normeperidine, methadone, alprazolam, α-OH-alprazolam, nordiazepam, oxazepam, and temazepam. None of the samples contained MDEA, 6-MAM, fentanyl, norfentanyl, PCP, chlordiazepoxide, flurazepam, 2-OH-ethylflurazepam, 7-NH2-flunitrazepam, and α-OH-triazolam.