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BMC Gastroenterology May 2013Despite recent advances in hepatitis C (HCV) treatment, specifically the addition of direct acting antivirals (DAAs), pegylated interferon-alpha remains the backbone of... (Review)
Review
BACKGROUND
Despite recent advances in hepatitis C (HCV) treatment, specifically the addition of direct acting antivirals (DAAs), pegylated interferon-alpha remains the backbone of HCV therapy. Therefore, the impact of DAAs on the management of co-morbid psychiatric illness and neuropsychiatric sequalae remains an ongoing concern during HCV therapy. This paper provides a review of the neuropsychiatric adverse effects of DAAs and drug-drug interactions (DDIs) between DAAs and psychiatric medications.
METHODS
We conducted a Pubmed search using relevant search terms and hand searched reference lists of related review articles. In addition, we searched abstracts for major hepatology conferences and contacted respective pharmaceutical companies for additional studies.
RESULTS
Limited data is available on the neuropsychiatric adverse effects of DAAs; however, data from major clinical trials suggest that DAAs have minimal neuropsychiatric risk. DAAs can potentially interact with a variety of psychotropic agents via cytochrome P450 and p-glycoprotein interactions. Triazolam, oral midazolam, St. John's Wort, carbamazepine and pimozide, are contraindicated with DAAs. DDIs between DAAs and antidepressants, anxiolytics, hypnotics, mood stabilizers, antipsychotics and treatments for opioid dependence are summarized.
CONCLUSIONS
Although DAAs do not add significant neuropsychiatric risk, the potential for DDIs is high. Consideration of DDIs is paramount to improving medication adherence and mitigating adverse effects during HCV therapy.
Topics: Antiviral Agents; Contraindications; Drug Interactions; Hepatitis C; Humans; Medication Adherence; Mental Disorders; Oligopeptides; Proline; Psychotropic Drugs
PubMed: 23672254
DOI: 10.1186/1471-230X-13-86 -
Psychopharmacology Sep 2016Benzodiazepines are effective anxiolytics, hypnotics, and anticonvulsants but unwanted side effects, including abuse potential, limit their use. A possible strategy to...
RATIONALE
Benzodiazepines are effective anxiolytics, hypnotics, and anticonvulsants but unwanted side effects, including abuse potential, limit their use. A possible strategy to increase the therapeutic index of this drug class is to combine benzodiazepines with neuroactive steroids.
OBJECTIVES
The present study evaluated the extent to which combinations of benzodiazepines (triazolam, clonazepam) and neuroactive steroids (pregnanolone, ganaxolone) induced additive, supra-additive, or infra-additive effects in an elevated zero maze and a drug discrimination procedure in rats.
METHODS
Male Sprague-Dawley rats (N = 7/group) were placed into an elevated zero maze apparatus following injections of multiple doses of triazolam and pregnanolone, alone and combined, or clonazepam and ganaxolone, alone and combined. These drugs/drug combinations also were evaluated in rats (N = 8) trained to discriminate triazolam (0.1 mg/kg, i.p.) from vehicle. Drug interactions were evaluated using isobolographic and dose-addition analysis.
RESULTS
In the elevated zero maze, all drugs engendered dose-dependent increases in time spent in the open quadrant when administered alone. Triazolam and pregnanolone, as well as clonazepam and ganaxolone combinations produced additive or supra-additive effects depending on the fixed-proportion that was tested. In triazolam discrimination, all drugs engendered dose-dependent increases in triazolam-lever responding. In combination, triazolam and pregnanolone and clonazepam and ganaxolone produced predominantly additive discriminative stimulus effects, except for one fixed proportion of clonazepam and ganaxolone which had supra-additive effects.
CONCLUSIONS
Although drug interactions depended on the constituent drugs, the combination tested, and the behavioral endpoint; a combination was identified that would be predicted to result in supra-additive anxiolytic-like effects with predominantly additive discriminative stimulus effects.
Topics: Anesthetics; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Clonazepam; Discrimination Learning; Drug Interactions; Hypnotics and Sedatives; Male; Pregnanolone; Rats; Rats, Sprague-Dawley; Triazolam
PubMed: 27356519
DOI: 10.1007/s00213-016-4369-8 -
Medication use and the risk of motor vehicle collisions among licensed drivers: A systematic review.Accident; Analysis and Prevention Nov 2016Driving under the influence of prescription and over-the-counter medication is a growing public health concern. A systematic review of the literature was performed to... (Review)
Review
OBJECTIVES
Driving under the influence of prescription and over-the-counter medication is a growing public health concern. A systematic review of the literature was performed to investigate which specific medications were associated with increased risk of motor vehicle collision (MVC).
METHODS
The a priori inclusion criteria were: (1) studies published from English-language sources on or after January 1, 1960, (2) licensed drivers 15 years of age and older, (3) peer-reviewed publications, master's theses, doctoral dissertations, and conference papers, (4) studies limited to randomized control trials, cohort studies, case-control studies, or case-control type studies (5) outcome measure reported for at least one specific medication, (6) outcome measure reported as the odds or risk of a motor vehicle collision. Fourteen databases were examined along with hand-searching. Independent, dual selection of studies and data abstraction was performed.
RESULTS
Fifty-three medications were investigated by 27 studies included in the review. Fifteen (28.3%) were associated with an increased risk of MVC. These included Buprenorphine, Codeine, Dihydrocodeine, Methadone, Tramadol, Levocitirizine, Diazepam, Flunitrazepam, Flurazepam, Lorazepam, Temazepam, Triazolam, Carisoprodol, Zolpidem, and Zopiclone.
CONCLUSIONS
Several medications were associated with an increased risk of MVC and decreased driving ability. The associations between specific medication use and the increased risk of MVC and/or affected driving ability are complex. Future research opportunities are plentiful and worthy of such investigation.
Topics: Accidents, Traffic; Adult; Analgesics, Opioid; Antidepressive Agents; Automobile Driving; Cohort Studies; Dose-Response Relationship, Drug; Driving Under the Influence; Humans; Male; Middle Aged; Motor Vehicles; Risk Factors; Young Adult
PubMed: 27569655
DOI: 10.1016/j.aap.2016.08.001 -
The Science of the Total Environment Jul 2018Reuse of treated wastewater for irrigation of crops is growing in arid and semi-arid regions, whilst increasing amounts of biosolids are being applied to fields to...
Reuse of treated wastewater for irrigation of crops is growing in arid and semi-arid regions, whilst increasing amounts of biosolids are being applied to fields to improve agricultural outputs. Due to incomplete removal in the wastewater treatment processes, pharmaceuticals present in treated wastewater and biosolids can contaminate soil systems. Benzodiazepines are a widely used class of pharmaceuticals that are released following wastewater treatment. Benzodiazepines are represented by a class of compounds with a range of physicochemical properties and this study was therefore designed to evaluate the influence of soil properties on the sorption behaviour and subsequent uptake of seven benzodiazepines (chlordiazepoxide, clonazepam, diazepam, flurazepam, oxazepam, temazepam and triazolam) in two plant species. The sorption and desorption behaviour of benzodiazepines was strongly influenced by soil type and hydrophobicity of the chemical. The partitioning behaviour of these chemicals in soil was a key controller of the uptake and accumulation of benzodiazepines by radish (Raphanus sativus) and silverbeet (Beta vulgaris). Benzodiazepines such as oxazepam that were neutral, had low sorption coefficients (K) or had pH-adjusted log octanol-water partition coefficients (log D, pH6.3) values close to 2 had the greatest extent of uptake. Conversely, benzodiazepines such as flurazepam that had an ionised functional groups and greater K values had comparatively limited accumulation in the selected plant species. Results also revealed active in-plant metabolism of benzodiazepines, potentially analogous to the known metabolic transformation pathway of benzodiazepines in humans. Along with this observed biological transformation of benzodiazepines in exposed plants, previously work has established the widespread presence of the plant signalling molecule γ-amino butyric acid (GABA), which is specifically modulated by benzodiazepines in humans. This highlights the need for further assessment of the potential for biological activity of benzodiazepines following their plant uptake.
Topics: Benzodiazepines; Crops, Agricultural; Humans; Soil; Soil Pollutants; Wastewater
PubMed: 29428856
DOI: 10.1016/j.scitotenv.2018.01.337 -
Anaesthesia Mar 1987
Topics: Anxiety; Humans; Preanesthetic Medication; Triazolam
PubMed: 3578735
DOI: 10.1111/j.1365-2044.1987.tb03052.x -
British Journal of Clinical Pharmacology Feb 1980Effects of flunitrazepam and triazolam (0.25 and 0.5 mg) on sleep and on performance were studied in six healthy adult males. Sleep was assessed by... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Effects of flunitrazepam and triazolam (0.25 and 0.5 mg) on sleep and on performance were studied in six healthy adult males. Sleep was assessed by electroencephalography and analogue scales, and performance by a visuo-motor coordination task. Over the same dose range triazolam had a more pronounced effect than flunitrazepam. Total sleep time was increased by 0.25 and 0.5 mg triazolam, and by 0.5 mg flunitrazepam. Both drugs decreased awake activity and drowsy sleep, though the effect of flunitrazepam was limited to the 0.5 mg dose and restricted to the first 6 h after sleep onset. There were no changes in slow wave sleep. Latency to the first period of rapid eye movement (REM) sleep was increased with 0.5 mg triazolam, and when doses were combined (0.25-0.5 mg) the latencies with both drugs were increased. Both doses of triazolam reduced the duration and percentage of REM sleep during the early part of the night, though the whole night duration of REM sleep was not changed. After the morning ingestion of 0.25 mg flunitrazepam performance was impaired for 2.0 h, but there were no residual effects when 0.25 or 0.5 mg were taken at night. With the morning ingestion of 0.25 mg triazolam performance was impaired from 0.5 to at least 5.0 h after ingestion. There were no residual effects with 0.25 mg overnight, but with 0.5 mg triazolam there was an effect on performance 10 h after ingestion with recovery within 1.5 h (11.5 h of ingestion). Triazolam (0.25 mg) and 0.5 mg flunitrazepam provide useful hypnotic activity when impaired performance the next day is to be avoided. The activity of 0.5 mg triazolam is accompanied by only limited residual sequelae compared with some other benzodiazepines of comparable efficacy, and so may prove to be useful when a more powerful effect is required.
Topics: Adult; Anti-Anxiety Agents; Flunitrazepam; Humans; Hypnotics and Sedatives; Male; Motor Skills; Sleep; Sleep Stages; Time Factors; Triazolam
PubMed: 6101959
DOI: 10.1111/j.1365-2125.1980.tb05832.x -
Journal of Neural Transmission (Vienna,... Aug 2020There are contradictory publications and reports regarding the dependence liability of the 3-hydroxy-benzo-1,4-diazepine derivative lormetazepam, one of the most often... (Review)
Review
There are contradictory publications and reports regarding the dependence liability of the 3-hydroxy-benzo-1,4-diazepine derivative lormetazepam, one of the most often prescribed hypnotic benzodiazepines which is now also available as an intravenous (i.v.) product for anesthetists. The author was involved in the preclinical and subsequently in the clinical development and post-marketing surveillance of lormetazepam. Here, he reviews the published and unpublished data about lormetazepam dependence and proposes explanations for contradictory views from other authors. On this basis and in contrast to class labeling from regulatory bodies and WHO, the author comes to the conclusion that use of lormetazepam definitely carries a lower risk of inducing dependence and causing abuse than most other benzodiazepines. This applies as well to Sedalam, the new i.v. application form of lormetazepam, which is much better tolerated than propofol. Because of its pharmacokinetic properties and because all its effects can be fully antagonized with the benzodiazepine antagonist flumazenil, this innovative intravenous application form of lormetazepam provides an excellent method for premedication, symptomatic treatment of excitation and anxiety in the context of surgical or diagnostic procedures including outpatient interventions and for basic sedation during anesthesia.
Topics: Anesthetics; Anti-Anxiety Agents; Benzodiazepines; Humans; Lorazepam; Male
PubMed: 32468272
DOI: 10.1007/s00702-020-02209-8 -
Clinical Pharmacokinetics Feb 2023Obese individuals are often underrepresented in clinical trials, leading to a lack of dosing guidance.
BACKGROUND
Obese individuals are often underrepresented in clinical trials, leading to a lack of dosing guidance.
OBJECTIVE
This study aimed to investigate which physiological parameters and drug properties determine drug disposition changes in obese using our physiologically based pharmacokinetic (PBPK) framework, informed with obese population characteristics.
METHODS
Simulations were performed for ten drugs with clinical data in obese (i.e., midazolam, triazolam, caffeine, chlorzoxazone, acetaminophen, lorazepam, propranolol, amikacin, tobramycin, and glimepiride). PBPK drug models were developed and verified first against clinical data in non-obese (body mass index (BMI) ≤ 30 kg/m) and subsequently in obese (BMI ≥ 30 kg/m) without changing any drug parameters. Additionally, the PBPK model was used to study the effect of obesity on the pharmacokinetic parameters by simulating drug disposition across BMI, starting from 20 up to 60 kg/m.
RESULTS
Predicted pharmacokinetic parameters were within 1.25-fold (71.5%), 1.5-fold (21.5%) and twofold (7%) of clinical data. On average, clearance increased by 1.6% per BMI unit up to 64% for a BMI of 60 kg/m, which was explained by the increased hepatic and renal blood flows. Volume of distribution increased for all drugs up to threefold for a BMI of 60 kg/m; this change was driven by pK for ionized drugs and logP for neutral and unionized drugs. C decreased similarly across all drugs while t remained unchanged.
CONCLUSION
Both physiological changes and drug properties impact drug pharmacokinetics in obese subjects. Clearance increases due to enhanced hepatic and renal blood flows. Volume of distribution is higher for all drugs, with differences among drugs depending on their pK/logP.
Topics: Humans; Obesity; Midazolam; Caffeine; Propranolol; Body Mass Index; Models, Biological; Pharmacokinetics; Computer Simulation
PubMed: 36571702
DOI: 10.1007/s40262-022-01194-3 -
British Medical Journal (Clinical... Jul 1983
Topics: Anti-Anxiety Agents; Humans; Hypnotics and Sedatives; Kinetics; Middle Aged; Time Factors; Triazolam
PubMed: 6135488
DOI: No ID Found