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Medicine Apr 2015The aim of this study was to compare system efficiency and analysis duration regarding the solvent consumption and system maintenance in high-pressure liquid... (Comparative Study)
Comparative Study Observational Study
The aim of this study was to compare system efficiency and analysis duration regarding the solvent consumption and system maintenance in high-pressure liquid chromatography (HPLC) and ultra high-pressure liquid chromatography (UHPLC). In a case-control study, standard solutions of 7 benzodiazepines (BZs) and 73 biological samples such as urine, tissue, stomach content, and bile that screened positive for BZs were analyzed by HPLC and UHPLC in laboratory of forensic toxicology during 2012 to 2013. HPLC analysis was performed using a Knauer by 100-5 C-18 column (250 mm × 4.6 mm) and Knauer photodiode array detector (PAD). UHPLC analysis was performed using Knauer PAD detector with cooling autosampler and Eurospher II 100-3 C-18 column (100 mm × 3 mm) and also 2 pumps. The mean retention time, standard deviation, flow rate, and repeatability of analytical results were compared by using 2 methods. Routine runtimes in HPLC and UHPLC took 40 and 15 minutes, respectively. Changes in mobile phase composition of the 2 methods were not required. Flow rate and solvent consumption in UHPLC decreased. Diazepam and flurazepam were detected more frequently in biological samples. In UHPLC, small particle size and short length of column cause effective separation of BZs in a very short time. Reduced flow rate, solvent consumption, and injection volume cause more efficiency and less analysis costs. Thus, in the detection of BZs, UHPLC is an accurate, sensitive, and fast method with less cost of analysis.
Topics: Autopsy; Benzodiazepines; Case-Control Studies; Chromatography, High Pressure Liquid; Humans
PubMed: 25860209
DOI: 10.1097/MD.0000000000000640 -
Proceedings of the National Academy of... Jun 2014Use of the highly toxic and easily prepared rodenticide tetramethylenedisulfotetramine (TETS) was banned after thousands of accidental or intentional human poisonings,...
Use of the highly toxic and easily prepared rodenticide tetramethylenedisulfotetramine (TETS) was banned after thousands of accidental or intentional human poisonings, but it is of continued concern as a chemical threat agent. TETS is a noncompetitive blocker of the GABA type A receptor (GABAAR), but its molecular interaction has not been directly established for lack of a suitable radioligand to localize the binding site. We synthesized [(14)C]TETS (14 mCi/mmol, radiochemical purity >99%) by reacting sulfamide with H(14)CHO and s-trioxane then completion of the sequential cyclization with excess HCHO. The outstanding radiocarbon sensitivity of accelerator mass spectrometry (AMS) allowed the use of [(14)C]TETS in neuroreceptor binding studies with rat brain membranes in comparison with the standard GABAAR radioligand 4'-ethynyl-4-n-[(3)H]propylbicycloorthobenzoate ([(3)H]EBOB) (46 Ci/mmol), illustrating the use of AMS for characterizing the binding sites of high-affinity (14)C radioligands. Fourteen noncompetitive antagonists of widely diverse chemotypes assayed at 1 or 10 µM inhibited [(14)C]TETS and [(3)H]EBOB binding to a similar extent (r(2) = 0.71). Molecular dynamics simulations of these 14 toxicants in the pore region of the α1β2γ2 GABAAR predict unique and significant polar interactions for TETS with α1T1' and γ2S2', which are not observed for EBOB or the GABAergic insecticides. Several GABAAR modulators similarly inhibited [(14)C]TETS and [(3)H]EBOB binding, including midazolam, flurazepam, avermectin Ba1, baclofen, isoguvacine, and propofol, at 1 or 10 μM, providing an in vitro system for recognizing candidate antidotes.
Topics: Amides; Animals; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; Bridged-Ring Compounds; Carbon Isotopes; Carbon Radioisotopes; Formaldehyde; GABA Agonists; GABA-A Receptor Antagonists; Heterocyclic Compounds; Humans; Hypnotics and Sedatives; Insecticides; Isonicotinic Acids; Models, Molecular; Molecular Conformation; Molecular Structure; Propofol; Pyridoxine; Radioligand Assay; Rats; Receptors, GABA-A; Sulfur; Vitamin B Complex
PubMed: 24912155
DOI: 10.1073/pnas.1407379111 -
Open Access Macedonian Journal of... Sep 2019Insomnia is a symptom complex that comprises difficulties falling asleep, staying asleep or non-refreshing sleep in combination with daytime dysfunction or distress....
BACKGROUND
Insomnia is a symptom complex that comprises difficulties falling asleep, staying asleep or non-refreshing sleep in combination with daytime dysfunction or distress. Most people experience insomnia at some time during their lives. Because of its high incidence, and also because its symptoms are usually mild and transient, the importance of insomnia is frequently underestimated. Various conditions are associated with insomnia and can contribute to its development. They can be related to neurological or psychiatric disorders, which in turn may be aggravated by a deficiency of restorative sleep and daytime fatigue.
AIM
In this study, the authors compare the hypnotically effect of Flurazepam and Zolpidem applied on psychiatric cases treated in the Mental Health Centre "Prolet" in Skopje, Republic of Macedonia.
METHODS
The investigation covers 45 patients who have insomnia, in addition to their primary mental illness. The examination took six weeks, and it was divided into 3 equal phases. In the first phase of three weeks, Zolpidem was used, and in the third phases, Flurazepam was administrated. We used a self-estimating scale of 13 items and methods of global clinical estimation in the evaluation of received effects.
RESULTS
The results show that referring to the induction of the sleeping period, its duration and quality and the number of awakenings, there are no significant differences between the two medicaments used, but there was a significant difference between hypnotic medicaments and placebo.
CONCLUSION
The termination with the therapy, didn`t lead to the appearance of abstinential symptoms.
PubMed: 31844437
DOI: 10.3889/oamjms.2019.711 -
Quarterly Journal of Experimental... Jul 1985Intracellular recordings have been made from CA1, CA3 and dentate cells of the mouse hippocampal slice. Gamma-aminobutyric acid (GABA) and the water-soluble...
Intracellular recordings have been made from CA1, CA3 and dentate cells of the mouse hippocampal slice. Gamma-aminobutyric acid (GABA) and the water-soluble benzodiazepines, midazolam and flurazepam were applied close to the impaled cell somata by microelectrophoresis. GABA always caused a fall in input resistance, although the associated changes in membrane potential were variable. These were consistent with reports which have defined a hyperpolarizing response to somatic and a depolarizing response to dendritic application of GABA to CA1 and CA3 cells in the rat and guinea-pig. In this study, the phenomenon was seen in CA1, CA3 and dentate cells. The reversal potential for the hyperpolarizing, somatic response to GABA lay between -70 and -75 mV, similar to the reversal potential of the evoked recurrent inhibitory post-synaptic potential (i.p.s.p.). The change in cell input conductance caused by GABA was larger at membrane potentials positive to the resting potential and smaller at hyperpolarized membrane potentials. Extracellular recordings of action potential frequency were made from ten cells in which the application of either midazolam or flurazepam increased the inhibitory potency of GABA. In three of these cells, the benzodiazepine reduced action potential frequency slightly when applied alone. Neither midazolam nor flurazepam had a consistent effect on membrane potential, resting input resistance or the current-voltage (I-V) relations of the cells when ejected alone. In twenty-eight of forty-one cells examined in detail, ejection of either midazolam or flurazepam was found to increase the response to GABA. In six cells, the response to GABA was significantly reduced by the benzodiazepine tested whilst in the remainder, no interaction of the drugs could be demonstrated. Examination of the dose-response relation for GABA alone and in the presence of midazolam or flurazepam showed that the maximal response to GABA was increased by the benzodiazepine in some cells while it was unchanged in others. When intracellular electrodes were filled with potassium chloride, spontaneous depolarizing GABA-mediated post-synaptic potentials (p.s.p.s) were seen. Measurement of the interval and amplitude distributions of these events showed that flurazepam increased their amplitude but not their frequency.
Topics: Action Potentials; Animals; Benzodiazepines; Dose-Response Relationship, Drug; Drug Interactions; Hippocampus; In Vitro Techniques; Male; Membrane Potentials; Mice; Receptors, GABA-A; Synaptic Membranes; gamma-Aminobutyric Acid
PubMed: 2994165
DOI: 10.1113/expphysiol.1985.sp002917 -
Psychiatria Danubina 2022To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and...
Quetiapine Add-On Therapy May Improve Persistent Sleep Disturbances in Patients with PTSD on Stabile Combined SSRI and Benzodiazepine Combination: A One-Group Pretest-Posttest Study.
BACKGROUND
To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and benzodiazepine therapy, who previously failed to respond to various benzodiazepine and non-benzodiazepine hypnotic adjuvant treatment as well as to first-generation antipsychotic add-on treatment.
SUBJECTS AND METHODS
Fifty-two male PTSD outpatients on stable combination treatment with SSRI and benzodiazepines, with persistent sleep disturbances not responding to prescription of zolpidem, flurazepam, nitrazepam, promazine, and levopromazine, were assessed for sleep disturbances improvements after prescription of quetiapine in the evening. Each patient met both ICD-10 and DSM-IV criteria for PTSD. Psychiatric comorbidity and premorbidity were excluded using the Mini-International Neuropsychiatric Interview (MINI). Improvement on the CAPS recurrent distressing dream item, reduction in the amount of time needed to fall asleep, prolongation of sleep duration, and reduction in average number of arousals per night in the last 7 days before the assessment period were used as efficacy measures.
RESULTS
All sleep-related parameters improved significantly at the end of a five-week follow-up: sleep duration increased by one hour (p<0.001), sleep latency decreased by 52.5 minutes (p<0.001), median number of arousals per night decreased from two to one (p<0.001), CAPS recurrent distressing dream item median decreased from five to four (p<0.001), and the number of patients dissatisfied with their sleep quality and quantity decreased from 45 to two (p<0.001).
CONCLUSION
Quetiapine prescribed in the evening may be successful therapy for persistent sleep disturbances in patients with PTSD and generally good response to an SSRI and benzodiazepine combination, who previously failed to respond to some of the usual hypnotic medication or addition of first-generation antipsychotics: zolpidem, flurazepam, nitrazepam, promazine, and levopromazine.
Topics: Antipsychotic Agents; Benzodiazepines; Flurazepam; Humans; Hypnotics and Sedatives; Male; Methotrimeprazine; Nitrazepam; Promazine; Quetiapine Fumarate; Sleep; Sleep Wake Disorders; Stress Disorders, Post-Traumatic; Zolpidem
PubMed: 35772134
DOI: 10.24869/psyd.2022.245 -
Canadian Family Physician Medecin de... Jul 1979
PubMed: 21297824
DOI: No ID Found -
Japanese Journal of Pharmacology Mar 1987Behavioral effects of zopiclone were investigated in mice and rats and compared with the data on diazepam, nitrazepam and flurazepam. The electroencephalographic effect...
Behavioral effects of zopiclone were investigated in mice and rats and compared with the data on diazepam, nitrazepam and flurazepam. The electroencephalographic effect of the drug was also examined in unanesthetized rabbits with chronic electrode implants and compared with that of diazepam. The present results indicate that zopiclone possesses pharmacological properties qualitatively similar to benzodiazepines, which are characterized by potent anticonflict and antiaggressive effects and much weaker anticonvulsant, muscle relaxant, ataxiogenic, sedative and anesthesia potentiating effects; the properties of this drug were compared with those of diazepam, nitrazepam and flurazepam. Zopiclone suppressed the EEG arousal responses and inhibited afterdischarges induced by electrical stimulation of the hippocampus and amygdala. The effects of zopiclone on EEG and afterdischarges were approximately 1/10 those of diazepam.
Topics: 5-Hydroxytryptophan; Aggression; Anesthesia; Animals; Azabicyclo Compounds; Behavior, Animal; Conflict, Psychological; Electroencephalography; Hypnotics and Sedatives; Male; Mescaline; Mice; Motor Activity; Piperazines; Postural Balance; Rabbits; Rats; Rats, Inbred Strains; Seizures
PubMed: 3495682
DOI: 10.1254/jjp.43.309 -
British Journal of Pharmacology May 2008Benzodiazepines (BDZs) are widely used in clinical practice and are known as positive modulators of GABAergic currents. BDZs increase binding affinity and recently they...
BACKGROUND AND PURPOSE
Benzodiazepines (BDZs) are widely used in clinical practice and are known as positive modulators of GABAergic currents. BDZs increase binding affinity and recently they were found to affect GABA(A) receptor gating, including desensitization. Binding and desensitization are also strongly modulated by extracellular pH, a factor that may be severely altered in a pathological brain. It is thus of interest to examine the combined action of BDZ and protons.
EXPERIMENTAL APPROACH
Pharmacokinetic analysis was based on patch clamp recordings of miniature IPSCs (mIPSCs) and current responses to GABA applications in rat cultured hippocampal neurons. High temporal resolution of currents evoked by exogenous GABA was achieved by using an ultrafast perfusion system (exchange time ca. 80 micros).
KEY RESULTS
At acidic pH, flurazepam produced a stronger enhancement of mIPSC amplitudes than at physiological pH. At low GABA concentrations, flurazepam markedly enhanced current amplitudes both at normal and acidic pH, but at the latter, the relative effect was larger. In contrast, at saturating GABA concentrations, flurazepam reduced current amplitudes at both pH 7.2 and 6.0. The slowing of deactivation kinetics by flurazepam decreased with GABA concentration, but at pH 6.0, this trend was shifted toward a higher GABA concentration.
CONCLUSIONS AND IMPLICATIONS
Acidification of extracellular medium may significantly affect the susceptibility of phasic and tonic components of GABAergic currents to modulation by BDZs. Quantitative analysis and model simulations indicate that protons and flurazepam additively affect binding and desensitization of GABA(A) receptors.
Topics: Animals; Electrophysiology; Excitatory Postsynaptic Potentials; Extracellular Space; Flurazepam; GABA Modulators; Hippocampus; Hydrogen-Ion Concentration; In Vitro Techniques; Kinetics; Models, Neurological; Patch-Clamp Techniques; Rats; Rats, Wistar; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 18362897
DOI: 10.1038/bjp.2008.90 -
SAGE Open Medicine 2016Benzodiazepines are frequently screened drugs in emergency toxicology, drugs of abuse testing, and in forensic cases. As the variations of benzodiazepines concentrations...
OBJECTIVE
Benzodiazepines are frequently screened drugs in emergency toxicology, drugs of abuse testing, and in forensic cases. As the variations of benzodiazepines concentrations in biological samples during bleeding, postmortem changes, and redistribution could be biasing forensic medicine examinations, hence selecting a suitable sample and a validated accurate method is essential for the quantitative analysis of these main drug categories. The aim of this study was to develop a valid method for the determination of four benzodiazepines (flurazepam, lorazepam, alprazolam, and diazepam) in vitreous humor using liquid-liquid extraction and high-performance liquid chromatography.
METHODS
Sample preparation was carried out using liquid-liquid extraction with n-hexane: ethyl acetate and subsequent detection by high-performance liquid chromatography method coupled to diode array detector. This method was applied to quantify benzodiazepines in 21 authentic vitreous humor samples. Linear curve for each drug was obtained within the range of 30-3000 ng/mL with coefficient of correlation higher than 0.99.
RESULTS
The limit of detection and quantitation were 30 and 100 ng/mL respectively for four drugs. The method showed an appropriate intra- and inter-day precision (coefficient of variation < 10%). Benzodiazepines recoveries were estimated to be over 80%. The method showed high selectivity; no additional peak due to interfering substances in samples was observed.
CONCLUSION
The present method was selective, sensitive, accurate, and precise for the quantitative analysis of benzodiazepines in vitreous humor samples in forensic toxicology laboratory.
PubMed: 27635251
DOI: 10.1177/2050312116666243 -
Sleep Feb 2014To determine current patterns and predictors of use of prescription medications commonly used for insomnia (MCUFI) in the U.S.
STUDY OBJECTIVES
To determine current patterns and predictors of use of prescription medications commonly used for insomnia (MCUFI) in the U.S.
DESIGN
Cross-sectional study.
SETTING
National Health and Nutrition Examination Survey, 1999-2010.
PARTICIPANTS
32,328 noninstitutionalized community-dwelling U.S. adults.
INTERVENTIONS
N/A.
MEASUREMENTS AND RESULTS
WE DEFINED MCUFI USE AS USE OF ANY OF THE FOLLOWING MEDICATIONS IN THE PRECEDING MONTH: benzodiazepine receptor agonists (eszopiclone, zaleplon, zolpidem, estazolam, flurazepam, quazepam, temazepam, triazolam), barbiturates (amobarbital, amobarbitalsecobarbital, chloral hydrate), doxepin, quetiapine, ramelteon, and trazodone. We estimated prevalence of MCUFI use and concurrent use of another sedating medication. We determined predictors of MCUFI use using multivariate logistic regression. Overall, 3% percent of adults used a MCUFI within the preceding month. Zolpidem and trazodone were used most commonly. Overall MCUFI use increased between 1999-2000 and 2009-2010 (P value for trend < 0.001). Concurrent use of other sedating medications was high, with 55% of MCUFI users taking at least one other sedating medication and 10% taking ≥ 3 other sedating medications. Concurrent use of MCUFIs with opioids (24.6%) and non-MCUFI benzodiazepines (19.5%) were most common. After adjustment, adults seeing a mental health provider (aOR 4.68, 95% C.I. 3.79, 5.77), using other sedating medications (aOR 4.18, 95% C.I. 3.36, 5.19), and age ≥ 80 years (aOR 2.55, 95% C.I. 1.63, 4.01) had highest likelihood of MCUFI use.
CONCLUSION
In this nationally representative sample, reported use of prescription medications commonly used for insomnia (MCUFIs) within the preceding month was common, particularly among older adults and those seeing a mental health provider, with high use of sedative polypharmacy among MCUFI users.
Topics: Adult; Aged; Aged, 80 and over; Cross-Sectional Studies; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Nutrition Surveys; Prescriptions; Sleep Initiation and Maintenance Disorders; United States; Young Adult
PubMed: 24497662
DOI: 10.5665/sleep.3410