Manic espisode, confusional syndrome and reversible splenial lesion after abrupt withdrawal of oxcarbazepine.

PubMed

Merizalde, Milton; Navalón, Pablo; González, María Fernanda; Domínguez, Alberto; Livianos, Lorenzo; Martínez, Juan Carlos

2017-03-01

Anticonvulsants are considered a second line option for bipolar disorder, it is known that the abrupt withdrawal is rarely related with demyelinated lesions of the splenium of the corpus callosum. Oxcarbazepine is used in bipolar disorder although it is not stated in the data sheet. We presented a case of a 50 years old woman with bipolar disorder who is treated with lithium and oxcarbazepine, she presented a manic episode and a confusional syndrome after she stopped taking the medication. The magnetic resonance showed a restricted diffusion area at the splenium of the corpus callosum and bifrontal hygromas that disappear two weeks later. The results of this study suggest that for a patient presenting with a mild encephalopathy and reversible splenial lesion, one should consider whether it is related to withdrawal of oxcarbazepine. Published by Elsevier B.V.

Self-harm and suicide associated with benzodiazepine usage

PubMed Central

Neale, Greg; Smith, Allan J

2007-01-01

Benzodiazepines are commonly prescribed in primary care for anxiety disorders and insomnia. However, they can cause dependence with withdrawal symptoms that are both physical and psychological. These complications are also more common with short-acting benzodiazepines such as lorazepam. This case report describes a previously stable 62-year-old male who inflicted serious stab wounds to himself, twice within a month, during changes in his benzodiazepine regime. PMID:17504594

Zolpidem dependence and withdrawal seizure--report of two cases.

PubMed

Wang, Liang-Jen; Ree, Shao-Chun; Chu, Chin-Lin; Juang, Yeong-Yuh

2011-03-01

Zolpidem is a non-benzodiazepine property which binds selectively to the ?1-GABAA receptors, and has been widely prescribed to patients suffering from insomnia. We report two cases of zolpidem dependence with withdrawal seizure in the Asian population. The first case is a 43-year-old woman who took zolpidem up to the dosage of 200 to 400 mg per night. The second case is a 35-year-old woman who even began to take zolpidem every 15 to 30 minutes to get euphoric and relaxed, and she gradually increased the dosage to 400 to 500mg per day. After abrupt discontinuation of zolpidem, both cases immediately developed anxiety, global insomnia, restlessness, and tonic seizure. The purpose of this case report is to suggest that clinicians should pay close attention to the potential of zolpidem tolerance, abuse and dependence. The possibility of withdrawal seizure cannot be excluded especially at high doses.

Severe Carisoprodol Withdrawal After a 14-Year Addiction and Acute Overdose.

PubMed

Vo, Kathy T; Horng, Howard; Smollin, Craig G; Benowitz, Neal L

2017-05-01

Carisoprodol, a centrally acting muscle relaxant with a high abuse potential, has barbiturate-like properties at the GABA-A receptor, leading to central nervous system depression and desired effects. Its tolerance and dependence has been previously demonstrated in an animal model, and withdrawal has been described in several recent case reports. Many cases can be effectively managed with a short course of benzodiazepines or antipsychotic agents. However, abrupt cessation in a patient with a history of long-term and high-dose carisoprodol abuse may result in symptoms that are more difficult for providers to treat. We present a case of a 34-year-old man with a long history of carisoprodol abuse who was found unresponsive after having ingested 7.5 grams of carisoprodol. He was intubated and admitted to the intensive care unit. He was given propofol, dexmedetomidine, fentanyl, ketamine, lorazepam, midazolam, quetiapine, and haloperidol, some at high-dose infusions, before his agitation and ventilator asynchrony could be controlled. His improvement coincided with the addition of carisoprodol and phenobarbital to his treatment regimen. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Trends show increasing emergency department presentations for drug-related disorders and treatment. This case highlights an uncommon case of carisoprodol withdrawal that may be encountered by emergency physicians, and demonstrates that benzodiazepines may not be sufficient to suppress severe withdrawal symptoms. Treatment with carisoprodol and phenobarbital provided additional benefit and can be considered in cases of severe carisoprodol withdrawal. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of an Alcohol Withdrawal Protocol and a Preprinted Order Set at a Tertiary Care Hospital

PubMed Central

Ng, Karen; Dahri, Karen; Chow, Ivy; Legal, Michael

2011-01-01

Background: Alcohol withdrawal protocols involving symptom-triggered administration of benzodiazepine have been established to reduce the duration of treatment and the cumulative benzodiazepine dose (relative to usual care). However, the effects of a protocol combining fixed-schedule and symptom-triggered benzodiazepine dosing are less clear. Objective: To assess the efficacy and safety of a combination fixed-scheduled and symptom-triggered benzodiazepine dosing protocol for alcohol withdrawal, relative to usual care, for medical inpatients at a tertiary care hospital. Methods: A chart review of admissions to the internal medicine service for alcohol withdrawal was conducted to compare treatment outcomes before (October 2005 to April 2007) and after (October 2007 to April 2009) implementation of the combination protocol. The primary outcome was duration of benzodiazepine treatment for alcohol withdrawal. The secondary outcomes were cumulative benzodiazepine dose administered, safety implications, and use of adjunctive medications. Results: A total of 159 patients met the inclusion criteria. Assessable data were available for 71 charts from the pre-implementation period and 72 charts from the post-implementation period. The median duration of benzodiazepine treatment was 91 h before implementation and 57 h after implementation (p < 0.001). Use of the protocol was also associated with a significant reduction in severe complications of alcohol withdrawal (50% versus 33%, p = 0.019), median cumulative benzodiazepine dose (in lorazepam equivalents) (20.0 mg versus 15.5 mg, p = 0.026), and use of adjunctive medications (65% versus 38%, p = 0.001). The incidence of serious adverse outcomes of treatment with benzodiazepines was not significantly different between the 2 groups. Conclusions: Implementation of an alcohol withdrawal protocol with a combination of fixed-schedule and symptom-triggered benzodiazepine dosing in a medical ward was associated with a shorter duration

Challenges of the pharmacological management of benzodiazepine withdrawal, dependence, and discontinuation.

PubMed

Fluyau, Dimy; Revadigar, Neelambika; Manobianco, Brittany E

2018-05-01

Benzodiazepines (BZDs) are among the most prescribed sedative hypnotics and among the most misused and abused medications by patients, in parallel with opioids. It is estimated that more than 100 million Benzodiazepine (BZD) prescriptions were written in the United States in 2009. While medically useful, BZDs are potentially dangerous. The co-occurring abuse of opioids and BZD, as well as increases in BZD abuse, tolerance, dependence, and short- and long-term side effects, have prompted a worldwide discussion about the challenging aspects of medically managing the discontinuation of BZDs. Abrupt cessation can cause death. This paper addresses the challenges of medications suggested for the management of BZD discontinuation, their efficacy, the risks of abuse and associated medical complications. The focus of this review is on the challenges of several medications suggested for the management of BZD discontinuation, their efficacy, the risks of abuse, and associated medical complications. An electronic search was performed of Medline, Worldwide Science, Directory of Open Access Journals, Embase, Cochrane Library, Google Scholar, PubMed Central, and PubMed from 1990 to 2017. The review includes double-blind, placebo-controlled studies for the most part, open-label pilot studies, and animal studies, in addition to observational research. We expand the search to review articles, naturalistic studies, and to a lesser extent, letters to the editor/case reports. We exclude abstract and poster presentations, books, and book chapters. The efficacy of these medications is not robust. While some of these medicines are relatively safe to use, some of them have a narrow therapeutic index, with severe, life-threatening side effects. Randomized studies have been limited. There is a paucity of comparative research. The review has several limitations. The quality of the documents varies according to whether they are randomized studies, nonrandomized studies, naturalistic studies

Anticonvulsants for alcohol withdrawal.

PubMed

Minozzi, Silvia; Amato, Laura; Vecchi, Simona; Davoli, Marina

2010-03-17

Alcohol abuse and dependence represents a most serious health problem worldwide with major social, interpersonal and legal interpolations. Besides benzodiazepines, anticonvulsants are often used for the treatment of alcohol withdrawal symptoms. Anticonvulsants drugs are indicated for the treatment of alcohol withdrawal syndrome, alone or in combination with benzodiazepine treatments. In spite of the wide use, the exact role of the anticonvulsants for the treatment of alcohol withdrawal has not yet bee adequately assessed. To evaluate the effectiveness and safety of anticonvulsants in the treatment of alcohol withdrawal. We searched Cochrane Drugs and Alcohol Group' Register of Trials (December 2009), PubMed, EMBASE, CINAHL (1966 to December 2009), EconLIT (1969 to December 2009). Parallel searches on web sites of health technology assessment and related agencies, and their databases. Randomized controlled trials (RCTs) examining the effectiveness, safety and overall risk-benefit of anticonvulsants in comparison with a placebo or other pharmacological treatment. All patients were included regardless of age, gender, nationality, and outpatient or inpatient therapy. Two authors independently screened and extracted data from studies. Fifty-six studies, with a total of 4076 participants, met the inclusion criteria. Comparing anticonvulsants with placebo, no statistically significant differences for the six outcomes considered.Comparing anticonvulsant versus other drug, 19 outcomes considered, results favour anticonvulsants only in the comparison carbamazepine versus benzodiazepine (oxazepam and lorazepam) for alcohol withdrawal symptoms (CIWA-Ar score): 3 studies, 262 participants, MD -1.04 (-1.89 to -0.20), none of the other comparisons reached statistical significance.Comparing different anticonvulsants no statistically significant differences in the two outcomes considered.Comparing anticonvulsants plus other drugs versus other drugs (3 outcomes considered), results

Dexmedetomidine in addition to benzodiazepine-based sedation in patients with alcohol withdrawal delirium.

PubMed

Tolonen, Jukka; Rossinen, Juhani; Alho, Hannu; Harjola, Veli-Pekka

2013-12-01

Alcohol withdrawal delirium (AWD) is often refractory to conventional medication. We report a prospective series of patients treated with α2-agonist dexmedetomidine added to conventional sedation. Eighteen patients with AWD were diagnosed by Confusion assessment method for ICU score. Treatment, complications, length of stay (LOS) in ICU and hospital were recorded. In addition, hospital and 1-year mortality were assessed. Dexmedetomidine was given for 23.9 (18.4) h [mean (SD)]. All the patients also received benzodiazepines but three patients were given haloperidole. No patient was intubated. The maximum infusion rate of dexmedetomidine was 1.5 (1.2) µg/kg/h. Time to resolution of AWD was 3.8 (1.3) days. The ICU LOS was 7.1 (2.7) days and in-hospital LOS 12.1 (4.5) days. No adverse events were observed although one patient died from acute pancreatitis. The use of dexmedetomidine in AWD seems safe but warrants further studies.

Withdrawal strategies for outpatients

PubMed Central

Mezciems, Edgar

1996-01-01

This article discusses outpatient withdrawal strategies for patients addicted to alcohol, benzodiazepines, barbiturates, and opiates and describes some practical ways to support recovery. PMID:8828877

Challenges of the pharmacological management of benzodiazepine withdrawal, dependence, and discontinuation

PubMed Central

Revadigar, Neelambika; Manobianco, Brittany E.

2018-01-01

Background: Benzodiazepines (BZDs) are among the most prescribed sedative hypnotics and among the most misused and abused medications by patients, in parallel with opioids. It is estimated that more than 100 million Benzodiazepine (BZD) prescriptions were written in the United States in 2009. While medically useful, BZDs are potentially dangerous. The co-occurring abuse of opioids and BZD, as well as increases in BZD abuse, tolerance, dependence, and short- and long-term side effects, have prompted a worldwide discussion about the challenging aspects of medically managing the discontinuation of BZDs. Abrupt cessation can cause death. This paper addresses the challenges of medications suggested for the management of BZD discontinuation, their efficacy, the risks of abuse and associated medical complications. The focus of this review is on the challenges of several medications suggested for the management of BZD discontinuation, their efficacy, the risks of abuse, and associated medical complications. Methods: An electronic search was performed of Medline, Worldwide Science, Directory of Open Access Journals, Embase, Cochrane Library, Google Scholar, PubMed Central, and PubMed from 1990 to 2017. The review includes double-blind, placebo-controlled studies for the most part, open-label pilot studies, and animal studies, in addition to observational research. We expand the search to review articles, naturalistic studies, and to a lesser extent, letters to the editor/case reports. We exclude abstract and poster presentations, books, and book chapters. Results: The efficacy of these medications is not robust. While some of these medicines are relatively safe to use, some of them have a narrow therapeutic index, with severe, life-threatening side effects. Randomized studies have been limited. There is a paucity of comparative research. The review has several limitations. The quality of the documents varies according to whether they are randomized studies, nonrandomized

Electroacupuncture for tapering off long-term benzodiazepine use: study protocol of randomized controlled trial.

PubMed

Yeung, Wing-Fai; Chung, Ka-Fai; Zhang, Zhang-Jin; Chan, Wai-Chi; Zhang, Shi-Ping; Ng, Roger Man-Kin; Chan, Connie Lai-Wah; Ho, Lai-Ming; Yu, Yee-Man; Lao, Li-Xing

2017-03-31

Conventional approaches for benzodiazepine tapering have their limitations. Anecdotal studies have shown that acupuncture is a potential treatment for facilitating successful benzodiazepine tapering. As of today, there was no randomized controlled trial examining its efficacy and safety. The purpose of the study is to evaluate the efficacy of using electroacupuncture as an adjunct treatment to gradual tapering of benzodiazepine doses in complete benzodiazepine cessation in long-term benzodiazepine users. The study protocol of a randomized, assessor- and subject-blinded, controlled trial is presented. One hundred and forty-four patients with histories of using benzodiazepines in ≥50% of days for more than 3 months will be randomly assigned in a 1:1 ratio to receive either electroacupuncture or placebo electroacupuncture combined with gradual benzodiazepine tapering schedule. Both experimental and placebo treatments will be delivered twice per week for 4 weeks. Major assessments will be conducted at baseline, week 6 and week 16 post-randomization. Primary outcome is the cessation rate of benzodiazepine use. Secondary outcomes include the percentage change in the doses of benzodiazepine usage and the severity of withdrawal symptoms experienced based on the Benzodiazepine Withdrawal Symptom Questionnaire, insomnia as measured by the Insomnia Severity Index, and anxiety and depressive symptoms as evaluated by the Hospital Anxiety and Depression Scale. Adverse events will also be measured at each study visit. Results of this study will provide high quality evidence of the efficacy and safety of electroacupuncture as an adjunct treatment for benzodiazepine tapering in long-term users. ClinicalTrials.gov NCT02475538 .

Review of adjunctive dexmedetomidine in the management of severe acute alcohol withdrawal syndrome.

PubMed

Wong, Adrian; Smithburger, Pamela L; Kane-Gill, Sandra L

2015-01-01

The primary management of alcohol withdrawal involves the administration of a γ-aminobutyric acid agonist, such as benzodiazepines, for management of symptoms and to prevent further progression to seizure or delirium tremens. Despite escalating doses of benzodiazepines, published literature indicates that some patient's alcohol withdrawal syndrome symptoms do not respond, and that the use of adjunctive agents may be beneficial in these patients. Dexmedetomidine, an α2-agonist, serves as a potential adjunctive agent through management of associated autonomic symptoms. Understanding of recent literature evaluating its use is necessary for appropriate selection. To review available literature supporting the use of adjunctive dexmedetomidine for management of severe alcohol withdrawal syndrome. A total of 13 published articles evaluating the efficacy and safety of dexmedetomidine as an adjunctive agent for the treatment of alcohol withdrawal in adult patients were identified from a MEDLINE search using the key words alcohol withdrawal, delirium tremens and dexmedetomidine. Evaluation of the literature indicates that dexmedetomidine is associated with a decrease in short-term benzodiazepine requirements after initiation, and improvement in hemodynamic parameters in relation to the adrenergic drive present in alcohol withdrawal. The use of dexmedetomidine in the management of severe alcohol withdrawal should be considered as an adjunctive agent. Dexmedetomidine appears to be well tolerated, with an expected decrease in blood pressure and heart rate. Seizures have occurred in patients with alcohol withdrawal despite the use of dexmedetomidine, with and without benzodiazepines, due to lack of γ-aminobutyric acid agonist administration.

Duration of treatment and activation of α1-containing GABAA receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats

PubMed Central

Kovačević, Jovana; Timić, Tamara; Tiruveedhula, Veera V.; Batinić, Bojan; Namjoshi, Ojas A.; Milić, Marija; Joksimović, Srđan; Cook, James M.; Savić, Miroslav M.

2014-01-01

Long-term use of benzodiazepine-type drugs may lead to physical dependence, manifested by withdrawal syndrome after abrupt cessation of treatment. The aim of the present study was to investigate the influence of duration of treatment, as well as the role of α1-containing GABAA receptors, in development of physical dependence to diazepam, assessed through the level of anxiety and susceptibility to pentylenetetrazole (PTZ)-induced seizures, 24 h after withdrawal from protracted treatment in rats. Withdrawal of 2 mg/kg diazepam after 28, but not after 14 or 21 days of administration led to an anxiety-like behavior in the elevated plus maze. Antagonism of the diazepam effects at α1-containing GABAA receptors, achieved by daily administration of the neutral modulator βCCt (5 mg/kg), did not affect the anxiety level during withdrawal. An increased susceptibility to PTZ-induced seizures was observed during diazepam withdrawal after 21 and 28 days of treatment. Daily co-administration of βCCt further decreased the PTZ-seizure threshold after 21 days of treatment, whilst it prevented the diazepam withdrawal-elicited decrease of the PTZ threshold after 28 days of treatment. In conclusion, the current study suggests that the role of α1-containing GABAA receptors in mediating the development of physical dependence may vary based on the effect being studied and duration of protracted treatment. Moreover, the present data supports previous findings that the lack of activity at α1-containing GABAA receptors is not sufficient to eliminate physical dependence liability of ligands of the benzodiazepine type. PMID:24695241

Differential expression of benzodiazepine anticonvulsant cross-tolerance according to time following flurazepam or diazepam treatment.

PubMed

Rosenberg, H C

1995-01-01

In previous studies in which the anti-pentylenetetrazol (PTZ) effect of benzodiazepines was used to measure tolerance, the results depended on the benzodiazepine used for chronic treatment as well as the benzodiazepine given acutely to test for tolerance. In this study, the time course of tolerance reversal was studied in rats given two treatments known to cause anticonvulsant tolerance, 1-week flurazepam (FZP), and 3-week diazepam (DZP). Neither treatment altered convulsive threshold for IV PTZ, but both treatments decreased the convulsive threshold for bicuculline. Withdrawing DZP, but not FZP, treatment resulted in a loss of body weight. Twelve hours after 1-week FZP treatment, all benzodiazepines were significantly less effective, showing tolerance. Forty-eight hours after the 1-week FZP treatment, tolerance was still observed with DZP, FZP, and zolpidem, but was no longer present with clonazepam or bretazenil. After the 3-week DZP treatment, rats were tolerant to all benzodiazepines tested at 12 h of withdrawal, but had lost tolerance to all the drugs except bretazenil by 48 h. The results suggest differences in the way these benzodiazepines interact with their receptors, allowing differential expression of tolerance, and that chronic DZP and FZP treatments affected interactions of the benzodiazepines with their receptors, but not in the same fashion.

A guide to benzodiazepine selection. Part II: Clinical aspects.

PubMed

Teboul, E; Chouinard, G

1991-02-01

To suit the specific needs of various clinical situations, selection of an appropriate benzodiazepine derivative should be based on consideration of their different pharmacokinetic and pharmacodynamic properties. Benzodiazepine derivatives that are rapidly eliminated produce the most pronounced rebound and withdrawal syndromes. Benzodiazepines that are slowly absorbed and slowly eliminated are most appropriate for the anxious patient, since these derivatives produce a gradual and sustained anxiolytic effect. Rapidly absorbed and slowly eliminated benzodiazepines are usually more appropriate for patients with sleep disturbances, since the rapid absorption induces sleep and the slower elimination rate may induce less tolerance to the sedative effect. Rational selection of a benzodiazepine for the elderly and for the suspected drug abuser is more problematic. The relevant pharmacokinetic and clinical considerations for these users are discussed. Certain derivatives may possess pharmacodynamic properties not shared by the entire benzodiazepine class; empirical studies have suggested the existence of anti-panic properties for alprazolam and clonazepam, antidepressant properties for alprazolam, and anti-manic properties for clonazepam and possibly lorazepam.

Low efficacy of non-opioid drugs in opioid withdrawal symptoms.

PubMed

Hermann, Derik; Klages, Eckard; Welzel, Helga; Mann, Karl; Croissant, Bernhard

2005-06-01

Opioid withdrawal, stress or cues associated with opioid consumption can induce opioid craving. If opioids are not available, opioid-dependent patients usually search for alternative drugs. Because several non-opioid drugs stimulate the endogenous opioidergic system, this concept may explain their frequent use by opioid-dependent patients. We hypothesized that non-opioid drugs alleviate opioid withdrawal symptoms and are therefore consumed by opioid addicts. We asked 89 opioid-dependent patients participating in an out-patient opioid maintenance program to estimate the potential of several non-opioid drugs in being able to alleviate opioid withdrawal. We applied a five-point Lickert scale (1 = very good reduction of opioid withdrawal; 5 = no reduction of opioid withdrawal). Patients could also indicate a worsening of opioid withdrawal. Values (mean +/- SD) were: for benzodiazepines, 3.2 +/- 1.1; tricyclic antidepressants, 3.6 +/- 1.1; cannabis, 3.6 +/- 1.0; alcohol, 4.1 +/- 1.1; cocaine, 4.2 +/- 1.1; amphetamine, 4.4 +/- 0.9; nicotine, 4.7 +/- 0.7; and caffeine, 4.9 +/- 0.5. A worsening of opioid withdrawal was reported by 62% of the patients for cocaine, 62% for amphetamine, 50% for caffeine, 37.5% for cannabis, 27% for nicotine, 26% for alcohol, 8% for tricyclic antidepressants and 3% for benzodiazepines. Our study shows a low efficacy of non-opioid drugs in alleviating opioid withdrawal symptoms. The data basis of this study was good and the sample was suitable to be asked for estimations of drug-drug interactions. Of the patients, 26 - 62% even reported a worsening of opioid withdrawal for cannabis, alcohol, cocaine and amphetamine. Only benzodiazepines and tricyclic antidepressants were reported to have a moderate positive effect on opioid withdrawal.

Intractable nausea caused by zolpidem withdrawal: a case report.

PubMed

Baruch, Edward; Vernon, Leonard F; Hasbun, Rafael J

2007-03-01

First launched in France in 1988, zolpidem (Ambien®) is a short-acting hypnotic agent. Early studies reported that that the development of physical dependence and tolerance to sedative-hypnotic drugs, such as the depressant and anticonvulsant effects evidenced with benzodiazepines, is not found with zolpidem. Direct to consumer advertising by the manufacturer continues to state that the risk for dependency is low; however, recent publications seem to contradict this. Additionally, adverse drug reactions affecting the central nervous system, gastrointestinal tract, and respiratory system have been reported. Other studies have examined the interactions of selective serotonin reuptake inhibitors and zolpidem as a possible cause of hallucinations. With continued physician marketing efforts touting the safety and efficacy of zolpidem, there is a high likelihood to overlook the risk of dependency and the symptoms related to zolpidem withdrawal. We report a case of a 41-year-old female who developed a dependency to zolpidem, who on her own decided to decrease her dosage, resulting in intractable nausea requiring hospitalization. Reported cases of zolpidem withdrawal have occurred with doses in excess of 160 mg per day, none of these have reported with intractable nausea as the sole symptom. In our reported case, although exceeding recommended dosage withdrawal phenomenon seemed to be severe after withdrawal from a comparatively low dose of zolpidem. Before zolpidem is prescribed, patient education should include warnings about the potential problems associated with dependency and abrupt discontinuation. Education about this common and likely underrecognized clinical phenomenon will help prevent future episodes and minimize the risk of misdiagnosis.

[Benzodiazepin addiction: a silent addiction among older people].

PubMed

Oude Voshaar, R C

2012-06-01

Benzodiazepines are frequently prescribed for a longer period of time for anxiety disorders and insomnia in spite of the many guidelines to prescribe these drugs only short-term. These guidelines are based on the risk-benefit balance between long-term effectiveness and side effects like addiction, anterograde amnesia, and increased risk on falling (resulting in hip fractures), traffic accidents and even mortality. Also low-dose benzodiazepine use can lead to benzodiazepine dependence. Although initially most attention has been paid to the physical withdrawal syndrome, psychological aspects of benzodiazepine dependence have received more and more attention in the past decades. Recently, a relationship between the brain-reward system, involved in addiction, and benzodiazepine use, was demonstrated. When long-term benzodiazepine use is recognised as problematic by both physician and patient, different treatment modalities are available to support patients in achieving abstinence. One of every four patients is able to stop by themselves with the aid of a minimal intervention providing psychoeducation and encouragement. Two out of three long-term uses are able to stop their usage with the aid of systematic tapering protocols guided by a physician or psychologist. In case of an underlying insomnia or anxiety disorder, cognitive-behavioural therapy should be added to the tapering protocol. In contrast to the general opinion, advanced old age has no negative impact on the treatment response.

Sleep disturbance and the effects of extended-release zolpidem during cannabis withdrawal

PubMed Central

Vandrey, Ryan; Smith, Michael T.; McCann, Una D.; Budney, Alan J.; Curran, Erin M.

2011-01-01

Background Sleep difficulty is a common symptom of cannabis withdrawal, but little research has objectively measured sleep or explored the effects of hypnotic medication on sleep during cannabis withdrawal. Methods Twenty daily cannabis users completed a within-subject crossover study. Participants alternated between periods of ad-libitum cannabis use and short-term cannabis abstinence (3 days). Placebo was administered at bedtime during one abstinence period (withdrawal test) and extended-release zolpidem, a non-benzodiazepine GABAA receptor agonist, was administered during the other. Polysomnographic (PSG) sleep architecture measures, subjective ratings, and cognitive performance effects were assessed each day. Results During the placebo-abstinence period, participants had decreased sleep efficiency, total sleep time, percent time spent in Stage 1 and Stage 2 sleep, REM latency and subjective sleep quality, as well as increased sleep latency and time spent in REM sleep compared with when they were using cannabis. Zolpidem attenuated the effects of abstinence on sleep architecture and normalized sleep efficiency scores, but had no effect on sleep latency. Zolpidem was not associated with any significant side effects or next-day cognitive performance impairments. Conclusions These data extend prior research that indicates abrupt abstinence from cannabis can lead to clinically significant sleep disruption in daily users. The findings also indicate that sleep disruption associated with cannabis withdrawal can be attenuated by zolpidem, suggesting that hypnotic medications might be useful adjunct pharmacotherapies in the treatment of cannabis use disorders. PMID:21296508

Successful withdrawal from high-dose benzodiazepine in a young patient through electronic monitoring of polypharmacy: a case report in an ambulatory setting.

PubMed

Loscertales, Hèctor R; Wentzky, Valerie; Dürsteler, Kenneth; Strasser, Johannes; Hersberger, Kurt E; Arnet, Isabelle

2017-05-01

Dependence on high-dose benzodiazepines (BZDs) is well known and discontinuation attempts are generally unsuccessful. A well established protocol for high-dose BZD withdrawal management is lacking. We present the case of withdrawal from high-dose lorazepam (>20 mg daily) in an unemployed 35-year-old male outpatient through agonist substitution with long-acting clonazepam and electronic monitoring over 28 weeks. All medicines were repacked into weekly 7 × 4 cavity multidose punch cards with an electronic monitoring system. The prescribed daily dosages of BZDs were translated into an optimal number of daily tablets, divided into up to four units of use. Withdrawal was achieved by individual leftover of a small quantity of BZDs that was placed in a separate compartment. Feedback with visualization of intake over the past week was given during weekly psychosocial sessions. Stepwise reduction was obtained by reducing the mg content of the cavities proportionally to the leftovers, keeping the number of cavities in order to maintain regular intake behavior, and to determine the dosage decrease. At week 28, the primary objectives were achieved, that is, lorazepam reduction to 5 mg daily and cannabis abstinence. Therapy was continued using multidrug punch cards without electronic monitoring to maintain the management system. At week 48, a smaller size weekly pill organizer with detachable daily containers was dispensed. At week 68, the patient's therapy was constant with 1.5 mg clonazepam + 5 mg lorazepam daily for anxiety symptoms and the last steps of withdrawal were started. Several key factors led to successful withdrawal from high-dose BZD in this outpatient, such as the use of weekly punch cards coupled with electronic monitoring, the patient's empowerment over the withdrawal process, and the collaboration of several healthcare professionals. The major implication for clinical care is reduction by following the leftovers, and not a diktat from the healthcare

[Treatment of gamma-hydroxybutyrate withdrawal].

PubMed

Strand, Niels August Willer; Petersen, Tonny Studsgaard; Nielsen, Lars Martin; Boegevig, Soren

2017-12-11

Gamma-hydroxybutyrate (GHB) is a drug of abuse, for which physical addiction develops quickly. GHB withdrawal can develop into a life-threatening condition and has previously been treated mainly with benzodiazepines. These have not always proven effective, leading to long hospitalizations in intensive care units. Based on successful Dutch treatment results for using GHB to treat GHB withdrawal symptoms, we propose to implement a similar method in Denmark. The method requires an interdisciplinary effort for which The Danish Poison Information Centre should be consulted for expertise.

The long-term use of benzodiazepines: patients' views, accounts and experiences.

PubMed

Barter, G; Cormack, M

1996-12-01

Although a decrease in new prescribing has occurred for anxiolytic benzodiazepines, concerns have been raised that a 'core' of long-term users has been left behind. Typically, elderly people represent this 'core', using the benzodiazepines as hypnotics. The present study focuses on the reasons why hypnotic benzodiazepines are used for protracted lengths of time. By examining patient experiences and cognitions, a deeper understanding may be gained of why patients continue to use benzodiazepines. Elderly, long-term users of benzodiazepine hypnotics were interviewed using a semi-structured interview procedure. A comparison group of non-users of the drugs were given a brief interview to collect comparative data. Interview data were analysed from transcripts using qualitative methodology; statistical comparisons between the groups were made using non-parametric statistics. The long-term users had significantly fewer hours of sleep per night than the non-users. There was some evidence of tolerance and a suggestion that symptoms of withdrawal were maintaining continual use. None of the long-term users had clean knowledge of what their doctors thought of their use of benzodiazepines. The data suggest that the power of the doctor may not be utilized to its full potential in the prevention of long-term use, that at least 50% of elderly benzodiazepine users would like to discontinue use, and that patients need information and advice on how to discontinue these drugs.

Benzodiazepine-induced hippocampal CA1 neuron alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid (AMPA) receptor plasticity linked to severity of withdrawal anxiety: differential role of voltage-gated calcium channels and N-methyl-D-aspartic acid receptors.

PubMed

Xiang, Kun; Tietz, Elizabeth I

2007-09-01

Withdrawal from 1-week oral administration of the benzodiazepine, flurazepam (FZP) is associated with increased alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid (AMPA) receptor (AMPAR) miniature excitatory postsynaptic currents (mEPSCs) but reduction of N-methyl-D-aspartic acid (NMDA) receptor (NMDAR)-evoked (e)EPSCs in hippocampal CA1 neurons. A positive correlation was observed between increased AMPAR-mediated mEPSC amplitude and anxiety-like behavior in 1-day FZP-withdrawn rats. These effects were disrupted by systemic AMPAR antagonist administration (GYKI-52466, 0.5 mg/kg, intraperitoneal) at withdrawal onset, strengthening the hypothesis that CA1 neuron AMPAR-mediated hyperexcitability is a central component of a functional anatomic circuit associated with the expression of withdrawal anxiety. Abolition of AMPAR current upregulation in 2-day FZP withdrawn rats by GYKI-52466 injection also reversed the reduction in NMDAR-mediated eEPSC amplitude in CA1 neurons from the same rats, suggesting that downregulation of NMDAR function may serve a protective, negative-feedback role to prevent AMPAR-mediated neuronal overexcitation. NMDAR antagonist administration (MK-801, 0.25 mg/kg intraperitoneally) had no effect on modifying increased glutamatergic strength or on withdrawal anxiety, whereas injection of an L-type voltage-gated calcium channel antagonist, nimodipine (10 mg/kg, intraperitoneally) averted AMPAR current enhancement and anxiety-like behavior, suggesting that these manifestations may be initiated by a voltage-gated calcium channel-dependent signal transduction pathway. An evidence-based model of likely cellular mechanisms in the hippocampus contributing to benzodiazepine withdrawal anxiety was proposed implicating regulation of multiple CA1 neuron ion channels.

Abrupt withdrawal of beta-blocking agents in patients with arterial hypertension. Effect on blood pressure, heart rate and plasma catecholamines and prolactin.

PubMed

Lederballe Pedersen, O; Mikkelsen, E; Lanng Nielsen, J; Christensen, N J

1979-04-17

Chronic treatment with beta-blockers was interrupted abruptly in six patients with arterial hypertension. Three patients, who had experienced symptoms during a previous withdrawal, again complained of transient palpitations, tremor, sweating, headache and general malaise. A significant increase in standing blood pressure (BP) and heart rate (HR) was noted after 24 h. The standing HR reached a maximum after 48 h and had decreased significantly on the 7th day (p less than 0.005). There was a strong tendency to greater increase in standing BP and HR in the patients who experienced symptoms than in those who did not. Plasma concentrations of noradrenaline, adrenaline and prolactin did not change significantly. Thus, beta-blocker withdrawal symptoms are reproducible and are indicative of a transient sympathetic hyperresponse. The increased activity is not likely to be caused by increased production of circulating catecholamines, but rather by increased sensitivity of the beta-receptor.

Something old, something new: a successful case of meprobamate withdrawal.

PubMed

James, Alexander Owen; Nicholson, Timothy R; Hill, Robert; Bearn, Jennifer

2016-02-29

Meprobamate, a benzodiazepine-like drug, was commonly prescribed for anxiety in the 1960s and 1970s, but fell out of favour, at least in part, due to the risk of dependence, for which there is little published evidence to guide clinical management. We discuss a 70-year-old man with a 45-year history of meprobamate dependency and multiple failed previous withdrawal attempts who was successfully withdrawn from meprobamate using diazepam during a 2-week inpatient stay on a specialist Addictions ward. An appropriate diazepam dose was established using the Clinical Institute Withdrawal Assessment scale for benzodiazepines (CIWA-B). This dose was then slowly reduced over 12 days. Multidisciplinary input, especially psychological therapy tackling his underlying anxiety disorder during his admission, was thought to be particularly helpful. 2016 BMJ Publishing Group Ltd.

Psychosocial characteristics of benzodiazepine addicts compared to not addicted benzodiazepine users.

PubMed

Konopka, Anna; Pełka-Wysiecka, Justyna; Grzywacz, Anna; Samochowiec, Jerzy

2013-01-10

Although the addictive potential of benzodiazepine drugs has been known for a long time, new cases of benzodiazepine addictions keep emerging in clinical practice. The etiology of benzodiazepine addiction seems to be multifactorial. The objective of this study was to investigate and measure psychological and situational factors differentiating benzodiazepine addicts from not addicted users. A psychological profile and situational factors of patients with the diagnosis of benzodiazepine addiction and a carefully matched control group of not addicted former benzodiazepine users were defined and investigated. The investigated benzodiazepine addicts differed significantly from the control group in particular psychological dimensions, such as higher neuroticism and introversion, prevalence of emotional rather than task based coping mechanisms. There were also significant correlations between the addiction and situational factors such as BZD - treatment circumstances and adverse life events previous to the treatment. The results show psychological and situational factors which differentiate benzodiazepine addicts from not addicted benzodiazepine users. This data suggest that benzodiazepine addiction might be associated with higher neuroticism, introversion and less effective coping mechanisms as well as with previous accumulation of adverse life events and/or inadequate BZD treatment. The psychological and situational factors mentioned above might be considered as potential risk factors for benzodiazepine addiction. Copyright © 2012 Elsevier Inc. All rights reserved.

[Physical performance and sedation: comparative study of the effects of a benzodiazepine (temazepam) and of a non-benzodiazepine hypnotic (zolpidem)].

PubMed

Gremion, G; Sutter-Weyrich, C; Rostan, A; Forster, A

1992-09-01

It is well-known that many athletes experience some form of precompetition stress that may result in insomnia during the night before their competition. Yet, sleep withdrawal even if only partial, has a negative influence on performance, particularly when the type of exercise requires good psychomotor performance The purpose of the present study was to investigate whether the intake of a hypnotic drug would have negative effects on physical performance capacity. The authors have compared the effects of oral temazepam, a medium half-life benzodiazepine vs oral zolpidem, a short half-life non-benzodiazepine drug, vs placebo. A randomized double-blind trial was used to assess endurance, resistance, strength and coordination in 26 athletes. The results did not show any differences between the three groups, neither in physical performance characteristic nor in coordination. It is concluded that as regards the performance capacity, there is no risk for stressed athletes to use sleep inducers the night before their competition.

Benzodiazepines

MedlinePlus

... acting benzodiazepine, is utilized for sedation, anxiety, and amnesia in critical care settings and prior to anesthesia. ... abusers. Affect on mind Benzodiazepines are associated with amnesia, hostility, irritability, and vivid or disturbing dreams. Affect ...

Abrupt opium discontinuation has no significant triggering effect on acute myocardial infarction.

PubMed

Masoomi, Mohammad; Zare, Jahangir; Nasri, Hamidreza; Mirzazadeh, Ali; Sheikhvatan, Mehrdad

2011-04-01

A deleterious effect of withdrawal symptoms due to abrupt discontinuation of opium on the cardiovascular system is one of the recent interesting topics in the cardiovascular field. The current study hypothesized that the withdrawal syndrome due to discontinuing opium might be an important trigger for the appearance of acute myocardial infarction. Eighty-one opium-addicted individuals who were candidates for cardiovascular clinical evaluation and consecutively hospitalized in the coronary care unit (CCU) ward of Shafa Hospital in Kerman between January and July 2009 were included in the study and categorized in the case group, including patients experiencing withdrawal symptoms within 6-12 h after the reduced or discontinued use of opium according to the Diagnostic and Statistical Manual of Mental Disorders-revised IV version (DSM-IV-R) criteria for opium dependence and withdrawal, and the control group, without opium withdrawal symptoms. The appearance of acute myocardial infarction was compared between the two groups using multivariable regression models. Acute myocardial infarction occurred in 50.0% of those with withdrawal symptoms and in 45.1% of patients without evidence of opium withdrawal (P = 0.669). Multivariable analysis showed that opium withdrawal symptoms were not a trigger for acute myocardial infarction adjusting for demographic characteristics, marital status, education level and common coronary artery disease risk profiles [odds ratio (OR) = 0.920, 95% confidence interval (CI) = 0.350-2.419, P = 0.866]. Also, daily dose of opium before reducing or discontinuing use did not predict the appearance of myocardial infarction in the presence of confounder variables (OR = 0.975, 95% CI = 0.832-1.143, P = 0.755). Withdrawal syndrome due to abrupt discontinuation of opium does not have a triggering role for appearance of acute myocardial infarction.

[Long-term prescription of benzodiazepines and non-benzodiazepines].

PubMed

Verthein, U; Martens, M S; Raschke, P; Holzbach, R

2013-07-01

The number of persons with a dependence on prescription drugs such as sedatives or tranquilizers in Germany is estimated at between 1.4 and 1.9 million. According to national addiction treatment documentations only very few of them seek help in specialised treatment services. The majority of prescription drug-dependent people use benzodiazepines. This medication is usually prescribed by physicians and according to German guidelines it should be prescribed only for limited, short periods and in low doses. This study aims to determine the extent of the problematic prescription of benzodiazepines and non-benzodiazepines. We used prescription data from the Northern Germany Computing Centre for Pharmacies registered between 2005 and 2007. For the German regions of Hamburg, Bremen and Schleswig-Holstein, benzodiazepine prescriptions during an individual prospective period of 12 months were analysed. From July 2005 to June 2006, 294 143 prescriptions of benzodiazepines and non-benzodiazepines were recorded for 78 456 citizens of Hamburg and billed at the expenses of the governmental health insurance funds. In the course of one observed patient year, 51.1% of benzodiazepine prescriptions were in accordance with the German guidelines. 15.6% of the patients were supplied on a long-term basis (0.5-1 DDD during at least 2 months). Prescriptions for women and persons older than 70 years were disproportionately high. Compared with the Federal states of Bremen and Schleswig-Holstein, Hamburg does not show an exceptional position. The prescription of benzodiazepines which is not in accordance with the relevant national guidelines is widespread and calls for discussion and education among physicians and pharmacists. Furthermore, professional addiction services should reconsider ways to help and attract prescription drug-dependent people to cover their needs, as their numbers will grow in an aging society. © Georg Thieme Verlag KG Stuttgart · New York.

Drug Discontinuation Effects Are Part of the Pharmacology of a Drug

PubMed Central

2011-01-01

Most reviews of drug withdrawal effects focus on drugs of potential abuse such as opioids, benzodiazepines, etc. Abrupt discontinuation of many other drugs used in medicine cause withdrawal syndromes, some of which can be fatal. Discontinuation of a number of cardiovascular drugs can increase risk of cardiovascular events above that of people not taking these drugs. These include β-adrenergic receptor antagonists, aspirin, HMG-CoA reductase inhibitors (statins), and heparin. Rebound hypertension occurs after abrupt cessation of many antihypertensive drugs. The possibility of discontinuation syndromes has usually been neglected until adverse clinical events force them to be noticed. Attention to the possibility of drug discontinuation effects is an important part of drug safety evaluation. PMID:21849624

A Review of Alprazolam Use, Misuse, and Withdrawal

PubMed Central

Ait-Daoud, Nassima; Hamby, Allan Scott; Sharma, Sana; Blevins, Derek

2018-01-01

Alprazolam is one of the most widely prescribed benzodiazepines for the treatment of generalized anxiety disorder and panic disorder. Its clinical use has been a point of contention as most addiction specialists consider it to be highly addictive, given its unique psychodynamic properties which limit its clinical usefulness, whereas many primary care physicians continue to prescribe it for longer periods than recommended. Clinical research data has not fully shed light on its “abuse liability,” yet it is one of the most frequently prescribed benzodiazepines. “Abuse liability” is the degree to which a psychoactive drug has properties that facilitate people misusing it, or becoming addicted to it, and is commonly used in the literature. We have replaced it in our manuscript with “misuse liability” as it reflects a more updated terminology consistent with the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In this paper, we have reviewed alprazolam’s indications for use, its effect on pregnant women, misuse liability, withdrawal syndrome, pharmacodynamic properties, and suggest better clinical prescription practice of alprazolam by presenting an indepth theory of its clinical effects with use and withdrawal. PMID:28777203

Prolonged, severe intrathecal baclofen withdrawal syndrome: a case report.

PubMed

Hansen, Colby R; Gooch, Judith L; Such-Neibar, Teresa

2007-11-01

Intrathecal baclofen (ITB) withdrawal is a well-recognized complication when drug delivery is disrupted for any reason. ITB withdrawal varies widely in its severity and poses the very real possibility of death if not promptly managed. Cases of withdrawal lasting greater than 1 or 2 weeks, however, are sparse. We report the case of an 11-year-old girl with spastic quadriplegic cerebral palsy who developed an infected pump and subsequent meningitis, prompting the removal of her pump and catheter. She subsequently developed a severe, prolonged baclofen withdrawal syndrome marked by increased spasticity, agitation, hypertension, and tachycardia that lasted nearly 2 months, requiring intensive care and continuous intravenous sedation with benzodiazepines and opiates. Her pump was eventually replaced on hospital day 56 and within 24 hours her symptoms dramatically improved. She was eventually weaned off sedating medications and returned to baseline functional status. Typical management of baclofen withdrawal is reviewed. To date, the literature has not discussed the potential role for opiates in managing baclofen withdrawal, yet a growing body of literature is examining the interplay between opiates and gamma-aminobutyric acid B pathways. A potential role for opiates in managing severe baclofen withdrawal is proposed.

Evaluation of the appropriate use of a CIWA-Ar alcohol withdrawal protocol in the general hospital setting.

PubMed

Eloma, Amanda S; Tucciarone, Jason M; Hayes, Edmund M; Bronson, Brian D

2018-01-01

The Clinical Institute Withdrawal Assessment-Alcohol, Revised (CIWA-Ar) is an assessment tool used to quantify alcohol withdrawal syndrome (AWS) severity and inform benzodiazepine treatment for alcohol withdrawal. To evaluate the prescribing patterns and appropriate use of the CIWA-Ar protocol in a general hospital setting, as determined by the presence or absence of documented AWS risk factors, patients' ability to communicate, and provider awareness of the CIWA-Ar order. This retrospective chart review included 118 encounters of hospitalized patients placed on a CIWA-Ar protocol during one year. The following data were collected for each encounter: patient demographics, admitting diagnosis, ability to communicate, and admission blood alcohol level; and medical specialty of the clinician ordering CIWA-Ar, documentation of the presence or absence of established AWS risk factors, specific parameters of the protocol ordered, service admitted to, provider documentation of awareness of the active protocol within 48 h of initial order, total benzodiazepine dose equivalents administered and associated adverse events. 57% of patients who started on a CIWA-Ar protocol had either zero or one documented risk factor for AWS (19% and 38% respectively). 20% had no documentation of recent alcohol use. 14% were unable to communicate. 19% of medical records lacked documentation of provider awareness of the ordered protocol. Benzodiazepine associated adverse events were documented in 15% of encounters. The judicious use of CIWA-Ar protocols in general hospitals requires mechanisms to ensure assessment of validated alcohol withdrawal risk factors, exclusion of patients who cannot communicate, and continuity of care during transitions.

Assessment of the Availability, Cost, and Motivations for Use over Time of the New Psychoactive Substances-Benzodiazepines Diclazepam, Flubromazepam, and Pyrazolam-in the UK.

PubMed

Abouchedid, Rachelle; Gilks, Thea; Dargan, Paul I; Archer, John R H; Wood, David M

2018-06-01

There has been increasing interest in the availability of non-prescription benzodiazepines and their sale as new psychoactive substances. We wanted to determine UK availability from Internet suppliers and motivations for use of three benzodiazepines (diclazepam, flubromazepam, and pyrazolam). In November 2014 and March 2016, using the European Monitoring Centre for Drugs and Drug Addiction Snapshot Methodology, Internet search engines ( google.co.uk , uk. yahoo.com and ask.com.uk ) were searched using the terms 'buy diclazepam', 'buy flubromazepam' and 'buy pyrazolam'. Threads from drug-user forums ( bluelight.org , drugs-forum.com , erowid.org , legalhighsforum.com ) were analysed using a general inductive approach. Data were converted into price per gram/pellet to allow cost comparisons and to determine motivations for use. There was an increase in websites selling these benzodiazepines between 2014 and 2016: diclazepam (49 in 2014 to 55 in 2016), pyrazolam (33 to 35), and flubromazepam (39 to 45). Thirty-eight (63.3%) sites were based in the UK/Europe. Drugs were sold as pellets (49 websites, 81.7%), powder (19, 31.7%), and blotters (1, 1.7%). Pill forms were not available, and one (1.7%) website sold diclazepam/flubromazepam in liquid form. The cost reduced with increasing purchase quantities. Main motivations for use included anxiolysis, management of benzodiazepine withdrawal, sedation/sleep aid, and management of stimulant withdrawal. These three benzodiazepines are widely available online, most commonly as pellets, and are (mis)used for a number of reasons. This study could be used to support triangulation of data from other sources to inform harm minimisation strategies.

Benzodiazepine poisoning in elderly.

PubMed

Vukcević, Natasa Perković; Ercegović, Gordana Vuković; Segrt, Zoran; Djordjević, Snezana; Stosić, Jasmina Jović

2016-03-01

Benzodiazepines are among the most frequently ingested drugs in self-poisonings. Elderly may be at greater risk compared with younger individuals due to impaired metabolism and increased sensitivity to benzodiazepines. The aim of this study was to assess toxicity of benzodiazepines in elderly attempted suicide. A retrospective study of consecutive presentations to hospital after self-poisoning with benzodiazepines was done. Collected data consisted of patient's characteristics (age, gender), benzodiazepine ingested with its blood concentrations at admission, clinical findings including vital signs and Glasgow coma score, routine blood chemistry, complications of poisoning, details of management, length of hospital stay and outcome. According the age, patients are classified as young (15-40-year old), middle aged (41-65-year old) and elderly (older than 65). During a 2-year observational period 387 patients were admitted because of pure benzodiazepine poisoning. The most frequently ingested drug was bromazepam, the second was diazepam. The incidence of coma was significantly higher, and the length of hospital stay significantly longer in elderly. Respiratory failure and aspiration pneumonia occurred more frequently in old age. Also, flumazenil was more frequently required in the group of elderly patients. Massive benzodiazepines overdose in elderly may be associated with a significant morbidity, including deep coma with aspiration pneumonia, respiratory failure, and even death. Flumazenil is indicated more often to reduce CNS depression and prevent complications of prolonged unconsciousness, but supportive treatment and proper airway management of comatose patients is the mainstay of the treatment of acute benzodiazepine poisoning.

Purification of a benzodiazepine from bovine brain and detection of benzodiazepine-like immunoreactivity in human brain.

PubMed Central

Sangameswaran, L; Fales, H M; Friedrich, P; De Blas, A L

1986-01-01

An endogenous brain substance that binds to the central-type benzodiazepine receptors with agonist properties is present in both rat and bovine brains. This substance has been purified to homogeneity from bovine brain by immunoaffinity chromatography on immobilized monoclonal anti-benzodiazepine antibody followed by gel filtration on Sephadex G-25 and two reversed-phase HPLC steps. The purified substance was characterized as the benzodiazepine N-desmethyldiazepam (nordiazepam). The techniques used for the identification were mass spectrometry, HPLC, spectrophotometry, benzodiazepine receptor binding, and immunological techniques. Benzodiazepine-like immunoreactivity was also found in all the human brains tested, including six brains that had been stored in paraffin since 1940, fifteen years before the first synthesis of benzodiazepines. These results show that benzodiazepine-like molecules of natural origin--and possibly benzodiazepines themselves--are present in human and other mammalian brains. Images PMID:3024172

Assessment of GABA(A)benzodiazepine receptor (GBzR) sensitivity in patients on benzodiazepines.

PubMed

Potokar, J; Coupland, N; Wilson, S; Rich, A; Nutt, D

1999-09-01

To measure GABA(A) benzodiazepine receptor sensitivity in patients taking benzodiazepines and compare with matched controls. Seven patients who were on prescribed benzodiazepines for an anxiety disorder or insomnia were recruited from general practice and an adult mental health service outpatient clinic. They were matched with seven volunteers. All subjects received an intravenous injection of midazolam 50 microgram/kg in 10 ml normal saline over 10 min. Objective responses to midazolam were assessed using saccadic eye movement velocity slowing and subjective assessments using visual analogue scales. Measurements were recorded for 120 min and plasma midazolam concentrations obtained at 15-min intervals post-infusion to 120 min. Ratios of pharmacodynamic/pharmacokinetic effects were obtained for each individual to estimate GABA(A) benzodiazepine receptor sensitivity. Patients had an attenuated response to midazolam on both subjective and objective measures. GABA(A) benzodiazepine receptor sensitivity was significantly reduced in the patient group. Chronic treatment with benzodiazepines was associated with reduced effects of midazolam. Saccadic eye movement velocity was especially sensitive as a measure of attenuated response.

Benzodiazepines and Pregnancy

MedlinePlus

... heard that benzodiazepines can cause birth defects like cleft lip and palate. Is this true? Probably not. Some early studies ... a slight increase in the risk for cleft lip and/or cleft palate if a benzodiazepine was taken during the first ...

Anticonvulsants for the treatment of alcohol withdrawal syndrome and alcohol use disorders.

PubMed

Hammond, Christopher J; Niciu, Mark J; Drew, Shannon; Arias, Albert J

2015-04-01

Alcoholic patients suffer from harmful allostatic neuroplastic changes in the brain causing an acute withdrawal syndrome upon cessation of drinking followed by a protracted abstinence syndrome and an increased risk of relapse to heavy drinking. Benzodiazepines have long been the treatment of choice for detoxifying patients and managing alcohol withdrawal syndrome (AWS). Non-benzodiazepine anticonvulsants (NBACs) are increasingly being used both for alcohol withdrawal management and for ongoing outpatient treatment of alcohol dependence, with the goal of either abstinence or harm reduction. This expert narrative review summarizes the scientific basis and clinical evidence supporting the use of NBACs in treating AWS and for reducing harmful drinking patterns. There is less evidence in support of NBAC therapy for AWS, with few placebo-controlled trials. Carbamazepine and gabapentin appear to be the most promising adjunctive treatments for AWS, and they may be useful as monotherapy in select cases, especially in outpatient settings and for the treatment of mild-to-moderate low-risk patients with the AWS. The body of evidence supporting the use of the NBACs for reducing harmful drinking in the outpatient setting is stronger. Topiramate appears to have a robust effect on reducing harmful drinking in alcoholics. Gabapentin is a potentially efficacious treatment for reducing the risk of relapse to harmful drinking patterns in outpatient management of alcoholism. Gabapentin's ease of use, rapid titration, good tolerability, and efficacy in both the withdrawal and chronic phases of treatment make it particularly appealing. In summary, several NBACs appear to be beneficial in treating AWS and alcohol use disorders.

Anticonvulsants for the Treatment of Alcohol Withdrawal Syndrome and Alcohol Use Disorders

PubMed Central

Hammond, Christopher J.; Niciu, Mark J.; Drew, Shannon; Arias, Albert J.

2015-01-01

Alcoholic patients suffer from harmful allostatic neuroplastic changes in the brain causing an acute withdrawal syndrome upon cessation of drinking followed by a protracted abstinence syndrome and an increased risk of relapse to heavy drinking. Benzodiazepines have long been the treatment of choice for detoxifying patients and managing alcohol withdrawal syndrome (AWS). Non-benzodiazepine anticonvulsants (NBACs) are increasingly being used both for alcohol withdrawal management and for ongoing outpatient treatment of alcohol dependence, with the goal of either abstinence or harm reduction. This expert narrative review summarizes the scientific basis and clinical evidence supporting the use of NBACs in treating AWS and for reducing harmful drinking patterns. There is less evidence in support of NBAC therapy for AWS, with few placebo-controlled trials. Carbamazepine and gabapentin appear to be the most promising adjunctive treatments for AWS, and they may be useful as monotherapy in select cases, especially in outpatient settings and for the treatment of mild-to-moderate low-risk patients with the AWS. The body of evidence supporting the use of the NBACs for reducing harmful drinking in the outpatient setting is stronger. Topiramate appears to have a robust effect on reducing harmful drinking in alcoholics. Gabapentin is a potentially efficacious treatment for reducing the risk of relapse to harmful drinking patterns in outpatient management of alcoholism. Gabapentin's ease of use, rapid titration, good tolerability, and efficacy in both the withdrawal and chronic phases of treatment make it particularly appealing. In summary, several NBACs appear to be beneficial in treating AWS and alcohol use disorders. PMID:25895020

Prescribing benzodiazepines for noninstitutionalized elderly.

PubMed Central

Thomson, M.; Smith, W. A.

1995-01-01

OBJECTIVE: To describe benzodiazepine prescribing for elderly people living in the community in British Columbia, and to compare such prescribing with an indicator of current guidelines. DESIGN: Descriptive analysis of pharmacy billing data. SETTING: Province of British Columbia. PARTICIPANTS: All elderly persons (age 65 and older) dispensed benzodiazepines by community pharmacies in British Columbia during 1990. MAIN OUTCOME MEASURE: Potentially inappropriate prescriptions were defined by a maximum 2-month limit of 20 diazepam equivalents daily, as determined by the BC Drug Usage Review Program in consultation with experts in the field. Physicians' rates of potentially inappropriate prescribing were determined per 100 benzodiazepine prescriptions written. RESULTS: Almost 24% of elderly people in British Columbia were prescribed benzodiazepines at least once during 1990. Of these, 17.1% were given potentially inappropriate prescriptions. Physicians who prescribed benzodiazepines most frequently had the highest rates of potentially inappropriate prescriptions. CONCLUSION: Prescribing practice does not correspond with our indicator of current guidelines. PMID:7756916

Sorption, plant uptake and metabolism of benzodiazepines.

PubMed

Carter, Laura J; Williams, Mike; Martin, Sheridan; Kamaludeen, Sara P B; Kookana, Rai S

2018-07-01

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 d ) or had pH-adjusted log octanol-water partition coefficients (log D ow , 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 d 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

Nabilone therapy for cannabis withdrawal presenting as protracted nausea and vomiting.

PubMed

Lam, Philip W; Frost, David W

2014-09-22

Cannabis is one of the most commonly used recreational drugs worldwide. Psychoactive properties of the principal compound, δ-9-tetrahydrocannabinol include euphoria, a sense of relaxation and increased appetite. Chronic cannabis use has been associated with the development of a withdrawal syndrome on abrupt discontinuation. Withdrawal symptoms typically begin within 24 h of abstinence and manifest as irritability, nervousness, sleep disturbances and decreased appetite. There is growing evidence that supports the use of plant-derived and synthetic cannabinoids for the treatment of cannabis withdrawal. In this case report, we present 20-year-old woman who developed protracted nausea and vomiting secondary to cannabis withdrawal and was successfully treated with nabilone. Nausea and vomiting is not listed in the Diagnostic and Statistical Manual-5 diagnostic criteria for cannabis withdrawal syndrome and is an uncommon symptom presentation. 2014 BMJ Publishing Group Ltd.

Methadone Management of Withdrawal Associated With Loperamide-related Opioid Use Disorder.

PubMed

Leo, Raphael J; Ghazi, Muhammad A; Jaziri, Kelly S

: Loperamide hydrochloride is an over-the-counter anti-diarrheal agent, acting via mu-opioid receptor agonist effects in the intestinal myenteric plexus. Although preclinical investigations suggested that abuse liability associated with loperamide use is low, there are increasing numbers of cases reported to the US Food and Drug Administration, of abuse, dependence, and withdrawal associated with loperamide use. A case of a patient with opioid use disorder, that is, in the form of protracted loperamide excess use, requiring management of withdrawal with methadone is presented. Management of withdrawal from abrupt loperamide discontinuation has not been discussed in the literature. Long-term treatment issues are also described.

Benzodiazepine-associated atrioventricular block.

PubMed

Arroyo Plasencia, Anna M; Ballentine, Lynn M; Mowry, James B; Kao, Louise W

2012-01-01

Dysrhythmias, although common in overdose situations, are not often seen after benzodiazepine exposures. We report two cases of transient atrioventricular block after benzodiazepine misuse. Case 1 is a 4-year-old boy who was found unresponsive after an ingestion of clonazepam. An electrocardiogram (EKG) performed on emergency department presentation demonstrated first-degree atrioventricular block (PR 206 ms). After flumazenil administration, he developed second-degree atrioventricular block (Mobitz Type 1). EKG abnormalities resolved by morning. Serum clonazepam was 478 ng/mL (laboratory clonazepam reference range, 10-75 ng/mL with a dose of up to 6 mg/day) 5 hours after being found unresponsive. Case 2 is a 23-year-old man who presented to the emergency department after ingesting risperidone, combination hydrocodone/acetaminophen, and alprazolam. On arrival, his EKG demonstrated sinus bradycardia with a PR interval of 182 msec. He subsequently developed second-degree atrioventricular block (Mobitz Type I). Sinus bradycardia with resolution of his atrioventricular block (PR 200 ms) was seen on a third EKG performed 5 hours after presentation. These two patients demonstrated transient first- and second-degree atrioventricular block after benzodiazepine exposure. Benzodiazepines have been shown to alter L-type Ca2+ channel function. This alteration in function may account for the dysrhythmias seen in our patients. Together, these cases serve to remind clinicians of this rare but potentially serious complication associated with benzodiazepine exposure.

Adjunct Ketamine Use in the Management of Severe Ethanol Withdrawal.

PubMed

Pizon, Anthony F; Lynch, Michael J; Benedict, Neal J; Yanta, Joseph H; Frisch, Adam; Menke, Nathan B; Swartzentruber, Greg S; King, Andrew M; Abesamis, Michael G; Kane-Gill, Sandra L

2018-05-08

Ketamine offers a plausible mechanism with favorable kinetics in treatment of severe ethanol withdrawal. The purpose of this study is to determine if a treatment guideline using an adjunctive ketamine infusion improves outcomes in patients suffering from severe ethanol withdrawal. Retrospective observational cohort study. Academic tertiary care hospital. Patients admitted to the ICU and diagnosed with delirium tremens by Diagnostic and Statistical Manual of Mental Disorders V criteria. Pre and post guideline, all patients were treated in a symptom-triggered fashion with benzodiazepines and/or phenobarbital. Postguideline, standard symptom-triggered dosing continued as preguideline, plus, the patient was initiated on an IV ketamine infusion at 0.15-0.3 mg/kg/hr continuously until delirium resolved. Based upon withdrawal severity and degree of agitation, a ketamine bolus (0.3 mg/kg) was provided prior to continuous infusion in some patients. A total of 63 patients were included (29 preguideline; 34 postguideline). Patients treated with ketamine were less likely to be intubated (odds ratio, 0.14; p < 0.01; 95% CI, 0.04-0.49) and had a decreased ICU stay by 2.83 days (95% CI, -5.58 to -0.089; p = 0.043). For ICU days outcome, correlation coefficients were significant for alcohol level and total benzodiazepine dosing. For hospital days outcome, correlation coefficients were significant for patient age, aspartate aminotransferase, and alanine aminotransferase level. Regression revealed the use of ketamine was associated with a nonsignificant decrease in hospital stay by 3.66 days (95% CI, -8.40 to 1.08; p = 0.13). Mechanistically, adjunctive therapy with ketamine may attenuate the demonstrated neuroexcitatory contribution of N-methyl-D-aspartate receptor stimulation in severe ethanol withdrawal, reduce the need for excessive gamma-aminobutyric acid agonist mediated-sedation, and limit associated morbidity. A ketamine infusion in patients with delirium tremens was

Rapid reduction versus abrupt quitting for smokers who want to stop soon: a randomised controlled non-inferiority trial

PubMed Central

Lindson, Nicola; Aveyard, Paul; Ingram, Jackie T; Inglis, Jennie; Beach, Jane; West, Robert; Michie, Susan

2009-01-01

Background The standard way to stop smoking is to stop abruptly on a quit day with no prior reduction in consumption of cigarettes. Many smokers feel that reduction is natural and if reduction programmes were offered, many more might take up treatment. Few trials of reduction versus abrupt cessation have been completed. Most are small, do not use pharmacotherapy, and do not meet the standards necessary to obtain a marketing authorisation for a pharmacotherapy. Design/Methods We will conduct a non-inferiority randomised trial of rapid reduction versus standard abrupt cessation among smokers who want to stop smoking. In the reduction arm, participants will be advised to reduce smoking consumption by half in the first week and to 25% of baseline in the second, leading up to a quit day at which participants will stop smoking completely. This will be assisted by nicotine patches and an acute form of nicotine replacement therapy. In the abrupt arm participants will use nicotine patches only, whilst smoking as normal, for two weeks prior to a quit day, at which they will also stop smoking completely. Smokers in either arm will have standard withdrawal orientated behavioural support programme with a combination of nicotine patches and acute nicotine replacement therapy post-cessation. Outcomes/Follow-up The primary outcome of interest will be prolonged abstinence from smoking, with secondary trial outcomes of point prevalence, urges to smoke and withdrawal symptoms. Follow up will take place at 4 weeks, 8 weeks and 6 months post-quit day. Trial Registration Current Controlled Trials ISRCTN22526020 PMID:19682359

[Choosing the correct benzodiazepine: mechanism of action and pharmacokinetics].

PubMed

Vinkers, Christiaan H; Tijdink, Joeri K; Luykx, Jurjen J; Vis, Roeland

2012-01-01

There is a discrepancy between the recommendation for caution and daily practice in the prescription of benzodiazepines. Although there is heterogeneity in the registered indications, all benzodiazepine agonists have almost the same mechanism of action. There are, however, substantial pharmacokinetic differences between individual benzodiazepine agonists. During short-term use of benzodiazepines, the elimination half-life is no measure of duration of action. Benzodiazepine lipophilicity determines the speed of action. If a rapid effect is desired, for instance in acute anxiety or agitation, then regarding oral medication the use of a lipophilic benzodiazepine such as diazepam is a rational choice. An accumulation factor can be used to estimate benzodiazepine accumulation during chronic use. In theory, accumulation does not occur with once-daily dosage of benzodiazepines that have an elimination half-life markedly shorter than 24 h, such as oxazepam, temazepam, and lorazepam.

[Benzodiazepines and forensic aspects].

PubMed

Michel, L; Lang, J-P

2003-01-01

Adverse effects of benzodiazepines are well known since the first one was used in 1958 (chlordiazepoxide). The literature collects study-cases or rarely controlled studies concerning side effects or paradoxical reactions to benzodiazepines. They mostly described drowsiness and behavioral disinhibition, including increased well-being feeling but also hostility, rage access with feeling of invulnerability, serious crimes and sometimes homicides. Delusional, manic, confusional or depressive states are also pointed out. Rate for aggressive behaviour is 0.3 to 0.7% but distinction should be done between accidental or "idiosyncratic" reaction and voluntary sought disinhibition, clearly more frequent. No benzodiazepine has any specificity for these adverse effects but pharmacology, doses, associated drugs (or alcohol) and psychopathology interact to produce hazardous psychic states. Pharmacology: GABA induces a decrease in serotonin compound and vigilance. Pharmacokinetic: first dose effect or over-dose effect, short half-life, lipophily, affinity, digestive absorption, active metabolites interact. Psychopathology: age, alcohol association, psychological status (high initial level of hostility, impulsivity, frustration, personality disorder and depressive status). External conditions: chronic illness, affective and professional frustrations, physical or psychic exhaustion contribute also. Some benzodiazepines (flunitrazepam, diazepam, clorazepate, triazolam, alprazolam, lorazepam, for example) are more often concerned for pharmacokinetics characteristics but also prescription habits. Forensic aspects should be considered in case of homicide. Especially, reality of benzodiazepines consumption and awareness of the potential paradoxical reaction should be precisely evaluated. Special focus on voluntary induced disinhibition has to be done for forensic considerations. Relationship but also crime facilitations are sometimes consciously sought. Some benzodiazepines have already

"Diazepam loading": ¿Can a strategy for preventing alcohol withdrawal be used to treat benzodiazepine use disorder?

PubMed

Oliveras, Clara; Fortea, Adriana; Espinosa, Laura; Barrio, Pablo; Lligoña, Anna; Balcells-Olivero, Mercè

2018-04-15

Benzodiazepines (BZDs) are central nervous system (CNS) depressants which are widely used to treat insomnia and anxiety, despite having long-term adverse side effects. (Fortea González, Oriolo, Balcells Oliveró, Sánchez Del Valle & Castellvi, 2017). As with alcohol, continued use can lead to tolerance and dependence phenomena. Discontinuation in such cases can produce abstinence symptoms such as tremors, anxiety, seizures and, occasionally, death (Brett y Murnion, 2015).

S100B protein in benzodiazepine overdose.

PubMed

Ambrozic, J; Bunc, M; Osredkar, J; Brvar, M

2008-02-01

Severe benzodiazepine overdose can result in coma and respiratory depression that might cause brain hypoxia, necrosis and delayed post-anoxic leucoencephalopathy with permanent neurological sequelae. The aim of this study was to assess the possible role of S100B, a structural protein of astroglial cells, as a biochemical marker of brain injury in acute benzodiazepine overdose. Serum S100B determination was performed in 38 consecutive patients admitted to the emergency department (ED) in Ljubljana with benzodiazepine overdose. The level of consciousness and respiratory insufficiency on the scene were assessed by responsiveness to a verbal stimulus and pulse oximetry. Blood samples were taken immediately after arrival at the ED and S100B concentrations were measured with a commercial immunoluminometric assay. 20 healthy sex- and age-matched volunteers formed a control group. There were significant differences in S100B levels between the control group and the patients with benzodiazepine overdose according to their responsiveness to a verbal stimulus. Post hoc test results showed that S100B levels in patients with benzodiazepine overdose who were unresponsive to a verbal stimulus were significantly higher than those in patients responsive to a verbal stimulus (median 0.31 vs 0.11 microg/l; p = 0.001). Both groups of patients with benzodiazepine overdose had significantly higher S100B levels than the control group (median 0.07 microg/; both p = 0.001). Arterial oxygen saturation of patients with benzodiazepine overdose unresponsive to a verbal stimulus was significantly lower than in patients responsive to a verbal stimulus (median 83% vs 94%; p = 0.001). There was no significant difference in the systolic blood pressure of patients with benzodiazepine overdose responsive or unresponsive to a verbal stimulus. Raised levels of S100B protein are associated with depressed levels of consciousness and respiratory insufficiency in patients with benzodiazepine overdose.

Genetic markers of a Munc13 protein family member, BAIAP3, are gender specifically associated with anxiety and benzodiazepine abuse in mice and humans.

PubMed

Wojcik, Sonja M; Tantra, Martesa; Stepniak, Beata; Man, Kwun-Nok M; Müller-Ribbe, Katja; Begemann, Martin; Ju, Anes; Papiol, Sergi; Ronnenberg, Anja; Gurvich, Artem; Shin, Yong; Augustin, Iris; Brose, Nils; Ehrenreich, Hannelore

2013-07-24

Anxiety disorders and substance abuse, including benzodiazepine use disorder, frequently occur together. Unfortunately, treatment of anxiety disorders still includes benzodiazepines, and patients with an existing comorbid benzodiazepine use disorder or a genetic susceptibility for benzodiazepine use disorder may be at risk of adverse treatment outcomes. The identification of genetic predictors for anxiety disorders, and especially for benzodiazepine use disorder, could aid the selection of the best treatment option and improve clinical outcomes. The brain-specific angiogenesis inhibitor I-associated protein 3 (Baiap3) is a member of the mammalian uncoordinated 13 (Munc13) protein family of synaptic regulators of neurotransmitter exocytosis, with a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, with the latter being more pronounced in female than in male animals. We hypothesized that genetic variation in human BAIAP3 may also be associated with anxiety. By using a phenotype-based genetic association study, we identified two human BAIAP3 single-nucleotide polymorphism risk genotypes (AA for rs2235632, TT for rs1132358) that show a significant association with anxiety in women and, surprisingly, with benzodiazepine abuse in men. Returning to mice, we found that male, but not female, Baiap3 knockout (KO) mice develop tolerance to diazepam more quickly than control animals. Analysis of cultured Baiap3 KO hypothalamus slices revealed an increase in basal network activity and an altered response to diazepam withdrawal. Thus, Baiap3/BAIAP3 is gender specifically associated with anxiety and benzodiazepine use disorder, and the analysis of Baiap3/BAIAP3-related functions may help elucidate mechanisms underlying the development of both disorders.

Genetic Markers of a Munc13 Protein Family Member, BAIAP3, Are Gender Specifically Associated with Anxiety and Benzodiazepine Abuse in Mice and Humans

PubMed Central

Wojcik, Sonja M; Tantra, Martesa; Stepniak, Beata; Man, Kwun-nok M; Müller-Ribbe, Katja; Begemann, Martin; Ju, Anes; Papiol, Sergi; Ronnenberg, Anja; Gurvich, Artem; Shin, Yong; Augustin, Iris; Brose, Nils; Ehrenreich, Hannelore

2013-01-01

Anxiety disorders and substance abuse, including benzodiazepine use disorder, frequently occur together. Unfortunately, treatment of anxiety disorders still includes benzodiazepines, and patients with an existing comorbid benzodiazepine use disorder or a genetic susceptibility for benzodiazepine use disorder may be at risk of adverse treatment outcomes. The identification of genetic predictors for anxiety disorders, and especially for benzodiazepine use disorder, could aid the selection of the best treatment option and improve clinical outcomes. The brain-specific angiogenesis inhibitor I–associated protein 3 (Baiap3) is a member of the mammalian uncoordinated 13 (Munc13) protein family of synaptic regulators of neurotransmitter exocytosis, with a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, with the latter being more pronounced in female than in male animals. We hypothesized that genetic variation in human BAIAP3 may also be associated with anxiety. By using a phenotype-based genetic association study, we identified two human BAIAP3 single-nucleotide polymorphism risk genotypes (AA for rs2235632, TT for rs1132358) that show a significant association with anxiety in women and, surprisingly, with benzodiazepine abuse in men. Returning to mice, we found that male, but not female, Baiap3 knockout (KO) mice develop tolerance to diazepam more quickly than control animals. Analysis of cultured Baiap3 KO hypothalamus slices revealed an increase in basal network activity and an altered response to diazepam withdrawal. Thus, Baiap3/BAIAP3 is gender specifically associated with anxiety and benzodiazepine use disorder, and the analysis of Baiap3/BAIAP3-related functions may help elucidate mechanisms underlying the development of both disorders. PMID:23698091

Management of acute overdose or withdrawal state in intrathecal baclofen therapy.

PubMed

Watve, S V; Sivan, M; Raza, W A; Jamil, F F

2012-02-01

Individuals who are treated with intrathecal Baclofen (ITB) pump delivery system for intractable spasticity can suffer from severe morbidity as a result of acute overdose or withdrawal of ITB, which can also be life threatening. Current literature has a number of single case studies with different approaches to the management in such states. The aim of this article is to consolidate available evidence and develop treatment pathways for acute ITB overdose and withdrawal states. We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library databases using the keywords 'intrathecal', 'baclofen', 'withdrawal', 'overdose' to identify studies (published up to December 2010) that focused on presentation or treatment of acute overdose and withdrawal state in ITB therapy. Only original articles in English involving adult population were included. Initial search revealed 130 articles. After reading the abstract, 13 studies on ITB overdose and 23 studies on ITB withdrawal were deemed suitable for inclusion. All studies were either single-case studies or case series. Acute ITB overdose is managed with immediate cessation of baclofen delivery through the system, reducing the baclofen load by cerebrospinal fluid aspiration and by providing supportive treatment in an intensive care setting. There is no specific antidote for reversing overdose symptoms. Acute ITB withdrawal is managed by restoring the delivery of ITB, providing supportive care in an intensive care setting and using drugs like low dose propofol or benzodiazepines in selected cases. Early involvement of ITB physicians is strongly recommended.

Reasons for Benzodiazepine Use Among Persons Seeking Opioid Detoxification.

PubMed

Stein, Michael D; Kanabar, Mitika; Anderson, Bradley J; Lembke, Anna; Bailey, Genie L

2016-09-01

Over the past decade, patients admitted to addiction treatment programs have reported increasing rates of concurrent opioid and benzodiazepine (BZD) use. This drug combination places individuals at high risk for accidental overdose. Little is known about reasons for BZD use among individuals seeking treatment for opioid use disorders. We surveyed consecutive persons initiating inpatient opioid detoxification and identified 176 out of 438 who reported BZD use in the past 30 days and/or had a positive toxicology. Forty percent of persons surveyed used a BZD in the month prior to admission, and 25% of these met criteria for BZD dependence (DSM IV). BZD users averaged 32.0 years of age, 63.6% were male, 85.2% used heroin, and reported, on average, 13.3 (±11.2) days of BZD use during the past month. Alprazolam (Xanax) was the most commonly used BZD (52%), and buying it on the street the most common source (48%). The most commonly reported reason for BZD use was 'to manage anxiety' (42.6%), followed by 'to get or enhance a high' (27.7%), 'to help with sleep' (11.4%), and 'to decrease opioid withdrawal' (10.2%). The most common reason for BZD use was significantly associated (p<.001) with most likely source of BZDs, with persons who got their BZDs from a prescriber (23%) more likely to report BZD anxiety as their primary reason for use, while persons who bought BZDs on "the street" (48%) had the highest likelihood of reporting using BZD to get or enhance a high. Participants using BZDs most commonly for anxiety did not endorse lower anxiety than those using BZDs for other reasons. Two in five persons seeking detoxification for an opioid use disorder used a BZD in the prior month. Anxiety was the most common reason patients reported using a benzodiazepine, but they also reported using BZDs to enhance a 'high' and manage opioid withdrawal. Evidence-based discussions about the risks of combining BZDs and opioids, and alternatives to BZDs should be a high priority in

Contribution of prolonged-release melatonin and anti-benzodiazepine campaigns to the reduction of benzodiazepine and Z-drugs consumption in nine European countries.

PubMed

Clay, Emilie; Falissard, Bruno; Moore, Nicholas; Toumi, Mondher

2013-04-01

Benzodiazepines (BZD) and benzodiazepine receptor agonists (zolpidem, zaleplon, zopiclone, altogether Z-drugs) are most commonly prescribed for the treatment of insomnia. However, long-term use of BZD/Z-drugs is associated with major adverse events including, but not limited to, falls and fractures, domestic and traffic accidents, confusion, cognitive impairment, Alzheimer's disease and cancer. The prolonged use of these drugs is thought to be related to severe withdrawal symptoms and potential dependency. The chronic and extensive use of BZD/Z drugs has become a public health issue and has led to multiple campaigns to reduce both prescription and consumption of BZD/Z-drugs. Prolonged-release (PR) melatonin is the first of a new class of melatonin receptor agonist drugs that has demonstrated clinically relevant efficacy on improving quality of sleep and morning alertness, with a good safety profile. This study aimed to analyze and evaluate the impact of anti-BZD/Z-drugs campaigns and the availability of alternative pharmacotherapy (PR-melatonin) on the consumption of BZD and Z-drugs in several European countries. Annual sales data from nine European countries were extracted from the IMS sales database and analyzed to determine whether trends in use of these treatment options were attributed to campaigns and/or availability and affordability of safer alternatives on the market. Campaigns aiming to reduce the use of BZD/Z-drugs failed when they were not associated with the availability and market uptake of PR-melatonin. The reimbursement of PR-melatonin supports better penetration rates and a higher reduction in sales for BZD/Z-drugs.

Gamma-aminobutyric acid-modulated benzodiazepine binding sites in bacteria

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lummis, S.C.R.; Johnston, G.A.R.; Nicoletti, G.

1991-01-01

Benzodiazepine binding sites, which were once considered to exist only in higher vertebrates, are here demonstrated in the bacteria E. coli. The bacterial ({sup 3}H)diazepam binding sites are modulated by GABA; the modulation is dose dependent and is reduced at high concentrations. The most potent competitors of E.Coli ({sup 3}H)diazepam binding are those that are active in displacing ({sup 3}H)benzodiazepines from vertebrate peripheral benzodiazepine binding sites. These vertebrate sites are not modulated by GABA, in contrast to vertebrate neuronal benzodiazepine binding sites. The E.coli benzodiazepine binding sites therefore differ from both classes of vertebrate benzodiazepine binding sites; however the ligandmore » spectrum and GABA-modulatory properties of the E.coli sites are similar to those found in insects. This intermediate type of receptor in lower species suggests a precursor for at least one class of vertebrate benzodiazepine binding sites may have existed.« less

[Treatment of Alcohol Withdrawal Syndrome with Oxazepam or Clomethiazole - A Naturalistic Observational Study].

PubMed

Verthein, Uwe; Kuhn, Silke; Gabriel, Katrin; Mautsch, Ulrich; Reimer, Jens; Behrendt, Klaus

2018-03-01

Whilst internationally benzodiazepines are first choice for treatment of alcohol withdrawal syndrome, Germany has a long tradition with clomethiazole. This study explores effectiveness of clomethiazole versus oxazepam in the treatment of alcohol withdrawal syndrome within an observational, stratified, non-inferiority study in routine care. Main outcome criterion was severity of the alcohol withdrawal syndrome (Alcohol Withdrawal Syndrome [AWS]) Scale in the first five days. Additionally, the association between the detoxification protocol (five vs. ten days) and AWS-Score was examined. 453 patients (74.2 % male, average age 47.1 years [± 9.2]) took part; 249 received oxazepam (55.0 %) and 204 clomethiazole (45.0 %). The average duration of inpatient treatment was 14.0 days (± 6.3) in both groups. The average AWS-score was lower in the oxazepam group compared to the clomethiazole group (50.0 [± 26.5] vs. 56.2 [± 31.5]; p < .05; effect size d = - .25). Patients with a shorter detoxification protocol had a lower AWS sum score compared to patients with a longer protocol (p < .001; d = - .46). In treatment of alcohol withdrawal syndrome in routine care oxazepam yields at least comparable results to clomethiazole. © Georg Thieme Verlag KG Stuttgart · New York.

The use of benzodiazepines in depression

PubMed Central

Johnson, D. A. W.

1985-01-01

1 In clinical practice the benzodiazepines are prescribed almost as frequently as the tricyclic antidepressants for the treatment of depression. 2 The therapeutic effects of the benzodiazepines and tricyclic antidepressants in depression have been compared in only 29 double-blind studies. The antidepressants proved overwhelmingly superior with only one study (alprazolam) even suggesting a possible parity of action. 3 A symptom response analysis failed to show any true antidepressant action for the benzodiazepines. 4 No clear indication for the use of a combination of drugs was revealed, although certain symptoms may show a more rapid response initially with combination therapy. PMID:2859876

[Clinical choice of a benzodiazepine].

PubMed

Villeneuve, A

1983-01-01

If the differential specific anxiolytic activity between various benzodiazepines remains controverted , the clinician nevertheless now possesses scientific data allowing him to make a more rational selection, in order to obtain a better overall efficacy, either for an anxiolytic or hypnotic action. In other respects, the concept of anxiety has evolved and given rise to distinctions that will need to be taken into account in the choice of the adequate psychotropic medication, either a benzodiazepine or another psychotropic drug. When a benzodiazepine must be prescribed, the main criteria involved in its choice need to be considered. As anxiolytic medication, besides a selective action on anxiety, the absence of cumbersome effect on psychomotor activity and vigilance, pharmacokinetics constitute an important factor that must be looked at. Although the classification of benzodiazepines according to their half-life is only an approximation, some overlapping being possible between the various groups, it proves nevertheless extremely useful with respect to the therapeutic goal considered and the various clinical parameters involved. Some other aspects must also be considered, for example the rebound phenomenon. Finally, the variability of individual responses to drug treatment must be remembered.

Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2

PubMed Central

Abulseoud, Osama A; Camsari, Ulas M; Ruby, Christina L; Kasasbeh, Aimen; Choi, Sun; Choi, Doo-Sup

2014-01-01

Alcohol withdrawal syndrome (AWS) is a potentially fatal outcome of severe alcohol dependence that presents a significant challenge to treatment. Although AWS is thought to be driven by a hyperglutamatergic brain state, benzodiazepines, which target the GABAergic system, comprise the first line of treatment for AWS. Using a rat model of ethanol withdrawal, we tested whether ceftriaxone, a β-lactam antibiotic known to increase the expression and activity of glutamate uptake transporter EAAT2, reduces the occurrence or severity of ethanol withdrawal manifestations. After a 2-week period of habituation to ethanol in two-bottle choice, alcohol-preferring (P) and Wistar rats received ethanol (4.0 g/kg) every 6 h for 3–5 consecutive days via gavage. Rats were then deprived of ethanol for 48 h during which time they received ceftriaxone (50 or 100 mg/kg, IP) or saline twice a day starting 12 h after the last ethanol administration. Withdrawal manifestations were captured by continuous video recording and coded. The evolution of ethanol withdrawal was markedly different for P rats vs Wistar rats, with withdrawal manifestations occurring >12 h later in P rats than in Wistar rats. Ceftriaxone 100 mg/kg per injection twice per day (200 mg/kg/day) reduced or abolished all manifestations of ethanol withdrawal in both rat variants and prevented withdrawal-induced escalation of alcohol intake. Finally, ceftriaxone treatment was associated with lasting upregulation of ethanol withdrawal-induced downregulation of EAAT2 in the striatum. Our data support the role of ceftriaxone in alleviating alcohol withdrawal and open a novel pharmacologic avenue that requires clinical evaluation in patients with AWS. PMID:24452391

21 CFR 862.3170 - Benzodiazepine test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862... benzodiazepine use or overdose and in monitoring levels of benzodiazepines to ensure appropriate therapy. (b...

Craving and nicotine withdrawal in a Spanish smoking cessation sample.

PubMed

Piñeiro, Bárbara; López-Durán, Ana; Fernández del Río, Elena; Martínez, Úrsula; Brandon, Thomas H; Becoña, Elisardo

2014-01-01

Craving and nicotine withdrawal syndrome (NWS) are components of the tobacco use disorder in DSM-5. They both appear after smoking cessation or an abrupt reduction in tobacco use, and they are associated with both short and long-term smoking-cessation outcomes. The aim of the present study was to examine the association of craving and withdrawal with smoking cessation at the end of the treatment and relapse at 3 months follow-up in a Spanish sample of smokers. The sample comprised 342 smokers (37.7% men; 62.3% women) receiving a cognitive-behavioral treatment for smoking cessation. The assessments of craving and withdrawal were conducted using the Minnesota Nicotine Withdrawal Scale. Abstainers at the end of the treatment, compared to non abstainers, showed significantly lower post-treatment withdrawal, and post-treatment craving. Furthermore, they had lower scores in pre-treatment nicotine dependence. Among abstainers, craving decreased significantly from pre-cessation levels, while in those participants who did not quit smoking it remained on the same levels. High nicotine dependence was a predictor of smoking at the end of the treatment, whereas high nicotine withdrawal predicted relapse at 3 months. Findings support the robust role of craving and NWS in smoking cessation and relapse, although they differ in their specific patterns of change over time.

Levetiracetam for the treatment of alcohol withdrawal syndrome: a multicenter, prospective, randomized, placebo-controlled trial.

PubMed

Richter, Christoph; Hinzpeter, Axel; Schmidt, Folkhard; Kienast, Thorsten; Preuss, Ulrich W; Plenge, Thomas; Heinz, Andreas; Schaefer, Martin

2010-12-01

Treatment of alcohol withdrawal syndrome (AWS) with benzodiazepines is limited by risk of abuse, intoxication, respiratory problems, and liver toxicity. Alternatives such as carbamazepine and valproate may also have safety problems, such as hepatotoxicity or central nervous adverse effects. We therefore investigated the safety and efficacy of levetiracetam (LV), a newer antiepileptic with a potentially favorable adverse-effect profile, for the treatment of AWS. One hundred six patients were enrolled in a prospective, randomized, double-blind, multicenter, placebo-controlled trial. Levetiracetam was administered in a fixed dose schedule over 6 days. Diazepam was added when symptom triggered as rescue medication. Severity of the AWS was measured with the AWS and Clinical Institute Withdrawal Assessment Scale. Although tolerability and safety data were similar in the LV group when compared with placebo, the total daily and weekly dose of diazepam as rescue medication and the severity of alcohol withdrawal symptoms did not differ significantly between groups. Our data so far do not support an additional effect of LV on the reduction of alcohol withdrawal symptoms.

Alprazolam is relatively more toxic than other benzodiazepines in overdose

PubMed Central

Isbister, Geoffrey K; O'Regan, Luke; Sibbritt, David; Whyte, Ian M

2004-01-01

Aims To describe alprazolam poisoning and the relative toxicity of alprazolam compared with other benzodiazepines. Methods A database of consecutive poisoning admissions to a regional toxicology service was searched to identify consecutive benzodiazepine deliberate self poisonings, which were coded as alprazolam, diazepam or other benzodiazepine. Major outcomes used were length of stay (LOS), intensive care (ICU) admission, coma (GCS < 9), flumazenil administration and requirement for mechanical ventilation. Prescription data were obtained for benzodiazepines for the study period. Results There were 2063 single benzodiazepine overdose admissions: 131 alprazolam overdoses, 823 diazepam overdoses and 1109 other benzodiazepine overdoses. The median LOS for alprazolam overdoses was 19 h which was 1.27 (95% CI 1.04, 1.54) times longer compared with other benzodiazepines by multiple linear regression. For patients with alprazolam overdoses, 22% were admitted to ICU which was 2.06 (95% CI 1.27, 3.33) times more likely compared with other benzodiazepines after multivariate analysis adjusting for age, dose, gender, time to ingestion and co-ingested drugs. Flumazenil was administered to 14% of alprazolam patients and 16% were ventilated, which was significantly more than for other benzodiazepine overdoses (8% and 11%, respectively). Twelve percent of alprazolam overdoses had a GCS < 9 compared with 10% for other benzodiazepines. From benzodiazepine prescription data, total alprazolam prescriptions in Australia increased from 0.13 million in 1992 to 0.41 million in 2001. Eighty five percent of prescriptions were for panic disorder, anxiety, depression or mixed anxiety/depression. Conclusions Alprazolam was significantly more toxic than other benzodiazepines. The increased prescription of alprazolam to groups with an increased risk of deliberate self poisoning is concerning and needs review. PMID:15206998

Non-convulsive status epilepticus resistant to benzodiazepines.

PubMed Central

Livingston, J H; Brown, J K

1987-01-01

We describe the failure of an intravenous benzodiazepine to control non-convulsive status epilepticus occurring in six patients with the Lennox-Gastaut syndrome. In one patient the benzodiazepine induced a paradoxical response with clinical and electroencephalographic seizures. PMID:3545098

Benzodiazepine use and aggressive behaviour: a systematic review.

PubMed

Albrecht, Bonnie; Staiger, Petra K; Hall, Kate; Miller, Peter; Best, David; Lubman, Dan I

2014-12-01

The relationship between benzodiazepine consumption and subsequent increases in aggressive behaviour in humans is not well understood. The current study aimed to identify, via a systematic review, whether there is an association between benzodiazepine consumption and aggressive responding in adults. A systematic review was conducted and reported in line with the PRISMA statement. English articles within MEDLINE, PsycARTICLES, PsycINFO, Academic Search Complete, and Psychology and Behavioural Sciences Collection databases were searched. Additional studies were identified by searching reference lists of reviewed articles. Only articles that explicitly investigated the relationship between benzodiazepine consumption and subsequent aggressive behaviour, or a lack thereof, in human adults were included. Forty-six studies met the inclusion criteria. It was not possible to conduct a meta-analysis due to the heterogeneity of study design and benzodiazepine type and dose. An association between benzodiazepine use and subsequent aggressive behaviour was found in the majority of the more rigorous studies, although there is a paucity of high-quality research with clinical or forensic populations. Diazepam and alprazolam have received the most attention. Dose-related findings are inconsistent: therapeutic doses may be more likely to be associated with aggressive responding when administered as a once-off, whereas higher doses may be more risky following repeated administration. Trait levels of anxiety and hostility may indicate a vulnerability to the experience of benzodiazepine-related aggression. There appears to be a moderate association between some benzodiazepines and subsequent aggressive behaviour in humans. The circumstances under which aggressive responding may be more likely to follow benzodiazepine use remain unclear, although some evidence suggests dose and/or personality factors may influence this effect. © The Royal Australian and New Zealand College of

Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses.

PubMed

Leone, Maurizio A; Vigna-Taglianti, Federica; Avanzi, Giancarlo; Brambilla, Romeo; Faggiano, Fabrizio

2010-02-17

Chronic excessive alcohol consumption may lead to dependence, and to alcohol withdrawal syndrome (AWS) in case of abrupt drinking cessation. Gamma-hydroxybutyric acid (GHB) can prevent and suppress withdrawal symptoms, and improve the medium-term abstinence rate. A clear balance between effectiveness and harmfulness has not been yet established. To evaluate the efficacy and safety of GHB for treatment of AWS and prevention of relapse We searched Cochrane Drugs and Alcohol Group' Register of Trials (October 2008), PubMed, EMBASE, CINAHL (January 2005 - October 2008), EconLIT (1969 to February 2008), reference list of retrieved articles Randomized controlled trials (RCTs) and Controlled Prospective Studies (CPS) evaluating the efficacy and the safety of GHB vs placebo or other pharmacological treatments. Three authors independently extracted data and assessed the methodological quality of studies. Thirteen RCTs were included. Eleven studies were conducted in Italy.For withdrawal syndrome, comparing GHB 50mg with placebo, results from 1 study, 23 participants favour GHB for withdrawal symptoms: WMD -12.1 (95% CI, -15.9 to -8.29) and side effects were more frequent in the placebo group: RR 16.2 (95% CI, 1.04 to 254.9).In the comparison with Chlormetiazole, for GHB 50mg, results from 1 study, 21 participants favour GHB for withdrawal symptoms: MD -3.40 (95% CI -5.09 to -1.71), for GHB 100mg, results from 1 study, 98 participants favour anticonvulsants for side effects: RR 1.84 (95% CI 1.19 to 2.85).At mid-term, comparing GHB with placebo, results favour GHB for abstinence rate (RR 5.35; 1.28-22.4), controlled drinking (RR 2.13; 1.07-5.54), relapses (RR 0.36; 0.21-0.63), and number of daily drinks (WMD -4.60; -6.18 to -3.02). GHB performed better than NTX and Disulfiram on abstinence (RR 2.59; 1.35-4.98, RR 1.66; 0.99-2.80 respectively). The association of GHB and NTX was better than NTX on abstinence (RR 12.2; 1.79-83.9), as well was the association of NTX, GHB and

Chronic agmatine treatment prevents behavioral manifestations of nicotine withdrawal in mice.

PubMed

Kotagale, Nandkishor R; Chopde, Chandrabhan T; Umekar, Milind J; Taksande, Brijesh G

2015-05-05

Smoking cessation exhibits an aversive withdrawal syndrome characterized by both increases in somatic signs and affective behaviors including anxiety and depression. In present study, abrupt withdrawal of daily nicotine injections (2mg/kg, s.c., four times daily, for 10 days) significantly increased somatic signs viz. rearing, grooming, jumping, genital licking, leg licking, head shakes with associated depression (increased immobility in forced swim test) as well as anxiety (decreased the number of entries and time spent in open arm in elevated plus maze) in nicotine dependent animals. The peak effect was observed at 24h time point of nicotine withdrawal. Repeated administration of agmatine (40-80µg/mouse, i.c.v.) before the first daily dose of nicotine from day 5 to 10 attenuated the elevated scores of somatic signs and abolished the depression and anxiety like behavior induced by nicotine withdrawal in dependent animals. However, in separate groups, its acute administration 30min before behavior analysis of nicotine withdrawal was ineffective. This result clearly shows the role of agmatine in development of nicotine dependence and its withdrawal. In extension to behavioral experiments, brain agmatine analyses, carried out at 24h time point of nicotine withdrawal demonstrated marked decrease in basal brain agmatine concentration as compared to control animals. Taken together, these data support the role of agmatine as common biological substrate for somatic signs and affective symptoms of nicotine withdrawal. This data may project therapies based on agmatine in anxiety, depression and mood changes associated with tobacco withdrawal. Copyright © 2015 Elsevier B.V. All rights reserved.

Prescribing of benzodiazepines by casualty officers.

PubMed Central

Nazareth, I D; King, M B

1989-01-01

The prescribing of benzodiazepines by casualty officers in a busy district hospital over a three month period was examined by a retrospective review of case notes. Benzodiazepines, mainly diazepam, were given to 1.1% of attenders, the majority of whom had disorders involving minor muscle spasm. The efficacy of diazepam in these conditions, as well as its potential for dependence, is discussed. PMID:2569040

Modeling the Fluid Withdraw and Injection Induced Earthquakes

NASA Astrophysics Data System (ADS)

Meng, C.

2016-12-01

We present an open source numerical code, Defmod, that allows one to model the induced seismicity in an efficient and standalone manner. The fluid withdraw and injection induced earthquake has been a great concern to the industries including oil/gas, wastewater disposal and CO2 sequestration. Being able to numerically model the induced seismicity is long desired. To do that, one has to consider at lease two processes, a steady process that describes the inducing and aseismic stages before and in between the seismic events, and an abrupt process that describes the dynamic fault rupture accompanied by seismic energy radiations during the events. The steady process can be adequately modeled by a quasi-static model, while the abrupt process has to be modeled by a dynamic model. In most of the published modeling works, only one of these processes is considered. The geomechanicists and reservoir engineers are focused more on the quasi-static modeling, whereas the geophysicists and seismologists are focused more on the dynamic modeling. The finite element code Defmod combines these two models into a hybrid model that uses the failure criterion and frictional laws to adaptively switch between the (quasi-)static and dynamic states. The code is capable of modeling episodic fault rupture driven by quasi-static loading, e.g. due to reservoir fluid withdraw and/or injection, and by dynamic loading, e.g. due to the foregoing earthquakes. We demonstrate a case study for the 2013 Azle earthquake.

[Smoking abstinence rate and its associated factors between abrupt and gradual smoking cessation].

PubMed

Hao, R; Zhou, J P; Ni, L; Li, Q Y; Shi, G C

2017-12-12

Objective: To analyze and compare the abstinence rate of smoking quitting methods and its associated factors between abrupt and gradual smoking cessation in smokers with drug-based therapy. Methods: A prospective clinical study was conducted in patients undergoing quitting smoking intervention in Ruijin Hospital smoking cessation clinic between June 2013 and May 2016. All the subjects were randomized in a 1∶1 ratio into the abrupt smoking cessation group (smoking as usual over 3 weeks before a planned quit day, and then stopping smoking abruptly) and the gradual smoking cessation group (gradually reducing tobacco use over 3 weeks before a planned quit day, and then stopping smoking totally). The primary outcome was the complete abstinence rate, and the secondary outcomes included 1-month, 3-month and 6 month 7-day point prevalence of abstinence rates and 3 month sustained abstinence rates. Changes of body weight and drug adverse events were also compared. Results: A total of 314 moderate to severe nicotine-dependent patients were admitted in the study, including 157 patients in the abrupt smoking cessation and 157 patients in the gradual smoking cessation group. Fourteen patients fell off during the follow-up. For the complete abstinence rate, the gradual smoking cessation group was higher than the abrupt smoking cessation group(55.0% vs . 36.9%, χ(2)=9.841, P =0.002) .For 7-d smoking abstinence rate in the 1st, 3rd, 6th month, there was no significant difference between the 2 groups (all P >0.05). As for the 3-month sustained abstinence rate, a higher smoking quitting rate was seen in the gradual smoking cessation group compared to the abrupt smoking cessation group in the 6-month follow-up (17.9% vs .8.7%, χ(2)=5.441, P =0.020). The adverse drug reaction incidence was higher in the abrupt smoking cessation group than the gradual smoking cessation group (Gastrointestinal discomfort: 39.2% vs . 17.7%, χ(2)=12.336, P =0.000; Dreaminess: 40.2% vs . 13.3%, χ(2

[Benzodiazepines in the treatment of anxiety].

PubMed

Boulenger, J P; Pellet, V; Zarifian, E

1991-09-28

During the last ten years, the treatment of anxiety disorders has changed considerably. Cognitive-behavioural therapies and new chemotherapies have been added to benzodiazepine therapy and psychotherapy which for a long time had been the only treatment of these frequent and invalidating disorders. Recent reports of possible drawbacks in prolonged benzodiazepine therapy provide another reason to reconsider the indications of these drugs now that other drugs are available. Benzodiazepines remain the treatment of choice for recent anxiety states requiring some degree of sedation and rapid relief, but their long-term administration should be reserved to patients who did not respond to other treatments. The authors propose several guidelines for a better prescription of these anxiolytic agents and for more rational indications taking into account the advantages of other available treatments.

Micromolar-Affinity Benzodiazepine Receptors Regulate Voltage-Sensitive Calcium Channels in Nerve Terminal Preparations

NASA Astrophysics Data System (ADS)

Taft, William C.; Delorenzo, Robert J.

1984-05-01

Benzodiazepines in micromolar concentrations significantly inhibit depolarization-sensitive Ca2+ uptake in intact nerve-terminal preparations. Benzodiazepine inhibition of Ca2+ uptake is concentration dependent and stereospecific. Micromolar-affinity benzodiazepine receptors have been identified and characterized in brain membrane and shown to be distinct from nanomolar-affinity benzodiazepine receptors. Evidence is presented that micromolar, and not nanomolar, benzodiazepine binding sites mediate benzodiazepine inhibition of Ca2+ uptake. Irreversible binding to micromolar benzodiazepine binding sites also irreversibly blocked depolarization-dependent Ca2+ uptake in synaptosomes, indicating that these compounds may represent a useful marker for identifying the molecular components of Ca2+ channels in brain. Characterization of benzodiazepine inhibition of Ca2+ uptake demonstrates that these drugs function as Ca2+ channel antagonists, because benzodiazepines effectively blocked voltage-sensitive Ca2+ uptake inhibited by Mn2+, Co2+, verapamil, nitrendipine, and nimodipine. These results indicate that micromolar benzodiazepine binding sites regulate voltage-sensitive Ca2+ channels in brain membrane and suggest that some of the neuronal stabilizing effects of micromolar benzodiazepine receptors may be mediated by the regulation of Ca2+ conductance.

Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations.

PubMed Central

Taft, W C; DeLorenzo, R J

1984-01-01

Benzodiazepines in micromolar concentrations significantly inhibit depolarization-sensitive Ca2+ uptake in intact nerve-terminal preparations. Benzodiazepine inhibition of Ca2+ uptake is concentration dependent and stereospecific. Micromolar-affinity benzodiazepine receptors have been identified and characterized in brain membrane and shown to be distinct from nanomolar-affinity benzodiazepine receptors. Evidence is presented that micromolar, and not nanomolar, benzodiazepine binding sites mediate benzodiazepine inhibition of Ca2+ uptake. Irreversible binding to micromolar benzodiazepine binding sites also irreversibly blocked depolarization-dependent Ca2+ uptake in synaptosomes, indicating that these compounds may represent a useful marker for identifying the molecular components of Ca2+ channels in brain. Characterization of benzodiazepine inhibition of Ca2+ uptake demonstrates that these drugs function as Ca2+ channel antagonists, because benzodiazepines effectively blocked voltage-sensitive Ca2+ uptake inhibited by Mn2+, Co2+, verapamil, nitrendipine, and nimodipine. These results indicate that micromolar benzodiazepine binding sites regulate voltage-sensitive Ca2+ channels in brain membrane and suggest that some of the neuronal stabilizing effects of micromolar benzodiazepine receptors may be mediated by the regulation of Ca2+ conductance. PMID:6328498

The impact of benzodiazepine use on methadone maintenance treatment outcomes.

PubMed

Brands, Bruna; Blake, Joan; Marsh, David C; Sproule, Beth; Jeyapalan, Renuka; Li, Selina

2008-01-01

The purposes of this study were to examine predictors of benzodiazepine use among methadone maintenance treatment patients, to determine whether baseline benzodiazepine use influenced ongoing use during methadone maintenance treatment, and to assess the effect of ongoing benzodiazepine use on treatment outcomes (i.e., opioid and cocaine use and treatment retention). A retrospective chart review of 172 methadone maintenance treatment patients (mean age = 34.6 years; standard deviation = 8.5 years; 64% male) from January 1997 to December 1999 was conducted. At baseline, 29% were "non-users" (past year) of benzodiazepine, 36% were "occasional users," and 35% were "regular/problem users." Regular/problem users were more likely to have started opioid use with prescription opioids, experienced more overdoses, and reported psychiatric comorbidity. Being female, more years of opioid use, and a history of psychiatric treatment were significant predictors of baseline benzodiazepine use. Ongoing benzodiazepine users were more likely to have opioid-positive and cocaine-positive urine screens during methadone maintenance treatment. Only ongoing cocaine use was negatively related to retention. Benzodiazepine use by methadone maintenance treatment patients is associated with a more complex clinical picture and may negatively influence treatment outcomes.

Catatonia Secondary to Sudden Clozapine Withdrawal: A Case with Three Repeated Episodes and a Literature Review

PubMed Central

Bilbily, John; McCollum, Betsy

2017-01-01

A literature search identified 9 previously published cases that were considered as possible cases of catatonia secondary to sudden clozapine withdrawal. Two of these 9 cases did not provide enough information to make a diagnosis of catatonia according to the Diagnostic and Statistical Manual, 5th Edition (DSM-5). The Liverpool Adverse Drug Reaction (ADR) Causality Scale was modified to assess ADRs secondary to drug withdrawal. From the 7 published cases which met DSM-5 catatonia criteria, using the modified scale, we established that 3 were definitive and 4 were probable cases of catatonia secondary to clozapine withdrawal. A new definitive case is described with three catatonic episodes which (1) occurred after sudden discontinuation of clozapine in the context of decades of follow-up, (2) had ≥3 of 12 DSM-5 catatonic symptoms and serum creatinine kinase elevation, and (3) required medical hospitalization and intravenous fluids. Clozapine may be a gamma-aminobutyric acid (GABA) receptor agonist; sudden clozapine withdrawal may explain a sudden decrease in GABA activity that may contribute to the development of catatonic symptoms in vulnerable patients. Based on the limited information from these cases, the pharmacological treatment for catatonia secondary to sudden clozapine withdrawal can include benzodiazepines and/or restarting clozapine. PMID:28396815

Self-perceived motivation for benzodiazepine use and behavior related to benzodiazepine use among opiate-dependent patients.

PubMed

Fatséas, Mélina; Lavie, Estelle; Denis, Cécile; Auriacombe, Marc

2009-12-01

Clinical observations have shown a high prevalence of benzodiazepine use among opiate-dependent patients. Our objective was to identify if distinct patterns of behavior could be associated with three different self-perceived motivations for benzodiazepine use: (a) exclusive self-therapeutic motivation, (b) exclusive hedonic motivation, and (c) combined self-therapeutic and hedonic motivation. Data were collected through a self-administered questionnaire in 92 opiate users in treatment in France (Aquitaine). The behaviors associated with exclusive self-therapeutic motivation included the search for an anxiolytic effect, oral administration, use within the context of a medical prescription, and use without other substances. The behaviors associated with exclusive hedonic motivation were use in combination with other substances, the obtaining of benzodiazepines by the black market, and use of other routes of administration in search of a "blackout." Among patients who reported both motivations, there were distinct trends of behavior according to motivation.

Antidepressants and benzodiazepines for panic disorder in adults.

PubMed

Bighelli, Irene; Trespidi, Carlotta; Castellazzi, Mariasole; Cipriani, Andrea; Furukawa, Toshi A; Girlanda, Francesca; Guaiana, Giuseppe; Koesters, Markus; Barbui, Corrado

2016-09-12

A panic attack is a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. Panic disorder is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, antidepressants and benzodiazepines are the mainstay of treatment for panic disorder. Different classes of antidepressants have been compared; and the British Association for Psychopharmacology, and National Institute for Health and Care Excellence (NICE) consider antidepressants (mainly selective serotonin reuptake inhibitors (SSRIs)) as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). In addition to antidepressants, benzodiazepines are widely prescribed for the treatment of panic disorder. To assess the evidence for the effects of antidepressants and benzodiazepines for panic disorder in adults. The Specialised Register of the Cochrane Common Mental Disorders Group (CCMDCTR) to 11 September 2015. This register includes relevant randomised controlled trials from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950-), Embase (1974-) and PsycINFO (1967-). Reference lists of relevant papers and previous systematic reviews were handsearched. We contacted experts in this field for supplemental data. All double-blind randomised controlled trials allocating adult patients with panic disorder to antidepressants or benzodiazepines versus any other active treatment with antidepressants or benzodiazepines. Two review authors independently checked eligibility and extracted data using a standard form. Data were

What can be learned from the effects of benzodiazepines on exploratory behavior?

PubMed

File, S E

1985-01-01

The purpose of this review is to assess the value of using tests of exploratory behavior to study the actions of benzodiazepines. The methods of measuring exploration and the factors influencing it are briefly described. The effects of benzodiazepines on exploratory behavior of rats and mice are reviewed; and the dangers of interpreting the results of such tests in terms of any of the clinical effects of the benzodiazepines is stressed. Finally, the interactions between benzodiazepines and other drugs acting at the GABA-benzodiazepine receptor complex are described. The results of these experiments caution against global classification of compounds as benzodiazepine "antagonists."

A novel non-opioid protocol for medically supervised opioid withdrawal and transition to antagonist treatment.

PubMed

Rudolf, Gregory; Walsh, Jim; Plawman, Abigail; Gianutsos, Paul; Alto, William; Mancl, Lloyd; Rudolf, Vania

2018-01-01

The clinical feasibility of a novel non-opioid and benzodiazepine-free protocol was assessed for the treatment of medically supervised opioid withdrawal and transition to subsequent relapse prevention strategies. A retrospective chart review of DSM-IV diagnosed opioid-dependent patients admitted for inpatient medically supervised withdrawal examined 84 subjects (52 males, 32 females) treated with a 4-day protocol of scheduled tizanidine, hydroxyzine, and gabapentin. Subjects also received ancillary medications as needed, and routine counseling. Primary outcomes were completion of medically supervised withdrawal, and initiation of injectable extended release (ER) naltrexone treatment. Secondary outcomes included the length of hospital stay, Clinical Opiate Withdrawal Scale (COWS) scores, and facilitation to substance use disorder treatment intervention. Ancillary medication use and adverse effects were also assessed. A total of 79 (94%) of subjects completed medically supervised withdrawal. A total of 27 (32%) subjects chose to pursue transition to ER naltrexone, and 24 of the 27 (89%) successfully received the injection prior to hospital discharge. The protocol subjects had a mean length of hospital stay of 3.6 days, and the mean COWS scores was 3.3, 3.4, 2.8, and 2.4 on Day 1, 2, 3, and 4, respectively. Furthermore, 71 (85%) engaged in an inpatient or outpatient substance use disorder (SUD) treatment program following protocol completion. This retrospective chart review suggests the feasibility of a novel protocol for medically supervised opioid withdrawal and transition to relapse prevention strategies, including injectable ER naltrexone. This withdrawal protocol does not utilize opioid agonists or other controlled substances.‬‬‬‬.

Acamprosate attenuates the handling induced convulsions during alcohol withdrawal in Swiss Webster mice

PubMed Central

Farook, Justin M.; Krazem, Ali; Littleton, John M.; Barron, Susan

2008-01-01

In the present study, we examined the effects of acamprosate for its ability to reduce handling induced convulsions (HICs) during alcohol withdrawal. Diazepam was used as a positive control. Swiss Webster male mice received three daily IP injections of alcohol (2.5 g/kg) or alcohol (2.5 g/kg) + methylpyrazole (4-MP) (9 mg/kg). (4-MP, being an alcohol dehydrogenase inhibitor slows down the breakdown of alcohol. 4-MP in combination with alcohol exhibits a dramatic increase in blood alcohol level compared to alcohol alone). Ten hours following the last alcohol injection, the mice were picked up by the tail and examined for their seizure susceptibility (HICs). Diazepam, a benzodiazepine known to reduce seizures during alcohol withdrawal, significantly reduced these HICs at doses of 0.25, 0.5 and 1mg/kg (p’s < 0.001). Acamprosate, an anti-relapse compound used clinically in newly abstinent alcoholics, also reduced these HICs at doses of 100, 200 and 300mg/kg (p’s < 0.05). This study supports the use of acamprosate during periods of alcohol withdrawal as well as during abstinence. PMID:18577392

Benzodiazepine sensitivity in normal human subjects.

PubMed

Hommer, D W; Matsuo, V; Wolkowitz, O; Chrousos, G; Greenblatt, D J; Weingartner, H; Paul, S M

1986-06-01

Increasing intravenous doses of diazepam or placebo were administered to ten healthy normal volunteers, and the changes in saccadic eye velocity, self-rated sedation and anxiety, and plasma cortisol and growth hormone concentrations were measured. Diazepam administration (4.4 to 140 micrograms/kg, cumulative dose) resulted in a dose-dependent decrease in saccadic eye velocity and plasma cortisol level as well as a dose-dependent increase in self-rated sedation and plasma growth hormone level. Self-rated anxiety was unaffected in these relatively nonanxious subjects. The diazepam-induced changes in saccadic eye velocity, sedation, and growth hormone and cortisol levels were highly correlated with each other and with increasing plasma diazepam concentration. These results are consistent with a benzodiazepine receptor-mediated action of diazepam. The highly quantifiable and dose-dependent decrease in saccadic eye velocity by benzodiazepines should make this a useful measure of benzodiazepine receptor sensitivity in humans.

Did the new French pay-for-performance system modify benzodiazepine prescribing practices?

PubMed

Rat, Cédric; Penhouet, Gaëlle; Gaultier, Aurélie; Chaslerie, Anicet; Pivette, Jacques; Nguyen, Jean Michel; Victorri-Vigneau, Caroline

2014-07-11

French general practitioners (GPs) were enrolled in a new payment system in January 2012. As part of a national agreement with the French National Ministry of Health, GPs were asked to decrease the proportion of patients who continued their benzodiazepine treatment 12 weeks after its initiation and to decrease the proportion of patients older than 65 who were prescribed long half-life benzodiazepines. In return, GPs could expect an extra payment of up to 490 euros per year. This study reports the evolution of the corresponding prescribing practices of French GPs during that period regarding patients who were prescribed a benzodiazepine for the first time. The national healthcare system's administrative database was used to report the longitudinal follow-up of two historical cohorts of French patients from the Pays de la Loire area. The "2011" and "2012" cohorts included all patients who initiated benzodiazepine regimens from April 1 to June 30 in 2011 and 2012, respectively.The primary outcomes were the proportion of those study patients who continued benzodiazepine treatment after 12 weeks and the proportion of study patients >65 years who were prescribed long half-life benzodiazepines.Analyses were performed using a multi-level regression. In total, 41,436 and 42,042 patients initiated benzodiazepine treatment in 2011 and 2012, respectively. A total of 18.97% of patients continued treatment for more than 12 weeks in 2012, compared with 18.18% in 2011. In all, 27.43% and 28.06% of patients >65 years continued treatment beyond 12 weeks in 2011 and 2012, respectively. The proportion of patients >65 years who were prescribed long half-life benzodiazepines decreased from 53.5% to 48.8% (p < 0.005) due to an increase in short half-life benzodiazepine prescriptions. Patients >65 years who were prescribed short half-life benzodiazepines were more likely to continue treatment after 12 weeks (p < 0.005). Despite the pay-for-performance strategy, the number of short half

Using Tutte polynomials to analyze the structure of the benzodiazepines

NASA Astrophysics Data System (ADS)

Cadavid Muñoz, Juan José

2014-05-01

Graph theory in general and Tutte polynomials in particular, are implemented for analyzing the chemical structure of the benzodiazepines. Similarity analysis are used with the Tutte polynomials for finding other molecules that are similar to the benzodiazepines and therefore that might show similar psycho-active actions for medical purpose, in order to evade the drawbacks associated to the benzodiazepines based medicine. For each type of benzodiazepines, Tutte polynomials are computed and some numeric characteristics are obtained, such as the number of spanning trees and the number of spanning forests. Computations are done using the computer algebra Maple's GraphTheory package. The obtained analytical results are of great importance in pharmaceutical engineering. As a future research line, the usage of the chemistry computational program named Spartan, will be used to extent and compare it with the obtained results from the Tutte polynomials of benzodiazepines.

Correlates of benzodiazepine use in major depressive disorder: The effect of anhedonia.

PubMed

Rizvi, Sakina J; Sproule, Beth A; Gallaugher, Laura; McIntyre, Roger S; Kennedy, Sidney H

2015-11-15

Current treatment guidelines emphasize the limited role of benzodiazepines in Major Depressive Disorder (MDD), mainly due to the absence of long-term data, risk of abuse and potential adverse effects. However, benzodiazepines continue to be prescribed for long-term use in a significant number of patients. This study sought to evaluate benzodiazepine use in a large sample of MDD patients seen at a tertiary care clinic, and determine whether use is related to illness severity or complexity, as well as to identify the clinical predictors of benzodiazepine use. This was a naturalistic cross-sectional study conducted in MDD patients seen at the Mood Disorders Pyschopharmacology Unit at the University Health Network (N=326). Detailed information on current medication regimens was collected. A structured diagnostic interview, in addition to measures of symptom severity, quality of life, and personality were administered. Participants were grouped according to the presence or absence of prescribed benzodiazepines for daily use. The prevalence of regular benzodiazepine use was 25%. Benzodiazepine users were more likely to be female, unemployed, have a history of child abuse, and have comorbid panic disorder. Depression and anxiety scores were not significantly different between groups, although anhedonia was greater in the benzodiazepine group. A logistic regression revealed anhedonia was the strongest predictor of regular benzodiazepine use. The groups were similar in clinical profile suggesting benzodiazepine use is not necessarily linked to greater illness complexity or severity. Benzodiazepine use appears to be associated with specific diagnostic and symptom characteristics, possibly providing insight into the potential pharmacodynamic and neurobiological effects of frequent use. Copyright © 2015 Elsevier B.V. All rights reserved.

Analytical methodologies for the determination of benzodiazepines in biological samples.

PubMed

Persona, Karolina; Madej, Katarzyna; Knihnicki, Paweł; Piekoszewski, Wojciech

2015-09-10

Benzodiazepine drugs belong to important and most widely used medicaments. They demonstrate such therapeutic properties as anxiolytic, sedative, somnifacient, anticonvulsant, diastolic and muscle relaxant effects. However, despite the fact that benzodiazepines possess high therapeutic index and are considered to be relatively safe, their use can be dangerous when: (1) co-administered with alcohol, (2) co-administered with other medicaments like sedatives, antidepressants, neuroleptics or morphine like substances, (3) driving under their influence, (4) using benzodiazepines non-therapeutically as drugs of abuse or in drug-facilitated crimes. For these reasons benzodiazepines are still studied and determined in a variety of biological materials. In this article, sample preparation techniques which have been applied in analysis of benzodiazepine drugs in biological samples have been reviewed and presented. The next part of the article is focused on a review of analytical methods which have been employed for pharmacological, toxicological or forensic study of this group of drugs in the biological matrices. The review was preceded by a description of the physicochemical properties of the selected benzodiazepines and two, very often coexisting in the same analyzed samples, sedative-hypnotic drugs. Copyright © 2015. Published by Elsevier B.V.

GHB Pharmacology and Toxicology: Acute Intoxication, Concentrations in Blood and Urine in Forensic Cases and Treatment of the Withdrawal Syndrome

PubMed Central

Busardò, Francesco P.; Jones, Alan W.

2015-01-01

The illicit recreational drug of abuse, γ-hydroxybutyrate (GHB) is a potent central nervous system depressant and is often encountered during forensic investigations of living and deceased persons. The sodium salt of GHB is registered as a therapeutic agent (Xyrem®), approved in some countries for the treatment of narcolepsy-associated cataplexy and (Alcover®) is an adjuvant medication for detoxification and withdrawal in alcoholics. Trace amounts of GHB are produced endogenously (0.5-1.0 mg/L) in various tissues, including the brain, where it functions as both a precursor and a metabolite of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). Available information indicates that GHB serves as a neurotransmitter or neuromodulator in the GABAergic system, especially via binding to the GABA-B receptor subtype. Although GHB is listed as a controlled substance in many countries abuse still continues, owing to the availability of precursor drugs, γ-butyrolactone (GBL) and 1,4-butanediol (BD), which are not regulated. After ingestion both GBL and BD are rapidly converted into GHB (t½ ~1 min). The Cmax occurs after 20-40 min and GHB is then eliminated from plasma with a half-life of 30-50 min. Only about 1-5% of the dose of GHB is recoverable in urine and the window of detection is relatively short (3-10 h). This calls for expeditious sampling when evidence of drug use and/or abuse is required in forensic casework. The recreational dose of GHB is not easy to estimate and a concentration in plasma of ~100 mg/L produces euphoria and disinhibition, whereas 500 mg/L might cause death from cardiorespiratory depression. Effective antidotes to reverse the sedative and intoxicating effects of GHB do not exist. The poisoned patients require supportive care, vital signs should be monitored and the airways kept clear in case of emesis. After prolonged regular use of GHB tolerance and dependence develop and abrupt cessation of drug use leads to unpleasant

Benzodiazepine antagonism by harmane and other beta-carbolines in vitro and in vivo.

PubMed

Rommelspacher, H; Nanz, C; Borbe, H O; Fehske, K J; Müller, W E; Wollert, U

1981-03-26

Harmane and other related beta-carbolines are putative endogenous ligands of the benzodiazepine receptor. Since the compounds are potent convulsants they may have agonist activities at the benzodiazepine receptor while the benzodiazepines may be antagonists. This hypothesis was proved by comparing the in vivo and in vitro antagonism of benzodiazepines by harmane and other beta-carbolines. Harmane is clearly a competitive inhibitor of benzodiazepine receptor binding in vitro. Moreover, harmane-induced convulsions can be inhibited reversibly by diazepam in a manner which is consistent with the assumption of competitive antagonism in vivo. For some beta-carboline derivatives a correlation was found between the affinity for the benzodiazepine receptor in vitro and the convulsive potency in vivo. Thus, the data reported suggest that harmane or other related beta-carbolines are putative endogenous agonists of the benzodiazepine receptor. This suggestion is further supported by the observation that diazepam is equally potent in inhibiting harmane- or picrotoxin-induced convulsions, indicating a convulsive mechanism within the GABA receptor-benzodiazepine receptor system.

Prevalence and correlates of inappropriate use of benzodiazepines in Kosovo.

PubMed

Tahiri, Zejdush; Kellici, Suela; Mone, Iris; Shabani, Driton; Qazimi, Musa; Burazeri, Genc

2017-08-01

In post-war Kosovo, the magnitude of inappropriate use of benzodiazepines is unknown to date. The aim of this study was to assess the prevalence and correlates of continuation of intake of benzodiazepines beyond prescription (referred to as "inappropriate use") in the adult population of Gjilan region in Kosovo. A cross-sectional study was conducted in Gjilan region in 2015 including a representative sample of 780 individuals attending different pharmacies and reporting use of benzodiazepines (385 men and 395 women; age range 18-87 years; response rate: 90%). A structured questionnaire was administered to all participants inquiring about the use of benzodiazepines and socio-demographic characteristics. Overall, the prevalence of inappropriate use of benzodiazepines was 58%. In multivariable-adjusted models, inappropriate use of benzodiazepines was significantly associated with older age (OR 1.7, 95% CI 1.1-2.7), middle education (OR 1.8, 95% CI 1.2-2.7), daily use (OR 1.4, 95% CI 1.1-2.0) and addiction awareness (OR 2.7, 95% CI 2.0-3.8). Furthermore, there was evidence of a borderline relationship with rural residence (OR 1.2, 95% CI 0.9-1.7). Our study provides novel evidence about the prevalence and selected correlates of inappropriate use of benzodiazepines in Gjilan region of Kosovo. Health professionals and policymakers in Kosovo should be aware of the magnitude and determinants of drug misuse in this transitional society.

Antianxiety effect of cannabis: involvement of central benzodiazepine receptors.

PubMed

Sethi, B B; Trivedi, J K; Kumar, P; Gulati, A; Agarwal, A K; Sethi, N

1986-01-01

The present work, involving clinical, behavioral, and biochemical studies, was undertaken to elucidate the probable mechanism of the observed antianxiety effects of cannabis. The population for the clinical study consisted of 50 male chronic cannabis users who were otherwise healthy and 50 matched controls. When evaluated on Taylor's Manifest Anxiety Scale (TMA), these subjects had low anxiety scores as compared with the controls. To explore the possible interaction of cannabis with the benzodiazepine receptors, behavioral and biochemical studies in mice were devised, involving acute and chronic cannabis administration. Behavioral study revealed that mice under chronic cannabis treatment scored significantly higher on foot shock-induced aggression, but this was significantly blocked by benzodiazepine receptor antagonist. Furthermore, chronic cannabis treatment significantly (p less than 0.001) increased the frequency of licking response periodically punished by shocks. This confirms the antianxiety effect of cannabis, which also appears to be mediated through a benzodiazepine receptor, as it was reduced significantly (p less than 0.001) by a benzodiazepine receptor blocker. Specific 3H-diazepam binding was carried out in frontal cortex to assess both the population and affinity of benzodiazepine receptors. Our results indicate that acute cannabis treatment has no significant effect, whereas chronic cannabis treatment significantly increased 3H-diazepam binding as compared with controls. Scatchard analysis further reveals that increased affinity is responsible for increased binding to these receptors. It is therefore our contention that the antianxiety effect of cannabis is mediated through central benzodiazepine receptors.

Chaotropic salts: novel modifiers for the capillary electrophoretic analysis of benzodiazepines.

PubMed

Su, Hsiu-Li; Lan, Min-Tsu; Lin, Kuan-Wen; Hsieh, You-Zung

2008-08-01

This paper describes a CE method for analyzing benzodiazepines using the chaotropic salts lithium trifluoromethanesulfonate (LiOTf), lithium hexafluorophosphate (LiPF(6)), and lithium bis(trifluoromethanesulfonyl)imide (LiNTf(2)) as modifiers in the running buffer. Although adequate resolution of seven benzodiazepine analytes occurred under the influence of each of the chaotropic anions, the separation efficiency was highest when bis(trifluoromethanesulfonyl)imide (Tf(2)N(-)) was the modifier. We applied affinity CE in conjunction with linear analysis to determine the association constants for the formation of complexes between the Tf(2)N(-) anion and the benzodiazepines. According to the estimated Gibbs free energies, the interactions between this chaotropic anion and the benzodiazepines were either ion-dipole or ion-induced dipole interactions. Adding chaotropic salts as modifiers into CE buffers is a simple and reproducible technique for separating benzodiazepines.

Experiences of Sleep and Benzodiazepine Use among Older Women

PubMed Central

Rubinstein, Robert L.

2015-01-01

Sleep disturbances are common among older women; however, little is known about sleep experiences among chronic benzodiazepine users. The experience of sleep, sleep troubles, and management of sleep problems were explored through semi-structured interviews with 12 women aged 65 to 92 who had used a benzodiazepine for three months or longer to treat a sleep disturbance. Themes that emerged from an interpretive phenomenological analysis included multiple reasons for sleep disruptions (health problems, mental disturbances, and sleeping arrangements); opposing effects of benzodiazepines on sleep (helps or does not work); and several supplemental sleep strategies (modification of the environment, distraction, and consumption). PMID:25581296

The pathogenesis of propranolol-withdrawal syndrome in essential hypertension.

PubMed

Kristensen, B O; Steiness, E; Weeke, J

1979-12-01

1. In hypertension, the beta-adrenoreceptor-blocker-withdrawal syndrome comprises tachycardia, sweating, tremor and general malaise, symptoms resembling thyrotoxicosis. 2. The effect of abrupt cessation of propranolol on serum concentrations of thyroxine (T4) and triiodothyronine (T3) was therefore investigated in five patients with uncomplicated essential hypertension, treated with propranolol in doses from 160 to 480 mg/day. 3. Four of the five patients developed one or more of the above-mentioned symptoms within 2-6 days after withdrawal of propranolol. 4. A mean relative increase in serum free T3 of 51% (range 22-74%) was found in these four patients on the day of onset of symptoms. 5. The increase in free T3 in the five patients correlated positively with total serum propranolol on the last day the drug was given (r = 0.91, 2P = 0.03). 6. As an increase in T3 was found only in patients suffering the withdrawal syndrome, and was maximal the day the symptoms appeared, despite a variation in time of onset from 2 to 6 days, it is suggested that the beta-adrenoreceptor-blocker-withdrawal syndrome, at least partially, is caused by rebound increased production of T3, induced by the well-known inhibition of the monodeiodination of T4 to T3 during beta-adrenoreceptor blockade. 7. This assumption may explain the clinical symptoms and the reported transient increased beta-adrenoreceptor sensitivity with unchanged serum concentrations of catecholamines.

Comparing the psychological stress between non-smoking patients and smoking patients who experience abrupt smoking cessation during hospitalization for acute myocardial infarction: a pilot study.

PubMed

Pfaff, Kathryn A; El-Masri, Maher M; Fox-Wasylyshyn, Susan M

2009-01-01

Stress is an untoward condition in patients with acute myocardial infarction (AMI). Abrupt nicotine withdrawal is associated with increased symptoms of stress. However, little is known about the impact of smoking cessation on the psychological indicators of stress among hospitalized AMI patients. In this pilot study we compared the psychological stressors between non-smoking AMI patients and smoking patients who abruptly ceased smoking following admission to the CCU. A cross-sectional survey was piloted on a sample of 57 AMI patients (29 smokers and 28 nonsmokers) on the second day of admission to the CCU. Psychological stress was measured using the Profile of Mood States and the Insomnia Severity Index. Multivariate analysis of covariance (MANCOVA) suggested that after adjusting for age, smokers experienced significantly higher overall levels of stress than non-smokers (F = 3.13; p = 0.016). Post-hoc analyses suggested that scores of depression (p = 0.033), anxiety (p = 0.007), and anger (p = 0.017) were particularly higher among smokers, as compared to non-smokers. However, the two groups were not different with regard to their scores on fatigue (p = 0.528) and insomnia (p = 0.299). Abrupt smoking cessation may expose patients admitted with AMI symptoms to higher levels of psychological stress. Given the potential damaging impact of psychological stressors on the physical outcomes of these patients, these findings demonstrate the need for continued assessment and research related to the management of nicotine withdrawal following AMI.

Benzodiazepines: a major component in unintentional prescription drug overdoses with opioid analgesics.

PubMed

Jann, Michael; Kennedy, William Klugh; Lopez, Gaylord

2014-02-01

The misuse and abuse of prescription medications in the United States continues to increase despite interventions by health care professionals, regulatory, and law enforcement agencies. Opioid analgesics are the leading class of prescription drugs that have caused unintentional overdose deaths. Benzodiazepines when taken alone are relatively safe agents in overdose. However, a 5-fold increase in deaths attributed to benzodiazepines occurred from 1999 to 2009. Emergency department visits related to opioid analgesics increased by 111% followed by benzodiazepines 89%. During 2003 to 2009, the 2 prescriptions drugs with the highest increase in death rates were oxycodone 264.6% and alprazolam 233.8%. Therefore, benzodiazepines have a significant impact on prescription drug unintentional overdoses second only to the opioid analgesics. The combination prescribing of benzodiazepines and opioid analgesics commonly takes place. The pharmacokinetic drug interactions between benzodiazepines and opioid analgesics are complex. The pharmacodynamic actions of these agents differ as their combined effects produce significant respiratory depression. Physician and pharmacy shopping by patients occurs, and prescription drug-monitoring programs can provide important information on benzodiazepine and opioid analgesic prescribing patterns and patient usage. Health care professionals need to inform patients and work closely with regulatory agencies and legislatures to stem the increasing fatalities from prescription drug unintentional overdoses.

Nonmedical Abuse of Benzodiazepines in Opiate-Dependent Patients in Tehran, Iran

PubMed Central

Babakhanian, Masuade; Sadeghi, Maliheh; Mansoori, Nader; Alam Mehrjerdi, Zahra; Tabatabai, Mahmood

2012-01-01

Objective: The purpose of the present preliminary study was to explore the prevalence of nonmedical abuse of benzodiazepines in a group of opiate-dependent patients who were on methadone maintenance treatment (MMT) program in outpatient clinics in the south-west of Tehran, Iran. Methods: 114 male and female opiate-dependent clients who met DSM.IV-TR criteria for opiate dependence with mean age 36.5 years participated in the study from 16 clinics and completed a self-report questionnaire on demographics and substance use details. Then the participants were interviewed on the details of nonmedical abuse of benzodiazepines. Results: The study findings indicated that the current nonmedical abuse of benzodiazepines was commonly prevalent among participants. The most common current benzodiazepines abused were alprazolam (100%) followed by chlordiazepoxide (96.5%), clonazepam (94.7%), diazepam (86.8%), lorazepam (79.8%) and oxazepam (73.7%) respectively. Depression (77%) and anxiety (72.8%) were frequently reported as the most important reasons associated with consuming benzodiazepines followed by problem in anger control (44.7%), suicide thought (12.3%), self-injury (7.9%), and suicide commitment (5.3%) respectively. Conclusion: Nonmedical abuse of benzodiazepines is an important problem among opiate addicts which should be considered in treatment interventions during MMT program. PMID:24644471

Diagnostic performance of the EMIT-tox benzodiazepine immunoassay, FPIA serum benzodiazepine immunoassay, and radioreceptor assay in suspected acute poisoning.

PubMed

Verstraete, A G; Belpaire, F M; Leroux-Roels, G G

1998-01-01

We evaluated the diagnostic performance of the EMIT-tox serum benzodiazepine assay adapted to a Hitachi 717 analyzer (EMIT), the Abbott ADx serum benzodiazepine fluorescence polarization immunoassay (FPIA), and a radioreceptor assay (RRA) in 113 patients with suspected acute poisoning. The reference method was high-performance liquid chromatography with ultraviolet detection after solid-phase extraction. For the discrimination between negative and positive samples, the areas under the receiver-operating characteristic (ROC) curves were 0.976, 0.991, and 0.991 for EMIT (cutoff, 50-ng/mL diazepam), FPIA (cutoff, 12-ng/mL nordiazepam), and RRA (cutoff, 50-ng/mL diazepam), respectively. For the discrimination between non-toxic and toxic concentrations, the areas under the ROC curves were 0.896, 0.893, and 0.933, respectively. EMIT (with the cutoff lowered to 50 ng/mL), FPIA, and RRA can be reliably used to screen for the presence of benzodiazepines in serum, but in many cases they cannot discriminate between toxic and nontoxic concentrations.

Abrupt climate change and extinction events

NASA Technical Reports Server (NTRS)

Crowley, Thomas J.

1988-01-01

There is a growing body of theoretical and empirical support for the concept of instabilities in the climate system, and indications that abrupt climate change may in some cases contribute to abrupt extinctions. Theoretical indications of instabilities can be found in a broad spectrum of climate models (energy balance models, a thermohaline model of deep-water circulation, atmospheric general circulation models, and coupled ocean-atmosphere models). Abrupt transitions can be of several types and affect the environment in different ways. There is increasing evidence for abrupt climate change in the geologic record and involves both interglacial-glacial scale transitions and the longer-term evolution of climate over the last 100 million years. Records from the Cenozoic clearly show that the long-term trend is characterized by numerous abrupt steps where the system appears to be rapidly moving to a new equilibrium state. The long-term trend probably is due to changes associated with plate tectonic processes, but the abrupt steps most likely reflect instabilities in the climate system as the slowly changing boundary conditions caused the climate to reach some threshold critical point. A more detailed analysis of abrupt steps comes from high-resolution studies of glacial-interglacial fluctuations in the Pleistocene. Comparison of climate transitions with the extinction record indicates that many climate and biotic transitions coincide. The Cretaceous-Tertiary extinction is not a candidate for an extinction event due to instabilities in the climate system. It is quite possible that more detailed comparisons and analysis will indicate some flaws in the climate instability-extinction hypothesis, but at present it appears to be a viable candidate as an alternate mechanism for causing abrupt environmental changes and extinctions.

Blood concentrations of new designer benzodiazepines in forensic cases.

PubMed

Høiseth, Gudrun; Tuv, Silja Skogstad; Karinen, Ritva

2016-11-01

A number of new designer benzodiazepines have reached the illegal drug market over the past years. Toxicological interpretation of concentrations of these drugs in blood is quite challenging as very limited human data have previously been published. The aim of this study was to report blood concentrations of new designer benzodiazepines in a population of drugged drivers as well as some other criminal offenders, and to relate this to clinical impairment. The present material represents cases involving new designer benzodiazepines (clonazolam, diclazepam, flubromazepam, flubromazolam and pyrazolam) and etizolam, submitted for analyses during the period July 1, 2013-May 31, 2016. Analyses were performed using an ultra-performance liquid chromatography-tandem mass spectrometry method. Blood concentrations and results from the clinical test of impairment are reported. New designer benzodiazepines were detected in 77 cases during the study period. The median (range) concentrations were 0.012mg/L (0.00048-0.10) for flubromazolam (n=25), 0.055mg/L (0.0047-1.2) for flubromazepam (n=24), 0.013mg/L (0.0021-0.057) for diclazepam (n=15), 0.050mg/L (0.019-0.17) for etizolam (n=14), 0.0053mg/L (0.0019-0.011) for clonazolam (n=7) and 0.074mg/L for pyrazolam (n=1). In six cases, designer benzodiazepines were the only drugs detected in blood, and in two of those cases, the physician had given the conclusion of "considerably impaired" upon performing the clinical test for impairment. Given the lack of previously published data on human concentrations, results presented in this study could be helpful in interpretation of blood concentrations of new designer benzodiazepines. This is crucial for the assessment of the importance of toxicological results in suspected drugged drivers, rape victims, etc. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Qualitative variation of photolabelled benzodiazepine receptors in different species.

PubMed

Hebebrand, J; Friedl, W; Lentes, K U; Propping, P

1986-01-01

In order to examine whether species differences of benzodiazepine receptor subunits exist, we compared the fluorographic pattern of photoaffinity labelled subunits after SDS-PAGE in five species: fish, frog, chicken, mouse and calf. Each species showed a distinct pattern of specifically labelled proteins. We conclude that species variation of benzodiazepine receptor does indeed exist.

Use of Benzodiazepines in Alzheimer’s Disease: A Systematic Review of Literature

PubMed Central

Defrancesco, Michaela; Marksteiner, Josef; Fleischhacker, W. Wolfgang; Blasko, Imrich

2015-01-01

Background: Benzodiazepines are frequently prescribed in patients with Alzheimer’s disease. Unfortunately, studies evaluating their benefits and risks in these patients are limited. Methods: Clinical trials focusing on the effect of benzodiazepines on cognitive functions, disease progression, behavioral symptoms, sleep disturbances, and the general frequency of benzodiazepine use were included in this review. Published articles from January 1983 to January 2015 were identified using specific search terms in MEDLINE and PubMed Library according to the recommendations of The Strengthening the Reporting of Observational Studies in Epidemiology initiative. Results: Of the 657 articles found, 18 articles met predefined selection criteria and were included in this review (8 on frequency, 5 on cognitive functions, 5 on behavioral and sleep disturbances). The frequency of benzodiazepine use ranged from 8.5% to 20%. Five studies reported accelerated cognitive deterioration in association with benzodiazepine use. Two studies reported clinical efficacy for lorazepam and alprazolam to reduce agitation in Alzheimer’s disease patients. No evidence was found for an improvement of sleep quality using benzodiazepines. Conclusion: This systematic review shows a relatively high prevalence of benzodiazepine use but limited evidence for clinical efficacy in Alzheimer’s disease patients. However, there is a paucity of methodologically high quality controlled clinical trials. Our results underscore a need for randomized controlled trials in this area. PMID:25991652

Benzodiazepine use and risk of mortality among patients with schizophrenia: a retrospective longitudinal study.

PubMed

Fontanella, Cynthia A; Campo, John V; Phillips, Gary S; Hiance-Steelesmith, Danielle L; Sweeney, Helen Anne; Tam, Kwok; Lehrer, Douglas; Klein, Robert; Hurst, Mark

2016-05-01

This study examined the association between benzodiazepine use alone or in combination with antipsychotics and risk of mortality in patients with schizophrenia. A retrospective longitudinal analysis was performed using Medicaid claims data merged with death certificate data for 18,953 patients (aged 18-58 years) with ICD-9-diagnosed schizophrenia followed from July 1, 2006, to December 31, 2013. Cox proportional hazard analyses were used to estimate the risk of all-cause mortality associated with benzodiazepine use; adjustment was made for a wide array of fixed and time-varying confounders, including demographics, psychiatric and medical comorbidities, and other psychotropic medications. Of the 18,953 patients diagnosed with schizophrenia, 13,741 (72.5%) were not prescribed a benzodiazepine, 3,476 (18.3%) were prescribed benzodiazepines in the absence of antipsychotic medication, and 1,736 (9.2%) were prescribed benzodiazepines in combination with antipsychotics. Controlling for a wide array of demographic and clinical variables, the hazard of mortality was 208% higher for patients prescribed benzodiazepines without an antipsychotic (HR = 3.08; 95% CI, 2.63-3.61; P < .001) and 48% higher for patients prescribed benzodiazepines in combination with antipsychotics (HR = 1.48; 95% CI, 1.15-1.91; P = .002). Benzodiazepine-prescribed patients were at greater risk of death by suicide and accidental poisoning as well as from natural causes. Benzodiazepine use is associated with increased mortality risk in patients with schizophrenia after adjusting for a wide range of potential confounders. Given unproven efficacy, physicians should exercise caution in prescribing benzodiazepines to schizophrenic patients. © Copyright 2016 Physicians Postgraduate Press, Inc.

Benzodiazepines, opioids and driving: an overview of the experimental research.

PubMed

Leung, Stefanie Y

2011-05-01

Road crashes contribute significantly to the total burden of injury in Australia, with the risk of injury being associated with the presence of drugs and/or alcohol in the driver's blood. Increasingly, some of the most commonly detected drugs include prescription medicines, the most notable of these being benzodiazepines and opioids. However, there is a paucity of experimental research into the effects of prescribed psychoactive drugs on driving behaviours. This paper provides an overview of experimental studies investigating the effects of prescribed doses of benzodiazepines and opioids on driving ability, and points to future directions for research. There is growing epidemiological evidence linking the therapeutic use of benzodiazepines and opioids to an increased crash risk. However, the current experimental literature remains unclear. Limitations to study methodologies have resulted in inconsistent findings. Limited experimental evidence exists to inform policy and guidelines regarding fitness-to-drive for patients taking prescribed benzodiazepines and opioids. Further experimental research is required to elucidate the effects of these medications on driving, under varying conditions and in different medical contexts. This will ensure that doctors prescribing benzodiazepines and opioids are well informed, and can appropriately advise patients of the risks associated with driving whilst taking these medications. © 2011 Australasian Professional Society on Alcohol and other Drugs.

A Case Report of Clonazepam Dependence

PubMed Central

Kacirova, Ivana; Grundmann, Milan; Silhan, Petr; Brozmanova, Hana

2016-01-01

Abstract Clonazepam is long-acting benzodiazepine agonist used in short-acting benzodiazepine withdrawal; however, recent observations suggest the existence of its abuse. We demonstrate a 40-year-old man with a 20-year history of psychiatric care with recently benzodiazepine dependence (daily intake of ∼60 mg of clonazepam and 10 mg of alprazolam). High serum levels of both drugs were analyzed 3 weeks before admission to hospitalization (clonazepam 543.9 ng/mL, alprazolam 110 ng/mL) and at the time of admission (clonazepam 286.2 ng/mL, alprazolam 140 ng/mL) without any signs of benzodiazepine intoxication. Gradual withdrawal of clonazepam with monitoring of its serum levels and increase of gabapentin dose were used to minimize physical signs and symptoms of clonazepam withdrawal. Alprazolam was discontinued promptly. Clinical consequences of the treatment were controllable tension, intermittent headache, and rarely insomia. It is the first case report showing utilization of therapeutic drug monitoring during withdrawal period in the patient with extreme toleration to severe benzodiazepine dependence. PMID:26945373

Increasing Benzodiazepine Prescriptions and Overdose Mortality in the United States, 1996–2013

PubMed Central

Hennessy, Sean; Cunningham, Chinazo O.; Starrels, Joanna L.

2016-01-01

Objectives. To describe trends in benzodiazepine prescriptions and overdose mortality involving benzodiazepines among US adults. Methods. We examined data from the Medical Expenditure Panel Survey and multiple-cause-of-death data from the Centers for Disease Control and Prevention. Results. Between 1996 and 2013, the percentage of adults filling a benzodiazepine prescription increased from 4.1% (95% confidence interval [CI] = 3.8%, 4.5%) to 5.6% (95% CI = 5.2%, 6.1%), with an annual percent change of 2.5% (95% CI = 2.1%, 3.0%). The quantity of benzodiazepines filled increased from 1.1 (95% CI = 0.9, 1.2) to 3.6 (95% CI = 3.0, 4.2) kilogram lorazepam equivalents per 100 000 adults (annual percent change = 9.0%; 95% CI = 7.6%, 10.3%). The overdose death rate increased from 0.58 (95% CI = 0.55, 0.62) to 3.07 (95% CI = 2.99, 3.14) per 100 000 adults, with a plateau seen after 2010. Conclusions. Benzodiazepine prescriptions and overdose mortality have increased considerably. Fatal overdoses involving benzodiazepines have plateaued overall; however, no evidence of decreases was found in any group. Interventions to reduce the use of benzodiazepines or improve their safety are needed. PMID:26890165

An exploratory study of cannabis withdrawal among Indigenous Australian prison inmates: study protocol.

PubMed

Rogerson, Bernadette; Copeland, Jan; Buttner, Petra; Bohanna, India; Cadet-James, Yvonne; Sarnyai, Zoltan; Clough, Alan R

2013-05-28

Cannabis use and dependence is a serious health and criminal justice issue among incarcerated populations internationally. Upon abrupt, enforced cessation of cannabis, prisoners may suffer irritability and anger that can lead to threatening behaviour, intimidation, violence, sleep disturbances and self-harm. Cannabis withdrawal syndrome, proposed for inclusion in the Diagnostic and Statistical Manual of Mental Disorders in 2013, has not been examined in Indigenous populations. Owing to the exceptionally high rates of cannabis use in the community, high proportions of Australian Indigenous prisoners may suffer from withdrawal upon entry to custody. 60 male and 60 female Indigenous prisoners (18-40 years) at a high risk of cannabis dependence will be recruited upon entry to custody. A pictorial representation of the standard Cannabis Withdrawal Scale will be tested for reliability and validity. Cortisol markers will be measured in saliva, as the indicators of onset and severity of cannabis withdrawal and psychological distress. The characteristics will be described as percentages and mean or median values with 95% CI. Receiver operator curve analysis will determine an ideal cut-off of the Cannabis Withdrawal Scale and generalised estimating equations modelling will test changes over time. The acceptability and efficacy of proposed resources will be assessed qualitatively using thematic analysis. A valid and reliable measure of cannabis withdrawal for use with Indigenous populations, the onset and time course of withdrawal symptoms in this population and the development of culturally acceptable resources and interventions to identify and manage cannabis withdrawal. The project has been approved by the James Cook University Human Research Ethics Committee (approval number H4651).The results will be reported via peer reviewed publications, conference, seminar presentations and on-line media for national and international dissemination.

Medication overuse headache: withdrawal and prophylactic therapeutic regimen.

PubMed

Trucco, Marco; Meineri, Piero; Ruiz, Luigi; Gionco, Maurizio

2010-06-01

Medication overuse headache (MOH) is a secondary headache, whose diagnostic criteria were settled by the Second Edition of the International Classification of Headache Disorders and its subsequent revisions. Its diagnosis and treatment represent a growing problem worldwide and a challenge for headache specialists. The aim of this study was to evaluate the efficacy of a therapeutic regimen for withdrawal of the overused drug and prophylaxis of headache in a population of patients suffering from MOH in 8 hospitals of Piemonte - Liguria - Valle d'Aosta. Seventy patients, 58 females (82.9%) and 12 males (17.1%), mean age at observation 51.04 +/- 12.59 years, affected by MOH following International Headache Society diagnostic revised criteria were treated as inpatients (n = 40) or in Day Hospital (n = 30). Headache Index (HI) and Daily Drug Intake (DDI) were used for evaluating the severity of headache and medication overuse. The patients were treated by abrupt discontinuation of the overused drug and by a therapeutic protocol including i.v. hydration, dexhamethasone, metoclopramide, and benzodiazepines for 7-15 days. Prophylactic medication was started at the beginning of therapeutic protocol. Patients underwent follow-up controls 1, 3, and 6 months after discharge. The initial diagnosis was MOH in all patients included in the study. The overused medications were simple analgesics in 18 cases (25.7%), combination analgesics in 26 cases (37.1%), triptans alone in 9 cases (12.9%), or in combination with analgesics in 13 cases (18.6%), and ergot derivatives (in combination) in 4 cases (5.7%). We collected data from 59 patients at first follow-up (1 month), 56 after 3 months, and 42 after 6 months. Mean HI was 0.92 at admission, 0.19 at discharge, 0.35 after 30 days, 0.39 after 3 months, and 0.42 after 6 months. Mean DDI was 2.72 at admission, 0.22 at discharge, 0.31 after 1 month, 0.38 after 3 months, and 0.47 after 6 months. These results proved to be highly

Metabolism of anxiolytics and hypnotics: benzodiazepines, buspirone, zoplicone, and zolpidem.

PubMed

Chouinard, G; Lefko-Singh, K; Teboul, E

1999-08-01

1. The benzodiazepines are among the most frequently prescribed of all drugs and have been used for their anxiolytic, anticonvulsant, and sedative/hypnotic properties. Since absorption rates, volumes of distribution, and elimination rates differ greatly among the benzodiazepine derivatives, each benzodiazepine has a unique plasma concentration curve. Although the time to peak plasma levels provides a rough guide, it is not equivalent to the time to clinical onset of effect. The importance of alpha and beta half-lives in the actions of benzodiazepines is discussed. 2. The role of cytochrome P450 isozymes in the metabolism of benzodiazepines and in potential pharmacokinetic interactions between the benzodiazepines and other coadministered drugs is discussed. 3. Buspirone, an anxiolytic with minimal sedative effects, undergoes extensive metabolism, with hydroxylation and dealkylation being the major pathways. Pharmacokinetic interactions of buspirone with other coadministered drugs seem to be minimal. 4. Zopiclone and zolpidem are used primarily as hypnotics. Both are extensively metabolized; N-demethylation, N-oxidation, and decarboxylation of zopiclone occur, and zolpidem undergoes oxidation of methyl groups and hydroxylation of a position on the imidazolepyridine ring system. Zopiclone has a chiral centre, and demonstrates stereoselective pharmacokinetics. Metabolic drug-drug interactions have been reported with zopiclone and erythromycin, trimipramine, and carbamazepine. Reports to date indicate minimal interactions of zolpidem with coadministered drugs; however, it has been reported to affect the Cmax and clearance of chlorpromazepine and to decrease metabolism of the antiviral agent ritonavin. Since CYP3A4 has been reported to play an important role in metabolism of zolpidem, possible interactions with drugs which are substrates and/or inhibitors of that CYP isozyme should be considered.

[Can one talk of benzodiazepine "drunkenness"? About acute benzodiazepine intoxication, without suicidal or mortiferous tendencies].

PubMed

Menecier, P; Texier, M A; Las, R; Ploton, L

2012-02-01

When we refer to "drunkenness", more often than not, we think of alcohol or cannabis being the instigator rather than pharmacological drugs, even if outside the toxic origins, "drunkenness" may also occur without any substance intake: one can be drunk on love, poetry, music and even mania. Benzodiazepine "drunkenness" is not a classical notion in medicine. But the concept of addictology allows one to enlarge different approaches and to consider the relationship with psychoactive substances according to the same references. So, in a single fashion, between use and misuse, is it possible to resort to the same concepts for pharmacological drugs, including "drunkenness"? Any intake of a psychoactive substance, limited in time, which will take the consumer some time to recover from, can be called simple use, intoxication or drunkenness. Intoxication is rather a classical medical concept linked with poisoning, and hence the toxicological aspects prevail particularly through the concept of a toxidrome. However, little research has been done on "drunkenness" in other medical aspects, neither psychological aspects nor sociological aspects. If poisoning is defined as soon as a poison is introduced into the body, the intoxication arises after a threshold (that toxicology usually defines), but no means are available to measure the onset of the inebriation, neither any ingested amounts nor any toxic concentration in the body. It is hard to define "drunkenness" simply. At first, it is most often seen as a pathology in medicine, unlike in every day life. "Drunkenness" can be the result of physiological disturbances, notably through the effects of substances and can therefore be the manifestation of a cerebral dysfunction. Alternatively, it can arise from a variation of emotional or sensorial stimuli. If the feelings associated with drunkenness are positive and pleasant a repetition will occur in the search to reproduce enjoyable effects in reference to neurophysiological models

Outcome of new benzodiazepine prescriptions to older adults in primary care.

PubMed

Simon, Gregory E; Ludman, Evette J

2006-01-01

The objective of this study was to examine the indications for benzodiazepine use, and the baseline characteristics, duration of use and clinical outcomes of older primary care patients prescribed benzodiazepines. Computerized records were used to identify outpatients (n=129) aged >or=60 years who received new benzodiazepine prescriptions from primary care physicians of a group model managed care organization. A baseline telephone survey assessed indications for prescription, sleep quality (Pittsburgh Sleep Quality Index), depression (Symptom Checklist depression scale and Structured Clinical Interview for DSM-IV), alcohol use (CAGE) and functional status (SF-36). A 2-month follow-up survey assessed benzodiazepine use, sleep quality and depression. The most common indications for prescription were insomnia (42%) and anxiety (36%). At baseline, participants reported moderate sleep disturbance (mean Pittsburgh Sleep Quality Index=9.3, S.D.=4.0), only 15% met criteria for current depressive episode and only 3% reported at-risk alcohol use. After 2 months, 30% of participants used benzodiazepines at least daily. Both those continuing daily use and those not continuing daily use reported significant improvements in sleep quality and depression, with no difference between groups in rates of improvement. Initial benzodiazepine prescriptions to older adults are typically intended for the treatment of anxiety or insomnia, with little evidence for occult depression or alcohol abuse. A significant minority develops a pattern of long-term use, raising concerns about tolerance and dependence.

Characterization of ( sup 3 H)alprazolam binding to central benzodiazepine receptors

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCabe, R.T.; Mahan, D.R.; Smith, R.B.

1990-10-01

The binding of the triazolobenzodiazepine ({sup 3}H)alprazolam was studied to characterize the in vitro interactions with benzodiazepine receptors in membrane preparations of rat brain. Studies using nonequilibrium and equilibrium binding conditions for ({sup 3}H)alprazolam resulted in high specific to nonspecific (signal to noise) binding ratios. The binding of ({sup 3}H)alprazolam was saturable and specific with a low nanomolar affinity for benzodiazepine receptors in the rat brain. The Kd was 4.6 nM and the Bmax was 2.6 pmol/mg protein. GABA enhanced ({sup 3}H)alprazolam binding while several benzodiazepine receptor ligands were competitive inhibitors of this drug. Compounds that bind to other receptormore » sites had a very weak or negligible effect on ({sup 3}H)alprazolam binding. Alprazolam, an agent used as an anxiolytic and in the treatment of depression, acts in vitro as a selective and specific ligand for benzodiazepine receptors in the rat brain. The biochemical binding profile does not appear to account for the unique therapeutic properties which distinguish this compound from the other benzodiazepines in its class.« less

Benzodiazepines impair smooth pursuit eye movements.

PubMed Central

Bittencourt, P R; Wade, P; Smith, A T; Richens, A

1983-01-01

Five healthy male volunteers received single oral doses of 10 mg diazepam, 20 mg temazepam and placebo, in a double-blind, randomised fashion. Smooth pursuit eye movement velocity and serum benzodiazepine concentration were measured before and after at 0.5,1,1.5,2,3,4,6,9 and 12 h after administration of the treatments. Significant decrease in smooth pursuit eye movement velocity as compared to placebo was observed between 0.5-2 h after temazepam, and between 1-2 h after diazepam. Smooth pursuit eye movement velocity was log-linearly correlated with serum temazepam and diazepam concentration. The results demonstrate the relationship between serum benzodiazepine concentration and its effect on an objective measure of oculomotor performance. PMID:6133544

29 CFR 4219.11 - Withdrawal liability upon mass withdrawal.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Withdrawal liability upon mass withdrawal. 4219.11 Section... Redetermination of Withdrawal Liability Upon Mass Withdrawal § 4219.11 Withdrawal liability upon mass withdrawal. (a) Initial withdrawal liability. The plan sponsor of a multiemployer plan that experiences a mass...

29 CFR 4219.11 - Withdrawal liability upon mass withdrawal.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 9 2011-07-01 2011-07-01 false Withdrawal liability upon mass withdrawal. 4219.11 Section... Redetermination of Withdrawal Liability Upon Mass Withdrawal § 4219.11 Withdrawal liability upon mass withdrawal. (a) Initial withdrawal liability. The plan sponsor of a multiemployer plan that experiences a mass...

Urine benzodiazepines screening of involuntarily drugged and robbed or raped patients.

PubMed

Boussairi, A; Dupeyron, J P; Hernandez, B; Delaitre, D; Beugnet, L; Espinoza, P; Diamant-Berger, O

1996-01-01

This study involved 35 patients who claimed to have been drugged before being robbed or raped, despite urine negative toxicologic screening by immunoenzymatic methods. The urines were frozen for further investigations, including enzymatic hydrolysis of urinary conjugates, liquid-solid extraction and, finally, immunoenzymatic screening of concentrated urine extract. Urine benzodiazepines were analyzed by immunoenzymatic assay before and after enzymatic hydrolysis combined with extraction. On direct immunoenzymatic screening, 17 of the 35 urine samples were benzodiazepine positive. Enrichment of preserved specimens improved the detection threshold from 200 ng/mL to 50 ng/mL and 10 of the 18 negative urines became positive. This method allowed us to demonstrate the benzodiazepines in half of previously negative urine samples. Benzodiazepine screening is particularly problematic because of low dosage, rapid elimination, failure to detect conjugated metabolites by immunoenzymatic reagents and high threshold of sensitivity for certain substances.

Racial disparities in access after regulatory surveillance of benzodiazepines.

PubMed

Pearson, Sallie-Anne; Soumerai, Stephen; Mah, Connie; Zhang, Fang; Simoni-Wastila, Linda; Salzman, Carl; Cosler, Leon E; Fanning, Thomas; Gallagher, Peter; Ross-Degnan, Dennis

2006-03-13

We examined the effects of a prescription-monitoring program on benzodiazepine access among Medicaid enrollees living in neighborhoods of different racial composition. We used interrupted time series and logistic regression to analyze data from noninstitutionalized persons aged 18 years or older (N = 124 867) enrolled continuously in New York Medicaid 12 months before and 24 months and 7 years after initiation of the program. We used census data to identify the racial composition of the neighborhoods. Outcome measures were nonproblematic use (short term, within dosing guidelines), potentially problematic use (>120 days' use or more than twice the recommended dose), and pharmacy hopping (filling prescriptions for the same benzodiazepine in different pharmacies within 7 days). There was a sudden, sustained reduction in benzodiazepine use in all the neighborhoods after the program's introduction. Despite the lowest rates of baseline use, enrollees in predominantly (> or = 75%) black neighborhoods experienced the highest rates of discontinuation after introduction of the program. This difference remained 7 years after policy initiation. Compared with white participants, black participants were more likely to discontinue nonproblematic (odds ratio, 1.78; 95% confidence interval, 1.47-2.17) and potentially problematic (odds ratio, 1.77; 95% confidence interval, 1.45-2.17) benzodiazepine use, after adjusting for sex, eligibility status, neighborhood poverty, and baseline use. The program almost completely eliminated pharmacy hopping in all racial groups, although less among white participants (82.6%) vs black participants (88.7%). A systematic benzodiazepine prescription-monitoring program reduced inappropriate prescribing, with a stronger effect in predominantly black neighborhoods despite lower baseline use. The policy may have resulted in an unintended decrease in nonproblematic use that disproportionately affects black populations.

Treating acute seizures with benzodiazepines: does seizure duration matter?

PubMed

Naylor, David E

2014-10-01

Several clinical trials have shown improved seizure control and outcome by early initiation of treatment with benzodiazepines, before arrival in the emergency department and before intravenous access can be established. Here, evidence is provided and reviewed for rapid treatment of acute seizures in order to avoid the development of benzodiazepine pharmacoresistance and the emergence of self-sustaining status epilepticus. Alterations in the physiology, pharmacology, and postsynaptic level of GABA-A receptors can develop within minutes to an hour and hinder the ability of synaptic inhibition to stop seizures while also impairing the efficacy of GABAergic agents, such as benzodiazepines, to boost impaired inhibition. In addition, heightened excitatory transmission further exacerbates the inhibitory/excitatory balance and makes seizure control even more resistant to treatment. The acute increase in the surface expression of NMDA receptors during prolonged seizures also may cause excitotoxic injury, cell death, and other pathological expressions and re-arrangements of receptor subunits that all contribute to long-term sequelae such as cognitive impairment and chronic epilepsy. In conclusion, a short window of opportunity exists when seizures are maximally controlled by first-line benzodiazepine treatment. After that, multiple pathological mechanisms quickly become engaged that make seizures increasingly more difficult to control with high risk for long-term harm.

[The efficacy of the native flumazenil for acute poisoning with benzodiazepines].

PubMed

Zhu, X H; Li, J X; Wang, F

2000-12-28

To evaluate the efficacy of the native flumazenil for acute self-poisoning with benzodiazepines. One hundred and twenty-six patients with unconsciousness from benzodiazepines-induced self-poisoning were randomly divided into two groups: flumazenil group(Group II, 63 cases) were treated with flumazenil, and conventional-medicine group(Group I, 63 cases) with placebo(glucose, vitamin C, KCl). A modified Glasgow Coma Scale(MGCS) and Observer's Assessment of Alertness/Sedation Scale(OAA/S) were used in the assessment of consciousness. MGCS were increased by 5.3, 8.0, 9.4 and 7.3 at 15 min, 30 min, 60 min and 180 min after intravenous flumazenil(P < 0.01) and by 5.2, 7.7, 8.7 and 6.9 in comparison with conventional-medicine group(P < 0.01). OAA/S increased by 1.9 compared with conventional-medicine group(P < 0.01). No severe side-effects were found in the treatment. Flumazenil might improve benzodiazepines-induced unconsciousness markedly and may be the most effective antagonist of benzodiazepines.

A Short-Term, Multicenter, Placebo-Controlled, Randomized Withdrawal Study of a Metabotropic Glutamate 2/3 Receptor Agonist Using an Electronic Patient-Reported Outcome Device in Patients With Schizophrenia

PubMed Central

Stauffer, Virginia L.; Baygani, Simin K.; Kinon, Bruce J.; Krikke-Workel, Judith O.

2014-01-01

Abstract This 6-week, multicenter, randomized withdrawal, placebo-controlled trial sought to determine whether symptoms of physical dependence occur after abrupt cessation of pomaglumetad methionil (LY2140023 monohydrate), a metabotropic glutamate 2/3 receptor agonist, in patients with schizophrenia. Eligible outpatients, 18 to 65 years old who required a modification or initiation of antipsychotic medication received 4 weeks of pomaglumetad methionil during open-label treatment and then were randomized, double-blind, to continue pomaglumetad methionil or receive placebo for 2 weeks. The primary outcome compared results of the 3-day moving mean of the total score on the Discontinuation Symptom Checklist-Modified Rickels for pomaglumetad methionil-treated patients with those on placebo during the randomized withdrawal phase. An electronic patient-reported outcome (ePRO) device was used daily to record these results. During the withdrawal phase, 103 patients were randomized, and 98 patients completed the trial. There was no statistically significant evidence of withdrawal symptoms associated with placebo compared with pomaglumetad methionil continuation as measured by Discontinuation Symptom Checklist-Modified Rickels (P = 0.170). The results are supported by secondary analyses with the clinician-rated, Clinical Institute Withdrawal Assessment of Alcohol Scale Revised, which showed no statistically significant differences between treatment groups. Using the ePRO device, 82.5% of the patients achieved 75% to 100% of compliance. No discontinuations due to worsening of schizophrenia, serious adverse events, deaths, or seizures were reported during either phase of the study. These findings suggest that there is no evidence of withdrawal symptoms associated with the abrupt discontinuation of pomaglumetad methionil and that an ePRO device can be successfully used in a multicenter schizophrenia trial. PMID:25006819

Benzodiazepine Prescribing in Older Adults in U.S. Ambulatory Clinics and Emergency Departments (2001-10).

PubMed

Marra, Erin M; Mazer-Amirshahi, Maryann; Brooks, Gillian; van den Anker, John; May, Larissa; Pines, Jesse M

2015-10-01

To assess trends in benzodiazepine use from 2001 to 2010 in older adults in U.S. ambulatory clinics and emergency departments (EDs). Retrospective analysis. 2001 to 2010 National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS). Individuals aged 65 and older for whom the reason for visit might prompt a physician to use a benzodiazepine (e.g., anxiety, detoxification, back sprain). The NAMCS and NHAMCS were used to evaluate U.S. ambulatory clinic and ED visits. Encounters involving individuals aged 65 and older for whom a benzodiazepine might be prescribed were analyzed. Trends in benzodiazepine use in these visits were explored, and predictors of use were assessed using survey-weighted chi-square tests and logistic regression. From 2001 to 2010, benzodiazepines were used in 16.6 million of 133.3 million ambulatory clinic visits and 1.9 million of 18.1 million ED visits with the selected reasons for the visits. There was no change in benzodiazepine use in either setting over the study period, although benzodiazepine use for those aged 85 and older increased from 8.9% to 19.3% in ambulatory clinics and 10.1% to 17.2% in EDs. Individuals visiting clinics with anxiety were five times as likely to receive benzodiazepines (odds ratio (OR) = 4.8), and those in EDs were twice as likely (OR = 2.3). Despite safety concerns, benzodiazepine use in older adults in U.S. ambulatory clinics and EDs did not change from 2001 to 2010. In the oldest individuals, who are at higher risk of adverse events, a greater increase was seen than in those aged 65 to 84. Additional measures may be needed to promote alternatives to benzodiazepines. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.

Reasons for Benzodiazepine Use Among Persons Seeking Opioid Detoxification

PubMed Central

Stein, Michael D.; Kanabar, Mitika; Anderson, Bradley J.; Lembke, Anna; Bailey, Genie L.

2016-01-01

Background Over the past decade, patients admitted to addiction treatment programs have reported increasing rates of concurrent opioid and benzodiazepine (BZD) use. This drug combination places individuals at high risk for accidental overdose. Little is known about reasons for BZD use among individuals seeking treatment for opioid use disorders. Methods We surveyed consecutive persons initiating inpatient opioid detoxification and identified 176 out of 438 who reported BZD use in the past 30 days and/or had a positive toxicology. Results Forty percent of persons surveyed used a BZD in the month prior to admission, and 25% of these met criteria for BZD dependence (DSM IV). BZD users averaged 32.0 years of age, 63.6% were male, 85.2% used heroin, and reported, on average, 13.3 (± 11.2) days of BZD use during the past month. Alprazolam (Xanax) was the most commonly used BZD (52%), and buying it on the street the most common source (48%). The most commonly reported reason for BZD use was ‘to manage anxiety’ (42.6%), followed by ‘to get or enhance a high’ (27.7%), ‘to help with sleep’ (11.4%), and ‘to decrease opioid withdrawal’ (10.2%). The most common reason for BZD use was significantly associated (p < .001) with most likely source of BZDs, with persons who got their BZDs from a prescriber (23%) more likely to report BZD anxiety as their primary reason for use, while persons who bought BZDs on “the street” (48%) had the highest likelihood of reporting using BZD to get or enhance a high. Participants using BZDs most commonly for anxiety did not endorse lower anxiety than those using BZDs for other reasons. Conclusions Two in five persons seeking detoxification for an opioid use disorder used a BZD in the prior month. Anxiety was the most common reason patients reported using a benzodiazepine, but they also reported using BZDs to enhance a ‘high’ and manage opioid withdrawal. Evidence-based discussions about the risks of combining BZDs and

[Benzodiazepine dependence and the risk of depression and anxiety disorders: seniors' health study].

PubMed

Nkogho Mengue, P-G; Abdous, B; Berbiche, D; Preville, M; Voyer, P

2014-06-01

The objective of this study is to examine the relationship between benzodiazepine dependence and anxiety disorders and depression in people aged 65 years and over. We referred to the data from the study on the health of seniors, a survey of a representative sample of 707 benzodiazepine users living in the community in Quebec, Canada. Benzodiazepine dependence, anxiety disorders and depression were measured using self-reported questionnaires based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth revised edition. Seniors have consumed an average daily dose of 6.1±7.6mg diazepam equivalent to an average of 205±130 days. The prevalence of benzodiazepine dependence has been estimated at 9.5%. This dependence increases the risk of minor depression for females (relative risk [RR]=4.36, confidence interval 95% [95% CI]=1.19 to 15.99). The results of this study suggest that the use of benzodiazepines is far from being optimal among seniors in Quebec. The proportion of seniors who develop an addiction is important. The results illustrate the need to develop and implement programs to improve the quality of benzodiazepine use among this population. Copyright © 2013 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Quantitative analysis of benzodiazepines in vitreous humor by high-performance liquid chromatography

PubMed Central

Bazmi, Elham; Behnoush, Behnam; Akhgari, Maryam; Bahmanabadi, Leila

2016-01-01

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. PMID:27635251

[The effects of ethanol on the evolution of the acute benzodiazepine poisoning].

PubMed

Puha, Gabriela; Hurjui, J; Lupuşoru, Cătălina Elena; Sorodoc, L

2011-01-01

The depressing effects on the nervous central system (NCS) induced by benzodiazepines and ethanol are similar. The complications are rare in the benzodiazepine poisoning, but are a lot more frequent in association with other depressing drugs for the NCS (especially alcohol). We analyzed retrospectively patients with benzodiazepine poisoning admitted in the Internal Medicine Clinic - Toxicology during 2003 - 2009.The study attempted a complex evaluation of the consequences of acute and chronic alcoholism on the evolution of acute benzodiazepinepoisoning and the description of the clinic evolution and paraclinical particularities of the patients under investigation. 343 patients with benzodiazepine poisoning were admitted, 150 were tested through measurement of alcohol level, leading to values between 1 - 415 mg/dl. Chronic alcoholism in personal pathological antecedents of the patients determined a relative risk of intoxication 1.46 times higher. The hospitalization period varied from 1 to 8 days for patients with chronic alcoholism and from 1 to 14 days for patients with acute alcoholism, a statistically important difference. During the period under investigation, from the total of patients admitted for acute benzodiazepine poisoning, 2 deaths were registered. Of the two deaths, one patient showed ethanol coingestion.

Effects of convection patterns on freckle formation of directionally solidified Nickel-based superalloy casting with abruptly varying cross-sections

NASA Astrophysics Data System (ADS)

Qin, Ling; Shen, Jun; Li, Qiudong; Shang, Zhao

2017-05-01

The effects of convection patterns on freckle formation of directionally solidified Nickel-based superalloy sample with abruptly varying cross-sections were investigated experimentally and numerically. The experimental results demonstrate that freckles were only observed at the bottom of larger cross-section. Numerical results indicate that this phenomenon should be attributed to the different convection patterns at front of solidification interface. As the withdrawal rate increased, the primary dendrites spacing has an obvious influence on freckle formation. A more in-depth investigation of the convection patterns can provide a better understanding of freckle formation and perhaps offer methods to minimize freckles in turbine blades.

Abrupt climate change: can society cope?

PubMed

Hulme, Mike

2003-09-15

Consideration of abrupt climate change has generally been incorporated neither in analyses of climate-change impacts nor in the design of climate adaptation strategies. Yet the possibility of abrupt climate change triggered by human perturbation of the climate system is used to support the position of both those who urge stronger and earlier mitigative action than is currently being contemplated and those who argue that the unknowns in the Earth system are too large to justify such early action. This paper explores the question of abrupt climate change in terms of its potential implications for society, focusing on the UK and northwest Europe in particular. The nature of abrupt climate change and the different ways in which it has been defined and perceived are examined. Using the example of the collapse of the thermohaline circulation (THC), the suggested implications for society of abrupt climate change are reviewed; previous work has been largely speculative and has generally considered the implications only from economic and ecological perspectives. Some observations about the implications from a more social and behavioural science perspective are made. If abrupt climate change simply implies changes in the occurrence or intensity of extreme weather events, or an accelerated unidirectional change in climate, the design of adaptation to climate change can proceed within the existing paradigm, with appropriate adjustments. Limits to adaptation in some sectors or regions may be reached, and the costs of appropriate adaptive behaviour may be large, but strategy can develop on the basis of a predicted long-term unidirectional change in climate. It would be more challenging, however, if abrupt climate change implied a directional change in climate, as, for example, may well occur in northwest Europe following a collapse of the THC. There are two fundamental problems for society associated with such an outcome: first, the future changes in climate currently being

Precipitated withdrawal from nicotine reduces reinforcing effects of a visual stimulus for rats.

PubMed

Weaver, Matthew T; Sweitzer, Maggie; Coddington, Sarah; Sheppard, Jaimee; Verdecchia, Nicole; Caggiula, Anthony R; Sved, Alan F; Donny, Eric C

2012-07-01

Research has identified at least two positive reinforcement-related effects of nicotine: (a) primary reinforcement and (b) enhancement of reinforcement from concurrently available stimuli. Prior examples of the reinforcement-enhancing effects with rats showed that repeated, intermittent nicotine exposure increased responding for non-nicotine reinforcers, and this effect remained robust over several weeks. However, the effects of continuous nicotine exposure on responding for a non-nicotine reinforcer are unknown, as are the effects of abruptly withdrawing continuous nicotine on behavior maintained by the same reinforcer. Lever pressing for a visual reinforcer under a fixed ratio schedule was assessed while rats were maintained on a chronic, continuous infusion of nicotine (3.16 mg/kg/day; osmotic minipump). The effects of precipitated withdrawal on responding, following 16 days of continuous nicotine exposure, were assessed by pre-session subcutaneous injections of mecamylamine (1.0 mg/kg). Continuous nicotine initially increased active responding for the visual reinforcer; however, continued exposure resulted in an attenuation of this effect. Precipitated withdrawal from nicotine resulted in a significant decline in active responding. The initial increase in responding for the visual reinforcer with chronic nicotine exposure is consistent with prior research showing that intermittent exposure to nicotine acts as a reinforcement enhancer. However, the attenuation of this enhancement following prolonged nicotine exposure is in contrast with the persistent effects previously reported. Finally, the decrease in visual reinforcers below control levels (nicotine-naive animals) following nicotine withdrawal highlights a potential for affective withdrawal, which may serve as a motive for continued nicotine use.

Reduced benzodiazepine sensitivity in patients with premenstrual syndrome: a pilot study.

PubMed

Sundström, I; Ashbrook, D; Bäckström, T

1997-01-01

Premenstrual syndrome (PMS) is characterized by cyclical changes in psychological and physical symptoms related to the formation of the corpus luteum and the fluctuations of gonadal hormones. Ovarian steroids have direct effects on neurotransmission, exemplified by the binding of certain metabolites of progesterone to the gamma-amino-butyric acid (GABAA) receptor where they exert a facilitating effect on inhibitory neurotransmission. There is also evidence for steroids with inverse-agonist actions on the GABAA-receptor with opposite effects on the GABAergic transmission. The purpose of this pilot study was to examine a possible decrease in GABAA/benzodiazepine-receptor sensitivity in PMS patients using saccadic eye velocity and self-ratings of sedation as dependent measures. Seven patients with proven PMS and seven control subjects were recruited for the study. Saccadic eye velocity (SEV) and visual analogue ratings for sedation and mood were measured after increasing doses of placebo and diazepam. The PMS patients responded with a significantly less decrease in saccadic eye velocity after benzodiazepine injections compared with control subjects, the difference being most prominent in the luteal phase. This group difference was due to an increased SEV responsiveness to benzodiazepines among control subjects in the luteal phase compared with the follicular phase. The PMS patients in the luteal phase responded with less increase in sedation change scores following benzodiazepine injections compared with control subjects. This group difference in the luteal phase was due to a decreased sedation response to benzodiazepines across the menstrual cycle in the PMS patients. There was no correlation between sedation change scores and SEV in PMS patients. These results support evidence for a reduced or dysregulated sensitivity at the GABAA/ benzodiazepine-receptor complex in patients with PMS.

Abrupt Change in Ecological Systems: Inference and Diagnosis.

PubMed

Ratajczak, Zak; Carpenter, Stephen R; Ives, Anthony R; Kucharik, Christopher J; Ramiadantsoa, Tanjona; Stegner, M Allison; Williams, John W; Zhang, Jien; Turner, Monica G

2018-05-18

Abrupt ecological changes are, by definition, those that occur over short periods of time relative to typical rates of change for a given ecosystem. The potential for such changes is growing due to anthropogenic pressures, which challenges the resilience of societies and ecosystems. Abrupt ecological changes are difficult to diagnose because they can arise from a variety of circumstances, including rapid changes in external drivers (e.g., climate, or resource extraction), nonlinear responses to gradual changes in drivers, and interactions among multiple drivers and disturbances. We synthesize strategies for identifying causes of abrupt ecological change and highlight instances where abrupt changes are likely. Diagnosing abrupt changes and inferring causation are increasingly important as society seek to adapt to rapid, multifaceted environmental changes. Copyright © 2018 Elsevier Ltd. All rights reserved.

New benzodiazepine and Z-hypnotic users and disability pension: an eight-year nationwide observational follow-up study.

PubMed

Tvete, Ingunn F; Bjørner, Trine; Skomedal, Tor

2017-09-01

To compare how newly initiated treatment with benzodiazepines, Z-hypnotics or both associates with the reception of disability pension among 40,661 individuals of a working age. Prescription register study. Norwegian nationwide prescriptions socio-economic and disability status data. Cox regression analyses. New benzodiazepine or Z-hypnotic users. Time to receive disability pension given benzodiazepine or Z-hypnotic use or both. Additional analyses focused on the benzodiazepine first redeemed. Among new users 8.65% of Z-hypnotic users, 12.29% of benzodiazepines users and 13.96% of combined Z-hypnotic and benzodiazepine users became disability pensioners. Z-hypnotic users were weaker associated with becoming disability pensioners (HR = 0.78, CI: 0.73-0.84) and combined users were stronger associated (HR = 1.09, CI: 1.01-1.17), than benzodiazepine users. Women had higher risk than men for becoming disability pensioners. Higher age, lower education, previous drug use and psychiatrist as first prescriber were risk factors. Comparing first benzodiazepine redeemed; clonazepam initiators were stronger associated with becoming disability pensioners than diazepam initiators were (HR = 2.22, CI: 1.81-2.71). No differences between other benzodiazepine users were found. Adjusting for known risk factors gave lower risk for Z-hypnotic users compared to benzodiazepine users for receiving disability pension. Combined use increased the risk further. Clonazepam initiators are especially at risk. These findings may be helpful in prescribing situations to identify and guide individuals at risk for becoming disability pensioners.

A Case Report of Nystagmus with Acute Comitant Esotropia Secondary to Heroin Withdrawal: A Novel Presentation

PubMed Central

Rabin, Richard L.

2015-01-01

Background Acute comitant esotropia secondary to heroin withdrawal is a rarely reported phenomenon that has never been described with nystagmus. Adverse effects of heroin on eye alignment were first reported in soldiers returning from Vietnam, yet no theory is generally accepted as the cause of these abnormalities. Method We present a case of a 22-year-old female who developed 40 prism diopters of alternating comitant esotropia with nystagmus 8 days after abrupt heroin cessation, review the existing literature, and propose a novel hypothesis for this phenomenon. Results After 76 days, her esotropia resolved, and she was left with 7 prism diopters of esophoria. Conclusion This case demonstrates that acquired nystagmus can present in addition to acute-onset esotropia after abrupt heroin cessation. We compare and contrast the theories of this mechanism and review the literature. PMID:26483678

No role for benzodiazepines in posttraumatic stress disorder? A surplus of certainty despite scarce evidence.

PubMed

Starcevic, Vladan

2017-08-01

This article addresses some of the controversies about the role of benzodiazepines in the treatment of posttraumatic stress disorder. Benzodiazepines have been admonished in treatment guidelines for posttraumatic stress disorder, but this is based on very little solid evidence. Although benzodiazepines do not seem to be effective in the treatment of the core posttraumatic stress disorder symptoms, their careful use as adjunctive agents for the symptoms such as anxiety and sleep disturbance may be useful. Future research needs to identify predictors of improved treatment outcomes in posttraumatic stress disorder with use of benzodiazepines.

Epidemic Use of Benzodiazepines among Older Adults in Israel: Epidemiology and Leverage Points for Improvement.

PubMed

Steinman, Michael A; Low, Marcelo; Balicer, Ran D; Shadmi, Efrat

2017-08-01

Benzodiazepines and benzodiazepine-receptor agonists (BDZRAs, often known as "Z-drugs") are commonly used in older adults despite well-documented harms. To evaluate patterns of benzodiazepine and BDZRA use in Israel, focusing on potential leverage points where quality improvement initiatives might effectively curtail new use or the transition from intermittent to chronic use. We used national electronic medical data to assess a 10% random sample of adults receiving care in Clalit Health Services, which serves half of Israel's population. The sample included 267,221 adults, of whom 56,808 (21%) were age 65 and older. Medication use from 2013 to 2015 was ascertained using pharmacy dispensing data. In 2014, 7% of adults age 21-64 and 32% of adults age 65 and older received at least one benzodiazepine/BDZRA, including 49% of adults age 85 and older (P < 0.001). The majority of older users (59%) were long-term users of the drugs, and 21% of older adults who were short-term users in 2014 transitioned to medium- or long-term use in 2015. Older Arab Israelis were much less likely to receive benzodiazepine/BDZRAs than older Jewish Israelis (adjusted OR 0.28, 95% 0.25-0.31), but within each community there was no major variation in prescribing rates across clinics. Depression diagnosis was associated with particularly high rates of benzodiazepine/BDZRA use: 17% of older adults with depression received a benzodiazepine/BDZRA but no antidepressant, and 42% received both. Recent hospitalization increased the risk of new benzodiazepine/BDZRA use (adjusted OR 1.41, 95% CI 1.01-1.96), but the absolute risk increase was only 3%. Benzodiazepines/BDZRAs are used at exceptionally high rates by older Israeli adults, especially the oldest old. Important leverage points for quality improvement efforts include curtailing the transition from short-term to long-term use, reducing use in older adults with depression, and identifying reasons that explain large differences in benzodiazepine

Initiation and long-term use of benzodiazepines and Z-drugs in bipolar disorder.

PubMed

Wingård, Louise; Taipale, Heidi; Reutfors, Johan; Westerlund, Anna; Bodén, Robert; Tiihonen, Jari; Tanskanen, Antti; Andersen, Morten

2018-02-16

Increasing evidence points to the harmful effects of long-term benzodiazepine treatment. Our objective was to study the incidence of, and predictors for, long-term use of benzodiazepines and Z-drugs in bipolar disorder. We conducted a population-based cohort study, using data from Swedish national registers. Swedish residents aged 18-75 years with a recorded diagnosis of bipolar disorder or mania between July 2006 and December 2012, and no history of benzodiazepine/Z-drug use in the past year, were included. Patients were followed for 1 year with regard to prescription fills of benzodiazepines/Z-drugs. Initiators were followed for another year during which continuous use for >6 months was defined as "long-term". Patient and prescription characteristics were investigated as potential predictors for long-term use in multivariate logistic regression models. Out of the 21 883 patients included, 29% started benzodiazepine/Z-drug treatment, of whom one in five became long-term users. Patients who were prescribed clonazepam or alprazolam had high odds for subsequent long-term use (adjusted odds ratios [aORs] 3.78 [95% confidence interval (CI) 2.24-6.38] and 2.03 [95% CI 1.30-3.18], respectively), compared to those prescribed diazepam. Polytherapy with benzodiazepines/Z-drugs also predicted long-term use (aOR 2.46, 95% CI 1.79-3.38), as did age ≥60 years (aOR 1.93, 95% CI 1.46-2.53, compared to age <30 years), and concomitant treatment with psychostimulants (aOR 1.78, 95% CI 1.33-2.39). The incidence of subsequent long-term use among bipolar benzodiazepine initiators is high. Patients on clonazepam, alprazolam or benzodiazepine/Z-drug polytherapy have the highest risk of becoming long-term users, suggesting that these treatments should be used restrictively. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Benzodiazepines for neuroleptic-induced acute akathisia.

PubMed

Lima, A R; Soares-Weiser, K; Bacaltchuk, J; Barnes, T R

2002-01-01

Neuroleptic-induced akathisia is one of the most common and distressing early-onset adverse effects of antipsychotic drugs, being associated with poor compliance with treatment, and thus, ultimately, to an increase risk of relapse. This review assesses the role of benzodiazepines in the pharmacological treatment of this problem. To determine the effects of benzodiazepines versus placebo for people with neuroleptic-induced acute akathisia. Biological Abstracts (January 1982-March 1999), The Cochrane Library (Issue 3 1999), The Cochrane Schizophrenia Group's Register (May 2001), EMBASE (January 1980-March 1999), LILACS (January 1982-March 1999), MEDLINE (January 1964-March 1999), PsycLIT (January 1974-March 1999), and SCISEARCH were searched. Further references were sought from published trials and their authors. All randomised clinical trials comparing benzodiazepines with placebo for people with antipsychotic-induced acute akathisia. Two reviewers, working independently, selected, quality assessed and extracted data. These data were then analysed on an intention-to-treat basis. For homogeneous dichotomous data the fixed effects relative risk (RR), the 95% confidence intervals (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data, reviewers calculated weighted mean differences. Two small (total N=27) randomised controlled trials were included. By seven to 14 days, there was a reduction in symptoms for those patients receiving clonazepam compared with placebo (2 RCTs, N=26, RR 0.09 CI 0.01 to 0.6, NNT 1.2 CI 0.9 to 1.5). No significant difference was found for adverse events (2 RCTs, N=26, RR 3.00 CI 0.2 to 62) or the need for anticholinergic medication (2 RCTs, N=26, RR 1.56 CI 0.9 to 2.7). No one left the two studies early. Data on mental, social and family outcomes could not be pooled and there was little or no data on user satisfaction, deaths, violence, criminal behaviour and costs. Over

Risk of pneumonia associated with incident benzodiazepine use among community-dwelling adults with Alzheimer disease.

PubMed

Taipale, Heidi; Tolppanen, Anna-Maija; Koponen, Marjaana; Tanskanen, Antti; Lavikainen, Piia; Sund, Reijo; Tiihonen, Jari; Hartikainen, Sirpa

2017-04-10

Knowledge regarding whether benzodiazepines and similarly acting non-benzodiazepines (Z-drugs) are associated with an increased risk of pneumonia among older adults is lacking. We sought to investigate this association among community-dwelling adults with Alzheimer disease, a condition in which both sedative/hypnotic use and pneumonia are common. We obtained data on all community-dwelling adults with a recent diagnosis of Alzheimer disease in Finland (2005-2011) from the Medication use and Alzheimer disease (MEDALZ) cohort, which incorporates national registry data on prescriptions, reimbursement, hospital discharges and causes of death. Incident users of benzodiazepines and Z-drugs were identified using a 1-year washout period and matched with nonusers using propensity scores. The association with hospital admission or death due to pneumonia was analyzed with the Cox proportional hazards model and adjusted for use of other psychotropic drugs in a time-dependent manner. Among 49 484 eligible participants with Alzheimer disease, 5232 taking benzodiazepines and 3269 taking Z-drugs were matched 1:1 with those not taking these drugs. Collectively, use of benzodiazepines and Z-drugs was associated with an increased risk of pneumonia (adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.05-1.42). When analyzed separately, benzodiazepine use was significantly associated with an increased risk of pneumonia (adjusted HR 1.28, 95% CI 1.07-1.54), whereas Z-drug use was not (adjusted HR 1.10, 95% CI 0.84-1.44). The risk of pneumonia was greatest within the first 30 days of benzodiazepine use (HR 2.09, 95% CI 1.26-3.48). Benzodiazepine use was associated with an increased risk of pneumonia among patients with Alzheimer disease. Risk of pneumonia should be considered when weighing the benefits and risks of benzodiazepines in this population. © 2017 Canadian Medical Association or its licensors.

Risk of pneumonia associated with incident benzodiazepine use among community-dwelling adults with Alzheimer disease

PubMed Central

Taipale, Heidi; Tolppanen, Anna-Maija; Koponen, Marjaana; Tanskanen, Antti; Lavikainen, Piia; Sund, Reijo; Tiihonen, Jari; Hartikainen, Sirpa

2017-01-01

BACKGROUND: Knowledge regarding whether benzodiazepines and similarly acting non-benzodiazepines (Z-drugs) are associated with an increased risk of pneumonia among older adults is lacking. We sought to investigate this association among community-dwelling adults with Alzheimer disease, a condition in which both sedative/hypnotic use and pneumonia are common. METHODS: We obtained data on all community-dwelling adults with a recent diagnosis of Alzheimer disease in Finland (2005–2011) from the Medication use and Alzheimer disease (MEDALZ) cohort, which incorporates national registry data on prescriptions, reimbursement, hospital discharges and causes of death. Incident users of benzodiazepines and Z-drugs were identified using a 1-year washout period and matched with nonusers using propensity scores. The association with hospital admission or death due to pneumonia was analyzed with the Cox proportional hazards model and adjusted for use of other psychotropic drugs in a time-dependent manner. RESULTS: Among 49 484 eligible participants with Alzheimer disease, 5232 taking benzodiazepines and 3269 taking Z-drugs were matched 1:1 with those not taking these drugs. Collectively, use of benzodiazepines and Z-drugs was associated with an increased risk of pneumonia (adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.05–1.42). When analyzed separately, benzodiazepine use was significantly associated with an increased risk of pneumonia (adjusted HR 1.28, 95% CI 1.07–1.54), whereas Z-drug use was not (adjusted HR 1.10, 95% CI 0.84–1.44). The risk of pneumonia was greatest within the first 30 days of benzodiazepine use (HR 2.09, 95% CI 1.26–3.48). INTERPRETATION: Benzodiazepine use was associated with an increased risk of pneumonia among patients with Alzheimer disease. Risk of pneumonia should be considered when weighing the benefits and risks of benzodiazepines in this population. PMID:28396328

Benzodiazepine use among adults residing in the urban settlements of Karachi, Pakistan: A cross sectional study

PubMed Central

2011-01-01

Background There are hardly any studies carried out in Pakistan on the usage of benzodiazepines at the level of community. This research was aimed to determine the frequency of benzodiazepine use, along with its associations with socio-demographic and clinical characteristics among community dwelling adults, residing in two urban settlements of Karachi, Pakistan. Methods We performed a cross sectional study from August 2008 to December 2009, in 2 areas of Karachi, namely Garden and Sultanabad. We followed the systematic sampling strategy to randomly select the households, with an adult of either sex and of age 18 years or more. Data collection was carried out through interview, using a pre-tested questionnaire, with items on socio-demographic position, medical history and benzodiazepine use. Student's t-test and χ2 test was employed to determine the associations between socio-demographic and clinical characteristics, and their relationship with benzodiazepine use was determined using applied logistic regression. Results The overall percentage of benzodiazepine consumption was estimated to be 14%. There were significantly more benzodiazepine users in the peri-urban Sultanabad community to the urban community of Garden (p-value = 0.001). The mean age (± SD) for users was 51.3 (± 15.6) years compared to 37.1 (± 14.4) years among non-users. Bromazepam was the most widely used benzodiazepine (29%); followed by diazepam, with a median duration on primary use being 144 weeks (IQR = 48-240). The adjusted logistic regression model revealed that increasing age, location, female sex, unemployment and psychiatric consultation were associated with increased likelihood of benzodiazepine use. Conclusion We believe the unregulated over-the-counter sales of benzodiazepines and social conditions might be playing a role in this high consumption of benzodiazepines in the community. PMID:21801457

Benzodiazepines prescription in Dakar: a study about prescribing habits and knowledge in general practitioners, neurologists and psychiatrists.

PubMed

Dièye, Amadou Moctar; Sylla, Mbaye; Ndiaye, Awa; Ndiaye, Mamadou; Sy, Guata Yoro; Faye, Babacar

2006-06-01

Benzodiazepines are relatively well-tolerated medicines but can induce serious problems of addiction and that is why their use is regulated. However, in developing countries like Senegal, these products are used without clear indications on their prescription, their dispensation or their use. This work focuses on the prescription of these medicines with a view to make recommendations for their rational use. Benzodiazepine prescription was studied with psychiatrists or neurologists and generalists in 2003. Specialist doctors work in two Dakar university hospitals and generalists in the 11 health centres in Dakar. We did a survey by direct interview with 29 of 35 specialists and 23 of 25 generalists. All doctors were interviewed in their office. The questionnaire focused on benzodiazepine indications, their pharmacological properties, benzodiazepines prescribed in first intention against a given disease and the level of training in benzodiazepines by doctors. Comparisons between specialists and generalists were made by chi-square test. Benzodiazepines were essentially used for anxiety, insomnia and epilepsy. With these diseases, the most benzodiazepines prescribed are prazepam against anxiety and insomnia and diazepam against epilepsy. About 10% of doctors do not know that there is a limitation for the period of benzodiazepine use. The principal reasons of drugs choice are knowledge of the drugs, habit and low side effects of drugs. All generalists (100%) said that their training on benzodiazepines is poor vs. 62.1% of specialists, and doctors suggest seminars, journals adhesions and conferences to complete their training in this field. There are not many differences between specialists and generalists except the fact that specialists prefer prazepam in first intention in the insomnia treatment where generalists choose bromazepam. In addition, our survey showed that specialists' training in benzodiazepines is better than that of generalists. Overall, benzodiazepine

Synthesis of a Benzodiazepine-derived Rhodium NHC Complex by C-H Bond Activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bergman, Roberg G.; Gribble, Jr., Michael W.; Ellman, Jonathan A.

2008-01-30

The synthesis and characterization of a Rh(I)-NHC complex generated by C-H activation of 1,4-benzodiazepine heterocycle are reported. This complex constitutes a rare example of a carbene tautomer of a 1,4-benzodiazepine aldimine stabilized by transition metal coordination and demonstrates the ability of the catalytically relevant RhCl(PCy{sub 3}){sub 2} fragment to induce NHC-forming tautomerization of heterocycles possessing a single carbene-stabilizing heteroatom. Implications for the synthesis of benzodiazepines and related pharmacophores via C-H functionalization are discussed.

[Characteristics of alcohol withdrawal delirium in surgical patients and recommendations for treatment].

PubMed

Naber, M; Franz, W; Overbeck, W

1991-02-01

An alcohol withdrawal syndrome affects the patient in a 'vulnerable phase' either after an operation or posttraumatically. It can be shown pathophysiologically, that the symptoms are caused by a hyperactivity of the central sympathetic nervous system and a disbalance of the neurotransmitters. As for these complex symptoms, a multi-layered treatment is required. We report on our experiences with 23 patients who were treated in our intensive care unit. The treatment included a benzo-diazepine and a drug effecting central alpha 2-receptors. Only three of these patients had to be intubated or ventilated. Because of the induced bradycardia monitor observation was required in all cases. The patients could be wakened up at any time and thus were co-operative for basic care. One patient died of pulmonary embolism, a second patient died of cardiovascular failure as a consequence of cardiac insufficiency.

End-tidal concentration of sevoflurane for preventing rocuronium-induced withdrawal of the arm in pediatric patients.

PubMed

Yeom, Jong Hoon; Kim, Yong Oh; Lee, Jae Min; Jeon, Woo Jae

2014-04-01

During induction of general anesthesia, the intravenous injection of rocuronium is often associated with withdrawal movement of the arm due to pain, and this abrupt withdrawal may result in dislodgement of the venous catheter, injury, or inadequate injection of rocuronium. We performed this study to evaluate the 50 and 95% effective end-tidal concentrations of sevoflurane (ETsev) for preventing rocuronium-induced withdrawal of the arm. We conducted a prospective double-blind study in 31 pediatric patients. After free flow of lactated Ringer's IV fluid was confirmed, anesthesia was induced in the patients by using 2.5% thiopental sodium (4 mg/kg) and sevoflurane (4 vol%) with 6 L/min of oxygen. When the target ETsev was reached, preservative-free 1% lidocaine (1.5 mg/kg) was intravenously injected during manual venous occlusion and rocuronium (0.6 mg/kg) was injected after lidocaine injection under free-flow intravenous fluid. A nurse who was an investigator and was blinded to the ETsev injected the rocuronium. The nurse evaluated the response. Non-withdrawal movement was observed in 5 out of 11 patients with ETsev 3.0 vol% and in 5 out of 6 patients with ETsev 3.5 vol%. By Dixon's up-and-down method, the 50% effective concentration (EC50) of sevoflurane for non-withdrawal movement at rocuronium injection was 3.1 ± 0.4 vol%. A logistic regression curve of the probability of non-withdrawal movements showed that the 50% effective ETsev for abolishing withdrawal movement at rocuronium injection was 2.9 vol% (95% confidence interval [CI] 2.4-3.8 vol%) and the 95% effective ETsev was 4.3 vol% (95% CI 3.6-9.8 vol%). This study showed that the 50 and 95% effective ETsev that prevent withdrawal movement at rocuronium injection are 2.9 and 4.3 vol%, respectively.

[Impact of benzodiazepine dependence on the use of health services: study of the health of seniors].

PubMed

Nkogho Mengue, Pamphile-Gervais; Abdous, Belkacem; Berbiche, Djamal; Préville, Michel; Voyer, Philippe

2013-03-01

The use of benzodiazepines is common among seniors. This consumption can cause an addiction whose criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition revised (DSM-IV-TR) do not always apply to the situation of the elderly. This research seeks to examine the link between the feeling of benzodiazepine dependence and the use of health services by seniors. A secondary objective is to describe the use of benzodiazepines among seniors living in the community. Data derive from a survey conducted in Quebec in 2005-2006 from a representative sample of 707 Francophones aged 65 and over living in the community. The feeling of benzodiazepine dependence was measured by a composite variable incorporating two questions inspired by the DSM-IV-TR. The use of health services was measured through the cumulative impact of consultation with health care professionals during a 12- month period. Older adults consumed a total of 745 benzodiazepines, including 117 (16.5%) which had a half-long life. The proportion of seniors who reported a feeling of dependence on benzodiazepines was estimated at 35.1 %. These seniors did not significantly make further use of health services for their addiction to benzodiazepines. The results of this study suggest that the use of benzodiazepines among seniors in Quebec is far from optimal. Moreover, the perceived need in addiction is not a significant factor in inducing seniors to use health services for the management of addiction. There is, therefore, a need for research to better understand the barriers associated with the use of health services by seniors addicted to benzodiazepines.

Benzodiazepine-like hypnotics and the associated risk of road traffic accidents.

PubMed

Orriols, L; Philip, P; Moore, N; Castot, A; Gadegbeku, B; Delorme, B; Mallaret, M; Lagarde, E

2011-04-01

The aim of the study was to investigate the association between the use of benzodiazepine or benzodiazepine-like hypnotics and the risk of road traffic accidents. Data from three French national databases were matched: the health-care insurance database, police reports, and the police database of injury-related traffic accidents. A total of 72,685 drivers involved in injury-related road traffic accidents in France, from 2005 to 2008, were included in the study. The risk of being responsible for a traffic accident was higher in users of benzodiazepine hypnotics (odds ratio (OR) = 1.39 (1.08-1.79)) and in the 155 drivers to whom a dosage of more than one pill of zolpidem a day had been dispensed during the 5 months before the collision (OR = 2.46 (1.70-3.56)). No association was found between the use of zopiclone and risk of traffic accidents. Although this study did not find any association between the use of zolpidem as recommended and causation of traffic accidents, the potential risk related to possible abuse of the drug and risky driving behaviors should be further investigated. The results related to benzodiazepine hypnotics are consistent with those of previous studies.

Anxiety Sensitivity and Nonmedical Benzodiazepine Use among Adults with Opioid Use Disorder

PubMed Central

McHugh, R. Kathryn; Votaw, Victoria; Bogunovic, Olivera; Karakula, Sterling L.; Griffin, Margaret L.; Weiss, Roger D.

2016-01-01

Nonmedical benzodiazepine use is common among adults with opioid use disorder; however, little is known about this co-occurrence. Anxiety sensitivity--the fear of anxiety symptoms and sensations--motivates behaviors to escape and avoid distressing states, and accordingly is associated with coping motives for substance use. This might be particularly relevant among women, who report using substances to cope with negative emotions more often than men. The aim of the current study was to examine whether nonmedical benzodiazepine use was associated with higher anxiety sensitivity among treatment-seeking adults diagnosed with opioid use disorder, and to investigate whether gender moderated this association. A sample of adults (ranging in age from 18–81 years) receiving inpatient treatment for opioid use disorder (N=257) completed measures of anxiety, anxiety sensitivity, and benzodiazepine use frequency. Results of an analysis of variance indicated that frequency of past-month nonmedical benzodiazepine use was associated with significantly higher anxiety sensitivity. This effect remained when controlling for the effect of anxiety symptoms (F[1, 251] = 3.91, p = .049, ηp2=.02). Gender moderated this association, and post-hoc analyses found a strong association between nonmedical benzodiazepine use and anxiety sensitivity in women, and not men. Anxiety sensitivity, which can be reduced with treatment, might be a candidate therapeutic target in this population, particularly in women. PMID:27575980

Analysis of abrupt transitions in ecological systems

USDA-ARS?s Scientific Manuscript database

The occurrence and causes of abrupt transitions, thresholds, or regime shifts between ecosystem states are of great concern and the likelihood of such transitions is increasing for many ecological systems. General understanding of abrupt transitions has been advanced by theory, but hindered by the l...

Benzodiazepine Synthesis and Rapid Toxicity Assay

ERIC Educational Resources Information Center

Fletcher, James T.; Boriraj, Grit

2010-01-01

A second-year organic chemistry laboratory experiment to introduce students to general concepts of medicinal chemistry is described. Within a single three-hour time window, students experience the synthesis of a biologically active small molecule and the assaying of its biological toxicity. Benzodiazepine rings are commonly found in antidepressant…

Cocaine withdrawal

MedlinePlus

... Substance use - cocaine withdrawal; Substance abuse - cocaine withdrawal; Drug abuse - cocaine withdrawal; Detox - cocaine ... Elsevier Saunders; 2016:chap 50. National Institute on Drug Abuse. What is cocaine? Updated May 2016. www.drugabuse. ...

CYP2C9 Genotypes Modify Benzodiazepine-Related Fall Risk: Original Results From Three Studies With Meta-Analysis.

PubMed

Ham, Annelies C; Ziere, Gijsbertus; Broer, Linda; Swart, Karin M A; Enneman, Anke W; van Dijk, Suzanne C; van Wijngaarden, Janneke P; van der Zwaluw, Nikita L; Brouwer-Brolsma, Elske M; Dhonukshe-Rutten, Rosalie A M; van Schoor, Natasja M; Zillikens, M Carola; van Gelder, Teun; de Vries, Oscar J; Lips, Paul; Deeg, Dorly J H; de Groot, Lisette C P G M; Hofman, Albert; Witkamp, Renger F; Uitterlinden, André G; Stricker, Bruno H; van der Velde, Nathalie

2017-01-01

To investigate whether the CYP2C9*2 and *3 variants modify benzodiazepine-related fall risk. Three prospective studies; the Rotterdam Study, B-PROOF, and LASA. Community-dwelling individuals living in or near five Dutch cities. There were 11,485 participants aged ≥55 years. Fall incidents were recorded prospectively. Benzodiazepine use was determined using pharmacy dispensing records or interviews. Cox proportional hazard models adjusted for age and sex were applied to determine the association between benzodiazepine use and fall risk stratified for CYP2C9 genotype and comparing benzodiazepine users to nonusers. The results of the three studies were combined applying meta-analysis. Within benzodiazepine users, the association between genotypes and fall risk was also assessed. Three thousand seven hundred five participants (32%) encountered a fall during 91,996 follow-up years, and 4% to 15% (depending on the study population) used benzodiazepines. CYP2C9 variants had frequencies of 13% for the *2 allele and 6% for the *3 allele. Compared to nonusers, current benzodiazepine use was associated with an 18% to 36% increased fall risk across studies with a combined hazard ratio (HR) = 1.26 (95% confidence interval [CI], 1.13; 1.40). CYP2C9*2 or *3 allele variants modified benzodiazepine-related fall risk. Compared to nonusers, those carrying a CYP2C9*2 or *3 allele and using benzodiazepines had a 45% increased fall risk (HR, 1.45 95% CI, 1.21; 1.73), whereas CYP2C9*1 homozygotes using benzodiazepines had no increased fall risk (HR, 1.14; 95% CI, 0.90; 1.45). Within benzodiazepine users, having a CYP2C9*2 or *3 allele was associated with an increased fall risk (HR, 1.35; 95% CI, 1.06; 1.72). Additionally, we observed an allele dose effect; heterozygous allele carriers had a fall risk of (HR = 1.30; 95% CI, 1.05; 1.61), and homozygous allele carriers of (HR = 1.91 95% CI, 1.23; 2.96). CYP2C9*2 and *3 allele variants modify benzodiazepine-related fall risk. Those

Controls on the abruptness of gravel-sand transitions

NASA Astrophysics Data System (ADS)

Venditti, J. G.; Church, M. A.; Lamb, M. P.; Domarad, N.; Rennie, C. D.

2014-12-01

As gravel-bedded rivers fine downstream, they characteristically exhibit an abrupt transition from gravel- to sand-bed. This is the only abrupt transition in grain-size that occurs in the fluvial system and has attracted considerable attention. A number of competing theories have been proposed to account for the abruptness of the transition, including base-level control, attrition of ~10mm gravel to produce sand, and sediment sorting processes. The prevailing theory for the emergence of abrupt transitions is size selective sorting of bimodal sediment wherein gravel deposits due to downstream declining shear stress, fining the bedload until a sand-bed emerges. We explored this hypothesis by examining grain-size, shear stress, gravel mobility and sand suspension thresholds through the gravel-sand transition (GST) of the Fraser River, British Columbia. The Fraser GST is an arrested gravel wedge with patches of gravel downstream of the wedge forming a diffuse extension. There is an abrupt change in bed slope through the transition that leads to an abrupt change in shear stress. The GST, bed-slope change and backwater caused by the ocean are all coincident spatially, which enhances the sharpness of the GST. Interestingly, the bimodal reach of the river occurs downstream of the GST and exhibits no downstream gradients in shear stress, suspended sediment flux, gravel mobility or sand suspension thresholds. This calls into question the prevailing theory for the emergence of an abrupt GST by size selective sorting. We provide evidence, both empirical and theoretical, that suggests the emergence of an abrupt GST is caused by rapid deposition of sand when fine gravel deposits. We argue that the emergence of gravel-sand transitions is a consequence of gravel-bedded rivers adopting a steeper slope than sand-bedded rivers. The abruptness arises because the bed slope required to convey the gravel load fixes the distal location of a terminal gravel wedge, and once the river has

Endogenous benzodiazepine-like compounds and diazepam binding inhibitor in serum of patients with liver cirrhosis with and without overt encephalopathy

PubMed Central

Avallone, R; Zeneroli, M; Venturini, I; Corsi, L; Schreier, P; Kleinschnitz, M; Ferrarese, C; Farina, F; Baraldi, C; Pecora, N; Frigo, M; Baraldi, M

1998-01-01

Background/Aim—Despite some controversy, it has been suggested that endogenous benzodiazepine plays a role in the pathogenesis of hepatic encephalopathy. The aim of the present study was to evaluate the concentrations of endogenous benzodiazepines and the peptide, diazepam binding inhibitor, in the blood of patients with liver cirrhosis with and without overt encephalopathy, and to compare these levels with those of consumers of commercial benzodiazepines. 
Subjects—Normal subjects (90), benzodiazepine consumers (14), and cirrhotic patients (113) were studied. 
Methods—Endogenous benzodiazepines were measured by the radioligand binding technique after high performance liquid chromatography (HPLC) purification. The presence of diazepam and N-desmethyldiazepam was assayed by HPLC-electrospray tandem mass spectrometry. Diazepam binding inhibitor was studied in serum by radioimmunoassay. 
Results—Endogenous benzodiazepines were below the limit of detection in 7% of patients with encephalopathy. When detectable, their levels were at least comparable with those of benzodiazepine consumers and correlated with the liver dysfunction but not the stage of encephalopathy. Serum levels of diazepam binding inhibitor tended to decrease when endogenous benzodiazepines levels increased. 
Conclusions—Endogenous benzodiazepines may accumulate in patients with liver cirrhosis during the course of the disease, and the phenomenon appears to be independent of the presence or absence of encephalopathy. 

 Keywords: benzodiazepine consumers; diazepam binding inhibitor; endogenous benzodiazepines; liver cirrhosis; overt hepatic encephalopathy PMID:9691927

Abrupt Impacts of Climate Change: Anticipating Surprises

NASA Astrophysics Data System (ADS)

White, James W. C.; Alley, Richard B.; Archer, David E.; Barnosky, Anthony D.; Dunlea, Edward; Foley, Jonathan; Fu, Rong; Holland, Marika M.; Lozier, M. Susan; Schmitt, Johanna; Smith, Laurence C.; Sugihara, George; Thompson, David W. J.; Weaver, Andrew J.; Wofsy, Steven C.

2014-05-01

Levels of carbon dioxide and other greenhouse gases in Earth's atmosphere are exceeding levels recorded in the past millions of years, and thus climate is being forced beyond the range of the recent geological era. Lacking concerted action by the world's nations, it is clear that the future climate will be warmer, sea levels will rise, global rainfall patterns will change, and ecosystems will be altered. However, there is still uncertainty about how we will arrive at that future climate state. Although many projections of future climatic conditions have predicted steadily changing conditions giving the impression that communities have time to gradually adapt, the scientific community has been paying increasing attention to the possibility that at least some changes will be abrupt, perhaps crossing a threshold or "tipping point" to change so quickly that there will be little time to react. This presentation will synopsize the new US National Research Council Report, Abrupt Impacts of Climate Change: Anticipating Surprises, highlighting areas of increased and decreased concern, as well as areas of new concern. Emphasis is placed on not only abrupt change in physical climate, but on abrupt changes in human and natural systems that can occur as a result of a slowly changing climate. The report calls for action now on an abrupt change early warning system (ACEWS) if societies are to be resilient to climate change.

Evaluation of the Anxiolytic Activity of NR-ANX-C (a Polyherbal Formulation) in Ethanol Withdrawal-Induced Anxiety Behavior in Rats.

PubMed

Mohan, L; Rao, U S C; Gopalakrishna, H N; Nair, V

2011-01-01

The present study investigates the anxiolytic activity of NR-ANX-C, a standardized polyherbal formulation containing the extracts of Withania somnifera, Ocimum sanctum, Camellia sinensis, Triphala, and Shilajit in ethanol withdrawal- (EW-) induced anxiety behavior in rats. Ethanol dependence in rats was produced by substitution of drinking water with 7.5% v/v alcohol for 10 days. Then, ethanol withdrawal was induced by replacing alcohol with drinking water, 12 hours prior to experimentation. After confirming induction of withdrawal symptoms in the alcohol deprived animals, the anxiolytic activity of the test compound in graded doses (10, 20, and 40 mg/kg) was compared to the standard drug alprazolam (0.08 mg/kg) in the elevated plus maze and bright and dark arena paradigms. In our study, single and repeated dose administration of NR-ANX-C reduced EW-induced anxiety in a dose-dependent manner. Even though the anxiolytic activity was not significant at lower doses, NR-ANX-C at the highest dose tested (40 mg/kg) produced significant anxiolytic activity that was comparable to the standard drug alprazolam. Based on our findings we believe that NR-ANX-C has the potential to be used as an alternative to benzodiazepines in the treatment of EW-induced anxiety.

Evaluation of the Anxiolytic Activity of NR-ANX-C (a Polyherbal Formulation) in Ethanol Withdrawal-Induced Anxiety Behavior in Rats

PubMed Central

Mohan, L.; Rao, U. S. C.; Gopalakrishna, H. N.; Nair, V.

2011-01-01

The present study investigates the anxiolytic activity of NR-ANX-C, a standardized polyherbal formulation containing the extracts of Withania somnifera, Ocimum sanctum, Camellia sinensis, Triphala, and Shilajit in ethanol withdrawal- (EW-) induced anxiety behavior in rats. Ethanol dependence in rats was produced by substitution of drinking water with 7.5% v/v alcohol for 10 days. Then, ethanol withdrawal was induced by replacing alcohol with drinking water, 12 hours prior to experimentation. After confirming induction of withdrawal symptoms in the alcohol deprived animals, the anxiolytic activity of the test compound in graded doses (10, 20, and 40 mg/kg) was compared to the standard drug alprazolam (0.08 mg/kg) in the elevated plus maze and bright and dark arena paradigms. In our study, single and repeated dose administration of NR-ANX-C reduced EW-induced anxiety in a dose-dependent manner. Even though the anxiolytic activity was not significant at lower doses, NR-ANX-C at the highest dose tested (40 mg/kg) produced significant anxiolytic activity that was comparable to the standard drug alprazolam. Based on our findings we believe that NR-ANX-C has the potential to be used as an alternative to benzodiazepines in the treatment of EW-induced anxiety. PMID:20953426

Effects of the mGluR2/3 agonist LY379268 and the mGluR5 antagonist MPEP on handling-induced convulsions during ethanol withdrawal in mice

PubMed Central

Olive, M. Foster; Becker, Howard C.

2008-01-01

In alcoholic patients, ethanol is often consumed in a repeated cyclic pattern of intoxication followed by abstinence and the emergence of withdrawal symptoms. Repeated cycles of ethanol intoxication and withdrawal lead to a sensitization of CNS hyperexcitability as a result of an imbalance between inhibitory GABAergic transmission and excitatory glutamatergic transmission. Symptoms of alcohol withdrawal are usually treated pharmacologically with either benzodiazepines or anticonvulsant medications. However, recent evidence suggests that inhibition of glutamate transmission by stimulation of presynaptic inhibitory metabotropic glutamate receptors (i.e., mGluR2/3 receptors) or inhibition of mGluR5 receptors produces anticonvulsant effects. Therefore, the present study was designed to determine the effects the mGluR2/3 agonist LY379268 and the mGluR5 antagonist MPEP on ethanol withdrawal-induced seizure activity. Adult male C3H/He mice received chronic 16 h of ethanol vapor exposure in inhalation chambers followed by 8 hr of withdrawal daily for 4 consecutive days. During the final (fourth) withdrawal cycle, mice were evaluated hourly for handling-induced convulsions (HIC), and were treated with vehicle, LY379268 (0.3, 1 and 3 mg/kg) or MPEP (1, 3 and 10 mg/kg) treatment at 4 and 8 hr into withdrawal. Significant reductions in overall HIC activity were not observed following administration of either compound. These results suggest that inhibition of glutamate transmission by mGluR2/3 agonists or mGluR5 antagonists does not alter HIC activity during withdrawal from repeated ethanol exposure, and as such these compounds may have limited usefulness in the treatment of CNS hyperexcitability during alcohol withdrawal. PMID:18420113

Synthesis, anticonvulsant, sedative and anxiolytic activities of novel annulated pyrrolo[1,4]benzodiazepines.

PubMed

Sorra, Kumaraswamy; Chen, Chien-Shu; Chang, Chi-Fen; Pusuluri, Srinivas; Mukkanti, Khagga; Wu, Chi-Rei; Chuang, Ta-Hsien

2014-09-18

Four new pentacyclic benzodiazepine derivatives (PBDTs 13-16) were synthesized by conventional thermal heating and microwave-assisted intramolecular cyclocondensation. Their anticonvulsant, sedative and anxiolytic activities were evaluated by drug-induced convulsion models, a pentobarbital-induced hypnotic model and an elevated plus maze in mice. PBDT 13, a triazolopyrrolo[2,1-c][1,4]benzodiazepin-8-one fused with a thiadiazolone ring, exhibited the best anticonvulsant, sedative and anxiolytic effects in our tests. There was no significant difference in potency between PBDT 13 and diazepam, and we proposed that the action mechanism of PBDT 13 could be similar to that of diazepam via benzodiazepine receptors.

Withdrawal from repeated treatment with ethanol induces a protracted decrease in novelty-seeking behavior and enhancement of environmental habituation in mice.

PubMed

Fukushiro, Daniela F; Saito, Luis P; Mári-Kawamoto, Elisa; Aramini, Tatiana C F; Costa, Jacqueline M; Josino, Fabiana S; Uehara, Regina A; Frussa-Filho, Roberto

2012-03-01

Ethanol withdrawal syndrome is characterized by somatic and behavioral symptoms, including increased anxiety and anhedonia. In animal models, however, there are many studies on the anxiogenic effects occurring during the first 24h after ethanol withdrawal, while anhedonia has been overlooked. Recently, we have found that amphetamine withdrawal reduced novelty seeking and enhanced environmental habituation in mice, two motivation-related behaviors. We now investigate the effects of withdrawal from ethanol, a drug of abuse with a different pharmacological profile, on these two motivation-related behaviors. Swiss male mice (3months old) were treated with 1.8g/kg ethanol for 21 consecutive days in their home cages. Seven days after ethanol withdrawal, mice were tested in a free-choice novelty apparatus containing one familiar and one novel compartment. Novelty-seeking behavior was assessed by comparing time spent in the novel compartment versus the familiar compartment, whereas environmental habituation was concomitantly evaluated by the time-response curve of total locomotion (novel+familiar). Novelty seeking was decreased and environmental habituation was enhanced during ethanol withdrawal. These anhedonic responses were not associated with concurrent changes in the anxiety-like behavior of mice (as confirmed in the elevated plus-maze test). We propose that the concomitant evaluation of novelty-seeking behavior and environmental habituation can be useful to study the behavioral consequences not only of amphetamine withdrawal but also of ethanol withdrawal. Furthermore, the present data support recent clinical findings that suggest the occurrence of protracted anhedonia well beyond the limited period immediately following the abrupt cessation of ethanol intake. Copyright © 2012. Published by Elsevier Inc.

Withdrawal

MedlinePlus

... However, withdrawal is considered a better method of contraception than none at all. Protection Against STDs Withdrawal ... 2013 More on this topic for: Teens Emergency Contraception Talking to Your Partner About Condoms Birth Control ...

Antagonism of methoxyflurane-induced anesthesia in rats by benzodiazepine inverse agonists.

PubMed

Miller, D W; Yourick, D L; Tessel, R E

1989-11-28

Injection of the partial benzodiazepine inverse agonist Ro15-4513 (1-32 mg/kg i.p.) or nonconvulsant i.v. doses of the full benzodiazepine inverse agonist beta-CCE immediately following cessation of exposure of rats to an anesthetic concentration of methoxyflurane significantly antagonized the duration of methoxyflurane anesthesia as measured by recovery of the righting reflex and/or pain sensitivity. This antagonism was inhibited by the benzodiazepine antagonist Ro15-1788 at doses which alone did not alter the duration of methoxyflurane anesthesia. In addition, high-dose Ro15-4513 pretreatment (32 mg/kg) antagonized the induction and duration of methoxyflurane anesthesia but was unable to prevent methoxyflurane anesthesia or affect the induction or duration of anesthesia induced by the dissociative anesthetic ketamine (100 mg/kg). These findings indicate that methoxyflurane anesthesia can be selectively antagonized by the inverse agonistic action of Ro15-4513 and beta-CCE.

Nebivolol withdrawal results in blood pressure returning toward pretreatment levels, but without rebound symptoms: phase IV randomized trial.

PubMed

Lewin, Andrew; Lasseter, Kenneth C; Dong, Fang; Whalen, John C

2012-01-01

Rapid withdrawal of antihypertensive drugs may lead to blood pressure (BP) increase above pretreatment values or symptoms such as palpitations, chest pain, and tremor. This phase IV trial assessed the consequences of abrupt and stepwise withdrawal of nebivolol, a β(1)-selective blocker, in individuals with stage I-II hypertension. After a 4- to 5-week placebo washout phase and 12-week single-blind nebivolol treatment (10-40 mg/day, titrated based on BP response), participants achieving BP control (systolic BP [SBP]/diastolic BP [DBP] <140/90 mm Hg) or response (SBP decrease ≥10 mm Hg or DBP decrease ≥5 mm Hg) entered a 4-week, randomized, double-blind phase of continued nebivolol treatment (n = 102) or withdrawal to placebo (n = 105). Primary and secondary efficacy measures were changes in mean sitting DBP and SBP, respectively, analyzed using an analysis of covariance model. Safety and tolerability were also assessed. In the withdrawal phase, nebivolol and placebo groups demonstrated mean DBP increases of 1.8 and 7.7 mm Hg, respectively (P < .001), and SBP increases of 3.5 and 7.6 mm Hg (P = .011). Twenty-three (22.5%) nebivolol-treated and 18 (17.1%) placebo-treated participants experienced a treatment-emergent adverse event. No adverse events associated with β-blocker withdrawal and considered causally related to nebivolol were reported. Nebivolol withdrawal resulted in a mean BP increase near pretreatment levels and was not associated with rebound hypertension. Copyright © 2012 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?

PubMed Central

Vinkers, Christiaan H.; Olivier, Berend

2012-01-01

Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABAA receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activated GABAA receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site. PMID:22536226

Cognitive impairments of alcoholic cirrhotic patients: correlation with endogenous benzodiazepine receptor ligands and increased affinity of platelet receptors.

PubMed Central

Kapczinski, F; Curran, H V; Przemioslo, R; Williams, R; Fluck, E; Fernandes, C; File, S E

1996-01-01

OBJECTIVES--To determine whether differences in cognitive function between alcoholic and non-alcoholic cirrhotic patients relate to differences in endogenous ligands for the benzodiazepine receptor and/or benzodiazepine binding. METHODS--Seventeen grade-I hepatic encephalopathic patients (nine alcoholic, eight non-alcoholic) were compared with 10 matched controls on plasma concentrations of endogenous ligands for the neuronal benzodiazepine receptor, benzodiazepine binding in platelets, and performance on tests of cognitive function. RESULTS--Both groups of patients were impaired on verbal recall and on reaction time tasks compared with controls; alcoholic patients were also impaired on Reitan's trails test and digit cancellation. Four of the 17 patients had detectable concentrations of endogenous benzodiazepine ligands and they were more impaired than other patients on trails and cancellation tests. The groups did not differ in the density of benzodiazepine platelet receptors, but receptor affinity was higher in alcoholic patients than in controls; furthermore, receptor affinity correlated with the time to complete the cancellation task and with reaction time. CONCLUSION--Alcoholic cirrhotic patients may have enhanced concentrations of ligands for neuronal and peripheral benzodiazepine receptors and these may contribute to cognitive impairments in these patients. PMID:8648337

Benzodiazepine and Z-drug prescribing in Ireland: analysis of national prescribing trends from 2005 to 2015.

PubMed

Cadogan, Cathal A; Ryan, Cristín; Cahir, Caitriona; Bradley, Colin P; Bennett, Kathleen

2018-06-01

The aim of this study was to examine prescribing trends for benzodiazepines and Z-drugs to General Medical Services (GMS) patients in Ireland. A repeated cross-sectional analysis of the national pharmacy claims database was conducted for GMS patients aged ≥16 years from 2005 to 2015. Prescribing rates per 1000 eligible GMS population were calculated with 95% confidence intervals (CIs). Negative binomial regression was used to determine longitudinal trends and compare prescribing rates across years, gender and age groups. Duration of supply and rates of concomitant benzodiazepine and Z-drug prescribing were determined. Age (16-44, 45-64, ≥65 years) and gender trends were investigated. Benzodiazepine prescribing rates decreased significantly from 225.92/1000 population (95% CI 224.94-226.89) in 2005 to 166.07/1000 population (95% CI 165.38-166.75) in 2015 (P < 0.0001). Z-drug prescribing rates increased significantly from 95.36/1000 population (95% CI 94.73-96.00) in 2005 to 109.11/1000 population (95% CI 108.56-109.67) in 2015 (P = 0.048). Approximately one-third of individuals dispensed either benzodiazepines or Z-drugs were receiving long-term prescriptions (>90 days). The proportion of those receiving >1 benzodiazepine and/or Z-drug concomitantly increased from 11.9% in 2005 to 15.3% in 2015. Benzodiazepine and Z-drug prescribing rates were highest for older women (≥65 years) throughout the study period. Benzodiazepine prescribing to the GMS population in Ireland decreased significantly from 2005 to 2015, and was coupled with significant increases in Z-drug prescribing. The study shows that benzodiazepine and Z-drug prescribing is common in this population, with high proportions of individuals receiving long-term prescriptions. Targeted interventions are needed to reduce potentially inappropriate long-term prescribing and use of these medications in Ireland. © 2018 The British Pharmacological Society.

Relationship between a GABAA alpha 6 Pro385Ser substitution and benzodiazepine sensitivity.

PubMed

Iwata, N; Cowley, D S; Radel, M; Roy-Byrne, P P; Goldman, D

1999-09-01

In humans, interindividual variation in sensitivity to benzodiazepine drugs may correlate with behavioral variation, including vulnerability to disease states such as alcoholism. In the rat, variation in alcohol and benzodiazepine sensitivity has been correlated with an inherited variant of the GABAA alpha 6 receptor. The authors detected a Pro385Ser [1236C > T] amino acid substitution in the human GABAA alpha 6 that may influence alcohol sensitivity. In this pilot study, they evaluated the contribution of this polymorphism to benzodiazepine sensitivity. Sensitivity to diazepam was assessed in 51 children of alcoholics by using two eye movement measures: peak saccadic velocity and average smooth pursuit gain. Association analysis was performed with saccadic velocity and smooth pursuit gain as dependent variables and comparing Pro385/Ser385 heterozygotes and Pro385/Pro385 homozygotes. The Pro385Ser genotype was associated with less diazepam-induced impairment of saccadic velocity but not with smooth pursuit gain. The Pro385Ser genotype may play a role in benzodiazepine sensitivity and conditions, such as alcoholism, that may be correlated with this trait.

[Documented effects of SSRI preparations in anxiety].

PubMed

Allgulander, C

1998-05-20

The article consists in a review of the clinical evidence for treating anxiety disorders with selective serotonin re-uptake inhibitors (SSRIs). Sufficient documentation now exists to support the use of SSRIs in treating panic and obsessive-compulsive disorders, and in Sweden moclobemide is now approved for use in treating social phobia, and buspirone for use in treating generalised anxiety disorder. Further documentation of the treatment of post-traumatic stress disorder with SSRIs is probably to be expected. Benzodiazepines remain the most commonly used anxiolytics. Although persistent adverse sexual reactions, and withdrawal symptoms upon abrupt termination of medication, are notable side effects of SSRIs, patients become measurably more self-confident and focused, and manage risks more adequately. This underscores the need of further research into the interrelationship of personality traits and anxiety symptoms.

Differential effects of chronic lorazepam and alprazolam on benzodiazepine binding and GABAA-receptor function.

PubMed Central

Galpern, W. R.; Miller, L. G.; Greenblatt, D. J.; Shader, R. I.

1990-01-01

1. Chronic benzodiazepine administration has been associated with tolerance and with downregulation of gamma-aminobutyric acidA (GABAA)-receptor binding and function. However, effects of individual benzodiazepines on brain regions have varied. 2. To compare the effects of chronic lorazepam and alprazolam, we have administered these drugs to mice for 1 and 7 days (2 mg kg-1 day-1) and determined benzodiazepine receptor binding in vivo with and without administration of CL 218,872, 25 mg kg-1 i.p., and GABA-dependent chloride uptake in 3 brain regions at these time points. 3. Benzodiazepine binding was decreased in the cortex and hippocampus at day 7 compared to day 1 of lorazepam, with an increase in CL 218,872-resistant (Type 2) sites in both regions. Maximal GABA-dependent chloride uptake was also decreased in the cortex and hippocampus at day 7. 4. Binding was decreased only in the cortex after 7 days of alprazolam, with no significant change in Type 2 binding. Maximal GABA-dependent chloride uptake was also decreased only in the cortex. 5. These data suggest that the effects of chronic benzodiazepine administration on the GABAA-receptor may be both region-specific and receptor subtype-specific. PMID:1964820

Effect of a centralized prescription network on inappropriate prescriptions for opioid analgesics and benzodiazepines.

PubMed

Dormuth, Colin R; Miller, Tarita A; Huang, Anjie; Mamdani, Muhammad M; Juurlink, David N

2012-11-06

Opioid analgesics and benzodiazepines are often misused in clinical practice. We determined whether implementation of a centralized prescription network offering real-time access to patient-level data on filled prescriptions (PharmaNet) reduced the number of potentially inappropriate prescriptions for opioids and benzodiazepines. We conducted a time series analysis using prescription records between Jan. 1, 1993, and Dec. 31, 1997, for residents of the province of British Columbia who were receiving social assistance or were 65 years or older. We calculated monthly percentages of filled prescriptions for an opioid or a benzodiazepine that were deemed inappropriate (those issued by a different physician and dispensed at a different pharmacy within 7 days after a filled prescription of at least 30 tablets of the same drug). Within 6 months after implementation of PharmaNet in July 1995, we observed a relative reduction in inappropriate filled prescriptions for opioids of 32.8% (95% confidence interval [CI] 31.0%-34.7%) among patients receiving social assistance; inappropriate filled prescriptions for benzodiazepines decreased by 48.6% (95% CI 43.2%-53.1%). Similar and statistically significant reductions were observed among residents 65 years or older. The implementation of a centralized prescription network was associated with a dramatic reduction in inappropriate filled prescriptions for opioids and benzodiazepines.

The economics of abrupt climate change.

PubMed

Perrings, Charles

2003-09-15

The US National Research Council defines abrupt climate change as a change of state that is sufficiently rapid and sufficiently widespread in its effects that economies are unprepared or incapable of adapting. This may be too restrictive a definition, but abrupt climate change does have implications for the choice between the main response options: mitigation (which reduces the risks of climate change) and adaptation (which reduces the costs of climate change). The paper argues that by (i) increasing the costs of change and the potential growth of consumption, and (ii) reducing the time to change, abrupt climate change favours mitigation over adaptation. Furthermore, because the implications of change are fundamentally uncertain and potentially very high, it favours a precautionary approach in which mitigation buys time for learning. Adaptation-oriented decision tools, such as scenario planning, are inappropriate in these circumstances. Hence learning implies the use of probabilistic models that include socioeconomic feedbacks.

A Pharmacist-Physician Collaboration to Optimize Benzodiazepine Use for Anxiety and Sleep Symptom Control in Primary Care.

PubMed

Furbish, Shannon M L; Kroehl, Miranda E; Loeb, Danielle F; Lam, Huong Mindy; Lewis, Carmen L; Nelson, Jennifer; Chow, Zeta; Trinkley, Katy E

2017-08-01

Benzodiazepines are prescribed inappropriately in up to 40% of outpatients. The purpose of this study is to describe a collaborative team-based care model in which clinical pharmacists work with primary care providers (PCPs) to improve the safe use of benzodiazepines for anxiety and sleep disorders and to assess the preliminary results of the impact of the clinical service on patient outcomes. Adult patients were eligible if they received care from the academic primary care clinic, were prescribed a benzodiazepine chronically, and were not pregnant or managed by psychiatry. Outcomes included baseline PCP confidence and knowledge of appropriate benzodiazepine use, patient symptom severity, and medication changes. Twenty-five of 57 PCPs responded to the survey. PCPs reported greater confidence in diagnosing and treating generalized anxiety and panic disorders than sleep disorder and had variable knowledge of appropriate benzodiazepine prescribing. Twenty-nine patients had at least 1 visit. Over 44 total patient visits, 59% resulted in the addition or optimization of a nonbenzodiazepine medication and 46% resulted in the discontinuation or optimization of a benzodiazepine. Generalized anxiety symptom severity scores significantly improved (-2.0; 95% confidence interval (CI): -3.57 to -0.43). Collaborative team-based models that include clinical pharmacists in primary care can assist in optimizing high-risk benzodiazepine use. Although these findings suggest improvements in safe medication use and symptoms, additional studies are needed to confirm these preliminary results.

21 CFR 862.3170 - Benzodiazepine test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Benzodiazepine test system. 862.3170 Section 862.3170 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3170 - Benzodiazepine test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Benzodiazepine test system. 862.3170 Section 862.3170 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3170 - Benzodiazepine test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Benzodiazepine test system. 862.3170 Section 862.3170 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3170 - Benzodiazepine test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Benzodiazepine test system. 862.3170 Section 862.3170 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

Benzodiazepines and related drugs for insomnia in palliative care.

PubMed

Hirst, A; Sloan, R

2002-01-01

Insomnia, a subjective complaint of poor sleep and associated impairment in daytime function, is a common problem. Currently, benzodiazepines are the most used pharmacological treatment for this complaint. They are considered helpful for occasional short-term use up to four weeks but longer term use is not advised due to potential problems regarding tolerance, dosing escalation, psychological addiction and physical dependence. There is no consensus on their utility in patients with progressive incurable conditions who may require assistance with sleep for many weeks as their condition deteriorates. To assess the effectiveness and safety of benzodiazepines or benzodiazepine receptor agonists such as Zolpidem, Zopiclone and Zaleplon for insomnia in palliative care. Several electronic databases were searched including Cochrane PaPaS Group specialized register, Cochrane Library Issue 4, 2001, MEDLINE, EMBASE, BNI plus, CINAHL, BIOLOGICAL ABSTRACTS, PSYCINFO, CANCERLIT, HEALTHSTAR, WEB OF SCIENCE, SIGLE, Dissertation Abstracts, ZETOC and the MetaRegister of ongoing trials. These were searched from 1960 to 2001 or as much of this range as possible. Additional articles were sought by handsearching reference lists in standard textbooks and reviews in the field and by contacting academic centres in palliative care and pharmaceutical companies. There were no language restrictions. Studies considered for inclusion were randomized controlled trials of adult patients in any setting, receiving palliative care or suffering an incurable progressive medical condition. (For example, cancers, AIDS, Motor Neurone Disease, Multiple Sclerosis, Parkinson's Disease, Chronic Obstructive Pulmonary Disease). There had to be an explicit complaint of insomnia in study participants, diagnosed by any of the three main classification systems (DSM-IV (APA 1994), ICSD (AASD 1990) or ICD (WHO 1992)), or as described in the study if it involved a subjective complaint of poor sleep. Studies had to

Anticancer activity and anti-inflammatory studies of 5-aryl-1,4-benzodiazepine derivatives.

PubMed

Sandra, Cortez-Maya; Eduardo, Cortes Cortes; Simon, Hernandez-Ortega; Teresa, Ramirez Apan; Antonio, Nieto Camacho; Lijanova, Irina V; Marcos, Martinez-Garcia

2012-07-01

A series of 5-aryl-1,4-benzodiazepines with chloro- or fluoro-substituents in the second ring have been synthesized and their anti-inflammatory, myeloperoxidase and anticancer properties studied. The synthesized compounds showed potential anti-inflammatory and anticancer activities, which were enhanced in the presence of a chloro-substituent in the second ring of the 5-aryl-1,4- benzodiazepine.

1-Methyl-beta-carboline (harmane), a potent endogenous inhibitor of benzodiazepine receptor binding.

PubMed

Rommelspacher, H; Nanz, C; Borbe, H O; Fehske, K J; Müller, W E; Wollert, U

1980-10-01

The interaction of several beta-carbolines with specific [3H]-flunitrazepam binding to benzodiazepine receptors in rat brain membranes was investigated. Out of the investigated compounds, harmane and norharmane were the most potent inhibitors of specific [3H]-flunitrazepam binding, with IC50-values in the micromolar range. All other derivatives, including harmine, harmaline, and several tetrahydroderivatives were at least ten times less potent. Harmane has been previously found in rat brain and human urine, so it is the most potent endogenous inhibitor of specific [3H]-flunitrazepam binding known so far, with a several fold higher affinity for the benzodiazepine receptor than inosine and hypoxanthine. Thus, we suggest that harmane or other related beta-carbolines could be potential candidates as endogenous ligands of the benzodiazepine receptor.

Effect of a centralized prescription network on inappropriate prescriptions for opioid analgesics and benzodiazepines

PubMed Central

Dormuth, Colin R.; Miller, Tarita A.; Huang, Anjie; Mamdani, Muhammad M.; Juurlink, David N.

2012-01-01

Background: Opioid analgesics and benzodiazepines are often misused in clinical practice. We determined whether implementation of a centralized prescription network offering real-time access to patient-level data on filled prescriptions (PharmaNet) reduced the number of potentially inappropriate prescriptions for opioids and benzodiazepines. Methods: We conducted a time series analysis using prescription records between Jan. 1, 1993, and Dec. 31, 1997, for residents of the province of British Columbia who were receiving social assistance or were 65 years or older. We calculated monthly percentages of filled prescriptions for an opioid or a benzodiazepine that were deemed inappropriate (those issued by a different physician and dispensed at a different pharmacy within 7 days after a filled prescription of at least 30 tablets of the same drug). Results: Within 6 months after implementation of PharmaNet in July 1995, we observed a relative reduction in inappropriate filled prescriptions for opioids of 32.8% (95% confidence interval [CI] 31.0%–34.7%) among patients receiving social assistance; inappropriate filled prescriptions for benzodiazepines decreased by 48.6% (95% CI 43.2%–53.1%). Similar and statistically significant reductions were observed among residents 65 years or older. Interpretation: The implementation of a centralized prescription network was associated with a dramatic reduction in inappropriate filled prescriptions for opioids and benzodiazepines. PMID:22949563

Use of benzodiazepine and risk of cancer: A meta-analysis of observational studies.

PubMed

Kim, Hong-Bae; Myung, Seung-Kwon; Park, Yon Chul; Park, Byoungjin

2017-02-01

Several observational epidemiological studies have reported inconsistent results on the association between the use of benzodiazepine and the risk of cancer. We investigated the association by using a meta-analysis. We searched PubMed, EMBASE, and the bibliographies of relevant articles to locate additional publications in January 2016. Three evaluators independently reviewed and selected eligible studies based on predetermined selection criteria. Of 796 articles meeting our initial criteria, a total of 22 observational epidemiological studies with 18 case-control studies and 4 cohort studies were included in the final analysis. Benzodiazepine use was significantly associated with an increased risk of cancer (odds ratio [OR] or relative risk [RR] 1.19; 95% confidence interval 1.16-1.21) in a random-effects meta-analysis of all studies. Subgroup meta-analyses by various factors such as study design, type of case-control study, study region, and methodological quality of study showed consistent findings. Also, a significant dose-response relationship was observed between the use of benzodiazepine and the risk of cancer (p for trend <0.01). The current meta-analysis of observational epidemiological studies suggests that benzodiazepine use is associated with an increased risk of cancer. © 2016 UICC.

Relative positioning of classical benzodiazepines to the γ2-subunit of GABAA receptors.

PubMed

Middendorp, Simon J; Hurni, Evelyn; Schönberger, Matthias; Stein, Marco; Pangerl, Michael; Trauner, Dirk; Sigel, Erwin

2014-08-15

GABAA receptors are the major inhibitory neurotransmitter receptors in the brain. Benzodiazepine exert their action via a high affinity-binding site at the α/γ subunit interface on some of these receptors. Diazepam has sedative, hypnotic, anxiolytic, muscle relaxant, and anticonvulsant effects. It acts by potentiating the current evoked by the agonist GABA. Understanding specific interaction of benzodiazepines in the binding pocket of different GABAA receptor isoforms might help to separate these divergent effects. As a first step, we characterized the interaction between diazepam and the major GABAA receptor isoform α1β2γ2. We mutated several amino acid residues on the γ2-subunit assumed to be located near or in the benzodiazepine binding pocket individually to cysteine and studied the interaction with three ligands that are modified with a cysteine-reactive isothiocyanate group (-NCS). When the reactive NCS group is in apposition to the cysteine residue this leads to a covalent reaction. In this way, three amino acid residues, γ2Tyr58, γ2Asn60, and γ2Val190 were located relative to classical benzodiazepines in their binding pocket on GABAA receptors.

Production of monoclonal antibody against clonazepam for immunoassay of benzodiazepine drugs in swine tissues.

PubMed

Shan, Wen C; Cui, Ya L; He, Xin; Zhang, Lei; Liu, Jing; Wang, Jian P

2015-01-01

The objective of the present study was to produce a generic monoclonal antibody for immunoassay of residues of benzodiazepine drugs in swine tissues. Clonazepam was used to synthesize a hapten that was coupled to bovine serum albumin as an immunogen for the production of monoclonal antibody. Results showed that the obtained monoclonal antibody was able to recognize five benzodiazepine drugs simultaneously (clonazepam, flunitrazepam nitrazepam, diazepam, and oxazepam). The cross-reactivities were in the range of 24-100% and the limits of detection were in the range of 0.2-1.5 ng mL(-1) depending on the drug. Then a competitive indirect enzyme-linked immunosorbent assay was developed to determine the residues of five benzodiazepines in swine tissues (muscle, liver and kidney). The recoveries of five analytes from the fortified blank samples were in the range of 74.5-96.5% with coefficients of variation lower than 16.7%. Therefore, this immunoassay could be used as a rapid and simple method for the screening of residues of five benzodiazepine drugs in animal-derived foods.

GABA/benzodiazepine receptor complex in long-sleep and short-sleep mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marley, R.J.

LS mice are more sensitive to benzodiazepine-induced anesthesia; however, the two lines do not differ in their hypothermic response to flurazepam. SS mice are more resistant to 3-mercaptopropionic acid-induced seizures and more sensitive to the anticonvulsant effects of benzodiazepines. The various correlates of GABA and benzodiazepine actions probably are the results of different mechanisms of action and/or differential regional control. Bicuculline competition for /sup 3/H-GABA binding sites is greater in SS cerebellar tissue and /sup 3/H-flunitrazepam binding is greater in the mid-brain region of LS mice. GABA enhancement of /sup 3/H-flunitrazepma binding is greater in SS mice. Ethanol also enhancesmore » /sup 3/H-flunitrazepam binding and increases the levels of /sup 3/H-flunitrazepam binding above those observed for GABA. Using correlational techniques on data from LS and SS mice and several inbred mouse strains, it was demonstrated that a positive relationship exists between the degree of receptor coupling within the GABA receptor complex and the degree of resistance to seizures.« less

GABAA-benzodiazepine-chloride receptor-targeted therapy for tinnitus control: preliminary report.

PubMed

Shulman, Abraham; Strashun, Arnold M; Goldstein, Barbara A

2002-01-01

Our goal was to attempt to establish neuropharmacological tinnitus control (i.e., relief) with medication directed to restoration of a deficiency in the gamma-aminobutyric acid-benzodiazepine-chloride receptor in tinnitus patients with a diagnosis of a predominantly central type tinnitus. Thirty tinnitus patients completed a medical audiological tinnitus patient protocol and brain magnetic resonance imaging and single-photon emission computed tomography of brain. Treatment with GABAergic and benzodiazepine medication continued for 4-6 weeks. A maintenance dose was continued when tinnitus control was positive. Intake and outcome questionnaires were completed. Of 30 patients, 21 completed the trial (70%). Tinnitus control lasting from 4-6 weeks to 3 years was reported by 19 of the 21 (90%). The trial was not completed by 9 of the 30 (30%). No patient experienced an increase in tinnitus intensity or annoyance. Sequential brain single-photon emission computed tomography in 10 patients revealed objective evidence of increased brain perfusion. Patients with a predominantly central type tinnitus experience significant tinnitus control with medication directed to the gamma-aminobutyric acid-benzodiazepine-chloride receptor.

Outpatient Benzodiazepine Prescribing, Adverse Events, and Costs

DTIC Science & Technology

2005-05-01

4. Frequency of prescribed benzodiazepines by strength (1999–2001), age 60+ Drug name mg Frequency Percent Alprazolam 0.25 6,827 11.59... Alprazolam 0.5 7,046 11.97 Alprazolam 1 2,283 3.88 Chorazepate 3.75 36 0.06 Chorazepate 7.5 43 0.07 Chlordiazepoxide 5 625 1.06

Variation among states in prescribing of opioid pain relievers and benzodiazepines--United States, 2012.

PubMed

Paulozzi, Leonard J; Mack, Karin A; Hockenberry, Jason M

2014-12-01

Overprescribing of opioid pain relievers (OPR) can result in multiple adverse health outcomes, including fatal overdoses. Interstate variation in rates of prescribing OPR and other prescription drugs prone to abuse, such as benzodiazepines, might indicate areas where prescribing patterns need further evaluation. CDC analyzed a commercial database (IMS Health) to assess the potential for improved prescribing of OPR and other drugs. CDC calculated state rates and measures of variation for OPR, long-acting/extended-release (LA/ER) OPR, high-dose OPR, and benzodiazepines. In 2012, prescribers wrote 82.5 OPR and 37.6 benzodiazepine prescriptions per 100 persons in the United States. State rates varied 2.7-fold for OPR and 3.7-fold for benzodiazepines. For both OPR and benzodiazepines, rates were higher in the South census region, and three Southern states were two or more standard deviations above the mean. Rates for LA/ER and high-dose OPR were highest in the Northeast. Rates varied 22-fold for one type of OPR, oxymorphone. Factors accounting for the regional variation are unknown. Such wide variations are unlikely to be attributable to underlying differences in the health status of the population. High rates indicate the need to identify prescribing practices that might not appropriately balance pain relief and patient safety. State policy makers might reduce the harms associated with the abuse of prescription drugs by implementing changes that will make the prescribing of these drugs more cautious and more consistent with clinical recommendations. Published by Elsevier Ltd.

Memory Effects of Benzodiazepines: Memory Stages and Types Versus Binding-Site Subtypes

PubMed Central

Savić, Miroslav M.; Obradović, Dragan I.; Ugrešić, Nenad D.; Bokonjić, Dubravko R.

2005-01-01

Benzodiazepines are well established as inhibitory modulators of memory processing. This effect is especially prominent when applied before the acquisition phase of a memory task. This minireview concentrates on the putative subtype selectivity of the acquisition-impairing action of benzodiazepines. Namely, recent genetic studies and standard behavioral tests employing subtype-selective ligands pointed to the predominant involvement of two subtypes of benzodiazepine binding sites in memory modulation. Explicit memory learning seems to be affected through the GABAA receptors containing the α1 and α1 subunits, whereas the effects on procedural memory can be mainly mediated by the α1 subunit. The pervading involvement of the α1 subunit in memory modulation is not at all unexpected because this subunit is the major subtype, present in 60% of all GABAA receptors. On the other hand, the role of α5 subunits, mainly expressed in the hippocampus, in modulating distinct forms of memory gives promise of selective pharmacological coping with certain memory deficit states. PMID:16444900

Analysis of benzodiazepines and their metabolites using DBS cards and LC-MS/MS.

PubMed

Lee, Heesang; Park, Yujin; Jo, Jiyeong; In, Sangwhan; Park, Yonghoon; Kim, Eunmi; Pyo, Jaesung; Choe, Sanggil

2015-10-01

Dried Blood Spot (DBS) has been used a blood extraction method for inherited metabolic disorder screening since 1960s. With introduction of LC-MS/MS, not only DBS could be used to analysis drugs in small blood volume, but in various fields, such as toxicology, drug therapeutic monitoring, drug diagnostic screening, and illicit drugs. In toxicology field, many drugs (e.g. benzodiazepines, acetaminophen, small molecule drugs) have been tested with DBS. Compared with earlier blood extraction methods (SPE and LLE), DBS has lots of advantages; lower blood volume (less than 50μL), shorter analysis time caused by a more concise analysis procedure and lower cost. We optimized the DBS procedure and LC-MS/MS conditions for 18 benzodiazepines, seven benzodiazepine metabolites, and one z-drug (zolpidem) analysis in blood. 30μL of whole blood was spotted on FTA DMPK card C and dried for 2h in a desiccator. A 6-mm disk was punched and vortexed for 1min in a centrifuge tube with 300μL methanol/acetonitrile mixture (1:1, v/v). After evaporation, redissolved in 100μL mobile phase of LC-MS/MS and 5μL was injected. In the analysis for 26 target compounds in blood, all of the method validation parameters - LLOD, LLOQ, accuracy (intra- and inter-assay), and precision (intra- and inter-assay) - were satisfied with method validation criteria, within 15%. The results of matrix effect, recovery, and process efficiency were good. We developed a fast and reliable sample preparation method using DBS for 26 benzodiazepines, benzodiazepine metabolites, and z-drug (zolpidem). Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The relationship between peak velocity of saccadic eye movements and serum benzodiazepine concentration.

PubMed Central

Bittencourt, P R; Wade, P; Smith, A T; Richens, A

1981-01-01

1 Six healthy male volunteers received single oral doses of 10 mg diazepam, 20 mg temazepam, 15 mg flurazepam, 5 mg nitrazepam, 10 mg desmethyl-diazepam and placebo in a double-blind randomized fashion. 2 Peak velocity of saccadic eye movements, serum benzodiazepine concentration, and subjective ratings of wakefulness and co-ordination were measured at intervals up to 12 h after drug administration. 3 All active treatments produced a statistically significant decrease in peak saccadic velocity. The effect of temazepam and diazepam was generally more pronounced than that of flurazepam, nitrazepam and desmethyl-diazepam. 4 There were log-linear correlations between peak saccadic velocity and serum benzodiazepine concentration after ingestion of temazepam, diazepam and nitrazepam. 5 These results demonstrate a clear relationship between serum benzodiazepine concentration and its effect on a convenient measure of brainstem reticular formation function. PMID:6794587

Alcohol involvement in opioid pain reliever and benzodiazepine drug abuse-related emergency department visits and drug-related deaths - United States, 2010.

PubMed

Jones, Christopher M; Paulozzi, Leonard J; Mack, Karin A

2014-10-10

The abuse of prescription drugs has led to a significant increase in emergency department (ED) visits and drug-related deaths over the past decade. Opioid pain relievers (OPRs) and benzodiazepines are the prescription drugs most commonly involved in these events. Excessive alcohol consumption also accounts for a significant health burden and is common among groups that report high rates of prescription drug abuse. When taken with OPRs or benzodiazepines, alcohol increases central nervous system depression and the risk for overdose. Data describing alcohol involvement in OPR or benzodiazepine abuse are limited. To quantify alcohol involvement in OPR and benzodiazepine abuse and drug-related deaths and to inform prevention efforts, the Food and Drug Administration (FDA) and CDC analyzed 2010 data for drug abuse-related ED visits in the United States and drug-related deaths that involved OPRs and alcohol or benzodiazepines and alcohol in 13 states. The analyses showed alcohol was involved in 18.5% of OPR and 27.2% of benzodiazepine drug abuse-related ED visits and 22.1% of OPR and 21.4% of benzodiazepine drug-related deaths. These findings indicate that alcohol plays a significant role in OPR and benzodiazepine abuse. Interventions to reduce the abuse of alcohol and these drugs alone and in combination are needed.

Heat and pregnancy-related emergencies: Risk of placental abruption during hot weather.

PubMed

He, Siyi; Kosatsky, Tom; Smargiassi, Audrey; Bilodeau-Bertrand, Marianne; Auger, Nathalie

2018-02-01

Outdoor heat increases the risk of preterm birth and stillbirth, but the association with placental abruption has not been studied. Placental abruption is a medical emergency associated with major morbidity and mortality in pregnancy. We determined the relationship between ambient temperature and risk of placental abruption in warm seasons. We performed a case-crossover analysis of 17,172 women whose pregnancies were complicated by placental abruption in Quebec, Canada from May to October 1989-2012. The main exposure measure was the maximum temperature reached during the week before abruption. We computed odds ratios (OR) and 95% confidence intervals (CI) for the association of temperature with placental abruption, adjusted for humidity and public holidays. We assessed whether associations were stronger preterm or at term, or varied with maternal age, parity, comorbidity and socioeconomic status. Compared with 15°C, a maximum weekly temperature of 30°C was associated with 1.07 times the odds of abruption (95% CI 0.99-1.16). When the timing of abruption was examined, the associations were significantly stronger at term (OR 1.12, 95% CI 1.02-1.24) than preterm (OR 0.96, 95% CI 0.83-1.10). Relationships were more prominent at term for women who were younger than 35years old, nulliparous or socioeconomically disadvantaged, but did not vary with comorbidity. Associations were stronger within 1 and 5days of abruption. Temperature was not associated with preterm abruption regardless of maternal characteristics. Elevated temperatures in warm seasons may increase the risk of abruption in women whose pregnancies are near or at term. Pregnant women may be more sensitive to heat and should consider preventive measures such as air conditioning and hydration during hot weather. Copyright © 2017 Elsevier Ltd. All rights reserved.

Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study.

PubMed

Park, Tae Woo; Saitz, Richard; Ganoczy, Dara; Ilgen, Mark A; Bohnert, Amy S B

2015-06-10

To study the association between benzodiazepine prescribing patterns including dose, type, and dosing schedule and the risk of death from drug overdose among US veterans receiving opioid analgesics. Case-cohort study. Veterans Health Administration (VHA), 2004-09. US veterans, primarily male, who received opioid analgesics in 2004-09. All veterans who died from a drug overdose (n=2400) while receiving opioid analgesics and a random sample of veterans (n=420,386) who received VHA medical services and opioid analgesics. Death from drug overdose, defined as any intentional, unintentional, or indeterminate death from poisoning caused by any drug, determined by information on cause of death from the National Death Index. During the study period 27% (n=112,069) of veterans who received opioid analgesics also received benzodiazepines. About half of the deaths from drug overdose (n=1185) occurred when veterans were concurrently prescribed benzodiazepines and opioids. Risk of death from drug overdose increased with history of benzodiazepine prescription: adjusted hazard ratios were 2.33 (95% confidence interval 2.05 to 2.64) for former prescriptions versus no prescription and 3.86 (3.49 to 4.26) for current prescriptions versus no prescription. Risk of death from drug overdose increased as daily benzodiazepine dose increased. Compared with clonazepam, temazepam was associated with a decreased risk of death from drug overdose (0.63, 0.48 to 0.82). Benzodiazepine dosing schedule was not associated with risk of death from drug overdose. Among veterans receiving opioid analgesics, receipt of benzodiazepines was associated with an increased risk of death from drug overdose in a dose-response fashion. © Park et al 2015.

Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study

PubMed Central

Saitz, Richard; Ganoczy, Dara; Ilgen, Mark A; Bohnert, Amy S B

2015-01-01

Objective To study the association between benzodiazepine prescribing patterns including dose, type, and dosing schedule and the risk of death from drug overdose among US veterans receiving opioid analgesics. Design Case-cohort study. Setting Veterans Health Administration (VHA), 2004-09. Participants US veterans, primarily male, who received opioid analgesics in 2004-09. All veterans who died from a drug overdose (n=2400) while receiving opioid analgesics and a random sample of veterans (n=420 386) who received VHA medical services and opioid analgesics. Main outcome measure Death from drug overdose, defined as any intentional, unintentional, or indeterminate death from poisoning caused by any drug, determined by information on cause of death from the National Death Index. Results During the study period 27% (n=112 069) of veterans who received opioid analgesics also received benzodiazepines. About half of the deaths from drug overdose (n=1185) occurred when veterans were concurrently prescribed benzodiazepines and opioids. Risk of death from drug overdose increased with history of benzodiazepine prescription: adjusted hazard ratios were 2.33 (95% confidence interval 2.05 to 2.64) for former prescriptions versus no prescription and 3.86 (3.49 to 4.26) for current prescriptions versus no prescription. Risk of death from drug overdose increased as daily benzodiazepine dose increased. Compared with clonazepam, temazepam was associated with a decreased risk of death from drug overdose (0.63, 0.48 to 0.82). Benzodiazepine dosing schedule was not associated with risk of death from drug overdose. Conclusions Among veterans receiving opioid analgesics, receipt of benzodiazepines was associated with an increased risk of death from drug overdose in a dose-response fashion. PMID:26063215

Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: the EMPOWER cluster randomized trial.

PubMed

Tannenbaum, Cara; Martin, Philippe; Tamblyn, Robyn; Benedetti, Andrea; Ahmed, Sara

2014-06-01

The American Board of Internal Medicine Foundation Choosing Wisely Campaign recommends against the use of benzodiazepine drugs for adults 65 years and older. The effect of direct patient education to catalyze collaborative care for reducing inappropriate prescriptions remains unknown. To compare the effect of a direct-to-consumer educational intervention against usual care on benzodiazepine therapy discontinuation in community-dwelling older adults. Cluster randomized trial (EMPOWER [Eliminating Medications Through Patient Ownership of End Results] study [2010-2012, 6-month follow-up]). Community pharmacies were randomly allocated to the intervention or control arm in nonstratified, blocked groups of 4. Participants (303 long-term users of benzodiazepine medication aged 65-95 years, recruited from 30 community pharmacies) were screened and enrolled prior to randomization: 15 pharmacies randomized to the educational intervention included 148 participants and 15 pharmacies randomized to the "wait list" control included 155 participants. Participants, physicians, pharmacists, and evaluators were blinded to outcome assessment. The active arm received a deprescribing patient empowerment intervention describing the risks of benzodiazepine use and a stepwise tapering protocol. The control arm received usual care. Benzodiazepine therapy discontinuation at 6 months after randomization, ascertained by pharmacy medication renewal profiles. A total of 261 participants (86%) completed the 6-month follow-up. Of the recipients in the intervention group, 62% initiated conversation about benzodiazepine therapy cessation with a physician and/or pharmacist. At 6 months, 27% of the intervention group had discontinued benzodiazepine use compared with 5% of the control group (risk difference, 23% [95% CI, 14%-32%]; intracluster correlation, 0.008; number needed to treat, 4). Dose reduction occurred in an additional 11% (95% CI, 6%-16%). In multivariate subanalyses, age greater than 80

Supercritical flow characteristics at abrupt expansion structure

NASA Astrophysics Data System (ADS)

Lim, Jia Jun; Puay, How Tion; Zakaria, Nor Azazi

2017-10-01

When dealing with the design of a hydraulic structure, lateral expansion is often necessary for flow emerging at high velocity served as a cross-sectional transition. If the abrupt expansion structure is made to diverge rapidly, it will cause the major part of the flow fail to follow the boundaries. If the transition is too gradual, it will result in a waste of structural material. A preliminary study on the flow structure near the expansion and its relationship with flow parameter is carried out in this study. A two-dimensional depth-averaged model is developed to simulate the supercritical flow at the abrupt expansion structure. Constrained Interpolation Profile (CIP) scheme (which is of third order accuracy) is adopted in the numerical model. Results show that the flow structure and flow characteristics at the abrupt expansion can be reproduced numerically. The validation of numerical result is done against analytical studies. The result from numerical simulation showed good agreement with the analytical solution.

Review of benzodiazepine use in children and adolescents.

PubMed

Witek, Malgorzata W; Rojas, Veronica; Alonso, Carmen; Minami, Haruka; Silva, Raul R

2005-01-01

Clinically, benzodiazepines are used in adult populations much more frequently than in children and adolescents. There may be a number of reasons for this disparity including a dearth of well controlled clinical studies and the issue of dependence associated with long term use. However, over a ten year span there has been nearly a three fold increase in the use patterns for these agents in the child population. In open studies much of the literature has indicated potentially useful results, but these findings have not been replicated when more refined methodological studies have been conducted. The lack of encouraging results in these later studies may be attributable to a number of factors such as modest sample sizes and less than optimal patient selection. Nonetheless, with increasing prescriptions being written for these agents it is not clear what is compelling clinicians to use them. In this paper we will review the available literature on benzodiazepine use in the child and adolescent population, focusing primarily on psychiatric applications.

Methane negative chemical ionization analysis of 1,3-dihydro-5-phenyl-1,4-benzodiazepin-2-ones.

PubMed Central

Garland, W A; Miwa, B J

1980-01-01

The methane negative chemical ionization (NCI) mass spectra of the medically important 1,3-dihydro-5-phenyl-1,4-benzodiazepin-2-ones generally consisted solely of M- and (M-H)- ions. Attempts to find the location of the H lost in the generation of the (M-H)- ion were unsuccessful, although many possibilities were eliminated. A Hammett correlation analysis of the relative sensitivities of a series of 7-substituted benzodiazepines suggested that the initial ionization takes place at the 4,5-imine bond. For certain benzodiazepines, the (M-H)- ion generated by methane NCI was 20 times more intense than the MH+ ion generated by methane positive chemical ionization (PCI). By using NCI, a sensitive and simple GC-MS assay for nordiazepam was developed that can quantitate this important metabolite of many of the clinically used benzodiazepines in the blood and brain of rats. PMID:6775944

Rapid enzymatic hydrolysis using a novel recombinant β-glucuronidase in benzodiazepine urinalysis.

PubMed

Morris, Ayodele A; Chester, Scot A; Strickland, Erin C; McIntire, Gregory L

2014-10-01

Only trace amounts of parent benzodiazepines are present in urine following extensive metabolism and conjugation. Thus, hydrolysis of glucuronides is necessary for improved detection. Enzyme hydrolysis is preferred to retain identification specificity, but can be costly and time-consuming. The assessment of a novel recombinant β-glucuronidase for rapid hydrolysis in benzodiazepine urinalysis is presented. Glucuronide controls for oxazepam, lorazepam and temazepam were treated with IMCSzyme™ recombinant β-glucuronidase. Hydrolysis efficiency was assessed at 55°C and at room temperature (RT) using the recommended optimum pH. Hydrolysis efficiency for four other benzodiazepines was evaluated solely with positive patient samples. Maximum hydrolysis of glucuronide controls at 5 min at RT (mean analyte recovery ≥ 94% for oxazepam and lorazepam and ≥ 80% for temazepam) was observed. This was considerably faster than the optimized 30 min incubation time for the abalone β-glucuronidase at 65°C. Mean analyte recovery increased at longer incubation times at 55°C for temazepam only. Total analyte in patient samples compared well to targets from abalone hydrolysis after recombinant β-glucuronidase hydrolysis at RT with no incubation. Some matrix effect, differential reactivity, conjugation variability and transformation impacting total analyte recovery were indicated. The unique potential of the IMCSzyme™ recombinant β-glucuronidase was demonstrated with fast benzodiazepine hydrolysis at RT leading to decreased processing time without the need for heat activation. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Repeated diazepam administration reversed working memory impairments and glucocorticoid alterations in the prefrontal cortex after short but not long alcohol-withdrawal periods.

PubMed

Dominguez, G; Henkous, N; Pierard, C; Belzung, C; Mons, N; Beracochea, Daniel

2018-04-30

The study was designed to assess whether repeated administration of diazepam (Valium®, Roche)-a benzodiazepine exerting an agonist action on GABA A receptors-may alleviate both the short (1 week, 1W) and long-term (6 weeks, 6W) deleterious effects of alcohol withdrawal occurring after chronic alcohol consumption (6 months; 12% v/v) in C57/BL6 male mice. More pointedly, we first evidenced that 1W and 6W alcohol-withdrawn mice exhibited working memory deficits in a sequential alternation task, associated with sustained exaggerated corticosterone rise and decreased pCREB levels in the prefrontal cortex (PFC). In a subsequent experiment, diazepam was administered i.p. for 9 consecutive days (1 injection/day) during the alcohol withdrawal period at decreasing doses ranging from 1.0 mg/kg to 0.25 mg/kg. Diazepam was not detected in the blood of withdrawn mice at the time of memory testing, occurring 24 hours after the last diazepam injection. Repeated diazepam administration significantly improved alternation rates and normalized levels of glucocorticoids and pCREB activity in the PFC in 1W but not in 6W withdrawn mice. Thus, repeated diazepam administration during the alcohol-withdrawal period only transitorily canceled out the working memory impairments and glucocorticoid alterations in the PFC of alcohol-withdrawn animals.

The active analog approach applied to the pharmacophore identification of benzodiazepine receptor ligands

NASA Astrophysics Data System (ADS)

Tebib, Souhail; Bourguignon, Jean-Jacques; Wermuth, Camille-Georges

1987-07-01

Applied to seven potent benzodiazepine-receptor ligands belonging to chemically different classes, the active analog approach allowed the stepwise identification of the pharmacophoric pattern associated with the recognition by the benzodiazepine receptor. A unique pharmacophore model was derived which involves six critical zones: (a) a π-electron rich aromatic (PAR) zone; (b) two electron-rich zones δ1 and δ2 placed at 5.0 and 4.5 Å respectively from the reference centroid in the PAR zone; (c) a freely rotating aromatic ring (FRA) region; (d) an out-of-plane region (OPR), strongly associated with agonist properties; and (e) an additional hydrophobic region (AHR). The model accommodates all presently known ligands of the benzodiazepine receptor, identifies sensitivity to steric hindrance close to the δ1 zone, accounts for R and S differential affinities and distinguishes requirements for agonist versus non-agonist activity profiles.

The lesser evil? Initiating a benzodiazepine prescription in general practice

PubMed Central

Anthierens, Sibyl; Habraken, Hilde; Petrovic, Mirko; Christiaens, Thierry

2007-01-01

Objective Chronic benzodiazepine (BZD) use is widespread and linked with adverse effects. There is consensus concerning the importance of initiating BZD as a crucial moment. Nevertheless specific research in this field is lacking. This paper addresses the views of GPs on why they start prescribing BZDs to first-time users. Design Qualitative study with five focus groups analysed using a systematic content analysis. Setting Regions of Ghent and Brussels in Belgium. Subjects A total of 35 general practitioners. Main outcome measure The GPs’ perspective on their initiating of BZD prescribing. Results GPs reported that they are cautious in initiating BZD usage. At the same time, GPs feel overwhelmed by the psychosocial problems of their patients. They show empathy by prescribing. They feel in certain situations there are no other solutions and they experience BZDs as the lesser evil. They admit to resorting to BZDs because of time restraint and lack of alternatives. GPs do not perceive the addictive nature of BZD consumption as a problem with first-time users. GPs do not specifically mention patients’ demand as an element for starting. Conclusion The main concern of GPs is to help the patient. GPs should be aware of the addictive nature of BZD even in low doses and a non-pharmacological approach should be seen as the best first approach. If GPs decide to prescribe a BZD they should make plain to the patient that the medication is only a “temporary” solution with clear agreements with regard to medication withdrawal. PMID:18041658

[Driving under the influence of benzodiazepines and antidepressants: prescription and abuse].

PubMed

Coutinho, Daniel; Vieira, Duarte Nuno; Teixeira, Helena M

2011-01-01

Benzodiazepines are drugs usually used in anxiety disorders, dyssomnias, convulsions, muscle disorders, alcohol and other drugs detoxification, as well as in preoperative sedation/amnesia. Moreover, antidepressants are mainly indicated in depression and as co-therapeutic drugs in other psychiatric disorders. The use of benzodiazepines and antidepressants is associated with some health and public safety problems. Decreased of attention, concentration, reflexes, visual capacity, motor coordination and reasoning, associated with increased reaction time and lack of awareness of driving impairment among these drug users, contributes to the increased risk on traffic safety linked with these drugs. This risk may further increase with non-compliance of medical prescription, drug abuse or concomitant use of alcohol. The relationship between the use of psychoactive drugs and road traffic safety is, however, an extremely complex subject and has a primordial importance in the clarification of the role of benzodiazepine and antidepressant effects on driving skills. The prevention of driving under the influence of these drugs depends on the awareness, among doctors, of the risks associated with their use. Thus, the consciousness of medical prescription, as well as providing clear information to patients is extremely important.

Abrupt tropical climate change: past and present.

PubMed

Thompson, Lonnie G; Mosley-Thompson, Ellen; Brecher, Henry; Davis, Mary; León, Blanca; Les, Don; Lin, Ping-Nan; Mashiotta, Tracy; Mountain, Keith

2006-07-11

Three lines of evidence for abrupt tropical climate change, both past and present, are presented. First, annually and decadally averaged delta(18)O and net mass-balance histories for the last 400 and 2,000 yr, respectively, demonstrate that the current warming at high elevations in the mid- to low latitudes is unprecedented for at least the last 2 millennia. Second, the continuing retreat of most mid- to low-latitude glaciers, many having persisted for thousands of years, signals a recent and abrupt change in the Earth's climate system. Finally, rooted, soft-bodied wetland plants, now exposed along the margins as the Quelccaya ice cap (Peru) retreats, have been radiocarbon dated and, when coupled with other widespread proxy evidence, provide strong evidence for an abrupt mid-Holocene climate event that marked the transition from early Holocene (pre-5,000-yr-B.P.) conditions to cooler, late Holocene (post-5,000-yr-B.P.) conditions. This abrupt event, approximately 5,200 yr ago, was widespread and spatially coherent through much of the tropics and was coincident with structural changes in several civilizations. These three lines of evidence argue that the present warming and associated glacier retreat are unprecedented in some areas for at least 5,200 yr. The ongoing global-scale, rapid retreat of mountain glaciers is not only contributing to global sea-level rise but also threatening freshwater supplies in many of the world's most populous regions.

Withdrawal from Buprenorphine/Naloxone and Maintenance with a Natural Dopaminergic Agonist: A Cautionary Note.

PubMed

Blum, Kenneth; Oscar-Berman, Marlene; Femino, John; Waite, Roger L; Benya, Lisa; Giordano, John; Borsten, Joan; Downs, William B; Braverman, Eric R; Loehmann, Raquel; Dushaj, Kristina; Han, David; Simpatico, Thomas; Hauser, Mary; Barh, Debmalya; McLaughlin, Thomas

2013-04-23

While numerous studies support the efficacy of methadone and buprenorphine for the stabilization and maintenance of opioid dependence, clinically significant opioid withdrawal symptoms occur upon tapering and cessation of dosage. We present a case study of a 35 year old Caucasian female (Krissie) who was prescribed increasing dosages of prescription opioids after carpel tunnel surgery secondary to chronic pain from reflex sympathetic dystrophy and fibromyalgia. Over the next 5 years, daily dosage requirements increased to over 80 mg of Methadone and 300 ug/hr Fentanyl transdermal patches, along with combinations of 12-14 1600 mcg Actig lollipop and oral 100 mg Morphine and 30 mg oxycodone 1-2 tabs q4-6hr PRN for breakthrough pain. Total monthly prescription costs including supplemental benzodiazepines, hypnotics and stimulants exceeded $50,000. The patient was subsequently transferred to Suboxone® in 2008, and the dosage was gradually tapered until her admission for inpatient detoxification with KB220Z a natural dopaminergic agonist. We carefully documented her withdrawal symptoms when she precipitously stopped taking buprenorphine/naloxone and during follow-up while taking KB220Z daily. We also genotyped the patient using a reward gene panel including (9 genes 18 alleles): DRD 2,3,4; MOA-A; COMT; DAT1; 5HTTLLR; OPRM1; and GABRA3. At 432 days post Suboxone® withdrawal the patient is being maintained on KB220Z, has been urine tested and is opioid free. Genotyping data revealed a moderate genetic risk for addiction showing a hypodopaminergic trait. This preliminary case data suggest that the daily use of KB220Z could provide a cost effective alternative substitution adjunctive modality for Suboxone®. We encourage double-blind randomized -placebo controlled studies to test the proposition that KB220Z may act as a putative natural opioid substitution maintenance adjunct.

[An examination of the determinants of social withdrawal and affinity for social withdrawal].

PubMed

Watanabe, Asami; Matsui, Yutaka; Takatsuka, Yusuke

2010-12-01

This study examined the determinants of social withdrawal using data from a survey by the Tokyo Metropolitan Government Office for Youth Affairs and Public Safety (2008). In addition, this study identified young people who showed an affinity for social withdrawal although they were not in a state of withdrawal, and examined the determinants of an affinity for social withdrawal. The results of stepwise discriminant analysis showed that factors such as social phobia, depression, violence, and emotional bonds with family differentiated between the general youth group and the social withdrawal group and the "affinity group". Social phobia, violence, and refusal to be interfered in self-decision making differentiated between the social withdrawal group and the "affinity group". This study shows that an "affinity group" should be cared as well as an actual withdrawal group.

A new series of potent benzodiazepine gamma-secretase inhibitors.

PubMed

Churcher, Ian; Ashton, Kate; Butcher, John W; Clarke, Earl E; Harrison, Timothy; Lewis, Huw D; Owens, Andrew P; Teall, Martin R; Williams, Susie; Wrigley, Jonathan D J

2003-01-20

A new series of benzodiazepine-containing gamma-secretase inhibitors with potential use in the treatment of Alzheimer's disease is disclosed. Structure-activity relationships of the pendant hydrocinnamate side-chain which led to the preparation of highly potent inhibitors are described.

Neural Modulation of the Immune Response through the Benzodiazepine/GABA Receptor Chloride Ionophore Complex

DTIC Science & Technology

1988-08-30

dose of Alprazolam (a triaobenzodiazepine with high affinty for "central" but not "peripheral" benzodiazepine receptbr). These results suggest that...1987), provide additional support for the hypothesis that the "supramolecular complex" (in the CNS) regulates NK cell activity. 3). Effect of Alprazolam ...this study the effects of alprazolam (a triazolobenzodiazepine with high affinity for "central" but not "peripheral" benzodiazepine receptors) on

Treatment for amphetamine withdrawal.

PubMed

Shoptaw, Steven J; Kao, Uyen; Heinzerling, Keith; Ling, Walter

2009-04-15

Few studies examined treatments for amphetamine withdrawal, although it is a common problem among amphetamine users. Its symptoms, in particular intense craving, may be a critical factor leading to relapse to amphetamine use. In clinical practice, medications for cocaine withdrawal are commonly used to manage amphetamine withdrawal although the pharmacodynamic and pharmacokinetic properties of these two illicit substances are different. To assess the effectiveness of pharmacological alone or in combination with psychosocial treatment for amphetamine withdrawals on discontinuation rates, global state, withdrawal symptoms, craving, and other outcomes. MEDLINE (1966 - 2008), CINAHL (1982 - 2008), PsycINFO (1806 - 2008), CENTRAL (Cochrane Library 2008 issue 2), references of obtained articles. All randomised controlled and clinical trials evaluating pharmacological and or psychosocial treatments (alone or combined) for people with amphetamine withdrawal symptoms. Two authors evaluated and extracted data independently. The data were extracted from intention-to-treat analyses. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess dichotomous outcomes. The Weighted Mean Difference (WMD) with 95% CI was used to assess continuous outcomes. Four randomised controlled trials (involving 125 participants) met the inclusion criteria for the review. Two studies found that amineptine significantly reduced discontinuation rates and improved overall clinical presentation, but did not reduce withdrawal symptoms or craving compared to placebo. The benefits of mirtazapine over placebo for reducing amphetamine withdrawal symptoms were not as clear. One study suggested that mirtazapine may reduce hyperarousal and anxiety symptoms associated with amphetamine withdrawal. A more recent study failed to find any benefit of mirtazapine over placebo on retention or on amphetamine withdrawal symptoms. No medication is effective for treatment of amphetamine

Medicare Part D Benzodiazepine Exclusion and Use of Psychotropic Medication by Patients With New Anxiety Disorders

PubMed Central

Ong, Michael K.; Zhang, Lily; Xu, Haiyong; Azocar, Francisca; Ettner, Susan L.

2015-01-01

Objective The Medicare Modernization Act (MMA) specifically excluded benzodiazepines from Medicare Part D coverage starting in 2006; however, benzodiazepines are an effective, low-cost treatment for anxiety. This study evaluated the effect of the Medicare Part D benzodiazepine coverage exclusion among patients with new anxiety disorders. Methods The authors used a quasi-experimental cohort design to study patients with new anxiety diagnoses from a large national health plan during the first six months of 2005, 2006, and 2007. Logistic and zero-truncated negative-binomial regression models using covered claims for behavioral, medical, and pharmaceutical care linked with eligibility files were used to estimate utilization and costs of psychotropic medication and health care utilization among elderly Medicare Advantage enrollees (N=8,397) subject to the MMA benzodiazepine exclusion and a comparison group of near-elderly (ages 60–64) enrollees (N=1,657) of a managed care plan. Results Medicare Advantage enrollees diagnosed in 2005 had significantly (p<.05) higher rates of covered claims for benzodiazepines and all psychotropic drugs, lower rates of covered claims for nonbenzodiazepines, and lower expenditures for psychotropic drugs than enrollees diagnosed in 2006 and 2007. There were no significant differences over time in utilization or expenditures related to psychotropic medication among the comparison group. There also were no significant changes over time in outpatient visits for behavioral care by either cohort. Conclusions Among elderly patients with new anxiety diagnoses, the MMA benzodiazepine exclusion increased use of nonbenzodiazepine psychotropic drugs without substitution of increased behavioral care. Overall, the exclusion was associated with a modest increase in covered claims for psychotropic medication. PMID:22549332

Going, Going, Gone: Localizing Abrupt Offsets of Moving Objects

ERIC Educational Resources Information Center

Maus, Gerrit W.; Nijhawan, Romi

2009-01-01

When a moving object abruptly disappears, this profoundly influences its localization by the visual system. In Experiment 1, 2 aligned objects moved across the screen, and 1 of them abruptly disappeared. Observers reported seeing the objects misaligned at the time of the offset, with the continuing object leading. Experiment 2 showed that the…

Opiate and opioid withdrawal

MedlinePlus

... opiate withdrawal; Oxycontin - opiate withdrawal; Hydrocodone - opiate withdrawal; Detox - opiates; Detoxification - opiates ... facilities set up to help people with detoxification (detox). In a regular hospital, if symptoms are severe. ...

Do drug warnings and market withdrawals have an impact on the number of calls to teratogen information services?

PubMed

Sheehy, O; Gendron, M-P; Martin, B; Bérard, A

2012-06-01

IMAGe provides information on risks and benefits of medication use during pregnancy and lactation. The aim of this study was to determine the impact of Health Canada warnings on the number of calls received at IMAGe. We analyzed calls received between January 2003 and March 2008. The impact of the following warning/withdrawal were studied: paroxetine and risk of cardiac malformations (09/29/2005), selective serotonin reuptake inhibitors (SSRIs) and risk of persistent pulmonary hypertension of the newborn (PPHN) (03/10/2006), and impact of rofecoxib market withdrawal (09/30/2004). Interrupted auto-regressive integrated -moving average (ARIMA) analyses were used to test the impact of each warning on the number of calls received to IMAGe. 61,505 calls were analyzed. The paroxetine warning had a temporary impact increasing the overall number of calls to IMAGe, and an abrupt permanent effect on the number of calls related to antidepressant exposures. The PPHN warning had no impact but we observed a significant increase in the number of calls following rofecoxib market withdrawal. Health Canada needs to consider the increase in the demand of information to IMAGe following warnings on the risk of medication use during pregnancy. © Georg Thieme Verlag KG Stuttgart · New York.

Thyroperoxidase and thyroglobulin antibodies in early pregnancy and placental abruption.

PubMed

Haddow, James E; McClain, Monica R; Palomaki, Glenn E; Neveux, Louis M; Lambert-Messerlian, Geralyn; Canick, Jacob A; Malone, Fergal D; Porter, T Flint; Nyberg, David A; Bernstein, Peter S; D'Alton, Mary E

2011-02-01

To estimate the relationship between thyroid antibodies and placental abruption. This cohort study assesses thyroperoxidase and thyroglobulin antibodies in relation to placental abruption among 10,062 women with singleton viable pregnancies (from the First and Second Trimester Risk of Aneuploidy [FaSTER] trial). A thyroperoxidase antibody cutoff of 50 international units/mL is used for comparison with published data from another cohort. Women with elevated thyroperoxidase antibody levels in the first and second trimesters have a higher rate of placental abruption than antibody-negative women. This relationship is less strong in the first trimester (1.51% compared with 0.83%; odds ratio [OR], 1.83; 95% confidence interval [CI], 0.99-3.37) than in the second trimester (1.78% compared with 0.82%; OR, 2.20; 95% CI, 1.21-3.99). A similar, but weaker, relationship is present for thyroglobulin antibodies. Sixty-four of 782 thyroperoxidase antibody-positive pregnancies without abruption become negative by the second trimester; one pregnancy with abruption becomes antibody-positive. Odds ratios for pregnancies with both thyroperoxidase and thyroglobulin antibody elevations are also higher (first trimester: OR, 2.10; 95% CI, 0.91-4.86; second trimester: OR, 2.73; 95% CI, 1.17-6.33). The present data confirm an association between thyroid antibody elevations and placental abruption described in a recent report. These findings, however, do not provide support for recommending routine testing for thyroid antibodies during pregnancy. II.

Withdrawal Method (Coitus Interruptus)

MedlinePlus

Withdrawal method (coitus interruptus) Overview The withdrawal method of contraception, also known as coitus interruptus, is the practice of withdrawing the penis from the vagina and away from a woman's external ...

Benzodiazepines and antipsychotic medications for treatment of acute cocaine toxicity in animal models--a systematic review and meta-analysis.

PubMed

Heard, Kennon; Cleveland, Nathan R; Krier, Shay

2011-11-01

There are no controlled human studies to determine the efficacy of benzodiazepines or antipsychotic medications for prevention or treatment of acute cocaine toxicity. The only available controlled data are from animal models and these studies have reported inconsistent benefits. The objective of this study was to quantify the reported efficacy of benzodiazepines and antipsychotic medication for the prevention of mortality due to cocaine poisoning. We conducted a systematic review to identify English language articles describing experiments that compared a benzodiazepine or antipsychotic medication to placebo for the prevention of acute cocaine toxicity in an animal model. We then used these articles in a meta-analysis with a random-effects model to quantify the absolute risk reduction observed in these experiments. We found 10 articles evaluating antipsychotic medications and 15 articles evaluating benzodiazepines. Antipsychotic medications reduced the risk of death by 27% (95% CI, 15.2%-38.7%) compared to placebo and benzodiazepines reduced the risk of death by 52% (42.8%-60.7%) compared to placebo. Both treatments showed evidence of a dose-response effect, and no experiment found a statistically significant increase in risk of death. We conclude that both benzodiazepines and antipsychotic medications are effective for the prevention of lethality from cocaine toxicity in animal models.

Is Long-term Use of Benzodiazepine a Risk for Cancer?

PubMed Central

Iqbal, Usman; Nguyen, Phung-Anh; Syed-Abdul, Shabbir; Yang, Hsuan-Chia; Huang, Chih-Wei; Jian, Wen-Shan; Hsu, Min-Huei; Yen, Yun; Li, Yu-Chuan (Jack)

2015-01-01

Abstract The carcinogenicity of benzodiazepines (BZDs) is still unclear. We aimed to assess whether long-term benzodiazepines use is risk for cancer. We conducted a longitudinal population-based case-control study by using 12 years from Taiwan National Health Insurance database and investigated the association between BZDs use and cancer risk of people aged over 20 years. During the study period, 42,500 cases diagnosed with cancer were identified and analyzed for BZDs use. For each case, six eligible controls matched for age, sex, and the index date (ie, free of any cancer in the date of case diagnosis) by using propensity score. For appropriate risk estimation, we observed the outcomes according to their length of exposure (LOE) and defined daily dose (DDD). To mimic bias, we adjusted with potential confounding factors such as medications and comorbid diseases which could influence for cancer risk during the study period. The data was analyzed by using Cox proportional hazard regression and conditional logistic regression. The finding unveils benzodiazepines use into safe and unsafe groups for their carcinogenicity. The use of diazepam (HR, 0.96; 95%CI, 0.92–1.00), chlorodizepoxide (HR, 0.98; 95%CI, 0.92–1.04), medazepam (HR, 1.01; 95%CI, 0.84–1.21), nitrazepam (HR, 1.06; 95%CI, 0.98–1.14), oxazepam (HR, 1.05; 95%CI, 0.94–1.17) found safer among BZDs. However, clonazepam (HR, 1.15; 95%CI, 1.09–1.22) were associated with a higher risk for cancers. Moreover, specific cancer risk among BZDs use was observed significantly increased 98% for brain, 25% for colorectal, and 10% for lung, as compared with non-BZDs use. Diazepam, chlordiazepoxide, medazepam, nitrazepam, and oxazepam are safe among BZDs use for cancer risk. Our findings could help physicians to select safer BZDs and provide an evidence on the carcinogenic effect of benzodiazepines use by considering the LOE and DDD for further research. PMID:25674736

Benzodiazepine and kainate receptor binding sites in the RCS rat retina.

PubMed

Stasi, Kalliopi; Naskar, Rita; Thanos, Solon; Kouvelas, Elias D; Mitsacos, Ada

2003-02-01

The effect of age and photoreceptor degeneration on the kainate subtype of glutamate receptors and on the benzodiazepine-sensitive gamma-aminobutyric acid-A receptors (GABA(A)) in normal and RCS (Royal College of Surgeons) rats were investigated. [(3)H]Kainate and [(3)H]flunitrazepam were used as radioligands for kainate and GABA(A)/benzodiazepine()receptors, respectively, using the quantitative receptor autoradiography technique. In both normal and RCS rat retina we observed that [(3)Eta]flunitrazepam and [(3)Eta]kainate binding levels were several times higher in inner plexiform layer (IPL) than in outer plexiform layer (OPL) at all four ages studied (P17, P35, P60 and P180). Age-related changes in receptor binding were observed in normal rat retina: [(3)Eta]flunitrazepam binding showed a significant decrease of 25% between P17 and P60 in IPL,and [(3)Eta]kainate binding showed significant decreases between P17 and P35 in both synaptic layers (71% in IPL and 63% in OPL). Degeneration-related changes in benzodiazepine and kainate receptor binding were observed in RCS rat retina. In IPL, [(3)Eta]flunitrazepam and [(3)Eta]kainate binding levels were higher than in normal retina at P35 (by 24% and 86%, respectively). In OPL, [(3)Eta]flunitrazepam binding was higher in RCS than in normal retina on P35 (74%) and also on P60 (62%). The results indicate that postnatal changes occur in kainate and benzodiazepine receptor binding sites in OPL and IPL of the rat retina up to 6 months of age. The data also suggest that the receptor binding changes observed in the RCS retina could be a consequence of the primary photoreceptor degeneration.

Assessment of affective and somatic signs of ethanol withdrawal in C57BL/6J mice using a short-term ethanol treatment.

PubMed

Perez, E E; De Biasi, M

2015-05-01

Alcohol is one of the most prevalent addictive substances in the world. Withdrawal symptoms result from abrupt cessation of alcohol consumption in habitual drinkers. The emergence of both affective and physical symptoms produces a state that promotes relapse. Mice provide a preclinical model that could be used to study alcohol dependence and withdrawal while controlling for both genetic and environmental variables. The use of a liquid ethanol diet offers a reliable method for the induction of alcohol dependence in mice, but this approach is impractical when conducting high-throughput pharmacological screens or when comparing multiple strains of genetically engineered mice. The goal of this study was to compare withdrawal-associated behaviors in mice chronically treated with a liquid ethanol diet vs. mice treated with a short-term ethanol treatment that consisted of daily ethanol injections containing the alcohol dehydrogenase inhibitor, 4-methylpyrazole. Twenty-four hours after ethanol treatment, mice were tested in the open field arena, the elevated plus maze, the marble burying test, or for changes in somatic signs during spontaneous ethanol withdrawal. Anxiety-like and compulsive-like behaviors, as well as physical signs, were all significantly elevated in mice undergoing withdrawal, regardless of the route of ethanol administration. Therefore, a short-term ethanol treatment can be utilized as a screening tool for testing genetic and pharmacological agents before investing in a more time-consuming ethanol treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Evaluation of the significance of abrupt changes in precipitation and runoff process in China

NASA Astrophysics Data System (ADS)

Xie, Ping; Wu, Ziyi; Sang, Yan-Fang; Gu, Haiting; Zhao, Yuxi; Singh, Vijay P.

2018-05-01

Abrupt changes are an important manifestation of hydrological variability. How to accurately detect the abrupt changes in hydrological time series and evaluate their significance is an important issue, but methods for dealing with them effectively are lacking. In this study, we propose an approach to evaluate the significance of abrupt changes in time series at five levels: no, weak, moderate, strong, and dramatic. The approach was based on an index of correlation coefficient calculated for the original time series and its abrupt change component. A bigger value of correlation coefficient reflects a higher significance level of abrupt change. Results of Monte-Carlo experiments verified the reliability of the proposed approach, and also indicated the great influence of statistical characteristics of time series on the significance level of abrupt change. The approach was derived from the relationship between correlation coefficient index and abrupt change, and can estimate and grade the significance levels of abrupt changes in hydrological time series. Application of the proposed approach to ten major watersheds in China showed that abrupt changes mainly occurred in five watersheds in northern China, which have arid or semi-arid climate and severe shortages of water resources. Runoff processes in northern China were more sensitive to precipitation change than those in southern China. Although annual precipitation and surface water resources amount (SWRA) exhibited a harmonious relationship in most watersheds, abrupt changes in the latter were more significant. Compared with abrupt changes in annual precipitation, human activities contributed much more to the abrupt changes in the corresponding SWRA, except for the Northwest Inland River watershed.

Topiramate in opiate withdrawal.

PubMed

Zullino, Daniele F; Cottier, Anne-Claude; Besson, Jacques

2002-10-01

The alpha2-adrenergic agonist clonidine is the mainly used drug for the opiate withdrawal. Its efficacy and tolerance in treating withdrawal symptoms is, however, suboptimal. The pharmacological profile of topiramate suggests it could be rather valuable for opiate withdrawal, as there is some evidence that topiramate acts, among others, through inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, which play an important role in the withdrawal-induced activation of the locus coeruleus (LC) by glutamate. Three patients undergoing an inpatient opiate detoxification program were treated with topiramate, which achieved a nearly complete control of withdrawal symptoms.

Development of Hiccup in Male Patients Hospitalized in a Psychiatric Ward: Is it Specifically Related to the Aripiprazole-Benzodiazepine Combination?

PubMed

Caloro, Matteo; Pucci, Daniela; Calabrò, Giuseppa; de Pisa, Eleonora; Mancinelli, Iginia; Rosini, Enrico; Montebovi, Franco; De Filippis, Sergio; Telesforo, Carla Ludovica; Cuomo, Ilaria; Kotzalidis, Georgios D; Girardi, Paolo

2016-01-01

The aim of this study was to identify hiccup cases among patients hospitalized in a psychiatric ward and focus on their treatment, so to establish intervention risk. We reviewed records of 354 consecutively admitted patients during the year 2013 to identify hiccup cases. Hiccup occurred in 7 patients on both aripiprazole and benzodiazepines and in one on delorazepam. No patient on aripiprazole alone developed hiccup. No patient on drugs other than aripiprazole or benzodiazepines developed hiccup. The symptom subsided in 3 cases upon discontinuing aripiprazole and in 5 cases after discontinuing the benzodiazepine (including the case on delorazepam alone); in 2 cases of persistent hiccup, the symptom resolved after adding the calcium channel blocker, pregabalin. All patients developing hiccup were male. There was a 70-fold increase in the risk for developing hiccup in the aripiprazole/benzodiazepine intake condition versus all other conditions, and it further increased if limiting to the male sex. The retrospective nature of the study was its limitation. Hospitalized psychiatric patients on both aripiprazole and benzodiazepines may be at significant risk of hiccup. This clinical awareness could lead to antipsychotic and/or benzodiazepine discontinuation or switch or to the addition of calcium channel blocker inhibitors.

INTERACTION BETWEEN DELTA OPIOID RECEPTORS AND BENZODIAZEPINES IN CO2- INDUCED RESPIRATORY RESPONSES IN MICE

PubMed Central

Borkowski, Anne H.; Barnes, Dylan C.; Blanchette, Derek R.; Castellanos, F. Xavier; Klein, Donald F.; Wilson, Donald A.

2011-01-01

The false-suffocation hypothesis of panic disorder (Klein, 1993) suggested δ-opioid receptors as a possible source of the respiratory dysfunction manifested in panic attacks occurring in panic disorder (Preter and Klein, 2008). This study sought to determine if a lack of δ-opioid receptors in a mouse model affects respiratory response to elevated CO2, and whether the response is modulated by benzodiazepines, which are widely used to treat panic disorder. In a whole-body plethysmograph, respiratory responses to 5% CO2 were compared between δ-opioid receptor knockout mice and wild-type mice after saline, diazepam (1 mg/kg), and alprazolam (0.3 mg/kg) injection. The results show that lack of δ-opioid receptors does not affect normal response to elevated CO2, but does prevent benzodiazepines from modulating that response. Thus, in the presence of benzodiazepine agonists, respiratory responses to elevated CO2 were enhanced in δ-opioid receptor knockout mice compared to wild-type mice. This suggests an interplay between benzodiazepine receptors and δ-opioid receptors in regulating the respiratory effects of elevated CO2, which might be related to CO2 induced panic. PMID:21561601

The association between maternal smoking and placenta abruption: a meta-analysis.

PubMed

Shobeiri, Fatemeh; Masoumi, Seyedeh Zahra; Jenabi, Ensiyeh

2017-08-01

Several epidemiological studies have determined that maternal smoking can increase the risk of placenta abruption. To date, only a meta-analysis has been performed for assessing the relationship between smoking and placenta abruption. This meta-analysis was conducted to estimate the association between smoking and the risk of placenta abruption. A literature search was conducted in major databases such as PubMed, Web of Science, and Scopus from the earliest possible year to April 2016. The heterogeneity across studies was explored by Q-test and I 2 statistic. The publication bias was assessed using Begg's and Egger's tests. The results were reported using odds ratio (OR) estimate with its 95% confidence intervals (CI) using a random effects model. The literature search yielded 1167 publications until April 2016 with 4 309 610 participants. Based on OR estimates obtained from case-control and cohort studies, there was a significant association between smoking and placenta abruption (1.80; 95% CI: 1.75, 1.85). Based on the results of cohort studies, smoking and placenta abruption had a significant association (relative risk ratio: 1.65; 95% CI: 1.51, 1.80). Based on reports in epidemiological studies, we showed that smoking is a risk factor for placenta abruption.

The Cannabis Withdrawal Scale development: patterns and predictors of cannabis withdrawal and distress.

PubMed

Allsop, David J; Norberg, Melissa M; Copeland, Jan; Fu, Shanlin; Budney, Alan J

2011-12-01

Rates of treatment seeking for cannabis are increasing, and relapse is common. Management of cannabis withdrawal is an important intervention point. No psychometrically sound measure for cannabis withdrawal exists, and as a result treatment developments cannot be optimally targeted. The aim is to develop and test the psychometrics of the Cannabis Withdrawal Scale and use it to explore predictors of cannabis withdrawal. A volunteer sample of 49 dependent cannabis users provided daily scores on the Cannabis Withdrawal Scale during a baseline week and 2 weeks of abstinence. Internal reliability (Cronbach's alpha=0.91), test-retest stability (average intra-class correlation=0.95) and content validity analysis show that the Cannabis Withdrawal Scale has excellent psychometric properties. Nightmares and/or strange dreams was the most valid item (Wald χ²=105.6, P<0.0001), but caused relatively little associated distress (Wald χ²=25.11, P=0.03). Angry outbursts were considered intense (Wald χ²=73.69, P<0.0001) and caused much associated distress (Wald χ²=45.54, P<0.0001). Trouble getting to sleep was also an intense withdrawal symptom (Wald χ²=42.31, P<0.0001) and caused significant associated distress (Wald χ²=47.76, P<0.0001). Scores on the Severity of Dependence Scale predicted cannabis withdrawal. The Cannabis Withdrawal Scale can be used as a diagnostic instrument in clinical and research settings where regular monitoring of withdrawal symptoms is required. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Overlapping buprenorphine, opioid, and benzodiazepine prescriptions among Veterans dually enrolled in VA and Medicare Part D

PubMed Central

Gellad, Walid F.; Zhao, Xinhua; Thorpe, Carolyn T.; Thorpe, Joshua M.; Sileanu, Florentina E.; Cashy, John P.; Mor, Maria; Hale, Jennifer A.; Radomski, Thomas; Hausmann, Leslie R. M.; Fine, Michael J.; Good, Chester B.

2016-01-01

Background Buprenorphine is a key tool in the management of opioid use disorder, but there are growing concerns about abuse, diversion and safety. These concerns are amplified for the Department of Veterans Affairs (VA), whose patients may receive care concurrently from multiple prescribers within and outside VA. To illustrate the extent of this challenge, we examined overlapping prescriptions for buprenorphine, opioids, and benzodiazepines among Veterans dually enrolled in VA and Medicare Part D. Methods We constructed a cohort of all Veterans dually enrolled in VA and Part D who filled an opioid prescription in 2012. We identified patients who received tablet or film buprenorphine products from either source. We calculated the proportion of buprenorphine recipients with any overlapping prescription (based on days supply) for a non-buprenorphine opioid or benzodiazepine, focusing on Veterans who received overlapping prescriptions from a different system than their buprenorphine prescription (Part D buprenorphine recipients receiving overlapping opioids or benzodiazepines from VA and vice versa). Results We identified 1,790 dually enrolled Veterans with buprenorphine prescriptions, including 760 (43%) from VA and 1,091 (61%) from Part D (61 Veterans with buprenorphine from both systems were included in each group). Among VA buprenorphine recipients, 199 (26%) received an overlapping opioid prescription and 11 (1%) received an overlapping benzodiazepine prescription from Part D. Among Part D buprenorphine recipients, 208 (19%) received an overlapping opioid prescription and 178 (16%) received an overlapping benzodiazepine prescription from VA. Among VA and Part D buprenorphine recipients with cross-system opioid overlap, 25% (49/199) and 35% (72/208), respectively, had >90 days of overlap. Conclusions Many buprenorphine recipients receive overlapping prescriptions for opioids and benzodiazepines from a different health care system than the one in which their

Effective treatment of catatonia by combination of benzodiazepine and electroconvulsive therapy.

PubMed

Unal, Ahmet; Bulbul, Feridun; Alpak, Gokay; Virit, Osman; Copoglu, U Sertan; Savas, Haluk A

2013-09-01

Catatonia, a motor dysregulation syndrome, can emerge in numerous psychiatric disorders, mainly in schizophrenia and mood disorders, and metabolic and endocrine disorders such as infections, toxic states, epilepsy, and traumatic brain injury. In our study, we aimed to investigate demographic, clinical, and treatment-related characteristics of catatonic patients managed in our inpatient clinic. The medical records of 57 patients diagnosed to have catatonia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria who were admitted to the inpatient psychiatry clinic of the Gaziantep University School of Medicine between 1 January, 2003, and 31 December, 2011, were retrospectively reviewed. In patients with catatonia, mood disorders (63.2%) were found to be the most common underlying or primary disease, whereas mutism (47.4%) was found to be the most common catatonic symptom. There was a comorbid medical condition in 9 patients (15.8%). Patients underwent an average of 9.00 electroconvulsive therapy (ECT) sessions. Among 57 patients with catatonia, catatonic symptoms were resolved in 57 patients (100%) by benzodiazepine and ECT. In our study, full recovery was achieved in catatonia by benzodiazepine plus ECT combination. As a result, we recommend combined ECT and benzodiazepine for catatonia.

Characterizing the Interrelationships of Prescription Opioid and Benzodiazepine Drugs With Worker Health and Workplace Hazards.

PubMed

Kowalski-McGraw, Michele; Green-McKenzie, Judith; Pandalai, Sudha P; Schulte, Paul A

2017-11-01

Prescription opioid and benzodiazepine drug use, which has risen significantly, can affect worker health. Exploration of the scientific literature assessed (1) interrelationships of such drug use, occupational risk factors, and illness and injury, and (2) occupational and personal risk factor combinations that can affect their use. The scientific literature from 2000 to 2015 was searched to determine any interrelationships. Evidence for eight conceptual models emerged based on the search yield of 133 articles. These models summarize interrelationships among prescription opioid and benzodiazepine use with occupational injury and illness. Factors associated with the use of these drugs included fatigue, impaired cognition, falls, motor vehicle crashes, and the use of multiple providers. Prescription opioid and benzodiazepine drugs may be both a personal risk factor for work-related injury and a consequence of workplace exposures.

High Prevalence of Inappropriate Benzodiazepine and Sedative Hypnotic Prescriptions among Hospitalized Older Adults.

PubMed

Pek, Elisabeth Anna; Remfry, Andrew; Pendrith, Ciara; Fan-Lun, Chris; Bhatia, R Sacha; Soong, Christine

2017-05-01

Benzodiazepines and sedative hypnotics are commonly used to treat insomnia and agitation in older adults despite significant risk. A clear understanding of the extent of the problem and its contributors is required to implement effective interventions. To determine the proportion of hospitalized older adults who are inappropriately prescribed benzodiazepines or sedative hypnotics, and to identify patient and prescriber factors associated with increased prescriptions. Single-center retrospective observational study. Urban academic medical center. Medical-surgical inpatients aged 65 or older who were newly prescribed a benzodiazepine or zopiclone. Our primary outcome was the proportion of patients who were prescribed a potentially inappropriate benzodiazepine or sedative hypnotic. Potentially inappropriate indications included new prescriptions for insomnia or agitation/anxiety. We used a multivariable random-intercept logistic regression model to identify patient- and prescriber-level variables that were associated with potentially inappropriate prescriptions. Of 1308 patients, 208 (15.9%) received a potentially inappropriate prescription. The majority of prescriptions, 254 (77.4%), were potentially inappropriate. Of these, most were prescribed for insomnia (222; 87.4%) and during overnight hours (159; 62.3%). Admission to a surgical or specialty service was associated with significantly increased odds of potentially inappropriate prescription compared to the general internal medicine service (odds ratio [OR], 6.61; 95% confidence interval [CI], 2.70-16.17). Prescription by an attending physician or fellow was associated with significantly fewer prescriptions compared to first-year trainees (OR, 0.28; 95% CI, 0.08-0.93). Nighttime prescriptions did not reach significance in initial bivariate analyses but were associated with increased odds of potentially inappropriate prescription in our regression model (OR, 4.48; 95% CI, 2.21-9.06). The majority of newly

The association between uterine leiomyoma and placenta abruption: A meta-analysis.

PubMed

Jenabi, Ensiyeh; Ebrahimzadeh Zagami, Samira

2017-11-01

Some epidemiological studies have found that uterine leiomyoma can increase the risk of placenta abruption. To date, the meta-analysis has not been performed for assessing the relationship between uterine leiomyoma and placenta abruption. This meta-analysis was conducted to estimate the association between uterine leiomyoma and the risk of placenta abruption. A literature search was conducted out in major databases PubMed, Web of Science, and Scopus from the earliest possible year to October 2016. The heterogeneity across studies was explored by Q-test and I 2 statistic. The publication bias was assessed by Begg's and Egger's tests. The results were showed using odds ratio (OR) estimate with its 95% confidence intervals (CI) using a random-effects model. The literature search included 953 articles until October 2016 with 232,024 participants. Based on OR estimates obtained from case-control and cohort studies, there was significant association between uterine leiomyoma and placenta abruption (2.63; 95% CI: 1.38, 3.88). We showed based on reports in observational studies that uterine leiomyoma is a risk factor for placenta abruption.

Implementation of an Intensive Care Unit-Specific Alcohol Withdrawal Syndrome Management Protocol Reduces the Need for Mechanical Ventilation.

PubMed

Heavner, Jason J; Akgün, Kathleen M; Heavner, Mojdeh S; Eng, Claire C; Drew, Matthew; Jackson, Peter; Pritchard, David; Honiden, Shyoko

2018-05-25

Alcohol use disorders are prevalent and put patients at risk for developing alcohol withdrawal syndrome (AWS). Treatment of AWS with a symptom-triggered protocol standardizes management and may avoid AWS-related complications. The objective of this study was to evaluate whether implementation of an intensive care unit (ICU)-specific, symptom-triggered protocol for management of AWS was associated with improved clinical outcomes and, in particular, would reduce the risk of patients with AWS requiring mechanical ventilation. Retrospective pre-post-protocol implementation study. Thirty-six-bed, closed medical ICU (MICU) at a large, tertiary care, teaching hospital in an urban setting. A total of 233 adults admitted to the MICU with any diagnosis of alcohol use disorders based on International Classification of Diseases, Ninth Revision codes and who received at least one dose of any benzodiazepine; of these patients, 139 were in the pre-protocol era (August 2009-January 2010 and August 2010-January 2011), and 94 were in the post-protocol era (August 2012-January 2013), after implementation of the Yale Alcohol Withdrawal Protocol (YAWP) in April 2012. The YAWP pairs a modified Minnesota Detoxification Scale with an order set that includes benzodiazepine dosing regimens and suggests adjuvant therapies. AWS was the primary reason for ICU admission (107/233 patients [45.9%]) and did not significantly vary between eras (P=0.2). Of the 233 patients included, 81.1% were male and 67.0% were white, which did not significantly differ by study era. Severity of illness at MICU admission did not significantly differ between patients in the pre-protocol and post-protocol eras (median [interquartile range] Acute Physiology and Chronic Health Evaluation [APACHE] II scores of 12 [9-17] and 12.5 [7-16], respectively, p=0.4). Median lorazepam-equivalent dose per MICU day, duration of benzodiazepine infusion, and use of adjuvant therapy were not significantly different between eras. MICU

An international contrast of rates of placental abruption: an age-period-cohort analysis.

PubMed

Ananth, Cande V; Keyes, Katherine M; Hamilton, Ava; Gissler, Mika; Wu, Chunsen; Liu, Shiliang; Luque-Fernandez, Miguel Angel; Skjærven, Rolv; Williams, Michelle A; Tikkanen, Minna; Cnattingius, Sven

2015-01-01

Although rare, placental abruption is implicated in disproportionately high rates of perinatal morbidity and mortality. Understanding geographic and temporal variations may provide insights into possible amenable factors of abruption. We examined abruption frequencies by maternal age, delivery year, and maternal birth cohorts over three decades across seven countries. Women that delivered in the US (n = 863,879; 1979-10), Canada (4 provinces, n = 5,407,463; 1982-11), Sweden (n = 3,266,742; 1978-10), Denmark (n = 1,773,895; 1978-08), Norway (n = 1,780,271, 1978-09), Finland (n = 1,411,867; 1987-10), and Spain (n = 6,151,508; 1999-12) were analyzed. Abruption diagnosis was based on ICD coding. Rates were modeled using Poisson regression within the framework of an age-period-cohort analysis, and multi-level models to examine the contribution of smoking in four countries. Abruption rates varied across the seven countries (3-10 per 1000), Maternal age showed a consistent J-shaped pattern with increased rates at the extremes of the age distribution. In comparison to births in 2000, births after 2000 in European countries had lower abruption rates; in the US there was an increase in rate up to 2000 and a plateau thereafter. No birth cohort effects were evident. Changes in smoking prevalence partially explained the period effect in the US (P = 0.01) and Sweden (P<0.01). There is a strong maternal age effect on abruption. While the abruption rate has plateaued since 2000 in the US, all other countries show declining rates. These findings suggest considerable variation in abruption frequencies across countries; differences in the distribution of risk factors, especially smoking, may help guide policy to reduce abruption rates.

Phase Memory Preserving Harmonics from Abruptly Autofocusing Beams.

PubMed

Koulouklidis, Anastasios D; Papazoglou, Dimitris G; Fedorov, Vladimir Yu; Tzortzakis, Stelios

2017-12-01

We demonstrate both theoretically and experimentally that the harmonics from abruptly autofocusing ring-Airy beams present a surprising property: They preserve the phase distribution of the fundamental beam. Consequently, this "phase memory" imparts to the harmonics the abrupt autofocusing behavior, while, under certain conditions, their foci coincide in space with the one of the fundamental. Experiments agree well with our theoretical estimates and detailed numerical calculations. Our findings open the way for the use of such beams and their harmonics in strong field science.

Effects of acute alcohol withdrawal on nest building in mice selectively bred for alcohol withdrawal severity

PubMed Central

Greenberg, Gian D.; Phillips, Tamara J.; Crabbe, John C.

2017-01-01

Nest building has been used to assess thermoregulatory behavior and positive motivational states in mice. There are known genetic influences on ethanol withdrawal severity as well as individual/thermoregulatory nest building. Withdrawal Seizure-Prone (WSP-1, WSP-2) and Withdrawal Seizure-Resistant (WSR-1, WSR-2) mice were selectively bred for high vs low handling-induced convulsion (HIC) severity, respectively, during withdrawal from chronic ethanol vapor inhalation. They also differ in HIC severity during withdrawal from an acute, 4 g/kg ethanol injection. In our initial study, withdrawal from an acute dose of ethanol dose-dependently impaired nest building over the initial 24 h of withdrawal in genetically segregating Withdrawal Seizure Control (WSC) mice. In two further studies, acute ethanol withdrawal suppressed nest building for up to two days in WSP-1 females. Deficits in nest building from ethanol were limited to the initial 10 h of withdrawal in WSR-1 females and to the initial 24 h of withdrawal in WSP-1 and WSR-1 males. Effects of ethanol on nest building for up to two days were found in WSP-2 and WSR-2 mice of both sexes. Nest building deficits in female mice from the first replicate could not be explained by a general decrease in locomotor behavior. These results suggest that nest building is a novel behavioral phenotype for indexing the severity of acute ethanol withdrawal, and that genes contributing to this trait differ from those affecting acute withdrawal HIC severity. PMID:27503811

40 CFR 74.18 - Withdrawal.

Code of Federal Regulations, 2014 CFR

2014-07-01

... opt-in source may request to withdraw from the Acid Rain Program by submitting an administrative... paragraph (f)(1) of this section. (b) Requesting withdrawal. To withdraw from the Acid Rain Program, the...-in source's prior violations. An opt-in source that withdraws from the Acid Rain Program shall comply...

40 CFR 74.18 - Withdrawal.

Code of Federal Regulations, 2013 CFR

2013-07-01

... opt-in source may request to withdraw from the Acid Rain Program by submitting an administrative... paragraph (f)(1) of this section. (b) Requesting withdrawal. To withdraw from the Acid Rain Program, the...-in source's prior violations. An opt-in source that withdraws from the Acid Rain Program shall comply...

40 CFR 74.18 - Withdrawal.

Code of Federal Regulations, 2012 CFR

2012-07-01

... opt-in source may request to withdraw from the Acid Rain Program by submitting an administrative... paragraph (f)(1) of this section. (b) Requesting withdrawal. To withdraw from the Acid Rain Program, the...-in source's prior violations. An opt-in source that withdraws from the Acid Rain Program shall comply...

40 CFR 74.18 - Withdrawal.

Code of Federal Regulations, 2011 CFR

2011-07-01

... opt-in source may request to withdraw from the Acid Rain Program by submitting an administrative... paragraph (f)(1) of this section. (b) Requesting withdrawal. To withdraw from the Acid Rain Program, the...-in source's prior violations. An opt-in source that withdraws from the Acid Rain Program shall comply...

40 CFR 74.18 - Withdrawal.

Code of Federal Regulations, 2010 CFR

2010-07-01

... opt-in source may request to withdraw from the Acid Rain Program by submitting an administrative... paragraph (f)(1) of this section. (b) Requesting withdrawal. To withdraw from the Acid Rain Program, the...-in source's prior violations. An opt-in source that withdraws from the Acid Rain Program shall comply...

[Appropriate use of benzodiazepines zolpidem and zopiclone in diseases attended in primary care].

PubMed

Granados Menéndez, M Isabel; Salinero Fort, Miguel Angel; Palomo Ancillo, Marta; Aliaga Gutiérrez, Laura; García Escalonilla, Carmen; Ortega Orcos, Rebeca

2006-01-01

To estimate the proportion of benzodiazepine prescriptions that comply with the guidelines for appropriate prescription. To identify the variables associated with appropriate prescription. Observational, cross-sectional study. Monóvar Health Centre in Area IV, Madrid, Spain. Random sample of 270 active benzodiazepine prescriptions in adult patients from the prescriptions record of the OMI-AP V. 5.0 computer system. The chosen dimensions for appropriate prescription were: a) correct diagnostic indication; b) absence of benzodiazepines with long half-life in the elderly; c) existence of support or monitoring visits; d) overall appropriateness or coexistence of correct diagnostic indications and monitoring visits. Independent variables were recorded in relation to patient, person prescribing and prescription. Diagnostic indication, 75.6%; absence of benzodiazepines with long half-life in the elderly, 79.8%; existence of support visits, 63.3%; overall appropriateness, 53%. Main diagnoses: pure anxiety, 29%; anxiety related to other illness, 18.6%; insomnia, 14.8%; cardiovascular illness, 14.8%; alcohol and drug abuse, 4.5%; osteo-muscular illness, 4.4%; schizophrenia, 4.4%. Most prescribed substances: lorazepam, 27.8%; bromazepam, 23.7%. Average life of prescriptions: 18.58 months. Origins: health centre, 68.5%; out-patient psychiatry, 10%; hospital, 10%. The variable that is most closely associated with overall appropriateness, fitted with the rest of the variables, is out-patient psychiatry prescription (OR, 6.67; 95% CI, 1.92-23.18). The mean duration of the prescriptions infringes all standards. The overall appropriateness or correct coexistence of adequate diagnostic indication with follow-up visits is associated with out-patient Psychiatry prescription.

Treatment for amphetamine withdrawal.

PubMed

Srisurapanont, M; Jarusuraisin, N; Kittirattanapaiboon, P

2001-01-01

Amphetamine withdrawal has been less studied although it is a common problem with a prevalent rate of 87% among amphetamine users. Its symptoms, in particular intense craving, may be a critical factor leading to relapse of amphetamine use. In clinical practice, treatment for cocaine withdrawal has been recommended for the management of amphetamine withdrawal although the pharmacodynamic and pharmacokinetic properties of these two substances are not the same. To search and determine risks, benefits, and costs of a variety of treatments for the management of amphetamine withdrawal. Electronic searches of MEDLINE (1966 - December 2000), EMBASE (1980 - February 2001), CINAHL (1982 - January 2001) and Cochrane Controlled Trials Register (Cochrane Library 2000 issue 4) were undertaken. References to the articles obtained by any means were searched. All relevant randomised controlled trials (RCTs) and controlled clinical trials (CCTs) were included. Participants were people with amphetamine withdrawal, diagnosed by any set of criteria. Any kinds of biological and psychological treatments both alone and combined were examined. A variety of outcomes, for example, number of treatment responders, score changes, were considered. Two reviewers evaluated and extracted the data independently. The dichotomous data were extracted on an intention-to-treat basis in which the dropouts were assigned as participants with the worst outcomes. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess the dichotomous data. The Weighted Mean Difference (WMD) with 95% CI was used to assessed the continuous data. The results of two studies have shown some benefits of amineptine in the treatment of amphetamine withdrawal. Those benefits can be seen in the respects of discontinuation rate and global state, as measured by Clinical Global Impression Scale. However, no direct benefit of amineptine on amphetamine withdrawal symptoms or craving was shown. The evidence about

Withdrawal: Expanding a Key Addiction Construct

PubMed Central

2015-01-01

Withdrawal is an essential component of classical addiction theory; it is a vital manifestation of dependence and motivates relapse. However, the traditional conceptualization of withdrawal as a cohesive collection of symptoms that emerge during drug deprivation and decline with either the passage of time or reinstatement of drug use, may be inadequate to explain scientific findings or fit with modern theories of addiction. This article expands the current understanding of tobacco withdrawal by examining: (1) withdrawal variability; (2) underlying causes of withdrawal variability, including biological and person factors, environmental influences, and the influence of highly routinized behavioral patterns; (3) new withdrawal symptoms that allow for enhanced characterization of the withdrawal experience; and (4) withdrawal-related cognitive processes. These topics provide guidance regarding the optimal assessment of withdrawal and illustrate the potential impact modern withdrawal conceptualization and assessment could have on identifying treatment targets. PMID:25744958

Gamma-Aminobutyric acid and benzodiazepine receptors in the kindling model of epilepsy: a quantitative radiohistochemical study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shin, C.; Pedersen, H.B.; McNamara, J.O.

1985-10-01

Quantitative radiohistochemistry was utilized to study alterations of gamma-aminobutyric acid (GABA) and benzodiazepine receptors in the kindling model of epilepsy. The radioligands used for GABA and benzodiazepine receptors were (TH) muscimol and (TH)flunitrazepam, respectively. GABA receptor binding was increased by 22% in fascia dentata of the hippocampal formation but not in neocortex or substantia nigra of kindled rats. Within fascia dentata, GABA receptor binding was increased to an equivalent extent in stratum granulosum and throughout stratum moleculare; no increase was found in dentate hilus or stratum lacunosummoleculare or stratum radiatum of CA1. The increased binding was present at 24 hrmore » but not at 28 days after the last kindled seizure. The direction, anatomic distribution, and time course of the increased GABA receptor binding were paralleled by increased benzodiazepine receptor binding. The anatomic distribution of the increased GABA receptor binding is consistent with a localization to somata and dendritic trees of dentate granule cells. The authors suggest that increased GABA and benzodiazepine receptor binding may contribute to enhanced inhibition of dentate granule cells demonstrated electrophysiologically in kindled animals.« less

Impulsivity in men with prescription of benzodiazepines and methadone in prison.

PubMed

Moreno-Ramos, Luis; Fernández-Serrano, María José; Pérez-García, Miguel; Verdejo-García, Antonio

2016-06-14

Benzodiazepines and methadone use has been associated with various neuropsychological impairments. However, to the best of our knowledge, no studies have been carried out on the effect of these substances (either separately or combined) on impulsive personality, including studies in prisoners. The aim of this study is to examine the impulsive personality of a sample of 134 male prisoners using the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (Torrubia, Avila, Molto, & Caseras, 2001) and the UPPS-P Scale (Cyders et al., 2007). Some of these were methadone users, methadone and benzodiazepines users, polydrug users in abstinence and non-dependent drug users. The results showed that drug users have greater sensitivity to reward, positive urgency, negative urgency and sensation seeking than non-dependent users. Methadone users showed more sensitivity to punishment and lack of perseverance with respect to other users. No differences were found between methadone+benzodiazepines users and other groups. The secondary aim is to examine which impulsive personality dimensions are related to the two motivational systems proposed by Gray (BIS-BAS) using exploratory factor analysis. Results showed two different components. One component was defined by the subscales sensitivity to reinforcement, positive urgency, negative urgency and sensation seeking. The second component was defined by the subscales sensitivity to punishment, lack of perseverance and lack of premeditation.

Pharmacological therapies for management of opium withdrawal.

PubMed

Rahimi-Movaghar, Afarin; Gholami, Jaleh; Amato, Laura; Hoseinie, Leila; Yousefi-Nooraie, Reza; Amin-Esmaeili, Masoumeh

2018-06-21

participants in the buprenorphine group at days 1 to 10. We found no difference between groups for all the other comparisons considering this outcome.Comparing different dosages of the same pharmacological detoxification treatment, a high dose of clonidine (1 to 1.2 mg/day) did not differ from a low dose of clonidine (0.5 to 0.6 mg/day) in completion of treatment in an inpatient setting (RR 1.00, 95% CI 0.84 to 1.19; 1 study, 68 participants), however a higher number of participants with hypotension was reported in the high-dose group (RR 3.25, 95% CI 1.77 to 5.98). Gradual reduction of methadone was associated with more adverse effects than abrupt withdrawal of methadone (RR 2.25, 95% CI 1.02 to 4.94; 1 study, 20 participants, very low-quality evidence). Results did not support using any specific pharmacological approach for the management of opium withdrawal due to generally very low-quality evidence and small or no differences between treatments. However, it seems that opium withdrawal symptoms are significant, especially at days 2 to 4 after discontinuation of opium. All of the assessed medications might be useful in alleviating symptoms. Those who receive clonidine might experience hypotension.

Trends in intentional abuse or misuse of benzodiazepines and opioid analgesics and the associated mortality reported to poison centers across the United States from 2000 to 2014.

PubMed

Calcaterra, S L; Severtson, S G; Bau, G E; Margolin, Z R; Bucher-Bartelson, B; Green, J L; Dart, R C

2018-04-03

Prior works demonstrates an increased risk of death when opioid analgesics and benzodiazepines are used concomitantly to gain a high. Using poison center data, we described trends in abuse or misuse of benzodiazepines and opioid analgesics. We quantified mortality risk associated with abuse or misuse of benzodiazepines, opioid analgesics and the combination of opioid analgesics and benzodiazepines. This was a retrospective chart review of data from the National Poison Data System which collects information from 55 poison centers located across the United States. We identified reported cases of "intentional abuse or misuse" of benzodiazepine and/or opioid analgesic exposures. Poisson regression was used to compare the number of cases from each year between 2001 and 2014 to the year 2000. Logistic regression was used to determine whether cases exposed to both benzodiazepines and opioids had greater odds of death relative to cases exposed to opioid analgesics alone. From 2000 to 2014, there were 125,485 benzodiazepine exposures and 84,627 opioid exposures among "intentional abuse or misuse" cases. Of the benzodiazepine exposures, 17.3% (n = 21,660) also involved an opioid. In 2010, exposures involving both opioids and benzodiazepines were 4.26-fold (95% CI: 3.87-4.70; p < .001) higher than in 2000. The risk of death was 1.55 (95% CI: 1.01-2.37; p = .04) times greater among those who used both an opioid and a benzodiazepine compared to opioids alone. This association held after adjusting for gender and age. Intentional abuse or misuse of benzodiazepines and opioids in combination increased significantly from 2000 to 2014. Benzodiazepine abuse or misuse far exceeded cases of opioid abuse or misuse. Death was greater with co-abuse or misuse of benzodiazepines and opioids. Population-level campaigns to inform the public about the risk of death with co-abuse or misuse of benzodiazepines and opioids are urgently needed to address this overdose epidemic.

Effects of acute alcohol withdrawal on nest building in mice selectively bred for alcohol withdrawal severity.

PubMed

Greenberg, Gian D; Phillips, Tamara J; Crabbe, John C

2016-10-15

Nest building has been used to assess thermoregulatory behavior and positive motivational states in mice. There are known genetic influences on ethanol withdrawal severity as well as individual/thermoregulatory nest building. Withdrawal Seizure-Prone (WSP-1, WSP-2) and Withdrawal Seizure-Resistant (WSR-1, WSR-2) mice were selectively bred for high vs low handling-induced convulsion (HIC) severity, respectively, during withdrawal from chronic ethanol vapor inhalation. They also differ in HIC severity during withdrawal from an acute, 4g/kg ethanol injection. In our initial study, withdrawal from an acute dose of ethanol dose-dependently impaired nest building over the initial 24h of withdrawal in genetically segregating Withdrawal Seizure Control (WSC) mice. In two further studies, acute ethanol withdrawal suppressed nest building for up to two days in WSP-1 females. Deficits in nest building from ethanol were limited to the initial 10h of withdrawal in WSR-1 females and to the initial 24h of withdrawal in WSP-1 and WSR-1 males. Effects of ethanol on nest building for up to two days were found in WSP-2 and WSR-2 mice of both sexes. Nest building deficits in female mice from the first replicate could not be explained by a general decrease in locomotor behavior. These results suggest that nest building is a novel behavioral phenotype for indexing the severity of acute ethanol withdrawal, and that genes contributing to this trait differ from those affecting acute withdrawal HIC severity. Published by Elsevier Inc.

Increased thermolability of benzodiazepine receptors in cerebral cortex of a baboon with spontaneous seizures: a case report.

PubMed

Squires, R; Naquet, R; Riche, D; Braestrup, C

1979-06-01

The benzodiazepine receptor in the cortex of 1 spontaneously epileptic baboon exhibited an increased rate of thermal inactivation at 65 degrees C when compared with those from 3 other baboons. In other respects (receptor concentration, affinities for flunitrazepam and diazepam, and response to changing pH), the benzodiazepine receptor from this animal was very similar to the receptors in the cortex of 3 other baboons. The 3H-QNB (muscarinic) and 3H-naloxone (opiate) binding sites in the brain of all 4 baboons appeared very similar with respect to all parameters studied (thermal stability, concentration, regional distribution, and affinities for respective ligands). An endogenous factor stabilizing the benzodiazepine receptor could be lacking in the spontaneously epileptic baboon.

Limited tryptic proteolysis of the benzodiazepine binding proteins in different species reveals structural homologies.

PubMed

Friedl, W; Lentes, K U; Schmitz, E; Propping, P; Hebebrand, J

1988-12-01

Peptide mapping can be used to elucidate further the structural similarities of the benzodiazepine binding proteins in different vertebrate species. Crude synaptic membrane preparations were photoaffinity-labeled with [3H]flunitrazepam and subsequently degraded with various concentrations of trypsin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by fluorography allowed a comparison of the molecular weights of photolabeled peptides in different species. Tryptic degradation led to a common peptide of 40K in all species investigated, a finding indicating that the benzodiazepine binding proteins are structurally homologous in higher bony fishes and tetrapods.

Withdrawal: Expanding a Key Addiction Construct.

PubMed

Piper, Megan E

2015-12-01

Withdrawal is an essential component of classical addiction theory; it is a vital manifestation of dependence and motivates relapse. However, the traditional conceptualization of withdrawal as a cohesive collection of symptoms that emerge during drug deprivation and decline with either the passage of time or reinstatement of drug use, may be inadequate to explain scientific findings or fit with modern theories of addiction. This article expands the current understanding of tobacco withdrawal by examining: (1) withdrawal variability; (2) underlying causes of withdrawal variability, including biological and person factors, environmental influences, and the influence of highly routinized behavioral patterns; (3) new withdrawal symptoms that allow for enhanced characterization of the withdrawal experience; and (4) withdrawal-related cognitive processes. These topics provide guidance regarding the optimal assessment of withdrawal and illustrate the potential impact modern withdrawal conceptualization and assessment could have on identifying treatment targets. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Flubromazolam--A new life-threatening designer benzodiazepine.

PubMed

Łukasik-Głębocka, Magdalena; Sommerfeld, Karina; Teżyk, Artur; Zielińska-Psuja, Barbara; Panieński, Paweł; Żaba, Czesław

2016-01-01

In addition to designer benzodiazepines such as etizolam, deschloroetizolam, pyrazolam, diclazepam, nifoxipam, or clonazolam, a new psychoactive substance like flubromazolam, triazole of flubromazepam has become available. Flubromazolam is currently not marketed as a medication but rather as a research chemical and recreational drug. It mostly causes sedative effects but also has moderate anti-anxiety and muscle relaxant effects. A case of a severe intoxication of flubromazolam has been reported. A 27-year-old man, presented with deep coma, bilateral pinpoint unreactive pupils, acute respiratory failure and hypotension, complicated by hypoxic ischemic changes in the central nervous system. A positive result of a urine screening test confirmed the presence of benzodiazepines, which resulted in administration of flumazenil and improved patient consciousness. Quantitative method of liquid chromatography indicated flubromazolam in the patient's serum at 59 ng/mL and urine at 105 ng/mL about 19 h after ingestion of 3 mg dose. On admission, serum creatine kinase was 15,960 U/L. The patient was treated with mechanical ventilation, intravenous fluids, flumazenil and continuous infusion of norepinephrine at a dose of 0.12 µg/kg/min. The patient survived and on the ninth day of hospitalization he was transferred to the Department of Neurology. Flubromazolam is a new designer drug. Recreational use may be a cause of prolonged, severe intoxication associated with coma, hypotension, and rhabdomyolysis.

Financial incentives to discontinue long-term benzodiazepine use: a discrete choice experiment investigating patient preferences and willingness to participate

PubMed Central

Marti, Joachim; Bachhuber, Marcus; Feingold, Jordyn; Meads, David; Richards, Michael; Hennessy, Sean

2017-01-01

Objectives Investigate the acceptability of financial incentives for initiating a medically supervised benzodiazepine discontinuation programme among people with long-term benzodiazepine use and to identify programme features that influence willingness to participate. Methods We conducted a discrete choice experiment in which we presented a variety of incentive-based programs to a sample of older adults with long-term benzodiazepine use identified using the outpatient electronic health record of a university-owned health system. We studied four programme variables: incentive amount for initiating the programme, incentive amount for successful benzodiazepine discontinuation, lottery versus certain payment and whether partial payment was given for dose reduction. Respondents reported their willingness to participate in the programmes and additional information was collected on demographics, history of use and anxiety symptoms. Results The overall response rate was 28.4%. Among the 126 respondents, all four programme variables influenced stated preferences. Respondents strongly preferred guaranteed cash-based incentives as opposed to a lottery, and the dollar amount of both the starting and conditional incentives had a substantial impact on choice. Willingness to participate increased with the amount of conditional incentive. Programme participation also varied by gender, duration of use and income. Conclusions Participation in an incentive-based benzodiazepine discontinuation programme might be relatively low, but is modifiable by programme variables including incentive amounts. These results will be helpful to inform the design of future trials of benzodiazepine discontinuation programmes. Further research is needed to assess the financial viability and potential cost-effectiveness of such economic incentives. PMID:28988167

Effects of chronic alcohol consumption, withdrawal and nerve growth factor on neuropeptide Y expression and cholinergic innervation of the rat dentate hilus.

PubMed

Pereira, Pedro A; Rocha, João P; Cardoso, Armando; Vilela, Manuel; Sousa, Sérgio; Madeira, M Dulce

2016-05-01

Several studies have demonstrated the vulnerability of the hippocampal formation (HF) to chronic alcohol consumption and withdrawal. Among the brain systems that appear to be particularly vulnerable to the effects of these conditions are the neuropeptide Y (NPY)-ergic and the cholinergic systems. Because these two systems seem to closely interact in the HF, we sought to study the effects of chronic alcohol consumption (6months) and subsequent withdrawal (2months) on the expression of NPY and on the cholinergic innervation of the rat dentate hilus. As such, we have estimated the areal density and the somatic volume of NPY-immunoreactive neurons, and the density of the cholinergic varicosities. In addition, because alcohol consumption and withdrawal are associated with impaired nerve growth factor (NGF) trophic support and the administration of exogenous NGF alters the effects of those conditions on various cholinergic markers, we have also estimated the same morphological parameters in withdrawn rats infused intracerebroventricularly with NGF. NPY expression increased after withdrawal and returned to control values after NGF treatment. Conversely, the somatic volume of these neurons did not differ among all groups. On other hand, the expression of vesicular acetylcholine transporter (VAChT) was reduced by 24% in ethanol-treated rats and by 46% in withdrawn rats. The administration of NGF to withdrawn rats increased the VAChT expression to values above control levels. These results show that the effects of prolonged alcohol intake and protracted withdrawal on the hilar NPY expression differ from those induced by shorter exposures to ethanol and by abrupt withdrawal. They also suggest that the normalizing effect of NGF on NPY expression might rely on the NGF-induced improvement of cholinergic neurotransmission in the dentate hilus. Copyright © 2016 Elsevier Inc. All rights reserved.

Pharmacology of saccadic eye movements in man. 1. Effects of the benzodiazepine receptor ligands midazolam and flumazenil.

PubMed

Ball, D M; Glue, P; Wilson, S; Nutt, D J

1991-01-01

A paradigm for assessing benzodiazepine receptor sensitivity was developed using intravenous midazolam in normal volunteers. After administration of incremental doses of midazolam, alterations in saccadic eye movement parameters and psychological self ratings were assessed. Significant changes included dose-dependent slowing of peak velocity, peak acceleration, peak deceleration, reduced saccade acceleration/deceleration ratio and saccade accuracy, and increased sedation self-ratings. Changes in saccade variables and sedation ratings were significantly correlated, and also correlated with plasma midazolam concentrations. No significant changes were seen in saccade latency or anxiety self-ratings. Pharmacological specificity of these changes was demonstrated by their reversal with the benzodiazepine antagonist flumazenil. This challenge paradigm appears to be a sensitive means of assessing benzodiazepine receptor function in man.

Steroid withdrawal in the mouse results in anxiogenic effects of 3alpha,5beta-THP: a possible model of premenstrual dysphoric disorder.

PubMed

Smith, Sheryl S; Ruderman, Yevgeniy; Frye, Cheryl; Homanics, Gregg; Yuan, Maoli

2006-06-01

3alpha-OH-5alpha[beta]-pregnan-20-one (THP) is a positive modulator of the GABAA receptor (GABAR), which underlies its reported anxiolytic effect. However, there are conditions such as premenstrual dysphoric disorder (PMDD) where increases in THP levels can be associated with adverse mood. In order to test for conditions where THP might be anxiogenic, we developed a mouse model of THP withdrawal. Because delta-containing GABAR are highly sensitive to THP modulation, results were compared in wild-type and delta knockout mice. Finasteride, a 5alpha-reductase blocker, was administered for 3 days to female wild-type or delta knockout mice. Then, animals were tested in the elevated plus maze, following acute administration of THP, lorazepam, flumazenil, or 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), and results compared to vehicle-injected controls. CA1 hippocampal GABAR alpha4 subunit levels were assessed by Western blot. After THP withdrawal, THP produced anxiogenic effects, decreasing open arm entries on the elevated plus maze, following a brief shock, in contrast to its expected anxiolytic effects. As we have shown in rats, THP withdrawal also resulted in increased expression of the alpha4 subunit in mouse CA1 hippocampus. As expected for increases in alpha4-containing GABAR, THP withdrawn mice were relatively insensitive to the benzodiazepine (BDZ) lorazepam and had atypical responses to the BDZ antagonist flumazenil when tested on the plus maze. In contrast, they showed a greater anxiolytic response to THIP, which has greater efficacy at alpha4betadelta than other GABAR. Although THP withdrawal in delta knockout mice also increased the alpha4 GABAR subunit, the anxiogenic effects of THP and the anxiolytic effects of THIP were not observed, implicating alpha4betadelta GABAR in these effects. Based on these behavioral and pharmacological findings, we suggest that THP withdrawal in the mouse may serve as a rodent model of PMDD.

Association between the use of benzodiazepines and opioids with the risk of falls and hip fractures in older adults.

PubMed

Machado-Duque, Manuel E; Castaño-Montoya, Juan Pablo; Medina-Morales, Diego A; Castro-Rodríguez, Alejandro; González-Montoya, Alexandra; Machado-Alba, Jorge E

2017-12-10

To determine the association between the use of opioids and benzodiazepines and the risk of falls with hip fracture in populations older than 65 years in Colombia. A case-control study with patients older than 65 years with diagnosis of hip fracture. Two controls were obtained per case. The drugs dispensed in the previous 30 days were identified. Sociodemographic, diagnostic, pharmacological (opioids and benzodiazepines), and polypharmacy variables were analyzed. A logistic regression model was used to analyze the risk of fall with hip fracture while using these drugs. We included 287 patients with hip fractures and 574 controls. There was a female predominance (72.1%) and a mean age of 82.4 ± 8.0 years. Of the patients, 12.7% had been prescribed with opioids and 4.2% with benzodiazepines in the previous month. The adjusted multivariate analysis found that using opioids (OR:4.49; 95%CI:2.72-7.42) and benzodiazepines (OR:3.73; 95%CI:1.60-8.70) in the month prior to the event was significantly associated with a greater probability of suffering a fall with hip fracture. People who are taking opioids and benzodiazepines have increased risk for hip fracture in Colombia. Strategies to educate physicians regarding the pharmacology of older adults should be strengthened.

Psychological determinants of the intention to educate patients about benzodiazepines

PubMed Central

Dijkstra, A.; Van Empelen, P.; Knuistingh Neven, A.; Zitman, F. G.

2007-01-01

Objective General practitioners and pharmacists do not properly educate their patients about the disadvantages of benzodiazepines. In order to increase and improve education, this study will investigate which psychological factors (i.e., beliefs, outcome expectation, social norm and self-efficacy) predict the intention to educate. Methods A cross-sectional survey study was conducted in which 339 general practitioners and 149 pharmacists in the Netherlands completed a questionnaire. Results The Results show that the above-mentioned factors play an important role in forming intentions to educate. However, differences exist between general practitioners and pharmacists. Conclusion General practitioners and pharmacists intend to educate in cases where they think that benzodiazepines have well-defined disadvantages, when the education they undertake leads to success, when they feel pressure to educate from their surroundings and when they are capable of educating. Implications for practice These findings contribute to a better understanding of patient education and are of great value in developing new interventions to improve education. PMID:18095183

Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines.

PubMed

Pera, Tonio; Deshpande, Deepak A; Ippolito, Michael; Wang, Bin; Gavrila, Adelina; Michael, James V; Nayak, Ajay P; Tompkins, Eric; Farrell, Eleni; Kroeze, Wesley K; Roth, Bryan L; Panettieri, Reynold A; Benovic, Jeffrey L; An, Steven S; Dulin, Nickolai O; Penn, Raymond B

2018-02-01

GPCRs have diverse signaling capabilities, based on their ability to assume various conformations. Moreover, it is now appreciated that certain ligands can promote distinct receptor conformations and thereby bias signaling toward a specific pathway to differentially affect cell function. The recently deorphanized G protein-coupled receptor OGR1 [ovarian cancer G protein-coupled receptor 1 ( GPR68)] exhibits diverse signaling events when stimulated by reductions in extracellular pH. We recently demonstrated airway smooth muscle cells transduce multiple signaling events, reflecting a diverse capacity to couple to multiple G proteins. Moreover, we recently discovered that the benzodiazepine lorazepam, more commonly recognized as an agonist of the γ-aminobutyric acid A (GABA A ) receptor, can function as an allosteric modulator of OGR1 and, similarly, can promote multiple signaling events. In this study, we demonstrated that different benzodiazepines exhibit a range of biases for OGR1, with sulazepam selectively activating the canonical Gs of the G protein signaling pathway, in heterologous expression systems, as well as in several primary cell types. These findings highlight the potential power of biased ligand pharmacology for manipulating receptor signaling qualitatively, to preferentially activate pathways that are therapeutically beneficial.-Pera, T., Deshpande, D. A., Ippolito, M., Wang, B., Gavrila, A., Michael, J. V., Nayak, A. P., Tompkins, E., Farrell, E., Kroeze, W. K., Roth, B. L., Panettieri, R. A. Jr Benovic, J. L., An, S. S., Dulin, N. O., Penn, R. B. Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines.

Development of the caffeine withdrawal symptom questionnaire: caffeine withdrawal symptoms cluster into 7 factors.

PubMed

Juliano, Laura M; Huntley, Edward D; Harrell, Paul T; Westerman, Ashley T

2012-08-01

Habitual caffeine consumers who abstain from caffeine experience withdrawal symptoms such as headache, fatigue, difficulty concentrating, mood disturbances, and flu-like symptoms (Juliano and Griffiths, 2004). The caffeine withdrawal syndrome has been documented across many experimental studies; however, little is known about how withdrawal symptoms co-vary during a discrete episode. Furthermore, a validated measure of caffeine withdrawal is lacking. To develop, evaluate, and reduce a 23-item measure of caffeine withdrawal symptoms; the Caffeine Withdrawal Symptom Questionnaire (CWSQ), to a set of composite variables. Caffeine consumers (N=213) completed the CWSQ after 16h of caffeine abstinence. A subset of participants also completed the CWSQ during a preceding baseline period and/or after double-blind consumption of caffeinated coffee. Principal components analysis resulted in a solution comprised of 7-factors: (1) Fatigue/drowsiness; (2) Low alertness/difficulty concentrating; (3) Mood disturbances; (4) Low sociability/motivation to work; (5) Nausea/upset stomach; (6) Flu-like feelings; and (7) Headache. With the exception of nausea/upset stomach, the CWSQ total score and individual composite scores were significantly greater during caffeine abstinence relative to both baseline and double-blind consumption of caffeinated coffee, thereby demonstrating sensitivity of the measure. Compared to non-daily coffee consumers, daily consumers had greater increases in total withdrawal, fatigue/drowsiness, low alertness/difficulty concentrating, mood disturbances, and headache. Future directions include replication, assessment on a clinical population, and further examination of psychometric properties of the CWSQ. The CWSQ should facilitate the assessment and diagnosis of caffeine withdrawal and increase our knowledge of the caffeine withdrawal syndrome. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Self-reported smoking habits and serum cotinine levels in women with placental abruption.

PubMed

Tikkanen, Minna; Surcel, Heljä-Marja; Bloigu, Aini; Nuutila, Mika; Ylikorkala, Olavi; Hiilesmaa, Vilho; Paavonen, Jorma

2010-12-01

smoking is an important risk factor for placental abruption with strong dose-dependency. Pregnant smokers often underreport tobacco use which can be objectively assessed by measuring serum cotinine levels. We examined the accuracy between self-reported smoking habits and early pregnancy serum cotinine levels in women with or without placental abruption. retrospective case-control study. university Hospital. a total of 175 women with placental abruption and 370 control women. serum samples collected during the first trimester were analyzed for serum cotinine levels. Cotinine concentration over 15 ng/ml was considered as the cutoff indicating active smoking. Smoking habits of the women and their partners were recorded at the same visit. placental abruption. of the cases of women with placental abruption, 27.4% reported smoking compared with 14.3% of the controls (p < 0.001). Based on serum cotinine levels, 30.3% of the case women and 17.6% of the control women were considered smokers (p = 0.003). Serum cotinine levels among smokers were higher in the abruption group than in the control group (median 229.5 ng/ml (interquartile range 169.8-418.1) vs. 153.5 ng/ml (56.6-241.4), p = 0.002). Self-reported number of cigarettes smoked daily correlated well with the cotinine levels (r = 0.68, p < 0.001). Of the women reporting as nonsmokers, approximately 7% were considered smokers based on cotinine testing. pregnant women with subsequent placental abruption are heavier smokers than pregnant control women. Self-reported smoking habits correlate well with serum cotinine levels in Finland. Therefore, self-reported smoking can be considered as a risk marker for placental abruption.

Abrupt warming of the Red Sea

NASA Astrophysics Data System (ADS)

Raitsos, D. E.; Hoteit, I.; Prihartato, P. K.; Chronis, T.; Triantafyllou, G.; Abualnaja, Y.

2011-07-01

Coral reef ecosystems, often referred to as “marine rainforests,” concentrate the most diverse life in the oceans. Red Sea reef dwellers are adapted in a very warm environment, fact that makes them vulnerable to further and rapid warming. The detection and understanding of abrupt temperature changes is an important task, as ecosystems have more chances to adapt in a slowly rather than in a rapid changing environment. Using satellite derived sea surface and ground based air temperatures, it is shown that the Red Sea is going through an intense warming initiated in the mid-90s, with evidence for an abrupt increase after 1994 (0.7°C difference pre and post the shift). The air temperature is found to be a key parameter that influences the Red Sea marine temperature. The comparisons with Northern Hemisphere temperatures revealed that the observed warming is part of global climate change trends. The hitherto results also raise additional questions regarding other broader climatic impacts over the area.

Finding Intervals of Abrupt Change in Earth Science Data

NASA Astrophysics Data System (ADS)

Zhou, X.; Shekhar, S.; Liess, S.

2011-12-01

In earth science data (e.g., climate data), it is often observed that a persistently abrupt change in value occurs in a certain time-period or spatial interval. For example, abrupt climate change is defined as an unusually large shift of precipitation, temperature, etc, that occurs during a relatively short time period. A similar pattern can also be found in geographical space, representing a sharp transition of the environment (e.g., vegetation between different ecological zones). Identifying such intervals of change from earth science datasets is a crucial step for understanding and attributing the underlying phenomenon. However, inconsistencies in these noisy datasets can obstruct the major change trend, and more importantly can complicate the search of the beginning and end points of the interval of change. Also, the large volume of data makes it challenging to process the dataset reasonably fast. In earth science data (e.g., climate data), it is often observed that a persistently abrupt change in value occurs in a certain time-period or spatial interval. For example, abrupt climate change is defined as an unusually large shift of precipitation, temperature, etc, that occurs during a relatively short time period. A similar change pattern can also be found in geographical space, representing a sharp transition of the environment (e.g., vegetation between different ecological zones). Identifying such intervals of change from earth science datasets is a crucial step for understanding and attributing the underlying phenomenon. However, inconsistencies in these noisy datasets can obstruct the major change trend, and more importantly can complicate the search of the beginning and end points of the interval of change. Also, the large volume of data makes it challenging to process the dataset fast. In this work, we analyze earth science data using a novel, automated data mining approach to identify spatial/temporal intervals of persistent, abrupt change. We first

Financial incentives to discontinue long-term benzodiazepine use: a discrete choice experiment investigating patient preferences and willingness to participate.

PubMed

Marti, Joachim; Bachhuber, Marcus; Feingold, Jordyn; Meads, David; Richards, Michael; Hennessy, Sean

2017-10-06

Investigate the acceptability of financial incentives for initiating a medically supervised benzodiazepine discontinuation programme among people with long-term benzodiazepine use and to identify programme features that influence willingness to participate. We conducted a discrete choice experiment in which we presented a variety of incentive-based programs to a sample of older adults with long-term benzodiazepine use identified using the outpatient electronic health record of a university-owned health system. We studied four programme variables: incentive amount for initiating the programme, incentive amount for successful benzodiazepine discontinuation, lottery versus certain payment and whether partial payment was given for dose reduction. Respondents reported their willingness to participate in the programmes and additional information was collected on demographics, history of use and anxiety symptoms. The overall response rate was 28.4%. Among the 126 respondents, all four programme variables influenced stated preferences. Respondents strongly preferred guaranteed cash-based incentives as opposed to a lottery, and the dollar amount of both the starting and conditional incentives had a substantial impact on choice. Willingness to participate increased with the amount of conditional incentive. Programme participation also varied by gender, duration of use and income. Participation in an incentive-based benzodiazepine discontinuation programme might be relatively low, but is modifiable by programme variables including incentive amounts. These results will be helpful to inform the design of future trials of benzodiazepine discontinuation programmes. Further research is needed to assess the financial viability and potential cost-effectiveness of such economic incentives. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

The application of supported liquid extraction in the analysis of benzodiazepines using surface enhanced Raman spectroscopy.

PubMed

Doctor, Erika L; McCord, Bruce

2015-11-01

Benzodiazepines are among the most frequently prescribed medicines for anxiety disorders and are present in many toxicological screens. These drugs are often administered in the commission of drug facilitated sexual assaults due their effects on the central nervous system. Due to the potency of the drugs, only small amounts are usually given to victims; therefore, the target detection limit for these compounds in biological samples has been set at 50 ng/mL. Currently the standard screening method for detection of this class of drug is the immunoassay; however, screening methods that are more sensitive and selective than immunoassays are needed to encompass the wide range of structural variants of this class of compounds. Surface enhanced Raman spectroscopy (SERS) can be highly sensitive and has been shown to permit analysis of various benzodiazepines with limits of detection as low as 6 ng/mL. This technique permits analytical results in less than 2 min when used on pure drug samples. For biological samples, a key issue for analysis by SERS is removal of exogenous salts and matrix components. In this paper we examine supported liquid extraction as a useful preparation technique for SERS detection. Supported liquid extraction has many of the benefits of liquid-liquid extraction along with the ability to be automated. This technique provides a fast and clean extraction for benzodiazepines from urine at a pH of 5.0, and does not produce large quantities of solvent waste. To validate this procedure we have determined figures of merit and examined simulated urine samples prepared with commonly appearing interferences. It was shown that at a pH 5.0 many drugs that are prevalent in urine samples can be removed, permitting a selective detection of the benzodiazepine of interest. This technique has been shown to provide rapid (less than 20 min), sensitive, and specific detection of benzodiazepines with limits of detection between 32 and 600 ng/mL and dynamic range of 32

Naturalistic conversation improves daytime motorway driving performance under a benzodiazepine: a randomised, crossover, double-blind, placebo-controlled study.

PubMed

Moták, Ladislav; Bayssac, Laëtitia; Taillard, Jacques; Sagaspe, Patricia; Huet, Nathalie; Terrier, Patrice; Philip, Pierre; Daurat, Agnès

2014-06-01

The adverse effects of benzodiazepines on driving are widely recognised. The aims of this study were both to determine the impact of naturalistic conversation on the driving ability of drivers under a benzodiazepine, and to measure the accuracy of drivers' assessments of the joint effects of the benzodiazepine and conversation. Sixteen healthy male participants (29.69 ± 3.30 years) underwent a randomised, crossover, double-blind, placebo-controlled study with the benzodiazepine lorazepam (2mg). They drove 200 km (125 miles) on a motorway in the morning. We measured two driving ability-related variables (i.e., lane-keeping performance), and collected a set of self-assessed variables (i.e., self-assessment of driving performance) during two 10-min sequences of interest (no conversation vs. conversation). An analysis of variance revealed an interaction whereby lane-keeping performance under lorazepam was worse in the no-conversation condition than in the conversation condition. No such difference was detected under placebo. Pearson's correlation coefficients revealed that self-assessments were (i) not at all predictive of lane-keeping when performed before the drive, but (ii) moderately predictive of lane-keeping performance when performed during or after the drive. We conclude that conversation with a passenger may contribute to safer lane-keeping when driving under a benzodiazepine. Moreover, a degree of awareness may be attained after some experience of driving under the influence of this type of medication. Copyright © 2014 Elsevier Ltd. All rights reserved.

Quantitative autoradiography of muscarinic and benzodiazepine receptors in the forebrain of the turtle, Pseudemys scripta

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schlegel, J.R.; Kriegstein, A.R.

1987-11-22

The distribution of muscarinic and benzodiazepine receptors was investigated in the turtle forebrain by the technique of in vitro receptor autoradiography. Muscarinic binding sites were labeled with 1 nM /sup 3/H-quinuclidinyl benzilate (/sup 3/H-QNB), and benzodiazepine sites were demonstrated with the aid of 1 nM /sup 3/H-flunitrazepam (/sup 3/H-FLU). Autoradiograms generated on /sup 3/H-Ultrofilm apposed to tissue slices revealed regionally specific distributions of muscarinic and benzodiazepine binding sites that are comparable with those for mammalian brain. Dense benzodiazepine binding was found in the anterior olfactory nucleus, the lateral and dorsal cortices, and the dorsal ventricular ridge (DVR), a structure withmore » no clear mammalian homologue. Muscarinic binding sites were most dense in the striatum, accumbens, DVR, lateral geniculate, and the anterior olfactory nucleus. Cortical binding sites were studied in greater detail by quantitative analysis of autoradiograms generated by using emulsion-coated coverslips. Laminar gradients of binding were observed that were specific for each radioligand; /sup 3/H-QNB sites were most dense in the inner molecular layer in all cortical regions, whereas /sup 3/H-FLU binding was generally most concentrated in the outer molecular layer and was least dense through all layers in the dorsomedial cortex. Because pyramidal cells are arranged in register in turtle cortex, the laminar patterns of receptor binding may reflect different receptor density gradients along pyramidal cell dendrites.« less

The mouse beam walking assay offers improved sensitivity over the mouse rotarod in determining motor coordination deficits induced by benzodiazepines.

PubMed

Stanley, Joanna L; Lincoln, Rachael J; Brown, Terry A; McDonald, Louise M; Dawson, Gerard R; Reynolds, David S

2005-05-01

The mouse rotarod test of motor coordination/sedation is commonly used to predict clinical sedation caused by novel drugs. However, past experience suggests that it lacks the desired degree of sensitivity to be predictive of effects in humans. For example, the benzodiazepine, bretazenil, showed little impairment of mouse rotarod performance, but marked sedation in humans. The aim of the present study was to assess whether the mouse beam walking assay demonstrates: (i) an increased sensitivity over the rotarod and (ii) an increased ability to predict clinically sedative doses of benzodiazepines. The study compared the effects of the full benzodiazepine agonists, diazepam and lorazepam, and the partial agonist, bretazenil, on the mouse rotarod and beam walking assays. Diazepam and lorazepam significantly impaired rotarod performance, although relatively high GABA-A receptor occupancy was required (72% and 93%, respectively), whereas beam walking performance was significantly affected at approximately 30% receptor occupancy. Bretazenil produced significant deficits at 90% and 53% receptor occupancy on the rotarod and beam walking assays, respectively. The results suggest that the mouse beam walking assay is a more sensitive tool for determining benzodiazepine-induced motor coordination deficits than the rotarod. Furthermore, the GABA-A receptor occupancy values at which significant deficits were determined in the beam walking assay are comparable with those observed in clinical positron emission tomography studies using sedative doses of benzodiazepines. These data suggest that the beam walking assay may be able to more accurately predict the clinically sedative doses of novel benzodiazepine-like drugs.

Evaluation of benzodiazepines and zolpidem in nails and their stability after prolonged exposure to chlorinated water.

PubMed

Moretti, Matteo; Andrello, Luisa; Visonà, Silvia; Vignali, Claudia; Groppi, Angelo; Freni, Francesca; Osculati, Antonio; Tajana, Luca; Morini, Luca

2018-04-15

The study aims the development and validation of a LC-MS/MS method for the identification and quantification of benzodiazepines and zolpidem in nails as alternative keratinized matrix to hair in long-term monitoring of anxiolytic and hypnotic drugs. Both fingernail and toenail samples (1-2 mm) were collected by clipping the excess overhang of the nail from volunteers and from postmortem cases. They were washed twice with organic solvents, dried under nitrogen stream, pulverized, immersed in a methanol solution (internal standard: diazepam-D5) and sonicated up to two hours. The solution was then direct injected in the LC-MS/MS system. Mass spectrometry was set in MRM mode, selecting two transitions for each substance. 32 analytes among benzodiazepines, metabolites and hypnotics were included in the list. The method fulfilled the internationally required criteria for validation. Limits of detection ranged from 0.03 pg/mg (zolpidem) to 13.1 pg/mg (bromazepam). 9 subjects under therapy were positive at 7 different benzodiazepines and/or metabolites (lorazepam, desalkylflurazepam, bromazepam, diazepam, alprazolam, lormetazepam and prazepam), while 5 molecules were measured in 4 postmortem cases (diazepam, desmethyldiazepam, delorazepam, 7-aminoclonazepam and zolpidem). In vitro experiments on eight authentic samples suggested that benzodiazepines in nails are influenced by the prolonged exposure to chlorinated water. Copyright © 2018 Elsevier B.V. All rights reserved.

Elderly benzodiazepine users at increased risk of activity limitations: influence of chronicity, indications, and duration of action--the three-city cohort.

PubMed

Carrière, Isabelle; Mura, Thibault; Pérès, Karine; Norton, Joanna; Jaussent, Isabelle; Edjolo, Arlette; Rouaud, Olivier; Berr, Claudine; Ritchie, Karen; Ancelin, Marie Laure

2015-08-01

To examine the cross-sectional and longitudinal associations between benzodiazepine use and daily activity limitations, according to drug indications and duration of action. Prospective cohort study. Population-based three-city study. 6,600 participants aged 65 years and over included between 1999 and 2001 and followed after 2, 4, and 7 years. Benzodiazepine users were separated into hypnotic, short-acting anxiolytic, and long-acting anxiolytic users and compared with non users. Three outcomes were examined assessing restrictions in mobility, instrumental activities of daily living (IADLs) and social participation. In multivariate simple or mixed logistic models adjusted for sociodemographic variables, impairments and comorbidity, and for anxiety, insomnia, and depression, hypnotic benzodiazepines were moderately associated with mobility limitation prevalence and IADL limitation incidence. Short-acting and long-acting anxiolytics were associated with IADL limitation prevalence and with mobility limitation prevalence and incidence and long-acting anxiolytics were also associated with IADL limitation incidence. Chronic benzodiazepines users were at a marked risk of developing restrictions for the three outcomes; odds ratio: 1.71 (95% CI: 1.23-2.39) for mobility, 1.54 (95% CI: 1.14-2.10) for IADL, and 1.74 (95% CI: 1.23-2.47) for participation limitations. Benzodiazepine users are at increased risk of activity limitations regardless of the duration of action or indication. Chronic use of benzodiazepines should be avoided in order to extend disability-free survival. Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Neuroleptic-induced catatonia: clinical presentation, response to benzodiazepines, and relationship to neuroleptic malignant syndrome.

PubMed

Lee, Joseph W Y

2010-02-01

Neuroleptic-induced catatonia (NIC), manifested in an extrapyramidal-catatonic syndrome, has been sporadically reported in the literature. Confusion surrounds its relationship to neuroleptic malignant syndrome (NMS) and extrapyramidal reactions to neuroleptics. This study examined (a) its clinical presentation and response to benzodiazepines, (b) the hypothesis that NIC and NMS are on the same spectrum with a continuum of symptom progression, and (c) its possible relationship to extrapyramidal reactions. Of 127 episodes of acute catatonia prospectively identified, 18 were diagnosed with NIC. All catatonia episodes received benzodiazepines. The NIC episodes were analyzed noting their clinical presentations, laboratory findings, and responses to treatments. Their responses to benzodiazepines were compared, with retrospective rating on a 7-point scale, to that for catatonia episodes associated with mania and schizophrenia. The progression of symptoms in each NIC episode was reviewed. The NIC episodes presented predominantly in the stuporous form associated with parkinsonism. Delirium, autonomic abnormality, and elevated serum creatine phosphokinase were all common. Neuroleptic malignant syndrome was diagnosed in 3 episodes (17%). The 3 catatonia groups did not differ significantly in their benzodiazepines responses: 78% (14/18) of NIC, 75% (12/16) of manic catatonia, and 67% (34/51) of schizophrenic catatonia episodes showed full responses. A spectrum of presentation across episodes was noted with simple NIC without delirium, autonomic disturbances, or fever at one end and NMS or malignant NIC at the other end. Symptoms in individual episodes showed a similar continuum progression. No extrapyramidal reactions immediately preceded the NIC episodes. Findings of this study support the hypothesis that NIC and NMS are disorders on the same spectrum and reveal no indication that extrapyramidal reactions progress to NIC.

Ultra-wideband horn antenna with abrupt radiator

DOEpatents

McEwan, Thomas E.

1998-01-01

An ultra-wideband horn antenna transmits and receives impulse waveforms for short-range radars and impulse time-of flight systems. The antenna reduces or eliminates various sources of close-in radar clutter, including pulse dispersion and ringing, sidelobe clutter, and feedline coupling into the antenna. Dispersion is minimized with an abrupt launch point radiator element; sidelobe and feedline coupling are minimized by recessing the radiator into a metallic horn. Low frequency cut-off associated with a horn is extended by configuring the radiator drive impedance to approach a short circuit at low frequencies. A tapered feed plate connects at one end to a feedline, and at the other end to a launcher plate which is mounted to an inside wall of the horn. The launcher plate and feed plate join at an abrupt edge which forms the single launch point of the antenna.

Visualization of groundwater withdrawals

USGS Publications Warehouse

Winston, Richard B.; Goode, Daniel J.

2017-12-21

Generating an informative display of groundwater withdrawals can sometimes be difficult because the symbols for closely spaced wells can overlap. An alternative method for displaying groundwater withdrawals is to generate a “footprint” of the withdrawals. WellFootprint version 1.0 implements the Footprint algorithm with two optional variations that can speed up the footprint calculation. ModelMuse has been modified in order to generate the input for WellFootprint and to read and graphically display the output from WellFootprint.

Risk of fetal death associated with maternal drug dependence and placental abruption: a population-based study.

PubMed

McDonald, Sarah D; Vermeulen, Marian J; Ray, Joel G

2007-07-01

Substance use in pregnancy is associated with placental abruption, but the risk of fetal death independent of abruption remains undetermined. Our objective was to examine the effect of maternal drug dependence on placental abruption and on fetal death in association with abruption and independent of it. To examine placental abruption and fetal death, we performed a retrospective population-based study of 1 854 463 consecutive deliveries of liveborn and stillborn infants occurring between January 1, 1995 and March 31, 2001, using the Canadian Institute for Health Information Discharge Abstract Database. Maternal drug dependence was associated with a tripling of the risk of placental abruption in singleton pregnancies (adjusted odds ratio [OR] 3.1; 95% confidence intervals [CI] 2.6-3.7), but not in multiple gestations (adjusted OR 0.88; 95% CI 0.12-6.4). Maternal drug dependence was associated with an increased risk of fetal death independent of abruption (adjusted OR 1.6: 95% CI 1.1-2.2) in singleton pregnancies, but not in multiples. Risk of fetal death was increased with placental abruption in both singleton and multiple gestations, even after controlling for drug dependence (adjusted OR 11.4 in singleton pregnancy; 95% CI 10.6-12.2, and 3.4 in multiple pregnancy; 95% CI 2.4-4.9). Maternal drug use is associated with an increased risk of intrauterine fetal death independent of placental abruption. In singleton pregnancies, maternal drug dependence is associated with an increased risk of placental abruption.

Overlapping buprenorphine, opioid, and benzodiazepine prescriptions among veterans dually enrolled in Department of Veterans Affairs and Medicare Part D.

PubMed

Gellad, Walid F; Zhao, Xinhua; Thorpe, Carolyn T; Thorpe, Joshua M; Sileanu, Florentina E; Cashy, John P; Mor, Maria; Hale, Jennifer A; Radomski, Thomas; Hausmann, Leslie R M; Fine, Michael J; Good, Chester B

2017-01-01

Buprenorphine is a key tool in the management of opioid use disorder, but there are growing concerns about abuse, diversion, and safety. These concerns are amplified for the Department of Veterans Affairs (VA), whose patients may receive care concurrently from multiple prescribers within and outside VA. To illustrate the extent of this challenge, we examined overlapping prescriptions for buprenorphine, opioids, and benzodiazepines among veterans dually enrolled in VA and Medicare Part D. We constructed a cohort of all veterans dually enrolled in VA and Part D who filled an opioid prescription in 2012. We identified patients who received tablet or film buprenorphine products from either source. We calculated the proportion of buprenorphine recipients with any overlapping prescription (based on days supply) for a nonbuprenorphine opioid or benzodiazepine, focusing on veterans who received overlapping prescriptions from a different system than their buprenorphine prescription (Part D buprenorphine recipients receiving overlapping opioids or benzodiazepines from VA and vice versa). There were 1790 dually enrolled veterans with buprenorphine prescriptions, including 760 (43%) from VA and 1091 (61%) from Part D (61 veterans with buprenorphine from both systems were included in each group). Among VA buprenorphine recipients, 199 (26%) received an overlapping opioid prescription and 11 (1%) received an overlapping benzodiazepine prescription from Part D. Among Part D buprenorphine recipients, 208 (19%) received an overlapping opioid prescription and 178 (16%) received an overlapping benzodiazepine prescription from VA. Among VA and Part D buprenorphine recipients with cross-system opioid overlap, 25% (49/199) and 35% (72/208), respectively, had >90 days of overlap. Many buprenorphine recipients receive overlapping prescriptions for opioids and benzodiazepines from a different health care system than the one in which their buprenorphine was filled. These findings highlight

Withdrawal When You’re Pregnant

Cancer.gov

The nicotine in cigarettes is addictive. That’s why many smokers who decide to quit go through some degree of withdrawal. Quitting smoking while you’re pregnant won’t change withdrawal symptoms. You may still be uncomfortable or feel not quite like yourself. But withdrawal from cigarettes will not harm your baby.

Modeling cumulative dose and exposure duration provided insights regarding the associations between benzodiazepines and injuries.

PubMed

Abrahamowicz, Michal; Bartlett, Gillian; Tamblyn, Robyn; du Berger, Roxane

2006-04-01

Accurate assessment of medication impact requires modeling cumulative effects of exposure duration and dose; however, postmarketing studies usually represent medication exposure by baseline or current use only. We propose new methods for modeling various aspects of medication use history and employment of them to assess the adverse effects of selected benzodiazepines. Time-dependent measures of cumulative dose or duration of use, with weighting of past exposures by recency, were proposed. These measures were then included in alternative versions of the multivariable Cox model to analyze the risk of fall related injuries among the elderly new users of three benzodiazepines (nitrazepam, temazepam, and flurazepam) in Quebec. Akaike's information criterion (AIC) was used to select the most predictive model for a given benzodiazepine. The best-fitting model included a combination of cumulative duration and current dose for temazepam, and cumulative dose for flurazepam and nitrazepam, with different weighting functions. The window of clinically relevant exposure was shorter for flurazepam than for the two other products. Careful modeling of the medication exposure history may enhance our understanding of the mechanisms underlying their adverse effects.

Anticipatory adjustments to abrupt changes of opposing forces.

PubMed

Rapp, Katrin; Heuer, Herbert

2015-01-01

Anticipatory adjustments to abrupt load changes are based on task-specific predictive information. The authors asked whether anticipatory adjustments to abrupt offsets of horizontal forces are related to expectancy. In two experiments participants held a position against an opposing force or moved against it. At force offset they had to stop rapidly. Duration of the opposing force or distance moved against it varied between blocks of trials and was constant within each block, or it varied from trial to trial. These two variations resulted in opposite changes of the expectancy of force offset with the passage of time or distance. With constant force durations or distances in each block of trials, anticipatory adjustments tended to be poorest with the longest duration or distance, but with variable force durations or distances they tended to be best with the longest duration or distance. Thus anticipatory adjustments were related to expectancy rather than time or distance per se. Anticipatory adjustments resulted in shorter peak amplitudes of the involuntary movements, accompanied by longer movement times in Experiment 1 and faster movement times in Experiment 2. Thus, for different states of the limb at abrupt dynamic changes anticipatory adjustments involve different mechanisms that modulate different mechanical characteristics.

Effects of anesthetic induction with a benzodiazepine plus ketamine hydrochloride or propofol on hypothermia in dogs undergoing ovariohysterectomy.

PubMed

Bornkamp, Jennifer L; Robertson, Sheilah; Isaza, Natalie M; Harrison, Kelly; DiGangi, Brian A; Pablo, Luisito

2016-04-01

To assess the effect of anesthetic induction with a benzodiazepine plus ketamine or propofol on hypothermia in dogs undergoing ovariohysterectomy without heat support. 23 adult sexually intact female dogs undergoing ovariohysterectomy. Baseline rectal temperature, heart rate, and respiratory rate were recorded prior to premedication with buprenorphine (0.02 mg/kg, IM) and acepromazine (0.05 mg/kg, IM). Anesthesia was induced with midazolam or diazepam (0.25 mg/kg, IV) plus ketamine (5 mg/kg, IV; n = 11) or propofol (4 mg/kg, IV; 12) and maintained with isoflurane in oxygen. Rectal temperature was measured at hospital intake, prior to premedication, immediately after anesthetic induction, and every 5 minutes after anesthetic induction. Esophageal temperature was measured every 5 minutes during anesthesia, beginning 30 minutes after anesthetic induction. After anesthesia, dogs were covered with a warm-air blanket and rectal temperature was measured every 10 minutes until normothermia (37°C) was achieved. Dogs in both treatment groups had lower rectal temperatures within 5 minutes after anesthetic induction and throughout anesthesia. Compared with dogs that received a benzodiazepine plus ketamine, dogs that received a benzodiazepine plus propofol had significantly lower rectal temperatures and the interval from discontinuation of anesthesia to achievement of normothermia was significantly longer. Dogs in which anesthesia was induced with a benzodiazepine plus propofol or ketamine became hypothermic; the extent of hypothermia was more profound for the propofol combination. Dogs should be provided with adequate heat support after induction of anesthesia, particularly when a propofol-benzodiazepine combination is administered.

A 5-year follow-up study of users of benzodiazepine: starting with diazepam versus oxazepam.

PubMed

Tvete, Ingunn Fride; Bjørner, Trine; Skomedal, Tor

2016-04-01

Drug dependency may develop during long-term benzodiazepine use, indicated, for example, by dose escalation. The first benzodiazepine chosen may affect the risk of dose escalation. To detect possible differences in benzodiazepine use between new users of diazepam and oxazepam over time. This 5-year prescription database study included 19 747 new benzodiazepine users, inhabitants of Norway, aged 30-60 years, with first redemption for diazepam or oxazepam. Individuals starting on diazepam versus oxazepam were analysed by logistic regression with sex, age, other drug redemptions, prescriber's specialty, household income, education level, type of work, and vocational rehabilitation support as background variables. Time to reach a daily average intake of ≥1 defined daily doses (DDD) over a 3-month period was analysed using a Cox proportional hazard regression model. New users of oxazepam had a higher risk for dose escalation compared with new users of diazepam. This was true even when accounting for differences in sociodemographic status and previous drug use (hazard ratio [HR] 1.33, 95% confidence interval = 1.17 to 1.51). Most doctors prescribed, according to recommendations, oxazepam to individuals they may have regarded as prone to and at risk of dependency. However, these individuals were at higher risk for dose escalation even when accounting for differences in sociodemographic status and previous drug use. Differences between the two user groups could be explained by different preferences for starting drug, DDD for oxazepam being possibly too low, and some unaccounted differences in illness. © British Journal of General Practice 2016.

Nicotine Withdrawal; Measure Your Symptoms (Quiz)

MedlinePlus

... Free Resources Medications Can Help You Quit Using Nicotine Replacement Therapy Busting NRT Myths Smokefree Phone Apps ... Withdrawal Understanding Withdrawal Quiz: How Strong is Your Nicotine Addiction? Quiz: What Are Your Withdrawal Symptoms? Dealing ...

Ultra-wideband horn antenna with abrupt radiator

DOEpatents

McEwan, T.E.

1998-05-19

An ultra-wideband horn antenna transmits and receives impulse waveforms for short-range radars and impulse time-of flight systems. The antenna reduces or eliminates various sources of close-in radar clutter, including pulse dispersion and ringing, sidelobe clutter, and feedline coupling into the antenna. Dispersion is minimized with an abrupt launch point radiator element; sidelobe and feedline coupling are minimized by recessing the radiator into a metallic horn. Low frequency cut-off associated with a horn is extended by configuring the radiator drive impedance to approach a short circuit at low frequencies. A tapered feed plate connects at one end to a feedline, and at the other end to a launcher plate which is mounted to an inside wall of the horn. The launcher plate and feed plate join at an abrupt edge which forms the single launch point of the antenna. 8 figs.

Abruptness of Cascade Failures in Power Grids

NASA Astrophysics Data System (ADS)

Pahwa, Sakshi; Scoglio, Caterina; Scala, Antonio

2014-01-01

Electric power-systems are one of the most important critical infrastructures. In recent years, they have been exposed to extreme stress due to the increasing demand, the introduction of distributed renewable energy sources, and the development of extensive interconnections. We investigate the phenomenon of abrupt breakdown of an electric power-system under two scenarios: load growth (mimicking the ever-increasing customer demand) and power fluctuations (mimicking the effects of renewable sources). Our results on real, realistic and synthetic networks indicate that increasing the system size causes breakdowns to become more abrupt; in fact, mapping the system to a solvable statistical-physics model indicates the occurrence of a first order transition in the large size limit. Such an enhancement for the systemic risk failures (black-outs) with increasing network size is an effect that should be considered in the current projects aiming to integrate national power-grids into ``super-grids''.

Abruptness of cascade failures in power grids.

PubMed

Pahwa, Sakshi; Scoglio, Caterina; Scala, Antonio

2014-01-15

Electric power-systems are one of the most important critical infrastructures. In recent years, they have been exposed to extreme stress due to the increasing demand, the introduction of distributed renewable energy sources, and the development of extensive interconnections. We investigate the phenomenon of abrupt breakdown of an electric power-system under two scenarios: load growth (mimicking the ever-increasing customer demand) and power fluctuations (mimicking the effects of renewable sources). Our results on real, realistic and synthetic networks indicate that increasing the system size causes breakdowns to become more abrupt; in fact, mapping the system to a solvable statistical-physics model indicates the occurrence of a first order transition in the large size limit. Such an enhancement for the systemic risk failures (black-outs) with increasing network size is an effect that should be considered in the current projects aiming to integrate national power-grids into "super-grids".

Involvement of NO/NMDA-R pathway in the behavioral despair induced by amphetamine withdrawal.

PubMed

Haj-Mirzaian, Arvin; Amiri, Shayan; Amini-Khoei, Hossein; Haj-Mirzaian, Arya; Hashemiaghdam, Arsalan; Ramezanzadeh, Kiana; Ghesmati, Maria; Afshari, Khashayar; Dehpour, Ahmad Reza

2018-05-01

Abrupt discontinuation of chronic amphetamine consumption leads to withdrawal symptoms including depression, anhedonia, dysphoria, fatigue, and anxiety. These irritating symptoms may result in continuing to take the drug or can lead to suicidal behavior. Past studies have shown the involvement of various biologic systems in depression induced following amphetamine withdrawal (AW). However, there is no evidence about the relation between nitric oxide (NO) with NMDA receptors on depression following AW. In this study, we examined the involvement of the NO/NMDA pathways on depressive-like behaviors after 24 h withdrawal following 5 continuous days of amphetamine administration in male NMRI mice. Behavioral tasks used for depression assessment included the forced swimming test (FST), the Splash test and the open field test (OFT). In order to evaluate the role of NO/NMDA pathways animals treated with MK-801 (NMDA-R antagonist), Aminoguanidine (AG), a selective iNOS inhibitor, Nω-Nitro-l-arginine (L-NNA), a non-selective NOS inhibitor and 7-Nitro indazole (7-NI), a selective nNOS inhibitor. We also measured the level of nitrite in the hippocampus. Our data showed that AW induced the depressive-like effect in the FST and the Splash test. We showed that administration of AG, L-NNA, and MK-801 mitigated AW induced depression, however, 7-NI was failed to decrease depressive-like behaviors. Also, the antidepressant-like effect of co-injection of sub-effective doses of MK-801 with AG suggested that inducible nitric oxide synthase (iNOS) is associated with NMDA-R in AW induced depression. In conclusion, both NO and NMDA-R pathways are involved and related to each other in depression induced following AW. Copyright © 2018. Published by Elsevier Inc.

Alpha1- and alpha2-containing GABAA receptor modulation is not necessary for benzodiazepine-induced hyperphagia.

PubMed

Morris, H V; Nilsson, S; Dixon, C I; Stephens, D N; Clifton, P G

2009-06-01

Benzodiazepines increase food intake, an effect attributed to their ability to enhance palatability. We investigated which GABA(A) receptor subtypes may be involved in mediating benzodiazepine-induced hyperphagia. The role of the alpha2 subtype was investigated by observing the effects of midazolam, on the behavioural satiety sequence in mice with targeted deletion of the alpha2 gene (alpha2 knockout). Midazolam (0.125, 0.25 and 0.5mg/kg) increased food intake and the amount of time spent feeding in alpha2 knockout mice, suggesting that BZ-induced hyperphagia does not involve alpha2-containing GABA(A) receptors. We further investigated the roles of alpha1- and alpha3-containing GABA(A) receptors in mediating BZ-induced hyperphagia. We treated alpha2(H101R) mice, in which alpha2-containing receptors are rendered benzodiazepine insensitive, with L-838417, a compound which acts as a partial agonist at alpha2-, alpha3- and alpha5-receptors but is inactive at alpha1-containing receptors. L-838417 (10 and 30 mg/kg) increased food intake and the time spent feeding in both wildtype and alpha2(H101R) mice, demonstrating that benzodiazepine-induced hyperphagia does not require alpha1- and alpha2-containing GABA(A) receptors. These observations, together with evidence against the involvement of alpha5-containing GABA(A) receptors, suggest that alpha3-containing receptors mediate BZ-induced hyperphagia in the mouse.

GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study.

PubMed

Lingford-Hughes, A R; Wilson, S J; Cunningham, V J; Feeney, A; Stevenson, B; Brooks, D J; Nutt, D J

2005-08-01

Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. We used positron emission tomography (PET) with [11C]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. Abstinent male alcohol dependent subjects underwent [11C]flumazenil PET to measure occupancy of BDZ receptors by midazolam whilst recording its pharmacodynamic effects on behavioural and physiological measures. Rate constants describing the exchange of [11C]flumazenil between the plasma and brain compartments were derived from time activity curves. A 50% reduction in electroencephalography (EEG)-measured sleep time was seen in the alcohol dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG beta1 power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metabolism were found between the groups. In summary, our study suggests that alcohol dependence in man is associated with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alcohol dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.

Abrupt Change of the Transboundary Runoff and Its Influence on Water Security of Lanstang-Mekong River

NASA Astrophysics Data System (ADS)

Sang, Y. F.; Xie, P.; Ziyi, W.; Jiangyan, Z.; Qianjin, D.; Xu, L.

2017-12-01

As a significant manifestation of hydrological variability, abrupt change will obviously impact on the water security. To analyze what does the variation bring under changing environment, abrupt change detection should be a basic task, as well as variation level evaluation and hydrological frequency analysis. However, there lacks an effective method to reach those purposes systematically. Here we derived correlation coefficient between the original series and the jump-component series which is related to the difference degree of mean value before and after the abrupt change. Based on it, we proposed the moving-correlation-coefficient-based detection method and evaluated the significance of abrupt change as different levels related to the value of correlation coefficient. Then, with the obtained results, we calculated hydrological frequency in different situation (before and after the abrupt change). The approach above was employed to investigate the transboundary runoff of Lanstang-Mekong River at some kinds of time scale. We obtained the abrupt changes from runoff series of year, flood season and dry season which are almost the same. All the abrupt changes were significant which could reach to the moderate level. Compared with the past situation (before the abrupt change), the hydrological frequency in the current situation (after the abrupt change) indicated the water security of the water supply and flood control in the lower reaches of Lanstang-Mekong River could be guaranteed better, which is owed to the construction and operation of the water conservancy projects on the upper Lanstang-Mekong River.

Effect of peripheral benzodiazepine receptor ligands on lipopolysaccharide-induced tumor necrosis factor activity in thioglycolate-treated mice.

PubMed Central

Matsumoto, T; Ogata, M; Koga, K; Shigematsu, A

1994-01-01

To investigate the effect of peripheral and central benzodiazepine receptor ligands on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) activity in mouse macrophages, three types of ligands, 4'-chlorodiazepam (pure peripheral), midazolam (mixed), and clonazepam (pure central), were compared. Midazolam and 4'-chlorodiazepam significantly suppressed LPS (1-microgram/ml)-induced TNF activity in thioglycolate-elicited mouse macrophages. In every concentration examined (0.001 to 100 microM), 4'-chlorodiazepam was the most effective agent, clonazepam was the least effective agent, and midazolam had an effect intermediate between those of the other two ligands. The peripheral benzodiazepine receptor ligands had a dose-dependent suppressive effect, and the 50% inhibitory concentrations were 0.01 microM for 4'-chlorodiazepam and 5 microM for midazolam. Concomitant use of PK 11195 (10 microM), an antagonist of the peripheral benzodiazepine receptor, reversed this suppressive effect with 4'-chlorodiazepam (10 microM) or midazolam (10 microM). PK 11195 showed this antagonistic effect in a dose-dependent manner. Intravenous 4'-chlorodiazepam (5 mg/kg of body weight) significantly suppressed LPS (100-micrograms)-induced TNF activity of sera (2 h postchallenge with LPS) from thioglycolate-treated mice. The present findings suggest that the peripheral benzodiazepine receptor plays an important role in modulating LPS-induced TNF activity in mouse macrophages. PMID:8031051

Climate Stability: Pathway to understand abrupt glacial climate shifts

NASA Astrophysics Data System (ADS)

Zhang, X.; Knorr, G.; Barker, S.; Lohmann, G.

2017-12-01

Glacial climate is marked by abrupt, millennial-scale climate changes known as Dansgaard-Oeschger (DO) cycles that have been linked to variations in the Atlantic meridional overturning circulation (AMOC). The most pronounced stadial coolings, Heinrich Stadials (HSs), are associated with massive iceberg discharges to the North Atlantic. This motivates scientists to consider that the North Atlantic freshwater perturbations is a common trigger of the associated abrupt transitions between weak and strong AMOC states. However, recent studies suggest that the Heinrich ice-surging events are triggered by ocean subsurface warming associated with an AMOC slow-down. Furthermore, the duration of ice-rafting events does not systematically coincide with the beginning and end of the pronounced cold conditions during HSs. In this context, we show that both, changes in atmospheric CO2 and ice sheet configuration can provide important control on the stability of the AMOC, using a coupled atmosphere-ocean model. Our simulations reveal that gradual changes in Northern Hemisphere ice sheet height and atmospheric CO2 can act as a trigger of abrupt glacial/deglacial climate changes. The simulated global climate responses—including abrupt warming in the North Atlantic, a northward shift of the tropical rain belts, and Southern Hemisphere cooling related to the bipolar seesaw—are generally consistent with empirical evidence. We further find that under a delicate configuration of atmospheric CO2 and ice sheet height the AMOC can be characterized by a self-oscillation (resonance) feature (Hopf Bifucation) with a 1000-year cycle that is comparable with observed small DO events during the MIS 3. This provides an alternative explanation for millennial-scale DO variability during glacial periods.

Comparison of intravenous ethanol versus diazepam for alcohol withdrawal prophylaxis in the trauma ICU: results of a randomized trial.

PubMed

Weinberg, Jordan A; Magnotti, Louis J; Fischer, Peter E; Edwards, Norma M; Schroeppel, Thomas; Fabian, Timothy C; Croce, Martin A

2008-01-01

Although benzodiazepines are the recommended first-line therapy for the prevention of alcohol withdrawal syndrome (AWS), the administration of intravenous ethanol as an alternative prophylactic agent persists in many surgical ICUs. Advocates of this therapy argue that ethanol provides effective prophylaxis against AWS without the excessive sedation observed with benzodiazepine therapy. No study to date, however, has compared the two therapies with regard to their sedative effects. The purpose of this study was to prospectively evaluate the efficacy of intravenous ethanol compared with benzodiazepines for the prevention of AWS with particular emphasis on the sedative effects of each therapy. During a 15-month period, trauma patients admitted to the ICU with a history of chronic daily alcohol consumption greater than or equal to five beverage equivalents per day were prospectively randomized to one of two 4-day prophylactic regimens: intravenous ethanol infusion (EtOH) versus scheduled-dose diazepam (BENZO). Patients were evaluated with the Riker sedation-agitation scale, a 7-point instrument for the subjective assessment of both sedation (1 = unarousable) and agitation (7 = dangerous agitation). According to protocol, regimens were titrated to achieve and maintain a Riker score of 4 (calm and cooperative). Deviation from a score of 4 during the course of treatment was compared between groups. Fifty patients met study criteria and were randomized after obtainment of informed consent (EtOH, n = 26; BENZO, n = 24). Overall, the EtOH group had a significantly greater proportion of patients who deviated from a score of 4 during the course of treatment (p = 0.020). In both groups, the majority of deviation from a score of 4 reflected periods of under-sedation rather than over-sedation. One patient in the EtOH group failed treatment, requiring diazepam and haloperidol for control of AWS symptoms as per protocol, whereas no patient in the BENZO group failed treatment (p

Evaluating Distal and Proximal Explanations for Withdrawal: A Rejoinder to Varnum and Kwon's "The Ecology of Withdrawal".

PubMed

Norasakkunkit, Vinai; Uchida, Yukiko; Takemura, Kosuke

2017-01-01

In their 2016 commentary on our theorizing about how youth withdrawal from economic and social participation in Japanese society (i.e., NEET and Hikikomori phenomena) stems from generational inequality of economic opportunities, Varnum and Kwon correctly point out that our explanation for withdrawal is yet untested. They then offered an alternative, evolutionary psychological explanation for withdrawal in which they claim that in resource-rich ecologies like Japan, the option to withdraw from participating in society is a possible life strategy, a strategy that would be much more costly in resource-poor ecologies. While we agree with this premise, we argue that this distal explanatory framework, at least in its current form, has limits in reconciling some of the more recent cross-cultural observations, as well as well-established sociological claims about the causes of withdrawal. Thus we argue that much work remains in refining and expanding the explanatory power of more distal explanations on the issue of withdrawal. Until then, the more proximal and culture-specific explanations are probably the useful and meaningful explanations for the withdrawal phenomenon.

Estimated freshwater withdrawals in Texas, 1990

USGS Publications Warehouse

Lurry, Dee L.

1994-01-01

This report presents 1990 freshwater withdrawal estimates for Texas by source and category. Withdrawal source is either ground water or surface water. Withdrawal categories include: self-supplied irrigation, thermoelectric-power generation, water supply, industrial and mining, and other (domestic, commercial, livestock). Withdrawal data are aggregated by county, major aquifer, and principal river basin. Only the four major categories of irrigation, thermoelectric-power generation, water supply, and industrial and mining are illustrated in this report, although all data are tabulated.

Abruptness of Cascade Failures in Power Grids

PubMed Central

Pahwa, Sakshi; Scoglio, Caterina; Scala, Antonio

2014-01-01

Electric power-systems are one of the most important critical infrastructures. In recent years, they have been exposed to extreme stress due to the increasing demand, the introduction of distributed renewable energy sources, and the development of extensive interconnections. We investigate the phenomenon of abrupt breakdown of an electric power-system under two scenarios: load growth (mimicking the ever-increasing customer demand) and power fluctuations (mimicking the effects of renewable sources). Our results on real, realistic and synthetic networks indicate that increasing the system size causes breakdowns to become more abrupt; in fact, mapping the system to a solvable statistical-physics model indicates the occurrence of a first order transition in the large size limit. Such an enhancement for the systemic risk failures (black-outs) with increasing network size is an effect that should be considered in the current projects aiming to integrate national power-grids into “super-grids”. PMID:24424239

Kinetic modeling of benzodiazepine receptor binding with PET and high specific activity [(11)C]Iomazenil in healthy human subjects.

PubMed

Bremner, J D; Horti, A; Staib, L H; Zea-Ponce, Y; Soufer, R; Charney, D S; Baldwin, R

2000-01-01

Quantitation of the PET benzodiazepine receptor antagonist, [(11)C]Iomazenil, using low specific activity radioligand was recently described. The purpose of this study was to quantitate benzodiazepine receptor binding in human subjects using PET and high specific activity [(11)C]Iomazenil. Six healthy human subjects underwent PET imaging following a bolus injection of high specific activity (>100 Ci/mmol) [(11)C]iomazenil. Arterial samples were collected at multiple time points after injection for measurement of unmetabolized total and nonprotein-bound parent compound in plasma. Time activity curves of radioligand concentration in brain and plasma were analyzed using two and three compartment model. Kinetic rate constants of transfer of radioligand between plasma, nonspecifically bound brain tissue, and specifically bound brain tissue compartments were fitted to the model. Values for fitted kinetic rate constants were used in the calculation of measures of benzodiazepine receptor binding, including binding potential (the ratio of receptor density to affinity), and product of BP and the fraction of free nonprotein-bound parent compound (V(3)'). Use of the three compartment model improved the goodness of fit in comparison to the two compartment model. Values for kinetic rate constants and measures of benzodiazepine receptor binding, including BP and V(3)', were similar to results obtained with the SPECT radioligand [(123)I]iomazenil, and a prior report with low specific activity [(11)C]Iomazenil. Kinetic modeling using the three compartment model with PET and high specific activity [(11)C]Iomazenil provides a reliable measure of benzodiazepine receptor binding. Synapse 35:68-77, 2000. Published 2000 Wiley-Liss, Inc.

An anxiogenic benzodiazepine receptor ligand induces learned helplessness.

PubMed

Drugan, R C; Maier, S F; Skolnick, P; Paul, S M; Crawley, J N

1985-07-31

Rats treated with the anxiogenic beta-carboline, N-methyl-beta-carboline-3-carboxamide (FG-7142), failed to acquire an escape response 24 h after treatment. Administration of FG-7142 resulted in a behavioral effect equivalent to a session of inescapable tailshock in this paradigm of learned helplessness. Pretreatment of rats with the selective benzodiazepine receptor antagonist Ro15-1788 blocked the development of learned helplessness elicited by FG-7142. These findings suggest that 'anxiety' may be a major factor in the development of learned helplessness.

The efficacy and safety of alprazolam versus other benzodiazepines in the treatment of panic disorder.

PubMed

Moylan, Steven; Staples, John; Ward, Stephanie Alison; Rogerson, Jan; Stein, Dan J; Berk, Michael

2011-10-01

We performed a meta-analysis of all single- or double-blind, randomized controlled trials comparing alprazolam to another benzodiazepine in the treatment of adult patients meeting the Diagnostic and Statistical Manual of Mental Disorders, Third or Fourth Edition, criteria for panic disorder or agoraphobia with panic attacks. Eight studies met inclusion criteria, describing a total of at least 631 randomized patients. In the pooled results, there were no significant differences in efficacy between alprazolam and the comparator benzodiazepines on any of the prespecified outcomes: improvement in mean panic attack frequency (between-arm weighted mean difference of 0.6 panic attacks per week; 95% confidence interval [CI], -0.3 to 1.6), improvement in Hamilton Anxiety Rating Scale score (weighted mean difference of 0.8 points; 95% CI, -0.5 to 2.1), and proportion of patients free of panic attacks at the final evaluation (pooled relative risk, 1.1; 95% CI, 0.9-1.4). Statistical heterogeneity on prespecified outcomes was not eliminated by stratification on baseline anxiety level. The available evidence fails to demonstrate alprazolam as superior to other benzodiazepines for the treatment of panic disorder.

Abrupt climate-independent fire regime changes

USGS Publications Warehouse

Pausas, Juli G.; Keeley, Jon E.

2014-01-01

Wildfires have played a determining role in distribution, composition and structure of many ecosystems worldwide and climatic changes are widely considered to be a major driver of future fire regime changes. However, forecasting future climatic change induced impacts on fire regimes will require a clearer understanding of other drivers of abrupt fire regime changes. Here, we focus on evidence from different environmental and temporal settings of fire regimes changes that are not directly attributed to climatic changes. We review key cases of these abrupt fire regime changes at different spatial and temporal scales, including those directly driven (i) by fauna, (ii) by invasive plant species, and (iii) by socio-economic and policy changes. All these drivers might generate non-linear effects of landscape changes in fuel structure; that is, they generate fuel changes that can cross thresholds of landscape continuity, and thus drastically change fire activity. Although climatic changes might contribute to some of these changes, there are also many instances that are not primarily linked to climatic shifts. Understanding the mechanism driving fire regime changes should contribute to our ability to better assess future fire regimes.

Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects.

PubMed

Cheng, Tianze; Wallace, Dominique Marie; Ponteri, Benjamin; Tuli, Mahir

2018-01-01

Benzodiazepines are one of the most prescribed medications as first-line treatment of anxiety, insomnia, and epilepsy around the world. Over the past two decades, advances in the neuropharmacological understanding of gamma aminobutyric acid (GABA) A receptors revealed distinct contributions from each subtype and produced effects. Recent findings have highlighted the importance of α 1 containing GABA A receptors in the mechanisms of addiction and tolerance in benzodiazepine treatments. This has shown promise in the development of tranquilizers with minimal side effects such as cognitive impairment, dependence, and tolerance. A valium-like drug without its side effects, as repeatedly demonstrated in animals, is achievable.

Maternal sleep duration and complaints of vital exhaustion during pregnancy is associated with placental abruption.

PubMed

Qiu, Chunfang; Sanchez, Sixto E; Gelaye, Bizu; Enquobahrie, Daniel A; Ananth, Cande V; Williams, Michelle A

2015-02-01

Sleep disorders are associated with cardiovascular complications and preterm delivery (PTD). Insufficient sleep results in metabolic alterations and increased inflammation, both known to contribute to placental abruption (abruption), a determinant of PTD. We examined associations of abruption with sleep duration and complaints of vital exhaustion. The study included 164 abruption cases and 160 controls in a multicenter study in Peru. Data on habitual sleep duration and vital exhaustion during the first 6 months of pregnancy were elicited during interviews conducted following delivery. Women were categorized according to short, normal and long sleep duration (≤6, 7-8 and ≥9 h); and frequency of feeling exhausted. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. Short and long sleep durations were associated with increased odds of abruption. The ORs of abruption in relation to short (≤6 h) and long (≥9 h) sleep duration were 2.0 (95% CI 1.1-3.7) and 2.1 (95% CI 1.1-4.1), compared with normal sleep duration (7-8 h). Complaints of vital exhaustion were also associated with abruption (OR = 2.37; 95% CI 1.46-3.85), and were independent of sleep duration. We extend the existing literature and support the thesis that maternal sleep habits and disorders should be assessed among pregnant women.

Slowing down as an early warning signal for abrupt climate change.

PubMed

Dakos, Vasilis; Scheffer, Marten; van Nes, Egbert H; Brovkin, Victor; Petoukhov, Vladimir; Held, Hermann

2008-09-23

In the Earth's history, periods of relatively stable climate have often been interrupted by sharp transitions to a contrasting state. One explanation for such events of abrupt change is that they happened when the earth system reached a critical tipping point. However, this remains hard to prove for events in the remote past, and it is even more difficult to predict if and when we might reach a tipping point for abrupt climate change in the future. Here, we analyze eight ancient abrupt climate shifts and show that they were all preceded by a characteristic slowing down of the fluctuations starting well before the actual shift. Such slowing down, measured as increased autocorrelation, can be mathematically shown to be a hallmark of tipping points. Therefore, our results imply independent empirical evidence for the idea that past abrupt shifts were associated with the passing of critical thresholds. Because the mechanism causing slowing down is fundamentally inherent to tipping points, it follows that our way to detect slowing down might be used as a universal early warning signal for upcoming catastrophic change. Because tipping points in ecosystems and other complex systems are notoriously hard to predict in other ways, this is a promising perspective.

Slowing down as an early warning signal for abrupt climate change

PubMed Central

Dakos, Vasilis; Scheffer, Marten; van Nes, Egbert H.; Brovkin, Victor; Petoukhov, Vladimir; Held, Hermann

2008-01-01

In the Earth's history, periods of relatively stable climate have often been interrupted by sharp transitions to a contrasting state. One explanation for such events of abrupt change is that they happened when the earth system reached a critical tipping point. However, this remains hard to prove for events in the remote past, and it is even more difficult to predict if and when we might reach a tipping point for abrupt climate change in the future. Here, we analyze eight ancient abrupt climate shifts and show that they were all preceded by a characteristic slowing down of the fluctuations starting well before the actual shift. Such slowing down, measured as increased autocorrelation, can be mathematically shown to be a hallmark of tipping points. Therefore, our results imply independent empirical evidence for the idea that past abrupt shifts were associated with the passing of critical thresholds. Because the mechanism causing slowing down is fundamentally inherent to tipping points, it follows that our way to detect slowing down might be used as a universal early warning signal for upcoming catastrophic change. Because tipping points in ecosystems and other complex systems are notoriously hard to predict in other ways, this is a promising perspective. PMID:18787119

[Reversible catatonia after the abrupt discontinuation of clozapine: Case report].

PubMed

Jaafari, M; Bout, A; Rammouz, I; Aalouane, R

2016-12-01

In this paper, we report the case of a patient, aged 26, with schizophrenia who was admitted to psychiatric emergencies for catatonia, one week after abrupt discontinuation of clozapine. An improvement was seen after only two days of the reintroduction of clozapine alone. This catatonia is reversible and it responds magnificently to the reintroduction of clozapine. And we conclude that patients and their caregivers need to be educated about the effects of abrupt cessation of clozapine administration. Copyright © 2016 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Benzodiazepine dependence in subjects with alcohol use disorders: what prevalence?

PubMed

Morel, A; Grall-Bronnec, M; Bulteau, S; Chauvin-Grelier, P; Gailledrat, L; Pinot, M L; Jolliet, P; Victorri-Vigneau, C

2016-10-01

To our knowledge, no studies have been conducted in France on benzodiazepine (BZD) dependence among outpatients with alcohol use disorders (AUD). Some international studies have been conducted on the consumption of BZD in this specific population, but the comparisons among them are difficult. We aimed to assess the current prevalence of probable benzodiazepine and BZD-like hypnotics (Z-drugs) dependence among outpatients seeking treatment for AUD. Participants were patients seeking treatment for AUD for the first time or repeating treatment after more than twelve months. Recruitment took place in seven addiction centres between January and December 2013 in the Nantes region (France). BZD/Z-drug dependence was assessed according to the DSM-IV diagnostic criteria for dependence. This information was gathered through a self-report questionnaire. Among the 1005 patients included in this study, 413 were BZD/Z-drug users (41.1%). Among the 413 patients, 217 were probably dependent on at least one substance, which represents 21.6% of the total population and 52.5% of BZD/Z-drug users. BZD/Z-drug dependence represents a public health concern. Prescribers should take the risks into account and keep treatment courses to a minimum.

Temperament and character traits associated with the use of alcohol, cannabis, cocaine, benzodiazepines, and hallucinogens: evidence from a large Brazilian web survey.

PubMed

Schneider, Ricardo; Ottoni, Gustavo L; de Carvalho, Hudson W; Elisabetsky, Elaine; Lara, Diogo R

2015-01-01

To evaluate how personality traits are associated with occasional use, abuse, and dependence of alcohol, cannabis, cocaine, benzodiazepines, and hallucinogens in a large availability sample of adults via online questionnaires. The sample consisted of 8,646 individuals (24.7% men and 75.3% women) who completed an anonymous web survey. Involvement with drugs and temperament/character traits were assessed through the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and the Temperament and Character Inventory - Revised (TCI-R), respectively. Interactions among variables were analyzed using MANOVA with Bonferroni adjustment. Novelty seeking was the trait most associated with increased involvement with alcohol, cannabis, and cocaine. There was a significant association between harm avoidance and benzodiazepine use. Persistence was lower in cannabis-, benzodiazepine-, and cocaine-dependent subjects, as well as in hallucinogen abusers. Self-directedness was reduced in dependents of all drug classes. No strong relationships were found between other temperament or character dimensions and the severity of drug use. Novelty seeking was associated with increased involvement with all drugs studied in this sample, although to a lesser extent with benzodiazepines and hallucinogens. The temperament and character profile for benzodiazepine use was different from that of other drugs due to the relationship with higher harm avoidance and self-transcendence and lower self-directedness.

A sex difference in oxidative stress and behavioral suppression induced by ethanol withdrawal in rats

PubMed Central

Jung, Marianna E.; Metzger, Daniel B.

2016-01-01

Ethanol withdrawal (EW) is referred to the abrupt termination of long-term heavy drinking, and provokes oxidative brain damage. Here, we investigated whether the cerebellum and hippocampus of female rats are less affected by prooxidant EW than male rats due to the antioxidant effect of 17β-estradiol (E2). Female and male rats received a four-week ethanol diet and three-week withdrawal per cycle for two cycles. Some female rats were ovariectomized with E2 or antioxidant (Vitamin E+Co-Q10) treatment. Measurements were cerebellum (Rotarod) and hippocampus (water-maze)-related behaviors, oxidative markers (O2•−, malondialdehyde, protein carbonyls), mitochondrial membrane swelling, and a key mitochondrial enzyme, cytochrome c oxidase (CcO). Separately, HT22 (hippocampal) cells were subjected to ethanol-exposure and withdrawal for two cycles to assess the effect of a CcO inhibitor on E2’s protection for mitochondrial respiration and cell viability. Ethanol-withdrawn female rats showed a smaller increase in oxidative markers in cerebellum and hippocampus than male rats, and E2 treatment decreased the oxidative markers. Compared to male counterparts, ethanol-withdrawn female rats showed better Rotarod but poorer water-maze performance, accompanied by more severe mitochondrial membrane swelling and CcO suppression in hippocampus. E2 or antioxidant treatment improved Rotarod but not water-maze performance. In the presence of a CcO inhibitor, E2 treatment failed to protect mitochondrial respiration and cell viability from EW. These data suggest that antioxidant E2 contributes to smaller oxidative stress in ethanol-withdrawn female than male rats. They also suggest that EW-induced severe mitochondrial damage in hippocampus may blunt E2’s antioxidant protection for hippocampus-related behavior. PMID:27503149

A Detection Model of College Withdrawal

ERIC Educational Resources Information Center

Pleskac, Timothy J.; Keeney, Jessica; Merritt, Stephanie M.; Schmitt, Neal; Oswald, Frederick L.

2011-01-01

Many students during their college careers consider withdrawing from their respective college or university. Understanding why some students decide to withdraw yet others persist has implications for both the well being of students as well as for institutes of higher education. The present study develops a model of the decision to withdraw drawing…

Feasibility and reliability of the SHOT: A short scale for measuring pretreatment severity of alcohol withdrawal in the emergency department.

PubMed

Gray, Sara; Borgundvaag, Bjug; Sirvastava, Anita; Randall, Ian; Kahan, Meldon

2010-10-01

Use of a symptom-triggered scale to measure the severity of alcohol withdrawal could reduce the rate of seizures and other complications. The current standard scale, the Clinical Institute of Withdrawal Assessment (CIWA), takes a mean (±SD) of 5 minutes to complete, requiring 30 minutes of nursing time per patient when multiple measures are required. The objective was to assess the feasibility and reliability of a brief scale of alcohol withdrawal severity. The SHOT is a brief scale designed to assess alcohol withdrawal in the emergency department (ED). It includes four items: sweating, hallucinations, orientation, and tremor (SHOT). It was developed based on a literature review and a consensus process by emergency and addiction physicians. The SHOT was first piloted in one ED, and then a prospective observational study was conducted at a different ED to measure its feasibility and reliability. Subjects included patients who were in alcohol withdrawal. One nurse administered the SHOT and CIWA, and the physician repeated the SHOT independently. The SHOT was done only at baseline, before treatment was administered. In the pilot study (12 patients), the SHOT took 1 minute to complete on average, and the CIWA took 5 minutes. Sixty-one patients participated in the prospective study. For the SHOT and the CIWA done by the same nurse, the kappa was 0.88 (95% confidence interval [CI] = 0.52 to 1.0; p < 0.0001), and the Pearson's r was 0.71 (p < 0.001). The kappa for the nurse's CIWA score and the physician's SHOT score was 0.61 (95% CI = 0.25 to 0.97; p < 0.0006), and the Pearson's r was 0.48 (p = 0.002). The SHOTs performed by the nurse and physician agreed on the need for benzodiazepine treatment in 30 of 37 cases (82% agreement, kappa = 0.35, 95% CI = 0.03 to 0.67; p < 0.02). The mean (±SD) time taken by nurses and physicians to complete the SHOT was 1 (± 0.52) minute (median = 0.6 minutes). Seventeen percent of patients scored positive on the SHOT for hallucinations

Deprescribing Benzodiazepines in Older Patients: Impact of Interventions Targeting Physicians, Pharmacists, and Patients.

PubMed

Ng, Brendan J; Le Couteur, David G; Hilmer, Sarah N

2018-04-28

Benzodiazepines (BZDs; including the related Z-drugs) are frequently targets for deprescribing; long-term use in older people is harmful and often not beneficial. BZDs can result in significant harms, including falls, fractures, cognitive impairment, car crashes and a significant financial and legal burden to society. Deprescribing BZDs is problematic due to a complex interaction of drug, patient, physician and systematic barriers, including concern about a potentially distressing but rarely fatal withdrawal syndrome. Multiple studies have trialled interventions to deprescribe BZDs in older people and are discussed in this narrative review. Reported success rates of deprescribing BZD interventions range between 27 and 80%, and this variability can be attributed to heterogeneity of methodological approaches and limited generalisability to cognitively impaired patients. Interventions targeting the patient and/or carer include raising awareness (direct-to-consumer education, minimal interventions, and 'one-off' geriatrician counselling) and resourcing the patient (gradual dose reduction [GDR] with or without cognitive behavioural therapy, teaching relaxation techniques, and sleep hygiene). These are effective if the patient is motivated to cease and is not significantly cognitively impaired. Interventions targeted to physicians include prescribing interventions by audit, algorithm or medication review, and providing supervised GDR in combination with medication substitution. Pharmacists have less frequently been the targets for studies, but have key roles in several multifaceted interventions. Interventions are evaluated according to the Behaviour Change Wheel. Research supports trialling a stepwise approach in the cognitively intact older person, but having a low threshold to use less-consultative methods in patients with dementia. Several resources are available to support deprescribing of BZDs in clinical practice, including online protocols.

Placental abruption possibly due to parvovirus B19 infection.

PubMed

Kawabe, Ayaka; Takai, Yasushi; Tamaru, Jun-Ichi; Samejima, Kouki; Seki, Hiroyuki

2016-01-01

There is concern about the development of anemia-associated fetal hydrops associated with maternal parvovirus B19 infection. Parvovirus B19 infection occurs via the globoside (P antigen) receptor, the main glycolipid of erythroid cells, which induces apoptosis. Similar findings have been reported for the P antigen of globoside-containing placental trophoblast cells. A 32-year-old woman was infected with human parvovirus B19 at week 32 of pregnancy, and had severe anemia at week 34. At week 37, an emergency cesarean section was performed because of sudden abdominal pain and fetal bradycardia; placental abruption was found. A live male infant was delivered with no sign of fetal hydrops or fetal infection. Placental tissue was positive for parvovirus B19 according to polymerase chain reaction. Immunohistochemical analysis using caspase-related M30 CytoDEATH monoclonal antibody revealed M30 staining of the placental villous trophoblasts. Placental trophoblasts and erythroid precursor cells have been reported to express globoside (P antigen), which is necessary for parvovirus B19 infectivity, and to show apoptotic activity as a result of infection. Placentas from three other pregnancies with documented abruption showed no M30 staining. The present case strongly suggests an association between placental abruption and apoptosis resulting from parvovirus B19 infection.

Prescriptions for schedule II opioids and benzodiazepines increase after the introduction of computer-generated prescriptions.

PubMed

McGerald, Genevieve; Dvorkin, Ronald; Levy, David; Lovell-Rose, Stephanie; Sharma, Adhi

2009-06-01

Prescriptions for controlled substances decrease when regulatory barriers are put in place. The converse has not been studied. The objective was to determine whether a less complicated prescription writing process is associated with a change in the prescribing patterns of controlled substances in the emergency department (ED). The authors conducted a retrospective nonconcurrent cohort study of all patients seen in an adult ED between April 19, 2005, and April 18, 2007, who were discharged with a prescription. Prior to April 19, 2006, a specialized prescription form stored in a locked cabinet was obtained from the nursing staff to write a prescription for benzodiazepines or Schedule II opioids. After April 19, 2006, New York State mandated that all prescriptions, regardless of schedule classification, be generated on a specialized bar-coded prescription form. The main outcome of the study was to compare the proportion of Schedule III-V opioids to Schedule II opioids and benzodiazepines prescribed in the ED before and after the introduction of a less cumbersome prescription writing process. Of the 26,638 charts reviewed, 2.1% of the total number of prescriptions generated were for a Schedule II controlled opioid before the new system was implemented compared to 13.6% after (odds ratio [OR] = 7.3, 95% confidence interval [CI] = 6.4 to 8.4). The corresponding percentages for Schedule III-V opioids were 29.9% to 18.1% (OR = 0.52, 95% CI = 0.49 to 0.55) and for benzodiazepines 1.4% to 3.9% (OR = 2.8, 95% CI = 2.4 to 3.4). Patients were more likely to receive a prescription for a Schedule II opioid or a benzodiazepine after a more streamlined computer-generated prescription writing process was introduced in this ED. (c) 2009 by the Society for Academic Emergency Medicine.

Long-term antipsychotic and benzodiazepine use and brain volume changes in schizophrenia: The Northern Finland Birth Cohort 1966 study.

PubMed

Huhtaniska, Sanna; Jääskeläinen, Erika; Heikka, Tuomas; Moilanen, Jani S; Lehtiniemi, Heli; Tohka, Jussi; Manjón, José V; Coupé, Pierrick; Björnholm, Lassi; Koponen, Hannu; Veijola, Juha; Isohanni, Matti; Kiviniemi, Vesa; Murray, Graham K; Miettunen, Jouko

2017-08-30

High doses of antipsychotics have been associated with loss in cortical and total gray matter in schizophrenia. However, previous imaging studies have not taken benzodiazepine use into account, in spite of evidence suggesting adverse effects such as cognitive impairment and increased mortality. In this Northern Finland Birth Cohort 1966 study, 69 controls and 38 individuals with schizophrenia underwent brain MRI at the ages of 34 and 43 years. At baseline, the average illness duration was over 10 years. Brain structures were delineated using an automated volumetry system, volBrain, and medication data on cumulative antipsychotic and benzodiazepine doses were collected using medical records and interviews. We used linear regression with intracranial volume and sex as covariates; illness severity was also taken into account. Though both medication doses associated to volumetric changes in subcortical structures, after adjusting for each other and the average PANSS total score, higher scan-interval antipsychotic dose associated only to volume increase in lateral ventricles and higher benzodiazepine dose associated with volume decrease in the caudate nucleus. To our knowledge, there are no previous studies reporting associations between benzodiazepine dose and brain structural changes. Further studies should focus on how these observations correspond to cognition and functioning. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Water withdrawals in Florida, 2012

USGS Publications Warehouse

Marella, Richard L.

2015-09-01

The largest percentage of freshwater withdrawals was from the South Florida Water Management District (46 percent), followed by the St. Johns River Water Management District (20 percent), Southwest Florida Water Management District (19 percent), Northwest Florida Water Management District (9 percent), and Suwannee River Water Management District (6 percent). The South Florida Water Management District accounted for the largest percentage of freshwater withdrawals for public-supply use (46 percent), commercial-industrial-mining self-supplied use (24 percent), agricultural self-supplied use (59 percent), and recreational-landscape irrigation use (63 percent). The Northwest Florida Water Management District accounted for the largest percentage of freshwater withdrawals for power-generation use (44 percent), and the Southwest Florida Water Management District accounted for the largest percentage of saline-water withdrawals for power-generation use (58 percent).

The lesser evil? Initiating a benzodiazepine prescription in general practice: a qualitative study on GPs' perspectives.

PubMed

Anthierens, Sibyl; Habraken, Hilde; Petrovic, Mirko; Christiaens, Thierry

2007-12-01

Chronic benzodiazepine (BZD) use is widespread and linked with adverse effects. There is consensus concerning the importance of initiating BZD as a crucial moment. Nevertheless specific research in this field is lacking. This paper addresses the views of GPs on why they start prescribing BZDs to first-time users. Qualitative study with five focus groups analysed using a systematic content analysis. Regions of Ghent and Brussels in Belgium. A total of 35 general practitioners. The GPs' perspective on their initiating of BZD prescribing. GPs reported that they are cautious in initiating BZD usage. At the same time, GPs feel overwhelmed by the psychosocial problems of their patients. They show empathy by prescribing. They feel in certain situations there are no other solutions and they experience BZDs as the lesser evil. They admit to resorting to BZDs because of time restraint and lack of alternatives. GPs do not perceive the addictive nature of BZD consumption as a problem with first-time users. GPs do not specifically mention patients' demand as an element for starting. The main concern of GPs is to help the patient. GPs should be aware of the addictive nature of BZD even in low doses and a non-pharmacological approach should be seen as the best first approach. If GPs decide to prescribe a BZD they should make plain to the patient that the medication is only a "temporary" solution with clear agreements with regard to medication withdrawal.

Total water withdrawals in Mississippi, 1990

USGS Publications Warehouse

Johnson, P.M.

1994-01-01

During 1990, the amount of water withdrawn from ground- and surface-water sources in Mississippi was about 3,600 Mgal/d (million gallons per day). Of this amount, 91 percent, or 3,300 Mgal/d, was withdrawn from freshwater sources. Of the total freshwater withdrawals, about 82 percent, or 2,700 Mgal/d, was withdrawn from ground-water sources. Total water withdrawals in Mississippi in 1990 for eight categories of use were as follows: irrigation, 1,900 Mgal/d; thermoelectric power, 700 Mgal/d; aquaculture, 400 Mgal/d; public supply, 320 Mgal/d; industrial and mining, 270 Mgal/d; domestic, 33 Mgal/d; commercial, 16 Mgal/d; and livestock, 16 Mgal/d. Overall, total withdrawals increased by 20 percent from 1985 to 1990, although the total population decreased about 2 percent. During the same period, total freshwater withdrawals increased by about 17 percent. Total saline with- drawals increased by about 60 percent from 1985 due to an increase in salin withdrawals for thermo- electric power generation. Total fresh and saline surface-water withdrawals decreased by about 6 percent from 1985, due to decrease in surface-water withdrawals for irrigation. Fresh ground-water withdrawals in Mississippi increased by about 33 percent, primarily due to an increase in irrigation. Since 1960, total ground- and surface-water with- drawals increased 70 percent for the same period. Irrigation had the greatest increase in with- drawals since 1960, with a 269 percent increase. Public supply had the second greatest, with a 178 percent increase.

Catalogue of abrupt shifts in Intergovernmental Panel on Climate Change climate models

NASA Astrophysics Data System (ADS)

Drijfhout, Sybren; Bathiany, Sebastian; Beaulieu, Claudie; Brovkin, Victor; Claussen, Martin; Huntingford, Chris; Scheffer, Marten; Sgubin, Giovanni; Swingedouw, Didier

2015-10-01

Abrupt transitions of regional climate in response to the gradual rise in atmospheric greenhouse gas concentrations are notoriously difficult to foresee. However, such events could be particularly challenging in view of the capacity required for society and ecosystems to adapt to them. We present, to our knowledge, the first systematic screening of the massive climate model ensemble informing the recent Intergovernmental Panel on Climate Change report, and reveal evidence of 37 forced regional abrupt changes in the ocean, sea ice, snow cover, permafrost, and terrestrial biosphere that arise after a certain global temperature increase. Eighteen out of 37 events occur for global warming levels of less than 2°, a threshold sometimes presented as a safe limit. Although most models predict one or more such events, any specific occurrence typically appears in only a few models. We find no compelling evidence for a general relation between the overall number of abrupt shifts and the level of global warming. However, we do note that abrupt changes in ocean circulation occur more often for moderate warming (less than 2°), whereas over land they occur more often for warming larger than 2°. Using a basic proportion test, however, we find that the number of abrupt shifts identified in Representative Concentration Pathway (RCP) 8.5 scenarios is significantly larger than in other scenarios of lower radiative forcing. This suggests the potential for a gradual trend of destabilization of the climate with respect to such shifts, due to increasing global mean temperature change.

Catalogue of abrupt shifts in Intergovernmental Panel on Climate Change climate models

PubMed Central

Drijfhout, Sybren; Bathiany, Sebastian; Beaulieu, Claudie; Brovkin, Victor; Claussen, Martin; Huntingford, Chris; Scheffer, Marten; Sgubin, Giovanni; Swingedouw, Didier

2015-01-01

Abrupt transitions of regional climate in response to the gradual rise in atmospheric greenhouse gas concentrations are notoriously difficult to foresee. However, such events could be particularly challenging in view of the capacity required for society and ecosystems to adapt to them. We present, to our knowledge, the first systematic screening of the massive climate model ensemble informing the recent Intergovernmental Panel on Climate Change report, and reveal evidence of 37 forced regional abrupt changes in the ocean, sea ice, snow cover, permafrost, and terrestrial biosphere that arise after a certain global temperature increase. Eighteen out of 37 events occur for global warming levels of less than 2°, a threshold sometimes presented as a safe limit. Although most models predict one or more such events, any specific occurrence typically appears in only a few models. We find no compelling evidence for a general relation between the overall number of abrupt shifts and the level of global warming. However, we do note that abrupt changes in ocean circulation occur more often for moderate warming (less than 2°), whereas over land they occur more often for warming larger than 2°. Using a basic proportion test, however, we find that the number of abrupt shifts identified in Representative Concentration Pathway (RCP) 8.5 scenarios is significantly larger than in other scenarios of lower radiative forcing. This suggests the potential for a gradual trend of destabilization of the climate with respect to such shifts, due to increasing global mean temperature change. PMID:26460042

Catalogue of abrupt shifts in Intergovernmental Panel on Climate Change climate models.

PubMed

Drijfhout, Sybren; Bathiany, Sebastian; Beaulieu, Claudie; Brovkin, Victor; Claussen, Martin; Huntingford, Chris; Scheffer, Marten; Sgubin, Giovanni; Swingedouw, Didier

2015-10-27

Abrupt transitions of regional climate in response to the gradual rise in atmospheric greenhouse gas concentrations are notoriously difficult to foresee. However, such events could be particularly challenging in view of the capacity required for society and ecosystems to adapt to them. We present, to our knowledge, the first systematic screening of the massive climate model ensemble informing the recent Intergovernmental Panel on Climate Change report, and reveal evidence of 37 forced regional abrupt changes in the ocean, sea ice, snow cover, permafrost, and terrestrial biosphere that arise after a certain global temperature increase. Eighteen out of 37 events occur for global warming levels of less than 2°, a threshold sometimes presented as a safe limit. Although most models predict one or more such events, any specific occurrence typically appears in only a few models. We find no compelling evidence for a general relation between the overall number of abrupt shifts and the level of global warming. However, we do note that abrupt changes in ocean circulation occur more often for moderate warming (less than 2°), whereas over land they occur more often for warming larger than 2°. Using a basic proportion test, however, we find that the number of abrupt shifts identified in Representative Concentration Pathway (RCP) 8.5 scenarios is significantly larger than in other scenarios of lower radiative forcing. This suggests the potential for a gradual trend of destabilization of the climate with respect to such shifts, due to increasing global mean temperature change.

Translating Benzodiazepine Utilization Data into Meaningful Population Exposure: Integration of Two Metrics for Improved Reporting.

PubMed

Brandt, Jaden; Alkabanni, Wajd; Alessi-Severini, Silvia; Leong, Christine

2018-04-04

Drug utilization research on benzodiazepines remains important for measuring trends in consumption within and across borders over time for the sake of monitoring prescribing patterns and identifying potential population safety concerns. The defined daily dose (DDD) system by the World Health Organization (WHO) remains the internationally accepted standard for measuring drug consumption; however, beyond consumption, DDD-based results are difficult to interpret when individual agents are compared with one another or are pooled into a total class-based estimate. The diazepam milligram equivalent (DME) system provides approximate conversions between benzodiazepines and Z-drugs (i.e. zopiclone, zolpidem, zaleplon) based on their pharmacologic potency. Despite this, conversion of total dispensed benzodiazepine quantities into DME values retains diazepam milligrams as the total unit of measurement, which is also impractical for population-level interpretation. In this paper, we propose the use of an integrated DME-DDD metric to obviate the limitations encountered when the component metrics are used in isolation. Through a case example, we demonstrate significant change in results between the DDD and DME-DDD method. Unlike the DDD method, the integrated DME-DDD metric offers estimation of population pharmacologic exposure, and enables superior interpretation of drug utilization results, especially for drug class summary reporting.

Specialty training and the personal use of benzodiazepines by physicians affect their proneness to prescribe tranquilizers.

PubMed

Linden, M; Gothe, H

1998-03-01

The decision on how to treat a patient does not depend on clinical matters or illness characteristics alone, but also on patient, physician and setting variables such as personality, training, or reimbursement. No research has yet been carried out to answer the question whether personal experience with medications also influences prescribing behavior. In this study, 124 physicians stratified according to specialty (neuropsychiatrists vs. general practitioners), type of institution (private practice vs. hospital), years of professional experience (young vs. old), and region (rural vs. urban) participated in a structured interview to evaluate their proneness to prescribe benzodiazepines for sleep disorders as well as their personal experience in taking benzodiazepines for their own sleep problems. Both specialty and personal experience were significantly related to proneness to prescribe. Other variables tested (region, institution, age, gender) did not help to explain the variance in benzodiazepine prescribing practice. Thus physician variables and, importantly, their own personal experience in taking the medication significantly influence treatment choice. Rational medical decision making and treatment guidelines must therefore take into account medical knowledge as well as knowledge of personal treatment preferences and professional biases.

Enhancement of GABAergic transmission by zolpidem, an imidazopyridine with preferential affinity for type I benzodiazepine receptors.

PubMed

Biggio, G; Concas, A; Corda, M G; Serra, M

1989-02-28

The effect of zolpidem, an imidazopyridine derivative with high affinity at the type I benzodiazepine recognition site, on the function of the GABAA/ionophore receptor complex was studied in vitro. Zolpidem, mimicking the action of diazepam, increased [3H]GABA binding, enhanced muscimol-stimulated 36Cl- uptake and reduced [35S]TBPS binding in rat cortical membrane preparations. Zolpidem was less effective than diazepam on the above parameters. Zolpidem induced a lower increase of [3H]GABA binding (23 vs. 35%) and muscimol-stimulated 36Cl- uptake (22 vs. 40%) and a smaller decrease of [35S]TBPS binding (47 vs. 77%) than diazepam. The finding that zolpidem enhanced the function of GABAergic synapses with an efficacy qualitatively and quantitatively different from that of diazepam suggests that this compound is a partial agonist at the benzodiazepine recognition site. Thus, our results are consistent with the view that the biochemical and pharmacological profile of a benzodiazepine recognition site ligand reflects its efficacy to enhance GABAergic transmission. Whether the preferential affinity of zolpidem at the type I site is involved in its atypical biochemical and pharmacological profile remains to be clarified.

Combination of psychotherapy and benzodiazepines versus either therapy alone for panic disorder: a systematic review

PubMed Central

Watanabe, Norio; Churchill, Rachel; Furukawa, Toshi A

2007-01-01

Background: The efficacy of combined psychotherapy and benzodiazepine treatment for panic disorder is still unclear despite its widespread use. The present systematic review aims to examine its efficacy compared with either monotherapy alone. Methods: All randomised trials comparing combined psychotherapy and benzodiazepine for panic disorder with either therapy alone were identified by comprehensive electronic search on the Cochrane Registers, by checking references of relevant studies and of other reviews, and by contacting experts in the field. Two reviewers independently checked eligibility of trials, assessed quality of trials and extracted data from eligible trials using a standardized data extraction form. Our primary outcome was "response" defined by global judgement. Authors of the original trials were contacted for further unpublished data. Meta-analyses were undertaken synthesizing data from all relevant trials. Results: Only two studies, which compared the combination with behaviour (exposure) therapy, met our eligibility criteria. Both studies had a 16-week intervention. Unpublished data were retrieved for one study. The relative risk for response for the combination was 1.25 (95%CI: 0.78 to 2.03) during acute phase treatment, 0.78 (0.45 to 1.35) at the end of treatment, and 0.62 (0.36 to 1.07) at 6–12 months follow-up. Some secondary outcomes hinted at superiority of the combination during acute phase treatment. One study was identified comparing the combination to benzodiazepine. The relative risk for response was 1.57 (0.83 to 2.98), 3.39 (1.03 to 11.21, statistically significant) and 2.31 (0.79 to 6.74) respectively. The superiority of the combination was observed on secondary outcomes at all the time points. No sub-group analyses were conducted due to the limited number of included trials. Conclusion: Unlike some narrative reviews in the literature, our systematic search established the paucity of high quality evidence for or against the

Detection of abrupt changes in dynamic systems

NASA Technical Reports Server (NTRS)

Willsky, A. S.

1984-01-01

Some of the basic ideas associated with the detection of abrupt changes in dynamic systems are presented. Multiple filter-based techniques and residual-based method and the multiple model and generalized likelihood ratio methods are considered. Issues such as the effect of unknown onset time on algorithm complexity and structure and robustness to model uncertainty are discussed.

Perinatal risk factors and social withdrawal behaviour.

PubMed

Guedeney, Antoine; Marchand-Martin, Laetitia; Cote, Sylvana J; Larroque, Béatrice

2012-04-01

The objectives of the study were (1) to assess prevalence of social withdrawal behaviour in infants aged 12 months included in the French Perinatal Risk Factor Study Eden; (2) To study the correlation between relational withdrawal and several perinatal and parental factors assessed in the EDEN study. A longitudinal study using the ADBB scale was conducted within the Eden Cohort in the year 2008. 1,586 infants were included in the study. Fourteen percent of the children who had an ADBB assessment had a score at 5 and over on the ADBB, a scale designed to assess social withdrawal behaviour at age 0-24 months. Social withdrawal at 12 months was associated with low birth weight, low gestational age and with intra uterine growth retardation. Social withdrawal was independently associated with several maternal and paternal risk factors. The level of social withdrawal behaviour increased with a score of maternal difficulties. This study on a large longitudinally followed volunteer sample demonstrate a clear association of social withdrawal behaviour at age one with low birth weight and preterm birth, possibly mediated by parental vulnerabilities. Social withdrawal behaviour seems to be an important alarm signal to detect early on particularly in premature and small for date babies. © Springer-Verlag 2012

Motor impairment: a new ethanol withdrawal phenotype in mice

PubMed Central

Philibin, Scott D.; Cameron, Andy J.; Metten, Pamela; Crabbe, John C.

2015-01-01

Alcoholism is a complex disorder with genetic and environmental risk factors. The presence of withdrawal symptoms is one criterion for alcohol dependence. Genetic animal models have followed a reductionist approach by quantifying various effects of ethanol withdrawal separately. Different ethanol withdrawal symptoms may have distinct genetic etiologies, and therefore differentiating distinct neurobiological mechanisms related to separate signs of withdrawal would increase our understanding of various aspects of the complex phenotype. This study establishes motor incoordination as a new phenotype of alcohol withdrawal in mice. Mice were made physically dependent on ethanol by exposure to ethanol vapor for 72 h. The effects of ethanol withdrawal in mice from different genetic backgrounds were measured on the accelerating rotarod, a simple motor task. Ethanol withdrawal disrupted accelerating rotarod behavior in mice. The disruptive effects of withdrawal suggest a performance rather than a learning deficit. Inbred strain comparisons suggest genetic differences in magnitude of this withdrawal phenotype. The withdrawal-induced deficits were not correlated with the selection response difference in handling convulsion severity in selectively bred Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant lines. The accelerating rotarod seems to be a simple behavioral measure of ethanol withdrawal that is suitable for comparing genotypes. PMID:18690115

Tobacco withdrawal among opioid-dependent smokers.

PubMed

Streck, Joanna M; Heil, Sarah H; Higgins, Stephen T; Bunn, Janice Y; Sigmon, Stacey C

2018-04-01

Prevalence of cigarette smoking among opioid-dependent individuals is 6-fold that of the general U.S. adult population and their quit rates are notoriously poor. One possible reason for the modest cessation outcomes in opioid-dependent smokers may be that they experience more severe tobacco withdrawal upon quitting. In this secondary analysis, we evaluated tobacco withdrawal in opioid-dependent (OD) smokers versus smokers without co-occurring substance use disorders (SUDs). Participants were 47 methadone- or buprenorphine-maintained smokers and 25 non-SUD smokers who completed 1 of several 2-week studies involving daily visits for biochemical monitoring, delivery of financial incentives contingent on smoking abstinence, and assessment of withdrawal via the Minnesota Nicotine Withdrawal Scale (MNWS). Prior to quitting smoking, OD smokers presented with higher baseline withdrawal scores than non-SUD smokers (1.7 ± 0.2 vs. 0.7 ± 0.2, respectively; F [1, 63] = 7.31, p < .001). Withdrawal scores in both groups decreased over the subsequent 2-week period with no group differences, F (1, 910) = 0.50, p = .48. A similar pattern was observed on craving (i.e., Desire to Smoke item of MNWS), although the trajectory of decrease over time on this item was also moderated by gender. Overall, there was no difference in withdrawal during biochemically verified smoking abstinence between OD and non-SUD smokers, suggesting that elevated withdrawal severity following quitting may not be a major factor contributing to the poor cessation outcomes consistently observed among OD smokers. Further scientific efforts are needed to improve our understanding of the high smoking rates and modest cessation outcomes in this challenging population. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Atmospheric CO2 and abrupt climate change on submillennial timescales

NASA Astrophysics Data System (ADS)

Ahn, Jinho; Brook, Edward

2010-05-01

How atmospheric CO2 varies and is controlled on various time scales and under various boundary conditions is important for understanding how the carbon cycle and climate change are linked. Ancient air preserved in ice cores provides important information on past variations in atmospheric CO2. In particular, concentration records for intervals of abrupt climate change may improve understanding of mechanisms that govern atmospheric CO2. We present new multi-decadal CO2 records that cover Greenland stadial 9 (between Dansgaard-Oeschger (DO) events 8 and 9) and the abrupt cooling event at 8.2 ka. The CO2 records come from Antarctic ice cores but are well synchronized with Greenland ice core records using new high-resolution CH4 records,precisely defining the timing of CO2 change with respect to abrupt climate events in Greenland. Previous work showed that during stadial 9 (40~38 ka), CO2 rose by about 15~20 ppm over around 2,000 years, and at the same time temperatures in Antarctica increased. Dust proxies indicate a decrease in dust flux over the same period. With more detailed data and better age controls we now find that approximately half of the CO2 increase during stadial 9 occurred abruptly, over the course of decades to a century at ~39.6 ka. The step increase of CO2 is synchronous with a similar step increase of Antarctic isotopic temperature and a small abrupt change in CH4, and lags after the onset of decrease in dust flux by ~400 years. New atmospheric CO2 records at the well-known ~8.2 ka cooling event were obtained from Siple Dome ice core, Antarctica. Our preliminary CO2 data span 900 years and include 19 data points within the 8.2 ka cooling event, which persisted for ~160 years (Thomas et al., Quarternary Sci. Rev., 2007). We find that CO2 increased by 2~4 ppm during that cooling event. Further analyses will improve the resolution and better constrain the CO2 variability during other times in the early Holocene to determine if the variations observed

Alcohol withdrawal

MedlinePlus

... Seeing or feeling things that aren't there (hallucinations) Seizures Severe confusion ... alcohol withdrawal. You will be watched closely for hallucinations and other signs of delirium tremens. Treatment may ...

Acute diabetes insipidus mediated by vasopressinase after placental abruption.

PubMed

Wallia, Amisha; Bizhanova, Aigerim; Huang, Wenyu; Goldsmith, Susan L; Gossett, Dana R; Kopp, Peter

2013-03-01

Postpartum, diabetes insipidus (DI) can be part of Sheehan's syndrome or lymphocytic hypophysitis in combination with anterior pituitary hormone deficiencies. In contrast, acute onset of isolated DI in the postpartum period is unusual. This patient presented at 33 weeks gestation with placental abruption, prompting a cesarean delivery of twins. Immediately after delivery, she developed severe DI. The DI could be controlled with the vasopressinase-resistant 1-deamino-8-D-arginine vasopressin (DDAVP), but not with arginine vasopressin (AVP), and it resolved within a few weeks. The aim of this study was to demonstrate that the postpartum DI in this patient was caused by the release of placental vasopressinase into the maternal bloodstream. Cells were transiently transfected with the AVP receptor 2 (AVPR2) and treated with either AVP or DDAVP in the presence of the patient's serum collected postpartum or 10 weeks after delivery. The response to the different treatments was evaluated by measuring the activity of a cAMP-responsive firefly luciferase reporter construct. The in vitro studies demonstrate that the patient's postpartum serum disrupts activation of the AVPR2 by AVP, but not by the vasopressinase-resistant DDAVP. Placental abruption can rarely be associated with acute postpartum DI caused by release of placental vasopressinase into the bloodstream. This clinical entity must be considered in patients with placental abruption and when evaluating patients presenting with DI after delivery.

5 CFR 362.407 - Withdrawal and readmission.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Withdrawal and readmission. 362.407 Section 362.407 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PATHWAYS PROGRAMS Presidential Management Fellows Program § 362.407 Withdrawal and readmission. (a) Withdrawal. (1...

5 CFR 362.407 - Withdrawal and readmission.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 1 2013-01-01 2013-01-01 false Withdrawal and readmission. 362.407 Section 362.407 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PATHWAYS PROGRAMS Presidential Management Fellows Program § 362.407 Withdrawal and readmission. (a) Withdrawal. (1...

Multidisciplinary Prerounding Meeting as a Continuous Quality Improvement Tool: Leveraging to Reduce Continuous Benzodiazepine Use at an Academic Medical Center.

PubMed

Flannery, Alexander H; Thompson Bastin, Melissa L; Montgomery-Yates, Ashley; Hook, Corrine; Cassity, Evan; Eaton, Phillip M; Morris, Peter E

2018-01-01

Evidence-based medicine often has many barriers to overcome prior to implementation in practice, hence the importance of continuous quality improvement. We report on a brief (≤10 minutes) multidisciplinary meeting prior to rounds to establish a dashboard for continuous quality improvement and studied the success of this meeting on a particular area of focus: continuous infusion benzodiazepine minimization. This was a prospective observational study of patients admitted to the medical intensive care unit (MICU) of a large academic medical center over a 4-month period. A morning multidisciplinary prerounding meeting was implemented to report on metrics required to establish a dashboard for MICU care for the previous 24 hours. Fellows and nurse practitioners on respective teams reported on key quality metrics and other important data related to patient census. Continuous benzodiazepines were tracked daily as the number of patients per team who had orders for a continuous benzodiazepine infusion. The aim of this report is to describe the development of the morning multidisciplinary prerounding meeting and its impact on continuous benzodiazepine use, along with associated clinical outcomes. The median number of patients prescribed a continuous benzodiazepine daily decreased over this time period and demonstrated a sustained reduction at 1 year. Furthermore, sedation scores improved, corresponding to a reduction in median duration of mechanical ventilation. The effectiveness of this intervention was mapped post hoc to conceptual models used in implementation science. A brief multidisciplinary meeting to review select data points prior to morning rounds establishes mechanisms for continuous quality improvement and may serve as a mediating factor for successful implementation when initiating and monitoring practice change in the ICU.

Conditional Switching of Vascular Endothelial Growth Factor (VEGF) Expression in Tumors: Induction of Endothelial Cell Shedding and Regression of Hemangioblastoma-Like Vessels by VEGF Withdrawal

NASA Astrophysics Data System (ADS)

Benjamin, Laura E.; Keshet, Eli

1997-08-01

We have recently shown that VEGF functions as a survival factor for newly formed vessels during developmental neovascularization, but is not required for maintenance of mature vessels. Reasoning that expanding tumors contain a significant fraction of newly formed and remodeling vessels, we examined whether abrupt withdrawal of VEGF will result in regression of preformed tumor vessels. Using a tetracycline-regulated VEGF expression system in xenografted C6 glioma cells, we showed that shutting off VEGF production leads to detachment of endothelial cells from the walls of preformed vessels and their subsequent death by apoptosis. Vascular collapse then leads to hemorrhages and extensive tumor necrosis. These results suggest that enforced withdrawal of vascular survival factors can be applied to target preformed tumor vasculature in established tumors. The system was also used to examine phenotypes resulting from over-expression of VEGF. When expression of the transfected VEGF cDNA was continuously ``on,'' tumors became hyper-vascularized with abnormally large vessels, presumably arising from excessive fusions. Tumors were significantly less necrotic, suggesting that necrosis in these tumors is the result of insufficient angiogenesis.

19 CFR 144.27 - Withdrawal from warehouse by transferee.

Code of Federal Regulations, 2012 CFR

2012-04-01

...; DEPARTMENT OF THE TREASURY (CONTINUED) WAREHOUSE AND REWAREHOUSE ENTRIES AND WITHDRAWALS Transfer of Right To Withdraw Merchandise from Warehouse § 144.27 Withdrawal from warehouse by transferee. At any time within... withdraw all or part of the merchandise covered by the transfer by filing any authorized kind of withdrawal...

19 CFR 144.27 - Withdrawal from warehouse by transferee.

Code of Federal Regulations, 2010 CFR

2010-04-01

...; DEPARTMENT OF THE TREASURY (CONTINUED) WAREHOUSE AND REWAREHOUSE ENTRIES AND WITHDRAWALS Transfer of Right To Withdraw Merchandise from Warehouse § 144.27 Withdrawal from warehouse by transferee. At any time within... withdraw all or part of the merchandise covered by the transfer by filing any authorized kind of withdrawal...

New mechanisms and perspectives in nicotine withdrawal

PubMed Central

Jackson, K.J.; Muldoon, P.P.; De Biasi, M.; Damaj, M.I.

2014-01-01

Diseases associated with tobacco use constitute a major health problem worldwide. Upon cessation of tobacco use, an unpleasant withdrawal syndrome occurs in dependent individuals. Avoidance of the negative state produced by nicotine withdrawal represents a motivational component that promotes continued tobacco use and relapse after smoking cessation. With the modest success rate of currently available smoking cessation therapies, understanding mechanisms involved in the nicotine withdrawal syndrome are crucial for developing successful treatments. Animal models provide a useful tool for examining neuroadaptative mechanisms and factors influencing nicotine withdrawal, including sex, age, and genetic factors. Such research has also identified an important role for nicotinic receptor subtypes in different aspects of the nicotine withdrawal syndrome (e.g., physical vs. affective signs). In addition to nicotinic receptors, the opioid and endocannabinoid systems, various signal transduction pathways, neurotransmitters, and neuropeptides have been implicated in the nicotine withdrawal syndrome. Animal studies have informed human studies of genetic variants and potential targets for smoking cessation therapies. Overall, the available literature indicates that the nicotine withdrawal syndrome is complex, and involves a range of neurobiological mechanisms. As research in nicotine withdrawal progresses, new pharmacological options for smokers attempting to quit can be identified, and treatments with fewer side effects that are better tailored to the unique characteristics of patients may become available. PMID:25433149

29 CFR 4219.12 - Employers liable upon mass withdrawal.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Employers liable upon mass withdrawal. 4219.12 Section 4219... Redetermination of Withdrawal Liability Upon Mass Withdrawal § 4219.12 Employers liable upon mass withdrawal. (a... experiences successive mass withdrawals, an employer that has been determined to be liable under this subpart...

29 CFR 4219.12 - Employers liable upon mass withdrawal.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 9 2011-07-01 2011-07-01 false Employers liable upon mass withdrawal. 4219.12 Section 4219... Redetermination of Withdrawal Liability Upon Mass Withdrawal § 4219.12 Employers liable upon mass withdrawal. (a... experiences successive mass withdrawals, an employer that has been determined to be liable under this subpart...

[Analysis of the binding capacity of the benzodiazepine site of gabaa receptor in mice C57BL/6 and BALB/C pretreated with anxiolytics].

PubMed

Iarkova, M A

2011-01-01

The level of specific 3H-flunitrazepam binding in synaptosomal membranes of C57BL/6 and BALB/c mice brain underwent to the stress of different types has been studied. Mild stress (Elevated Plus Maze) was shown to induce the decrease of benzodiazepine binding in BALB/c mice only, while the strong one (Exposure to a predator) was revealed to cause this decrease in both strains. Behavioral effects of different non-benzodiazepine drugs possessing anxiolytic properties (Afobazol, Ladasten and Noopept) was accompanied with the normalization of the level of benzodiazepine reception, reduced by the stress of both modalities.

29 CFR 1626.13 - Withdrawal of charge.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 4 2012-07-01 2012-07-01 false Withdrawal of charge. 1626.13 Section 1626.13 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION PROCEDURES-AGE DISCRIMINATION IN EMPLOYMENT ACT § 1626.13 Withdrawal of charge. Charging parties may request withdrawal of a...

29 CFR 1626.13 - Withdrawal of charge.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 4 2010-07-01 2010-07-01 false Withdrawal of charge. 1626.13 Section 1626.13 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION PROCEDURES-AGE DISCRIMINATION IN EMPLOYMENT ACT § 1626.13 Withdrawal of charge. Charging parties may request withdrawal of a...

29 CFR 1626.13 - Withdrawal of charge.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 4 2013-07-01 2013-07-01 false Withdrawal of charge. 1626.13 Section 1626.13 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION PROCEDURES-AGE DISCRIMINATION IN EMPLOYMENT ACT § 1626.13 Withdrawal of charge. Charging parties may request withdrawal of a...

29 CFR 1626.13 - Withdrawal of charge.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 4 2014-07-01 2014-07-01 false Withdrawal of charge. 1626.13 Section 1626.13 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION PROCEDURES-AGE DISCRIMINATION IN EMPLOYMENT ACT § 1626.13 Withdrawal of charge. Charging parties may request withdrawal of a...

29 CFR 1626.13 - Withdrawal of charge.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 4 2011-07-01 2011-07-01 false Withdrawal of charge. 1626.13 Section 1626.13 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION PROCEDURES-AGE DISCRIMINATION IN EMPLOYMENT ACT § 1626.13 Withdrawal of charge. Charging parties may request withdrawal of a...

21 CFR 870.1800 - Withdrawal-infusion pump.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Withdrawal-infusion pump. 870.1800 Section 870...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Diagnostic Devices § 870.1800 Withdrawal-infusion pump. (a) Identification. A withdrawal-infusion pump is a device designed to inject accurately drugs...

Pharmacological evaluation of an [(123)I] labelled imidazopyridine-3-acetamide for the study of benzodiazepine receptors.

PubMed

Mattner, Filomena; Mardon, Karine; Loc'h, Christian; Katsifis, Andrew

2006-06-13

In vitro binding of the iodinated imidazopyridine, N',N'-dimethyl-6-methyl-(4'-[(123)I]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide [(123)I]IZOL to benzodiazepine binding sites on brain cortex, adrenal and kidney membranes is reported. Saturation experiments showed that [(123)I]IZOL, bound to a single class of binding site (n(H)=0.99) on adrenal and kidney mitochondrial membranes with a moderate affinity (K(d)=30 nM). The density of binding sites was 22+/-6 and 1.2+/-0.4 pmol/mg protein on adrenal and kidney membranes, respectively. No specific binding was observed in mitochondrial-synaptosomal membranes of brain cortex. In biodistribution studies in rats, the highest uptake of [(123)I]IZOL was found 30 min post injection in adrenals (7.5% ID/g), followed by heart, kidney, lung (1% ID/g) and brain (0.12% ID/g), consistent with the distribution of peripheral benzodiazepine binding sites. Pre-administration of unlabelled IZOL and the specific PBBS drugs, PK 11195 and Ro 5-4864 significantly reduced the uptake of [(123)I]IZOL by 30% (p<0.05) in olfactory bulbs and by 51-86% (p<0.01) in kidney, lungs, heart and adrenals, while it increased by 30% to 50% (p<0.01) in the rest of the brain and the blood. Diazepam, a mixed CBR-PBBS drug, inhibited the uptake in kidney, lungs, heart, adrenals and olfactory bulbs by 32% to 44% (p<0.01) but with no effect on brain uptake and in blood concentration. Flumazenil, a central benzodiazepine drug and haloperidol (dopamine antagonist/sigma receptor drug) displayed no effect in [(123)I]IZOL in peripheral organs and in the brain. [(123)I]IZOL may deserve further development for imaging selectively peripheral benzodiazepine binding sites.

Barbiturates for the treatment of alcohol withdrawal syndrome: A systematic review of clinical trials.

PubMed

Mo, Yoonsun; Thomas, Michael C; Karras, George E

2016-04-01

To perform a systematic review of the clinical trials concerning the use of barbiturates for the treatment of acute alcohol withdrawal syndrome (AWS). A literature search of MEDLINE, EMBASE, and the Cochrane Library, together with a manual citation review was conducted. We selected English-language clinical trials (controlled and observational studies) evaluating the efficacy and safety of barbiturates compared with benzodiazepine (BZD) therapy for the treatment of AWS in the acute care setting. Data extracted from the included trials were duration of delirium, number of seizures, length of intensive care unit and hospital stay, cumulated doses of barbiturates and BZDs, and respiratory or cardiac complications. Seven studies consisting of 4 prospective controlled and 3 retrospective trials were identified. Results from all the included studies suggest that barbiturates alone or in combination with BZDs are at least as effective as BZDs in the treatment of AWS. Furthermore, barbiturates appear to have acceptable tolerability and safety profiles, which were similar to those of BZDs in patients with AWS. Although the evidence is limited, based on our findings, adding phenobarbital to a BZD-based regimen is a reasonable option, particularly in patients with BZD-refractory AWS. Copyright © 2015 Elsevier Inc. All rights reserved.

Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine.

PubMed

Perez, Erika; Quijano-Cardé, Natalia; De Biasi, Mariella

2015-09-01

Alcohol and nicotine are among the top causes of preventable death in the United States. Unfortunately, people who are dependent on alcohol are more likely to smoke than individuals in the general population. Similarly, smokers are more likely to abuse alcohol. Alcohol and nicotine codependence affects health in many ways and leads to poorer treatment outcomes in subjects who want to quit. This study examined the interaction of alcohol and nicotine during withdrawal and compared abstinence symptoms during withdrawal from one of the two drugs only vs both. Our results indicate that simultaneous withdrawal from alcohol and nicotine produces physical symptoms that are more severe and last longer than those experienced during withdrawal from one of the two drugs alone. In animals experiencing withdrawal after chronic ethanol treatment, acute nicotine exposure was sufficient to prevent abstinence symptoms. Similarly, symptoms were prevented when alcohol was injected acutely in mice undergoing nicotine withdrawal. These experiments provide evidence for the involvement of the nicotinic cholinergic system in alcohol withdrawal. Furthermore, the outcomes of intracranial microinfusions of mecamylamine, a nonselective nicotinic receptor antagonist, highlight a major role for the nicotinic receptors expressed in medial habenula and interpeduncular nucleus during withdrawal. Overall, the data support the notion that modulating the nicotinic cholinergic system might help to maintain long-term abstinence from alcohol.

Interrogation of Benzomalvin Biosynthesis Using Fungal Artificial Chromosomes with Metabolomic Scoring (FAC-MS): Discovery of a Benzodiazepine Synthase Activity.

PubMed

Clevenger, Kenneth D; Ye, Rosa; Bok, Jin Woo; Thomas, Paul M; Islam, Md Nurul; Miley, Galen P; Robey, Matthew T; Chen, Cynthia; Yang, KaHoua; Swyers, Michael; Wu, Edward; Gao, Peng; Wu, Chengcang C; Keller, Nancy P; Kelleher, Neil L

2018-03-20

The benzodiazepine benzomalvin A/D is a fungally derived specialized metabolite and inhibitor of the substance P receptor NK1, biosynthesized by a three-gene nonribosomal peptide synthetase cluster. Here, we utilize fungal artificial chromosomes with metabolomic scoring (FAC-MS) to perform molecular genetic pathway dissection and targeted metabolomics analysis to assign the in vivo role of each domain in the benzomalvin biosynthetic pathway. The use of FAC-MS identified the terminal cyclizing condensation domain as BenY-C T and the internal C-domains as BenZ-C 1 and BenZ-C 2 . Unexpectedly, we also uncovered evidence suggesting BenY-C T or a yet to be identified protein mediates benzodiazepine formation, representing the first reported benzodiazepine synthase enzymatic activity. This work informs understanding of what defines a fungal C T domain and shows how the FAC-MS platform can be used as a tool for in vivo analyses of specialized metabolite biosynthesis and for the discovery and dissection of new enzyme activities.

47 CFR 1.8 - Withdrawal of papers.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 47 Telecommunication 1 2011-10-01 2011-10-01 false Withdrawal of papers. 1.8 Section 1.8 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL PRACTICE AND PROCEDURE General Rules of Practice and Procedure General § 1.8 Withdrawal of papers. The granting of a request to dismiss or withdraw an...

47 CFR 1.8 - Withdrawal of papers.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 47 Telecommunication 1 2010-10-01 2010-10-01 false Withdrawal of papers. 1.8 Section 1.8 Telecommunication FEDERAL COMMUNICATIONS COMMISSION GENERAL PRACTICE AND PROCEDURE General Rules of Practice and Procedure General § 1.8 Withdrawal of papers. The granting of a request to dismiss or withdraw an...

Acute fatal posthypoxic leukoencephalopathy following benzodiazepine overdose: a case report and review of the literature.

PubMed

Aljarallah, Salman; Al-Hussain, Fawaz

2015-04-30

Among the rare neurological complications of substances of abuse is the selective cerebral white matter injury (leukoencephalopathy). Of which, the syndrome of delayed post hypoxic encephalopathy (DPHL) that follows an acute drug overdose, in addition to "chasing the dragon" toxicity which results from chronic heroin vapor inhalation remain the most commonly described syndromes of toxic leukoencephalopathy. These syndromes are reported in association with opioid use. There are very few cases in the literature that described leukoencephalopathy following benzodiazepines, especially with an acute and progressive course. In this paper, we present a patient who developed an acute severe fatal leukoencephalopathy following hypoxic coma and systemic shock induced by benzodiazepine overdose. A 19-year-old male was found comatose at home and brought to hospital in a deep coma, shock, hypoxia, and acidosis. Brain magnetic resonant imaging (MRI) revealed a strikingly selective white matter injury early in the course of the disease. The patient remained in a comatose state with no signs of neurologic recovery until he died few weeks later following an increase in the brain edema and herniation. Toxic leukoencephalopathy can occur acutely following an overdose of benzodiazepine and respiratory failure. This is unlike the usual cases of toxic leukoencephalopathy where there is a period of lucidity between the overdose and the development of white matter disease. Unfortunately, this syndrome remains of an unclear pathophysiology and with no successful treatment.

Quantifying the Clinical Significance of Cannabis Withdrawal

PubMed Central

Allsop, David J.; Copeland, Jan; Norberg, Melissa M.; Fu, Shanlin; Molnar, Anna; Lewis, John; Budney, Alan J.

2012-01-01

Background and Aims Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt. Methods and Results A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p = 0.0001). Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p = 0.03). Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p = 0.001). Conclusions Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes. PMID:23049760

Synthesis and in vivo evaluation of [11C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors.

PubMed

Dumont, Filip; Waterhouse, Rikki N; Montoya, Julie A; Mattner, Filomena; Katsifis, Andrew; Kegeles, Lawrence S; Laruelle, Marc

2003-05-01

The synthesis and evaluation of [(11)C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors, is reported herein. The reaction of desmethylzolpidem with [(11)C] methyl iodide afforded the title compound [(11)C]zolpidem in a yield of 19.19 +/- 3.23% in 41 +/- 2 min in specific activities of 0.995-1.19 Ci/micromol (1.115 +/- 0.105 Ci/micromol) (n = 3; decay corrected, EOB). The amount of radioactivity in the brain after tail vein injection in male Wistar rats was low, and the regional distribution was homogeneous and not consistent with the known distribution of the central benzodiazepine receptors. The frontal cortex/cerebellum ratio was not significantly greater than one (1.007 +/- 0.266 at 5 min) and did not increase from 5 to 40 min post-injection. A PET brain imaging study in one baboon confirmed the results obtained in rats. Therefore, it can be concluded that [(11)C]zolpidem is not a suitable tracer for in vivo visualization of central benzodiazepine receptors.

19 CFR 144.36 - Withdrawal for transportation.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 2 2010-04-01 2010-04-01 false Withdrawal for transportation. 144.36 Section 144... § 144.36 Withdrawal for transportation. (a) Time limit. Merchandise may be withdrawn from warehouse for transportation to another port of entry if withdrawal for consumption or exportation can be accomplished at the...

19 CFR 144.36 - Withdrawal for transportation.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 2 2013-04-01 2013-04-01 false Withdrawal for transportation. 144.36 Section 144... § 144.36 Withdrawal for transportation. (a) Time limit. Merchandise may be withdrawn from warehouse for transportation to another port of entry if withdrawal for consumption or exportation can be accomplished at the...

19 CFR 144.36 - Withdrawal for transportation.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 2 2011-04-01 2011-04-01 false Withdrawal for transportation. 144.36 Section 144... § 144.36 Withdrawal for transportation. (a) Time limit. Merchandise may be withdrawn from warehouse for transportation to another port of entry if withdrawal for consumption or exportation can be accomplished at the...

19 CFR 144.36 - Withdrawal for transportation.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 2 2012-04-01 2012-04-01 false Withdrawal for transportation. 144.36 Section 144... § 144.36 Withdrawal for transportation. (a) Time limit. Merchandise may be withdrawn from warehouse for transportation to another port of entry if withdrawal for consumption or exportation can be accomplished at the...

PTSD Symptom Severities, Interpersonal Traumas, and Benzodiazepines Are Associated with Substance-Related Problems in Trauma Patients

PubMed Central

Guina, Jeffrey; Nahhas, Ramzi W.; Goldberg, Adam J.; Farnsworth, Seth

2016-01-01

Background: Trauma is commonly associated with substance-related problems, yet associations between specific substances and specific posttraumatic stress disorder symptoms (PTSSs) are understudied. We hypothesized that substance-related problems are associated with PTSS severities, interpersonal traumas, and benzodiazepine prescriptions. Methods: Using a cross-sectional survey methodology in a consecutive sample of adult outpatients with trauma histories (n = 472), we used logistic regression to examine substance-related problems in general (primary, confirmatory analysis), as well as alcohol, tobacco, and illicit drug problems specifically (secondary, exploratory analyses) in relation to demographics, trauma type, PTSSs, and benzodiazepine prescriptions. Results: After adjusting for multiple testing, several factors were significantly associated with substance-related problems, particularly benzodiazepines (AOR = 2.78; 1.99 for alcohol, 2.42 for tobacco, 8.02 for illicit drugs), DSM-5 PTSD diagnosis (AOR = 1.92; 2.38 for alcohol, 2.00 for tobacco, 2.14 for illicit drugs), most PTSSs (especially negative beliefs, recklessness, and avoidance), and interpersonal traumas (e.g., assaults and child abuse). Conclusion: In this clinical sample, there were consistent and strong associations between several trauma-related variables and substance-related problems, consistent with our hypotheses. We discuss possible explanations and implications of these findings, which we hope will stimulate further research, and improve screening and treatment. PMID:27517964

Recommended Experimental Procedures for Evaluation of Abrupt Wing Stall Characteristics

NASA Technical Reports Server (NTRS)

Capone, F. J.; Hall, R. M.; Owens, D. B.; Lamar, J. E.; McMillin, S. N.

2003-01-01

This paper presents a review of the experimental program under the Abrupt Wing Stall (AWS) Program. Candidate figures of merit from conventional static tunnel tests are summarized and correlated with data obtained in unique free-to-roll tests. Where possible, free-to-roll results are also correlated with flight data. Based on extensive studies of static experimental figures of merit in the Abrupt Wing Stall Program for four different aircraft configurations, no one specific figure of merit consistently flagged a warning of potential lateral activity when actual activity was seen to occur in the free-to-roll experiments. However, these studies pointed out the importance of measuring and recording the root mean square signals of the force balance.

Estimated freshwater withdrawals in Washington, 2010

USGS Publications Warehouse

Lane, Ron C.; Welch, Wendy B.

2015-03-18

The amount of public- and self-supplied water used for domestic, irrigation, livestock, aquaculture, industrial, mining, and thermoelectric power was estimated for state, county, and eastern and western regions of Washington during calendar year 2010. Withdrawals of freshwater for offstream uses were estimated to be about 4,885 million gallons per day. The total estimated freshwater withdrawals for 2010 was approximately 15 percent less than the 2005 estimate because of decreases in irrigation and thermoelectric power withdrawals.

19 CFR 144.38 - Withdrawal for consumption.

Code of Federal Regulations, 2014 CFR

2014-04-01

... provided in § 141.61(e) of this chapter. (b) Withdrawal for exportation to Canada or Mexico. A withdrawal... withdrawal of cigars, cigarettes, or cigarette papers or tubes subject to internal revenue tax, the statement... will be finally due upon liquidation. (e) Permit for release of merchandise. When the duties and other...

19 CFR 144.38 - Withdrawal for consumption.

Code of Federal Regulations, 2011 CFR

2011-04-01

... provided in § 141.61(e) of this chapter. (b) Withdrawal for exportation to Canada or Mexico. A withdrawal... withdrawal of cigars, cigarettes, or cigarette papers or tubes subject to internal revenue tax, the statement... will be finally due upon liquidation. (e) Permit for release of merchandise. When the duties and other...

19 CFR 144.38 - Withdrawal for consumption.

Code of Federal Regulations, 2013 CFR

2013-04-01

... provided in § 141.61(e) of this chapter. (b) Withdrawal for exportation to Canada or Mexico. A withdrawal... withdrawal of cigars, cigarettes, or cigarette papers or tubes subject to internal revenue tax, the statement... will be finally due upon liquidation. (e) Permit for release of merchandise. When the duties and other...

19 CFR 144.38 - Withdrawal for consumption.

Code of Federal Regulations, 2012 CFR

2012-04-01

... provided in § 141.61(e) of this chapter. (b) Withdrawal for exportation to Canada or Mexico. A withdrawal... withdrawal of cigars, cigarettes, or cigarette papers or tubes subject to internal revenue tax, the statement... will be finally due upon liquidation. (e) Permit for release of merchandise. When the duties and other...

19 CFR 144.38 - Withdrawal for consumption.

Code of Federal Regulations, 2010 CFR

2010-04-01

... provided in § 141.61(e) of this chapter. (b) Withdrawal for exportation to Canada or Mexico. A withdrawal... withdrawal of cigars, cigarettes, or cigarette papers or tubes subject to internal revenue tax, the statement... will be finally due upon liquidation. (e) Permit for release of merchandise. When the duties and other...

5 CFR 1650.31 - Age-based withdrawals.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 5 Administrative Personnel 3 2012-01-01 2012-01-01 false Age-based withdrawals. 1650.31 Section... FUNDS FROM THE THRIFT SAVINGS PLAN In-Service Withdrawals § 1650.31 Age-based withdrawals. (a) A participant who has reached age 591/2 and who has not separated from Government employment is eligible to...

5 CFR 1650.31 - Age-based withdrawals.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Age-based withdrawals. 1650.31 Section... FUNDS FROM THE THRIFT SAVINGS PLAN In-Service Withdrawals § 1650.31 Age-based withdrawals. (a) A participant who has reached age 591/2 and who has not separated from Government employment is eligible to...

5 CFR 1650.31 - Age-based withdrawals.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 5 Administrative Personnel 3 2013-01-01 2013-01-01 false Age-based withdrawals. 1650.31 Section... FUNDS FROM THE THRIFT SAVINGS PLAN In-Service Withdrawals § 1650.31 Age-based withdrawals. (a) A participant who has reached age 591/2 and who has not separated from Government service is eligible to...

5 CFR 1650.31 - Age-based withdrawals.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 5 Administrative Personnel 3 2014-01-01 2014-01-01 false Age-based withdrawals. 1650.31 Section... FUNDS FROM THE THRIFT SAVINGS PLAN In-Service Withdrawals § 1650.31 Age-based withdrawals. (a) A participant who has reached age 591/2 and who has not separated from Government service is eligible to...

5 CFR 1650.31 - Age-based withdrawals.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 3 2011-01-01 2011-01-01 false Age-based withdrawals. 1650.31 Section... FUNDS FROM THE THRIFT SAVINGS PLAN In-Service Withdrawals § 1650.31 Age-based withdrawals. (a) A participant who has reached age 591/2 and who has not separated from Government employment is eligible to...

Acquisition of an Underway CTD System for the Flow Encountering Abrupt Topography DRI

DTIC Science & Technology

2015-09-30

Acquisition of an Underway CTD System for the Flow Encountering Abrupt Topography DRI T. M. Shaun Johnston Scripps Institution of Oceanography...westward flow in the North Equatorial Current (NEC) encounters tall, steep, submarine topography and islands. During the Flow Encountering Abrupt... Topography (FLEAT) DRI, investigators will determine: • Whether appreciable energy/momentum is lost from the large-scale NEC flow to smaller scales and

Comparative Evaluation of Partial α2 -Adrenoceptor Agonist and Pure α2 -Adrenoceptor Antagonist on the Behavioural Symptoms of Withdrawal after Chronic Alcohol Administration in Mice.

PubMed

Arora, Shivani; Vohora, Divya

2016-08-01

As an addictive drug, alcohol produces withdrawal symptoms if discontinued abruptly after chronic use. Clonidine (CLN), a partial α2 -adrenergic agonist, and mirtazapine (MRT), an antagonist of α2 -adrenoceptor, both clinically aid alcohol withdrawal. Considering different mechanisms of action of the two drugs, this study was designed to see how far these two mechanistically different drugs differ in their ability to decrease the severity of ethanol withdrawal syndrome. The effect of CLN and MRT on ethanol withdrawal-induced anxiety, depression and memory impairment was analysed using EPM, FST and PAR tests, respectively. Animals received distilled water, ethanol and/or either of the drugs (CLN and MRT) in different doses. Relapse to alcohol use was analysed by CPP test. Animals received ethanol as a conditioning drug and distilled water, CLN or MRT as test drug. CLN and MRT both alleviated anxiety in a dose-dependent manner. MRT (4 mg/kg) was more effective than CLN (0.1 mg/kg) in ameliorating the anxiogenic effect of alcohol withdrawal. However, CLN treatment increased depression. It significantly decreased swimming time and increased immobility time, whereas MRT treatment decreased immobility time and increased climbing and swimming time during abstinence. The effect was dose dependent for both drugs. The results of PAR test show that CLN treatment worsens working memory. Significant increase in SDE and TSZ and decrease in SDL were observed in CLN-treated animals. MRT treatment, on the other hand, improved working memory at both doses. Further, both CLN and MRT alleviated craving. A significant decrease in time spent in the ethanol-paired chamber was seen. MRT treatment at both doses showed better effect than CLN in preventing the development of preference in CPP test. These findings indicate a potential therapeutic use and better profile of mirtazapine over clonidine in improving memory, as well as in alleviating depression, anxiety and craving associated

The resilience of postglacial hunter-gatherers to abrupt climate change.

PubMed

Blockley, Simon; Candy, Ian; Matthews, Ian; Langdon, Pete; Langdon, Cath; Palmer, Adrian; Lincoln, Paul; Abrook, Ashley; Taylor, Barry; Conneller, Chantal; Bayliss, Alex; MacLeod, Alison; Deeprose, Laura; Darvill, Chris; Kearney, Rebecca; Beavan, Nancy; Staff, Richard; Bamforth, Michael; Taylor, Maisie; Milner, Nicky

2018-05-01

Understanding the resilience of early societies to climate change is an essential part of exploring the environmental sensitivity of human populations. There is significant interest in the role of abrupt climate events as a driver of early Holocene human activity, but there are very few well-dated records directly compared with local climate archives. Here, we present evidence from the internationally important Mesolithic site of Star Carr showing occupation during the early Holocene, which is directly compared with a high-resolution palaeoclimate record from neighbouring lake beds. We show that-once established-there was intensive human activity at the site for several hundred years when the community was subject to multiple, severe, abrupt climate events that impacted air temperatures, the landscape and the ecosystem of the region. However, these results show that occupation and activity at the site persisted regardless of the environmental stresses experienced by this society. The Star Carr population displayed a high level of resilience to climate change, suggesting that postglacial populations were not necessarily held hostage to the flickering switch of climate change. Instead, we show that local, intrinsic changes in the wetland environment were more significant in determining human activity than the large-scale abrupt early Holocene climate events.

Response of seafloor ecosystems to abrupt global climate change

PubMed Central

Moffitt, Sarah E.; Hill, Tessa M.; Roopnarine, Peter D.; Kennett, James P.

2015-01-01

Anthropogenic climate change is predicted to decrease oceanic oxygen (O2) concentrations, with potentially significant effects on marine ecosystems. Geologically recent episodes of abrupt climatic warming provide opportunities to assess the effects of changing oxygenation on marine communities. Thus far, this knowledge has been largely restricted to investigations using Foraminifera, with little being known about ecosystem-scale responses to abrupt, climate-forced deoxygenation. We here present high-resolution records based on the first comprehensive quantitative analysis, to our knowledge, of changes in marine metazoans (Mollusca, Echinodermata, Arthropoda, and Annelida; >5,400 fossils and trace fossils) in response to the global warming associated with the last glacial to interglacial episode. The molluscan archive is dominated by extremophile taxa, including those containing endosymbiotic sulfur-oxidizing bacteria (Lucinoma aequizonatum) and those that graze on filamentous sulfur-oxidizing benthic bacterial mats (Alia permodesta). This record, from 16,100 to 3,400 y ago, demonstrates that seafloor invertebrate communities are subject to major turnover in response to relatively minor inferred changes in oxygenation (>1.5 to <0.5 mL⋅L−1 [O2]) associated with abrupt (<100 y) warming of the eastern Pacific. The biotic turnover and recovery events within the record expand known rates of marine biological recovery by an order of magnitude, from <100 to >1,000 y, and illustrate the crucial role of climate and oceanographic change in driving long-term successional changes in ocean ecosystems. PMID:25825727

Response of seafloor ecosystems to abrupt global climate change

NASA Astrophysics Data System (ADS)

Moffitt, Sarah E.; Hill, Tessa M.; Roopnarine, Peter D.; Kennett, James P.

2015-04-01

Anthropogenic climate change is predicted to decrease oceanic oxygen (O2) concentrations, with potentially significant effects on marine ecosystems. Geologically recent episodes of abrupt climatic warming provide opportunities to assess the effects of changing oxygenation on marine communities. Thus far, this knowledge has been largely restricted to investigations using Foraminifera, with little being known about ecosystem-scale responses to abrupt, climate-forced deoxygenation. We here present high-resolution records based on the first comprehensive quantitative analysis, to our knowledge, of changes in marine metazoans (Mollusca, Echinodermata, Arthropoda, and Annelida; >5,400 fossils and trace fossils) in response to the global warming associated with the last glacial to interglacial episode. The molluscan archive is dominated by extremophile taxa, including those containing endosymbiotic sulfur-oxidizing bacteria (Lucinoma aequizonatum) and those that graze on filamentous sulfur-oxidizing benthic bacterial mats (Alia permodesta). This record, from 16,100 to 3,400 y ago, demonstrates that seafloor invertebrate communities are subject to major turnover in response to relatively minor inferred changes in oxygenation (>1.5 to <0.5 mLṡL-1 [O2]) associated with abrupt (<100 y) warming of the eastern Pacific. The biotic turnover and recovery events within the record expand known rates of marine biological recovery by an order of magnitude, from <100 to >1,000 y, and illustrate the crucial role of climate and oceanographic change in driving long-term successional changes in ocean ecosystems.

Nicotine Withdrawal Induces Neural Deficits in Reward Processing.

PubMed

Oliver, Jason A; Evans, David E; Addicott, Merideth A; Potts, Geoffrey F; Brandon, Thomas H; Drobes, David J

2017-06-01

Nicotine withdrawal reduces neurobiological responses to nonsmoking rewards. Insight into these reward deficits could inform the development of targeted interventions. This study examined the effect of withdrawal on neural and behavioral responses during a reward prediction task. Smokers (N = 48) attended two laboratory sessions following overnight abstinence. Withdrawal was manipulated by having participants smoke three regular nicotine (0.6 mg yield; satiation) or very low nicotine (0.05 mg yield; withdrawal) cigarettes. Electrophysiological recordings of neural activity were obtained while participants completed a reward prediction task that involved viewing four combinations of predictive and reward-determining stimuli: (1) Unexpected Reward; (2) Predicted Reward; (3) Predicted Punishment; (4) Unexpected Punishment. The task evokes a medial frontal negativity that mimics the phasic pattern of dopaminergic firing in ventral tegmental regions associated with reward prediction errors. Nicotine withdrawal decreased the amplitude of the medial frontal negativity equally across all trial types (p < .001). Exploratory analyses indicated withdrawal increased time to initiate the next trial following unexpected punishment trials (p < .001) and response time on reward trials during withdrawal was positively related to nicotine dependence (p < .001). Nicotine withdrawal had equivocal impact across trial types, suggesting reward processing deficits are unlikely to stem from changes in phasic dopaminergic activity during prediction errors. Effects on tonic activity may be more pronounced. Pharmacological interventions directly targeting the dopamine system and behavioral interventions designed to increase reward motivation and responsiveness (eg, behavioral activation) may aid in mitigating withdrawal symptoms and potentially improving smoking cessation outcomes. Findings from this study indicate nicotine withdrawal impacts reward processing signals that are observable in

Abrupt Climate Change: the View from the Past, the Present and the Future

NASA Astrophysics Data System (ADS)

White, J. W. C.

2014-12-01

Climate is changing as humans put more and more greenhouse gases into the atmosphere. With CO2 levels today around 400ppm, we are clearly committed to far more climate change, both in the near term, and well beyond our children's future. A key question is how that change will occur. Abrupt climate changes are those that exceed our expectations, preparedness, and ability to adapt. Such changes challenge us economically, physically, and socially. This talk will draw upon results from ice core research over the past twenty years, as well as a new NRC report on abrupt climate change in order to address abrupt change, as seen in the past in ice cores, as seen today in key environmental systems upon which humans depend, and what is may be coming in the future.

Temporal characteristics of stress-induced decrease in benzodiazepine reception in C57BL/6 and BALB/c mice.

PubMed

Yarkova, M A; Seredenin, S B

2014-10-01

We studied the duration of the drop of specific (3)H-flunitrazepam binding by synaptosomal membranes from the brain of C57Bl/6 and BALB/c mice after open-field and "contact with predator" tests. It was found that reduced benzodiazepine reception in BALB/c mice after open-field test persisted for 1.5 h, but no changes of this parameter were found in C57Bl/6 mice. After contact with predator, the binding capacity of the benzodiazepine site of GABAA receptor was reduced for 8 h in BALB/c mice and for 24 h in C57Bl/6 mice.

Abrupt change of Antarctic moisture origin at the end of Termination II

PubMed Central

Masson-Delmotte, V.; Stenni, B.; Blunier, T.; Cattani, O.; Chappellaz, J.; Cheng, H.; Dreyfus, G.; Edwards, R. L.; Falourd, S.; Govin, A.; Kawamura, K.; Johnsen, S. J.; Jouzel, J.; Landais, A.; Lemieux-Dudon, B.; Lourantou, A.; Marshall, G.; Minster, B.; Mudelsee, M.; Pol, K.; Röthlisberger, R.; Selmo, E.; Waelbroeck, C.

2010-01-01

The deuterium excess of polar ice cores documents past changes in evaporation conditions and moisture origin. New data obtained from the European Project for Ice Coring in Antarctica Dome C East Antarctic ice core provide new insights on the sequence of events involved in Termination II, the transition between the penultimate glacial and interglacial periods. This termination is marked by a north–south seesaw behavior, with first a slow methane concentration rise associated with a strong Antarctic temperature warming and a slow deuterium excess rise. This first step is followed by an abrupt north Atlantic warming, an abrupt resumption of the East Asian summer monsoon, a sharp methane rise, and a CO2 overshoot, which coincide within dating uncertainties with the end of Antarctic optimum. Here, we show that this second phase is marked by a very sharp Dome C centennial deuterium excess rise, revealing abrupt reorganization of atmospheric circulation in the southern Indian Ocean sector. PMID:20566887

20 CFR 408.355 - Can you withdraw your application?

Code of Federal Regulations, 2010 CFR

2010-04-01

... Section 408.355 Employees' Benefits SOCIAL SECURITY ADMINISTRATION SPECIAL BENEFITS FOR CERTAIN WORLD WAR II VETERANS Filing Applications Withdrawal of Application § 408.355 Can you withdraw your application? (a) Request for withdrawal filed before a determination is made. You may withdraw your application...

46 CFR 390.10 - Nonqualified withdrawals.

Code of Federal Regulations, 2011 CFR

2011-10-01

... expenditure is incident to new and advanced ship design, machinery and equipment; (iii) The withdrawal would be a qualified withdrawal except for the fact that there is no tax basis left that can be reduced; or...

46 CFR 390.10 - Nonqualified withdrawals.

Code of Federal Regulations, 2010 CFR

2010-10-01

... expenditure is incident to new and advanced ship design, machinery and equipment; (iii) The withdrawal would be a qualified withdrawal except for the fact that there is no tax basis left that can be reduced; or...

The Use of Benzodiazepine Receptor Agonists and Risk of Respiratory Failure in Patients with Chronic Obstructive Pulmonary Disease: A Nationwide Population-Based Case-Control Study

PubMed Central

Chen, Su-Jung; Yeh, Chiu-Mei; Chao, Tze-Fan; Liu, Chia-Jen; Wang, Kang-Ling; Chen, Tzeng-Ji; Chou, Pesus; Wang, Fu-Der

2015-01-01

Study Objectives: Insomnia is prevalent in patients with chronic obstructive pulmonary disease (COPD), and benzodiazepine receptor agonists (BZRAs) are the most commonly used drugs despite their adverse effects on respiratory function. The aim of this study was to investigate whether the use of BZRAs was associated with an increased risk of respiratory failure (RF) in COPD patients. Design: Matched case-control study. Setting: National Health Insurance Research Database (NHIRD) in Taiwan. Participants: The case group consisted of 2,434 COPD patients with RF, and the control group consisted of 2,434 COPD patients without RF, matched for age, sex, and date of enrollment. Measurements and Results: Exposure to BZRAs during the 180-day period preceding the index date was analyzed and compared in the case and control groups. Conditional logistic regression was performed, and the use of BZRAs was associated with an increased risk of RF (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.14–2.13). In subgroup analysis, we found that the benzodiazepine (BZD) users had a higher risk of RF (aOR 1.58, 95% CI 1.14–2.20), whereas the risk in non-benzodiazepine (non-BZD) users was insignificant (aOR 0.85, 95% CI 0.51–1.44). A greater than 2-fold increase in risk was found in those who received two or more kinds of BZRAs and those using a combination of BZD and non-BZD medications. Conclusions: The use of benzodiazepine receptor agonists was a significant risk factor for respiratory failure in patients with chronic obstructive pulmonary disease (COPD). Compared to benzodiazepine, the prescription of non-benzodiazepine may be safer for the management of insomnia in COPD patients. Citation: Chen SJ, Yeh CM, Chao TF, Liu CJ, Wang KL, Chen TJ, Chou P, Wang FD. The use of benzodiazepine receptor agonists and risk of respiratory failure in patients with chronic obstructive pulmonary disease: a nationwide population-based case-control study. SLEEP 2015;38(7):1045–1050

Severity of Withdrawal Symptoms, Plasma Oxytocin Levels, and Treatment Outcome in Heroin Users Undergoing Acute Withdrawal.

PubMed

Nikolaou, Kakia; Kapoukranidou, Dorothea; Ndungu, Samuel; Floros, Georgios; Kovatsi, Leda

2017-01-01

Pre-clinical studies show that, following chronic opioid exposure, oxytocin neurons exhibit over-excitation upon withdrawal, causing an increase in oxytocin brain and plasma levels. Relevant clinical data on humans are scarce. This study investigates the opioid withdrawal stress effect on oxytocin plasma levels in humans. We evaluated 57 male chronic heroin users in a residential detoxification program. We determined plasma oxytocin levels by ELISA and measured the stress effects of withdrawal using the COWS scale for opioid withdrawal, the VAS scale for craving, and the Hamilton scales for anxiety and depression on the second day of admission. Out of the 57 patients enrolled in the study, 27 completed the 21-day program, while the remaining 30 dropped out prior to completion. Plasma oxytocin levels were significantly higher in those individuals who dropped out than in those who completed the program. Participants who dropped out at some stage scored higher in the COWS, VAS-Craving, and Hamilton-anxiety scales, indicating a higher stress and explaining the higher oxytocin levels. In addition, plasma oxytocin levels correlated positively with the scores achieved in the COWS and Hamilton-anxiety scales. Higher withdrawal stress levels are associated with higher plasma oxytocin levels and early treatment discharge.

8 CFR 235.4 - Withdrawal of application for admission.

Code of Federal Regulations, 2010 CFR

2010-01-01

... right to withdraw his or her application for admission. Permission to withdraw an application for... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Withdrawal of application for admission... INSPECTION OF PERSONS APPLYING FOR ADMISSION § 235.4 Withdrawal of application for admission. The Attorney...

Estimated Freshwater Withdrawals in Oklahoma, 1990

USGS Publications Warehouse

Lurry, Dee L.; Tortorelli, Robert L.

1996-01-01

This report presents 1990 freshwater withdrawal estimates for Oklahoma by source and category. Withdrawal source is either ground water or surface water. Withdrawal categories include: irrigation, water supply, livestock, thermoelectric-power generation, domestic and commercial, and industrial and mining. Withdrawal data are aggregated by county, major aquifer, and principal river basin. Only the four major categories of irrigation, water supply, livestock, and thermoelectric-power generation are illustrated in this report, although data for all categories are tabulated. The U.S. Geological Survey (USGS) established the National Water-Use Information Program in 1977 to collect uniform, current, and reliable information on water use. The Oklahoma District of the USGS and the Oklahoma Water Resources Board participate in a cooperative program to collect and publish water-use information for Oklahoma. Data contained in this report were made available through the cooperative program.

The Atlantic Meridional Overturning Circulation and Abrupt Climate Change.

PubMed

Lynch-Stieglitz, Jean

2017-01-03

Abrupt changes in climate have occurred in many locations around the globe over the last glacial cycle, with pronounced temperature swings on timescales of decades or less in the North Atlantic. The global pattern of these changes suggests that they reflect variability in the Atlantic meridional overturning circulation (AMOC). This review examines the evidence from ocean sediments for ocean circulation change over these abrupt events. The evidence for changes in the strength and structure of the AMOC associated with the Younger Dryas and many of the Heinrich events is strong. Although it has been difficult to directly document changes in the AMOC over the relatively short Dansgaard-Oeschger events, there is recent evidence supporting AMOC changes over most of these oscillations as well. The lack of direct evidence for circulation changes over the shortest events leaves open the possibility of other driving mechanisms for millennial-scale climate variability.

The Use of Benzodiazepine Receptor Agonists and Risk of Respiratory Failure in Patients with Chronic Obstructive Pulmonary Disease: A Nationwide Population-Based Case-Control Study.

PubMed

Chen, Su-Jung; Yeh, Chiu-Mei; Chao, Tze-Fan; Liu, Chia-Jen; Wang, Kang-Ling; Chen, Tzeng-Ji; Chou, Pesus; Wang, Fu-Der

2015-07-01

Insomnia is prevalent in patients with chronic obstructive pulmonary disease (COPD), and benzodiazepine receptor agonists (BZRAs) are the most commonly used drugs despite their adverse effects on respiratory function. The aim of this study was to investigate whether the use of BZRAs was associated with an increased risk of respiratory failure (RF) in COPD patients. Matched case-control study. National Health Insurance Research Database (NHIRD) in Taiwan. The case group consisted of 2,434 COPD patients with RF, and the control group consisted of 2,434 COPD patients without RF, matched for age, sex, and date of enrollment. Exposure to BZRAs during the 180-day period preceding the index date was analyzed and compared in the case and control groups. Conditional logistic regression was performed, and the use of BZRAs was associated with an increased risk of RF (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.14-2.13). In subgroup analysis, we found that the benzodiazepine (BZD) users had a higher risk of RF (aOR 1.58, 95% CI 1.14-2.20), whereas the risk in non-benzodiazepine (non-BZD) users was insignificant (aOR 0.85, 95% CI 0.51-1.44). A greater than 2-fold increase in risk was found in those who received two or more kinds of BZRAs and those using a combination of BZD and non-BZD medications. The use of benzodiazepine receptor agonists was a significant risk factor for respiratory failure in patients with chronic obstructive pulmonary disease (COPD). Compared to benzodiazepine, the prescription of non-benzodiazepine may be safer for the management of insomnia in COPD patients. © 2015 Associated Professional Sleep Societies, LLC.

Acceptable Risk Analysis for Abrupt Environmental Pollution Accidents in Zhangjiakou City, China.

PubMed

Du, Xi; Zhang, Zhijiao; Dong, Lei; Liu, Jing; Borthwick, Alistair G L; Liu, Renzhi

2017-04-20

Abrupt environmental pollution accidents cause considerable damage worldwide to the ecological environment, human health, and property. The concept of acceptable risk aims to answer whether or not a given environmental pollution risk exceeds a societally determined criterion. This paper presents a case study on acceptable environmental pollution risk conducted through a questionnaire survey carried out between August and October 2014 in five representative districts and two counties of Zhangjiakou City, Hebei Province, China. Here, environmental risk primarily arises from accidental water pollution, accidental air pollution, and tailings dam failure. Based on 870 valid questionnaires, demographic and regional differences in public attitudes towards abrupt environmental pollution risks were analyzed, and risk acceptance impact factors determined. The results showed females, people between 21-40 years of age, people with higher levels of education, public servants, and people with higher income had lower risk tolerance. People with lower perceived risk, low-level risk knowledge, high-level familiarity and satisfaction with environmental management, and without experience of environmental accidents had higher risk tolerance. Multiple logistic regression analysis indicated that public satisfaction with environmental management was the most significant factor in risk acceptance, followed by perceived risk of abrupt air pollution, occupation, perceived risk of tailings dam failure, and sex. These findings should be helpful to local decision-makers concerned with environmental risk management (e.g., selecting target groups for effective risk communication) in the context of abrupt environmental accidents.

Acceptable Risk Analysis for Abrupt Environmental Pollution Accidents in Zhangjiakou City, China

PubMed Central

Du, Xi; Zhang, Zhijiao; Dong, Lei; Liu, Jing; Borthwick, Alistair G. L.; Liu, Renzhi

2017-01-01

Abrupt environmental pollution accidents cause considerable damage worldwide to the ecological environment, human health, and property. The concept of acceptable risk aims to answer whether or not a given environmental pollution risk exceeds a societally determined criterion. This paper presents a case study on acceptable environmental pollution risk conducted through a questionnaire survey carried out between August and October 2014 in five representative districts and two counties of Zhangjiakou City, Hebei Province, China. Here, environmental risk primarily arises from accidental water pollution, accidental air pollution, and tailings dam failure. Based on 870 valid questionnaires, demographic and regional differences in public attitudes towards abrupt environmental pollution risks were analyzed, and risk acceptance impact factors determined. The results showed females, people between 21–40 years of age, people with higher levels of education, public servants, and people with higher income had lower risk tolerance. People with lower perceived risk, low-level risk knowledge, high-level familiarity and satisfaction with environmental management, and without experience of environmental accidents had higher risk tolerance. Multiple logistic regression analysis indicated that public satisfaction with environmental management was the most significant factor in risk acceptance, followed by perceived risk of abrupt air pollution, occupation, perceived risk of tailings dam failure, and sex. These findings should be helpful to local decision-makers concerned with environmental risk management (e.g., selecting target groups for effective risk communication) in the context of abrupt environmental accidents. PMID:28425956

Benzodiazepine-site pharmacology on GABAA receptors in histaminergic neurons.

PubMed

May, A C; Fleischer, W; Kletke, O; Haas, H L; Sergeeva, O A

2013-09-01

The histaminergic tuberomamillary nucleus (TMN) of the posterior hypothalamus controls the cognitive aspects of vigilance which is reduced by common sedatives and anxiolytics. The receptors targeted by these drugs in histaminergic neurons are unknown. TMN neurons express nine different subunits of the GABAA receptor (GABAA R) with three α- (α1, α2 and α5) and two γ- (γ1, γ 2) subunits, which confer different pharmacologies of the benzodiazepine-binding site. We investigated the actions of zolpidem, midazolam, diazepam, chlordiazepoxide, flumazenil (Ro15-1788) and methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) in TMN neurons using mouse genetics, electrophysiological and molecular biological methods. We find the sensitivity of GABAA R to zolpidem, midazolam and DMCM significantly reduced in TMN neurons from γ2F77I mice, but modulatory activities of diazepam, chlordiazepoxide and flumazenil not affected. Potencies and efficacies of these compounds are in line with the dominance of α2- and α1-subunit containing receptors associated with γ2- or γ1-subunits. Functional expression of the γ1-subunit is supported by siRNA-based knock-down experiments in γ2F77I mice. GABAA R of TMN neurons respond to a variety of common sedatives with a high affinity binding site (γ2F77I) involved. The γ1-subunit likely contributes to the action of common sedatives in TMN neurons. This study is relevant for understanding the role of neuronal histamine and benzodiazepines in disorders of sleep and metabolism. © 2013 The British Pharmacological Society.

Allosteric modulation by benzodiazepines of GABA-gated chloride channels of an identified insect motor neurone.

PubMed

Buckingham, Steven D; Higashino, Yoshiaki; Sattelle, David B

2009-11-01

The actions of benzodiazepines were studied on the responses to GABA of the fast coxal depressor (D(f)) motor neurone of the cockroach, Periplaneta americana. Ro5-4864, diazepam and clonazepam were investigated. Responses to GABA receptors were enhanced by both Ro5-4864 and diazepam, whereas clonazepam, a potent-positive allosteric modulator of human GABA(A) receptors, was ineffective on the native insect GABA receptors of the D(f) motor neurone. Thus, clear pharmacological differences exist between insect and mammalian native GABA-gated chloride channels with respect to the actions of benzodiazepines. The results enhance our understanding of invertebrate GABA-gated chloride channels which have recently proved important in (a) comparative studies aimed at identifying human allosteric drug-binding sites and (b) understanding the actions of compounds used to control ectoparasites and insect crop pests.

Social Withdrawal in Childhood

PubMed Central

Rubin, Kenneth H.; Coplan, Robert J.; Bowker, Julie C.

2013-01-01

Socially withdrawn children frequently refrain from social activities in the presence of peers. The lack of social interaction in childhood may result from a variety of causes, including social fear and anxiety or a preference for solitude. From early childhood through to adolescence, socially withdrawn children are concurrently and predictively at risk for a wide range of negative adjustment outcomes, including socio-emotional difficulties (e.g., anxiety, low self-esteem, depressive symptoms, and internalizing problems), peer difficulties (e.g., rejection, victimization, poor friendship quality), and school difficulties (e.g., poor-quality teacher-child relationships, academic difficulties, school avoidance). The goals of the current review are to (a) provide some definitional, theoretical, and methodological clarity to the complex array of terms and constructs previously employed in the study of social withdrawal; (b) examine the predictors, correlates, and consequences of child and early-adolescent social withdrawal; and (c) present a developmental framework describing pathways to and from social withdrawal in childhood. PMID:18851686

Inpatient alcohol withdrawal syndrome.

PubMed

Monte-Secades, R; Rabuñal-Rey, R; Guerrero-Sande, H

2015-03-01

A 55-year-old man was admitted for a femur fracture; an alcohol fetor was noted on admission. The following day, the patient began to experience tremors and nervousness. Intravenous haloperidol was administered. Shortly afterwards, the patient experienced two generalized seizures and then began to experience delirium and uncontrollable agitation. The patient was diagnosed with alcohol withdrawal syndrome; high doses of intravenous midazolam were prescribed and infused. A few hours later, the patient presented signs of respiratory depression, requiring a transfer to the intensive care unit. After a review of the medical history, it was determined that the patient had been admitted on 3 previous occasions due to alcohol withdrawal and had progressed to delirium tremens after experiencing seizures. Can the risk of alcohol withdrawal syndrome and the need for prophylactic treatment be assessed on admission? Were appropriate monitoring and treatment measures employed? Would it have been possible to change his outcome? Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Preliminary results of a withdrawal and detoxification therapeutic regimen in patients with probable chronic migraine and probable medication overuse headache.

PubMed

Trucco, Marco; Meineri, Piero; Ruiz, Luigi

2005-09-01

Chronic migraine (CM) is an invalidating condition affecting a significant population of headache sufferers, frequently associated with medication overuse headache (MOH). Controlled trials and guidelines for the treatment of MOH are currently not available. We studied the efficacy of a therapeutic regimen for the withdrawal of the overused drug and detoxification in a sample of patients suffering from probable CM and probable MOH during admission in eight hospitals of Piemonte-Liguria-Valle d'Aosta. Fifty patients, 42 females (84%) and 8 males (16%), mean age at observation 50.66+/-13.08 years, affected by probable CM and daily medication overuse following IHS diagnostic criteria were treated as inpatients or in a day hospital. Headache index (HI) and daily drug intake (DDI) were used for evaluating the severity of headache and medication overuse. The patients were treated by abrupt discontinuation of the overused drug and by a therapeutic protocol including i.v. hydration, dexamethasone, metoclopramide and benzodiazepines for 7-10 days. Prophylactic medication was started immediately after admission. Analgesics or triptans were used under medical control only in cases of severe rebound headache. Diagnostic protocol included routine blood tests (at admission and at discharge), dosage of B12 and folic acid. Patients underwent follow-up controls one, three and six months after discharge. The initial diagnosis was probable CM in almost all patients included in the study (41 patients); in nine patients the diagnosis was not specified (coded only as CDH). The overused medications were simple analgesics in 17 cases (34%), combination analgesics in 19 cases (38%), triptans alone or with analgesics in 13 cases (26%) and ergotamine in 2 cases (4%). We collected data from 39 patients at first follow-up (1 month), 32 after 3 months and 14 after 6 months. Mean HI was 0.91 at admission, 0.22 at discharge, 0.38 after 30 days, 0.46 after 3 months and 0.48 after 6 months. Mean DDI

29 CFR 1956.24 - Procedures for withdrawal of approval.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 9 2010-07-01 2010-07-01 false Procedures for withdrawal of approval. 1956.24 Section 1956..., Change, Evaluation and Withdrawal of Approval Procedures § 1956.24 Procedures for withdrawal of approval... withdrawal of approval of plans approved under this part 1956, except that (because these plans, as do public...

THE ROLE OF DELTA OPIOID RECEPTORS IN THE ANXIOLYTIC ACTIONS OF BENZODIAZEPINES

PubMed Central

Primeaux, Stefany D.; Wilson, Steven P.; McDonald, Alexander J.; Mascagni, Franco; Wilson, Marlene A.

2007-01-01

The anxiolytic effects of benzodiazepines appear to involve opioid processes in the amygdala. In previous experiments, overexpression of enkephalin in the amygdala enhanced the anxiolytic actions of the benzodiazepine agonist diazepam in the elevated plus maze. The effects of systemically administered diazepam are also blocked by injections of naltrexone into the central nucleus of the amygdala. The current studies investigated the role of delta opioid receptors in the anxiety-related effects of diazepam. Three days following bilateral stereotaxic injections of viral vectors containing cDNA encoding proenkephalin or β-galactosidase (control vector), the delta opioid receptor antagonist naltrindole (10 mg/kg, s.c.) attenuated the enhanced anxiolytic effects of 1–2 mg/kg diazepam in rats overexpressing preproenkephalin in the amygdala. Despite this effect, naltrindole failed to attenuate the anxiolytic action of higher diazepam doses (3 mg/kg) in animals with normal amygdalar enkephalin expression. Similarly, the mu opioid receptor antagonist, β-funaltrexamine (20mg/kg, sc), had no effect on the anxiolytic effect of diazepam alone. These data support a role for delta opioid receptors in the opioid-enhanced anxiolytic effects of diazepam. PMID:17109943

Mechanism and Site of Inhibition of AMPA Receptors: Pairing a Thiadiazole with a 2,3-Benzodiazepine Scaffold

PubMed Central

2013-01-01

2,3-Benzodiazepine compounds are synthesized as drug candidates for treatment of various neurological disorders involving excessive activity of AMPA receptors. Here we report that pairing a thiadiazole moiety with a 2,3-benzodiazepine scaffold via the N-3 position yields an inhibitor type with >28-fold better potency and selectivity on AMPA receptors than the 2,3-benzodiazepine scaffold alone. Using whole-cell recording, we characterized two thiadiazolyl compounds, that is, one contains a 1,3,4-thiadiazole moiety and the other contains a 1,2,4-thiadiazole-3-one moiety. These compounds exhibit potent, equal inhibition of both the closed-channel and the open-channel conformations of all four homomeric AMPA receptor channels and two GluA2R-containing complex AMPA receptor channels. Furthermore, these compounds bind to the same receptor site as GYKI 52466 does, a site we previously termed as the “M” site. A thiadiazole moiety is thought to occupy more fully the side pocket of the receptor site or the “M” site, thereby generating a stronger, multivalent interaction between the inhibitor and the receptor binding site. We suggest that, as a heterocycle, a thiadiazole can be further modified chemically to produce a new class of even more potent, noncompetitive inhibitors of AMPA receptors. PMID:24313227

Unsaturated free fatty acids increase benzodiazepine receptor agonist binding depending on the subunit composition of the GABAA receptor complex.

PubMed

Witt, M R; Westh-Hansen, S E; Rasmussen, P B; Hastrup, S; Nielsen, M

1996-11-01

It has been shown previously that unsaturated free fatty acids (FFAs) strongly enhance the binding of agonist benzodiazepine receptor ligands and GABAA receptor ligands in the CNS in vitro. To investigate the selectivity of this effect, recombinant human GABAA/benzodiazepine receptor complexes formed by different subunit compositions (alpha x beta y gamma 2, x = 1, 2, 3, and 5; y = 1, 2, and 3) were expressed using the baculovirus-transfected Sf9 insect cell system. At 10(-4) M, unsaturated FFAs, particularly arachidonic (20:4) and docosahexaenoic (22:6) acids, strongly stimulated (> 200% of control values) the binding of [3H]flunitrazepam ([3H]FNM) to the alpha 3 beta 2 gamma 2 receptor combination in whole cell preparations. No effect or small increases in levels of unsaturated FFAs on [3H]FNM binding to alpha 1 beta x gamma 2 and alpha 2 beta x gamma 2 receptor combinations were observed, and weak effects (130% of control values) were detected using the alpha 5 beta 2 gamma 2 receptor combination. The saturated FFAs, stearic and palmitic acids, were without effect on [3H]FNM binding to any combination of receptor complexes. The hydroxylated unsaturated FFAs, ricinoleic and ricinelaidic acids, were shown to decrease the binding of [3H]FNM only if an alpha 1 beta 2 gamma 2 receptor combination was used. Given the heterogeneity of the GABAA/ benzodiazepine receptor subunit distribution in the CNS, the effects of FFAs on the benzodiazepine receptor can be assumed to vary at both cellular and regional levels.

The Roles of Maternal Depression, Serotonin Reuptake Inhibitor Treatment, and Concomitant Benzodiazepine Use on Infant Neurobehavioral Functioning Over the First Postnatal Month.

PubMed

Salisbury, Amy L; O'Grady, Kevin E; Battle, Cynthia L; Wisner, Katherine L; Anderson, George M; Stroud, Laura R; Miller-Loncar, Cynthia L; Young, Marion E; Lester, Barry M

2016-02-01

The purpose of this article was to systematically compare the developmental trajectory of neurobehavior over the first postnatal month for infants with prenatal exposure to pharmacologically untreated maternal depression, selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors (collectively: SSRIs), SSRIs with concomitant benzodiazepines (SSRI plus benzodiazepine), and no maternal depression or drug treatment (no exposure). Women (N=184) were assessed at two prenatal time points to determine psychiatric diagnoses, symptom severity, and prenatal medication usage. Infants were examined with a structured neurobehavioral assessment (Neonatal Intensive Care Unit Network Neurobehavioral Scale) at multiple time points across the first postnatal month. SSRI exposure was confirmed in a subset of participants with plasma SSRI levels. General linear-mixed models were used to examine group differences in neurobehavioral scores over time with adjustment for demographic variables and depression severity. Infants in the SSRI and SSRI plus benzodiazepine groups had lower motor scores and more CNS stress signs across the first postnatal month, as well as lower self-regulation and higher arousal at day 14. Infants in the depression group had low arousal throughout the newborn period. Infants in all three clinical groups had a widening gap in scores from the no-exposure group at day 30 in their response to visual and auditory stimuli while asleep and awake. Infants in the SSRI plus benzodiazepine group had the least favorable scores on the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Neonatal adaptation syndrome was not limited to the first 2 weeks postbirth. The profile of neurobehavioral development was different for SSRI exposure than depression alone. Concomitant benzodiazepine use may exacerbate adverse behavioral effects.

Factors Associated with Student Withdrawal from Community College

ERIC Educational Resources Information Center

Scoggin, Donna; Styron, Ronald

2006-01-01

Research was designed to identify commonalities of personal, enrollment, withdrawal, and evaluative factors as they relate to student withdrawal from community college. The study sought to identify interrelationships between identified reasons for student withdrawal and the variables of gender, race, classification status, degree sought, plans for…

20 CFR 416.355 - Withdrawal of an application.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Withdrawal of an application. 416.355 Section 416.355 Employees' Benefits SOCIAL SECURITY ADMINISTRATION SUPPLEMENTAL SECURITY INCOME FOR THE AGED, BLIND, AND DISABLED Filing of Applications Withdrawal of Application § 416.355 Withdrawal of an...

20 CFR 404.640 - Withdrawal of an application.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Withdrawal of an application. 404.640 Section 404.640 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Filing of Applications and Other Forms Withdrawal of Application § 404.640 Withdrawal of...

Withdrawal symptoms in internet gaming disorder: A systematic review.

PubMed

Kaptsis, Dean; King, Daniel L; Delfabbro, Paul H; Gradisar, Michael

2016-02-01

Internet gaming disorder (IGD) is currently positioned in the appendix of the DSM-5 as a condition requiring further study. The aim of this review was to examine the state of current knowledge of gaming withdrawal symptomatology, given the importance of withdrawal in positioning the disorder as a behavioral addiction. A total of 34 studies, including 10 qualitative studies, 17 research reports on psychometric instruments, and 7 treatment studies, were evaluated. The results indicated that the available evidence on Internet gaming withdrawal is very underdeveloped. Internet gaming withdrawal is most consistently referred to as 'irritability' and 'restlessness' following cessation of the activity. There exists a concerning paucity of qualitative studies that provide detailed clinical descriptions of symptoms arising from cessation of internet gaming. This has arguably compromised efforts to quantify withdrawal symptoms in empirical studies of gaming populations. Treatment studies have not reported on the natural course of withdrawal and/or withdrawal symptom trajectory following intervention. It is concluded that many more qualitative clinical studies are needed, and should be prioritised, to develop our understanding of gaming withdrawal. This should improve clinical descriptions of problematic internet gaming and in turn improve the quantification of IGD withdrawal and thus treatments for harmful internet gaming. Copyright © 2015 Elsevier Ltd. All rights reserved.

SSRI and SNRI withdrawal symptoms reported on an internet forum.

PubMed

Stockmann, Tom; Odegbaro, Dolapo; Timimi, Sami; Moncrieff, Joanna

2018-05-09

Antidepressant withdrawal symptoms are well-recognised, but their potential duration remains uncertain. We aimed to describe the characteristics of withdrawal associated with two popular classes of antidepressants, including duration. We analysed the content of a sample of posts on an antidepressant withdrawal website. We compared the characteristics of withdrawal associated with SSRIs and SNRIs, including time of onset, duration and nature of symptoms. 110 posts about SSRI withdrawal, and 63 concerning SNRI withdrawal, were analysed. The mean duration of withdrawal symptoms was significantly longer with SSRIs than SNRIs: 90.5 weeks (standard deviation, SD, 150.0) and 50.8 weeks (SD 76.0) respectively; p = 0.043). Neurological symptoms, such as 'brain zaps,' were more common among SNRI users (p = 0.023). Psychosexual/genitourinary symptoms may be more common among SSRI users (p = 0.054). The website aims to help people with antidepressant withdrawal, and is therefore likely to attract people who have difficulties. Length of prior use of antidepressants was long, with a mean of 252.2 weeks (SD 250.8). People accessing antidepressant withdrawal websites report experiencing protracted withdrawal symptoms. There are some differences in the characteristics of withdrawal associated with different classes of antidepressants.

Drug withdrawal conceptualized as a stressor

PubMed Central

Chartoff, Elena H.; Carlezon, William A.

2015-01-01

Drug withdrawal is often conceptualized as an aversive state that motivates drug-seeking and drug-taking behaviors in humans. Stress is more difficult to define, but is also frequently associated with aversive states. Here we describe evidence for the simple theory that drug withdrawal is a stress-like state, on the basis of common effects on behavioral, neurochemical, and molecular endpoints. We also describe data suggesting a more complex relationship between drug withdrawal and stress. As one example, we will highlight evidence that, depending on drug class, components of withdrawal can produce effects that have characteristics consistent with mood elevation. In addition, some stressors can act as positive reinforcers, defined as having the ability to increase the probability of a behavior that produces it. As such, accumulating evidence supports the general principles of opponent process theory, whereby processes that have an affective valence are followed in time by an opponent process that has the opposite valence. Throughout, we identify gaps in knowledge and propose future directions for research. A better understanding of the similarities, differences, and overlaps between drug withdrawal and stress will lead to the development of improved treatments for addiction, as well as for a vast array of neuropsychiatric conditions that are triggered or exacerbated by stress. PMID:25083570

The correlation between concentrations of zolpidem and benzodiazepines in segmental hair samples and use patterns.

PubMed

Kim, Hyojeong; Lee, Sangeun; In, Sanghwan; Park, Meejung; Cho, Sungnam; Shin, Junguk; Lee, Hunjoo; Han, Eunyoung

2018-01-01

The aim of this study was to investigate the correlation between histories of zolpidem and benzodiazepines use and their concentrations in hair as determined by segmental hair analysis, that is, by analyzing hair samples taken 0-1, 1-2, 2-3, 3-4, 4-5, and 5-6cm etc. and 0-3cm from the scalp, and whole hair. Of the 23 hair samples examined, 18 were collected from patients in a rehabilitation program and five were from patients that had taken zolpidem only once by prescription. All 23 patients provided written informed consent after reviewing the research plan, described their zolpidem and benzodiazepines use histories accurately, and provided hair samples, which were weighed, washed, cut into lengths of <1mm, and extracted in 100% methanol for 16h (diazepam-d 5 was used as an internal standard). Extracts were evaporated under reduced pressure and reconstituted with aqueous methanol (1:1 v/v). These extracts (10μL) were analyzed by Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS). The method used was validated by determining LOD, LOQ, calibration curves, intra- and inter-accuracies, precisions, matrix effects, process efficiencies, extraction efficiencies, and processed sample stabilities. Five hundred and ninety-five 1cm hair segments showed 61.59% positive probability and 86.71% negative probability of quality correlation between zolpidem and benzodiazepines use and concentrations in hair. Good qualitative correlations were observed between drug use and detection in hair. False positivity and false negativity were very low. Of the hair samples taken from patients in a rehabilitation program, subject nos. 4, 5, and 12 had correlation coefficients of 0.68, 0.54 and 0.71, respectively, for relationships between zolpidem use and concentration of zolpidem in hair. For the 5 patients taking only a single dose of zolpidem (10mg), the average zolpidem concentrations in hair were 20, 15 and 40pg/mg after 5, 30 and 60 days, respectively. This study shows a

12 CFR 925.26 - Voluntary withdrawal from membership.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Voluntary withdrawal from membership. 925.26 Section 925.26 Banks and Banking FEDERAL HOUSING FINANCE BOARD FEDERAL HOME LOAN BANK MEMBERS AND HOUSING ASSOCIATES MEMBERS OF THE BANKS Withdrawal and Removal From Membership § 925.26 Voluntary withdrawal from...

Improving alcohol withdrawal outcomes in acute care.

PubMed

Melson, Jo; Kane, Michelle; Mooney, Ruth; Mcwilliams, James; Horton, Terry

2014-01-01

Excessive alcohol consumption is the nation's third leading cause of preventable deaths. If untreated, 6% of alcohol-dependent patients experience alcohol withdrawal, with up to 10% of those experiencing delirium tremens (DT), when they stop drinking. Without routine screening, patients often experience DT without warning. Reduce the incidence of alcohol withdrawal advancing to DT, restraint use, and transfers to the intensive care unit (ICU) in patients with DT. In October 2009, the alcohol withdrawal team instituted a care management guideline used by all disciplines, which included tools for screening, assessment, and symptom management. Data were obtained from existing datasets for three quarters before and four quarters after implementation. Follow-up data were analyzed and showed a great deal of variability in transfers to the ICU and restraint use. Percentage of patients who developed DT showed a downward trend. Incidence of alcohol withdrawal advancing to DT and, in patients with DT, restraint use and transfers to the ICU. Initial data revealed a decrease in percentage of patients with alcohol withdrawal who experienced DT (16.4%-12.9%). In patients with DT, restraint use decreased (60.4%-44.4%) and transfers to the ICU decreased (21.6%-15%). Follow-up data indicated a continued downward trend in patients with DT. Changes were not statistically significant. Restraint use and ICU transfers maintained postimplementation levels initially but returned to preimplementation levels by third quarter 2012. Early identification of patients for potential alcohol withdrawal followed by a standardized treatment protocol using symptom-triggered dosing improved alcohol withdrawal management and outcomes.

Withdrawal-oriented therapy for smokers.

PubMed

Hajek, P

1989-06-01

The treatment approach of the Maudsley Hospital Smokers Clinic is described. It stems from the notion that smokers seeking help are dependent on nicotine, and that withdrawal discomfort is a major block to their success in quitting. Accordingly, therapy focuses on helping clients overcome nicotine deprivation. It uses nicotine replacement and a special format of group treatment. Details are given of preparation of clients, use of nicotine chewing gum, use of group-oriented groupwork, use of information about withdrawal, and training in withdrawal-oriented therapy. Data are presented concerning characteristics of the clientele, treatment adherence, and treatment results. A number of controversial issues are addressed, such as the optimal duration of treatment, timing of the quit date, the value of educational input, and the value of individualization of treatment goals.

42 CFR 457.170 - Withdrawal process.

Code of Federal Regulations, 2010 CFR

2010-10-01

...) STATE CHILDREN'S HEALTH INSURANCE PROGRAMS (SCHIPs) ALLOTMENTS AND GRANTS TO STATES Introduction; State Plans for Child Health Insurance Programs and Outreach Strategies § 457.170 Withdrawal process. (a... 42 Public Health 4 2010-10-01 2010-10-01 false Withdrawal process. 457.170 Section 457.170 Public...

27 CFR 19.729 - Withdrawal of fuel alcohol.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Withdrawal of fuel alcohol..., DEPARTMENT OF THE TREASURY ALCOHOL DISTILLED SPIRITS PLANTS Distilled Spirits for Fuel Use Rules for Use, Withdrawal, and Transfer of Spirits § 19.729 Withdrawal of fuel alcohol. (a) For each shipment or other...

27 CFR 19.729 - Withdrawal of fuel alcohol.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Withdrawal of fuel alcohol. 19.729 Section 19.729 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU..., Withdrawal, and Transfer of Spirits § 19.729 Withdrawal of fuel alcohol. (a) For each shipment or other...

Factor V Leiden, Prothrombin and MTHFR Mutation in Patients with Preeclamsia, Intrauterine Growth Restriction and Placental Abruption.

PubMed

Livrinova, Vesna; Lega, Marija Hadzi; Dimcheva, Anita Hristova; Samardziski, Igor; Isjanovska, Rozalinda

2015-12-15

Factor V Leiden, Prothrombin and MTHFR gene mutation, could have an influence in pregnancy with adverse outcome Preeclamsia, IUGR and Placental abruption. The aim of this study is to investigate the presence of above mentioned inherited thrombophilias and its statistical significance, distribution among the complicated and normal pregnancy, and relative risk for carrier of mutation to develop preeclampsia, IUGR and placental abruption. Prospective cohort study is implemented at University Clinic for Obstetric and Gynecology in Skopje, Republic of Macedonia. The study included 109 delivered patients: 40 with preeclapmsia, 22 with IUGR, 17 with placental abruption and 30 as control group with normal pregnancy. The amount of 3 ml venous blood has been used for detection of these point mutations using ThromboStrip -Opegen, QIAGEN kit manufactured for thrombotic risk. The highest frequency was found: in the group with preeclampsia 35% were MTHFR homozygous, IUGR -MTHFR heterozygous 45%, Placental abruption- 52.9% MTHFR heterozygous, and in the control group without thrombophilia 56.7%. There were combined thrombophilia in 3 patients. There aren`t statistical significance in presence of thrombophilia among groups (p > 0.05). Statistical significance (p < 0.05) was found between carriers of MTHFR homozygous in preeclampsia and group with placental abruption and control group. Relative risk in IUGR group for MTHFR homozygous was 5.54 (1.37abruption for Factor V Leiden heterozygous was 4.50 (0.47abruption. Further investigations with more patients are warranted.

Factor V Leiden, Prothrombin and MTHFR Mutation in Patients with Preeclamsia, Intrauterine Growth Restriction and Placental Abruption

PubMed Central

Livrinova, Vesna; Lega, Marija Hadzi; Dimcheva, Anita Hristova; Samardziski, Igor; Isjanovska, Rozalinda

2015-01-01

BACKGROUND: Factor V Leiden, Prothrombin and MTHFR gene mutation, could have an influence in pregnancy with adverse outcome Preeclamsia, IUGR and Placental abruption. AIM: The aim of this study is to investigate the presence of above mentioned inherited thrombophilias and its statistical significance, distribution among the complicated and normal pregnancy, and relative risk for carrier of mutation to develop preeclampsia, IUGR and placental abruption. MATERIAL AND METHODS: Prospective cohort study is implemented at University Clinic for Obstetric and Gynecology in Skopje, Republic of Macedonia. The study included 109 delivered patients: 40 with preeclapmsia, 22 with IUGR, 17 with placental abruption and 30 as control group with normal pregnancy. The amount of 3 ml venous blood has been used for detection of these point mutations using ThromboStrip -Opegen, QIAGEN kit manufactured for thrombotic risk. RESULTS: The highest frequency was found: in the group with preeclampsia 35% were MTHFR homozygous, IUGR -MTHFR heterozygous 45%, Placental abruption- 52.9% MTHFR heterozygous, and in the control group without thrombophilia 56.7%. There were combined thrombophilia in 3 patients. There aren`t statistical significance in presence of thrombophilia among groups (p > 0.05). Statistical significance (p < 0.05) was found between carriers of MTHFR homozygous in preeclampsia and group with placental abruption and control group. Relative risk in IUGR group for MTHFR homozygous was 5.54 (1.37abruption for Factor V Leiden heterozygous was 4.50 (0.47abruption. Further investigations with more patients are warranted. PMID:27275292

21 CFR 314.620 - Withdrawal procedures.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible § 314.620 Withdrawal procedures. (a) Reasons to withdraw...

21 CFR 314.620 - Withdrawal procedures.

Code of Federal Regulations, 2013 CFR

2013-04-01

... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible § 314.620 Withdrawal procedures. (a) Reasons to withdraw...

21 CFR 314.620 - Withdrawal procedures.

Code of Federal Regulations, 2014 CFR

2014-04-01

... Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Approval of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible § 314.620 Withdrawal procedures. (a) Reasons to withdraw...

37 CFR 10.40 - Withdrawal from employment,

Code of Federal Regulations, 2010 CFR

2010-07-01

... such request or such withdrawal is because: (1) The petitioner's client: (i) Insists upon presenting a... the Office, that the Office will find the existence of other good cause for withdrawal. ...

Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents.

PubMed

Burma, Nicole E; Bonin, Robert P; Leduc-Pessah, Heather; Baimel, Corey; Cairncross, Zoe F; Mousseau, Michael; Shankara, Jhenkruthi Vijaya; Stemkowski, Patrick L; Baimoukhametova, Dinara; Bains, Jaideep S; Antle, Michael C; Zamponi, Gerald W; Cahill, Catherine M; Borgland, Stephanie L; De Koninck, Yves; Trang, Tuan

2017-03-01

Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide ( 10 panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia.

31 CFR 103.84 - Withdrawing requests.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Withdrawing requests. 103.84 Section 103.84 Money and Finance: Treasury Regulations Relating to Money and Finance FINANCIAL RECORDKEEPING... requests. A person may withdraw a request for an administrative ruling at any time before the ruling has...

Methadone continuation versus forced withdrawal on incarceration in a combined US prison and jail: a randomised, open-label trial.

PubMed

Rich, Josiah D; McKenzie, Michelle; Larney, Sarah; Wong, John B; Tran, Liem; Clarke, Jennifer; Noska, Amanda; Reddy, Manasa; Zaller, Nickolas

2015-07-25

Methadone is an effective treatment for opioid dependence. When people who are receiving methadone maintenance treatment for opioid dependence are incarcerated in prison or jail, most US correctional facilities discontinue their methadone treatment, either gradually, or more often, abruptly. This discontinuation can cause uncomfortable symptoms of withdrawal and renders prisoners susceptible to relapse and overdose on release. We aimed to study the effect of forced withdrawal from methadone upon incarceration on individuals' risk behaviours and engagement with post-release treatment programmes. In this randomised, open-label trial, we randomly assigned (1:1) inmates of the Rhode Island Department of Corrections (RI, USA) who were enrolled in a methadone maintenance-treatment programme in the community at the time of arrest and wanted to remain on methadone treatment during incarceration and on release, to either continuation of their methadone treatment or to usual care--forced tapered withdrawal from methadone. Participants could be included in the study only if their incarceration would be more than 1 week but less than 6 months. We did the random assignments with a computer-generated random permutation, and urn randomisation procedures to stratify participants by sex and race. Participants in the continued-methadone group were maintained on their methadone dose at the time of their incarceration (with dose adjustments as clinically indicated). Patients in the forced-withdrawal group followed the institution's standard withdrawal protocol of receiving methadone for 1 week at the dose at the time of their incarceration, then a tapered withdrawal regimen (for those on a starting dose >100 mg, the dose was reduced by 5 mg per day to 100 mg, then reduced by 3 mg per day to 0 mg; for those on a starting dose >100 mg, the dose was reduced by 3 mg per day to 0 mg). The main outcomes were engagement with a methadone maintenance-treatment clinic after release from

Methadone continuation versus forced withdrawal on incarceration in a combined US prison and jail: a randomised, open-label trial

PubMed Central

Rich, Josiah D; McKenzie, Michelle; Larney, Sarah; Wong, John B; Tran, Liem; Clarke, Jennifer; Noska, Amanda; Reddy, Manasa; Zaller, Nickolas

2015-01-01

Summary Background Methadone is an effective treatment for opioid dependence. When people who are receiving methadone maintenance treatment for opioid dependence are incarcerated in prison or jail, most US correctional facilities discontinue their methadone treatment, either gradually, or more often, abruptly. This discontinuation can cause uncomfortable symptoms of withdrawal and renders prisoners susceptible to relapse and overdose on release. We aimed to study the effect of forced withdrawal from methadone upon incarceration on individuals’ risk behaviours and engagement with post-release treatment programmes. Methods In this randomised, open-label trial, we randomly assigned (1:1) inmates of the Rhode Island Department of Corrections (RI, USA) who were enrolled in a methadone maintenance-treatment programme in the community at the time of arrest and wanted to remain on methadone treatment during incarceration and on release, to either continuation of their methadone treatment or to usual care—forced tapered withdrawal from methadone. Participants could be included in the study only if their incarceration would be more than 1 week but less than 6 months. We did the random assignments with a computer-generated random permutation, and urn randomisation procedures to stratify participants by sex and race. Participants in the continued-methadone group were maintained on their methadone dose at the time of their incarceration (with dose adjustments as clinically indicated). Patients in the forced-withdrawal group followed the institution’s standard withdrawal protocol of receiving methadone for 1 week at the dose at the time of their incarceration, then a tapered withdrawal regimen (for those on a starting dose >100 mg, the dose was reduced by 5 mg per day to 100 mg, then reduced by 3 mg per day to 0 mg; for those on a starting dose ≤100 mg, the dose was reduced by 3 mg per day to 0 mg). The main outcomes were engagement with a methadone maintenance

Water Withdrawals, Use, and Trends in Florida, 2005

USGS Publications Warehouse

Marella, Richard L.

2009-01-01

In 2005, the total amount of water withdrawals in Florida was estimated at 18,359 million gallons per day (Mgal/d). Saline water accounted for 11,486 Mgal/d (63 percent), and freshwater accounted for 6,873 Mgal/d (37 percent). Groundwater accounted for 4,247 Mgal/d (62 percent) of freshwater withdrawals, and surface water accounted for the remaining 2,626 Mgal/d (38 percent). Surface water accounted for nearly all (99.9 percent) saline-water withdrawals. An additional 660 Mgal/d of reclaimed wastewater was used in Florida during 2005. The largest amount of freshwater was withdrawn from Palm Beach County, and the largest amount of saline water was withdrawn from Pasco County. Fresh groundwater provided drinking water (public supplied and self-supplied) for 16.19 million people (90 percent of Florida's population), and fresh surface water provided drinking water for 1.73 million people (10 percent). The majority of groundwater withdrawals (nearly 60 percent) in 2005 was obtained from the Floridan aquifer system which is present throughout the entire State. The majority of fresh surface-water withdrawals (59 percent) came from the southern Florida hydrologic unit subregion and is associated with Lake Okeechobee and the canals in the Everglades Agricultural Area of Glades, Hendry, and Palm Beach Counties, as well as the Caloosahatchee River and its tributaries in the agricultural areas of Collier, Glades, Hendry, and Lee Counties. Overall, agricultural irrigation accounted for 40 percent of the total freshwater withdrawals (ground and surface), followed by public supply with 37 percent. Public supply accounted for 52 percent of groundwater withdrawals, followed by agricultural self-supplied (31 percent), ommercial-industrial-mining self-supplied (8.5 percent), recreational irrigation and domestic self-supplied (4 percent each), and power generation (0.5 percent). Agricultural self-supplied accounted for 56 percent of fresh surface-water withdrawals, followed by power

Benzodiazepine Use in Pilots of Civil Aviation Accidents: 1990-2008 Toxicology and Autopsy Findings

DTIC Science & Technology

2011-02-01

are.analyzed.for.a.number.of.benzodi- azepines,.including.diazepam,.nordiazepam,.triazolam,. alprazolam ,.temazepam,.α-hydroxyalprazolam,.oxazepam...hydroxyalprazolam.(13),.midazolam.(12),. alprazolam . (9),.and.chlordiazepoxide.(4) ..Along.with.the.detected. benzodiazepines,.ethanol.was.found.in.21.(~22...in.which.it. was.determined.that.diazepam,.nordiazepam,. alprazolam ,. temazepam,. and. chlordiazepoxide. were. the. most. fre

GABAA-benzodiazepine receptors in the dorsomedial (Dm) telencephalon modulate restraint-induced antinociception in the fish Leporinus macrocephalus.

PubMed

Wolkers, Carla Patricia Bejo; Barbosa Junior, Augusto; Menescal-de-Oliveira, Leda; Hoffmann, Anette

2015-08-01

The possibility that fish experience pain has been denied based on the absence of the neural substrates to support this "experience". In this context, the identification of brain regions involved in nociception modulation could provide important insights regarding the processing of nociceptive information in fish. Our study evaluated the participation of the GABAA-benzodiazepine receptor in the dorsomedial (Dm) telencephalon in restraint-induced antinociception in the fish Leporinus macrocephalus through the microinjection of the anxiolytic drug midazolam. The microinjection of midazolam in the Dm did not alter the nocifensive response; however, this drug did block the inhibition of the nocifensive response to formaldehyde promoted by restraint stress. The fish that received midazolam (40nmol) microinjection prior to restraint (3 or 5min), followed by subcutaneous injection with formaldehyde presented a higher distance traveled than the fish that received saline microinjection. This effect might reflect the specific action of midazolam on benzodiazepine receptors in the Dm telencephalon, as pre-treatment with flumazenil, a benzodiazepine receptor antagonist, inhibited the effects of this drug. In the present study, we present the first evidence demonstrating a role for the dorsomedial telencephalic region in the modulation of stress-induced antinociception in fish, revealing new perspectives in the understanding of nociceptive information processing in this group. Copyright © 2015 Elsevier Inc. All rights reserved.

State survey of medical boards regarding abrupt loss of a prescriber of controlled substances.

PubMed

Sera, Leah; Brown, Micke; McPherson, Mary Lynn; Walker, Kathryn A; Klein-Schwartz, Wendy

The purpose of the study was to evaluate states' experiences with abrupt changes in controlled substances (CS) prescribing, to determine whether states have action plans in place to manage such situations, and describe the components of any such plans. A survey of executive directors of 51 medical boards was conducted to evaluate states' experiences with abrupt changes in CS prescribing, the extent of consumer complaints attributed to these events, and the types of plans in place to manage these situations. Forty-six executive directors of medical boards responded. Twenty boards (43.5 percent) confirmed that their state had experienced abrupt loss of CS providers and 11 (55 percent) of these executive directors indicated that the loss resulted in increased consumer complaints. The majority of executive directors (86 percent) had no action plan. Six executive directors reported some type of action plan or process consisting of regulatory action, patient-provider connection, professional education, patient education, or public notice. Most states do not have operational plans in place. However, a few have key strategies that may be useful in addressing potential problems following abrupt loss of a CS prescriber. State medical boards can play a significant role in the development of comprehensive preparedness plans to mitigate damage from the loss of CS prescribers in the community.

Increased QT interval variability index in acute alcohol withdrawal.

PubMed

Bär, Karl-Jürgen; Boettger, Michael Karl; Koschke, Mandy; Boettger, Silke; Grotelüschen, Marei; Voss, Andreas; Yeragani, Vikram K

2007-07-10

Acute alcohol withdrawal is associated with increased cardiovascular mortality, most likely due to cardiac arrhythmias. As the QT interval reflects the most critical phase for the generation of reentry and thus for arrhythmia, we examined QT variability in patients suffering from acute alcohol withdrawal. High resolution electrocardiographic recordings were performed in 18 male unmedicated patients suffering from acute alcohol withdrawal, 18 matched controls and 15 abstained alcoholics. From these, parameters of beat-to-beat heart rate and QT variability such as approximate entropy and QT variability index (QTvi) were calculated. Measures were correlated with the severity of withdrawal symptoms and with serum electrolyte concentrations. Heart rate and QTvi were significantly increased in acute alcohol withdrawal. Abstained alcoholics did not significantly differ from controls. While QTvi correlated with the severity of alcohol withdrawal symptoms, the mean QT interval duration showed an inverse relationship with serum potassium concentrations. Our data indicate increased QT variability and thus increased repolarization lability in acute alcohol withdrawal. This might add to the elevated risk for serious cardiac arrhythmias. In part, these changes might be related to increased cardiac sympathetic activity or low potassium, thus suggesting the latter as possible targets for adjuvant pharmacological therapy during withdrawal.

The Necessity of Awareness of Early Symptoms of Placental Abruption Among Pregnant Japanese Women

PubMed Central

Suzuki, Shunji; Shinmura, Hiroki

2016-01-01

Background In 2012, the recommendation for immediate contact and visit to obstetric institutions by pregnant women was emphasized by The Japan Obstetric Compensation System for Cerebral Palsy (JOCSC). In this study, we examined whether or not the increased awareness has led to the improvement of perinatal outcomes of placental abruption managed at private clinics. Methods We reviewed the obstetric records of 38 singleton pregnant women complicated by placental abruption that developed at home, and were managed at private clinics from April 2008 through April 2016. Results The perinatal outcomes, specifically the rate of cases with ≥ 1 hour time interval between symptom onset and clinic visit, have not changed significantly after the intervention. Conclusion The provision of information regarding the early clinical symptoms associated with placental abruption in pregnant women has not been well documented in Japan. PMID:27540442

High-resolution Greenland ice core data show abrupt climate change happens in few years.

PubMed

Steffensen, Jørgen Peder; Andersen, Katrine K; Bigler, Matthias; Clausen, Henrik B; Dahl-Jensen, Dorthe; Fischer, Hubertus; Goto-Azuma, Kumiko; Hansson, Margareta; Johnsen, Sigfús J; Jouzel, Jean; Masson-Delmotte, Valérie; Popp, Trevor; Rasmussen, Sune O; Röthlisberger, Regine; Ruth, Urs; Stauffer, Bernhard; Siggaard-Andersen, Marie-Louise; Sveinbjörnsdóttir, Arny E; Svensson, Anders; White, James W C

2008-08-01

The last two abrupt warmings at the onset of our present warm interglacial period, interrupted by the Younger Dryas cooling event, were investigated at high temporal resolution from the North Greenland Ice Core Project ice core. The deuterium excess, a proxy of Greenland precipitation moisture source, switched mode within 1 to 3 years over these transitions and initiated a more gradual change (over 50 years) of the Greenland air temperature, as recorded by stable water isotopes. The onsets of both abrupt Greenland warmings were slightly preceded by decreasing Greenland dust deposition, reflecting the wetting of Asian deserts. A northern shift of the Intertropical Convergence Zone could be the trigger of these abrupt shifts of Northern Hemisphere atmospheric circulation, resulting in changes of 2 to 4 kelvin in Greenland moisture source temperature from one year to the next.

Mitragynine Attenuates Withdrawal Syndrome in Morphine-Withdrawn Zebrafish

PubMed Central

Khor, Beng-Siang; Amar Jamil, Mohd Fadzly; Adenan, Mohamad Ilham; Chong Shu-Chien, Alexander

2011-01-01

A major obstacle in treating drug addiction is the severity of opiate withdrawal syndrome, which can lead to unwanted relapse. Mitragynine is the major alkaloid compound found in leaves of Mitragyna speciosa, a plant widely used by opiate addicts to mitigate the harshness of drug withdrawal. A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level. Using real-time PCR gene expression analysis, we also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway. PMID:22205946

Abrupt Depletion Layer Approximation for the Metal Insulator Semiconductor Diode.

ERIC Educational Resources Information Center

Jones, Kenneth

1979-01-01

Determines the excess surface change carrier density, surface potential, and relative capacitance of a metal insulator semiconductor diode as a function of the gate voltage, using the precise questions and the equations derived with the abrupt depletion layer approximation. (Author/GA)

5 CFR 831.1207 - Withdrawal of disability retirement applications.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Withdrawal of disability retirement...) CIVIL SERVICE REGULATIONS (CONTINUED) RETIREMENT Disability Retirement § 831.1207 Withdrawal of... any further consideration. (b) Withdrawal of a disability retirement application does not ensure the...

Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview.

PubMed

Bellantuono, Cesario; Tofani, Stefania; Di Sciascio, Guido; Santone, Giovanni

2013-01-01

Benzodiazepines (BDZs) safety profiles in pregnancy suggest that the risk of major malformations (MMs) cannot be considered simply as a "class effect". The aim of this paper was to review and update the available literature on the risks of MMs in women exposed to BDZs in the first trimester of pregnancy. PubMed was searched for English-language articles, from January 2001 to November 2011, introducing as keywords "teratogens", " major malformation", "foetus", "infant", "newborn", "pregnancy", in conjunction with "benzodiazepines" as a keyword or BDZ generic name as text words. Twelve studies were selected for the review. BDZ exposure during the first trimester of pregnancy seems not to be associated with an increasing risk of congenital MMs. Diazepam and chlordiazepoxide should be considered drugs of first choice. Data published in the last 10 years did not indicate an absolute contraindication in prescribing BDZs during the first gestational trimester. In any case, studies analyzed suffer from a number of methodological limitations such as lack of careful report of BDZ patterns of use in pregnancy, possible influences of recall bias, lack of controlling for confounding factors and lack of data concerning possible MMs in aborted fetuses. Copyright © 2013 Elsevier Inc. All rights reserved.

Precise interpolar phasing of abrupt climate change during the last ice age.

PubMed

2015-04-30

The last glacial period exhibited abrupt Dansgaard-Oeschger climatic oscillations, evidence of which is preserved in a variety of Northern Hemisphere palaeoclimate archives. Ice cores show that Antarctica cooled during the warm phases of the Greenland Dansgaard-Oeschger cycle and vice versa, suggesting an interhemispheric redistribution of heat through a mechanism called the bipolar seesaw. Variations in the Atlantic meridional overturning circulation (AMOC) strength are thought to have been important, but much uncertainty remains regarding the dynamics and trigger of these abrupt events. Key information is contained in the relative phasing of hemispheric climate variations, yet the large, poorly constrained difference between gas age and ice age and the relatively low resolution of methane records from Antarctic ice cores have so far precluded methane-based synchronization at the required sub-centennial precision. Here we use a recently drilled high-accumulation Antarctic ice core to show that, on average, abrupt Greenland warming leads the corresponding Antarctic cooling onset by 218 ± 92 years (2σ) for Dansgaard-Oeschger events, including the Bølling event; Greenland cooling leads the corresponding onset of Antarctic warming by 208 ± 96 years. Our results demonstrate a north-to-south directionality of the abrupt climatic signal, which is propagated to the Southern Hemisphere high latitudes by oceanic rather than atmospheric processes. The similar interpolar phasing of warming and cooling transitions suggests that the transfer time of the climatic signal is independent of the AMOC background state. Our findings confirm a central role for ocean circulation in the bipolar seesaw and provide clear criteria for assessing hypotheses and model simulations of Dansgaard-Oeschger dynamics.

40 CFR 97.86 - Withdrawal from NOX Budget Trading Program.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 22 2013-07-01 2013-07-01 false Withdrawal from NOX Budget Trading... PROGRAMS (CONTINUED) FEDERAL NOX BUDGET TRADING PROGRAM AND CAIR NOX AND SO2 TRADING PROGRAMS Individual Unit Opt-ins § 97.86 Withdrawal from NOX Budget Trading Program. (a) Requesting withdrawal. To withdraw...

40 CFR 97.86 - Withdrawal from NOX Budget Trading Program.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 22 2012-07-01 2012-07-01 false Withdrawal from NOX Budget Trading... PROGRAMS (CONTINUED) FEDERAL NOX BUDGET TRADING PROGRAM AND CAIR NOX AND SO2 TRADING PROGRAMS Individual Unit Opt-ins § 97.86 Withdrawal from NOX Budget Trading Program. (a) Requesting withdrawal. To withdraw...

40 CFR 97.86 - Withdrawal from NOX Budget Trading Program.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 21 2014-07-01 2014-07-01 false Withdrawal from NOX Budget Trading... PROGRAMS (CONTINUED) FEDERAL NOX BUDGET TRADING PROGRAM AND CAIR NOX AND SO2 TRADING PROGRAMS Individual Unit Opt-ins § 97.86 Withdrawal from NOX Budget Trading Program. (a) Requesting withdrawal. To withdraw...

Steroid withdrawal in lung transplant recipients.

PubMed

Borro, J M; Solé, A; De la Torre, M; Pastor, A; Tarazona, V

2005-11-01

Many of the long-term complications in lung transplantations are secondary effects of immunosuppression. Corticosteroids are partially responsible for the development of osteoporosis, raised blood pressure, diabetes, muscular disorders, gastric ulcers, and other conditions. We analyzed the long-term result of steroid withdrawal in our lung transplant recipients. When respiratory function stabilized, to avoid secondary effects, steroid treatment was withdrawn in 34 of the 375 lung transplant patients in our centers We evaluated the characteristics of the donors and recipients, their compatibility, the pre, and post-steroid withdrawal complications, and type of immunosuppressant. The mean age of patients was 42 +/- 7 years and of donors, 25 +/- 9 years. The primary diseases were: 15 emphysema, six pulmonary fibrosis, 10 cystic fibrosis, and three primary pulmonary hypertension. Twenty seven patients had double lung transplants and seven single lung. The mean steroid withdrawal period was 881 +/- 237 days posttransplantation. The most frequent treatment regimen at the time of steroid withdrawal was cyclosporine, azathioprine, and minimal steroid doses. Six recipients had to be restarted on steroids one patient who required a kidney transplant, three cases due to an infectious process with a differential diagnosis of rejection, and two cases due to loss of FEV1 (forced expiratory volume in 1 s), suggestive of chronic rejection. There was an improvement in blood pressure in five patients, in plasma cholesterol and triglyceride levels in eight patients, and insulin withdrawal in two diabetic patients. Steroid treatment may be suspended 2 to 3 years, posttransplant in selected lung transplant recipients. The usual patient profile shows few rejection episodes with cyclosporine and azathioprine immunosuppression. What is notable is the low mean age of donors. Close clinical monitoring and lung function testing are of major importance in the weeks following steroid

Detection of the designer benzodiazepine metizolam in urine and preliminary data on its metabolism.

PubMed

Kintz, Pascal; Richeval, Camille; Jamey, Carole; Ameline, Alice; Allorge, Delphine; Gaulier, Jean-Michel; Raul, Jean-Sébastien

2017-07-01

Designer benzodiazepines provide an attractive alternative to prescribed benzodiazepines for abuse purposes as they are readily available via the Internet without control. Metizolam was ordered via the Internet and a 2 mg blue tablet was orally administered to a 54-year-old man. Urine samples were collected over 6 days in polypropylene tubes. After liquid/liquid extraction at pH 9.5, metizolam was analyzed by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) using a standard method devoted to benzodiazepines, and ions transitions, at m/z 328.9 > 275.0 and 328.9 > 300.0. Metizolam was detectable in hydrolyzed urine during the 46-h period, with concentrations always lower than 11 ng/mL. About 0.3% of the initial dose was excreted in urines as total unchanged metizolam during the first 24 h. The most relevant potential CYP- and UGT-dependent metabolites of metizolam were investigated in vitro using human liver microsome incubation and, subsequently, liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF-MS) analysis. Three mono-hydroxylated metabolites were produced including a hydroxylation compound at the 2-ethyl moiety of metizolam (M1) as quantitatively main metabolite, and a N-hydroxymetiazolam (M2). The structure of the third metabolite (M3) could not be elucidated because of a too low experimental production rate. Two authentic urine samples were analyzed using the same analytical method to search for metabolites of metizolam. M1, together with its glucuronide (M1-Glu), and M2 were observed in urine at the 8 h mark, whereas only M1 and M1-Glu were still detected in urine at 30 h post administration. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Withdrawing to a Virtual World: Associations between Subtypes of Withdrawal, Media Use, and Maladjustment in Emerging Adults

ERIC Educational Resources Information Center

Nelson, Larry J.; Coyne, Sarah M.; Howard, Emily; Clifford, Brandon N.

2016-01-01

An approach-avoidance model of social withdrawal (Asendorpf, 1990) identifies 3 types of social withdrawal including shyness, unsociability, and avoidance. Each appears to be uniquely associated with varying indicators of maladjustment in emerging adulthood (Nelson, 2013) but little, if any, work has been done to see how they might be linked to…

Placebo caffeine reduces withdrawal in abstinent coffee drinkers.

PubMed

Mills, Llewellyn; Boakes, Robert A; Colagiuri, Ben

2016-04-01

Expectancies have been shown to play a role in the withdrawal syndrome of many drugs of addiction; however, no studies have examined the effects of expectancies across a broad range of caffeine withdrawal symptoms, including craving. The purpose of the current study was to use caffeine as a model to test the effect of expectancy on withdrawal symptoms, specifically whether the belief that one has ingested caffeine is sufficient to reduce caffeine withdrawal symptoms and cravings in abstinent coffee drinkers. We had 24-h abstinent regular coffee drinkers complete the Caffeine Withdrawal Symptom Questionnaire (CWSQ) before and after receiving decaffeinated coffee. One-half of the participants were led to believe the coffee was regular caffeinated coffee (the 'Told Caffeine' condition) and one-half were told that it was decaffeinated (the 'Told Decaf' condition). Participants in the Told Caffeine condition reported a significantly greater reduction in the factors of cravings, fatigue, lack of alertness and flu-like feelings of the CWSQ, than those in the Told Decaf condition. Our results indicated that the belief that one has consumed caffeine can affect caffeine withdrawal symptoms, especially cravings, even when no caffeine was consumed. © The Author(s) 2016.

Using the AUDIT-PC to predict alcohol withdrawal in hospitalized patients.

PubMed

Pecoraro, Anna; Ewen, Edward; Horton, Terry; Mooney, Ruth; Kolm, Paul; McGraw, Patty; Woody, George

2014-01-01

Alcohol withdrawal syndrome (AWS) occurs when alcohol-dependent individuals abruptly reduce or stop drinking. Hospitalized alcohol-dependent patients are at risk. Hospitals need a validated screening tool to assess withdrawal risk, but no validated tools are currently available. To examine the admission Alcohol Use Disorders Identification Test-(Piccinelli) Consumption (AUDIT-PC) ability to predict the subsequent development of AWS among hospitalized medical-surgical patients admitted to a non-intensive care setting. Retrospective case–control study of patients discharged from the hospital with a diagnosis of AWS. All patients with AWS were classified as presenting with AWS or developing AWS later during admission. Patients admitted to an intensive care setting and those missing AUDIT-PC scores were excluded from analysis. A hierarchical (by hospital unit) logistic regression was performed and receiver-operating characteristics were examined on those developing AWS after admission and randomly selected controls. Because those diagnosing AWS were not blinded to the AUDIT-PC scores, a sensitivity analysis was performed. The study cohort included all patients age ≥18 years admitted to any medical or surgical units in a single health care system from 6 October 2009 to 7 October 2010. After exclusions, 414 patients were identified with AWS. The 223 (53.9 %) who developed AWS after admission were compared to 466 randomly selected controls without AWS. An AUDIT-PC score ≥4 at admission provides 91.0 % sensitivity and 89.7 % specificity (AUC=0.95; 95 % CI, 0.94–0.97) for AWS, and maximizes the correct classification while resulting in 17 false positives for every true positive identified. Performance remained excellent on sensitivity analysis (AUC=0.92; 95 % CI, 0.90–0.93). Increasing AUDIT-PC scores were associated with an increased risk of AWS (OR=1.68, 95 % CI 1.55–1.82, p<0.001). The admission AUDIT-PC score is an excellent discriminator of AWS and could be

Analysis of Participant Withdrawal in Huntington Disease Clinical Trials.

PubMed

Banno, Haruhiko; Andrzejewski, Kelly L; McDermott, Michael P; Murphy, Alyssa; Majumder, Madhurima; de Blieck, Elisabeth A; Auinger, Peggy; Cudkowicz, Merit E; Atassi, Nazem

2017-01-01

Excellent retention in Huntington disease (HD) clinical trials is essential for testing new therapies. The stage of disease, cognitive status, and availability of a care partner may influence retention in HD clinical trials. We sought to analyze reasons for early withdrawal in three HD clinical trials, and evaluated if either baseline characteristics or follow-up assessments were associated with time to withdrawal. Analyses of participant withdrawal were performed for three randomized, double-blind, placebo-controlled trials including the CARE-HD (coenzyme Q10 and remacemide in HD, n = 347), DOMINO (pilot study of minocycline in HD, n = 114), and 2CARE (coenzyme Q10 in HD, n = 609) trials. Reasons for withdrawal were obtained by review of textual data in the study databases. Participant demographic and clinical characteristics were analyzed as potential predictors of time to withdrawal using Cox-proportional hazards models. Estimated probabilities of withdrawal at 12 months were 2.9% for CARE-HD, 10.5% for DOMINO, and 5.9% for 2CARE. The top reasons for withdrawal (202 in total), expressed as mean percentage across the three trials, were loss to follow-up (23.2%), death (15.9%), and loss of interest/desire to participate (15.2%). Baseline and time-dependent variables associated with time to withdrawal were mainly motor, behavioral, and functional scores. Age, gender, ethnicity, and educational level were not associated with time to withdrawal in any of the three studies. The estimated withdrawal probability at 12 months ranged from 2.9% to 10.5% in the three HD trials considered here. A possible strategy to improve retention of participants in future HD clinical trials is to enroll individuals with higher baseline functional and behavioral status.

Modulation of acetylcholine release from rat striatal slices by the GABA/benzodiazepine receptor complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Supavilai, P.; Karobath, M.

1985-02-04

GABA, THIP and muscimol enhance spontaneous and inhibit electrically induced release of tritium labelled compounds from rat striatal slices which have been pre-labelled with /sup 3/H-choline. Baclofen is inactive in this model. Muscimol can inhibit electrically induced release of tritiated material by approximately 75% with half maximal effects at 2 ..mu..M. The response to muscimol can be blocked by the GABA antagonists bicuculline methobromide, picrotoxin, anisatin, R 5135 and CPTBO (cyclopentylbicyclophosphate). Drugs which act on the benzodiazepine receptor (BR) require the presence of muscimol to be effective and they modulate the effects of muscimol in a bidirectional manner. Thus BRmore » agonists enhance and inverse BR agonists attenuate the inhibitory effects of muscimol on electrically induced release. Ro15-1788, a BR antagonist, does not modulate the inhibitory effects of muscimol but antagonizes the actions of clonazepam, a BR agonist, and of DMCM, an inverse BR agonist. These results demonstrate that a GABA/benzodiazepine receptor complex can modulate acetylcholine release from rat striatal slices in vitro. 24 references, 3 figures, 5 table.« less

Investigating Flow Features Near Abrupt Topography in the Mariana Basin

DTIC Science & Technology

2015-09-30

1 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. Investigating Flow Features Near Abrupt Topography in...waves generated by flow over topography and mesoscale eddies generated by flow past islands. Having identified the prime locations in the region for such

5 CFR 1650.16 - Required withdrawal date.

Code of Federal Regulations, 2011 CFR

2011-01-01

... FUNDS FROM THE THRIFT SAVINGS PLAN Post-Employment Withdrawals § 1650.16 Required withdrawal date. (a) A... date described in paragraph (a) of this section, but is not required to do so. (c) In the event that a...

Abrupt GaP/Si hetero-interface using bistepped Si buffer

DOE Office of Scientific and Technical Information (OSTI.GOV)