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Sample records for benzodiazepines

  1. Benzodiazepines

    Science.gov (United States)

    ... injectable preparation and as a syrup (primarily for pediatric patients). Benzodiazepines with a longer duration of ... and clorazepate are also used as anticonvulsants. Methods of abuse Abuse is frequently associated with ...

  2. Benzodiazepine poisoning in elderly

    OpenAIRE

    Perković-Vukčević Nataša; Vuković-Ercegović Gordana; Šegrt Zoran; Đorđević Snežana; Jović-Stošić Jasmina

    2016-01-01

    Background/Aim. 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. Methods. A retrospective study of consecutive presentations to hospital after self-poisoning with benzodiazepines was done. Collecte...

  3. [Suicidal poisoning with benzodiazepines].

    Science.gov (United States)

    Chodorowski, Z; Sein Anand, J

    1997-01-01

    In the period from 1987 to 1996, 103 patients with suicidal benzodiazepines poisoning were treated, including 62 women and 41 men from 16 to 79 (mean 34) years old. 23 persons were poisoned only by benzodiazepines, in 80 remaining cases intoxications were mixed eg. including benzodiazepines and alcohol, tricyclic antidepressants, barbiturates, opioids, phenothiazines. The main causes of suicides were mainly depression, drug addiction and alcoholism. Nobody died in the benzodiazepines group, while mortality rate in the group of mixed poisoning was 4%. Prescribing benzodiazepines by physicians was quite often not justified and facilitated, among others, accumulation of the dose sufficient for suicide attempt. Flumazenil was efficient for leading out from coma in 86% of cases with poisoning only by benzodiazepines and 13% of cases with mixed intoxications mainly containing benzodiazepines and alcohol or carbamazepine.

  4. Benzodiazepine poisoning in elderly.

    Science.gov (United States)

    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.

  5. Benzodiazepine absetzen im Alter

    DEFF Research Database (Denmark)

    Wolter, Dirk

    2017-01-01

    Although viewed critically in geriatrics, benzodiazepine use is still common among old people. Before reducing the dosage the following questions must be considered: 1. Are there indications for benzodiazepine treatment and will discontinuation cause relevant rebound symptoms of the initial disor...

  6. Benzodiazepine abuse among the elderly

    Directory of Open Access Journals (Sweden)

    Shalini Singh

    2016-01-01

    Full Text Available Benzodiazepines belong to the hypnotic-sedative class of drugs which have anxiolytic, sedative, and hypnotic properties. These drugs have been in clinical use for at least half a century. The propensity for development of dependence, especially on prescription benzodiazepines, coupled with the risk of falls and cognitive impairment due to benzodiazepines makes the elderly population susceptible to adverse outcomes with the use of benzodiazepines, and hence, cautious use is desired in this population. This review discusses the various aspects pertaining to benzodiazepine abuse in the elderly including pharmacology, prevalence of abuse, adverse consequences of benzodiazepine abuse, and subsequently assessment and management of elderly patients with benzodiazepine abuse.

  7. Benzodiazepine poisoning in elderly

    Directory of Open Access Journals (Sweden)

    Perković-Vukčević Nataša

    2016-01-01

    Full Text Available Background/Aim. 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. Methods. 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. Results. 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. Conclusion. 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.

  8. Isotopically labelled benzodiazepines

    International Nuclear Information System (INIS)

    Liebman, A.A.

    1987-01-01

    This paper reports on the benzodiazepines which are a class of therapeutic agents. Improvements in the analytical methodology in the areas of biochemistry and pharmacology were significant, particularly in the application of chromatographic and spectroscopic techniques. In addition, the discovery and subsequent development of tritium and carbon-14 as an analytical tool in the biological sciences were essentially post-world war II phenomena. Thus, as these new chemical entities were found to be biologically active, they could be prepared in labeled form for metabolic study, biological half-life determination (pharmacokinetics), tissue distribution study, etc. This use of tracer methodology has been liberally applied to the benzodiazepines and also more recently to the study of receptor-ligand interactions, in which tritium, carbon-11 or fluorine-18 isotopes have been used. The history of benzodiazepines as medicinal agents is indeed an interesting one; an integral part of that history is their use in just about every conceivable labeled form

  9. Predictors of long-term benzodiazepine abstinence in participants of a randomized controlled benzodiazepine withdrawal program.

    NARCIS (Netherlands)

    Oude Voshaar, R.C.; Gorgels, W.J.M.J.; Mol, A.J.J.; Balkom, A.J.L.M. van; Mulder, J.; Lisdonk, E.H. van de; Breteler, M.H.M.; Zitman, F.G.

    2006-01-01

    OBJECTIVE: To identify predictors of resumed benzodiazepine use after participation in a benzodiazepine discontinuation trial. METHOD: We performed multiple Cox regression analyses to predict the long-term outcome of a 3-condition, randomized, controlled benzodiazepine discontinuation trial in

  10. Predictors of long-term benzodiazepine abstinence in participants of a randomized controlled benzodiazepine withdrawal program

    NARCIS (Netherlands)

    Oude Voshaar, R.C.; Gorgels, W.J.M.J.; Mol, A.J.J.; Balkom, A.J.L.M. van; Mulder, J.; Lisdonk, E.H. van de; Breteler, M.H.M.; Zitman, F.G.

    2006-01-01

    Objective: To identify predictors of resumed benzodiazepine use after participation in a benzodiazepine discontinuation trial. Method: We performed multiple Cox regression analyses to predict the long-term outcome of a 3-condition, randomized, controlled benzodiazepine discontinuation trial in

  11. Stability of solubilized benzodiazepine receptors

    NARCIS (Netherlands)

    Janssen, M.J; Ensing, K; de Zeeuw, R.A

    1997-01-01

    According to the observations of other researchers, benzodiazepine receptors solubilized with sodium deoxycholate are unstable, but stability can be improved by exchanging deoxycholate for Triton X-100. In our experiments we conclude that the choice of detergent is not the restrictive factor for the

  12. Mitochondrial benzodiazepine receptors regulate steroid biosynthesis.

    OpenAIRE

    Mukhin, A G; Papadopoulos, V; Costa, E; Krueger, K E

    1989-01-01

    Recent observations on the steroid synthetic capability within the brain open the possibility that benzodiazepines may influence steroid synthesis in nervous tissue through interactions with peripheral-type benzodiazepine recognition sites, which are highly expressed in steroidogenic cells and associated with the outer mitochondrial membrane. To examine this possibility nine molecules that exhibit a greater than 10,000-fold difference in their affinities for peripheral-type benzodiazepine bin...

  13. Characterization of astrocytic and neuronal benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Bender, A.S.

    1988-01-01

    Primary cultures of astrocytes and neurons express benzodiazepine receptors. Neuronal benzodiazepine receptors were of high-affinity, K{sub D} values were 7.5-43 nM and the densities of receptors (B{sub max}) were 924-4131 fmol/mg protein. Astrocytes posses a high-affinity benzodiazepine receptor, K{sub D} values were 6.6-13 nM. The B{sub max} values were 6,033-12,000 fmol/mg protein. The pharmacological profile of the neuronal benzodiazepine receptor was that of the central-type benzodiazepine receptor, where clonazepam has a high-affinity and Ro 5-4864 (4{prime}-chlorodiazepam) has a low-affinity. Whereas astrocytic benzoidazepine receptor was characteristic of the so called peripheral-type benzodiazepine receptors, which shows a high-affinity towards Ro 5-4863, and a low-affinity towards clonazepam. The astrocytic benzodiazepine receptors was functionally correlated with voltage dependent calcium channels, since dihydropyridines and benzodiazepines interacted with ({sup 3}H) diazepam and ({sup 3}H) nitrendipine receptors with the same rank order of potency, showing a statistically significant correlation. No such correlation was observed in neurons.

  14. Benzodiazepine receptor antagonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy....

  15. Mitochondrial benzodiazepine receptors regulate steroid biosynthesis

    International Nuclear Information System (INIS)

    Mukhin, A.G.; Papadopoulos, V.; Costa, E.; Krueger, K.E.

    1989-01-01

    Recent observations on the steroid synthetic capability within the brain open the possibility that benzodiazepines may influence steroid synthesis in nervous tissue through interactions with peripheral-type benzodiazepine recognition sites, which are highly expressed in steroidogenic cells and associated with the outer mitochondrial membrane. To examine this possibility nine molecules that exhibit a greater than 10,000-fold difference in their affinities for peripheral-type benzodiazepine binding sites were tested for their effects on a well-established steroidogenic model system, the Y-1 mouse adrenal tumor cell line. 4'-Chlorodiazepam, PK 11195, and PK 14067 stimulated steroid production by 2-fold in Y-1 cells, whereas diazepam, flunitrazepam, zolpidem, and PK 14068 displayed a lower (1.2- to 1.5-fold) maximal stimulation. In contrast, clonazepam and flumazenil did not stimulate steroid synthesis. The potencies of these compounds to inhibit 3 H-labeled PK 11195 binding to peripheral-type benzodiazepine recognition sites correlated with their potencies to stimulate steroid production. Similar findings were observed in bovine and rat adrenocortical cell preparations. These results suggest that ligands of the peripheral-type benzodiazepine recognition site acting on this mitochondrial receptor can enhance steroid production. This action may contribute specificity to the pharmacological profile of drugs preferentially acting on the benzodiazepine recognition site associated with the outer membrane of certain mitochondrial populations

  16. Mitochondrial benzodiazepine receptors regulate steroid biosynthesis

    Energy Technology Data Exchange (ETDEWEB)

    Mukhin, A.G.; Papadopoulos, V.; Costa, E.; Krueger, K.E. (Georgetown Univ. School of Medicine, Washington, DC (USA))

    1989-12-01

    Recent observations on the steroid synthetic capability within the brain open the possibility that benzodiazepines may influence steroid synthesis in nervous tissue through interactions with peripheral-type benzodiazepine recognition sites, which are highly expressed in steroidogenic cells and associated with the outer mitochondrial membrane. To examine this possibility nine molecules that exhibit a greater than 10,000-fold difference in their affinities for peripheral-type benzodiazepine binding sites were tested for their effects on a well-established steroidogenic model system, the Y-1 mouse adrenal tumor cell line. 4{prime}-Chlorodiazepam, PK 11195, and PK 14067 stimulated steroid production by 2-fold in Y-1 cells, whereas diazepam, flunitrazepam, zolpidem, and PK 14068 displayed a lower (1.2- to 1.5-fold) maximal stimulation. In contrast, clonazepam and flumazenil did not stimulate steroid synthesis. The potencies of these compounds to inhibit {sup 3}H-labeled PK 11195 binding to peripheral-type benzodiazepine recognition sites correlated with their potencies to stimulate steroid production. Similar findings were observed in bovine and rat adrenocortical cell preparations. These results suggest that ligands of the peripheral-type benzodiazepine recognition site acting on this mitochondrial receptor can enhance steroid production. This action may contribute specificity to the pharmacological profile of drugs preferentially acting on the benzodiazepine recognition site associated with the outer membrane of certain mitochondrial populations.

  17. Chronic use of benzodiazepines among older adults

    Directory of Open Access Journals (Sweden)

    Jussara Mendonça Alvarenga

    2014-12-01

    Full Text Available OBJECTIVE To analyze the perception of and motivation for the chronic use of benzodiazepine among older adults. METHODS A qualitative study was conducted on 22 older adults living in Bambuí, MG, Southeastern Brazil, who were taking benzodiazepines and had the clinical and cognitive ability to respond to interview questions. The collected data were analyzed on the basis of the “signs, meanings, and actions” model. RESULTS The main reasons pointed out for the use of benzodiazepines were “nervousness”, “sleep problems”, and “worry” due to family and financial problems, everyday problems, and existential difficulties. None of the interviewees said that they used benzodiazepines in a dose higher than that recommended or had been warned by health professionals about any risks of their continuous use. Different strategies were used to obtain the prescription for the medication, and any physician would prescribe it, indicating that a bond was established with the drug and not with the health professional or healthcare service. Obtaining and consuming the medication turned into a crucial issue because benzodiazepine assumes the status of an essential food, which leads users to not think but sleep. It causes a feeling of relief from their problems such as awareness of human finitude and fragility, existential difficulties, and family problems. CONCLUSIONS Benzodiazepine assumes the characteristics of polyvalence among older adults, which extrapolate specific clinical indications, and of essentiality to deal with life’s problems in old age. Although it relieves the “nerves”, the chronic use of benzodiazepines buffers suffering and prevents older adults from going through the suffering. This shows important difficulties in the organization and planning of strategies that are necessary for minimizing the chronic use in this population.

  18. Electrocardiographic Manifestations of Benzodiazepine Toxicity

    Directory of Open Access Journals (Sweden)

    Nahid Kazemzadeh

    2014-11-01

    Full Text Available Background: The aim of this study was to evaluate and compare the clinical and electrocardiographic (ECG manifestations of benzodiazepines (BZs. Methods: In this retrospective study, all BZ-poisoned patients hospitalized at Loghman Hakim Hospital between September 2010 and March 2011 were evaluated. Patients’ information including age, sex, time elapsed between the ingestion and presentation, and type of the BZ used were extracted from the patients' charts and recorded. ECGs on presentation to the emergency department (ED were evaluated and parameters such as PR interval, QRS duration, corrected QT, amplitude of S wave in lead I, height of R wave and R/S ratio in the lead aVR were also measured and recorded. Results: Oxazepam, chlordiazepoxide, lorazepam, alprazolam, diazepam, and clonazepam were ingested by 9 (3%, 13 (4.4%, 29 (9.9%, 105 (35.8%, 65 (22.2%, and 72 (24.6% patients, respectively. Mean PR interval was reported to be 0.16 ± 0.03 sec and PR interval of greater than 200 msec was detected in 12 (4.5% patients. Mean QRS duration was 0.07 ± 0.01sec and QRS≥120 msec was observed in 7 (2.6% cases. Conclusion: Diazepam is the only BZ that does not cause QRS widening and oxazepam is the only one not causing PR prolongation. It can be concluded that if a patient refers with a decreased level of consciousness and accompanying signs of BZ toxicity, QRS widening in ECG rules out diazepam, whereas PR prolongation rules out oxazepam toxicity.

  19. Synthesis of 3-Substituted 1,4-Benzodiazepin-2-ones

    Directory of Open Access Journals (Sweden)

    Kyungjin Kim

    1998-01-01

    Full Text Available The preparation of 3-substituted 1,4-benzodiazepines by benzodiazepine enolate alkylation has been explored. Employing this approach, multigram quantities of benzodiazepine 1 have been prepared for animal studies to evaluate a new approach for the treatment of the autoimmune disease systemic lupus erythematosus (SLE.

  20. The benzodiazepine withdrawal syndrome and its management.

    OpenAIRE

    Onyett, S R

    1989-01-01

    The literature on benzodiazepine dependence and withdrawal is reviewed with an emphasis on social and psychological considerations. The problems of when to prescribe, identifying withdrawal symptoms, effective communication with the patient, the structure of withdrawal programmes, and the use of drugs, psychological approaches and other services are discussed.

  1. Benzodiazepine Synthesis and Rapid Toxicity Assay

    Science.gov (United States)

    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…

  2. Benzodiazepines: minder gebruiken is beter gebruiken

    NARCIS (Netherlands)

    Oei, T.T.; Loonen, A.J.M.

    1981-01-01

    The benzodiazepines take an important place in the treatment of anxiety and sleep-disorders. The pharmacokinetic, pharmacodynamic and therapeutic properties of these drugs are shortly dealt with, whereafter the development of tolerance and dependence is considered in more detail. The clinical

  3. Benzodiazepine maintenance for alcohol dependence: A case series

    Directory of Open Access Journals (Sweden)

    Shivanand Kattimani

    2017-01-01

    Full Text Available Alcohol addiction is a chronic relapsing syndrome. Benzodiazepines remain as the mainstay for detoxification, taking care of the acute withdrawal syndrome. There is fear of dependence and abuse of benzodiazepines on prolonged use. Here, we selectively interviewed ten cases who were on longer duration of benzodiazepines to elicit their potential perceived benefits, attitudes, and any adverse effect. Three patients experienced adverse effects. None of them had features of benzodiazepine dependence. We opine that in select cases, benzodiazepine use should persist beyond detox period, and its benefits continue beyond the acute withdrawal phase while monitoring their safety/adverse effects.

  4. Benzodiazepines for psychosis-induced aggression or agitation

    DEFF Research Database (Denmark)

    Zaman, Hadar; Sampson, Stephanie J; Beck, Alison Ls

    2017-01-01

    of global state, clearly more people receiving placebo showed no improvement in the medium term (one to 48 hours) (n = 102, 1 RCT, RR 0.62, 95% CI 0.40 to 0.97, very low quality evidence). Benzodiazepines versus antipsychoticsWhen compared with haloperidol, there was no observed effect for benzodiazepines...... improved when receiving benzodiazepines compared with olanzapine (n = 150, 1 RCT, RR 1.84, 95% CI 1.06 to 3.18, very low quality evidence). People receiving benzodiazepines were less likely to experience extrapyramidal effects in the medium term compared to people receiving haloperidol (n = 233, 6 RCTs, RR...... 0.13, 95% CI 0.04 to 0.41, low quality evidence).Benzodiazepines versus combined antipsychotics/antihistaminesWhen benzodiazepine was compared with combined antipsychotics/antihistamines (haloperidol plus promethazine), there was a higher risk of no improvement in people receiving benzodiazepines...

  5. Attention Span, Anxiety and Benzodiazepine Receptors

    Science.gov (United States)

    1991-02-26

    increasse the central and peripheral effects of emotional stress ,-- FL combines 0nly the clinically favorable attributes of both classes of drugs, as...Pieri, P. PoIc. E.P. Bonetti, P. Cumin , R. Schaffner and W. Haefely, 1981, Selective antagonist of benzodiazepines, Nature 290, 514. Karobath, M. and G...34intimidaring" and/or stressful stimuli. In such a condition, flumazenil can be expected to have a stabilizing effect on emotional responses normally triggered

  6. Qualitative variation of photolabelled benzodiazepine receptors in different species.

    Science.gov (United States)

    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.

  7. Memory impairment in those who attempted suicide by benzodiazepine overdose

    NARCIS (Netherlands)

    Verwey, B.; Eling, P.A.T.M.; Wientjes, H.J.F.M.; Zitman, F.G.

    2000-01-01

    Backgroud: a prospective study was done to investigate the presence of anterograde amnesia in suicide attempters who took benzodiazepines (BZ) and to study the correlation with sedation. Method: in 43 patients, who attempted suicide by taking benzodiazepines, memory perfomrance was tested on a

  8. Flumazenil in treatment benzodiazepine withdrawal syndrome: Case report

    Directory of Open Access Journals (Sweden)

    Ramah Aleksandar J.

    2015-01-01

    Full Text Available Background: Today in the world and in Serbia is growing number of people who are addicted to benzodiazepine. A particular problem is the process of detoxification and treatment of benzodiazepine withdrawal syndrome due to a recurrence of symptoms of anxiety disorder, availability of benzodiazepines, falling motivation. Standard procedures have often proved unsuccessful and the last decade, and the search for new protocols, including the flumazenil, benzodiazepine receptor antagonist, is actualized. Case report: The patient aged 48 years was admitted to the specialist psychiatric clinic, for treatment of benzodiazepine addiction. Anxiety disorder was diagnosed since adolescence perennial addiction on benzodiazepines and the initial withdrawal syndrome. Former motivated topical treatments for detoxification were unsuccessful. The presence of dual diagnosis, persistence of both disorders in perennial cycle, treatment resistance and actual motivation contributed to the decision to opt rapid detoxification from benzodiazepines by flumazenil application protocol, for hospital treatment by adjuvant therapy with lamotrigine. After discharge from hospital in stable condition it was with no signs of withdrawal syndrome and a rebound of anxiety symptoms. Lamotrigine medication continued including CBT, held during the one-year abstinence monitoring, with sufficient social functionality. Discussion: The efficacy and safety of flumazenil in the treatment of benzodiazepine withdrawal syndrome was investigated in numerous clinical trials, and the mechanism of action is complex, from the benzodiazepine antagonist to inverse agonist in certain circumstances, as well as 'up-regulation' receptors, which together leads to a reduction in symptoms of abstinence syndrome and anxiety in the longer term after treatment, thereby acting favorably to the adherence and remission. Conclusions: Flumazenil protocol is an efficient method in the treatment of the benzodiazepine

  9. Fluorescent-labeled ligands for the benzodiazepine receptor - Part 1 : Synthesis and characterization of fluorescent-labeled benzodiazepines

    NARCIS (Netherlands)

    Janssen, M.J; Hulst, A.J R L; Kellogg, R.M; Hendriks, M.M W B; Ensing, K; de Zeeuw, R.A

    Because radioactive labeled ligands in receptor assays have several disadvantages, we synthesized a number of fluorescent-labeled benzodiazepines. Several fluorophores were attached at different positions of 1,4-benzodiazepine molecules in order to assess the impact of the fluorophores and their

  10. Radioligands for PET studies of central benzodiazepine receptors and PK (peripheral benzodiazepine) binding sites -current status

    International Nuclear Information System (INIS)

    Pike, V.W.; Osman, S.; Shah, F.; Turton, D.R.; Waters, S.L.; Crouzel, C.; Nutt, D.J.

    1993-01-01

    The status of the radiochemical development and biological evaluation of radioligands for PET studies of central benzodiazepine (BZ) receptors and the so-called peripheral benzodiazepine binding sites, here discriminated and referred to as PK binding sites, is reviewed against current pharmacological knowledge, indicating those agents with present value and those with future potential. Practical recommendations are given for the preparation of two useful radioligands for PET studies, [N-methyl- 11 C]flumazenil for central BZ receptors, and [N-methyl- 11 C]PK 11195 for PK binding sites. Quality assurance and plasma metabolite analysis are also reviewed for these radioligands and practical recommendations are given on methodology for their performance. (Author)

  11. The impact of benzodiazepine use on methadone maintenance treatment outcomes.

    Science.gov (United States)

    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.

  12. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

    International Nuclear Information System (INIS)

    Weizman, R.; Weizman, A.; Kook, K.A.; Vocci, F.; Deutsch, S.I.; Paul, S.M.

    1989-01-01

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of [ 3 H]Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in [14C]iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress [an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures], although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results

  13. Repeated swim stress alters brain benzodiazepine receptors measured in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Weizman, R.; Weizman, A.; Kook, K.A.; Vocci, F.; Deutsch, S.I.; Paul, S.M.

    1989-06-01

    The effects of repeated swim stress on brain benzodiazepine receptors were examined in the mouse using both an in vivo and in vitro binding method. Specific in vivo binding of (/sup 3/H)Ro15-1788 to benzodiazepine receptors was decreased in the hippocampus, cerebral cortex, hypothalamus, midbrain and striatum after repeated swim stress (7 consecutive days of daily swim stress) when compared to nonstressed mice. In vivo benzodiazepine receptor binding was unaltered after repeated swim stress in the cerebellum and pons medulla. The stress-induced reduction in in vivo benzodiazepine receptor binding did not appear to be due to altered cerebral blood flow or to an alteration in benzodiazepine metabolism or biodistribution because there was no difference in (14C)iodoantipyrine distribution or whole brain concentrations of clonazepam after repeated swim stress. Saturation binding experiments revealed a change in both apparent maximal binding capacity and affinity after repeated swim stress. Moreover, a reduction in clonazepam's anticonvulsant potency was also observed after repeated swim stress (an increase in the ED50 dose for protection against pentylenetetrazol-induced seizures), although there was no difference in pentylenetetrazol-induced seizure threshold between the two groups. In contrast to the results obtained in vivo, no change in benzodiazepine receptor binding kinetics was observed using the in vitro binding method. These data suggest that environmental stress can alter the binding parameters of the benzodiazepine receptor and that the in vivo and in vitro binding methods can yield substantially different results.

  14. Disability pension as predictor of later use of benzodiazepines among benzodiazepine users

    OpenAIRE

    Hartz, Ingeborg; Tverdal, Aage; Skille, Eivind Å.; Skurtveit, Svetlana

    2010-01-01

    The original publication is available at: http://dx.doi.org/10.1016/j.socscimed.2009.11.015 The proportion of Norwegians on disability pensions has doubled since the 1980s. The Norwegian Government wants action to stimulate the working capacity in those disability pensioners who have the potential to work. Information on factors that may impair rehabilitation efforts, including the unfavourable use of benzodiazepines, may be useful in this context. A longitudinal design, including data on ...

  15. Imaging of a glioma using peripheral benzodiazepine receptor ligands

    Energy Technology Data Exchange (ETDEWEB)

    Starosta-Rubinstein, S.; Ciliax, B.J.; Penney, J.B.; McKeever, P.; Young, A.B.

    1987-02-01

    Two types of benzodiazepine receptors have been demonstrated in mammalian tissues, one which is localized on neuronal elements in brain and the other, on glial cells and in peripheral tissues such as kidney. In vivo administration of /sup 3/H-labeled PK 11195 (1-(2-chlorophenyl-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide) or (/sup 3/H)flunitrazepam with 5 mg of clonazepam per kg to rats with intracranial C6 gliomas resulted in high levels of tritiated-drug binding to the tumor as shown by quantitative autoradiography. Pharmacological studies indicated that the bound drugs labeled the peripheral benzodiazepine binding site. Binding to the peripheral benzodiazepine site was confirmed primarily to malignant cells with little binding to adjacent normal brain tissue or to necrotic tissue. Tumor cell binding was completely inhibited by preadministration of the peripheral benzodiazepine blocking agent PK 11195 at 5 mg/kg. The centrally selective benzodiazepine ligand clonazepam had no effect on PK 11195 binding to the tumor cells. When binding to other tumor cell lines grown in nude mice and nude athymic rats was evaluated, little or no peripheral benzodiazepine binding was detected on human pheochromocytoma (RN1) and neuroblastoma (SK-N-MC, SK-N-SH) tumor cells, respectively. However, high densities of peripheral benzodiazepine binding sites were observed on tumors derived from a human glioma cell line (ATCC HTB 14, U-87 MG). The presence of high concentrations of specific peripheral benzodiazepine receptors on glial tumors suggests that human primary central nervous system tumors could be imaged and diagnosed using peripheral benzodiazepine ligands labeled with positron- or gamma-emitting isotopes.

  16. Analytical methodologies for the determination of benzodiazepines in biological samples.

    Science.gov (United States)

    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.

  17. Benzodiazepines II: Waking Up on Sedatives: Providing Optimal Care When Inheriting Benzodiazepine Prescriptions in Transfer Patients

    Directory of Open Access Journals (Sweden)

    Jeffrey Guina

    2018-01-01

    Full Text Available This review discusses risks, benefits, and alternatives in patients already taking benzodiazepines when care transfers to a new clinician. Prescribers have the decision—sometimes mutually agreed-upon and sometimes unilateral—to continue, discontinue, or change treatment. This decision should be made based on evidence-based indications (conditions and timeframes, comorbidities, potential drug-drug interactions, and evidence of adverse effects, misuse, abuse, dependence, or diversion. We discuss management tools involved in continuation (e.g., monitoring symptoms, laboratory testing, prescribing contracts, state prescription databases, stages of change and discontinuation (e.g., tapering, psychotherapeutic interventions, education, handouts, reassurance, medications to assist with discontinuation, and alternative treatments.

  18. 1,4-Benzodiazepine N-Nitrosoamidines: Useful Intermediates in the Synthesis of Tricyclic Benzodiazepines

    Directory of Open Access Journals (Sweden)

    Carlos del Pozo

    2006-08-01

    Full Text Available 1,4-Benzodiazepine N-nitrosoamidines have been used as scaffolds for the preparation of different tricyclic derivatives. Replacement of the N-nitrosoamidine moiety through treatment with the nucleophiles acetylhydrazine, aminoacetaldehyde dimethylacetal and 1-amino-2-propanol, followed by an acid-catalyzed cyclization step, afforded triazolo and imidazobenzodiazepines 1, 6, and 7, respectively, in good yields. When acetylhydrazine is used as a nucleophile, the overall process provides an alternative route to alprazolam (1b and triazolam (1c, respectively.

  19. Benzodiazepines - Their role in aggression and why GPs should prescribe with caution.

    Science.gov (United States)

    Jones, Katy A; Nielsen, Suzanne; Bruno, Raimondo; Frei, Matthew; Lubman, Dan I

    2011-11-01

    Benzodiazepines are widely prescribed in Australia, despite concerns about their potential for abuse and dependence. Paradoxical reactions, disinhibition and amnesia are all associated with benzodiazepine use, misuse and intoxication. While violent and aggressive behaviour may be a consequence of such disinhibition, there is limited information available regarding the links between benzodiazepine use and violence. This article aims to examine the existing evidence on the relationship between benzodiazepines, violence and aggression. While current evidence suggests that benzodiazepines rarely induce violence, it is important to note that the available literature is limited in its scope and that benzodiazepine related violence is often severe and of potential concern to frontline workers. Mediating risk factors for benzodiazepine related violence include concurrent alcohol use, benzodiazepine dose, a history of aggression and underlying impulsivity. Comprehensive assessment and alternate nonpharmacological treatment options should be considered before prescribing benzodiazepines within primary care.

  20. AHR-11797: a novel benzodiazepine antagonist

    International Nuclear Information System (INIS)

    Johnson, D.N.; Kilpatrick, B.F.; Hannaman, P.K.

    1986-01-01

    AHR-11797(5,6-dihydro-6-methyl-1-phenyl- 3 H-pyrrolo[3,2,1-ij]quinazolin-3-one) displaced 3 H-flunitrazepam (IC 50 = 82 nM) and 3 H-Ro 15-1877 (IC 50 = 104 nM) from rat brain synaptosomes. AHR-11797 did not protect mice from seizures induced by maximal electroshock or subcutaneous Metrazol (scMET), nor did it induce seizures in doses up to the lethal dose. However, at 31.6 mg/kg, IP, it significantly increased the anticonvulsant ED 50 of chlordiazepoxide (CDPX) from 1.9 to 31.6 mg/kg, IP. With 56.7 mg/kg, IP, of AHR-11797, CDPX was inactive in doses up to 100 mg/kg, IP. AHR-11797 did not significantly increase punished responding in the Geller and Seifter conflict procedure, but it did attenuate the effects of diazepam. Although the compound is without anticonvulsant or anxiolytic activity, it did have muscle relaxant properties. AHR-11797 blocked morphine-induced Straub tail in mice (ED 50 = 31 mg/kg, IP) and it selectively suppressed the polysnaptic linguomandibular reflex in barbiturate-anesthetized cats. The apparent muscle relaxant activity of AHR-11797 suggests that different receptor sites are involved for muscle relaxant vs. anxiolytic/anticonvulsant activities of the benzodiazepines

  1. Benzodiazepine use in general population, the municipality of Berane, Montenegro

    Directory of Open Access Journals (Sweden)

    Šoškić Miomir

    2016-01-01

    Full Text Available Background: Benzodiazepines can be classified as one of the most frequently prescribed categories of medication. This medication category is distinguished by a high risk of tolerance and dependence, in the case of long-term, excessive use. Aim: The aim of our study was to analyse the use of benzodiazepines in the general population, municipality of Berane, Montenegro, during the previous year. Methods: Research was based on the analysis of 1000 prescriptions of benzodiazepines, issued by physicians in Primary Health Care. The diagnostic manual utilised for the purpose of this research was International Classification of Diseases (ICD-10. The survey was conducted for a period of 40 days during January and February 2015. Results: The study was performed in the general population, age from 18 to 98 years (621 females and 379 males. The average age of all participants in the study was 64.1±13.1 years. Analysis of data confirmed that the most frequently prescribed from the group of benzodiazepines were: diazepam (42.2%, bromazepam (30.3%, lorazepam (16.4%, alprazolam (6.4%, nitrazepam (2.6% and clonazepam (2.1%. The significant statistical difference (x2=58.664; p<0.001 was found between female patients who used benzodiazepines in 62.1% of cases, compared to male patients who used benzodiazepines in 37.9% of cases. It was confirmed that benzodiazepines were usually prescribed for 17 different diagnoses, mostly for diagnoses from the group I, viz. cluster-diseases of the circulatory system (39.7%, group F-mental and behavioural disorders (31.1% and group E-endocrine, nutritional and metabolic diseases (7.7%. Conclusion: Studies about drug utilisation provide plenty of useful information which can be further used with the aim of achieving more rational prescribing and more effective patient treating.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  4. Takotsubo Cardiomyopathy and Catatonia in the Setting of Benzodiazepine Withdrawal

    Directory of Open Access Journals (Sweden)

    Teng J. Peng

    2016-01-01

    Full Text Available We report two serious and unusual complications of benzodiazepine withdrawal in a single patient: takotsubo cardiomyopathy and catatonia. This 61-year-old female patient was brought to the emergency department with lethargy and within hours had declined into a state of catatonia. Although there was never a complaint of chest pain, ECG showed deep anterior T-wave inversions and cardiac enzymes were elevated. An echocardiogram was consistent with takotsubo cardiomyopathy. She later received 1 mg of midazolam and within minutes had resolution of catatonic symptoms. Careful history revealed that she had omitted her daily dose of lorazepam for 3 days prior to admission. To our knowledge, the case presented herein is the first report of simultaneous catatonia and takotsubo cardiomyopathy in the setting of benzodiazepine withdrawal. The pathogenesis of both conditions is poorly understood but may be indirectly related to the sudden decrease in γ-aminobutyric acid (GABA signaling during benzodiazepine withdrawal.

  5. Phenobarbital compared to benzodiazepines in alcohol withdrawal treatment

    DEFF Research Database (Denmark)

    Askgaard, Gro; Hallas, Jesper; Fink-Jensen, Anders

    2016-01-01

    BACKGROUND: Long-acting benzodiazepines such as chlordiazepoxide are recommended as first-line treatment for alcohol withdrawal. These drugs are known for their abuse liability and might increase alcohol consumption among problem drinkers. Phenobarbital could be an alternative treatment option......, possibly with the drawback of a more pronounced acute toxicity. We evaluated if phenobarbital compared to chlordiazepoxide decreased the risk of subsequent use of benzodiazepines, alcohol recidivism and mortality. METHODS: The study was a register-based cohort study of patients admitted for alcohol...... withdrawal 1998-2013 and treated with either phenobarbital or chlordiazepoxide. Patients were followed for one year. We calculated hazard ratios (HR) for benzodiazepine use, alcohol recidivism and mortality associated with alcohol withdrawal treatment, while adjusting for confounders. RESULTS: A total...

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

    Science.gov (United States)

    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.

  7. Prospective cohort study into post-disaster benzodiazepine use demonstrated only short-term increase.

    NARCIS (Netherlands)

    Dorn, T.; Yzermans, C.J.; Zee, J. van der

    2007-01-01

    OBJECTIVES: Benzodiazepines are typically prescribed for anxiety and insomnia, two complaints often reported after disasters. Benzodiazepines can cause mental or physical dependence, especially when taken for a long time. This study aims at evaluating benzodiazepine use in a disaster-stricken

  8. Bromine-75-labeled 1,4-benzodiazepines: potential agents for the mapping of benzodiazepine receptors in vivo: concise communication

    Energy Technology Data Exchange (ETDEWEB)

    Scholl, H.; Kloster, G.; Stoecklin, G.

    1983-05-01

    We have prepared four different 1,4-benzodiazepines, labeled at C-7 with the 1.6-hr positron emitter Br-75 or the 57-hr gamma emitter Br-77, as potential radio-pharmaceuticals for the mapping of cerebral benzodiazepine receptor areas. The triazene method was used and optimized. Yields at the no-carrier-added level were 20%. (7-/sup 75/Br)-5-(2-flophenyl)-1-methyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one (Br-75 BFB) was isolated with a minimum specific activity of 20,000 Ci/mmole. Biodistribution in mice shows that BFB is taken up rapidly by the brain and is retained there at useful concentrations for significant periods of time. The maximum uptake is observed at 0.25 min. Brain-to-blood concentration ratios are larger than 2 during the interval (0.25 to 10 min) investigated.

  9. Oral Pre-anaesthetic Medication with a New Benzodiazepine Hypnotic

    African Journals Online (AJOL)

    A new benzodiazepine derivative (Ro 5-4200) was used as a hypnotic in a pilot study on 30 patients the night before an operation. The dosage used was 2 mg (1 tablet). Results proved very encouraging, and it was then decided to conduct a controlled double-blind trial comparing Ro 5-4200, phenobarbital 100 mg and a ...

  10. Oral Pre-anaesthetic Medication with a New Benzodiazepine Hypnotic

    African Journals Online (AJOL)

    1973-01-20

    Jan 20, 1973 ... A new benzodiazepine derivative (Ro 5-4200) was used as a hypnotic in a pilot study on 30 patients the night before an operation. The dosage used was 2 mg (1 tablet). Results proved very encouraging, and it was then decided to conduct a controlled double-blind trial com- paring Ro 5-4200, ...

  11. Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Kjaergard, L L; Gluud, C

    2001-01-01

    The pathogenesis of hepatic encephalopathy is unknown. It has been suggested that liver failure leads to the accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition which may progress to coma. Several trials have assessed benzodiazepine receptor...

  12. Estimation of Cessation Rates among Danish Users of Benzodiazepines

    DEFF Research Database (Denmark)

    Støvring, Henrik; Gasse, Christiane

    Background: Widespread and longterm use of benzodiazepines constitute a public health problem. Health care authorities hence advice that use should not exceed three months, in particular for the elderly and patients with a past diagnosis of drug addiction. Objectives: Estimate the shape...

  13. Sex differences among recipients of benzodiazepines in Dutch general practice.

    NARCIS (Netherlands)

    Waals, F.W. van der; Mohrs, J.; Foets, M.

    1993-01-01

    Objective: To analyse sex differences among recipients of benzodiazepines in Dutch general practice. Design-Study of consultations and associated interventions as recorded in the Dutch national survey of general practice. Setting: Practices of 45 general practitioners monitored during 1 April to 30

  14. Phenylboronic acid catalysed synthesis of 1,5-benzodiazepines via ...

    Indian Academy of Sciences (India)

    Phenylboronic acid has been found to be an efficient catalyst for the synthesis of 1,5-benzodiazepine derivatives via cyclocondensation of -phenylenediamine and various ketones in good to excellent yields (82-91%) using acetonitrile as solvent at reflux condition. The remarkable advantages offered by this method are ...

  15. Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Kjaergard, L L; Gluud, C

    2001-01-01

    The pathogenesis of hepatic encephalopathy is unknown. It has been suggested that liver failure leads to the accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition which may progress to coma. Several trials have assessed benzodiazepine receptor...... antagonists for hepatic encephalopathy, but the results are conflicting....

  16. Phenylboronic acid catalysed synthesis of 1,5-benzodiazepines via ...

    Indian Academy of Sciences (India)

    J. Chem. Sci. Vol. 125, No. 4, July 2013, pp. 745–749. c Indian Academy of Sciences. Phenylboronic acid catalysed synthesis of 1,5-benzodiazepines via cyclocondensation of ... active compounds and gaining great consideration in the field of .... thesis of this heterocycles was accomplished by con- densation reaction of ...

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

    NARCIS (Netherlands)

    Oude Voshaar, R.C.

    2012-01-01

    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,

  18. Treating acute seizures with benzodiazepines: does seizure duration matter?

    Science.gov (United States)

    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.

  19. Psychological determinants of the intention to educate patients about benzodiazepines

    NARCIS (Netherlands)

    Ten Wolde, Geeske Brecht; Dijkstra, A.; Van Empelen, P.; Neven, A. Knuistingh; Zitman, F. G.

    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)

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

    Science.gov (United States)

    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.

  1. Gamma-aminobutyric acid-modulated benzodiazepine binding sites in bacteria

    International Nuclear Information System (INIS)

    Lummis, S.C.R.; Johnston, G.A.R.; Nicoletti, G.; Holan, 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 [ 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 [ 3 H]diazepam binding are those that are active in displacing [ 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 ligand 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

  2. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder

    DEFF Research Database (Denmark)

    Baandrup, Lone; Lindschou, Jane; Winkel, Per

    2016-01-01

    OBJECTIVES: We assessed if prolonged-release melatonin can facilitate withdrawal of long-term benzodiazepine usage in patients with schizophrenia or bipolar disorder. METHODS: Randomised, placebo-controlled, blinded, parallel superiority trial of 24 weeks duration. Participants were randomised...... to prolonged-release melatonin 2 mg daily versus matching placebo and were continuously guided to gradually reduce their usual benzodiazepine dosage. The primary outcome was mean benzodiazepine daily dosage at 24 weeks. Secondary outcomes included pattern of benzodiazepine dosage over time, benzodiazepine...... cessation proportion, and benzodiazepine withdrawal symptoms. RESULTS: In total, 86 patients (21-74 years) were enrolled: 42 were randomised to melatonin versus 44 to placebo. We found no significant effect of melatonin on mean benzodiazepine dosage at 24 weeks (melatonin group 8.01 mg versus placebo group...

  3. Cross-validation, predictive validity, and time course of the Benzodiazepine Dependence Self-Report Questionnaire in a benzodiazepine discontinuation trial.

    NARCIS (Netherlands)

    Oude Voshaar, R.C.; Mol, A.J.J.; Gorgels, W.J.M.J.; Breteler, M.H.M.; Balkom, A.J.L.M. van; Lisdonk, E.H. van de; Kan, C.C.; Zitman, F.G.

    2003-01-01

    The Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ) measures the severity of benzodiazepine (BZ) dependence on four domains: awareness of problematic use, preoccupation with the availability of BZ, lack of compliance with the therapeutic regimen, and withdrawal. Although promising

  4. Cross-validation, predictive validity and time course of the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ) in a benzodiazepine discontinuation trial

    NARCIS (Netherlands)

    Oude Voshaar, R.C.; Mol, A.J.J.; Gorgels, W.J.M.J.; Breteler, M.H.M.; Balkom, A.J.L.M. van; Lisdonk, E.H. van de; Zitman, F.G.

    2003-01-01

    The Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ) measures the severity of benzodiazepine (BZ) dependence on four domains: awareness of problematic use, preoccupation with the availability of BZ, lack of compliance with the therapeutic regimen, and withdrawal. Although promising

  5. Symptom-triggered benzodiazepine therapy for alcohol withdrawal syndrome in the emergency department: a comparison with the standard fixed dose benzodiazepine regimen.

    LENUS (Irish Health Repository)

    Cassidy, Eugene M

    2012-10-01

    The aim of the study was to compare symptom-triggered and standard benzodiazepine regimens for the treatment of alcohol withdrawal syndrome in an emergency department clinical decision unit. The authors found that the symptom-triggered approach reduced cumulative benzodiazepine dose and length of stay.

  6. Reducing Prescriptions of Long-acting Benzodiazepine Drugs in Denmark

    DEFF Research Database (Denmark)

    Eriksen, Sophie Isabel; Bjerrum, Lars

    2015-01-01

    Prolonged consumption of benzodiazepine drugs (BZD) and benzodiazepine receptor agonists (zolpidem, zaleplon, zopiclone; altogether Z drugs) is related to potential physiological and psychological dependence along with other adverse effects. This study aimed to analyse the prescribing of long...... to the prescription. The observed reduction in BZD use was correlated to the introduction of new national guidelines on prescription of addictive drugs, but this study was not designed to detect a causal relationship. The prescribing of long-acting BZD decreased considerably more than the prescribing of short......-acting BZD (half-life >10 hr), compared to short-acting BZD in Denmark during a 10-year period. Descriptive analysis of total sales data from the Danish Register of Medicinal Product Statistics, to individuals in the primary healthcare sector, of all BZD and Z-drugs in the period of 2003-2013. Prescription...

  7. Rectal benzodiazepines for premedication in children. Review and personal experience.

    Science.gov (United States)

    Govaerts, M J; Capouet, V

    1987-01-01

    Modern anesthetic techniques have modified the aims of premedication in pediatric practice. Anxiolysis, amnesia and easiness of induction are now the the main targets. This paper reviews both the literature and the personal experience of the authors on the subject. Many authors now prefer a benzodiazepine. Rectal instillation of benzodiazepine in solution avoids the trauma of the intramuscular route and produces a faster and more predictable effect, than suppositories. Diazepam (.1 to .2 mg/kg) and flunitrazepam (40 to 80 micrograms/kg) have been extensively used in this indication. Diazepam's duration of elimination being much longer than that of flunitrazepam, this last drug is preferred by many pediatric anesthetists. Midazolam (.4 to .5 mg/kg) has a much faster onset and shorter duration of action. It should thus be preferred if the environment enables the administration of premedication within 10 to 15 minutes of induction.

  8. Electronic and conformational properties of 2,3-benzodiazepine derivates

    International Nuclear Information System (INIS)

    Pelaggi, M.; Girlanda, R.; Chimirri, A.; Gitto, R.

    1996-01-01

    The molecular geometric and electronic structures of 2,3-benzodiazepine derivates have been studied by means of the MNDO-PM3 method. A number of electronic properties have been computed and examined in order to find indication of the role of the electronic characteristics of the different molecules and their pharmacological properties. Theoretical data indicate that both electronic and structural properties appear responsible for the varying degree of anticonvulsant activity exhibited by compounds 1-4

  9. Electronic and conformational properties of 2,3-benzodiazepine derivates

    Energy Technology Data Exchange (ETDEWEB)

    Pelaggi, M.; Girlanda, R. [Messina Univ. (Italy). Dip. di Fisica della Materia e Fisica dell`Ambiente; Chimirri, A.; Gitto, R. [Messina Univ. (Italy). Dip. Farmaco-Chimico

    1996-04-01

    The molecular geometric and electronic structures of 2,3-benzodiazepine derivates have been studied by means of the MNDO-PM3 method. A number of electronic properties have been computed and examined in order to find indication of the role of the electronic characteristics of the different molecules and their pharmacological properties. Theoretical data indicate that both electronic and structural properties appear responsible for the varying degree of anticonvulsant activity exhibited by compounds 1-4.

  10. Visualization of specific binding sites of benzodiazepine in human brain

    International Nuclear Information System (INIS)

    Shinotoh, H.; Yamasaki, T.; Inoue, O.; Itoh, T.; Suzuki, K.; Hashimoto, K.; Tateno, Y.; Ikehira, H.

    1986-01-01

    Using 11C-labeled Ro15-1788 and positron emission tomography, studies of benzodiazepine binding sites in the human brain were performed on four normal volunteers. Rapid and high accumulation of 11C activity was observed in the brain after i.v. injection of [11C]Ro15-1788, the maximum of which was within 12 min. Initial distribution of 11C activity in the brain was similar to the distribution of the normal cerebral blood flow. Ten minutes after injection, however, a high uptake of 11C activity was observed in the cerebral cortex and moderate uptake was seen in the cerebellar cortex, the basal ganglia, and the thalamus. The accumulation of 11C activity was low in the brain stem. This distribution of 11C activity was approximately parallel to the known distribution of benzodiazepine receptors. Saturation experiments were performed on four volunteers with oral administration of 0.3-1.8 mg/kg of cold Ro15-1788 prior to injection. Initial distribution of 11C activity following injection peaked within 2 min and then the accumulation of 11C activity decreased rapidly and remarkably throughout the brain. The results indicated that [11C] Ro15-1788 associates and dissociates to specific and nonspecific binding sites rapidly and has a high ratio of specific receptor binding to nonspecific binding in vivo. Carbon-11 Ro15-1788 is a suitable radioligand for the study of benzodiazepine receptors in vivo in humans

  11. Peripheral benzodiazepine receptors are decreased during cocaine withdrawal in humans.

    Science.gov (United States)

    Javaid, J I; Notorangelo, M P; Pandey, S C; Reddy, P L; Pandey, G N; Davis, J M

    1994-07-01

    In the present study, homovanillic acid in plasma (pHVA) and benzodiazepine receptors (3H-PK11195 binding) in neutrophil membranes were determined in blood obtained from cocaine-dependent (DSM-III-R) adult male inpatients at baseline-(within 72 hr of last cocaine use) and after 3 weeks of cocaine abstinence, and normal controls. The mean (+/- SEM) pHVA at baseline (10.3 ng/ml +/- 1.1) was similar to normals and did not change after 3 weeks of cocaine abstinence. Similarly, the binding indices of benzodiazepine receptors in cocaine-dependent subjects as a group were not significantly different than in normal controls. In 10 cocaine-dependent subjects, however, where both blood samples were available, the number of 3H-PK11195 binding sites was significantly (p < 0.05) decreased after 3 weeks of cocaine abstinence (mean +/- sem: Bmax = 6371 +/- 657 fmol/mg protein) compared with baseline (Bmax = 7553 +/- 925 fmol/mg protein), although there were no differences in the binding affinity (mean +/- sem: KD = 8.6 +/- 1.2 nmol/L after 3 weeks of abstinence compared with 8.1 +/- 1.0 nmol/L at baseline). These preliminary results suggest that peripheral benzodiazepine receptors may play an important role in the pathophysiology of cocaine withdrawal in cocaine-dependent human subjects.

  12. Stories of Hell and Healing: Internet Users’ Construction of Benzodiazepine Distress and Withdrawal

    OpenAIRE

    Fixsen, Alison; Ridge, Damien T.

    2017-01-01

    Abstract Benzodiazepines are a group of drugs used mainly as sedatives, hypnotics, antiepileptics, and muscle relaxants. Consumption is recommended for 2 to 4 weeks only, due to fast onset of dependency and potentially distressing withdrawal symptoms. Few peer-review studies have drawn on the user experiences and language to appreciate firsthand experiences of benzodiazepine withdrawal or discontinuation syndrome. We looked extensively at patient stories of benzodiazepine withdrawal and recov...

  13. Balneotherapy Together with a Psychoeducation Program for Benzodiazepine Withdrawal: A Feasibility Study

    Science.gov (United States)

    De Maricourt, P.; Hergueta, Th.; Galinowski, A.; Salamon, R.; Diallo, A.; Vaugeois, C.; Lépine, J. P.; Olié, J. P.

    2016-01-01

    Benzodiazepines should be prescribed on a short-term basis, but a significant proportion of patients (%) use them for more than 6 months, constituting a serious public health issue. Indeed, few strategies are effective in helping patients to discontinue long-term benzodiazepine treatments. The aim of this study was to assess the feasibility and the impact of a program including cognitive behavioural therapy, psychoeducation, and balneotherapy in a spa resort to facilitate long-term discontinuation of benzodiazepines. We conducted a prospective multicentre cohort study. Patients with long-term benzodiazepine use were recruited with the aim of anxiolytic withdrawal by means of a psychoeducational program and daily balneotherapy during 3 weeks. The primary efficacy outcome measure was benzodiazepine use 6 months after the program, compared to use at baseline. A total of 70 subjects were enrolled. At 6 months, overall benzodiazepine intake had decreased by 75.3%, with 41.4% of patients completely stopping benzodiazepine use. The results also suggest a significantly greater improvement in anxiety and depression symptoms among patients who discontinued benzodiazepines compared to patients who only reduced their use. Our findings suggest that balneotherapy in association with a psychoeducative program is efficient in subjects with benzodiazepine addiction. PMID:27956923

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

    Science.gov (United States)

    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.

  15. Balneotherapy Together with a Psychoeducation Program for Benzodiazepine Withdrawal: A Feasibility Study

    Directory of Open Access Journals (Sweden)

    P. De Maricourt

    2016-01-01

    Full Text Available Benzodiazepines should be prescribed on a short-term basis, but a significant proportion of patients (% use them for more than 6 months, constituting a serious public health issue. Indeed, few strategies are effective in helping patients to discontinue long-term benzodiazepine treatments. The aim of this study was to assess the feasibility and the impact of a program including cognitive behavioural therapy, psychoeducation, and balneotherapy in a spa resort to facilitate long-term discontinuation of benzodiazepines. We conducted a prospective multicentre cohort study. Patients with long-term benzodiazepine use were recruited with the aim of anxiolytic withdrawal by means of a psychoeducational program and daily balneotherapy during 3 weeks. The primary efficacy outcome measure was benzodiazepine use 6 months after the program, compared to use at baseline. A total of 70 subjects were enrolled. At 6 months, overall benzodiazepine intake had decreased by 75.3%, with 41.4% of patients completely stopping benzodiazepine use. The results also suggest a significantly greater improvement in anxiety and depression symptoms among patients who discontinued benzodiazepines compared to patients who only reduced their use. Our findings suggest that balneotherapy in association with a psychoeducative program is efficient in subjects with benzodiazepine addiction.

  16. Radioreceptor assay for benzodiazepines in biological fluids using a new dry and stable receptor preparation

    International Nuclear Information System (INIS)

    Lund, J.

    1981-01-01

    A method for determination of benzodiazepines in human blood, plasma, saliva and urine has been developed. The method is based upon the competition between 3 H-flunitrazepam and biologically active benzodiazepines in biological fluids for brain specific receptors, prepared in a stable, dry form and easy to handle. The pharmacological specificity for benzodiazepines of the dry stable receptor preparation is closely similar to that of fresh membrane-bound rat brain receptors. The method is specific for biologically active benzodiazepines; it is relatively rapid, sensitive and reproducible, and can be performed at room temperature. (author)

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

    Science.gov (United States)

    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 .

  18. Status epilepticus: Role for etiology in determining response to benzodiazepines.

    Science.gov (United States)

    Joshi, Suchitra; Rajasekaran, Karthik; Hawk, Kyle M; Chester, Stephen J; Goodkin, Howard P

    2018-04-01

    Clinical factors contributing to benzodiazepine failure in treating status epilepticus (SE) include suboptimal dosing and seizure duration. As many benzodiazepine-refractory episodes of SE arise from acute etiologies, we sought to determine whether etiology impacts SE treatment. The potency of diazepam to terminate SE induced by lithium-pilocarpine (LiPilo-SE) or kainic acid (KA-SE) in 3-week-old rats was studied by video-electroencephalography. Synaptic γ-aminobutyric acid type A receptor (GABAR)-mediated currents were recorded from dentate granule cells using voltage-clamp electrophysiology. Surface expression of γ2 subunit-containing GABARs and Kv4.2 potassium channels in hippocampal slices was determined using a biotinylation assay. Expression of phosphorylated forms of β2/3 and γ2 subunits was determined using phosphospecific antibodies and Western blotting. Diazepam failed to terminate late SE in LiPilo-SE animals but was successful in terminating KA-SE of 1- and 3-hour duration. One hour after SE onset, GABAR-mediated synaptic inhibition and γ2 subunit-containing GABAR surface expression were reduced in LiPilo-SE animals. These were unchanged in KA-SE animals at 1 and 3 hours. Phosphorylation of γ2 subunit residue S327 was unchanged in both models, although GABAR β3 subunit S408/409 residues were dephosphorylated in the LiPilo-SE animals. Kv4.2 potassium channel surface expression was increased in LiPilo-SE animals but reduced in KA-SE animals. SE-model-dependent differences support a novel hypothesis that the development of benzodiazepine pharmacoresistance may be etiologically predetermined. Further studies are required to investigate the mechanisms that underlie such etiological differences during SE and whether etiology-dependent protocols for the treatment of SE need to be developed. Ann Neurol 2018;83:830-841. © 2018 American Neurological Association.

  19. A control study on treatment for benzodiazepine dependence with trazodone

    Directory of Open Access Journals (Sweden)

    ZHANG Hong-ju

    2013-05-01

    Full Text Available Objective To determine the efficacy and safety of trazodone in the treatment of benzodiazepine dependence. Methods Forty insomnia patients who met the Classification and Diagnostic Criteria of Mental Disorders in China Third Edition (CCMD-3 of dependence syndrome due to benzodiazepine were involved in the study. Patients were randomly assigned to trazodone group and placebo group for 3 months. The efficacy were assessed by Withdrawal Symptoms Checklist, Hamilton Anxiety Rating Scale (HAMA and polysomnography (PSG. Adverse events were assessed by Treatment Emergent Symptom Scale (TESS. Results The Withdrawal Symptoms Checklist of trazodone group was significantly lower after 7 d treatment than that of placebo group (P = 0.000, and HAMA score of the trazodone group was also significantly lower after 15 d treatment than that of placebo group (P = 0.000. There were no difference in Withdrawal Symptoms Checklist and HAMA of placebo group before and after treatment. Withdrawal Symptoms Checklist and HAMA of the trazodone group were decreased after treatment (P = 0.000. In comparison with placebo group, sleep parameters of the trazodone, including total sleep time (TST, sleep efficiency (SE, sleep latency (SL and slow wave sleep (SWS time presented improvement after 7 d treatment (P = 0.000, for all. After trazodone treatment, total sleep time, slow wave sleep time, sleep efficiency and sleep latency were improved (P = 0.000, for all. No obvious adverse reaction occurred. There were no significant differences in TESS scores between pre? and post?treatment in both groups (P > 0.05. Conclusion Trazodone is markedly effective and safe in the treatment for benzodiazepine dependence.

  20. Benzodiazepine receptor and neurotransmitter studies in the brain of suicides

    Energy Technology Data Exchange (ETDEWEB)

    Manchon, M.; Kopp, N.; Rouzioux, J.J.; Lecestre, D.; Deluermoz, S.; Miachon, S.

    1987-12-14

    The characteristics of benzodiazepine binding sites were studied on frozen sections of hippocampus of 7 suicides and 5 controls subjects, using biochemical and autoradiographic techniques. /sup 3/H flunitrazepam was used as ligand, clonazepam and CL 218,872 as displacing agents. Some neurotransmitters or their derivatives were evaluated quantitatively in parallel in the hippocampal tissue by liquid chromatography. The authors observed mainly an increase in the Ki of CL 218,872 subtype I binding sites in suicides, and an increase in % of type I binding sites. Among neurotransmitters, only norepinephrine differed significantly between controls and suicides. 36 references, 3 figures, 1 table.

  1. Benzodiazepine receptor and neurotransmitter studies in the brain of suicides

    International Nuclear Information System (INIS)

    Manchon, M.; Kopp, N.; Rouzioux, J.J.; Lecestre, D.; Deluermoz, S.; Miachon, S.

    1987-01-01

    The characteristics of benzodiazepine binding sites were studied on frozen sections of hippocampus of 7 suicides and 5 controls subjects, using biochemical and autoradiographic techniques. 3 H flunitrazepam was used as ligand, clonazepam and CL 218,872 as displacing agents. Some neurotransmitters or their derivatives were evaluated quantitatively in parallel in the hippocampal tissue by liquid chromatography. The authors observed mainly an increase in the Ki of CL 218,872 subtype I binding sites in suicides, and an increase in % of type I binding sites. Among neurotransmitters, only norepinephrine differed significantly between controls and suicides. 36 references, 3 figures, 1 table

  2. Benzodiazepines still play a role in modern psychiatric therapy

    DEFF Research Database (Denmark)

    Jørgensen, Martin Balslev; Videbech, Poul; Osler, Merete

    2017-01-01

    Benzodiazepines (BZ) are widely used for anxiety across psychiatric diagnoses, but for the last decades regulation has been increasingly tight due to problems with tolerance, addiction, withdrawal symptoms and cognitive side effects. Some guidelines claim that BZ only work for a few weeks......, and that BZ cause traffic accidents, increased mortality and dementia. In Denmark, the use of BZ has been substantially reduced. In this article it is argued, that not all patients habituate, that most of the epidemiological findings are hampered by confounding, and that there still is a role for long...

  3. The relation between the blood benzodiazepine concentration and performance in suspected impaired drivers

    NARCIS (Netherlands)

    Smink, B.E.; Lusthof, K.J.; de Gier, J.J.; Uges, D.R.; Egberts, A.C.

    2008-01-01

    Several experimental studies have shown a negative influence of benzodiazepines on driving skills. The objective of this study is to study the relationship between the blood concentration of benzodiazepines and the influence on performance in field sobriety tests. A retrospective case file

  4. Benzodiazepines and risk for hepatic encephalopathy in patients with cirrhosis and ascites

    DEFF Research Database (Denmark)

    Grønbæk, Lisbet; Watson, Hugh; Vilstrup, Hendrik

    2018-01-01

    Background: There is limited evidence to support the belief that benzodiazepines increase cirrhosis patients’ risk of hepatic encephalopathy (HE). Objective: We aimed to examine the association between benzodiazepine use and HE development in cirrhosis patients. Methods: We used data on 865...

  5. Biochemical study of multiple drug recognition sites on central benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Trifiletti, R.R.

    1986-01-01

    The benzodiazepine receptor complex of mammalian brain possesses recognition sites which mediate (at least in part) the pharmacologic actions of the 1,4-benzodiazepines and barbiturates. Evidence is provided suggesting the existence of least seven distinct drug recognition sites on this complex. Interactions between the various recognition sites have been explored using radioligand binding techniques. This information is utilized to provide a comprehensive scheme for characterizing receptor-active drugs on an anxiolytic-anticonvulsant/proconvulsant continuum using radioligand binding techniques, as well as a comprehensive program for identifying potential endogenous receptor-active substances. Further evidence is provided here supporting the notion of benzodiazepine recognition site heterogeneity. Classical 1,4-benzodiazepines do not appear to differentiate two populations of benzodiazepine receptors in an equilibrium sense, but appear to do so in a kinetic sense. An apparent physical separation of the two receptor subtypes can be achieved by differential solubilization. The benzodiazepine binding subunit can be identified by photoaffinity labeling with the benzodiazepine agonist (/sup 3/H)flunitrazepan. Conditions for reproducible partial proteolytic mapping of (/sup 3/H)flunitrazepam photoaffinity labeled receptors are established. From these maps, it is concluded that there are probably no major differences in the primary sequence of the benzodiazepine binding subunit in various regions of the rat central nervous system.

  6. Differences in health status between long-term and short-term benzodiazepine users.

    NARCIS (Netherlands)

    Zandstra, S.M.; Furer, J.W.; Lisdonk, E.H. van de; Bor, J.H.J.; Zitman, F.G.; Weel, C. van

    2002-01-01

    BACKGROUND: Despite generally accepted advice to keep treatment short, benzodiazepines are often prescibed for more than six months. Prevention of long-term benzodiazepine use could be facilitated by the utilisation of risk indicators for long-term use. However, the characteristics of long-term

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

    Science.gov (United States)

    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.

  8. Tapering off benzodiazepines in long-term users : an economic evaluation

    NARCIS (Netherlands)

    Oude Voshaar, Richard C; Krabbe, Paul F M; Gorgels, Wim J M J; Adang, Eddy M M; van Balkom, Anton J L M; van de Lisdonk, Eloy H; Zitman, Frans G

    2006-01-01

    BACKGROUND: Discontinuation of benzodiazepine usage has never been evaluated in economic terms. This study aimed to compare the relative costs and outcomes of tapering off long-term benzodiazepine use combined with group cognitive behavioural therapy (TO+CBT), tapering off alone (TOA) and usual

  9. An audit of prescribing practices for benzodiazepines and Z-drugs.

    LENUS (Irish Health Repository)

    Cadogan, C

    2015-03-01

    Concerns persist over the use of benzodiazepines and Z-drugs in Ireland. A prospective prescription audit was conducted in 81 community pharmacies across Ireland over a four week period. The study sought to assess the level of prescription compliance with key components of benzodiazepine and Z-drug prescribing guidelines. 28% of audit booklets issued were returned, yielding data on 4,418 prescriptions. The findings suggest that little progress has been made in improving the prescribing of benzodiazepines and Z-drugs in Ireland in the decade since publication of the Benzodiazepine Committee\\'s report. Fewer than one fifth of prescriptions (18.8%) were fully compliant with the assessment criteria and the majority (53.7%) had multiple discrepancies. This study highlights the importance of monitoring and auditing benzodiazepine and Z-drug prescribing practices. Interventions involving patients, prescribers and pharmacists are required to improve the prescribing and use of these medications in Ireland.

  10. Pet imaging of peripheral benzodiazepine binding sites in brain tumors

    International Nuclear Information System (INIS)

    Junck, L.; Jewett, D.M.; Olsen, J.M.; Kilbourn, M.R.; Koeppe, R.A.; Young, A.B.; Greenberg, H.S.; Kuhl, D.E.

    1991-01-01

    Studies in vitro have shown that the peripheral-type benzodiazepine binding site (PBBS) is present in moderate to high density on malignant gliomas as well as in areas of reactive gliosis, but in low density in normal brain. PK 11195 is an isoquinoline derivative that binds selectively to the PBBS but not to the central benzodiazepine receptor. We have used [ 11 C]PK 11195 with positron emission tomography (PET) to study brain tumors and cerebral infarcts. Preliminary results showed that, in 13 of 18 patients with astrocytomas, [ 11 C]PK 11195 radioactivity was increased in tumor compared to remote brain and that the concentration ratios of tumor-to-remote brain were higher for high grade astrocytomas than for low grade astrocytomas. Pharmacokinetic analysis suggests that the increased activity in tumor probably does not result from alterations in blood flow or vascular permeability. Patients with lymphoma, meningioma, medulloblastoma, brain metastasis, and neurosarcoidosis have also shown increased radioactivity in tumor. Among eight patients with acute and subacute cerebral infarcts, activity in the infarct was increased in seven and was often greatest at the periphery. We conclude that [ 11 C]PK 11195 is a promising radiopharmaceutical for further investigation of brain tumors as well as diseases characterized by reactive gliosis

  11. Benzodiazepine prescription in relation to psychiatric diagnosis and patient characteristics: A pilot study

    Directory of Open Access Journals (Sweden)

    Marić Nađa P.

    2015-01-01

    Full Text Available Introduction: Benzodiazepines are widely used drugs which are often misused. Analysis of psychotropic drugs prescription in Serbia showed high prescription rate of benzodiazepines in the psychiatric patient population, with an increasing trend. Potential association between psychiatric diagnostic categories (organic brain syndrome, psychotic disorders, bipolar disorder, unipolar depression, anxiety disorder, personality disorder, or the sociodemographic characteristics of patients (gender, age, education, marital state and benzodiazepine prescribing practice was not thoroughly tested. Aim: By analyzing routine practice of the university clinic, the aim of this study was to examine whether there is an association between clinical or socio-demographic characteristics of the patients and benzodiazepine prescribing practice. Material and methods: This study was carried out by retrospective analysis of the patient's medical charts after hospital discharge (n=102. Data analysis included descriptive statistics, testing the difference between groups and correlation analysis. Results: At the discharge, 94.1% of patients had benzodiazepines prescribed, with an average dose of 4.6 ± 3.2mg lorazepam dose equivalents. It is shown that female patients were prescribed with higher doses of benzodiazepines than male patients (p=0.018, that the average dose was higher for patients treated with an overall larger number of psychiatric drugs (p = 0.013, as well as that hospital inpatients had higher doses compared to day hospital-treated patients (p = 0.011. Patients with a diagnosis of personality disorder had a slight upward trend of benzodiazepine dose (p=0.078. Conclusion: Current research provided a clear insight into the actual practice of benzodiazepine prescription at local university center. Similarly to our region, indications for prescribing benzodiazepines appear to be quite broad and not specific enough worldwide. This is why it is important to

  12. Benzodiazepine prescribing behaviour and attitudes: a survey among general practitioners practicing in northern Thailand

    Directory of Open Access Journals (Sweden)

    Critchley Julia

    2005-06-01

    Full Text Available Abstract Background Over-prescribing of benzodiazepines appears common in many countries, a better understanding of prescribing practices and attitudes may help develop strategies to reduce prescribing. This study aimed to evaluate benzodiazepine prescribing behaviour and attitudes in general practitioners practising in Chiang Mai and Lampoon, Thailand. Methods Questionnaire survey of general practitioners in community hospitals, to estimate: i use of benzodiazepines for anxiety/insomnia, panic disorder, depression, essential hypertension, and uncomplicated low back pain and ii views on the optimal duration of benzodiazepine use. Results Fifty-five of 100 general practitioners returned the completed questionnaires. They reported use of benzodiazepines for anxiety/insomnia (n = 51, 93%, panic disorder (n = 43, 78%, depression (n = 26, 43%, essential hypertension (n = 15, 27 % and uncomplicated low back pain (n = 10, 18%. Twenty-eight general practitioners would prescribe benzodiazepines for non-psychiatric conditions, 17 for use as muscle relaxants. Seventy-five per cent, 62% and 29% of the general practitioners agreed or totally agreed with the use of benzodiazepines for insomnia, anxiety and depression, respectively. Practitioners agreed that prescribing should be less than one week (80%; or from 1 week to 1 month (47%; or 1 to 4 months (16%; or 4 to 6 months (5% or more than 6 months (2%. Twenty-five general practitioners (45% accepted that they used benzodiazepines excessively in the past year. Conclusion A considerable proportion of general practitioners in Chiang Mai and Lampoon, Thailand inappropriately use benzodiazepines for physical illnesses, especially essential hypertension and uncomplicated low back pain. However, almost half of them thought that they overused benzodiazepines. General practitioner's lack of time, knowledge and skills should be taken into account in improving prescribing behaviour and attitudes.

  13. Use of benzodiazepines or benzodiazepine related drugs and the risk of cancer: a population-based case-control study

    DEFF Research Database (Denmark)

    Pottegård, Anton; Friis, Søren; Andersen, Morten

    2013-01-01

    AIM: Studies of the carcinogenic potential of benzodiazepines and related drugs (BZRD) have been equivocal. A recent study reported a 35% excess cancer risk among users of hypnotics, including benzodiazepines. METHOD: Using Danish nationwide registers, we conducted a matched case-control study...... of the association between BZRD and cancer risk. During 1 January 2002 and 31 December 2009, we identified 152 510 cases with a first time cancer who were matched (1:8) by age and gender to 1,220,317 cancer-free controls. A new-user design was applied by excluding all subjects who had used anxiolytics, hypnotics.......02), liver 1.81 (95% CI 1.18, 2.80), lung 1.38 (95% CI 1.23, 1.54), pancreas 1.35 (95% CI 1.02, 1.79) and kidney 1.39 (95% CI 1.01, 1.91). For tobacco-related cancers, the OR was 1.15 (95% CI 1.09, 1.22) and for the remaining cancer sites 1.01 (95% CI 0.94, 1.08). Sub-group analyses revealed only small...

  14. High density of benzodiazepine binding sites in the substantia innominata of the rat

    International Nuclear Information System (INIS)

    Sarter, M.; Schneider, H.H.

    1988-01-01

    In order to study the neuronal basis of the pharmacological interactions between benzodiazepine receptor ligands and cortical cholinergic turnover, we examined the regional distribution of specific benzodiazepine binding sites using in vitro autoradiography. In the basal forebrain, the substantia innominata contained a high density of [ 3 H]lormetazepam (LMZ) binding sites (Bmax = 277 fmol/mg tissue; Kd = 0.55 nM). The label could be displaced by diazepam (IC50 = 100 nM), the benzodiazepine receptor antagonist beta-carboline ZK 93426 (45 nM) and the partial inverse agonist beta-carboline FG 7142 (540 nM). It is hypothesized that the amnesic effects of benzodiazepine receptor agonists are exerted through benzodiazepine receptors which are situated on cholinergic neurons in the substantia innominata and are involved in a tonic inhibition of cortical acetylcholine release. The benzodiazepine receptor antagonist ZK 93426 may exert its nootropic effects via benzodiazepine receptors in the substantia innominata and, consequently, by disinhibiting cortical acetylcholine release

  15. Preliminary finding: consumption of benzodiazepines in Brazil during the years 1988 and 1989.

    Science.gov (United States)

    Nappo, S; Carlini, E A

    1993-06-01

    This work investigates consumption of benzodiazepines in Brazil during the years 1988 and 1989, using the following sources of information provided to the Brazilian Ministry of Health by institutions that deal with benzodiazepines: (a) benzodiazepine stocks recorded at the beginning and end of each year; (b) Brazilian (internal) production of benzodiazepines; (c) imported and exported amounts of benzodiazepines; (d) amounts employed in the manufacture of brand-name products and in the making of prescription formulas. The records a, b and c furnished the 'calculated consumption', of benzodiazepines, in kilograms. The d records, on the other hand, directly furnished the 'informed consumption', also in kilograms. The data obtained were also expressed in terms of defined daily doses (DDDs)/1,000 inhabitants/day, considering the informed consumption and the Brazilian population. As for the DDDs/1000 inhabitants/day, they were found to be 23.03 and 18.48 for the years 1988 and 1989, respectively. A striking discrepancy was detected between the calculated and the informed consumption figures, the latter having exceeded the former by 2096 kg in 1988 and by 4909 kg in 1989. Diazepam was the primary drug responsible for this difference. Such results may suggest that an illicit, unrecorded trade of benzodiazepines is occurring in Brazil.

  16. Physiology and physiopathology of central type Benzodiazepine receptors: Study in the monkey and in human brain using positron emission tomography

    International Nuclear Information System (INIS)

    Hantraye, P.

    1987-01-01

    A new non-invasive technique that allows to study in a living subject central type benzodiazepine receptors is developed. A combined approach is applied using a specific positron-emitting radiotracer for the in vivo labelling of the receptors and positron emission tomography allowing, by external detection, a quantitative determination of tissue radioactivity. The radioligand used for the in vivo labelling of benzodiazepine receptors is the antagonist RO 15-1788 labelled with carbon 11. The various stages of the study are described: in vivo characterization in the monkey of central type benzodiazepine receptors; characterization of central type benzodiazepine receptors in human brain using selective molecules for the BZ1 benzodiazepine subclass; demonstration of the heterogeneity of central type benzodiazepine receptors in the brain; study of pathological alteration of benzodiazepine receptors in experimental epilepsy [fr

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  19. Application of radioreceptor assay of benzodiazepines for toxicology

    International Nuclear Information System (INIS)

    Aaltonen, L.; Scheinin, M.

    1982-01-01

    A radioreceptor assay (RRA) for determining benzodiazepines (BZ) has been developed and applied to toxicological analysis of serum samples from 21 patients with acute BZ overdosage. The method was sensitive (e.g., lorazepam 17 nM, diazepam 41 nM), and specific for pharmacologically active BZ derivatives. The reproducibility of the results was good (intra-assay variation < 8%, inter-assay variation < 10%). Concentrations measured by the RRA showed a good correlation with those obtained by gas-liquid chromatographic analysis of the same samples. The quantitative results represent the sum of one or several parent substances and all biologically active metabolites, in proportion to their receptor binding affinities. (author)

  20. Simple synthesis, structure and ab initio study of 1,4-benzodiazepine-2,5-diones

    Science.gov (United States)

    Jadidi, Khosrow; Aryan, Reza; Mehrdad, Morteza; Lügger, Thomas; Ekkehardt Hahn, F.; Ng, Seik Weng

    2004-04-01

    A simple procedure for the synthesis of pyrido[2,1-c][1,4] benzodiazepine-6,12-dione ( 1) and 1,4-benzodiazepine-2,5-diones ( 2a- 2d), using microwave irradiation and/or conventional heating is reported. The configuration of 1 was determined by single-crystal X-ray diffraction. A detailed ab initio B3LYP/6-31G* calculation of structural parameters and substituent effects on ring inversion barriers (Δ G#) and also free energy differences (Δ G0) for benzodiazepines are reported.

  1. Synthesis, Anticonvulsant, Sedative and Anxiolytic Activities of Novel Annulated Pyrrolo[1,4]benzodiazepines

    Directory of Open Access Journals (Sweden)

    Kumaraswamy Sorra

    2014-09-01

    Full Text Available 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  3. QuEChERS extraction of benzodiazepines in biological matrices

    Directory of Open Access Journals (Sweden)

    Jessica L. Westland

    2013-12-01

    Full Text Available Two common analytical chemical problems often encountered when using chromatographic techniques in drug analysis are matrix interferences and ion suppression. Common sample preparation often involves the dilution of the sample prior to injection onto an instrument, especially for liquid chromatography–mass spectrometry (LC–MS analyses. This practice frequently does not minimize or eliminate conditions that may cause ion-suppression and therefore, suffer more from reduced method robustness. In order to achieve higher quality results and minimize possible interferences, various sample preparation techniques may be considered. Through the use of QuEChERS (“catchers”, a novel sample preparation technique used for high aqueous content samples, benzodiazepines can be extracted from biological fluids, such as blood and urine. This approach has shown increased recoveries of target compounds when using quantification by both external and internal standard. This increase in the recoveries has been attributed to a matrix enhancement and was determined through the use of the method of standard addition. While improving the overall analytical method for gas chromatography–mass spectrometry (GC–MS analysis, it is not clear if this approach represents an overall benefit for laboratories that have both GC–MS and high performance liquid chromatography tandem mass spectrometry (HPLC–MS/MS capability. Demonstrating evidence of variable ionization (enhancement, ion source inertness, etc., the method of quantification should be focused on in future studies. Keywords: Forensic science, QuEChERS, Drug analysis, Benzodiazepines, Gas Chromatography–Mass Spectrometry, Biological samples

  4. Benzodiazepine effect of 125I-iomazenil-benzodiazepine receptor binding and serum corticosterone level in a rat model

    International Nuclear Information System (INIS)

    Fukumitsu, Nobuyoshi; Ogi, Shigeyuki; Uchiyama, Mayuki; Mori, Yutaka

    2005-01-01

    To test the change in free or unoccupied benzodiazepine receptor (BZR) density in response to diazepam, we investigated 125 I-iomazenil ( 125 I-IMZ) binding and serum corticosterone levels in a rat model. Wistar male rats, which received psychological stress using a communication box for 5 days, were divided into two groups according to the amount of administered diazepam: no diazepam [D (0)] group and 10 mg/kg per day [D (10)] group of 12 rats each. The standardized uptake value (SUV) of 125 I-IMZ of the D (10) group were significantly lower (P 125 I-IMZ, it is clear that diazepam competed with endogenous ligand for the free BZR sites, and the frontal, parietal and temporal cortices, globus pallidus, hippocampus, amygdala and hypothalamus are important areas in which 125 I-IMZ binding is strongly affected by administration of diazepam

  5. Intramolecular Azide to Alkene Cycloadditions for the Construction of Pyrrolobenzodiazepines and Azetidino-Benzodiazepines

    Czech Academy of Sciences Publication Activity Database

    Hemming, K.; Chambers, Christopher S.; Jamshaid, F.; O´Gorman, Paul A.

    2014-01-01

    Roč. 19, č. 10 (2014), s. 16737-16756 ISSN 1420-3049 Institutional support: RVO:61388971 Keywords : azide * cycloadditions * benzodiazepines Subject RIV: CC - Organic Chemistry Impact factor: 2.416, year: 2014

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

    Science.gov (United States)

    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 treatment. Flumazenil might improve benzodiazepines-induced unconsciousness markedly and may be the most effective antagonist of benzodiazepines.

  7. Iodine-125 radioimmunoassay for the direct detection of benzodiazepines in blood and urine

    Energy Technology Data Exchange (ETDEWEB)

    Goddard, C.P.; Stead, A.H.; Mason, P.A.; Law, B.; Moffat, A.C.; McBrien, M.; Cosby, S.

    1986-05-01

    A radioimmunoassay (RIA) for the direct detection of benzodiazepines in blood and urine is described. It is based on a commercially available antiserum and an easily synthesised radio-iodinated derivative of clonazepam that allows the use of relatively simple gamma-counting procedures. The assay can detect low therapeutic levels of all of the benzodiazepines currently available in the UK in 50-..mu..l samples of blood and urine (1-50 ng ml/sup -1/, depending on the drug); no prior sample preparation is required. It is inexpensive, rapid, simple to perform and is broadly specific for the benzodiazepine class of drugs. The assay offers a most suitable means of screening large numbers of samples of forensic interest for the presence of the benzodiazepines.

  8. Circadian rest-activity rhythms during benzodiazepine tapering covered by melatonin versus placebo add-on

    DEFF Research Database (Denmark)

    Baandrup, Lone; Fasmer, Ole Bernt; Glenthøj, Birte Yding

    2016-01-01

    is associated with changes in circadian rhythm parameters. METHOD: Data were derived from a randomized, double-blinded clinical trial with 24 weeks follow-up. Participants were randomized to add-on treatment with prolonged-release melatonin (2 mg) or matching placebo, and usual benzodiazepine dosage...... significantly increased the interdaily stability and at a trend level decreased the intradaily variability compared with placebo. Benzodiazepine dose reduction was not associated with these circadian rhythm parameters. Activity counts were generally higher after benzodiazepine dose reduction compared with pre......BACKGROUND: Patients with severe mental illness often suffer from disruptions in circadian rest-activity cycles, which might partly be attributed to ongoing psychopharmacological medication. Benzodiazepines are frequently prescribed for prolonged periods despite recommendations of only short...

  9. An iodine-125 radioimmunoassay for the direct detection of benzodiazepines in blood and urine

    International Nuclear Information System (INIS)

    Goddard, C.P.; Stead, A.H.; Mason, P.A.; Law, B.; Moffat, A.C.; McBrien, M.; Cosby, S.

    1986-01-01

    A radioimmunoassay (RIA) for the direct detection of benzodiazepines in blood and urine is described. It is based on a commercially available antiserum and an easily synthesised radio-iodinated derivative of clonazepam that allows the use of relatively simple gamma-counting procedures. The assay can detect low therapeutic levels of all of the benzodiazepines currently available in the UK in 50-μl samples of blood and urine (1-50 ng ml -1 , depending on the drug); no prior sample preparation is required. It is inexpensive, rapid, simple to perform and is broadly specific for the benzodiazepine class of drugs. The assay offers a most suitable means of screening large numbers of samples of forensic interest for the presence of the benzodiazepines. (author)

  10. Benzodiazepines and risk of all cause mortality in adults: cohort study.

    Science.gov (United States)

    Patorno, Elisabetta; Glynn, Robert J; Levin, Raisa; Lee, Moa P; Huybrechts, Krista F

    2017-07-06

    Objectives  To evaluate the risk of all cause mortality associated with initiating compared with not initiating benzodiazepines in adults, and to address potential treatment barriers and confounding related to the use of a non-active comparator group. Design  Retrospective cohort study. Setting  Large de-identified US commercial healthcare database (Optum Clinformatics Datamart). Participants  1:1 high dimensional propensity score matched cohort of benzodiazepine initiators, and randomly selected benzodiazepine non-initiators with a medical visit within 14 days of the start of benzodiazepine treatment (n=1 252 988), between July 2004 and December 2013. To address treatment barriers and confounding, patients were required to have filled one or more prescriptions for any medication in the 90 days and 91-180 days before the index date (ie, the date of starting benzodiazepine treatment for initiators and the date of the selected medical visit for benzodiazepine non-initiators) and the high dimensional propensity score was estimated on the basis of more than 300 covariates. Main outcome measure  All cause mortality, determined by linkage with the Social Security Administration Death Master File. Results  Over a six month follow-up period, 5061 and 4691 deaths occurred among high dimensional propensity score matched benzodiazepine initiators versus non-initiators (9.3 v 9.4 events per 1000 person years; hazard ratio 1.00, 95% confidence interval 0.96 to 1.04). A 4% (95% confidence interval 1% to 8%) to 9% (2% to 7%) increase in mortality risk was observed associated with the start of benzodiazepine treatment for follow-ups of 12 and 48 months and in subgroups of younger patients and patients initiating short acting agents. In secondary analyses comparing 1:1 high dimensional propensity score matched patients initiating benzodiazepines with an active comparator, ie, patients starting treatment with selective serotonin reuptake inhibitor antidepressants

  11. Synthesis of Riboflavines, Quinoxalinones and Benzodiazepines through Chemoselective Flow Based Hydrogenations

    Directory of Open Access Journals (Sweden)

    Marcus Baumann

    2014-07-01

    Full Text Available Robust chemical routes towards valuable bioactive entities such as riboflavines, quinoxalinones and benzodiazepines are described. These make use of modern flow hydrogenation protocols enabling the chemoselective reduction of nitro group containing building blocks in order to rapidly generate the desired amine intermediates in situ. In order to exploit the benefits of continuous processing the individual steps were transformed into a telescoped flow process delivering selected benzodiazepine products on scales of 50 mmol and 120 mmol respectively.

  12. Engagement in leisure activities and benzodiazepine use in a French community-dwelling elderly population.

    Science.gov (United States)

    Bazin, Fabienne; Noize, Pernelle; Dartigues, Jean-François; Ritchie, Karen Anne; Tavernier, Beatrice; Moore, Nicholas; Pariente, Antoine; Fourrier-Reglat, Annie

    2012-07-01

    The prevalence of benzodiazepine use among community-dwelling older persons varies between 10% and 30%. The aim of this study was to explore the association between leisure activities and the use of benzodiazepine among older persons living at home. The study population included 4848 persons aged 65 years and over living in either of two French cities. Information was collected from a questionnaire administered to the respondents by trained psychologists during face-to-face interviews at home and from a self-administered questionnaire. Baseline examination included socio-demographic characteristics, drug use and leisure activities. We classified as benzodiazepine users subjects who reported use of at least one benzodiazepine during the month preceding the interview. The association between the use of benzodiazepine and leisure activities was assessed by logistic regression adjusted on known potential confounders. More than 18% of participants reported use of at least one benzodiazepine. The adjusted odds ratio (OR) of benzodiazepine use associated with no or lower participation versus participation in the following activities were as follows: OR = 1.31 (95% confidence interval (CI): 1.09 to 1.58) for mental activity; OR = 1.50 (CI: 1.12 to 2.03) for physical activity; OR = 1.28 (CI: 1.05 to 1.55) for productive activity and OR = 0.82 (CI: 0.69 to 0.97) for recreational activity. Low engagement in stimulating activities and high engagement in sedentary activities were associated with recent benzodiazepine use. Copyright © 2011 John Wiley & Sons, Ltd.

  13. Benzodiazepine receptor binding in vivo with (/sup 3/)-Ro 15-1788

    Energy Technology Data Exchange (ETDEWEB)

    Goeders, N.E.; Kuhar, M.J.

    1985-07-29

    In vivo benzodiazepine receptor binding has generally been studied by ex vivo techniques. In this investigation, the authors identify the conditions where (/sup 3/H)-Ro 15-1788 labels benzodiazepine receptors by true in vivo binding, i.e. where workable specific to nonspecific ratios are obtained in intact tissues without homogenization or washing. (/sup 3/H)-Flunitrazepam and (/sup 3/H)-clonazepam did not exhibit useful in vivo receptor binding. 39 references, 5 figures, 1 table.

  14. Intramolecular Azide to Alkene Cycloadditions for the Construction of Pyrrolobenzodiazepines and Azetidino-Benzodiazepines

    Directory of Open Access Journals (Sweden)

    Karl Hemming

    2014-10-01

    Full Text Available The coupling of proline- and azetidinone-substituted alkenes to 2-azidobenzoic and 2-azidobenzenesulfonic acid gives precursors that undergo intramolecular azide to alkene 1,3-dipolar cycloadditions to give imine-, triazoline- or aziridine-containing pyrrolo[1,4]benzodiazepines (PBDs, pyrrolo[1,2,5]benzothiadiazepines (PBTDs, and azetidino[1,4]benzodiazepines. The imines and aziridines are formed after loss of nitrogen from a triazoline cycloadduct. The PBDs are a potent class of antitumour antibiotics.

  15. Addressing the Issue of Chronic, Inappropriate Benzodiazepine Use: How Can Pharmacists Play a Role?

    Directory of Open Access Journals (Sweden)

    Helen C. Gallagher

    2013-09-01

    Full Text Available Prescribing guidelines do not recommend the long-term use of benzodiazepines since their effectiveness with chronic use is out-weighed by risks including dependence, memory and cognitive impairment, hip fractures and traffic accidents. Despite these guidelines, historical data points to an increasing proportion of inappropriate, repeat prescribing of benzodiazepines in Ireland and elsewhere, with up to 33% of patients who use these drugs doing so long-term. The typical long-term benzodiazepine user is an older, socio-economically disadvantaged patient who has been prescribed these medicines by their general practitioner (GP and dispensed them by their community pharmacist. Misuse of benzodiazepines in nursing homes and psychiatric institutions is also of concern, with one Irish study indicating that almost half of all admissions to a psychiatric hospital were prescribed these drugs, usually despite a lack of clear clinical need. Discontinuation of benzodiazepines has proven to be of benefit, as it is followed by improvements in cognitive and psychomotor function, particularly in elderly patients. It is obvious that an inter-professional effort, focusing on the primary care setting, is required to address benzodiazepine misuse and to ensure appropriate pharmaceutical care. Pharmacists must be an integral part of this inter-professional effort, not least because they are uniquely positioned as the health professional with most frequent patient contact. There is already some supporting evidence that pharmacists’ involvement in interventions to reduce benzodiazepine use can have positive effects on patient outcomes. Here, this evidence is reviewed and the potential for pharmacists to play an expanded role in ensuring the appropriate use of benzodiazepines is discussed.

  16. Phenobarbital compared to benzodiazepines in alcohol withdrawal treatment: A register-based cohort study of subsequent benzodiazepine use, alcohol recidivism and mortality.

    Science.gov (United States)

    Askgaard, Gro; Hallas, Jesper; Fink-Jensen, Anders; Molander, Anna Camilla; Madsen, Kenneth Grønkjær; Pottegård, Anton

    2016-04-01

    Long-acting benzodiazepines such as chlordiazepoxide are recommended as first-line treatment for alcohol withdrawal. These drugs are known for their abuse liability and might increase alcohol consumption among problem drinkers. Phenobarbital could be an alternative treatment option, possibly with the drawback of a more pronounced acute toxicity. We evaluated if phenobarbital compared to chlordiazepoxide decreased the risk of subsequent use of benzodiazepines, alcohol recidivism and mortality. The study was a register-based cohort study of patients admitted for alcohol withdrawal 1998-2013 and treated with either phenobarbital or chlordiazepoxide. Patients were followed for one year. We calculated hazard ratios (HR) for benzodiazepine use, alcohol recidivism and mortality associated with alcohol withdrawal treatment, while adjusting for confounders. A total of 1063 patients treated with chlordiazepoxide and 1365 patients treated with phenobarbital were included. After one year, the outcome rates per 100 person-years in the phenobarbital versus the chlordiazepoxide cohort were 9.20 vs. 5.13 for use of benzodiazepine, 37.9 vs. 37.9 for alcohol recidivism and 29 vs. 59 for mortality. Comparing phenobarbital to chlordiazepoxide treated, the HR of subsequent use of benzodiazepines was 1.56 (95%CI 1.05-2.30). Similarly, the HR for alcohol recidivism was 0.99 (95%CI 0.84-1.16). Lastly, the HR for 30-days and 1 year mortality was 0.25 (95%CI 0.08-0.78) and 0.51 (95%CI 0.31-0.86). There was no decreased risk of subsequent benzodiazepine use or alcohol recidivism in patients treated with phenobarbital compared to chlordiazepoxide. Phenobarbital treatment was associated with decreased mortality, which might be confounded by somatic comorbidity among patients receiving chlordiazepoxide. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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

  19. An Update on the Synthesis of Pyrrolo[1,4]benzodiazepines

    Directory of Open Access Journals (Sweden)

    George Varvounis

    2016-01-01

    Full Text Available Pyrrolo[1,4]benzodiazepines are tricyclic compounds that are considered “privileged structures” since they possess a wide range of biological activities. The first encounter with these molecules was the isolation of anthramycin from cultures of Streptomyces, followed by determination of the X-ray crystal structure of the molecule and a study of its interaction with DNA. This opened up an intensive synthetic and biological study of the pyrrolo[2,1-c][1,4]benzodiazepines that has culminated in the development of the dimer SJG-136, at present in Phase II clinical trials. The synthetic efforts have brought to light some new synthetic methodology, while the contemporary work is focused on building trimeric pyrrolo[2,1-c][1,4]benzodiazepines linked together by various heterocyclic and aliphatic chains. It is the broad spectrum of biological activities of pyrrolo[1,2-a][1,4]benzodiazepines that has maintained the interest of researchers to date whereas several derivatives of the even less studied pyrrolo[1,2-d][1,4]benzodiazepines were found to be potent non-nucleoside HIV-1 reverse transcriptase inhibitors. The present review is an update on the synthesis of pyrrolo[2,1-c][1,4]benzodiazepines since the last major review of 2011, while the overview of the synthesis of the other two tricyclic isomers is comprehensive.

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

    Science.gov (United States)

    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 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/BDZRA prescribing between

  1. Pattern of utilization of benzodiazepines in patients with hypertension: A pilot study

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    Divac Nevena

    2006-01-01

    Full Text Available Background/Aim. The analysis of drug prescribing in general practice in Serbia showed that the use of benzodiazepines is most frequently associated with hypertension. The aim of this study was to establish the correlation of the characteristics of patients with hypertension to antihypertensive drug therapy, and the intake of benzodiazepines. Methods. A special questionnaire was used for interviewing the patients (n = 171 chronically treated for hypertenson. Statistical tests used were χ2-test and Student's t-test. Results. No differences were noted in terms of age, gender, education, body weight, smoking habits and blood pressure (155±4.9/100±2.7 mmHg vs. 160±2.2/105±3.7 mmHg, between the group I (antihypertensive drugs+benzodiazepines: n = 79, and the group II (antihypertensives only: n = 92. The patients taking benzodiazepines received a lower number of different antihypertensive drugs (2.3±0.09 vs. 2.7±0.10; p < 0.01, but the total antihypertensive drug load was significantly greater than in the group II (2.6±0.10 vs. 1.9±0.15 defined daily doses (DDD/patient/day; p < 0.01. Benzodiazepines were taken for anxiety (62% and hypertension (21%, rarely for insomnia, mostly once a day, at bedtime. About half the patients took benzodiazepines regularly for months or years aware of the risk for addiction. Diazepam was used by 82% of the patients. The average daily exposure to benzodiazepines was 0.45±0.05 DDD/patient/day. The drug was bought without prescription in 25% of the patients, and without consulting a physician in 12% of them. Conclusion. The study confirmed a close association of hypertension with the use of benzodiazepines. The frequent use of benzodiazepines in the patients with hypertension might be caused by an inadequate response to antihypertensive drug therapy, besides anxiety and insomnia. The therapeutic efficacy of a long-term use of low doses of benzodiazepines in hypertension requires further investigation.

  2. The lesser evil? Initiating a benzodiazepine prescription in general practice

    Science.gov (United States)

    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

  3. Autoradiographic localization of benzodiazepine receptors in the rat kidney

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    Beaumont, K.; Healy, D.P.; Fanestil, D.D.

    1984-11-01

    The localization of benzodiazepine (BZD) receptors in the rat kidney was studied by autoradiography after in vitro labeling of kidney slices with flunitrazepam. The affinity, density, and rank order of displacement of (/sup 3/H)-flunitrazepam by several BZDs (RO 5-4864 > diazepam > clonazepam) demonstrated that binding was to BZD receptors of the peripheral type. In autoradiograms obtained with tritium-sensitive film, a high density of silver grains was obtained in the outer medulla, with lower densities in the cortex. Binding was absent from the inner medulla (papilla). In higher resolution autoradiograms obtained with an emulsion-coated cover slip procedure, silver grains were seen to be concentrated over a tubular element in both outer medulla and cortex, identifiable by morphology and distribution as the thick ascending limb of the loop of Henle and the distal convoluted tubule. The identity of the labeled tubules was confirmed by immunofluorescent localization in adjacent slices of Tamm-Horsfall protein, a specific marker for these segments of tubules. Investigation of the effects of peripherally specific BZDs such as RO 5-4864 on distal tubule function is indicated.

  4. Effect of chronic (-)-nicotine treatment on rat cerebral benzodiazepine receptors

    International Nuclear Information System (INIS)

    Magata, Yasuhiro; Kitano, Haruhiro; Shiozaki, Toshiki; Iida, Yasuhiko; Nishizawa, Sadahiko; Saji, Hideo; Konishi, Junji

    2000-01-01

    The purpose of this study was to clarify the effect of (-)-nicotine on cerebral benzodiazepine receptors (BzR) with radiotracer methods. The effect of (-)-nicotine on BzR was examined in in vitro studies using chronic (-)-nicotine-treated rats using 3 H-diazepam. The in vitro radioreceptor assay showed a 14% increase in the maximum number of binding sites of BzR in chronic (-)-nicotine-treated rats in comparison with the control rats. Moreover, a convenient in vivo uptake index of 125 I-iomazenil was calculated and a higher uptake of the radioactivity was observed in the chronic (-)-nicotine-treated group than in the control group. Although further studies of the mechanism of (-)-nicotine on such BzR changes are required, an increase in the amount of BzR in the cerebral cortex was found in rats that underwent chronic (-)-nicotine treatment, and this result contributed to the understanding of the effects of (-)-nicotine and smoking on neural functions

  5. Sleep architecture in insomniacs with severe benzodiazepine abuse.

    Science.gov (United States)

    Manconi, Mauro; Ferri, Raffaele; Miano, Silvia; Maestri, Michelangelo; Bottasini, Valentina; Zucconi, Marco; Ferini-Strambi, Luigi

    2017-06-01

    Benzodiazepines (BZDs) are the most commonly prescribed compounds in insomnia. A long-term of BZDs use may cause dependence and abuse. The aim of this study was to evaluate sleep architecture and microstructure (in terms of cyclic alternating pattern - CAP - analysis and of sleep EEG power spectral analysis) in a group of long-term users of high doses of BZDs for their primary chronic insomnia. Twenty patients consecutively admitted at the Sleep Centre for drug discontinuation and 13 matched healthy controls underwent a full nocturnal video-polysomnographic recording, after one adaptation night. Significant differences were found in time in bed, REM sleep latency and sleep stage 1% which were increased in patients compared to controls, while CAP rate was dramatically decreased. During NREM sleep, patients showed a clear decrease in the relative power of delta band. Our data demonstrate that in adults with chronic insomnia, long-term use of high doses of BZDs induces a severe disruption of sleep microstructure, while sleep architecture seems to be much less affected. The long term use of high doses of BZDs for chronic insomnia induces a marked depression of slow wave activity and of its physiological instability. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

  6. Are the effects of benzodiazepines on discrimination and punishment dissociable?

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    Hodges, H; Green, S

    1987-01-01

    Studies have shown that benzodiazepines (BZs) both disrupt discrimination and increase resistance to punishment. Using a delayed response task, we provide evidence that effects of BZs on discrimination cannot be fully explained by deficits in either short or long term memory, or by intolerance for delay of reward. A schedule with rewarded, nonrewarded (Time out: TO) and conflict components was used to investigate effects in rats of compounds active at the BZ receptor on successive discrimination and punished responding in parallel. The GABA transaminase inhibitor ethanolamine-O-sulphate exerted additive effects with chlordiazepoxide (CDP) on punished but not TO responding. Both GABA and CDP injected into the amygdala selectively increased conflict rates, but with peripheral treatment CDP also increased TO rates. Two inverse BZ agonists, CGS 8216 and FG 7142 antagonzied the anti-conflict effects of GABA and CDP, given within the amygdala or peripherally, but the increase in TO rates induced by systemic CDP was counteracted only by peripheral treatments. These compounds also reduced rates of conflict responding below baseline, consistent with anxiogenic activity. Effects of the BZ antagonist Ro 15-1788 were broadly similar to those of the inverse agonists, except that it did not antagonise the anti-conflict action of intra-amygdaloid GABA, nor significantly reduce punished responding at the single dose used. We conclude from these results that the anti-conflict effects of BZs are mediated by a GABAergic amygdaloid mechanism, but that the same mechanism is not involved in BZ effects on discrimination.

  7. High enhancer, downer, withdrawal helper: Multifunctional nonmedical benzodiazepine use among young adult opioid users in New York City.

    Science.gov (United States)

    Mateu-Gelabert, Pedro; Jessell, Lauren; Goodbody, Elizabeth; Kim, Dongah; Gile, Krista; Teubl, Jennifer; Syckes, Cassandra; Ruggles, Kelly; Lazar, Jeffrey; Friedman, Sam; Guarino, Honoria

    2017-08-01

    Benzodiazepines are a widely prescribed psychoactive drug; in the U.S., both medical and nonmedical use of benzodiazepines has increased markedly in the past 15 years. Long-term use can lead to tolerance and dependence, and abrupt withdrawal can cause seizures or other life-threatening symptoms. Benzodiazepines are often used nonmedically in conjunction with other drugs, and with opioids in particular-a combination that can increase the risk for fatal and non-fatal overdose. This mixed-methods study examines nonmedical use of benzodiazepines among young adults in New York City and its relationship with opioid use. For qualitative analysis, 46 90-minute semi-structured interviews were conducted with young adult opioid users (ages 18-32). Interviews were transcribed and coded for key themes. For quantitative analysis, 464 young adult opioid users (ages 18-29) were recruited using Respondent-Driven Sampling and completed structured interviews. Benzodiazepine use was assessed via a self-report questionnaire that included measures related to nonmedical benzodiazepine and opioid use. Participants reported using benzodiazepines nonmedically for a wide variety of reasons, including: to increase the high of other drugs; to lessen withdrawal symptoms; and to come down from other drugs. Benzodiazepines were described as readily available and cheap. There was a high prevalence (93%) of nonmedical benzodiazepine use among nonmedical opioid users, with 57% reporting regular nonmedical use. In bivariate analyses, drug-related risk behaviours such as polysubstance use, drug binging, heroin injection and overdose were strongly associated with regular nonmedical benzodiazepine use. In multivariate analysis, growing up in a middle-income household (earning between $51,000 and $100,000 annually), lifetime overdose experience, having ever used cocaine regularly, having ever been prescribed benzodiazepines, recent drug binging, and encouraging fellow drug users to use benzodiazepines to

  8. An electronic intervention to improve safety for pain patients co-prescribed chronic opioids and benzodiazepines.

    Science.gov (United States)

    Zaman, Tauheed; Rife, Tessa L; Batki, Steven L; Pennington, David L

    2018-03-29

    Co-prescribing opioids and benzodiazepines increases overdose risk. A paucity of literature exists evaluating strategies to improve safety of co-prescribing. This study evaluated an electronic intervention to improve safety for patients co-prescribed chronic opioids for pain and benzodiazepines at 3 and 6 months. A prospective cohort study was conducted from December 2015 through May 2016 at San Francisco Veterans Affairs Health Care System. A clinical dashboard identified 145 eligible patients prescribed chronic opioids and benzodiazepines. Individualized taper and safety recommendations were communicated to prescribers via electronic medical record progress note and encrypted e-mail at baseline. Primary outcome was number of patients co-prescribed chronic opioids and benzodiazepines. Secondary outcomes included daily dose of opioids and benzodiazepines and number prescribed ≥100 mg morphine equivalent daily dose. Safety outcomes included number with opioid overdose education and naloxone distribution, annual urine drug screening, annual prescription drug monitoring program review, and signed opioid informed consent. Linear mixed models and generalized estimating equations were used to examine within-group change in outcomes between baseline and 3 and 6 months. Among the 145 patients, mean (standard deviation) age was 62 (11) years and 91.7% (133/145) were male. Number co-prescribed significantly decreased from 145/145 (100%) at baseline to 93/139 (67%) at 6-month follow-up (odds ratio [OR] = 0.53, 95% confidence interval [CI]: 0.34-0.81, P = .003). Mean opioid and benzodiazepine doses significantly decreased from 84.61 to 65.63 mg (95% CI: 8.32-27.86, P improve safety for patients co-prescribed chronic opioids for pain and benzodiazepines.

  9. Benzodiazepine effect of {sup 125}I-iomazenil-benzodiazepine receptor binding and serum corticosterone level in a rat model

    Energy Technology Data Exchange (ETDEWEB)

    Fukumitsu, Nobuyoshi [Proton Medical Research Center, University of Tsukuba, Ibaragi, 305-8575 (Japan)]. E-mail: gzl13162@nifty.ne.jp; Ogi, Shigeyuki [Department of Radiology, Jikei University School of Medicine, Tokyo, 105-8461 (Japan); Uchiyama, Mayuki [Department of Radiology, Jikei University School of Medicine, Tokyo, 105-8461 (Japan); Mori, Yutaka [Department of Radiology, Jikei University School of Medicine, Tokyo, 105-8461 (Japan)

    2005-01-01

    To test the change in free or unoccupied benzodiazepine receptor (BZR) density in response to diazepam, we investigated {sup 125}I-iomazenil ({sup 125}I-IMZ) binding and serum corticosterone levels in a rat model. Wistar male rats, which received psychological stress using a communication box for 5 days, were divided into two groups according to the amount of administered diazepam: no diazepam [D (0)] group and 10 mg/kg per day [D (10)] group of 12 rats each. The standardized uptake value (SUV) of {sup 125}I-IMZ of the D (10) group were significantly lower (P<.05) than those of the D (0) group in the frontal, parietal and temporal cortices, globus pallidus, hippocampus, amygdala and hypothalamus. The serum corticosterone level ratio in the D (10) group was significantly lower than that in the D (0) group (P<.05). From the change in serum corticosterone levels, diazepam attenuated the psychological stress produced by the physical stress to animals in adjacent compartments. From the reduced binding of {sup 125}I-IMZ, it is clear that diazepam competed with endogenous ligand for the free BZR sites, and the frontal, parietal and temporal cortices, globus pallidus, hippocampus, amygdala and hypothalamus are important areas in which {sup 125}I-IMZ binding is strongly affected by administration of diazepam.

  10. Benzodiazepine receptor ligand influences on learning: an endogenous modulatory mechanism mediated by benzodiazepines possibly of alimentary origin

    Directory of Open Access Journals (Sweden)

    I. Izquierdo

    1991-01-01

    Full Text Available In rats pre-but not post-training ip administration of either flumazenil, a central benzodiazepine (BSD receptor antagonist, or of n-butyl-B-carboline-carboxylate (BCCB, an inverse agonist, enhanced retention of inhibitory avoidance learning. Flumazenil vlocked the enhancing effect of BCCB, and the inhibitory effect of the BZD agonists clonazepam and diazepam also given pre-training. Post-training administration of these drugs had no effects. The peripheral BZD receptor agonist/chloride channel blocker Ro5-4864 had no effect on the inhibitory avoidance task when given ip prior to training, buth it caused enhancement when given immediately post-training either ip or icv. This effect was blocked by PK11195, a competitive antagonist of Ro5-4864. These results suggest that ther is an endogenous mechanism mediated by BZD agonists, which is sensitive to inverse agonists and that normally down-regulates the formation of memories through a mechanism involving GABA-A receptors and the corresponding chloride channels. The most likely agonists for the endogenous mechanism suggested are the diazepam-like BZDs found in brain whose origin is possibly alimentary. Levels of these BZDs in the cortex were found to sharply decrease after inhibitory acoidance training or mere exposure to the training apparatus.

  11. Benzodiazepine use in medical out-patient clinics: a study from a developing country

    International Nuclear Information System (INIS)

    Patel, M.J.; Ahmer, S.; Khan, F.; Qureshi, A.W.A.; Shehzad, M.F.

    2013-01-01

    Objective: To estimate the prevalence of Benzodiazepine use in the outpatient setting of general medicine clinics at a single tertiary care centre. Methods: The prospective prevalence study was conducted in the outpatient setting of Internal Medicine Clinics at Aga Khan University Hospital, Karachi, from November to December 2009. All subjects were interviewed after informed consent and variables were recorded on a specially-designed proforma. Apart from basic demographics and comorbid conditions, duration, frequency and route of benzodiazepine use, as well as the reason and who initiated it was noted. Chi-square test and t test was applied to see the association of socio demographic or clinical factors with the use of benzodiazepine. Results: Of the 355 patients, 129 (36.33%) reported using the drug. The majority (n=86; 24.2%) were taking it on a daily basis. The highest numbers of patients using the drug were suffering from cardiovascular problems, 32 (25%) followed by 22 (17%) from endocrinology. Diazepam equivalent dose was around 7.04+-4, with a inter-quartile range of 3-96 weeks. Alprazolam (9%) was the most frequently prescribed Benzodiazepine. Conclusion: Benzodiazepine use is alarmingly high in the outpatient clinics of General Internal Medicine Department. There is no implementation of law to prevent its hazardous sale. In this regard all concerned should work collectively for awareness and irrational drug sale and use. (author)

  12. Degradation of benzodiazepines after 120 days of EMS deployment.

    Science.gov (United States)

    McMullan, Jason T; Jones, Elizabeth; Barnhart, Bruce; Denninghoff, Kurt; Spaite, Daniel; Zaleski, Erin; Silbergleit, Robert

    2014-01-01

    EMS treatment of status epilepticus improves outcomes, but the benzodiazepine best suited for EMS use is unclear, given potential high environmental temperature exposures. To describe the degradation of diazepam, lorazepam, and midazolam as a function of temperature exposure and time over 120 days of storage on active EMS units. Study boxes containing vials of diazepam, lorazepam, and midazolam were distributed to 4 active EMS units in each of 2 EMS systems in the southwestern United States during May-August 2011. The boxes logged temperature every minute and were stored in EMS units per local agency policy. Two vials of each drug were removed from each box at 30-day intervals and underwent high-performance liquid chromatography to determine drug concentration. Concentration was analyzed as mean (and 95%CI) percent of initial labeled concentration as a function of time and mean kinetic temperature (MKT). 192 samples were collected (2 samples of each drug from each of 4 units per city at 4 time-points). After 120 days, the mean relative concentration (95%CI) of diazepam was 97.0% (95.7-98.2%) and of midazolam was 99.0% (97.7-100.2%). Lorazepam experienced modest degradation by 60 days (95.6% [91.6-99.5%]) and substantial degradation at 90 days (90.3% [85.2-95.4%]) and 120 days (86.5% [80.7-92.3%]). Mean MKT was 31.6°C (95%CI 27.1-36.1). Increasing MKT was associated with greater degradation of lorazepam, but not midazolam or diazepam. Midazolam and diazepam experienced minimal degradation throughout 120 days of EMS deployment in high-heat environments. Lorazepam experienced significant degradation over 120 days and appeared especially sensitive to higher MKT exposure.

  13. Therapeutic response to benzodiazepine in panic disorder subtypes

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    Alexandre Martins Valença

    Full Text Available CONTEXT: This study makes a comparison between two subtypes of panic disorder regarding the clinical efficacy of clonazepam, a benzodiazepine. OBJECTIVES: To evaluate the clinical efficacy of clonazepam in a fixed dosage (2 mg/day, compared to placebo, in the treatment of panic disorder patients and to verify whether there are any differences in the responses to clonazepam between panic disorder patients with the respiratory and non-respiratory subtypes. TYPE OF STUDY: Randomized study with clonazepam and placebo. SETTING: Outpatient Anxiety and Depression Unit of the Institute of Psychiatry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. PARTICIPANTS: 34 patients with a diagnosis of panic disorder with agoraphobia, between 18 and 55 years old. PROCEDURES: Administration of clonazepam or placebo for 6 weeks, in panic disorder patients, after they were classified within two subtypes of panic disorder: respiratory and non-respiratory. MAIN MEASUREMENTS: Changes in the number of panic attacks in comparison with the period before the beginning of the study; Hamilton Anxiety Scale; Global Clinical Impression Scale; and Patient's Global Impression scale. RESULTS: In the group that received clonazepam, by the end of the 6th week there was a statistically significant clinical improvement, shown by the remission of panic attacks (p < 0.001 and decrease in anxiety (p = 0.024. In the group that received clonazepam there was no significant difference between the respiratory and non-respiratory subtypes of panic disorder, regarding the therapeutic response to clonazepam. CONCLUSION: Clonazepam was equally effective in the treatment of the respiratory and non-respiratory subtypes of panic disorder, suggesting there is no difference in the therapeutic response between the two subtypes.

  14. The association between benzodiazepine use and sleep quality in residential aged care facilities: a cross-sectional study

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    Lynna Chen

    2016-11-01

    Full Text Available Abstract Background Benzodiazepines are commonly prescribed in residential aged care facilities (RACFs for their sedative and anxiolytic effects. The objective of this study was to investigate the association between benzodiazepine use and sleep quality in residents of RACFs. Methods A cross-sectional study involving 383 participants was conducted in six Australian RACFs. Night-time sleep quality, day-time drowsiness and day-time napping behavior were assessed using a validated questionnaire. Logistic regression was used to compute adjusted odds ratios (AORs and 95% confidence intervals (CIs for the association between benzodiazepine use and sleep quality. Covariates included pain, dementia severity, depression, insomnia and other sedative use. Results Of the 383 residents (mean age 87.5 years, 77.5% female, 96(25.1% used a benzodiazepine on a regular basis. Residents who used long-acting benzodiazepines on a regular basis had higher night-time sleep quality than non-users (AOR = 4.00, 95%CI 1.06 – 15.15. Residents who used short-acting benzodiazepines on a PRN only basis had longer daytime napping times than non-users (AOR = 1.77, 95%CI 1.01 – 3.08. No benzodiazepine category was associated with day-time drowsiness. Conclusions The association between benzodiazepine use and sleep quality is dependent on the half-life and prescribing pattern of the benzodiazepine. Short-acting PRN benzodiazepines were associated with lower night time sleep quality and longer day-time napping compared to long-acting regular benzodiazepines. Longitudinal studies are needed to determine whether these findings reflect channeling of short-acting agents to residents at higher risk of sleep disorders.

  15. Genetic and psychosocial factors for benzodiazepine addiction. An analysis based on the results of the authors’ own research conducted in a group of benzodiazepine addicted and non-addicted individuals

    Directory of Open Access Journals (Sweden)

    Anna Konopka

    2017-03-01

    Full Text Available Purpose: In spite of the fact that the addictive potential of benzodiazepine (BDZ drugs has been known for a long time, benzodiazepine addiction remains a common problem for psychiatry to deal with. The etiology of benzodiazepine addiction is very complex. Among the risk factors, the course of the treatment, demographic status and psychological features of a patient seem to play an important role. The aim of this study was to investigate both psychological and genetic factors differentiating benzodiazepine addicts from non-addicted users.Methods: We analysed a cohort of 120 individuals treated with benzodiazepines divided into two groups: benzodiazepine addicts and non-addicted benzodiazepine users (the control group. In both groups we measured genetic polymorphisms of GABA A2 and MAOA. In both groups some psychometric measurements were performed – we investigated the level of depression, anxiety as a state and as a trait, personality features and the dominant coping style using the Beck Depression Scale, Hamilton Anxiety Scale, Five-Factor Personality Inventory NEO-FFI and the Coping Inventory for Stressful Situations [4,10,17,36,41,44].Results: There are some psychological and situational risk factors for benzodiazepine addiction such as high neuroticism, introversion and lack of the ability to release tension through interpersonal contacts, dominance of emotional coping style and high accumulation of critical life events during both childhood and adulthood. The genetic background still remains a field for further exploration.

  16. Stories of Hell and Healing: Internet Users' Construction of Benzodiazepine Distress and Withdrawal.

    Science.gov (United States)

    Fixsen, Alison M; Ridge, Damien

    2017-11-01

    Benzodiazepines are a group of drugs used mainly as sedatives, hypnotics, antiepileptics, and muscle relaxants. Consumption is recommended for 2 to 4 weeks only, due to fast onset of dependency and potentially distressing withdrawal symptoms. Few peer-review studies have drawn on the user experiences and language to appreciate firsthand experiences of benzodiazepine withdrawal or discontinuation syndrome. We looked extensively at patient stories of benzodiazepine withdrawal and recovery on Internet support sites and YouTube. Our analysis indicated that users employ rich metaphors to portray the psychologically disturbing and protracted nature of their suffering. We identified seven major themes: hell and isolation, anxiety and depression, alienation, physical distress, anger and remorse, waves and windows, and healing and renewal. By posting success stories, ex-users make known that "healing" can be a long, unpredictable process, but distress does lessen, and recovery can happen.

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

    Science.gov (United States)

    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.

  18. Early ontogeny of the central benzodiazepine receptor in human embryos and fetuses

    Energy Technology Data Exchange (ETDEWEB)

    Hebebrand, J.; Hofmann, D.; Reichelt, R.; Schnarr, S.; Knapp, M.; Propping, P.; Foedisch, H.J.

    1988-01-01

    The early ontogeny of the central benzodiazepine receptor (BZR) was investigated in human embryos and fetuses between 7 and 26 weeks of gestation. Brain tissue was gained from terminated pregnancies or spontaneous abortions. Binding studies, which were performed with /sup 3/H-flunitrazepam (FNZ), revealed that specific benzodiazepine binding is already detectable at an embryonal age of 7 weeks post conception. Binding at this early stage can be displaced potently by clonazepam and the inverse agonist ..beta..-CCE. Additionally, /sup 3/H-FNZ binding is enhanced by GABA. Thus, benzodiazepine binding is of the central type. Receptor density increases steeply in whole brain between weeks 8 and 11 of gestation. In frontal cortex receptor density increases gradually between weeks 12 and 26 of gestation. No specific fetal disease entity (including trisomy 21) was consistently associated with exceptionally high or low B/sub max/-values.

  19. Daily rhythms of benzodiazepine receptor numbers in frontal lobe and cerebellum of the rat

    International Nuclear Information System (INIS)

    Brennan, M.J.W.; Volicer, L.; Moore-Ede, M.C.; Borsook, D.

    1985-01-01

    Behavioral, biochemical and neurophysiological evidence suggests that gamma-aminobutyric acid (GABA) may play an important role in the neural control of circadian rhythms. Central receptors for benzodiazepines are functionally coupled to GABA receptors and appear to mediate behavioral effects of exogenous benzodiazepines. The binding of 3 H-flunitrazepam to synaptic plasma membranes prepared from various regions of rat brain was examined at 6-hour intervals over a 36-hour period. Prominent daily rhythms in receptor number (Bmax) were observed in the frontal lobe and the cerebellum but not in the temporoparietal regions, hypothalamus or medulla/pons. Binding was highest during periods of sleep/low activity with a significant decrease occurring just prior to waking. These results suggest that daily fluctuations in benzodiazepine receptor numbers may be related to the temporal control of sleep/wake and muscle activity cycles. 23 references, 1 figure, 1 table

  20. 1-Methyl-beta-carboline (harmane), a potent endogenous inhibitor of benzodiazepine receptor binding.

    Science.gov (United States)

    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.

  1. Dependence and withdrawal reactions to benzodiazepines and selective serotonin reuptake inhibitors. How did the health authorities react?

    DEFF Research Database (Denmark)

    Nielsen, Margrethe; Hansen, Ebba Holme; Gøtzsche, Peter C

    2013-01-01

    Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time.......Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time....

  2. Does tailoring really make a difference? : the development and evaluation of tailored interventions aimed at benzodiazepine cessation

    NARCIS (Netherlands)

    Wolde, Geeske Brecht ten

    2008-01-01

    Because of the problems associated with chronic benzodiazepine use, there is impetus to prevent and reduce chronic benzodiazepine use. The overall aim was to develop a 'tailor-made' intervention in order to reduce chronic use. Before developing tailored patient education, it is first of all

  3. The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat

    NARCIS (Netherlands)

    Bosman, D. K.; van den Buijs, C. A.; de Haan, J. G.; Maas, M. A.; Chamuleau, R. A.

    1991-01-01

    Two benzodiazepine-receptor partial inverse agonists (Ro 15-4513, Ro 15-3505) and one benzodiazepine-receptor antagonist (flumazenil) were administered to rats with hepatic encephalopathy due to acute liver ischemia. Significant improvement (P less than 0.002) of both the clinical grade of hepatic

  4. Twenty-year trends in benzodiazepine dispensing in the Australian population.

    Science.gov (United States)

    Islam, M M; Conigrave, K M; Day, C A; Nguyen, Y; Haber, P S

    2014-01-01

    Considerable concern has been expressed about overprescribing of benzodiazepines and related harms. Past analyses have relied on World Health Organization-defined daily doses (DDD) which are sometimes out of keeping with clinical usage. This study examines 20-year (1992-2011) trends of benzodiazepine dispensing in Australia using both DDD and Ashton equivalent dose. Data from the Drug Utilisation Sub-Committee and the Pharmaceutical Benefits Scheme (PBS) website were analysed. Trends in number of prescriptions, DDD/1000 people/day and DDD/prescription were examined over time, and between states/territories. In the 20-year period, 174 080 904 scripts were recorded, with temazepam the most dispensed benzodiazepine (35% of scripts), followed by diazepam (23%). Overall recorded utilisation fell from 27.7 DDD/1000 people/day in 1992 to 20.8 in 2011 (24.9% decrease). There were striking changes in use of individual benzodiazepines over time, with reductions in oxazepam and flunitrazepam and dramatic increases in alprazolam. Since 1998, there has been a steady increase, albeit modest, in per script DDD. The DDD/1000 people/day for items dispensed through PBS/Repatriaton-PBS was highest in Tasmania and lowest in Northern Territory. Despite a modest overall decline in the amount of benzodiazepine dispensed, the level of use is still likely to reflect relative over-prescribing given the paucity of accepted indications for long-term use. Since 1998, there was a polynomial increase in quantity dispensed per script. The WHO-defined DDD for clonazepam seems inappropriate and could impede monitoring of its abuse. Other problems include lack of national data for medications not subsidised on PBS/Repatriation PBS. A broad policy approach is required, not one which targets only one particular benzodiazepine. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

  5. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol

    DEFF Research Database (Denmark)

    Baandrup, Lone; Fagerlund, Birgitte; Jennum, Poul

    2011-01-01

    Treatment of schizophrenia frequently includes prolonged benzodiazepine administration despite a lack of evidence of its use. It is often difficult to discontinue benzodiazepines because of the development of dependence. We aim to assess if melatonin can facilitate the withdrawal of prolonged...... benzodiazepine administration in patients with schizophrenia. Furthermore, we aim to investigate the association of benzodiazepine dose reduction with the following clinically important variables: sleep, psychophysiology, cognition, social function, and quality of life....

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

    Science.gov (United States)

    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.

  7. Neurocognitive performance, subjective well-being, and psychosocial functioning after benzodiazepine withdrawal in patients with schizophrenia or bipolar disorder

    DEFF Research Database (Denmark)

    Baandrup, Lone; Fagerlund, Birgitte; Glenthoj, Birte

    2017-01-01

    -tapering compared with normative data. Neither benzodiazepine withdrawal nor treatment group affected subjective well-being or psychosocial functioning. In conclusion, add-on melatonin does not seem to affect cognition, well-being, or psychosocial functioning in patients with severe mental illness. The observed......Chronic benzodiazepine use is common in patients with mental illness and is associated with cognitive impairment. It is unclear whether benzodiazepine-induced cognitive impairment is reversible. Amelioration of cognitive dysfunction may be facilitated during benzodiazepine tapering by add......-on melatonin due to its anti-inflammatory and neuroprotective properties. We examined how melatonin and benzodiazepine withdrawal affect cognition, subjective well-being, and psychosocial functioning. Eighty patients with schizophrenia or bipolar disorder were randomized to add-on treatment once daily...

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  10. Benzodiazepine Use Among Low Back Pain Patients Concurrently Prescribed Opioids in the Military Health System

    Science.gov (United States)

    2017-08-27

    TYPE 08/27/2017 Poster 4. TITLE AND SUBTITLE Benzodiazepine Lise Among Lo\\v Back Pain Patients Concurrently Prescribed Opioids in the tvfilitary...PRO’-:iRAM ELEMENT NUMBER 5d. PROJECT NUMBER Se. TASK NUMBER Sf. WORK UNIT NUMBER 8. PERFORMING ORGANIZATION REPORT NUMBER 17356 10. SPONSOR

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

    Science.gov (United States)

    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.

  12. Peripheral-type benzodiazepine receptor: a protein of mitochondrial outer membranes utilizing porphyrins as endogenous ligands

    International Nuclear Information System (INIS)

    Snyder, S.H.; Verma, A.; Trifiletti, R.R.

    1987-01-01

    The peripheral-type benzodiazepine receptor is a site identified by its nanomolar affinity for [ 3 H]diazepam, similar to the affinity of diazepam for the central-type benzodiazepine receptor in the brain. The peripheral type benzodiazepine receptor occurs in many peripheral tissues but has discrete localizations as indicated by autoradiographic studies showing uniquely high densities of the receptors in the adrenal cortex and in Leydig cells of the testes. Subcellular localization studies reveal a selective association of the receptors with the outer membrane of mitochondria. Photoaffinity labeling of the mitochondrial receptor with [ 3 H]flunitrazepam reveals two discrete labeled protein bands of 30 and 35 kDa, respectively. The 35-kDa band appears to be identical with the voltage-dependent anion channel protein porin. Fractionation of numerous peripheral tissues reveals a single principal endogenous ligand for the receptor, consisting of porphyrins, which display nanomolar affinity. Interactions of porphyrins with the mitochondrial receptor may clarify its physiological role and account for many pharmacological actions of benzodiazepines

  13. SEX-DIFFERENCES AMONG RECIPIENTS OF BENZODIAZEPINES IN DUTCH GENERAL-PRACTICE

    NARCIS (Netherlands)

    van der Waals, F. W.; Mohrs, J.; Foets, M.

    1993-01-01

    Objective-To analyse sex differences among recipients of benzodiazepines in Dutch general practice. Design-Study of consultations and associated interventions as recorded in the Dutch national survey of general practice. Setting-Practices of 45 general practitioners monitored during 1 April to 30

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

    International Nuclear Information System (INIS)

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

    1987-01-01

    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 3 H-quinuclidinyl benzilate ( 3 H-QNB), and benzodiazepine sites were demonstrated with the aid of 1 nM 3 H-flunitrazepam ( 3 H-FLU). Autoradiograms generated on 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 with 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; 3 H-QNB sites were most dense in the inner molecular layer in all cortical regions, whereas 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

  15. Consequences of early postnatal benzodiazepines exposure in rats. I. Cognitive-like behavior

    Czech Academy of Sciences Publication Activity Database

    Mikulecká, Anna; Šubrt, Martin; Stuchlík, Aleš; Kubová, Hana

    2014-01-01

    Roč. 8, Mar 28 (2014), s. 101 ISSN 1662-5153 R&D Projects: GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GA305/09/0846 Institutional support: RVO:67985823 Keywords : benzodiazepines * clonazepam * cognitive functions * development * rats Subject RIV: FH - Neurology Impact factor: 3.270, year: 2014

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

    Science.gov (United States)

    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 forensic toxicology laboratory. PMID:27635251

  17. ACUTE POISONING WITH BENZODIAZEPINES AND OTHER HYPNOTICS: ETIOLOGIC CAUSE, SEX/AGE DISTRIBUTION AND CLINICAL OUTCOME

    Directory of Open Access Journals (Sweden)

    Petko Marinov

    2016-11-01

    Full Text Available Purpose: Poisoning with drugs occupies a leading position among the causes of acute intoxications. Etiological distribution of medicated poisoning in different countries, even if they are adjacent, is different. In the most studies it was reported that the highest incidence of poisoning is with benzodiazepines or other psychoactive drugs. A retrospective analysis of acute poisoning with benzodiazepines and other hypnotic drugs in the Varna region for 25 years period – from 1991 to 2015 was carried out. Material and Methods: The number of patients who received hospital treatment after poisoning with benzodiazepines is 1741, and those with other hypnotics is 293, representing respectively 26.37% and 4.44% of all drug intoxications. Results: The share of poisoning with benzodiazepines and hypnotics compared to all acute intoxications is 11.66%. They are more common in women – 1566 (77%. Men are 468 (23%, the ratio of men to women was 3.34:1. The largest number of intoxications is in the age group up to 24 years - 1123 (55.2%, and only 4.1% of patients over 60 years. Intentional suicide attempts are 1896 (93.2%. Death is registered in 8 (0.4% patients.

  18. Imaging benzodiazepine receptors in man with C-11-suriclone and positron emission tomography

    International Nuclear Information System (INIS)

    Frost, J.J.; Dannals, R.F.; Ravert, H.T.; Wilson, A.A.; Links, J.M.; Trifiletti, R.; Snyder, S.H.; Wagner, H.N. Jr.

    1985-01-01

    Suriclone is a potent cyclopyrrolone, anti-anxiety drug which binds to the benzodiazepine receptor complex (BZR) with high affinity. Suriclone binds to a site on the BZR distinct from the site where benzodiazepines bind. The K/sub D/ of suriclone at 37oC is 0.03 nM. C-11-suriclone (SUR) was synthesized by reacting C-CH3I with the appropriate amine precursor. SUR (1 μg/kg) was injected IV into a baboon alone or with 1 mg/kg of Ro-151788, a benzodiazepine antagonist, and serial PET scans of the brain were obtained. High radioactivity concentrations were observed in the cerebral cortex and cerebellum which contain high densities of BZR, intermediate concentrations in thalamus and low concentrations in the striatum. When Ro-151788 was given a uniform distribution of radioactivity was observed; the radioactivity was reduced to ca. 25% of control values in the brain which was contained within the PET slice. SUR (0.2 μg/kg) was next administered to a human subject. From 30-60 minutes after injection high radioactivity concentrations were observed in the cerebral cortex and cerebellum, intermediate concentrations in the thalamus and a low concentration in the caudate. Radioactivity in the cerebral cortex and cerebellum decreased slowly with time, implying that binding of SUR to a high affinity site had occurred. These results demonstrate utility of SUR for measuring binding to the benzodiazepine receptor complex non-invasively in man

  19. Consequences of early postnatal benzodiazepines exposure in rats. II. Social behavior

    Czech Academy of Sciences Publication Activity Database

    Mikulecká, Anna; Šubrt, Martin; Pařízková, Martina; Mareš, Pavel; Kubová, Hana

    2014-01-01

    Roč. 8, May 8 (2014), s. 169 ISSN 1662-5153 R&D Projects: GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GA305/09/0846 Institutional support: RVO:67985823 Keywords : benzodiazepines * clonazepam * social behavior * development * rats Subject RIV: FH - Neurology Impact factor: 3.270, year: 2014

  20. Correlates of benzodiazepine dependence in the Netherlands Study of Depression and Anxiety

    NARCIS (Netherlands)

    Manthey, L.; Lohbeck, M.; Giltay, E.J.; van Veena, T.; Zitman, F.G.; Penninx, B.W.J.H.

    2012-01-01

    Aims: Benzodiazepines (BZDs) are effective in the short term against anxiety and insomnia. However, some BZD users develop BZD dependence after a relatively short period of time. Therefore, we aimed to identify the risk factors of BZD dependence. Design: An observational cohort study. Setting: The

  1. Latent trait standardization of the benzodiazepine dependence self-report questionnaire using the Rasch scaling model.

    NARCIS (Netherlands)

    Kan, C.C.; Ven, A.H.G.S. van der; Breteler, M.H.M.; Zitman, F.G.

    2001-01-01

    The aim of the present study was to obtain standardized scores that correspond with the raw scores on the four Rasch scales of the Benzodiazepine Dependence-Self Report Questionnaire (Bendep-SRQ). The eligible normative group for standardization of the Bendep-SRQ scales consisted of 217 general

  2. Latent Trait Standardization of the Benzodiazepine Dependence Self-Report Questionnaire using the Rasch Scaling Model

    NARCIS (Netherlands)

    Kan, C.C.; Ven, A.H.G.S. van der; Breteler, M.H.M.; Zitman, F.G.

    2001-01-01

    The aim of the present study was to obtain standardized scores that correspond with the raw scores on the four Rasch scales of the Benzodiazepine Dependence-Self Report Questionnaire (Bendep-SRQ). The eligible normative group for standardization of the Bendep-SRQ scales consisted of 217 general

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

    Science.gov (United States)

    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

  4. Assessment of dependence and anxiety among benzodiazepine users in a provincial municipality in Rio Grande do Sul, Brazil

    Directory of Open Access Journals (Sweden)

    Janaína Barden Schallemberger

    Full Text Available Abstract Introduction: Benzodiazepines are among the most prescribed drugs for anxiety and one of the most used drug classes in the world and have a high potential for addiction. The objective of this study was to assess levels of dependence and anxiety among users of these drugs in the public health system. Methods: This was a cross-sectional, descriptive and quantitative study. Benzodiazepine users treated on the public health system were selected. Anxiety levels were assessed with the Hamilton Anxiety Scale and dependency with the Benzodiazepine Dependence Self-Report Questionnaire. Results: Benzodiazepine use was higher among women and in older age groups. Duration of benzodiazepine use was greater than 1 year for all respondents. The dependence assessment indicated that more than half of users were dependent on taking benzodiazepines and most had a severe degree of anxiety. Conclusion: This study found evidence of prolonged and inappropriate use of benzodiazepines. It is necessary to educate users about the risks of these drugs and to develop strategies to rationalize use of these drugs by working with prescribers and dispensers.

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

    Science.gov (United States)

    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.

  6. Le benzodiazepine nel trattamento dell’ansia: profilo clinico e farmacoeconomico

    Directory of Open Access Journals (Sweden)

    Barbara Cascio

    2005-12-01

    Full Text Available Anxiety disorders impose a significant economic burden on healthcare system, patients and society as a whole. A patient with anxiety disorders, especially with panic disorder, shows some difficulties to work or to maintain an acceptable social functioning, and, frequently, needs more medical care than a normal subject, often due to unnecessary or inappropriate diagnostic tests. Adequate psychiatric treatment of anxiety disorders can lead to higher direct specialists costs (psychiatric drugs and visits but this may be offset by a decrease in non-specialist care costs and in indirect costs. Benzodiazepines have been extensively used for the treatment of anxiety and related disorders since the 1960s. Although new pharmacological and psychological treatments for anxiety are available, a lot of psychiatrists continue to endorse benzodiazepines as primary or adjunctive treatment for these disturbs, especially in the early or acute phases of the illness. In Italy, benzodiazepines have been available also as generic drugs for some years. In order to be accepted for marketing, a generic drug has to demonstrate bioequivalence, considered a reliable proxy of therapeutic equivalence, with the standard formulation and its price has to be at least 20% cheaper than the originator drug. The use of generic drugs can contain drug expenditures and facilitate a competitive market. Despite that their prices are considerably higher than those of generics, branded benzodiazepines are still widely prescribed, because of prejudices and lack of information in the community of physicians and patients. In conclusion, benzodiazepines may treat anxiety disorders, mainly in early and acute phases, increasing quality of life and saving medical resources. The availability of generics allows for marginal reduction in initial investment in drug costs.

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

    Science.gov (United States)

    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.

  8. Peripheral-type benzodiazepine receptors in the central nervous system: localization to olfactory nerves.

    Science.gov (United States)

    Anholt, R R; Murphy, K M; Mack, G E; Snyder, S H

    1984-02-01

    Binding levels of [3H]Ro5-4864, a ligand selective for peripheral-type benzodiazepine receptors, are substantially higher in homogenates of the olfactory bulb than in the rest of the brain. Among peripheral tissues evaluated, high levels of [3H]Ro5-4864 binding are found in the nasal epithelium. Drug displacement studies show that these binding sites are pharmacologically of the peripheral type. Their presence in the nasal epithelium and in the olfactory bulb can be demonstrated in several different mammalian species. Autoradiographic studies of murine nose reveal a bipolar staining pattern around the cell bodies of the olfactory receptor cells, suggesting the presence of peripheral-type benzodiazepine receptors on both processes of these bipolar neurons. In the brain a high density of [3H]Ro5-4864 binding sites occurs in the nerve fiber and glomerular layers of the olfactory bulb. Throughout the rest of the brain [3H]Ro5-4864-associated silver grains are diffusely distributed with intense staining over the choroid plexus and along the ependymal linings of the ventricles. Both the distribution and the ontogenic development of the peripheral-type benzodiazepine receptors differ from the central-type receptors. Intranasal irrigation with 5% ZnSO4 results in a 50% reduction of peripheral-type benzodiazepine receptors in the olfactory bulb without affecting the density of central-type benzodiazepine receptors. Thus, [3H]Ro5-4864 binding sites in the olfactory bulb appear in large part to be localized to olfactory nerves which originate in the nasal epithelium.

  9. Benzodiazepine Consumption Is Associated With Lower Blood Pressure in Ambulatory Blood Pressure Monitoring (ABPM): Retrospective Analysis of 4938 ABPMs.

    Science.gov (United States)

    Mendelson, Nitsan; Gontmacher, Bella; Vodonos, Allina; Novack, Victor; Abu-AjAj, Muhammad; Wolak, Arik; Shalev, Haddar; Wolak, Talya

    2018-03-10

    The effect of chronic benzodiazepine use on blood pressure has not been documented. We aimed to evaluate whether regular benzodiazepine use can be associated to the results of ambulatory blood pressure monitoring (ABPM). A retrospective analysis of the ABPM database between 2009 and 2015 was performed. The study groups were divided according to benzodiazepine treatment at least 3 months before ABPM. Generalized estimating equation (GEE) model analysis was conducted to estimate the association between benzodiazepine treatment and ABPM test measurements. Multivariable COX regression survival analysis model for mortality and cardiovascular (CV) events was performed. A total of 4,938 ABPM studies were included in final analysis, 670 ABPMs of benzodiazepine-treated patients, and 4,268 of untreated patients. The benzodiazepine-treated group was significantly older, with a predominance of female patients, comprised more diabetic patients and consumed more antihypertensive medications. Adjustment for age, gender, diabetes mellitus, and number of antihypertensive medications, showed an association between benzodiazepine treatment and significantly lower ABPM measurements. When the analysis was split into those ≥60 years old and the other ABPM measurements only among ≥60 years old. Multivariable Cox regression survival analysis showed that regular benzodiazepine consumption was not associated with increased mortality or CV events (mean follow-up period of 42.4 ± 19.8 and 42.1 ± 20.0 months, respectively). Long-term use of benzodiazepines by ≥60 years old was independently associated with lower diastolic and systolic blood pressure in all parameters of ABPM, but not among younger patients.

  10. High-dose benzodiazepine dependence: a qualitative study of patients' perception on cessation and withdrawal.

    Science.gov (United States)

    Liebrenz, Michael; Gehring, Marie-Therese; Buadze, Anna; Caflisch, Carlo

    2015-05-13

    Benzodiazepine withdrawal syndrome has been reported following attempts to withdraw even from low or therapeutic doses and has been compared to barbiturate and alcohol withdrawal. This experience is known to deter patients from future cessation attempts. Research on other psychotropic substances shows that the reasons and motivations for withdrawal attempts - as well as the experiences surrounding those attempts - at least partially predict future efforts at discontinuation as well as relapse. We therefore aimed to qualitatively explore what motivates patients to discontinue this medication as well as to examine their experiences surrounding previous and current withdrawal attempts and treatment interventions in order to positively influence future help-seeking behavior and compliance. To understand these patients better, we conducted a series of 41 unstructured, narrative, in-depth interviews among adult Swiss patients with a long-term dependent use of benzodiazepines in doses equivalent to more than 40 mg diazepam per day and/or otherwise problematic use (mixing benzodiazepines, escalating dosage, recreational use or illegal purchase). Mayring's qualitative content analysis was used to evaluate findings. These high-dose benzodiazepine-dependent patients decision to change consumption patterns were affected by health concerns, the feeling of being addicted and social factors. Discontinuation attempts were frequent and not very successful with fast relapse. Withdrawal was perceived to be a difficult, complicated, and highly unpredictable process. The first attempt at withdrawal occurred at home and typically felt better than at the clinic. Inpatient treatment was believed to be more effective with long term treatment (approaches) than short term. Patients preferred gradual reduction of usage to abrupt cessation (and had experienced both). While no clear preferences for withdrawal were found for benzodiazepines with specific pharmacokinetic properties, participants

  11. Synthesis of substituted 1,4-diazepines and 1,5-benzodiazepines using an efficient heteropolyacid-catalyzed procedure.

    Science.gov (United States)

    Kaoua, Rachedine; Bennamane, Norah; Bakhta, Saliha; Benadji, Sihame; Rabia, Cherifa; Nedjar-Kolli, Bellara

    2010-12-28

    An efficient and improved procedure for the synthesis of 1,4-diazepine and 1,5-benzodiazepine derivatives via the reaction of ketimine intermediates with aldehydes in the presence of Keggin-type heteropolyacids (HPAs) was developed. High yields and short reaction times were obtained for both electron-releasing and electron-withdrawing substituted 1,4-diazepine  and 1,5-benzodiazepines derivatives.

  12. Synthesis of Substituted 1,4-Diazepines and 1,5-Benzodiazepines Using an Efficient Heteropolyacid-Catalyzed Procedure

    Directory of Open Access Journals (Sweden)

    Sihame Benadji

    2010-12-01

    Full Text Available An efficient and improved procedure for the synthesis of 1,4-diazepine and 1,5-benzodiazepine derivatives via the reaction of ketimine intermediates with aldehydes in the presence of Keggin-type heteropolyacids (HPAs was developed. High yields and short reaction times were obtained for both electron-releasing and electron-withdrawing substituted 1,4-diazepine  and 1,5-benzodiazepines derivatives.

  13. An Organocatalyzed and Ultrasound Accelerated Expeditious Synthetic Route to 1,5-Benzodiazepines under Solvent-Free Conditions

    Energy Technology Data Exchange (ETDEWEB)

    Shinde, Pravin V.; Shingate, Bapurao B.; Shingare, Murlidhar S. [Babasaheb Ambedkar Marathwada University, Aurngabad (India)

    2011-04-15

    In the present work, successful implementation of ultrasound irradiations for the rapid synthesis of 1,5- benzodiazepine derivatives under solvent-free conditions is demonstrated. Use of a novel catalyst i.e. camphor sulphonic acid in combination with ultrasound technique is reported for the first time. Comparative study for the synthesis of 1,5-benzodiazepines using conventional as well as ultrasonication method is discussed.

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

    Science.gov (United States)

    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.

  15. Acute myocardial infarction with multiple coronary thromboses in a young addict of amphetamines and benzodiazepines

    Directory of Open Access Journals (Sweden)

    Mohammed A. Al Shehri

    2016-07-01

    Full Text Available A 35-year-old man of average build and a smoker, with a background of a psychiatric disorder, was brought by his neighbor to the emergency department after an hour of severe chest pain. Upon arrival at the hospital he had cardiac arrest, was resuscitated, and moved to the catheterization laboratory with inferior, posterior, and lateral myocardial infarction. Coronary angiography showed an unusual thrombosis in multiple coronary branches. Toxicology report showed high levels of amphetamines and benzodiazepines in the patient’s original blood sample. The patient was kept under ventilation for 18 days, with difficult recovery due to severe withdrawal manifestations, ventilation acquired pneumonia, and rhabdomyolysis inducing acute renal failure. The patient regained near normal left ventricular function after baseline severe regional and global dysfunction. We postulate a relationship between the use of amphetamines, potentiated by benzodiazepines, and occurrence of acute thrombosis of multiple major coronary arteries.

  16. The benzodiazepine/GABA receptor complex during severe ethanol intoxication and withdrawal in the rat

    International Nuclear Information System (INIS)

    Hemmingsen, R.; Braestrup, C.; Nielsen, M.; Barry, D.I.

    1982-01-01

    The benzodiazepine/GABA (gammaaminobutyric acid) receptor complex was investigated during severe ethanol intoxication and withdrawal in the rat. The intragastric intubation technique was used to establish physical ethanol dependence in the animals. Cerebral cortex from male Wistar rats was studied 1) after 31/2 days of severe ethanol intoxication, 2) during the ethanol withdrawal reaction and 3) in a control group. The effect of GABA-ergic activation by muscimol and THIP (4,5,6,7-tetrahydroisoxazole(5,4-c)pyridin-3-01) on 3 H-diazepam binding was unchanged during ethanol intoxication and withdrawal, as was the affinity constant (Ksub(D)) and the maximal number of binding sites (Bsub(max)) for 3 H-flunitrazepam. In conclusion, the benzodiazepine/GABA receptor complex is unlikely to play any causual part in physical ethanol dependence. (author)

  17. Characteristics of benzodiazepine receptors in rats differing in predisposition to experimental alcoholism

    International Nuclear Information System (INIS)

    Burov, Yu.V.; Maiskii, A.I.; Yukhananov, R.Yu.

    1986-01-01

    This paper studies the number and affinity of benzodiazepine receptors for diazepam in the cerebral cortex and hippocampus of rats differently predisposed to the development of experimental alcoholism. Ethanol was injected once intraperitoneally, in a dose of 2.5 g/kg. Control animals received the same volume of physiological saline. Bound and free N-methyl-tritium-diazepam were separated by means of GF/B filters. The characteristics of benzodiazepine receptors are shown in rats differing in predisposition to the development of experimental alcoholism and in rats during voluntary chronic alcoholization. It is shown that weakening of functional acitivity of the GABA-benzodiazepam complex in animals predisposed to the development of experimental alcoholism is one of the neurochemical mechanisms of development of the abstinence syndrome

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  20. Pharmacological evaluation of an [(123)I] labelled imidazopyridine-3-acetamide for the study of benzodiazepine receptors.

    Science.gov (United States)

    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.

  1. A New Terminal Cyano Group-containing Benzodiazepine Alkaloid from the Mangrove Endophytic Fungus Penicillium sp. .

    Science.gov (United States)

    Li, Jing; Zhong, Yi-sheng; Yuan, Jie; Zhu, Xun; Lu, Yong-jun; Lin, Yong-cheng; Liu, Lan

    2015-09-01

    A new benzodiazepine alkaloid containing terminal cyano group has been isolated from a mangrove endophytic fungus, Penicillium 299#. Structure elucidation was determined by 1D and 2D NMR spectroscopy and the absolute configuration was determined by electronic circular dichroism (ECD). The new compound showed no cytotoxic activities in vitro against human cancer lines MDA-MB-435, HepG2, HCT-116, and Calu-3.

  2. Structure-Aided Design of Novel Inhibitors of HIV Protease Based on a Benzodiazepine Scaffold

    Czech Academy of Sciences Publication Activity Database

    Schimer, Jiří; Cígler, Petr; Veselý, J.; Grantz Šašková, Klára; Lepšík, Martin; Brynda, Jiří; Řezáčová, Pavlína; Kožíšek, Milan; Císařová, I.; Oberwinkler, H.; Kraeusslich, H. G.; Konvalinka, Jan

    2012-01-01

    Roč. 55, č. 22 (2012), s. 10130-10135 ISSN 0022-2623 R&D Projects: GA ČR GBP208/12/G016; GA ČR GAP207/11/1798 Institutional research plan: CEZ:AV0Z40550506; CEZ:AV0Z50520514 Keywords : HIV protease inhibitor * rational drug design * 1,4-benzodiazepines Subject RIV: CE - Biochemistry Impact factor: 5.614, year: 2012

  3. Synthesis of spiro[indolo-1,5-benzodiazepines] from 3-acetyl ...

    Indian Academy of Sciences (India)

    Unknown

    also as potent virucides and non-nucleoside inhibi- tors of HIV-1 reverse transcriptase.2 Beside this,. 1,5-benzodiazepines ... printed circuits.8 Here we report the synthesis of spiro ... 3d. 5,6-Benzo 1727. 1701. 1672. 3218 3382. 4⋅22 (d, 2H, J = 17⋅91 Hz), 3⋅81 (d, 2H,. J = 17⋅8 .... R1 = R2 = CH3 show 88⋅88% inhibition.

  4. Maternal Characteristics of Women Exposed to Hypnotic Benzodiazepine Receptor Agonist during Pregnancy

    OpenAIRE

    Askaa, Bjarke; Jimenez-Solem, Espen; Enghusen Poulsen, Henrik; Traerup Andersen, Jon

    2014-01-01

    Background. There is little knowledge regarding the characteristics of women treated with hypnotic benzodiazepine receptor agonists (HBRAs) during pregnancy. In this large Danish cohort study, we characterize women exposed to HBRA during pregnancy. We determined changes in prevalence of HBRA use from 1997 to 2010 and exposure to HBRAs in relation to pregnancy. Methods. We performed a retrospective cohort study including 911,017 pregnant women in the period from 1997 to 2010. Information was r...

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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

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

    International Nuclear Information System (INIS)

    Marley, R.J.

    1987-01-01

    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 3 H-GABA binding sites is greater in SS cerebellar tissue and 3 H-flunitrazepam binding is greater in the mid-brain region of LS mice. GABA enhancement of 3 H-flunitrazepma binding is greater in SS mice. Ethanol also enhances 3 H-flunitrazepam binding and increases the levels of 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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  10. Micellar Liquid Chromatography for the Determination of Some Less Prescribed Benzodiazepines

    Directory of Open Access Journals (Sweden)

    Hoonka Subhra

    2012-01-01

    Full Text Available A simple chromatographic procedure is reported for the determination of some less prescribed but equally important benzodiazepines (Clotiazepam, clozapine and pinazepam in serum. The optimization studies have been made in CN, C18 and C8 columns, using mobile phase containing sodium dodecyl sulphate (SDS modified with either propanol, butanol or pentanol. The method proposed for the determination of the three benzodiazepines using a mobile phase of 0.13 M SDS, 2.4% pentanol-0.01 M phosphate buffer- 0.1% triethylamine (pH 7 at 25°C and UV detection (240 nm in a C8 column. The serum samples was injected directly, without any pretreatment, eluted in less than 8 min, in accordance to their relative polarities, as indicated by their octanol-water partition coefficients. The limits of detection (ng/mL was in the 1.6 to 5.6 and 7 to 87 range, for aqueous and serum samples, respectively. Repeatability and intermediate precision was tested for three different concentrations of the drugs, resulting in the 0.1 to 2 range. The results obtained here for the separation of the three benzodiazepines in serum were also counter checked at Department of Bio-analytical Chemistry, Universitat Jaume I, Castelló, Spain.

  11. GABA and benzodiazepine receptors in the gerbil brain after transient ischemia: demonstration by quantitative receptor autoradiography

    International Nuclear Information System (INIS)

    Onodera, H.; Sato, G.; Kogure, K.

    1987-01-01

    Quantitative receptor autoradiography was used to measure the binding of gamma-aminobutyric acid (GABA) and benzodiazepine receptors after ischemia by means of transient occlusion of bilateral common carotid arteries in the gerbil. [ 3 H]Muscimol was used to label the GABAA receptors and [ 3 H]flunitrazepam to label central type benzodiazepine receptors. In the superolateral convexities of the frontal cortices, [ 3 H]muscimol binding was increased in 60% of the animals killed 3 days after ischemia, and decreased in 67% of the animals killed 27 days after ischemia. Twenty-seven days after ischemia, [ 3 H]flunitrazepam binding in the substantia nigra pars reticulata increased to 252% of the control, though the increase in [ 3 H]muscimol binding was not significant. In the dorsolateral region of the caudate putamen, marked neuronal necrosis and depletion of both [ 3 H]muscimol and [ 3 H]flunitrazepam binding sites were observed 27 days after ischemia, the ventromedial region being left intact. In spite of the depletion of pyramidal cells in the CA1 region of the hippocampus, both [ 3 H]muscimol and [ 3 H]flunitrazepam binding sites were preserved 27 days after ischemia. Since our previous study revealed that adenosine A1 binding sites were depleted in the CA1 subfield of the hippocampus after ischemia correlating with neuronal damage, GABAA and benzodiazepine receptors may not be distributed predominantly on the pyramidal cells in the CA1 region

  12. High daily doses of benzodiazepines among Quebec seniors: prevalence and correlates

    Directory of Open Access Journals (Sweden)

    Moride Yola

    2001-11-01

    Full Text Available Abstract Background Use of high daily doses of benzodiazepines is generally contraindicated for seniors. While both patient and physician factors may influence the use of high daily doses, previous research on the effect of patient factors has been extremely limited. The objectives of this study were to determine the one year prevalence of use of high daily doses of benzodiazepines, and examine physician and patient correlates of such use among Quebec community-dwelling seniors. Methods Patient information for 1423 community-dwelling Quebec seniors who participated in the Canadian Study of Health and Aging was linked to provincial health insurance administrative data bases containing detailed information on prescriptions received and prescribers. Results The standardized one year period prevalence of use of high daily doses of benzodiazepines was 7.9%. Use of high daily doses was more frequent among younger seniors and those who had reported anxiety during the previous year. Patients without cognitive impairment were more likely to receive high dose prescriptions from general practitioners, while those with cognitive impairment were more likely to receive high dose prescriptions from specialists. Conclusion High dose prescribing appears to be related to both patient and physician factors.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  15. Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy

    International Nuclear Information System (INIS)

    Basile, A.S.; Pannell, L.; Jaouni, T.; Gammal, S.H.; Fales, H.M.; Jones, E.A.; Skolnick, P.

    1990-01-01

    Brain extracts from rats with hepatic encephalopathy due to thioacetamide-induced fulminant hepatic failure contained 4- to 6-fold higher concentrations of substances that inhibit radioligand binding to benzodiazepine receptors than corresponding control rat extracts. Both isocratic and gradient-elution HPLC indicated that this inhibitory activity was localized in 3-8 peaks with retention times corresponding to deschlorodiazepam, deschlorolorazepam, lorazepam, oxazepam, diazepam, and N-desmethyldiazepam. The presence of diazepam and N-desmethyldiazepam was confirmed by mass spectroscopy. Both mass spectroscopic and radiometric techniques indicated that the concentrations of N-desmethyldiazepam and diazepam in brain extracts from encephalopathic rats were 2-9 and 5-7 times higher, respectively, than in control brain extracts. While benzodiazepines have been identified previously in mammalian and plant tissues, this report demonstrates that concentrations of these substances are increased in a pathophysiological condition. These findings provide a rational basis for the use of benzodiazepine receptor antagonists in the management of hepatic encephalopathy in humans

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

    Directory of Open Access Journals (Sweden)

    Miroslav M. Savic

    2005-01-01

    Full Text Available 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 α5 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.

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

    Science.gov (United States)

    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.

  18. [18F]Fluoroethylflumazenil: a novel tracer for PET imaging of human benzodiazepine receptors

    International Nuclear Information System (INIS)

    Gruender, G.; Lange-Asschenfeldt, C.; Vernaleken, I.; Lueddens, H.; Siessmeier, T.; Buchholz, H.-G.; Bartenstein, P.; Stoeter, P.; Drzezga, A.; Roesch, F.

    2001-01-01

    5-(2'-[ 18 F]Fluoroethyl)flumazenil ([ 18 F]FEF) is a fluorine-18 labelled positron emission tomography (PET) tracer for central benzodiazepine receptors. Compared with the established [ 11 C]flumazenil, it has the advantage of the longer half-life of the fluorine-18 label. After optimisation of its synthesis and determination of its in vitro receptor affinities, we performed first PET studies in humans. PET studies in seven healthy human volunteers were performed on a Siemens ECAT EXACT whole-body scanner after injection of 100-280 MBq [ 18 F]FEF. In two subjects, a second PET scan was conducted after pretreatment with unlabelled flumazenil (1 mg or 2.5 mg i.v., 3 min before tracer injection). A third subject was studied both with [ 18 F]FEF and with [ 11 C]flumazenil. Brain radioactivity was measured for 60-90 min p.i. and analysed with a region of interest-oriented approach and on a voxelwise basis with spectral analysis. Plasma radioactivity was determined from arterial blood samples and metabolites were determined by high-performance liquid chromatography. In human brain, maximum radioactivity accumulation was observed 4±2 min p.i., with a fast clearance kinetics resulting in 50% and 20% of maximal activities at about 10 and 30 min, respectively. [ 18 F]FEF uptake followed the known central benzodiazepine receptor distribution in the human brain (occipital cortex >temporal cortex >cerebellum >thalamus >pons). Pretreatment with unlabelled flumazenil resulted in reduced tracer uptake in all brain areas except for receptor-free reference regions like the pons. Parametric images of distribution volume and binding potential generated on a voxelwise basis revealed two- to three-fold lower in vivo receptor binding of [ 18 F]FEF compared with [ 11 C]flumazenil, while relative uptake of [ 18 F]FEF was higher in the cerebellum, most likely owing to its relatively higher affinity for benzodiazepine receptors containing the α6 subunit. Metabolism of [ 18 F]FEF was very

  19. The interaction of substituted benzamides with brain benzodiazepine binding sites in vitro.

    OpenAIRE

    Horton, R. W.; Lowther, S.; Chivers, J.; Jenner, P.; Marsden, C. D.; Testa, B.

    1988-01-01

    1. The interaction of substituted benzamides with brain benzodiazepine (BDZ) binding sites was examined by their ability to displace [3H]-flunitrazepam ([3H]-FNM) from specific binding sites in bovine cortical membranes in vitro. 2. Clebopride, Delagrange 2674, Delagrange 2335 and BRL 20627 displayed concentration-dependent displacement of [3H]-FNM with IC50 values of 73 nM, 132 nM, 7.7 microM and 5.9 microM, respectively. Other substituted benzamides including metoclopramide, sulpiride, tiap...

  20. The GABA-A benzodiazepine receptor complex: Role of pet and spect in neurology and psychiatry

    International Nuclear Information System (INIS)

    Juengling, F.D.; Schaefer, M.; Heinz, A.

    2002-01-01

    Nuclear medicine imaging techniques such as positron emission tomography (PET) and single photon emission tomography (SPECT) for selective depiction of GABA-A-benzodiazepine receptor (GBZR) binding are complementary investigations in the diagnostic process of neurological and psychiatric disorders. This review summarizes the current knowledge about options and limitations of PET and SPECT for in vivo diagnostics in neurology and psychiatry. The growing importance of GBZR-imaging for the understanding of pathophysiology and pharmacological treatment in different psychiatric syndromes is discussed. (orig.) [de

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

    Science.gov (United States)

    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.

  2. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol

    DEFF Research Database (Denmark)

    Baandrup, Lone; Fagerlund, Birgitte; Jennum, Poul

    2011-01-01

    Treatment of schizophrenia frequently includes prolonged benzodiazepine administration despite a lack of evidence of its use. It is often difficult to discontinue benzodiazepines because of the development of dependence. We aim to assess if melatonin can facilitate the withdrawal of prolonged...

  3. SYNTHESIS OF 1,2 FUSED SYSTEMS BASED ON THE 3-ARYLIDENE-5-PHENYL-1,2-DIHYDRO-3H-1,4- BENZODIAZEPINE-2-ONES

    Directory of Open Access Journals (Sweden)

    V. I. Pavlovsky

    2014-12-01

    Full Text Available By the reaction of 7-bromo-5-aryl-1,2-dihydro-3H-1,4-benzodiazepine-2-ones with Lawesson reagent, 7-bromo-5-aryl-1,2-dihydro-3H-1,4-benzodiazepine-2-tiones were synthesized from which 3-arylidene-7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepines were obtained by the reaction with hydrazine hydrate. The condensation of 3-arylidene-7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepines with triethylorthoformate (triethylorthoacetate or formic acid (acetic acid gave 4-arylidene-8-bromo-6-phenyl-4H-[1,2,4]triazolo[4,3-а][1,4]-benzodiazepines. Latter were also synthesized by the reaction of 7-bromo-5-aryl-1,2-dihydro-3H-1,4-benzodiazepine-2-tiones with acetylhydrazine. 4-Arylidene-8-bromo-6-phenyl-4H-[1,2,3,4] tetrazolo[1,5-а][1,4]-benzodiazepines were obtained by the reaction of 3-arylidene-7-bromo-2-hydrazino-5-phenyl-3H-1,4-benzodiazepines with sodium nitrite.

  4. Application of gamma-aminobutyric acid type A-benzodiazepine receptor imaging for study of neuropsychiatric disorders

    International Nuclear Information System (INIS)

    Bao Weiqi; Qiu Chun; Guan Yihui

    2012-01-01

    Gamma-aminobutyric acid type A-benzodiazepine receptors are heterogeneous polypeptide pentamers widely spread in the central nervous system on the neuron membrane. Different subunit combinations educe various neuro-inhibitory pharmacological effects such as sedative, hypnosis, anticonvulsion and anxiolysis. PET can be utilized to study the binding of the receptors in vivo. PET radioligands of gamma-aminobutyric acid type A-benzodiazepine receptors can be classified into 3 types: antagonists,agonists and reverse agonists, of which antagonist radiotracer 11 C-flumazenil is the most commonly applied in epilepsy, anxiety disorders, depression, vegetative state,addiction and other neuro-psychiatric disorders. (authors)

  5. Temporal characteristics of stress-induced decrease in benzodiazepine reception in C57BL/6 and BALB/c mice.

    Science.gov (United States)

    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.

  6. Midazolam inhibits chondrogenesis via peripheral benzodiazepine receptor in human mesenchymal stem cells.

    Science.gov (United States)

    Chen, Yung-Ching; Wu, King-Chuen; Huang, Bu-Miin; So, Edmund Cheung; Wang, Yang-Kao

    2018-05-01

    Midazolam, a benzodiazepine derivative, is widely used for sedation and surgery. However, previous studies have demonstrated that Midazolam is associated with increased risks of congenital malformations, such as dwarfism, when used during early pregnancy. Recent studies have also demonstrated that Midazolam suppresses osteogenesis of mesenchymal stem cells (MSCs). Given that hypertrophic chondrocytes can differentiate into osteoblast and osteocytes and contribute to endochondral bone formation, the effect of Midazolam on chondrogenesis remains unclear. In this study, we applied a human MSC line, the KP cell, to serve as an in vitro model to study the effect of Midazolam on chondrogenesis. We first successfully established an in vitro chondrogenic model in a micromass culture or a 2D high-density culture performed with TGF-β-driven chondrogenic induction medium. Treatment of the Midazolam dose-dependently inhibited chondrogenesis, examined using Alcian blue-stained glycosaminoglycans and the expression of chondrogenic markers, such as SOX9 and type II collagen. Inhibition of Midazolam by peripheral benzodiazepine receptor (PBR) antagonist PK11195 or small interfering RNA rescued the inhibitory effects of Midazolam on chondrogenesis. In addition, Midazolam suppressed transforming growth factor-β-induced Smad3 phosphorylation, and this inhibitory effect could be rescued using PBR antagonist PK11195. This study provides a possible explanation for Midazolam-induced congenital malformations of the musculoskeletal system through PBR. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  7. Food deprivation modulates gamma-aminobutyric acid receptors and peripheral benzodiazepine binding sites in rats.

    Science.gov (United States)

    Weizman, A; Bidder, M; Fares, F; Gavish, M

    1990-12-03

    The effect of 5 days of food deprivation followed by 5 days of refeeding on gamma-aminobutyric acid (GABA) receptors, central benzodiazepine receptors (CBR), and peripheral benzodiazepine binding sites (PBzS) was studied in female Sprague-Dawley rats. Starvation induced a decrease in the density of PBzS in peripheral organs: adrenal (35%; P less than 0.001), kidney (33%; P less than 0.01), and heart (34%; P less than 0.001). Restoration of [3H]PK 11195 binding to normal values was observed in all three organs after 5 days of refeeding. The density of PBzS in the ovary, pituitary, and hypothalamus was not affected by starvation. Food deprivation resulted in a 35% decrease in cerebellar GABA receptors (P less than 0.01), while CBR in the hypothalamus and cerebral cortex remained unaltered. The changes in PBzS observed in the heart and kidney may be related to the long-term metabolic stress associated with starvation and to the functional changes occurring in these organs. The down-regulation of the adrenal PBzS is attributable to the suppressive effect of hypercortisolemia on pituitary ACTH release. The reduction in cerebellar GABA receptors may be an adaptive response to food deprivation stress and may be relevant to the proaggressive effect of hunger.

  8. Inhibition of benzodiazepine binding in vitro by amentoflavone, a constituent of various species of Hypericum.

    Science.gov (United States)

    Baureithel, K H; Büter, K B; Engesser, A; Burkard, W; Schaffner, W

    1997-06-01

    Flower extracts of Hypericum perforatum, Hypericum hirsutum, Hypericum patulum and Hypericum olympicum efficiently inhibited binding of [3H]flumazenil to rat brain benzodiazepine binding sites of the GABAA-receptor in vitro with IC50 values of 6.83, 6.97, 13.2 and 6.14 micrograms/ml, respectively. Single constituents of the extracts like hypericin, the flavones quercetin and luteolin, the glycosylated flavonoides rutin, hyperoside and quercitrin and the biflavone 13, II8-biapigenin did not inhibit binding up to concentrations of 1 microM. In contrast, amentoflavone revealed an IC50 = 14.9 +/- 1.9 nM on benzodiazepine binding in vitro. Comparative HPLC analyses of hypericin and amentoflavone in extracts of different Hypericum species revealed a possible correlation between the amentoflavone concentration and the inhibition of flumazenil binding. For hypericin no such correlation was observed. Our experimental data demonstrate that amentoflavone, in contrast to hypericin, presents a very active compound with regard to the inhibition of [3H]-flumazenil binding in vitro and thus might be involved in the antidepressant effects of Hypericum perforatum extracts.

  9. Modulation of benzodiazepine by lysine and pipecolic acid on pentylenetetrazol-induced seizures

    International Nuclear Information System (INIS)

    Chang, Y.F.; Hargest, V.; Chen, J.S.

    1988-01-01

    L-lysine and its metabolite pipecolic acid (PA) have been studied for their effects on pentylenetetrazol (PTZ)-induced seizures in mice. L-Lysine of L-Pa i.p. significantly increased clonic and tonic latencies in a dose-dependent manner against 90 mg/kg PTZ-induced seizures. L-Lysine but not L-Pa enhanced the anticonvulsant effect of diazepam (DZ). L-Pa i.c.v. showed a slight decrease in clonic latency; it did not enhance the antiseizure activity of DZ; it caused seizures at 0.6 mmol/kg. D-PA i.c.v. displayed an opposite effect compared to its L-isomer. The anticonvulsant effect of L-lysine in terms of increase in seizure latency and survival was even more amplified when tested with a submaximal PTZ concentration. L-Lysine showed an enhancement of specific 3 H-flunitrazepam(FZ) binding to mouse brain membranes both in vitro an din vivo. The possibility of L-lysine acting as a modulator for the GABA/benzodiazepine receptors was demonstrated. Since L-PA showed enhancement of 3 H-FZ binding only in vitro but not in vivo, the anticonvulsant effect of L-PA may not be linked to the GABA/benzodiazepine receptor

  10. Soman- or kainic acid-induced convulsions decrease muscarinic receptors but not benzodiazepine receptors

    International Nuclear Information System (INIS)

    Churchill, L.; Pazdernik, T.L.; Cross, R.S.; Nelson, S.R.; Samson, F.E.

    1990-01-01

    [3H]Quinuclidinyl benzilate (QNB) binding to muscarinic receptors decreased in the rat forebrain after convulsions induced by a single dose of either soman, a potent inhibitor of acetylcholinesterase, or kainic acid, an excitotoxin. A Rosenthal plot revealed that the receptors decreased in number rather than affinity. When the soman-induced convulsions were blocked, the decrease in muscarinic receptors at 3 days was less extensive than when convulsions occurred and at 10 days they approached control levels in most of the brain areas. The most prominent decrements in QNB binding were in the piriform cortex where the decline in QNB binding is probably related to the extensive convulsion-associated neuropathology. The decrements in QNB binding after convulsions suggest that the convulsive state leads to a down-regulation of muscarinic receptors in some brain areas. In contrast to the decrease in QNB binding after convulsions, [3H]flunitrazepam binding to benzodiazepine receptors did not change even in the piriform cortex where the loss in muscarinic receptors was most prominent. Thus, it appears that those neuronal processes that bear muscarinic receptors are more vulnerable to convulsion-induced change than those with benzodiazepine receptors

  11. Modulation of acetylcholine release from rat striatal slices by the GABA/benzodiazepine receptor complex

    Energy Technology Data Exchange (ETDEWEB)

    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 BR 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.

  12. Analysis of subcomponents of the gamma-aminobutyric acid/benzodiazepine receptor macromolecular complex in mammalian central nervous system

    International Nuclear Information System (INIS)

    McCabe, R.T.

    1987-01-01

    Since the presence of endogenous gamma-aminobutyric acid (GABA) may affect benzodiazepine binding to tissue sections in autoradiographic studies, a protocol designed to check for this influence has been investigated. [ 3 H]Flunitrazepam (1 nM) was used to label benzodiazepine receptors for autoradiographic localization. Bicuculline was added to the incubation medium of an additional set of tissue sections to antagonize any potential effect of endogenous GABA. Binding in these sections was compared to that occurring in another set in which excess GABA was added to create further GABA enhancement. Binding was also compared to adjacent sections which were treated similarly but also preincubated in distilled-deionized water to burst the cells by osmotic shock and eliminate endogenous GABA, thereby preventing any effect on benzodiazepine binding. The results indicated that endogenous GABA is indeed present in the slide-mounted tissue sections and is affecting benzodiazepine receptor binding differentially in various regions of the brain depending on the density of GABAergic innervation. Scatchard analysis of saturation data demonstrated that the alteration in BZ binding due to GABA was a result of a change in the affinity rather than number of receptors present

  13. Size-exclusion chromatographic reconstitution of the bovine brain benzodiazepine receptor : Effects of lipid environment on the binding characteristics

    NARCIS (Netherlands)

    Viel, G.T; Yang, Q; Lundahl, P; Ensing, K; de Zeeuw, R.A

    1997-01-01

    The benzodiazepine receptor from calf brain was solubilized with sodium deoxycholate (2 mg/ml) in the presence of 0.5 M KCl and protease inhibitors, and bound flunitrazepam with an equilibrium dissociation constant (K-d) of 2.7+/-1.2 nM and with 0.40+/-0.04 pmol binding sites per mg protein (B-max).

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

    NARCIS (Netherlands)

    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

  15. Dependence and withdrawal reactions to benzodiazepines and selective serotonin reuptake inhibitors. How did the health authorities react?

    Science.gov (United States)

    Nielsen, Margrethe; Hansen, Ebba Holme; Gøtzsche, Peter C

    2013-01-01

    Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time. Documentary study. We searched the web-sites of the European Medicines Agency and the drug agencies in USA, UK, and Denmark for documents mentioning benzodiazepines or SSRIs. We supplemented with other relevant literature that could contribute to our study. The searches were performed in 2009 in PubMed, Google, BMJ and JAMA. It took many years before the drug regulators acknowledged benzodiazepine dependence and SSRI withdrawal reactions and before the prescribers and the public were informed. Drug regulators relied mainly on the definitions of dependence and withdrawal reactions from the diagnostic psychiatric manuals, which contributed to the idea that SSRIs do not cause dependence, although it is difficult for many patients to stop treatment. In the perspective of a precautionary principle, drug agencies have failed to acknowledge that SSRIs can cause dependence and have minimised the problem with regard to its frequency and severity. In the perspective of a risk management principle, the drug agencies have reacted in concordance with the slowly growing knowledge of adverse drug reactions and have sharpened the information to the prescribers and the public over time. However, solely relying on spontaneous reporting of adverse effects leads to underestimation and delayed information about the problems. Given the experience with the benzodiazepines, we believe the regulatory bodies should have required studies from the manufacturers that could have elucidated the dependence potential of the SSRIs before marketing authorization was granted.

  16. Bioassay-guided isolation of apigenin with GABA-benzodiazepine activity from Tanacetum parthenium

    DEFF Research Database (Denmark)

    Jäger, Anna Katharina; Krydsfeldt, Katrine; Rasmussen, Hasse Bonde

    2009-01-01

    Extracts of Tanacetum parthenium are used in the prophylactic treatment of migraine and have also been used in Danish folk medicine for the treatment of epilepsy. An ethanol extract of T. parthenium showed high affinity for the GABA(A)-benzodiazepine site. An ethanol extract of T. parthenium was ...

  17. AC-3933, a benzodiazepine partial inverse agonist, improves memory performance in MK-801-induced amnesia mouse model.

    Science.gov (United States)

    Hashimoto, Takashi; Iwamura, Yoshihiro

    2016-05-01

    AC-3933, a novel benzodiazepine receptor partial inverse agonist, is a drug candidate for cognitive disorders including Alzheimer's disease. We have previously reported that AC-3933 enhances acetylcholine release in the rat hippocampus and ameliorates scopolamine-induced memory impairment and age-related cognitive decline in both rats and mice. In this study, we further evaluated the procognitive effect of AC-3933 on memory impairment induced by MK-801, an N-methyl-d-aspartate receptor antagonist, in mice. Unlike the acetylcholinesterase inhibitor donepezil and the benzodiazepine receptor inverse agonist FG-7142, oral administration of AC-3933 significantly ameliorated MK-801-induced memory impairment in the Y-maze test and in the object location test. Interestingly, the procognitive effects of AC-3933 on MK-801-induced memory impairment were not affected by the benzodiazepine receptor antagonist flumazenil, although this was not the case for the beneficial effects of AC-3933 on scopolamine-induced memory deficit. Moreover, the onset of AC-3933 ameliorating effect on scopolamine- or MK-801-induced memory impairment was different in the Y-maze test. Taken together, these results indicate that AC-3933 improves memory deficits caused by both cholinergic and glutamatergic hypofunction and suggest that the ameliorating effect of AC-3933 on MK-801-induced memory impairment is mediated by a mechanism other than inverse activation of the benzodiazepine receptor. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. GABA(A)-benzodiazepine receptor complex sensitivity in 5-HT(1A) receptor knockout mice on a 129/Sv background.

    NARCIS (Netherlands)

    Pattij, T.; Groenink, L.; Oosting, R.S.; Gugten, J. van der; Maes, R.A.A.; Olivier, B.

    2002-01-01

    Previous studies in 5-HT(1A) receptor knockout (1AKO) mice on a mixed Swiss Websterx129/Sv (SWx129/Sv) and a pure 129/Sv genetic background suggest a differential gamma-aminobutyric acid (GABA(A))-benzodiazepine receptor complex sensitivity in both strains, independent from the anxious phenotype. To

  19. Identification, characterization and potent antitumor activity of ECO-4601, a novel peripheral benzodiazepine receptor ligand.

    Science.gov (United States)

    Gourdeau, Henriette; McAlpine, James B; Ranger, Maxime; Simard, Bryan; Berger, Francois; Beaudry, Francis; Farnet, Chris M; Falardeau, Pierre

    2008-05-01

    ECO-4601 is a structurally novel farnesylated dibenzodiazepinone discovered through DECIPHER technology, Thallion's proprietary drug discovery platform. The compound was shown to have a broad cytotoxic activity in the low micromolar range when tested in the NCI 60 cell line panel. In the work presented here, ECO-4601 was further evaluated against brain tumor cell lines. Preliminary mechanistic studies as well as in vivo antitumor evaluation were performed. Since ECO-4601 has a benzodiazepinone moiety, we first investigated if it binds the central and/or peripheral benzodiazepine receptors. ECO-4601 was tested in radioligand binding assays on benzodiazepine receptors obtained from rat hearts. The ability of ECO-4601 to inhibit the growth of CNS cancers was evaluated on a panel of mouse, rat and human glioma cell lines using a standard MTT assay. Antitumor efficacy studies were performed on gliomas (rat and human), human breast and human prostate mouse tumor xenografts. Antitumor activity and pharmacokinetic analysis of ECO-4601 was evaluated following intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) bolus administrations. ECO-4601 was shown to bind the peripheral but not the central benzodiazepine receptor and inhibited the growth of CNS tumor cell lines. Bolus s.c. and i.p. administration gave rise to low but sustained drug exposure, and resulted in moderate to significant antitumor activity at doses that were well tolerated. In a rat glioma (C6) xenograft model, ECO-4601 produced up to 70% tumor growth inhibition (TGI) while in a human glioma (U-87MG) xenograft, TGI was 34%. Antitumor activity was highly significant in both human hormone-independent breast (MDA-MB-231) and prostate (PC-3) xenografts, resulting in TGI of 72 and 100%, respectively. On the other hand, i.v. dosing was followed by rapid elimination of the drug and was ineffective. Antitumor efficacy of ECO-4601 appears to be associated with the exposure parameter AUC and/or sustained

  20. Identification, characterization, and purification of a 65,000 dalton protein in rat brain is photolabeled by nitro-containing benzodiazepines

    Energy Technology Data Exchange (ETDEWEB)

    Bowling, A.C.

    1988-01-01

    Benzodiazepines bind to two well-characterized classes of nanomolar-affinity binding sites, the central and the peripheral types. Although these sites appear to mediate many of the effects of these compounds, they cannot account for all of the biochemical and physiologic effects of the benzodiazepines. In this investigation, a protein that is photolabeled by NO{sub 2}-containing benzodiazepines was identified and characterized in rat brain by performing photaffinity labeling experiments with ({sup 3}H)-clonazepam and ({sup 3}H)-flunitrazepam. These experiments demonstrate that this photolabeled protein has a molecular weight of 65,000 daltons. Photolabeling of the protein was saturable, inhibited in a stereoselective manner by benzodiazepine enantiomers, inhibited by therapeutically-relevant concentrations of many different NO{sub 2}-containing benzodiazepines, and was not inhibited by more than 70 non-benzodiazepine compounds. The photolabeled protein is distinct from the central and peripheral sites on the basis of molecular weight, benzodiazepine inhibitory potencies, subcellular localization, and tissue distribution.

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

    Science.gov (United States)

    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.

  2. Preservation of peripheral benzodiazepine receptors: differential effects of freezing on [3H]Ro 5-4864 and [3H]PK 11195 binding

    International Nuclear Information System (INIS)

    Basile, A.S.; Ostrowski, N.L.; Skolnick, P.

    1987-01-01

    A statistically significant decrease in the density of peripheral benzodiazepine receptors was observed in renal membranes of rats beginning 2 weeks after adrenalectomy when compared with sham-operated controls. This decrease in peripheral benzodiazepine receptor density was manifest as a decrease in the Bmax of two ligands [ 3 H]Ro 5-4864 and [ 3 H]PK 11195, without accompanying changes in their apparent affinity (Kd) for this site. Similar changes were not seen in another aldosterone-sensitive organ, the submandibular salivary gland. The decrease in peripheral benzodiazepine receptor density in observed in adrenalectomized rat renal membranes was restored to control levels after 1 week of aldosterone administration using a dose (12.5 micrograms/kg/day) that had no effect on peripheral benzodiazepine receptor density in sham-operated animals. In contrast, dexamethasone administration (50 micrograms/kg/day, 1 week) had no effect on renal peripheral benzodiazepine receptor density when administered to either adrenalectomized or sham-operated rats. Further, adrenal demedullation had no effect on renal peripheral benzodiazepine receptor density or affinity. The decrease in peripheral benzodiazepine receptor density was localized to the renal cortex and the outer stripe of the medulla by gross dissection of renal slices and renal tissue section autoradiography. The specific effect of adrenalectomy on renal peripheral benzodiazepine receptor density, the lack of direct effect of aldosterone on [ 3 H]Ro 5-4864 binding, and the localization of the change in peripheral benzodiazepine receptor density to the renal cortex and outer stripe suggests that these changes may reflect an adaptation of the renal nephron (possibly the distal convoluted tubule, intermediate tubule and/or the collecting duct) to the loss of mineralocorticoid hormones

  3. Synthesis and antimicrobial, antifungal and anthelmintic activities of 3H-1,5-benzodiazepine derivatives

    Directory of Open Access Journals (Sweden)

    RAJESH KUMAR

    2008-10-01

    Full Text Available The diazonium salt of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide in the presence of sodium hydroxide was condensed with different β-diketones/β-ketoesters, 3a–e, to obtain new β-diketones/β-ketoesters, 4a–e. The β-diketones/β-ketoesters 4a–e were condensed with o-phenylenediamine (o-PDA in presence of p-toluenesulfonic acid/SiO2 to give biologically active 3H-1,5-benzodiazepines, 5a–e. All the newly synthesized compounds were characterized by elemental analysis and spectral studies. The compounds 5a–e was screened for their antimicrobial, antifungal and anthelmintic activities.

  4. Polysubstance Abuse: Alcohol, Opioids and Benzodiazepines Require Coordinated Engagement by Society, Patients, and Physicians

    Directory of Open Access Journals (Sweden)

    Ogbu, Uzor C

    2015-03-01

    Full Text Available The Centers for Disease Control and Prevention (CDC has published significant data trends related to substance abuse involving opioid pain relievers (OPR, benzodiazepines and alcohol in the United States. The CDC describes opioid misuse and abuse as an epidemic, with the use of OPR surpassing that of illicit drugs. Alcohol has also been a persistent problem and is associated with a number of emergency department visits and deaths independent of other substances. The use of these drugs in combination creates an additive effect with increased central nervous system suppression and a heightened risk of an overdose. We present a summary of the findings from the Morbidity and Mortality Weekly Report (MMWR with commentary on strategies to combat prescription drug and alcohol abuse. [West J Emerg Med. 2015;16(1:76–79.

  5. Benzodiazepine receptor distribution and cerebral blood flow in early blindness. A PET study

    International Nuclear Information System (INIS)

    Mishina, Masahiro; Senda, Michio; Kiyosawa, Motohiro

    2000-01-01

    We studied benzodiazepine receptor (BZR) distribution, which is thought to be affected by neuronal density in the cerebral cortex, and CBF using [ 11 C]flumazenil and [ 15 O]water PET in early blind (EB) and in blindfold sighted control (SC) subjects. PET images were co-registered to the subject's MRI. Using SPM96, MRI images were normalized in the Talairach and Tournoux coordinate system, and accordingly MRI-registered PET images were spatially normalized. Statistical parametric maps were computed on a voxel-by-voxel basis, using the general linear model. CBF for EB was significantly larger in the Brodmann area 17 and 18, especially anterior area, than that for SC, while there was no significant difference in BZR distribution. Our BZR data suggest that the amount of neurons do not change due to early visual deprivation in the visual cortex, in spite of high CBF in visual cortex of EB subjects. (author)

  6. Methodology for benzodiazepine receptor binding assays at physiological temperature. Rapid change in equilibrium with falling temperature

    International Nuclear Information System (INIS)

    Dawson, R.M.

    1986-01-01

    Benzodiazepine receptors of rat cerebellum were assayed with [ 3 H]-labeled flunitrazepam at 37 0 C, and assays were terminated by filtration in a cold room according to one of three protocols: keeping each sample at 37 degrees C until ready for filtration, taking the batch of samples (30) into the cold room and filtering sequentially in the order 1-30, and taking the batch of 30 samples into the cold room and filtering sequentially in the order 30-1. the results for each protocol were substantially different from each other, indicating that rapid disruption of equilibrium occurred as the samples cooled in the cold room while waiting to be filtered. Positive or negative cooperativity of binding was apparent, and misleading effects of gamma-aminobutyric acid on the affinity of diazepam were observed, unless each sample was kept at 37 0 C until just prior to filtration

  7. [Ion-dependency of the GABA-potentiating effects of benzodiazepine tranquilizers and harmane].

    Science.gov (United States)

    Abramets, I I; Komissarov, I V

    1984-06-01

    Experiments on an isolated spinal cord of 8-15-day-old rats have shown that one of the possible mechanisms of the GABA-potentiating action of the benzodiazepine tranquilizer, chlorodiazepoxide, may be a decrease in the intraneuronal concentration of Ca2+. This is evidenced by the enhancement of the GABA-potentiating action of chlorodiazepoxide under Ca2+ deficiency in the medium and in the presence of the blockers of the voltage-dependent Ca2+ ionic channels--Mn2+ and Co2+, and by the reduction of the effect in question under Ca2+ excess in the medium and in the presence of the K+ channels blockers--tetraethylammonium and 4-aminopyridine. The GABA-potentiating action of harmane is likely to be related to the blockade of the voltage-dependent K+ channels and elevation of the intracellular concentration of Ca2+.

  8. Benzodiazepine temazepam suppresses the transient auditory 40-Hz response amplitude in humans.

    Science.gov (United States)

    Jääskeläinen, I P; Hirvonen, J; Saher, M; Pekkonen, E; Sillanaukee, P; Näätänen, R; Tiitinen, H

    1999-06-18

    To discern the role of the GABA(A) receptors in the generation and attentive modulation of the transient auditory 40-Hz response, the effects of the benzodiazepine temazepam (10 mg) were studied in 10 healthy social drinkers, using a double-blind placebo-controlled design. Three hundred Hertz standard and 330 Hz rare deviant tones were presented to the left, and 1000 Hz standards and 1100 Hz deviants to the right ear of the subjects. Subjects attended to a designated ear and were to detect deviants therein while ignoring tones to the other. Temazepam significantly suppressed the amplitude of the 40-Hz response, the effect being equal for attended and non-attended tone responses. This suggests involvement of GABA(A) receptors in transient auditory 40-Hz response generation, however, not in the attentive modulation of the 40-Hz response.

  9. Clonazepam as Agonist Substitution Treatment for Benzodiazepine Dependence: A Case Report

    Directory of Open Access Journals (Sweden)

    Angelo Giovanni Icro Maremmani

    2013-01-01

    Full Text Available Nowadays, the misuse of benzodiazepines (BZDs is a cause for a serious concern among pharmacologically inexperienced patients, whether treated or untreated, that could lead to significant complications, including tolerance, dependence, and addiction. We present a case report in which an Italian patient affected by anxiety disorder and treated with BZDs presented a severe case of dependence on BZDs. We treated him according to an agonist substitution approach, switching from the abused BZD to a slow-onset, long-acting, high potency agonist (clonazepam, and looking at the methadone treatment model as paradigm. We decided to use clonazepam for its pharmacokinetic properties. The advantage of choosing a slow-onset, long-lasting BZD for the treatment of our patient was that it led us to a remarkable improvement in the clinical situation, including the cessation of craving, absence of withdrawal symptoms, reduced anxiety, improvements in social functioning, and a better cognition level.

  10. Zolpidem displays heterogeneity in its binding to the nonhuman primate benzodiazepine receptor in vivo.

    Science.gov (United States)

    Schmid, L; Bottlaender, M; Fuseau, C; Fournier, D; Brouillet, E; Mazière, M

    1995-10-01

    The distinctive pharmacological activity of zolpidem in rats compared with classical benzodiazepines has been related to its differential affinity for benzodiazepine receptor (BZR) subtypes. By contrast, in nonhuman primates the pharmacological activity of zolpidem was found to be quite similar to that of classical BZR agonists. In an attempt to explain this discrepancy, we examined the ability of zolpidem to differentiate BZR subtypes in vivo in primate brain using positron emission tomography. The BZRs were specifically labeled with [11C]flumazenil. Radiotracer displacement by zolpidem was monophasic in cerebellum and neocortex, with in vivo Hill coefficients close to 1. Conversely, displacement of [11C]flumazenil was biphasic in hippocampus, amygdala, septum, insula, striatum, and pons, with Hill coefficients significantly smaller than 1, suggesting two different binding sites for zolpidem. In these cerebral regions, the half-maximal inhibitory doses for the high-affinity binding site were similar to those found in cerebellum and neocortex and approximately 100-fold higher for the low-affinity binding site. The low-affinity binding site accounted for zolpidem binding characteristics contrast with those reported for rodents, where three different binding sites were found. Species differences in binding characteristics may explain why zolpidem has a distinctive pharmacological activity in rodents, whereas its pharmacological activity in primates is quite similar to that of classical BZR agonists, except for the absence of severe effects on memory functions, which may be due to the lack of substantial zolpidem affinity for a distinct BZR subtype in cerebral structures belonging to the limbic system.

  11. The elimination half-life of benzodiazepines and fall risk: two prospective observational studies.

    Science.gov (United States)

    de Vries, Oscar J; Peeters, Geeske; Elders, Petra; Sonnenberg, Caroline; Muller, Majon; Deeg, Dorly J H; Lips, Paul

    2013-11-01

    the STOPP criteria advise against the use of long-acting benzodiazepines (LBs). to study whether LBs are associated with a higher fall risk than short-acting benzodiazepines (SBs) (elimination half-life ≤ 10 h). we used base-line data and prospective fall follow-up from the Longitudinal Aging Study Amsterdam, a longitudinal cohort study including 1,509 community-dwelling older persons (Study 1) and from a separate fall prevention study with 564 older persons after a fall (Study 2). Time to the first fall after inclusion and number of falls in the first year after inclusion were the primary endpoints. both in Study 1 and Study 2 the use of SBs was associated with time to the first fall, hazard ratio (HR) 1.62 (95% CI: 1.03-2.56) and HR 1.64 (95% CI: 1.19-2.26),respectively. LBs were not significantly associated with time to first fall, HR 1.40 (0.85-2.31) and HR 1.08 (0.72-1.62). In both studies, the use of SBs was also associated with number of falls, odds ratio (OR) 1.28 (95% CI: 1.01-1.61) and OR 1.37 (95% CI: 1.10-1.70). LBs were not significantly associated with number of falls, OR 1.23 (0.96-1.57) and 1.10 (0.82-1.48). the use of SBs is not associated with a lower fall risk compared with LBs. The use of both SBs and LBs by old persons should be strongly discouraged.

  12. Benzodiazepines: rat pinealocyte binding sites and augmentation of norepinephrine-stimulated N-acetyltransferase activity

    Energy Technology Data Exchange (ETDEWEB)

    Matthew, E.; Parfitt, A.G.; Sugden, D.; Engelhardt, D.L.; Zimmerman, E.A.; Klein, D.C.

    1984-02-01

    Studies of (/sup 3/H)diazepam binding to intact rat pineal cells were carried out in tissue culture preparations. The binding was saturable, reversible and proportional to the number of cells used. Scatchard analysis resulted in a linear plot (Kd . 23 nM, maximum binding sites (Bmax) . 1.56 pmol/mg of protein for cells in monolayer culture; Kd . 7 nM, Bmax . 1.3 pmol/mg of protein for cells in suspension culture). Inhibition constants (Ki) for clonazepam (500 nM), flunitrazepam (38 nM) and Ro-5-4864 (5 nM) indicated that the binding sites were probably of the ''peripheral'' type. In addition, the effects of diazepam on norepinephrine-stimulated N-acetyltransferase (NAT) activity were studied in organ culture and dissociated cell culture. Diazepam (10-50 microM) both prolonged and increased the magnitude of the norepinephrine-induced increase in NAT activity but did not affect the initial rate of rise of enzyme activity. The effect was dose-dependent and was also seen with clonazepam, flunitrazepam and Ro-5-4864, but not with Ro-15-1788. Diazepam, by itself, at these concentrations, had no effect on NAT, but enzyme activity was increased by higher concentrations (0.1-1 mM). Although a relationship between the (/sup 3/H)diazepam binding sites described here and the effect of benzodiazepines on NAT cannot be established from these studies, the data suggest that the benzodiazepines may alter melatonin levels through their action on NAT.

  13. Premedication with benzodiazepines for upper gastrointestinal endoscopy: Comparison between oral midazolam and sublingual alprazolam

    Directory of Open Access Journals (Sweden)

    Vahid Sebghatollahi

    2017-01-01

    Full Text Available Background: Premedication with orally administered benzodiazepines is effective in reducing anxiety and discomfort related to endoscopic procedures. We evaluated the efficacy and safety of oral midazolam in comparison to sublingual alprazolam as premedication for esophagogastroduodenoscopy (EGD. Materials and Methods: Adult candidates for diagnostic EGD received either oral midazolam (7.5 mg in 15 cc apple juice or sublingual alprazolam (0.5 mg 30 min before EGD. Procedural anxiety and pain/discomfort were assessed using 11-point numerical rating scales. Patients' overall tolerance (using a four-point Likert scale and willingness to repeat the EGD, if necessary, were also assessed. Blood pressure, heart rate, and arterial oxygen saturation were monitored from medication to 30 min after the procedure. Results: Patients experienced a similar reduction in procedural anxiety after medication with oral midazolam and sublingual alprazolam; mean (standard deviation [SD] of 1.86 [1.63] and 2.02 [1.99] points, respectively, P = 0.91. Compared to oral midazolam, pain/discomfort scores were lower with sublingual alprazolam; mean (SD of 4.80 (3.01 versus 3.68 (3.28, P = 0.024. There was no significant difference between the two groups in patients' tolerance, willingness to repeat the procedure, or hemodynamic events. Conclusion: Oral midazolam and sublingual alprazolam are equally effective in reducing EGD-related anxiety; however, EGD-related pain/discomfort is lower with alprazolam. Both benzodiazepines are equally safe and can be used as premedication for patients undergoing diagnostic EGD.

  14. Determination of benzodiazepines in beverages using green extraction methods and capillary HPLC-UV detection.

    Science.gov (United States)

    Piergiovanni, Maurizio; Cappiello, Achille; Famiglini, Giorgio; Termopoli, Veronica; Palma, Pierangela

    2018-05-30

    Dispersive liquid-liquid microextraction with and without ultrasound assistance (DLLME, UA-DLLME) and microextraction with packed sorbent (MEPS) methods for the extraction and determination of eight different benzodiazepines (BDZ) (chlordiazepoxide, flurazepam, bromazepam, oxazepam, lorazepam, clobazam, clonazepam, and flunitrazepam) in three commercial non-alcoholic and light alcoholic beverages were optimized and compared. Benzodiazepines are frequently used for their extensive diffusion and strong numbing effect in drug-facilitated crimes (DFC). The tiny small amount of sample required for DLLME and MEPS extraction makes them very suitable for specimens collected at the crime scene of DFCs. Microextraction techniques are of increasing interest thanks to their accordance to green analytical chemistry (GAC) guidelines providing good recovery values. Ultrasound assistance (UA-DLLME) was used to investigate whether this type of energy can improve the recoveries of the analytes. Analyses of the extracts were performed with reverse-phase capillary high-performance liquid chromatography with UV detection (HPLC - UV), thanks to low environmental impact, robustness, diffusion, and affordability. Recovery percentages at three different concentrations in the three beverages were between 14.30% and 103.28% with intraday and interday RSD lower than ±2.78%. The same samples were extracted using a MEPS protocol, and the results were compared with those obtained with DLLME. MEPS gave recoveries between 20.90% and 101.88% for all matrices showing a better performance than DLLME at higher concentrations, though lower recoveries were observed with diluted samples. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Risk of hip fractures associated with benzodiazepines: Applying common protocol to a multi-database nested case-control study. The protect project

    NARCIS (Netherlands)

    Requena, Gema; Logie, John; González-González, Rocío; Gardarsdottir, Helga|info:eu-repo/dai/nl/321858131; Afonso, Ana; Souverein, Patrick C.|info:eu-repo/dai/nl/243074948; Merino, Elisa Martin; Boudiaf, Nada; Huerta, Consuelo; Bate, Andrew; Alvarez, Yolanda; García-Rodríguez, Luis A.; Reynolds, Robert; Schlienger, Raymond G.; De Groot, Mark C.H.|info:eu-repo/dai/nl/313936455; Klungel, Olaf H.|info:eu-repo/dai/nl/181447649; De Abajo, Francisco J.

    2014-01-01

    Background: The association between benzodiazepines (BZD) and hip fractures has been estimated in several observational studies although diverse methodologies and definitions have hampered comparability. Objectives: To evaluate the discrepancies in the risk estimates of hip/femur fractures

  16. (4Z-1-Dodecyl-4-(2-oxopropylidene-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

    Directory of Open Access Journals (Sweden)

    Jihad Sebhaoui

    2016-11-01

    Full Text Available In the title compound, C24H36N2O2, the orientation of the 2-oxopropylidene substituent is determined by the formation of an intramolecular N—H...O hydrogen bond. The benzodiazepine seven-membered ring adopts a slightly twisted boat conformation. The molecules pack in a bilayer fashion with the dodecyl chains intercalated to form the inner portion, and the benzodiazepine moieties on the outer surfaces.

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

    Science.gov (United States)

    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.

  18. Evidence for involvement of the astrocytic benzodiazepine receptor in the mechanism of action of convulsant and anticonvulsant drugs

    International Nuclear Information System (INIS)

    Bender, A.S.; Hertz, L.

    1988-01-01

    The anticonvulsant drugs carbamazepine, phenobarbital, trimethadione, valproic acid and ethosuximide at pharmacologically relevant concentrations inhibit [ 3 H]diazepam binding to astrocytes in primary cultures but have much less effect on a corresponding preparation of neurons. Phenytoin as well as pentobarbital (which is not used chronically as an anticonvulsant) are equipotent in the two cell types. The convulsants picrotoxinin and pentylenetetrazol, the convulsant benzodiazepine RO 5-3663 and the two convulsant barbiturates DMBB and CHEB similarly inhibit diazepam binding to astrocytes but have little effect on neurons. On the basis of these findings it is suggested that these convulsants and anticonvulsants owe at least part of their effect to an interaction with the astrocytic benzodiazepine receptor, perhaps by interference with a calcium channel

  19. 125I-iomazenil - benzodiazepine receptor binding and serum corticosterone level during psychological stress in a rat model

    International Nuclear Information System (INIS)

    Fukumitsu, Nobuyoshi; Ogi, Shigeyuki; Uchiyama, Mayuki; Mori, Yutaka

    2004-01-01

    To test the hypothesis that benzodiazepine receptor density decreases in response to stress, we correlated 125 I-iomazenil ( 125 I-IMZ) binding with serum corticosterone levels in a rat model. Wistar male rats were divided into four groups; control group (CON, 10 rats), no physical or psychological stress; and one-, three-, and five-day stress groups of 12 rats each (1-DAY, 3-DAY, and 5-DAY, respectively), receiving psychological stress for the given number of days. Psychological stress were given to rats with a communication box. The standardized uptake value (SUV) of 125 I-iomazenil of the 3-DAY and 5-DAY showed that 125 I-iomazenil - benzodiazepine receptor binding was significantly reduced in the cortices, accumbens nuclei, amygdala and caudate putamen (p 125 I-IMZ is a useful radioligand to reflect received stress and its binding in the cortices, accumbens nuclei, amygdala and caudate putamen is strongly affected by psychological stress

  20. Synthesis of iodine-123 labelled analogues of imidazenil and ethyl-imidazenil for studying benzodiazepine receptors using SPECT

    International Nuclear Information System (INIS)

    Katsifis, A.; Mattner, F.; Dikic, B.; Najdovski, L.; Kassiou, M.

    1996-01-01

    The [ 123 I]iodinated analogues of the benzodiazepine receptor partial agonist imidazenil and N-ethyl imidazenil have been synthesised for the study of the central benzodiazepine receptor using SPECT. [ 123 I]Iodomidazenil and [ 123 I]N-ethyliodoimidazenil were prepared by nucleophilic bromine-iodine exchange in acetic acid at 150 o . The products were purified by semi-preparative reverse-phase HPLC with average radiochemical yields of 80% in a total synthesis time of 80 minutes. The specific activity was determined to be greater than 2500 Ci/mmol. The radiochemical and chemical purity assessed by radio-TLC and HPLC were found to be 98%. Alternatively, iododestannylation reactions via the trimethyltin precursors with Na[ 123 I] in the presence of Chloramine-T or peracetic acid resulted in yields of only 20-25% with the bulk of activity being lost as volatile methyl [ 123 I]iodide. (author)

  1. Synthesis, biological evaluation, and structure-activity relationship of clonazepam, meclonazepam, and 1,4-benzodiazepine compounds with schistosomicidal activity.

    Science.gov (United States)

    Menezes, Carla M S; Rivera, Gildardo; Alves, Marina A; do Amaral, Daniel N; Thibaut, Jean Pierre B; Noël, François; Barreiro, Eliezer J; Lima, Lídia M

    2012-06-01

    The inherent morbidity and mortality caused by schistosomiasis is a serious public health problem in developing countries. Praziquantel is the only drug in therapeutic use, leading to a permanent risk of parasite resistance. In search for new schistosomicidal drugs, meclonazepam, the 3-methyl-derivative of clonazepam, is still considered an interesting lead-candidate because it has a proven schistosomicidal effect in humans but adverse effects on the central nervous system did not allow its clinical use. Herein, the synthesis, in vitro biological evaluation, and molecular modeling of clonazepam, meclonazepam, and analogues are reported to establish the first structure-activity relationship for schistosomicidal benzodiazepines. Our findings indicate that the amide moiety [N(1) H-C(2) (=O)] is the principal pharmacophoric unit of 1,4-benzodiazepine schistosomicidal compounds and that substitution on the amide nitrogen atom (N(1) position) is not tolerated. © 2012 John Wiley & Sons A/S.

  2. Novel one-pot one-step synthesis of 2'-[(18)F]fluoroflumazenil (FFMZ) for benzodiazepine receptor imaging.

    Science.gov (United States)

    Yoon, Young Hyun; Jeong, Jae Min; Kim, Hyung Woo; Hong, Sung Hyun; Lee, Yun-Sang; Kil, Hee Sup; Chi, Dae Yoon; Lee, Dong Soo; Chung, June-Key; Lee, Myung Chul

    2003-07-01

    We describe the synthesis of 2'-[(18)F]fluoroflumazenil (FFMZ), which differs from the typically used [(18)F]fluoroethylflumazenil (FEFMZ) for benzodiazepine receptor imaging. For one-pot one-step labeling, the precursors, 2'-tosyloxyflumazenil (TFMZ) and 2'-mesyloxyflumazenil (MFMZ), were synthesized in three steps. The precursors were successfully labeled with no-carrier-added (18)F-fluoride which was activated by repeated azeotropic distillation with Kryptofix 2.2.2./potassium carbonate in MeCN. An automated system for labeling and purification of [(18)F]FFMZ was developed. Labeling efficiency and radiochemical purity of [(18)F]FFMZ after synthesis by the automated system were 68% and 98%, respectively. Specific binding of [(18)F]FFMZ to central benzodiazepine receptor of rats was demonstrated by phosphoimaging.

  3. Novel one-pot one-step synthesis of 2'-[18F]fluoroflumazenil (FFMZ) for benzodiazepine receptor imaging

    International Nuclear Information System (INIS)

    Young, Hyun Yoon; Jae, Min Jeong; Hyung, Woo Kim; Sung, Hyun Hong; Lee, Yun-Sang; Hee, Sup Kil; Dae, Yoon Chi; Dong, Soo Lee; Chung, June-Key; Myung, Chul Lee

    2003-01-01

    We describe the synthesis of 2'-[ 18 F]fluoroflumazenil (FFMZ), which differs from the typically used [ 18 F]fluoroethylflumazenil (FEFMZ) for benzodiazepine receptor imaging. For one-pot one-step labeling, the precursors, 2'-tosyloxyflumazenil (TFMZ) and 2'-mesyloxyflumazenil (MFMZ), were synthesized in three steps. The precursors were successfully labeled with no-carrier-added 18 F-fluoride which was activated by repeated azeotropic distillation with Kryptofix 2.2.2./potassium carbonate in MeCN. An automated system for labeling and purification of [ 18 F]FFMZ was developed. Labeling efficiency and radiochemical purity of [ 18 F]FFMZ after synthesis by the automated system were 68% and 98%, respectively. Specific binding of [ 18 F]FFMZ to central benzodiazepine receptor of rats was demonstrated by phosphoimaging

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

    Science.gov (United States)

    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).

  5. Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis

    OpenAIRE

    Tokuda, Kazuhiro; O’Dell, Kazuko A.; Izumi, Yukitoshi; Zorumski, Charles F.

    2010-01-01

    Benzodiazepines (BDZs) enhance γ-aminobutyric acid-A (GABAA) receptor inhibition by direct actions on central BDZ receptors (CBRs). Although some BDZs also bind mitochondrial receptors (translocator protein 18kDa, TSPO) and promote the synthesis of GABA-enhancing neurosteroids, the role of neurosteroids in the clinical effects of BDZs is unknown. In rat hippocampal slices, we compared midazolam, an anesthetic BDZ with clonazepam, an anticonvulsant/anxiolytic BDZ that activates CBRs selectivel...

  6. Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array recording study

    OpenAIRE

    Puia, Giulia; Gullo, Francesca; Dossi, Elena; Lecchi, Marzia; Wanke, Enzo

    2012-01-01

    The balance between glutamate- and GABA-mediated neurotransmission in the brain is fundamental in the nervous system, but it is regulated by the “tonic” release of a variety of endogenous factors. One such important group of molecules are the neurosteroids (NSs) which, similarly to benzodiazepines (BDZs), enhance GABAergic neurotransmission. The purpose of our work was to investigate, at in vivo physiologically relevant concentrations, the effects of NSs and BDZs as GABA modulators on dissoci...

  7. Benzodiazepines have high-affinity binding sites and induce melanogenesis in B16/C3 melanoma cells.

    OpenAIRE

    Matthew, E; Laskin, J D; Zimmerman, E A; Weinstein, I B; Hsu, K C; Engelhardt, D L

    1981-01-01

    We found that two markers of differentiation, tyrosinase (monophenol, dihydroxyphenylalanine:oxygen oxidoreductase, EC 1.14.18.1) activity and melanin synthesis, are induced by diazepam in B16/C3 mouse melanoma cells. We also demonstrated high-affinity binding sites for [3H]diazepam in these cells by radioreceptor assay, and we visualized binding to the cell surface by fluorescence microscopy with a benzodiazepine analog conjugated to a fluorescein-labeled protein. Our studies also showed tha...

  8. Unsaturated free fatty acids increase benzodiazepine receptor agonist binding depending on the subunit composition of the GABAA receptor complex.

    Science.gov (United States)

    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.

  9. Impact of benzodiazepines on brain FDG-PET quantification after single-dose and chronic administration in rats

    International Nuclear Information System (INIS)

    Silva-Rodríguez, Jesús; García-Varela, Lara; López-Arias, Esteban; Domínguez-Prado, Inés; Cortés, Julia; Pardo-Montero, Juan; Fernández-Ferreiro, Anxo

    2016-01-01

    Introduction: Current guidelines for brain PET imaging advice against the injection of diazepam prior to brain FDG-PET examination in order to avoid possible interactions of benzodiazepines with the radiotracer uptake. Nevertheless, many patients undergoing PET studies are likely to be under chronic treatment with benzodiazepines, for example due to the use of different medications such as sleeping pills. Animal studies may provide an extensive and accurate estimation of the effect of benzodiazepines on brain metabolism in a well-defined and controlled framework. Aim: This study aims at evaluating the impact of benzodiazepines on brain FDG uptake after single-dose administration and chronic treatment in rats. Methods: Twelve Sprague–Dawley healthy rats were randomly divided into two groups, one treated with diazepam and the other used as control group. Both groups underwent PET/CT examinations after single-dose and chronic administration of diazepam (treated) or saline (controls) during twenty-eight days. Different atlas-based quantification methods were used to explore differences on the total uptake and uptake patterns of FDG between both groups. Results: Our analysis revealed a significant reduction of global FDG uptake after acute (−16.2%) and chronic (−23.2%) administration of diazepam. Moreover, a strong trend pointing to differences between acute and chronic administrations (p < 0.08) was also observed. Uptake levels returned to normal after interrupting the administration of diazepam. On the other hand, patterns of FDG uptake were not affected by the administration of diazepam. Conclusions: The administration of diazepam causes a progressive decrease of the FDG global uptake in the rat brain, but it does not change local patterns within the brain. Under these conditions, visual assessment and quantification methods based on regional differences such as asymmetry indexes or SPM statistical analysis would still be valid when administrating this

  10. Risk factors associated with iatrogenic opioid and benzodiazepine withdrawal in critically ill pediatric patients: a systematic review and conceptual model.

    Science.gov (United States)

    Best, Kaitlin M; Boullata, Joseph I; Curley, Martha A Q

    2015-02-01

    Analgesia and sedation are common therapies in pediatric critical care, and rapid titration of these medications is associated with iatrogenic withdrawal syndrome. We performed a systematic review of the literature to identify all common and salient risk factors associated with iatrogenic withdrawal syndrome and build a conceptual model of iatrogenic withdrawal syndrome risk in critically ill pediatric patients. Multiple databases, including PubMed/Medline, EMBASE, CINAHL, and the Cochrane Central Registry of Clinical Trials, were searched using relevant terms from January 1, 1980, to August 1, 2014. Articles were included if they were published in English and discussed iatrogenic withdrawal syndrome following either opioid or benzodiazepine therapy in children in acute or intensive care settings. Articles were excluded if subjects were neonates born to opioid- or benzodiazepine-dependent mothers, children diagnosed as substance abusers, or subjects with cancer-related pain; if data about opioid or benzodiazepine treatment were not specified; or if primary data were not reported. In total, 1,395 articles were evaluated, 33 of which met the inclusion criteria. To facilitate analysis, all opioid and/or benzodiazepine doses were converted to morphine or midazolam equivalents, respectively. A table of evidence was developed for qualitative analysis of common themes, providing a framework for the construction of a conceptual model. The strongest risk factors associated with iatrogenic withdrawal syndrome include duration of therapy and cumulative dose. Additionally, evidence exists linking patient, process, and system factors in the development of iatrogenic withdrawal syndrome. Most articles were prospective observational or interventional studies. Given the state of existing evidence, well-designed prospective studies are required to better characterize iatrogenic withdrawal syndrome in critically ill pediatric patients. This review provides data to support the

  11. A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein.

    Science.gov (United States)

    Guo, Fang; Wu, Shuo; Julander, Justin; Ma, Julia; Zhang, Xuexiang; Kulp, John; Cuconati, Andrea; Block, Timothy M; Du, Yanming; Guo, Ju-Tao; Chang, Jinhong

    2016-09-21

    Although a highly effective vaccine is available, the number of yellow fever cases has increased over the past two decades, which highlights the pressing need for antiviral therapeutics. In a high throughput screening campaign, we identified an acetic acid benzodiazepine (BDAA) compound, which potently inhibits yellow fever virus (YFV). Interestingly, while treatment of YFV infected cultures with 2 μM of BDAA reduced the virion production by greater than 2 logs, the compound is not active against 21 other viruses from 14 different viral families. Selection and genetic analysis of drug resistant viruses revealed that substitution of proline at amino acid 219 (P219) of the nonstructural protein 4B (NS4B) with serine, threonine or alanine confers YFV resistance to BDAA without apparent loss of replication fitness in cultured mammalian cells. However, substitution of P219 with glycine confers BDAA resistance with significant loss of replication ability. Bioinformatics analysis predicts that the P219 localizes at the endoplasmic reticulum lumen side of the fifth putative trans-membrane domain of NS4B and the mutation may render the viral protein incapable of interacting with BDAA. Our studies thus revealed important role and structural basis for NS4B protein in supporting YFV replication. Moreover, in YFV-infected hamsters, oral administration of BDAA protected 90% of the animals from death, significantly reduced viral load by greater than 2 logs and attenuated viral infection-induced liver injury and body weight loss. The encouraging preclinical results thus warrant further development of BDAA or its derivatives as antiviral agents to treat yellow fever. Yellow fever is an acute viral hemorrhagic disease which threatens approximately one billion people living in tropical areas of Africa and Latin America. Although a highly effective yellow fever vaccine has been available for more than seven decades, the low vaccination rate fails to prevent outbreaks in at

  12. Synthesis and in vivo evaluation of [11C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors

    International Nuclear Information System (INIS)

    Dumont, Filip; Waterhouse, Rikki N.; Montoya, Julie A.; Mattner, Filomena; Katsifis, Andrew; Kegeles, Lawrence S.; Laruelle, Marc

    2003-01-01

    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/μmol (1.115 ± 0.105 Ci/μmol) (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

  13. PTSD Symptom Severities, Interpersonal Traumas, and Benzodiazepines Are Associated with Substance-Related Problems in Trauma Patients

    Science.gov (United States)

    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

  14. PTSD Symptom Severities, Interpersonal Traumas, and Benzodiazepines Are Associated with Substance-Related Problems in Trauma Patients

    Directory of Open Access Journals (Sweden)

    Jeffrey Guina

    2016-08-01

    Full Text Available 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.

  15. Synthesis and in vivo evaluation of [{sup 11}C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Dumont, Filip; Waterhouse, Rikki N. E-mail: rnw7@columbia.edu; Montoya, Julie A.; Mattner, Filomena; Katsifis, Andrew; Kegeles, Lawrence S.; Laruelle, Marc

    2003-05-01

    The synthesis and evaluation of [{sup 11}C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors, is reported herein. The reaction of desmethylzolpidem with [{sup 11}C] methyl iodide afforded the title compound [{sup 11}C]zolpidem in a yield of 19.19 {+-} 3.23% in 41 {+-} 2 min in specific activities of 0.995-1.19 Ci/{mu}mol (1.115 {+-} 0.105 Ci/{mu}mol) (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 [{sup 11}C]zolpidem is not a suitable tracer for in vivo visualization of central benzodiazepine receptors.

  16. Synthesis and in vivo evaluation of [11C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors.

    Science.gov (United States)

    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.

  17. Simultaneous identification of abused drugs, benzodiazepines, and new psychoactive substances in urine by liquid chromatography tandem mass spectrometry

    Directory of Open Access Journals (Sweden)

    Hei-Hwa Lee

    2016-03-01

    Full Text Available A literature search reveals no studies concerning simultaneous identification of commonly abused drugs, benzodiazepines, and new psychoactive substances in urine by liquid chromatography tandem mass spectrometry (LC–MS/MS. We developed and validated an LC–MS/MS method for simultaneous identification of multiple abused drugs, benzodiazepines, and new psychoactive substances in urine from suspected drug abusers. The instrument was operated in multiple-reaction monitoring using an electrospray ionization mode. Chromatograms were separated using an ACE5 C18 column on a gradient of acetonitrile. After liquid–liquid extraction, samples were passed through a 0.22-μm polyvinylidene difluoride filter before injection into the LC–MS/MS. The limits of quantitation ranged from 0.5 ng/mL to 31.3 ng/mL. The linearity ranged from 0.5 ng/mL to 200 ng/mL. The precision results were below 15.4% (intraday and 18.7% (interday. The intraday accuracy ranged from 85.9% to 121.0%; interday accuracy ranged from 66.1% to 128.7%. The proposed method was applied to 769 urine samples. The most common three drugs identified were ketamine, amphetamine, and opiates. The drug positive rate for one or more drugs was 79.6%. Our results demonstrate the suitability of the LC–MS/MS method for simultaneous identification of multiple abused drugs, benzodiazepines, and new psychoactive substances in urine.

  18. A Review of the Updated Pharmacophore for the Alpha 5 GABA(A Benzodiazepine Receptor Model

    Directory of Open Access Journals (Sweden)

    Terry Clayton

    2015-01-01

    Full Text Available An updated model of the GABA(A benzodiazepine receptor pharmacophore of the α5-BzR/GABA(A subtype has been constructed prompted by the synthesis of subtype selective ligands in light of the recent developments in both ligand synthesis, behavioral studies, and molecular modeling studies of the binding site itself. A number of BzR/GABA(A α5 subtype selective compounds were synthesized, notably α5-subtype selective inverse agonist PWZ-029 (1 which is active in enhancing cognition in both rodents and primates. In addition, a chiral positive allosteric modulator (PAM, SH-053-2′F-R-CH3 (2, has been shown to reverse the deleterious effects in the MAM-model of schizophrenia as well as alleviate constriction in airway smooth muscle. Presented here is an updated model of the pharmacophore for α5β2γ2 Bz/GABA(A receptors, including a rendering of PWZ-029 docked within the α5-binding pocket showing specific interactions of the molecule with the receptor. Differences in the included volume as compared to α1β2γ2, α2β2γ2, and α3β2γ2 will be illustrated for clarity. These new models enhance the ability to understand structural characteristics of ligands which act as agonists, antagonists, or inverse agonists at the Bz BS of GABA(A receptors.

  19. Association between benzodiazepines and recurrent falls: a cross-sectional elderly population-based study.

    Science.gov (United States)

    Rossat, A; Fantino, B; Bongue, B; Colvez, A; Nitenberg, C; Annweiler, C; Beauchet, O

    2011-01-01

    While the association between benzodiazepines (BZD) and single fall is long-known, the association between BZD and recurrent falls has been few studied. The aims of this study were 1) to examine whether BZD were associated with recurrent falls while taking into account the effect of potential confounders, and 2) to determine whether there was an interaction in terms of risk of falls between BZD and balance impairment in a community-dwelling population-based adults aged 65 and older. Cross-sectional. Three health centers in North-East of France. 7643 community-dwelling volunteers aged 65 and older. The use of BZD, the Mini Mental State Examination (MMSE) score, the Clock Drawing Test (CDT), the One Leg Balance (OLB) test, the Five Times Sit-To-Stand test (FTSS), and a history of falls were recorded. Subjects were separated into 4 groups based on the number of falls: 0, 1, 2 and ≥ 3 falls. Among the 1456 (19.2%) fallers, 994 (13.0%) were single fallers and 462 (6.1%) were recurrent fallers (i.e., > 2 falls). The number of falls increased significantly with age (Incident Rate Ratio (IRR)=1.04, P falls. After adjustment only the advance in age (IRR=1.02, P falls. The current study shows that the age, the female gender, the use of clobazam or prazepam and a low score at OLB are related to the recurrence of falls.

  20. Limazepines A-F, pyrrolo[1,4]benzodiazepine Antibiotics from an Indonesian Micrococcus sp.

    Science.gov (United States)

    Fotso, Serge; Zabriskie, T Mark; Proteau, Philip J; Flatt, Patricia M; Santosa, Dwi Andreas; Mahmud, Taifo

    2009-04-01

    In our screening of Indonesian microorganisms for novel bioactive natural products we have isolated seven new compounds, designated as limazepines A, B1 and B2 (isolated as an isomeric mixture), C, D, E, and F, from the culture broth of Micrococcus sp. strain ICBB 8177. In addition, the known natural products prothracarcin and 7-O-succinylmacrolactin A, as well as two previously reported synthetic compounds, 2-amino-3-hydroxy-4-methoxybenzoic acid methyl ester and 4-ethylpyrrole-2-carboxaldehyde, were obtained from the extract. Chemical structures were determined by spectroscopic methods and by comparison with the NMR data of structurally related compounds. The limazepines belong to the growing group of the pyrrolo[1,4]benzodiazepine antitumor antibiotics isolated from various soil bacteria. Limazepines B1/B2 mixture, C, and E were active against the Gram-positive bacterium Staphylococcus aureus and the Gram-negative bacterium Escherichia coli. Limazepine D was also active against S. aureus, but was not active against E. coli. Interestingly, only the limazepines B1/B2 mixture and D were active against Pseudomonas aeruginosa.

  1. Benzodiazepine receptor imaging with iomazenil SPECT in aphasic patients with cerebral infarction

    Energy Technology Data Exchange (ETDEWEB)

    Koshi, Yasuhiko; Kitamura, Shin; Ohyama, Masashi [Nippon Medical School, Tokyo (Japan)] (and others)

    1999-08-01

    To investigate the relationship between prognosis of aphasia and neuronal damage in the cerebral cortex, we evaluated the distribution of central-type benzodiazepine receptor (BZR) binding in post-stroke aphasics with [{sup 123}I]iomazenil and SPECT. We performed iomazenil SPECT in six aphasic patients (aged from 45 to 75 years; all right-handed) with unilateral left cerebral infarction. Three patients showed signs of Broca's aphasia and the other three Wernicke's aphasia. Cerebral blood flow (CBF) imaging was performed with [{sup 123}I]iodoamphetamine (IMP). The regions of interest (ROIs) on both images were set in the cerebral cortex, cerebellar cortex and language relevant area in both hemispheres. Three patients were classified in the mild prognosis group and the other three in the moderate prognosis group. The left language-relevant area was more closely concerned with the difference in aphasic symptoms than the right one in both BZR and CBF distribution, but the ipsilateral to the contralateral ratio (I/C ratio) in the language-relevant areas in the BZR distribution was significantly lower in the moderate prognosis group than in the mild prognosis group, although no difference was seen for these values between the two groups in the CBF distribution. These results suggest that BZR imaging, which makes possible an increase in neuronal cell viability in the cerebral cortex, is useful not only for clarifying the aphasic symptoms but also for evaluating the prognosis of aphasia in patients with cerebral infarction. (author)

  2. Benzodiazepine receptor imaging with iomazenil SPECT in aphasic patients with cerebral infarction

    International Nuclear Information System (INIS)

    Koshi, Yasuhiko; Kitamura, Shin; Ohyama, Masashi

    1999-01-01

    To investigate the relationship between prognosis of aphasia and neuronal damage in the cerebral cortex, we evaluated the distribution of central-type benzodiazepine receptor (BZR) binding in post-stroke aphasics with [ 123 I]iomazenil and SPECT. We performed iomazenil SPECT in six aphasic patients (aged from 45 to 75 years; all right-handed) with unilateral left cerebral infarction. Three patients showed signs of Broca's aphasia and the other three Wernicke's aphasia. Cerebral blood flow (CBF) imaging was performed with [ 123 I]iodoamphetamine (IMP). The regions of interest (ROIs) on both images were set in the cerebral cortex, cerebellar cortex and language relevant area in both hemispheres. Three patients were classified in the mild prognosis group and the other three in the moderate prognosis group. The left language-relevant area was more closely concerned with the difference in aphasic symptoms than the right one in both BZR and CBF distribution, but the ipsilateral to the contralateral ratio (I/C ratio) in the language-relevant areas in the BZR distribution was significantly lower in the moderate prognosis group than in the mild prognosis group, although no difference was seen for these values between the two groups in the CBF distribution. These results suggest that BZR imaging, which makes possible an increase in neuronal cell viability in the cerebral cortex, is useful not only for clarifying the aphasic symptoms but also for evaluating the prognosis of aphasia in patients with cerebral infarction. (author)

  3. Prescribing Antidepressants and Benzodiazepines in the Netherlands: Is Chronic Physical Illness Involved?

    Directory of Open Access Journals (Sweden)

    Jacques Th. M. van Eijk

    2010-01-01

    Full Text Available In this study we assessed differences in new and repeat prescriptions of psycho-tropics between patients receiving prescriptions for drugs to treat a common chronic disease and people without such prescriptions. The study used the databases of two Dutch health insurance companies (3 million people. We selected all Dutch men and women aged 45 and older who were registered for six consecutive years (1999–2004. Our analyses both found a consistent relation between psycho-tropics on the one hand and physical illness on the other. People with multi-morbidity were prescribed these drugs most often, especially men and those younger than 65. Epidemiological studies showed a prevalence of depression among people with multi-morbidity to be twice as high as among people without such conditions. According to recent guidelines non-drug treatment may be the first therapy option for patients with non severe depression. If prescribed for a long time, benzodiazepine prescriptions are especially known to be addictive. Our data raise the question to what extent patients with a chronic physical disease suffering from co-occurring mental problems are prescribed psycho-tropics in accord with the guidelines that also advise mental support in case of non severe mental problems. Further research can answer this important question.

  4. Peripheral benzodiazepines receptor (PBR stimulates steroidogenesis: A potential neuroprotective pathway following brain damage

    Directory of Open Access Journals (Sweden)

    George E. Barreto

    2015-04-01

    Full Text Available The effects of neuroactive steroids have been highly assessed for their significance on inflammation resolution induced by cytotoxic agents. Steroids are derived from cholesterol, and this regulatory pathway may be a target for possible protective strategies. For example, the increased expression of peripheral benzodiazepine receptor (PBR stimulates steroids production, and the action of specific ligands on PBR favors the reduction of glial activity and act as a protective mechanism. The augmented expression of PBR and steroidogenic acute regulatory protein (StAR after injury is associated with local production of steroids by glial cells. For instance, cholesterol is captured by StAR in the outer mitochondrial membrane that transfers it to PBR, which uses it as substrate for the enzyme P450scc in the inner mitochondrial membrane. Some ligands, such as 4'-Chlorodiazepam (Ro5-4864 and isoquinoline carboxamide (PK 11195, act as agonists of the PBR receptor. Previous studies indicate that Ro5-4864 reduces neuronal loss, thus implying the regulation of mitochondrial transition after a traumatic brain injury. In this work, we assess the effects of PBR ligands directly involved in neuronal cell survival and proliferation after injury, thereby activating potential downstream targets as novel therapeutic approaches.

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

    Science.gov (United States)

    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.

  6. A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites

    DEFF Research Database (Denmark)

    Kongsbak, Kristine Grønning; Bergmann, Rikke; Sørensen, Pernille Louise

    2013-01-01

    We present a full-length a1b2c2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate......-gated chloride channel (GluCl) from C. elegans and includes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Available mutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest a GABA binding mode...... of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interact with two threonines a1T206 and c2T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near the important a1H101 and the N-methyl group near a1Y159, a1T206, and a1Y209. We present a binding mode...

  7. Influence of benzodiazepines on body weight and food intake in obese and lean Zucker rats.

    Science.gov (United States)

    Blasi, C

    2000-05-01

    1. The gamma-aminobutyric acid (GABA)-ergic system, which is functionally altered in obese (fa/fa) Zucker rats, plays an important role in controlling energy balance within the central nervous system. 2. GABA receptors seem to be involved in the dysfunction of the hypothalamic energy homeostasis-controlling mechanisms in these animals due to a genetically-induced defect of the leptin-neuropeptide Y system. 3. To shed further light on the possible role played by the GABA system in the pathogenesis of this rat model, two benzodiazepine (BDZ) receptor agonists (diazepam and clonazepam) and one BDZ antagonist (flumazenil) were administered intraperitoneally in obese and lean Zucker rats. 4. Body weight gain was reduced by the BDZ agonists in both phenotypes, and one receptor-agonist (diazepam) lowered insulin concentration in obese rats. In GABA-antagonist-treated obese rats, the daily amount of body weight gain and food intake acquired an oscillatory rhythm similar to that of normal rodents. 5. By demonstrating the role of BDZ receptors, these findings may help clarify the pathophysiology of obesity and insulin resistance in fatty Zucker rats.

  8. Nootropic nefiracetam inhibits proconvulsant action of peripheral-type benzodiazepines in epileptic mutant EL mice.

    Science.gov (United States)

    Nakamoto, Yurie; Shiotani, Tadashi; Watabe, Shigeo; Nabeshima, Toshitaka; Yoshii, Mitsunobu

    2004-10-01

    Piracetam and structurally related nootropics are known to potentiate the anticonvulsant effects of antiepileptic drugs. It remains to be seen, however, whether these nootropics inhibit proconvulsant actions of many toxic agents including Ro 5-4864, a specific agonist for peripheral-type benzodiazepine receptors (PBR). The present study was designed to address this issue using EL mice, an animal model of epilepsy. In behavioral pharmacological experiments, EL mice were highly susceptible to convulsions induced by Ro 5-4864 (i.p.) in comparison with nonepileptic DDY mice. Nefiracetam administered orally to EL mice inhibited spontaneous seizures. In DDY mice, convulsions induced by Ro 5-4864 were prevented by nefiracetam when administered by i.v. injection. Aniracetam (i.v.) was partially effective, but piracetam and oxiracetam were ineffective as anticonvulsants. Binding assay for brain tissues revealed a higher density of mitochondrial PBR in EL mice compared with DDY mice. Binding of the PBR ligands Ro 5-4864 to either EL or DDY mouse brain was inhibited by micromolar concentrations of these nootropic agents in the sequence of nefiracetam > aniracetam > oxiracetam, piracetam. This rank order is identical to potency as anticonvulsants. These data suggest that nefiracetam may prevent toxic effects of PBR agonists through interacting with PBR.

  9. Quality of life in a cohort of high-dose benzodiazepine dependent patients.

    Science.gov (United States)

    Lugoboni, Fabio; Mirijello, Antonio; Faccini, Marco; Casari, Rebecca; Cossari, Anthony; Musi, Gessica; Bissoli, Giorgia; Quaglio, Gianluca; Addolorato, Giovanni

    2014-09-01

    Benzodiazepines (BZD) are among the most widely prescribed drugs in developed countries. Since BZD can produce tolerance and dependence even in a short time, their use is recommended for a very limited time. However, these recommendations have been largely disregarded. The chronic use of BZD causes a number of serious side effects, i.e., cognitive impairment, falls, traffic accidents, dependence and tolerance. The aim of the present study was to evaluate quality of life (QoL) in a cohort of 62 consecutive high-dose BZD-dependent patients seeking a BZD detoxification. Patients seeking BZD detoxification were evaluated using the General Health Questionnaire (GHQ-12) and the short form-36 questionnaire (SF-36). Patients showed a significant reduction of QoL as measured by either SF-36 or GHQ-12. In particular, the greater impairment was observed in the items exploring physical and emotional status. Physical functioning was the item more influenced by the length of BZD abuse. Female patients showed a greater reduction of QoL compared to male, at least in some of the explored items. Social functioning scores were greatly reduced. The present study shows for the first time that high-doses BZD dependent patients have a reduced QoL and a reduced social functioning, along with high levels of psychological distress. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Cognitive effects of pregabalin in the treatment of long-term benzodiazepine-use and dependence.

    Science.gov (United States)

    Oulis, Panagiotis; Kalogerakou, Stamatina; Anyfandi, Eleni; Konstantakopoulos, George; Papakosta, Vassiliki-Maria; Masdrakis, Vasilios; Tsaltas, Eleftheria

    2014-05-01

    Long-term benzodiazepine (BDZ) use and dependence affect cognitive functioning adversely and partly irreversibly. Emerging evidence suggests that pregabalin (PGB) might be a safe and efficacious treatment of long-term BDZ use. The aim of the present study was to investigate the changes in several core cognitive functions after successful treatment of long-term BDZ use and dependence with PGB. Fourteen patients with long-term BDZ use (mean duration >15 years) underwent neuropsychological assessment with the mini-mental state examination and four tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) battery before the initiation of PGB treatment and at a two months follow-up after the cessation of BDZs. Patients' CANTAB percentile score distributions were compared with normative CANTAB data. Patients improved on cognitive measures of global cognitive functioning, time orientation, psychomotor speed, and visuospatial memory and learning with strong effect sizes. By contrast, they failed to improve on measures of attentional flexibility. Despite their significant improvement, patients' scores on most tests remained still at the lower percentiles of CANTAB normative scores. Although preliminary, our findings suggest that successful treatment of long-term BDZ use with PGB is associated with a substantial, though only partial, recovery of BDZ-compromised neuropsychological functioning, at least at a 2-month follow-up. Copyright © 2014 John Wiley & Sons, Ltd.

  11. Decreasing Trend in the Use and Long-Term Use of Benzodiazepines Among Young Adults.

    Science.gov (United States)

    Tähkäpää, Sanna-Mari; Saastamoinen, Leena; Airaksinen, Marja; Tuulio-Henriksson, Annamari; Aalto-Setälä, Terhi; Kurko, Terhi

    2018-03-14

    Patterns of benzodiazepine (BZD) use and long-term use among young adults are not well known. Our aim was to study trends in BZD use and long-term use among 18-25-year-old young adults by gender and active substance in a nationwide retrospective longitudinal register-based setting. All Finns aged 18-25 years with reimbursed purchases of BZDs in 2006-2014 recorded to the Finnish Prescription Register were included. Annual prevalence rates of BZD use and long-term use among young adults were reported overall, according to gender, drug group (anxiolytic or hypnotic), and active substance. Long-term use of BZDs was defined as purchasing ≥180 Defined Daily Doses (DDDs) in at least two drug purchases during a calendar year. Overall prevalence of BZD use among young adults decreased from 24.0 to 18.8 users per 1000 inhabitants in 2006-2014. Prevalence of long-term use decreased from 5.5 to 3.3 users per 1000 inhabitants. Overall BZD use was higher among females, whereas long-term use was more common among males. Use of anxiolytics was more common than use of hypnotics. Oxazepam, alprazolam, zopiclone, and zolpidem were the most used BZDs, whereas alprazolam and clonazepam were the substances with most long-term use. The use and long-term use of BZDs have decreased annually since 2008 among Finnish young adults. Further research is needed to investigate the reasons behind the decline.

  12. 125I-iomazenil-benzodiazepine receptor binding during psychological stress in rats

    International Nuclear Information System (INIS)

    Fukumitsu, Nobuyoshi; Tsuchida, Daisuke; Ogi, Shigeyuki; Uchiyama, Mayuki; Mori, Yutaka

    2002-01-01

    We investigated the changes in 125 I-iomazenil ( 125 I-IMZ) benzodiazepine receptor (BZR) binding with psychological stress in a rat model. Six male Wistar rats were placed under psychological stress for 1 hour by using a communication box. No physical stress was not received. 1.85 MBq of 125 I-IMZ was injected into the lateral tail vein and the rat was killed 3 hours later. Twenty-micormeter-thick sections of the brain were collected and % injected dose per body weight (% ID/BW) of eleven regions (frontal, parietal, temporal, occipital cortices, caudate putamen, accumubens nuclei, globus pallidus, amygdala, thalamus, hippocampus and hypothalamus) were calculated by autoradiography. The %ID/BW of rats which were placed under psychological stress was compared with that of 6 control rats. The %ID/BW of rats which were placed under psychological stress diffusely tended to show a reduction in 125 I-IMZ-BZR binding. A significant decrease in BZR binding was observed in the hippocampus of the rats which were placed under psychological stress. 125 I-IMZ-BZR binding tended to decrease throughout the brain. (author)

  13. Mathematical modeling of tetrahydroimidazole benzodiazepine-1-one derivatives as an anti HIV agent

    Science.gov (United States)

    Ojha, Lokendra Kumar

    2017-07-01

    The goal of the present work is the study of drug receptor interaction via QSAR (Quantitative Structure-Activity Relationship) analysis for 89 set of TIBO (Tetrahydroimidazole Benzodiazepine-1-one) derivatives. MLR (Multiple Linear Regression) method is utilized to generate predictive models of quantitative structure-activity relationships between a set of molecular descriptors and biological activity (IC50). The best QSAR model was selected having a correlation coefficient (r) of 0.9299 and Standard Error of Estimation (SEE) of 0.5022, Fisher Ratio (F) of 159.822 and Quality factor (Q) of 1.852. This model is statistically significant and strongly favours the substitution of sulphur atom, IS i.e. indicator parameter for -Z position of the TIBO derivatives. Two other parameter logP (octanol-water partition coefficient) and SAG (Surface Area Grid) also played a vital role in the generation of best QSAR model. All three descriptor shows very good stability towards data variation in leave-one-out (LOO).

  14. {sup 125}I-iomazenil-benzodiazepine receptor binding during psychological stress in rats

    Energy Technology Data Exchange (ETDEWEB)

    Fukumitsu, Nobuyoshi; Tsuchida, Daisuke; Ogi, Shigeyuki; Uchiyama, Mayuki; Mori, Yutaka [Jikei Univ., Tokyo (Japan). School of Medicine

    2002-05-01

    We investigated the changes in {sup 125}I-iomazenil ({sup 125}I-IMZ) benzodiazepine receptor (BZR) binding with psychological stress in a rat model. Six male Wistar rats were placed under psychological stress for 1 hour by using a communication box. No physical stress was not received. 1.85 MBq of {sup 125}I-IMZ was injected into the lateral tail vein and the rat was killed 3 hours later. Twenty-micormeter-thick sections of the brain were collected and % injected dose per body weight (% ID/BW) of eleven regions (frontal, parietal, temporal, occipital cortices, caudate putamen, accumubens nuclei, globus pallidus, amygdala, thalamus, hippocampus and hypothalamus) were calculated by autoradiography. The %ID/BW of rats which were placed under psychological stress was compared with that of 6 control rats. The %ID/BW of rats which were placed under psychological stress diffusely tended to show a reduction in {sup 125}I-IMZ-BZR binding. A significant decrease in BZR binding was observed in the hippocampus of the rats which were placed under psychological stress. {sup 125}I-IMZ-BZR binding tended to decrease throughout the brain. (author)

  15. Regulation of GABA and benzodiazepine receptors following neurotoxin-induced striatal and medial forebrain bundle lesions

    International Nuclear Information System (INIS)

    Pan, H.S.I.

    1985-01-01

    GABA, a major inhibitory transmitter, is used by many projection neurons of the striatum. To investigate the role of GABA in striatal function, the GABA receptor complex was studied after lesions of the striatum or the nigrostriatal neurons. Quantitative receptor autoradiography using thaw-mounted tissue slices was developed for the study of GABA and benzodiazepine (BDZ) receptors. With the technique established, binding to GABA and BDZ receptors after unilateral striatal kainate lesions was examined. Subsequently, changes in GABA and BDZ receptors were studied following the destruction of dopaminergic nigrostriatal cells by unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. In summary, quantitative receptor autoradiography allowed the detection of GABA and BDZ receptor changes in multiple small areas in each lesioned brain. This technique made it feasible to carry out kinetic saturation, and competition studies using less than 1 mg of tissue. The data suggest that dopamine is functionally inhibitory on striatopallidal neurons but is functionally excitatory on striatoentopeduncular and striatonigral cells which in turn inhibit the thalamus. This quantitative autoradiographic technique can be generalized to study other transmitter receptors and can be combined with 2-deoxyglucose uptake studies

  16. Synthesis and biological activity of fused tetracyclic Pyrrolo[2,1-c][1,4]benzodiazepines

    Directory of Open Access Journals (Sweden)

    Joel K. Annor-Gyamfi

    2018-02-01

    Full Text Available Cancer remains the second major cause of death in the world. Thus, there is a pressing need to identify potential synthetic route for the development of novel anticancer agents which will serve as lead compounds to effectively combat this life-threatening epidemic. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs have sparked a great interest as lead compounds because of their cancerostatic and anti-infective properties. The twisted molecular structure of PBD analogs provides both helical and chiral elements. In an effort to expand novel PBDs that interact with the key exocyclic amino group of the DNA-guanine base, we hypothesized that construction of a fused cyclic active system, would likely serve as an electrophilic site when compared to traditional electrophilic C11-N10 imine group. To examine our theory, we report herein the synthesis and cell viability/cytotoxicity of a series of PBD analogs using NCI-60 cell lines screening. Thus, compounds 1–13 were synthesized and fully characterized. The selected PBDs were found to have marginal inhibition of growth, up to 30%, for certain cell lines.

  17. Benzodiazepine receptor turnover in embryonic chick brain and spinal cord cell cultures

    International Nuclear Information System (INIS)

    Borden, L.A.

    1985-01-01

    The turnover (synthesis and degradation) of the benzodiazepine receptor (BZD-R) in embryonic chick brain and spinal cord cell cultures was monitored using flunitrazepam (GNZM) as a photoaffinity label. To measure BZD-R appearance, intact cell cultures were incubated with 100 nM RNZM and irradiated with ultraviolet light; this process, referred to as photoinactivation, resulted in a 75% decrease in the subsequent reversible binding of 5 nM [ 3 H]FNZM. Following photoinactivation, [ 3 H]FNZM binding sites reappeared at a rate of 6 +/- 1.5%/hour (n = 7) in brain cultures and at 8%/hour (n = 2) in spinal cord cultures. Reappearance reflects de novo receptors synthesis. To examine the degradation of existing receptors, cultures were photolabeled with 5 nM [ 3 H]FNZM, washed, and then the decrease in cell-associated radioactivity, or the efflux of radioactivity into the medium, was monitored. The released radioactivity did not comigrate with authentic FNZM on thin-layer-chromatographs, indicating that release did not represent dissociation of ligand from the photolabeled receptor. The BZD-R appears to be degraded by an energy-dependent, non-lysosomal pathway. These experiments represent the first direct examination of the turnover of a neurotransmitter receptor localized to the central nervous system; this information will be valuable in elucidating the mechanisms by which receptor levels are altered following chronic drug treatment

  18. Anticonflict effect of alpidem as compared with the benzodiazepine alprazolam in rats.

    Science.gov (United States)

    Hascoët, M; Bourin, M

    1997-02-01

    A comparative study between two drugs acting on the GABAA receptor, alprazolam and alpidem was undertaken, using simple tests such as measurement of spontaneous locomotor activity, four plates test and rotarod in mice. Additional conflict test was further performed using a new conflict paradigm where the opportunity existed for rats to choose during punished periods between immediate, punished reinforcement and delayed non-punished reinforcement. The benzodiazepine alprazolam, demonstrated, as expected, strong anxiolytic effects in mice and increased punished response in rats at non sedative doses (0.5, 1 mg/kg). High doses of alprazolam decreased spontaneous locomotor activity and induced myorelaxant effects in mice. Alpidem, an imidazopyridine derivative, induced motor impairment in mice and only very weak anxiolytic effects in the four plates test in mice (4 mg/kg) and in punished procedure in rats (32 mg/kg). As alprazolam is a full agonist for the GABAA receptor complex and alpidem is a partial agonist acting with specificity on omega 1 GABAA receptor subtypes, the results are discussed. Activity on omega 1 receptor subtypes is perhaps not sufficient in order to obtain a true anti-conflict effect and compounds such as alpidem only relieve some of the symptoms of anxiety disorders.

  19. Benzodiazepines Withdrawal: Initial Outcomes and Long-Term Impact on Falls in a French Nursing Home

    Directory of Open Access Journals (Sweden)

    Hervé Javelot

    2018-04-01

    Full Text Available Long-term use of benzodiazepines (BZDs is known to induce tolerance and dependence, and increase the risk of falls-related injuries in older adults. We present a study carried out in a French nursing home that concerns the implementation of a BZD withdrawal program reassessed at one year. BZD deprescription was achieved by gradual cessation of doses. A secondary benefit of this program was assessed by comparing the number of falls among residents before and after withdrawal. The number of falls was recorded over a six-month period prior to the onset of withdrawal (T1 and then over a six-month period after reassessment at one year (T2. At the beginning, 31 (28.7% of the patients were under BZD. Total deprescription was obtained for 11 patients. The number of falls per patient over the T1 period was not different between the two groups (future non-withdrawn and withdrawn patients in BZD: 2.1 ± 1.3 and 2.3 ± 0.6 falls per resident, respectively. Conversely, the number of falls per patient was significantly decreased in the population completely withdrawn in BZD between the T1 and T2 periods (2.3 ± 0.6 vs. 0.5 ± 0.2 falls, p = 0.01. The results show that BZD deprescription, through a gradual reduction of doses, is possible to achieve.

  20. Maternal Characteristics of Women Exposed to Hypnotic Benzodiazepine Receptor Agonist during Pregnancy

    Directory of Open Access Journals (Sweden)

    Bjarke Askaa

    2014-01-01

    Full Text Available Background. There is little knowledge regarding the characteristics of women treated with hypnotic benzodiazepine receptor agonists (HBRAs during pregnancy. In this large Danish cohort study, we characterize women exposed to HBRA during pregnancy. We determined changes in prevalence of HBRA use from 1997 to 2010 and exposure to HBRAs in relation to pregnancy. Methods. We performed a retrospective cohort study including 911,017 pregnant women in the period from 1997 to 2010. Information was retrieved from The Danish Birth Registry and The Registry of Medicinal Product Statistics to identify pregnant women redeeming a prescription of HBRAs. Results. We identified 2,552 women exposed to HBRAs during pregnancy, increasing from 0.18% in 1997 to 0.23% in 2010. Compared to unexposed women, exposed women were characterized by being older, with higher BMI, in their third or fourth parity, of lower income and education level, more frequently smokers, and more likely to be comedicated with antipsychotic, anxiolytic, or antidepressant drugs (P<0.0001. Conclusion. Women using HBRAs during their pregnancy differ from unexposed women in socioeconomic factors and were more likely to receive comedication. The consumption of HBRAs was reduced during pregnancy compared to before conception.

  1. Further characterization of benzodiazepine receptor differences in long-sleep and short-sleep mice

    International Nuclear Information System (INIS)

    Marley, R.J.; Stinchcomb, A.; Wehner, J.M.

    1988-01-01

    Molecular and conformational characteristics of benzodiazepine (BZ) receptors in cortex and cerebellum from long-sleep and mice were investigated using heat inactivation and beta-carboline competition techniques. To investigate differences in the allosteric coupling between GABA and BZ receptors, the protection of BZ receptors from heat inactivation, by GABA, was also evaluated. The two genotypes do not differ in the affinity or number of BZ receptors in the cortex or cerebellum. They do, however, appear to differ in the molecular structure and/or regulation of the conformational state of the receptor in the cortex, as indicated by a greater sensitivity of LS mice to both heat inactivation and beta-carboline competition of 3 H-flunitrazepam (FNZ) binding in this region. Evidence for differences in the nature of coupling between GABA and BZ receptors is provided by the finding in that in both regions, GABA protected BZ receptors from inactivation to a greater degree in LS mice. The relationship between these differences and the multiplicity of expression of BZ receptors is discussed

  2. Interactions of pyrethroid insecticides with GABAA and peripheral-type benzodiazepine receptors

    International Nuclear Information System (INIS)

    Devaud, L.L.

    1988-01-01

    Pyrethroid insecticides are potent proconvulsants in the rat. All pyrethroids evincing proconvulsant activity elicited a similar 25-30% maximal reduction of seizure threshold. The Type II pyrethroids were the most potent proconvulsants with 1RαS, cis cypermethrin having an ED 50 value of 6.3 nmol/kg. The proconvulsant activity of both Type I and Type II pyrenthroids was blocked by pretreatment with PK 11195, the peripheral-type benzodiazepine receptor (PTBR) antagonist. In contrast, phenytoin did not antagonize the proconvulsant activity of either deltamethrin or permethrin. Pyrethroids displaced the specific binding of [ 3 H]Ro5-4864 to rat brain membranes with a significant correlation between the log EC 50 values for their activities as proconvulsants and the log IC 50 values for their inhibition of [ 3 H]Ro5-4864 binding. Both Ro5-4864 and pyrethroid insecticides were found to influence specific [ 35 S]TBPS binding in a GABA-dependent manner. PK 11195 and the Type II pyrethroid, deltamethrin antagonized the Ro5-4864-induced modulation of [ 35 S]TBPS binding. Pyrethroid insecticides, Ro5-4864 and veratridine influenced GABA-gated 36 Chloride influx. Moreover, the Type II pyrethroids elicited an increase in 36 chloride influx in the absence of GABA-stimulation. Both of these actions were antagonized by PK 11195 and tetrodotoxin

  3. Blockade of alcohol's amnestic activity in humans by an alpha5 subtype benzodiazepine receptor inverse agonist.

    Science.gov (United States)

    Nutt, David J; Besson, Marie; Wilson, Susan J; Dawson, Gerard R; Lingford-Hughes, Anne R

    2007-12-01

    Alcohol produces many subjective and objective effects in man including pleasure, sedation, anxiolysis, plus impaired eye movements and memory. In human volunteers we have used a newly available GABA-A/benzodiazepine receptor inverse agonist that is selective for the alpha5 subtype (a5IA) to evaluate the role of this subtype in mediating these effects of alcohol on the brain. After pre-treatment with a5IA, we found almost complete blockade of the marked impairment caused by alcohol (mean breath concentration 150mg/100ml) of word list learning and partial but non-significant reversal of subjective sedation without effects on other measures such as intoxication, liking, and slowing of eye movements. This action was not due to alterations in alcohol kinetics and so provides the first proof of concept that selectively decreasing GABA-A receptor function at a specific receptor subtype can offset some actions of alcohol in humans. It also supports growing evidence for a key role of the alpha5 subtype in memory. Inverse agonists at other GABA-A receptor subtypes may prove able to reverse other actions of alcohol, and so offer a new approach to understanding the actions of alcohol in the human brain and in the treatment of alcohol related disorders in humans.

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

    Science.gov (United States)

    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.

  5. Circadian rest-activity rhythms during benzodiazepine tapering covered by melatonin versus placebo add-on: data derived from a randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Lone Baandrup

    2016-10-01

    Full Text Available Abstract Background Patients with severe mental illness often suffer from disruptions in circadian rest-activity cycles, which might partly be attributed to ongoing psychopharmacological medication. Benzodiazepines are frequently prescribed for prolonged periods despite recommendations of only short-term usage. Melatonin, a naturally occurring nocturnal hormone, has the potential to stabilize disrupted circadian rhythmicity. Our aim was to investigate how prolonged-release melatonin affects rest-activity patterns in medicated patients with severe mental illness and if benzodiazepine dose reduction is associated with changes in circadian rhythm parameters. Method Data were derived from a randomized, double-blinded clinical trial with 24 weeks follow-up. Participants were randomized to add-on treatment with prolonged-release melatonin (2 mg or matching placebo, and usual benzodiazepine dosage was gradually tapered. Here we report the results of 72 h of actigraphic assessment of activity-rest cycles performed pre and post tapering. Changes in rest-activity rhythm parameters between the melatonin and placebo group were analyzed using the univariate general linear model. Change in activity counts per 6 h, from baseline to follow-up, in the whole sample was analyzed using paired samples t-test. Results A subsample of 48 patients participated in the actigraphic assessment: 20 in the melatonin group and 28 in the placebo group. Rest-activity cycles varied from regular to highly disrupted. Melatonin significantly increased the interdaily stability and at a trend level decreased the intradaily variability compared with placebo. Benzodiazepine dose reduction was not associated with these circadian rhythm parameters. Activity counts were generally higher after benzodiazepine dose reduction compared with pre tapering, but differences did not reach statistical significance. Conclusion Our data suggest melatonin as an aid during benzodiazepine withdrawal for

  6. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia: a randomized clinical trial - the SMART trial protocol

    Directory of Open Access Journals (Sweden)

    Oranje Bob

    2011-10-01

    Full Text Available Abstract Background Treatment of schizophrenia frequently includes prolonged benzodiazepine administration despite a lack of evidence of its use. It is often difficult to discontinue benzodiazepines because of the development of dependence. We aim to assess if melatonin can facilitate the withdrawal of prolonged benzodiazepine administration in patients with schizophrenia. Furthermore, we aim to investigate the association of benzodiazepine dose reduction with the following clinically important variables: sleep, psychophysiology, cognition, social function, and quality of life. Methods/Design Randomized, blinded, two-armed, parallel superiority trial. We plan to include 80 consenting outpatients diagnosed with schizophrenia or schizoaffective disorder, 18-55 years of age, treated with antipsychotic drug(s and at least one benzodiazepine derivative for the last three months before inclusion. Exclusion criteria: currently under treatment for alcohol or drug abuse, aggressive or violent behavior, known mental retardation, pervasive developmental disorder, dementia, epilepsy, terminal illness, severe co morbidity, inability to understand Danish, allergy to melatonin, lactose, starch, gelatin, or talc, hepatic impairment, pregnancy or nursing, or lack of informed consent. After being randomized to prolonged-release melatonin (Circadin® 2 mg daily or matching placebo, participants are required to slowly taper off their benzodiazepine dose. The primary outcome measure is benzodiazepine dose at 6 months follow-up. Secondary outcome measures include sleep, psychophysiological, and neurocognitive measures. Data are collected at baseline and at 6 months follow-up regarding medical treatment, cognition, psychophysiology, sleep, laboratory tests, adverse events, psychopathology, social function, and quality of life. Data on medical treatment, cognition, psychophysiology, adverse events, social function, and quality of life are also collected at 2 and 4

  7. Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice

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    Dell’Osso B

    2015-07-01

    Public Health, Clinical and Molecular Medicine, Unit of Psychiatry, University of Cagliari, Cagliari, 18Department of Clinical and Experimental Medicine, Psychiatric Division, University of Insubria, Varese, 19Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Sant’ Andrea Hospital, Sapienza University of Rome, Rome, 20Department of Medical and Surgical Sciences, Bologna University, Bologna, 21Section of Psychiatry, Department of Public Health and Community Medicine, University of Verona, Verona, Italy *These authors contributed equally as first authors Abstract: More than half a century after their discovery, benzodiazepines (BDZs still represent one of the largest and most widely prescribed groups of psychotropic compounds, not only in clinical psychiatry but also in the entire medical field. Over the last two decades, however, there has been an increased focus on the development of antidepressants and antipsychotics on the part of the pharmaceutical industry, clinicians, and researchers, with a reduced interest in BDZs, in spite of their widespread clinical use. As a consequence, many psychiatric residents, medical students, nurses, and other mental health professionals might receive poor academic teaching and training regarding these agents, and have the false impression that BDZs represent an outdated chapter in clinical psychopharmacology. However, recent advances in the field, including findings concerning epidemiology, addiction risk, and drug interactions, as well as the introduction of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition with related diagnostic changes, strongly encourage an updated appraisal of the use of BDZs in clinical practice. During a recent thematic event convened with the aim of approaching this topic in a critical manner, a group of young Italian psychiatrists attempted to highlight possible flaws in current teaching pathways, identify the main clinical pros and cons

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

    Directory of Open Access Journals (Sweden)

    Ricardo Schneider Jr.

    2015-03-01

    Full Text Available Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

  9. Development and validation of an EI-GC-MS method for the determination of benzodiazepine drugs and their metabolites in blood: applications in clinical and forensic toxicology.

    Science.gov (United States)

    Papoutsis, Ioannis I; Athanaselis, Sotirios A; Nikolaou, Panagiota D; Pistos, Constantinos M; Spiliopoulou, Chara A; Maravelias, Constantinos P

    2010-08-01

    Benzodiazepines are used widely in daily clinical practice, due to their multiple pharmacological actions. The frequent problems associated with the wide use of benzodiazepines, as well as the multiple incidents of poisonings, led to the necessity for the development of a precise, sensitive and rapid method for the simultaneous determination of the 23 most commonly used benzodiazepines (diazepam, nordiazepam, oxazepam, bromazepam, alprazolam, lorazepam, medazepam, flurazepam, fludiazepam, tetrazepam, chlordiazepoxide, clobazam, midazolam, flunitrazepam, 7-amino-flunitrazepam, triazolam, prazepam, nimetazepam, nitrazepam, temazepam, lormetazepam, clonazepam, camazepam) in blood. A gas chromatographic method combined with mass spectrometric detection was developed, optimized and validated for the determination of the above substances. This method includes liquid-liquid extraction with chloroform at pH 9 and two stages of derivatization using tetramethylammonium hydroxide and propyliodide (propylation), as well as a mixture of triethylamine:propionic anhydride (propionylation). The recoveries were higher than 74% for all the benzodiazepines. The calibration curves were linear within the dynamic range of each benzodiazepine with a correlation coefficient higher than 0.9981. The limits of detection and quantification for each analyte were statistically calculated from the relative calibration curves. Accuracy and precision were also calculated and were found to be less than 8.5% and 11.1%, respectively. The developed method was successfully applied for the investigation of both forensic and clinical toxicological cases of accidental and suicidal poisoning. Copyright (c) 2010 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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.

  11. Polysomnographic findings in a cohort of chronic insomnia patients with benzodiazepine abuse.

    Science.gov (United States)

    Mazza, Marianna; Losurdo, Anna; Testani, Elisa; Marano, Giuseppe; Di Nicola, Marco; Dittoni, Serena; Gnoni, Valentina; Di Blasi, Chiara; Giannantoni, Nadia Mariagrazia; Lapenta, Leonardo; Brunetti, Valerio; Bria, Pietro; Janiri, Luigi; Mazza, Salvatore; Della Marca, Giacomo

    2014-01-15

    To evaluate sleep modifications induced by chronic benzodiazepine (BDZ) abuse. Cohort study, comparison of sleep measures between BDZs abusers and controls. Drug Addiction Unit (Institute of Psychiatry) and Unit of Sleep Disorders (Institute of Neurology) of the Catholic University in Rome. Six outpatients affected by chronic BDZ abuse were enrolled, (4 men, 2 women, mean age 53.3 ± 14.8, range: 34-70 years); 55 healthy controls were also enrolled (23 men, 32 women, mean age 54.2 ± 13.0, range: 27-76 years). All patients underwent clinical evaluation, psychometric measures, ambulatory polysomnography, scoring of sleep macrostructure and microstructure (power spectral fast-frequency EEG arousal, cyclic alternating pattern [CAP]), and heart rate variability. BDZ abusers had relevant modification of sleep macrostructure and a marked reduction of fast-frequency EEG arousal in NREM (patients: 6.6 ± 3.7 events/h, controls 13.7 ± 4.9 events/h, U-test: 294, p = 0.002) and REM (patients: 8.4 ± 2.4 events/h, controls 13.3 ± 5.1 events/h, U-test: 264, p = 0.016), and of CAP rate (patients: 15.0 ± 8.6%, controls: 51.2% ± 12.1%, U-test: 325, p < 0.001). BDZ abusers have reduction of arousals associated with increased number of nocturnal awakenings and severe impairment of sleep architecture. The effect of chronic BDZ abuse on sleep may be described as a severe impairment of arousal dynamics; the result is the inability to modulate levels of vigilance.

  12. Synthesis and evaluation of radioiodinated ligands for the study of peripheral benzodiazepine receptors using SPECT

    International Nuclear Information System (INIS)

    Katsifis, A.; Mattner, F.; Mardon, K.; Dikic, B.; Papazian, V.; Greguric, I.

    2002-01-01

    Full text: The peripheral benzodiazepine receptor (PBR) is a multimeric protein complex located in the outer mitochondrial membrane and predominantly found in steroid producing organs and glial cells in the brain. The PBR have been implicated in the control of cell proliferation and differentiation and shown to display increased levels in a variety of malignant tumours and neurodegenerative disorders. A series of potent imidazo[1,2-a]pyridines have been prepared for development as radiopharmaceuticals to study these disorders in patients using nuclear medicine imaging techniques. In vitro studies indicate that compounds substituted with an electronegative atom in the 6 position of the pyridine ring, a lipophilic group or halogen in the 4'-position of the 2-phenyl ring, and lower alkyl methyl or ethyl substituents on the amide nitrogens of the side chain, exhibit high affinity and selective binding. ' N'N'-dimethyl- and the N'N'-diethyl 6-chloro-(4'-iodophenyl)imidazo[1,2-a]pyridine-3-acetamide 1 and 2 displayed optimum in vitro properties and were thus selected for radiolabelling with the diagnostic radionuclide iodine-123. Radioiodination was achieved by iododestannylation of the corresponding tributyl stannane precursor in the presence of peracetic acid. Purification by C-18 reverse phase HPLC gave the desired products in 70-80% radiochemical yields and in greater than 98% radiochemical purity. Biodistribution studies in normal rodents indicated high uptake of radioactivity in tissues with known PBR sites. Preliminary imaging studies in rodents bearing mammary adenocarcinomas indicated high uptake in the tumour with retention of activity after 24 h. The synthesis, structure activity studies, radiolabelling and biological studies of these compounds will be presented

  13. Selective pharmacological modulation of renal peripheral-type benzodiazepine binding by treatment with diuretic drugs

    International Nuclear Information System (INIS)

    Lukeman, D.S.; Vaughn, D.A.; Fanestil, D.D.

    1988-01-01

    The authors have assessed the effects of in vivo administration of different classes of diuretic drugs on the expression of the peripheral-type benzodiazepine binding site (PBBS) in crude membranes derived from the cortex and outer medulla of rat kidney by saturation analysis with the PBBS-selective ligands [ 3 H]RO5-4864 and [ 3 H]PH 11195 in cortex and [ 3 H]RO5-4864 in outer medulla. Administration for 14-15 days of furosemide, a drug that blocks NaCl-KCl coupled transport in the thick ascending limb of the loop of Henle, produced a significant doubling in the PBBS density (B/sub max/) in outer medulla, a region of the kidney rich in thick ascending limbs, and produced a lesser but significant increase in PBBS density in the cortex. Conversely, administration for 14-15 days of the carbonic anhydrase inhibitor acetazolamide, which acts predominantly in the proximal tubule, and hydrochlorothiazide, which acts predominantly in the early distal tubule, elicited statistically significant increases in PBBS density in renal cortex but not in renal outer medulla. Furthermore, all drug treatments were without effect on the equilibrium dissociation constants (K/sub d/s) of [ 3 H]RO5-4864 and [ 3 H]PK 11195 binding to cortical and outer medullary membrane preparations. These findings demonstrate that the PBBS can be selectively up-regulated in different regions of the kidney by diuretic drugs with different modes/sites of action. 50 references, 1 table

  14. Comparison of UHPLC and HPLC in benzodiazepines analysis of postmortem samples: a case-control study.

    Science.gov (United States)

    Behnoush, Behnam; Sheikhazadi, Ardeshir; Bazmi, Elham; Fattahi, Akbar; Sheikhazadi, Elham; Saberi Anary, Seyed Hossein

    2015-04-01

    The aim of this study was to compare system efficiency and analysis duration regarding the solvent consumption and system maintenance in high-pressure liquid chromatography (HPLC) and ultra high-pressure liquid chromatography (UHPLC). In a case-control study, standard solutions of 7 benzodiazepines (BZs) and 73 biological samples such as urine, tissue, stomach content, and bile that screened positive for BZs were analyzed by HPLC and UHPLC in laboratory of forensic toxicology during 2012 to 2013. HPLC analysis was performed using a Knauer by 100-5 C-18 column (250 mm × 4.6 mm) and Knauer photodiode array detector (PAD). UHPLC analysis was performed using Knauer PAD detector with cooling autosampler and Eurospher II 100-3 C-18 column (100 mm × 3 mm) and also 2 pumps. The mean retention time, standard deviation, flow rate, and repeatability of analytical results were compared by using 2 methods. Routine runtimes in HPLC and UHPLC took 40 and 15 minutes, respectively. Changes in mobile phase composition of the 2 methods were not required. Flow rate and solvent consumption in UHPLC decreased. Diazepam and flurazepam were detected more frequently in biological samples. In UHPLC, small particle size and short length of column cause effective separation of BZs in a very short time. Reduced flow rate, solvent consumption, and injection volume cause more efficiency and less analysis costs. Thus, in the detection of BZs, UHPLC is an accurate, sensitive, and fast method with less cost of analysis.

  15. Prevention of organophosphate-induced chronic epilepsy by early benzodiazepine treatment.

    Science.gov (United States)

    Shrot, Shai; Ramaty, Erez; Biala, Yoav; Bar-Klein, Guy; Daninos, Moshe; Kamintsky, Lyn; Makarovsky, Igor; Statlender, Liran; Rosman, Yossi; Krivoy, Amir; Lavon, Ophir; Kassirer, Michael; Friedman, Alon; Yaari, Yoel

    2014-09-02

    Poisoning with organophosphates (OPs) may induce status epilepticus (SE), leading to severe brain damage. Our objectives were to investigate whether OP-induced SE leads to the emergence of spontaneous recurrent seizures (SRSs), the hallmark of chronic epilepsy, and if so, to assess the efficacy of benzodiazepine therapy following SE onset in preventing the epileptogenesis. We also explored early changes in hippocampal pyramidal cells excitability in this model. Adult rats were poisoned with the paraoxon (450μg/kg) and immediately treated with atropine (3mg/kg) and obidoxime (20mg/kg) to reduce acute mortality due to peripheral acetylcholinesterase inhibition. Electrical brain activity was assessed for two weeks during weeks 4-6 after poisoning using telemetric electrocorticographic intracranial recordings. All OP-poisoned animals developed SE, which could be suppressed by midazolam. Most (88%) rats which were not treated with midazolam developed SRSs, indicating that they have become chronically epileptic. Application of midazolam 1min following SE onset had a significant antiepileptogenic effect (only 11% of the rats became epileptic; p=0.001 compared to non-midazolam-treated rats). Applying midazolam 30min after SE onset did not significantly prevent chronic epilepsy. The electrophysiological properties of CA1 pyramidal cells, assessed electrophysiologically in hippocampal slices, were not altered by OP-induced SE. Thus we show for the first time that a single episode of OP-induced SE in rats leads to the acquisition of chronic epilepsy, and that this epileptogenic outcome can be largely prevented by immediate, but not delayed, administration of midazolam. Extrapolating these results to humans would suggest that midazolam should be provided together with atropine and an oxime in the immediate pharmacological treatment of OP poisoning. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Tryptic mapping and membrane topology of the benzodiazepine receptor alpha-subunit

    Energy Technology Data Exchange (ETDEWEB)

    Lentes, K.U.; Venter, J.C.

    1986-05-01

    Rat brain membrane benzodiazepine receptors (BZR) were photoaffinity labelled specifically (in presence or absence of 6 ..mu..M clonazepam) with 10 nM /sup 3/H-flunitrazepam (FNZ). Digestion of the FNZ-labelled, membrane-bound BZR with 200 ..mu..g trypsin/mg membrane protein yielded H/sub 2/O-soluble BZR-fragments of molecular mass (M/sub r/) 34, 31, 28, 24, 21, 18, 16, 12, 10 and 7kDa. Because the 34kDa-peptide is the largest fragment containing a FNZ-binding site they conclude that this represents the extracellular domain of the BZR. In the remaining pellet two labelled peptides with M/sub r/ of 44kDa and 28kDa were found that required the use of detergents for their solubilization; they therefore contain the membrane anchoring domain. Digestion of the 0.5% Na-deoxycholate solubilized, intact BZR (M/sub r/ 51kDa) resulted in the same tryptic pattern as the membrane form of the receptor plus two larger fragments of M/sub r/ 45kDa and 40kDa. Arrangement of all tryptic fragments with reference to the FNZ binding site reveals a membrane topology of the BZR alpha-subunit with 67% (34kDa) for the extracellular domain, 21% (11kDa) for the membrane anchoring domain and 12% (6kDa) for a putative cytoplasmic domain. The overlap between some of the labelled fragments suggest that the BZ binding site must be located near the membrane surface of the extracellular domain.

  17. Reduction in the use of benzodiazepines and cyclopyrrolones in general practice

    Directory of Open Access Journals (Sweden)

    Jørgensen VR

    2008-09-01

    Full Text Available In 2003, the Danish Minister for the Interior and Health instructed general practitioners to reduce prescriptions of benzodiazepines (BZD and cyclopyrrolones (CP by 50%. However, no effective methods were specified. In Denmark, it is estimated that there are approximately 100,000 BZD-dependent patients, constituting approximately 2% of the population. Objective: This article describes the implementation of a successful, simple and voluntary intervention to reduce the use of dependence-inducing drugs, while at the same time challenging practitioners' ingrained habits and prejudices in this field.Methods: The rules implemented were essentially in accordance with the official Danish rules, such that a prescription for BZD and CP could only be issued for one month at a time, and only following consultation. Use was monitored using the Danish registration system, Ordiprax, which monitors sales of prescription medicine. Two Danish general practices, comprising a patient base of approximately 2300 were studied. With the exception of the severely physically or mentally ill, all users of BZD and CP were included.Results: After 2½ years, the use of BZD and CP was reduced by 75% and 90%, respectively. The reorganization of prescription patterns was seen to be significantly easier than physicians had expected. During the first three months, only four to five additional visits per week per 1000 patients were required. Subsequently, this number was stabilized at one to two additional visits. The usual collaborative partners, such as psychiatrists, homecare services, hospitals and substance abuse units were essentially not deployed. No serious withdrawal effects arose.Conclusion: The implementation of the aforementioned simple procedures is to be recommended for the prescription of BZD and CP drugs, as the effect is immediate and easily attainable, with a reasonable work input required on the part of general practitioners.

  18. The interaction of substituted benzamides with brain benzodiazepine binding sites in vitro.

    Science.gov (United States)

    Horton, R W; Lowther, S; Chivers, J; Jenner, P; Marsden, C D; Testa, B

    1988-08-01

    1. The interaction of substituted benzamides with brain benzodiazepine (BDZ) binding sites was examined by their ability to displace [3H]-flunitrazepam ([3H]-FNM) from specific binding sites in bovine cortical membranes in vitro. 2. Clebopride, Delagrange 2674, Delagrange 2335 and BRL 20627 displayed concentration-dependent displacement of [3H]-FNM with IC50 values of 73 nM, 132 nM, 7.7 microM and 5.9 microM, respectively. Other substituted benzamides including metoclopramide, sulpiride, tiapride, sultopride and cisapride were inactive at 10(-5) M. 3. Inhibition by clebopride and Delagrange 2674 of [3H]-FNM binding was apparently competitive and readily reversible. 4. In the presence of gamma-aminobutyric acid (GABA), the ability of diazepam and Delagrange 2674 to displace [3H]-Ro 15-1788 binding was increased 3.6 and 1.6 fold respectively, compared to the absence of GABA, while ethyl beta-carboline-3-carboxylate (beta CCE) and clebopride were less potent in the presence of GABA. 5. Diazepam was 30 fold less potent at displacing [3H]-Ro 15-1788 in membranes that had been photoaffinity labelled with FNM than in control membranes, whereas the potency of beta CCE did not differ. Clebopride and Delagrange 2674 showed a less than two fold loss of potency in photoaffinity labelled membranes. 6. The pattern of binding of clebopride and Delagrange 2674 in these in vitro tests is similar to that found previously with partial agonists or antagonists at BDZ binding sites. 7. Clebopride and Delagrange 2674 inhibited [3H]-FNM binding with similar potency in rat cerebellar and hippocampal membranes, suggesting they have no selectivity for BDZ1 and BDZ2 binding sites. 8. Clebopride and Delagrange 2674 are structurally dissimilar to other BDZ ligands and represent another chemical structure to probe brain BDZ binding sites.

  19. Peripheral-type benzodiazepine receptors in bronchoalveolar lavage cells of patients with interstitial lung disease

    International Nuclear Information System (INIS)

    Branley, Howard M.; Bois, Roland M. du; Wells, Athol U.; Jones, Hazel A.

    2007-01-01

    Introduction: PK11195 is a ligand with high affinity for peripheral benzodiazepine receptors (PBRs), which are present in large numbers in macrophages. PBRs play a role in antioxidant pathways and apoptosis, key factors in control of lung health. Intrapulmonary PBRs, assessed in vivo by positron emission tomography (PET), are decreased in interstitial lung disease (ILD) despite increased macrophage numbers. We wished to ascertain whether the observed decrease in in vivo expression of PBRs in the PET scans could be accounted for by a reduction in PBRs per cell by saturation-binding assays of R-PK11195 in cells obtained by bronchoalveolar lavage (BAL). Methods: We performed receptor saturation-binding assays with [ 3 H]-R-PK11195 on a mixed population of cells recovered by BAL to quantify the number of R-PK11195 binding sites per macrophage in 10 subjects with ILD and 10 normal subjects. Results: Receptor affinity [dissociation constant (Kd)] was similar in ILD patients and controls. However, R-PK11195 binding sites per cell [(maximal binding sites available (B max )] were decreased in macrophages obtained by BAL from subjects with ILD compared to normal (P<.0005). Microautoradiography confirmed localization of R-PK11195 to macrophages in a mixed inflammatory cell population obtained by BAL. Conclusion: These results demonstrate that in vitro PBR expression per cell on macrophages obtained by BAL is reduced in patients with ILD indicating a potentially functionally different macrophage phenotype. As PBRs are involved in the orchestration of lung inflammatory responses, this finding offers further insight into the role of macrophages in the pathogenesis of ILDs and offers a potential avenue for pharmacological strategy

  20. Comparison of UHPLC and HPLC in Benzodiazepines Analysis of Postmortem Samples

    Science.gov (United States)

    Behnoush, Behnam; Sheikhazadi, Ardeshir; Bazmi, Elham; Fattahi, Akbar; Sheikhazadi, Elham; Saberi Anary, Seyed Hossein

    2015-01-01

    Abstract The aim of this study was to compare system efficiency and analysis duration regarding the solvent consumption and system maintenance in high-pressure liquid chromatography (HPLC) and ultra high-pressure liquid chromatography (UHPLC). In a case–control study, standard solutions of 7 benzodiazepines (BZs) and 73 biological samples such as urine, tissue, stomach content, and bile that screened positive for BZs were analyzed by HPLC and UHPLC in laboratory of forensic toxicology during 2012 to 2013. HPLC analysis was performed using a Knauer by 100-5 C-18 column (250 mm × 4.6 mm) and Knauer photodiode array detector (PAD). UHPLC analysis was performed using Knauer PAD detector with cooling autosampler and Eurospher II 100-3 C-18 column (100 mm × 3 mm) and also 2 pumps. The mean retention time, standard deviation, flow rate, and repeatability of analytical results were compared by using 2 methods. Routine runtimes in HPLC and UHPLC took 40 and 15 minutes, respectively. Changes in mobile phase composition of the 2 methods were not required. Flow rate and solvent consumption in UHPLC decreased. Diazepam and flurazepam were detected more frequently in biological samples. In UHPLC, small particle size and short length of column cause effective separation of BZs in a very short time. Reduced flow rate, solvent consumption, and injection volume cause more efficiency and less analysis costs. Thus, in the detection of BZs, UHPLC is an accurate, sensitive, and fast method with less cost of analysis. PMID:25860209

  1. Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors

    International Nuclear Information System (INIS)

    Wilson, Alan A.; Garcia, Armando; Parkes, Jun; McCormick, Patrick; Stephenson, Karin A.; Houle, Sylvain; Vasdev, Neil

    2008-01-01

    Introduction: A novel [ 18 F]-radiolabelled phenoxyanilide, [ 18 F]-FEPPA, has been synthesized and evaluated, in vitro and ex vivo, as a potential positron emission tomography imaging agent for the peripheral benzodiazepine receptor (PBR). Methods: [ 18 F]-FEPPA and two other radiotracers for imaging PBR, namely [ 11 C]-PBR28 and [ 11 C]-PBR28-d3, were synthesised and evaluated in vitro and ex vivo as potential PBR imaging agents. Results: [ 18 F]-FEPPA is efficiently prepared in one step from its tosylate precursor and [ 18 F]-fluoride in high radiochemical yields and at high specific activity. FEPPA displayed a K i of 0.07 nM for PBR in rat mitochondrial membrane preparations and a suitable lipophilicity for brain penetration (log P of 2.99 at pH 7.4). Upon intravenous injection into rats, [ 18 F]-FEPPA showed moderate brain uptake [standard uptake value (SUV) of 0.6 at 5 min] and a slow washout (SUV of 0.35 after 60 min). Highest uptake of radioactivity was seen in the hypothalamus and olfactory bulb, regions previously reported to be enriched in PBR in rat brain. Analysis of plasma and brain extracts demonstrated that [ 18 F]-FEPPA was rapidly metabolized, but no lipophilic metabolites were observed in either preparation and only 5% radioactive metabolites were present in brain tissue extracts. Blocking studies to determine the extent of specific binding of [ 18 F]-FEPPA in rat brain were problematic due to large perturbations in circulating radiotracer and the lack of a reference region. Conclusions: Further evaluation of the potential of [ 18 F]-FEPPA will require the employment of rigorous kinetic models and/or appropriate animal models

  2. Learning and memory deficits in male adult mice treated with a benzodiazepine sleep-inducing drug during the juvenile period

    Directory of Open Access Journals (Sweden)

    Yusuke Furukawa

    2016-07-01

    Full Text Available Gamma-aminobutyric acid (GABA, the major inhibitory neurotransmitter in the mammalian central nervous system, is also known to be important for brain development. Therefore, disturbances of GABA receptor (GABA-R mediated signaling (GABA-R signal during brain development may influence normal brain maturation and cause late-onset brain malfunctions. In this study, we examined whether the temporal stimulation of the GABA-R signal during brain development induces late-onset adverse effects on the brain in adult male mice. To stimulate the GABA-R signal, we used either the benzodiazepine sleep-inducing drug triazolam (TZ or the non-benzodiazepine drug zolpidem (ZP. We detected deficits in learning and memory in mice treated with TZ during the juvenile period, as seen in the fear conditioning test. On the other hand, ZP administration during the juvenile period had little effect. In addition, decreased protein expression of GluR1 and GluR4, which are excitatory neurotransmitter receptors, was detected in the hippocampi of mice treated with TZ during the juvenile period. We measured mRNA expression of the immediate early genes (IEGs, which are neuronal activity markers, in the hippocampus shortly after the administration of TZ or ZP to juvenile mice. Decreased IEG expression was detected in mice with juvenile TZ administration, but not in mice with juvenile ZP administration. Our findings demonstrate that TZ administration during the juvenile period can induce irreversible brain dysfunction in adult mice. It may need to take an extra care for the prescription of benzodiazepine sleep-inducing drugs to juveniles because it might cause late onset learning and memory defects.

  3. Drug facilitated sexual assault: detection and stability of benzodiazepines in spiked drinks using gas chromatography-mass spectrometry.

    Directory of Open Access Journals (Sweden)

    Lata Gautam

    Full Text Available Benzodiazepines are detected in a significant number of drug facilitated sexual assaults (DFSA. Whilst blood and urine from the victim are routinely analysed, due to the delay in reporting DFSA cases and the short half lives of most of these drugs in blood and urine, drug detection in such samples is problematic. Consideration of the drinks involved and analysis for drugs may start to address this. Here we have reconstructed the 'spiking' of three benzodiazepines (diazepam, flunitrazepam and temazepam into five drinks, an alcopop (flavoured alcoholic drink, a beer, a white wine, a spirit, and a fruit based non-alcoholic drink (J2O chosen as representative of those drinks commonly used by women in 16-24 year old age group. Using a validated GC-MS method for the simultaneous detection of these drugs in the drinks we have studied the storage stability of the benzodiazepines under two different storage conditions, uncontrolled room temperature and refrigerator (4°C over a 25 day period. All drugs could be detected in all beverages over this time period. Diazepam was found to be stable in all of the beverages, except the J2O, under both storage conditions. Flunitrazepam and temazepam were found not to be stable but were detectable (97% loss of temazepam and 39% loss of flunitrazepam from J2O. The recommendations from this study are that there should be a policy change and that drinks thought to be involved in DFSA cases should be collected and analysed wherever possible to support other evidence types.

  4. Dependence and withdrawal reactions to benzodiazepines and sellective serotonin reuptake inhibitors: How did the health authorities react?

    DEFF Research Database (Denmark)

    Nielsen, Margrethe

    2013-01-01

    AIM: Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time. METHODS: Documentary study. We searched the web-sites of the European Medicines Agency and the drug agencies in USA...... it is difficult for many patients to stop treatment. In the perspective of a precautionary principle, drug agencies have failed to acknowledge that SSRIs can cause dependence and have minimised the problem with regard to its frequency and severity. In the perspective of a risk management principle, the drug...

  5. Benzodiazepine Use Among Low Back Pain Patients Concurrently Prescribed Opioids in the Military Health System Between 2012 and 2013

    Science.gov (United States)

    2017-06-16

    CUil:RENITL Y IN UBE CAN BE VS-ED BENZODIAZEPINE USE AMONG LOW BACK PAIN PATIENTS CONCURRENn Y PRESCRJBED OPIOIDS IN THE MILITARY HEAL TH SYSTEM BETWEEN...increases in the amount of opiotds p.rescrtl>ed for chronic non-cancer pain , particularly low back pain , exist amoog those served by the milit:a ry health...be11ZOdiazepine prescribing practices among active duty service members with low back pain . It is important to understand factors associated with

  6. Studies of the electronic structure and biological activity of chosen 1,4-benzodiazepines by {sup 35}Cl NQR spectroscopy and DFT calculations

    Energy Technology Data Exchange (ETDEWEB)

    Bronisz, K. [Department of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznan (Poland); Ostafin, M. [Department of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznan (Poland)], E-mail: ostifnqr@amu.edu.pl; Poleshchuk, O. Kh. [Department of Chemistry, Tomsk Pedagogical University, Komsomolskii 75, 634041 Tomsk (Russian Federation); Mielcarek, J. [Faculty of Pharmacy, University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan (Poland); Nogaj, B. [Department of Physics, Adam Mickiewicz University, Umultowska 85, 61-614 Poznan (Poland)

    2006-11-08

    Selected derivatives of 1,4-benzodiazepine: lorazepam, lormetazepam, oxazepam and temazepam, used as active substances in anxiolytic drugs, have been studied by {sup 35}Cl NQR method in order to find the correlation between electronic structure and biological activity. The {sup 35}Cl NQR resonance frequencies ({nu} {sub Q}) measured at 77 K have been correlated with the following parameters characterising their biological activity: biological half-life period (t {sub 0.5}), affinity to benzodiazepine receptor (IC{sub 50}) and mean dose equivalent. The results of experimental study of some benzodiazepine derivatives by nuclear quadrupole resonance of {sup 35}Cl nuclei are compared with theoretical results based on DFT calculations which were carried out by means of Gaussian'98 W software.

  7. Change in healthcare utilization and costs following initiation of benzodiazepine therapy for long-term treatment of generalized anxiety disorder: a retrospective cohort study

    Directory of Open Access Journals (Sweden)

    Berger Ariel

    2012-10-01

    Full Text Available Abstract Background Selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and benzodiazepine anxiolytics are used in the US to treat generalized anxiety disorder (GAD. While benzodiazepines typically provide rapid symptomatic relief, long-term use is not recommended due to risks of dependency, sedation, falls, and accidents. Methods Using a US health insurance database, we identified all persons with GAD (ICD-9-CM diagnosis code 300.02 who began a long-term course of treatment (≥90 days with a benzodiazepine anxiolytic between 1/1/2003 and 12/31/2007, We compared healthcare utilization and costs over the six-month periods preceding and following the date of treatment initiation (“pretreatment” and “post-treatment”, respectively, and focused attention on accident-related encounters (e.g., for treatment of fractures and care received for other reasons possibly related benzodiazepine use (e.g., sedation, dizziness. Results A total of 866 patients met all study entry criteria; 25% of patients began treatment on an add-on basis (i.e., adjunctive to escitalopram, paroxetine, sertraline, or venlafaxine, while 75% of patients did not receive concomitant therapy. Mean total healthcare costs increased by $2334 between the pretreatment and post-treatment periods (from $4637 [SD=$9840] to $6971 [$17,002]; p Conclusions Healthcare costs increase in patients with GAD beginning long-term (≥90 days treatment with a benzodiazepine anxiolytic; a substantial proportion of this increase is attributable to care associated with accidents and other known sequelae of long-term benzodiazepine use.

  8. Improving the use of benzodiazepines-Is it possible? A non-systematic review of interventions tried in the last 20 years

    Directory of Open Access Journals (Sweden)

    Tett Susan E

    2010-11-01

    Full Text Available Abstract Background Benzodiazepines are often used on a long term basis in the elderly to treat various psychological disorders including sleep disorders, some neurological disorders and anxiety. This is despite the risk of dependence, cognitive impairment, and falls and fractures. Guidelines, campaigns and prescribing restrictions have been used to raise awareness of potentially inappropriate use, however long term use of benzodiazepine and related compounds is currently increasing in Australia and worldwide. The objective of this paper is to explore interventions aimed at improving the prescribing and use of benzodiazepines in the last 20 years. Methods Medline, EMBASE, PsychINFO, IPA were searched for the period 1987 to June 2007. Results Thirty-two articles met the study eligibility criteria (interventions solely focusing on increasing appropriate prescribing and reducing long term use of benzodiazepines and were appraised. Insufficient data were presented in these studies for systematic data aggregation and synthesis, hence critical appraisal was used to tabulate the studies and draw empirical conclusions. Three major intervention approaches were identified; education, audit and feedback, and alerts. Conclusions Studies which used a multi-faceted approach had the largest and most sustained reductions in benzodiazepines use. It appears that support groups for patients, non-voluntary recruitment of GPs, and oral delivery of alerts or feedback may all improve the outcomes of interventions. The choice of outcome measures, delivery style of educational messages, and requests by GPs to stop benzodiazepines, either in a letter or face to face, showed no differences on the success rates of the intervention.

  9. 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.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  11. Functional characterization of the 1,5-benzodiazepine clobazam and its major active metabolite N-desmethylclobazam at human GABAA receptors expressed in Xenopus laevis oocytes

    DEFF Research Database (Denmark)

    Hammer, Harriet; Ebert, Bjarke; Jensen, Henrik S.

    2015-01-01

    different in vivo adverse effects and addiction liability profile than the classic 1,4-benzodiazepines. In this study, it was investigated whether the in vitro pharmacological properties of clobazam and its major active metabolite N-desmethylclobazam could explain some of these clinical differences...... by the 1,4-benzodiazepine clonazepam. All three compounds potentiated GABA EC20-evoked responses through the α1,2,3,5β2γ2S GABAARs in a reversible and concentration-dependent manner, with each displaying similar EC50 values at the four subtypes. Furthermore, the degrees of potentiation of the GABA EC20...

  12. (/sup 3/H)Clonazepam, like (/sup 3/H)flunitrazepam, is a photoaffinity label for the central type of benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Sieghart, W. (Vienna Univ. (Austria)); Moehler, H. (Hoffmann-La Roche (F.) and Co., Basel (Switzerland))

    1982-06-16

    (/sup 3/H)Clonazepam, like (/sup 3/H)flunitrazepam, is irreversibly bound to membrane proteins of brain tissue when exposed to UV light. In polyacrylamide gel electrophoresis followed by fluorography, the same pattern of photolabelled proteins was obtained in cerebellum and in hippocampus when either (/sup 3/H)clonazepam or (/sup 3/H)flunitrazepam was used as photoaffinity label. Since (/sup 3/H)clonazepam does not interact with the peripheral type of benzodiazepine binding site present in the brain, these results confirm previous evidence that the proteins photolabelled with (/sup 3/H)flunitrazepam are associated with the central type of benzodiazepine receptor.

  13. Association of prenatal exposure to benzodiazepines and child internalizing problems: A sibling-controlled cohort study.

    Directory of Open Access Journals (Sweden)

    Ragnhild E Brandlistuen

    Full Text Available During pregnancy, many women experience sleep problems and anxiety that require treatment. The long-term safety for the child of maternal benzodiazepine (BZD and z-hypnotic use during pregnancy remains controversial.We conducted a cohort and a sibling control study using data from the Norwegian Mother and Child Cohort Study. Data on use of BZD and z-hypnotics, internalizing and externalizing outcomes, and covariates were collected from mothers at gestational weeks 17 and 30 and when children were 0.5, 1.5, and 3 years of age. The total sample consisted of 71,996 children (19,297 siblings at 1.5 years and 55,081 children (13,779 siblings at 3 years. Short-term use was defined as use in one pregnancy period only. Long-term use was defined as use in two or more pregnancy periods. Linear full cohort random-effect and sibling-matched fixed-effect regression models were used to compare internalizing and externalizing behavior in children prenatally exposed compared to those unexposed in the full cohort of pregnancies accounting for family clusters, as well as within sibling clusters comparing pregnancies with discordant exposures. Propensity score (PS adjustment included variables on indication for use (sleep problems, symptoms of anxiety and depression and other potential confounding factors.Long-term prenatal exposure to BZD or z-hypnotics was associated with increased internalizing behavior in crude cohort analyses and at age 1.5 years after PS adjustment in sibling-matched fixed-effect models [β 0.60, 95% confidence interval 0.17-0.95]. Analyses on specific drug groups showed that prenatal exposure to BZD-anxiolytics was associated with increased internalizing problems at both 1.5 years [β 0.25, 0.01-0.49] and 3 years [β 0.26, 0.002-0.52] while exposure to z-hypnotics was not associated with any adverse outcomes after adjustment.The findings suggest a moderate association between BZD-anxiolytic exposure and child internalizing problems that is

  14. Peripheral benzodiazepine receptors in the brain of cirrhosis patients with manifest hepatic encephalopathy

    Energy Technology Data Exchange (ETDEWEB)

    Iversen, Peter; Bender, Dirk; Munk, Ole L.; Cumming, Paul [Aarhus University Hospital, PET Centre, Aarhus (Denmark); Aagaard Hansen, Dorthe; Keiding, Susanne [Aarhus University Hospital, PET Centre, Aarhus (Denmark); Aarhus University Hospital, Department of Medicine V (Hepatology), Aarhus (Denmark); Rodell, Anders [Aarhus University Hospital, Centre of Functionally Integrative Neuroscience (CFIN), Aarhus (Denmark)

    2006-07-15

    It has been suggested that ammonia-induced enhancement of peripheral benzodiazepine receptors (PBRs) in the brain is involved in the development of hepatic encephalopathy (HE). This hypothesis is based on animal experiments and studies of post-mortem human brains using radiolabelled PK11195, a specific ligand for PBR, but to our knowledge has not been tested in living patients. The aim of the present study was to test this hypothesis by measuring the number of cerebral PBRs in specific brain regions in cirrhotic patients with an acute episode of clinically manifest HE and healthy subjects using dynamic {sup 11}C-PK11195 brain PET. Eight cirrhotic patients with an acute episode of clinically manifest HE (mean arterial ammonia 81 {mu}mol/l) and five healthy subjects (22 {mu}mol/l) underwent dynamic {sup 11}C-PK11195 and {sup 15}O-H{sub 2}O PET, co-registered with MR images. Brain regions (putamen, cerebellum, cortex and thalamus) were delineated on co-registered {sup 15}O-H{sub 2} {sup 15}O and MR images and copied to the dynamic {sup 15}O-H{sub 2}O and {sup 11}C-PK11195 images. Regional cerebral blood flow (CBF) ({sup 15}O-H{sub 2}O scan) and the volume of distribution of PK11195 ({sup 11}C-PK11195 scan) were calculated by kinetic analysis. There were regional differences in the CBF, with lowest values in the cortex and highest values in the putamen in both groups of subjects (p<0.05), but no significant differences between the groups. There were no significant differences in the volume of distribution of PK11195 (V{sub d}) between regions or between the two groups of subjects. Mean values of V{sub d} ranged from 1.0 to 1.1 in both groups of subjects. The results do not confirm the hypothesis of an increased number of PBRs in patients with HE. (orig.)

  15. Comparison of benzodiazepine receptor and regional cerebral blood flow imagings of epileptiform foci in hippocampal kindled rabbits

    International Nuclear Information System (INIS)

    Kurokawa, Kenzo

    1993-01-01

    To compare the benzodiazepine (Bz) receptor imaging and regional cerebral blood flow (rCBF) imaging in the detection of epileptic foci, the distribution pattern of the Bz receptor and rCBF in hippocampal kindled rabbits was examined by a double tracer autoradiography using ethyl 7-[ 125 I]-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5-a][1,4] benzodiazepine-3-carboxylate ( 125 I-Ro 16-0154) and 99m Tc-hexamethyl-propyleneamine oxime ( 99m Tc-HMPAO). In visual and quantitative analyses, 125 I-Ro 16-0154 accumulation in brain slices extracted after the completion of the kindling was markedly and extensively decreased in the kindled CA1 region mimicking a primary epileptic focus. 125 I-Ro 16-0154 accumulation was moderately decreased in the ipsilateral temporal lobe, dentate gyrus, CA2, CA4, and bilateral CA3 regions, regarded as the propagated sites of seizure discharges. 99m Tc-HMPAO accumulation was found to be decreased in the ipsilateral CA1, frontal, temporal and dentate gyri. However, the decrease was much more slight and less extensive than that in 125 I-Ro 16-0154 accumulation. These results suggest that Bz receptor imaging is much more sensitive in the detection of epileptic foci than rCBF imaging, and therefore that Bz receptor imaging is useful in clinical epilepsy. (author)

  16. Pharmacological and biochemical properties of the benzodiazepine-GABA receptor in codfish brain in comparison with mammalian brain

    International Nuclear Information System (INIS)

    Deng, L.

    1989-01-01

    The GABA receptor of codfish brain is encoded by an ancestral gene of the mammalian GABA receptor based on phylogenetic studies. The mammalian GABA receptor consists of at least two subunits (β and α) which could be photoaffinity labeled by the GABA agonist [ 3 H]muscimol (57 kDa) and the benzodiazepine (BZ) agonist [ 3 H]flunitrazepam (52 kDa), respectively. In contrast, electrophoresis of codfish GABA receptor photoaffinity labeled by the same ligands showed a single radioactive peak on sodium dodecyl surface polyarcylamide gel, giving rise to a relative molecular weight of 56-57 kDa equivalent to the β subunit of 57 kDa in mammals. The homogeneity of purified receptor using benzodiazepine (Ro 7-1986/1) affinity chromatography was further verified by two-dimensional gel electrophoresis based on isoelectric point and molecular weight, in addition to a single band on a silver stained gel and specific activity. The receptor density and affinity constant for [ 3 H]muscimol and [ 3 H]flunitrazepam are comparable to those in bovine, rate, and human brain

  17. Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants.

    Science.gov (United States)

    Moreau, J. L.; Pieri, L.; Prud'hon, B.

    1989-01-01

    1. Convulsions were induced reproducibly by intracerebroventricular injection of N-methyl-D-aspartic acid (NMDA) to conscious mice. 2. Competitive (carboxypiperazine-propylphosphonic acid, CPP; 2-amino-7-phosphonoheptanoic acid, AP7) and non-competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA-induced convulsions. 3. Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16-6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA-induced convulsions. 4. Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect. 5. Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801. 6. Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered. 7. This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically-induced seizure models for characterizing anticonvulsants not acting at NMDA receptors. PMID:2574061

  18. Lysine and pipecolic acid and some of their derivatives show anticonvulsant activity, and stimulation of benzodiazepine receptor activity

    International Nuclear Information System (INIS)

    Chang, Yung-Feng; Gao, Xue-Min

    1989-01-01

    Benzodiazepines are one of the most widely prescribed drugs in the treatment of anxiety, epilepsy and muscle tension. The natural products lysine and pipecolic acid known to be present in the animal, plant and microorganism, have been shown to be anticonvulsant against pentetrazol (PTZ)-induced seizures in mice. Methyl and ethyl esters of L-lysine and the N-isopropanol derivative of pipecolic acid appear to increase the anticonvulsant potency of the parent compounds, presumably due to their increase in hydrophobicity. Lysine and pipecolic acid showed significant stimulation of specific [ 3 H]flunitrazepam (FZ) binding to mouse brain membranes. This stimulation was enhanced by chloride ions and stereospecific with L-isomer having higher effect. The dose-dependent anticonvulsant activity of lysine and pipecolic acid, and their stimulation of [ 3 H]FZ binding appear to be correlated. The antiepileptic activity lysine, pipecolic acid and their derivatives therefore may be mediated through the γ-aminobutyric acid-benzodiazepine receptor complex

  19. Comparison of the Effects of Haloperidol and Benzodiazepines Used for Postictal Psychiatric Symptoms on Seizure Recurrence: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Pınar Hanife Kara

    2017-09-01

    Full Text Available Aim: Patients with epilepsy may experience a number of psychiatric and cognitive symptoms or behavioral manifestations during the period of a seizure and the postictal period. The aim of this pilot study was to compare the effects medications commonly used in emergency departments for postictal psychiatric symptoms on seizure recurrence. Methods: Data of 32 epileptic patients, who presented to İzmir Katip Çelebi University Atatürk Research and Training Hospital Emergency Department with postictal psychiatric symptoms between January 2013 and December 2014, were retrospectively collected. Demographic and clinical data were obtained from the emergency department charts and neurology and psychiatry consultation records. Data regarding administered drugs were obtained from the hospital data processing system. The chi-square test, Mann-Whitney U test and the Kruskal-Wallis test were used as statistical methods. Bonferroni correction was performed for post-hoc analysis. Results: There were no differences in the seizure recurrence rate between benzodiazepine, haloperidol and without medication groups (p>0.05. Conclusion: Our results suggest that benzodiazepines and haloperidol do not affect the development of recurrent seizures when administered for postictal symptoms.

  20. {sup 125}I-iomazenil - benzodiazepine receptor binding and serum corticosterone level during psychological stress in a rat model

    Energy Technology Data Exchange (ETDEWEB)

    Fukumitsu, Nobuyoshi E-mail: GZL13162@nifty.ne.jp; Ogi, Shigeyuki; Uchiyama, Mayuki; Mori, Yutaka

    2004-02-01

    To test the hypothesis that benzodiazepine receptor density decreases in response to stress, we correlated {sup 125}I-iomazenil ({sup 125}I-IMZ) binding with serum corticosterone levels in a rat model. Wistar male rats were divided into four groups; control group (CON, 10 rats), no physical or psychological stress; and one-, three-, and five-day stress groups of 12 rats each (1-DAY, 3-DAY, and 5-DAY, respectively), receiving psychological stress for the given number of days. Psychological stress were given to rats with a communication box. The standardized uptake value (SUV) of {sup 125}I-iomazenil of the 3-DAY and 5-DAY showed that {sup 125}I-iomazenil - benzodiazepine receptor binding was significantly reduced in the cortices, accumbens nuclei, amygdala and caudate putamen (p<0.05). Serum corticosterone level ratio appeared to be slightly elevated in 3-DAY and 5-DAY, although this elevation was not significant. These data suggest that {sup 125}I-IMZ is a useful radioligand to reflect received stress and its binding in the cortices, accumbens nuclei, amygdala and caudate putamen is strongly affected by psychological stress.

  1. Benzodiazepine prescribing in children under 15 years of age receiving free medical care on the General Medical Services scheme in Ireland.

    LENUS (Irish Health Repository)

    O'Sullivan, K

    2015-06-01

    To examine the prevalence and secular trends in benzodiazepine (BZD) prescribing in the Irish paediatric population. In addition, we examine coprescribing of antiepileptic, antipsychotic, antidepressant and psychostimulants in children receiving BZD drugs and compare BZD prescribing in Ireland to that in other European countries.

  2. Systemic or Intra-Amygdala Injection of a Benzodiazepine (Midazolam) Impairs Extinction but Spares Re-Extinction of Conditioned Fear Responses

    Science.gov (United States)

    Hart, Genevra; Harris, Justin A.; Westbrook, R. Frederick

    2009-01-01

    Rats were subjected to one or two cycles of fear conditioning and extinction, injected with a benzodiazepine, midazolam, before the first or second extinction, and tested for long-term inhibition of fear responses (freezing). In Experiment 1, inhibition of context-conditioned fear was spared when midazolam was injected before the second…

  3. Systemic or Intra-Amygdala Infusion of the Benzodiazepine, Midazolam, Impairs Learning, but Facilitates Re-Learning to Inhibit Fear Responses in Extinction

    Science.gov (United States)

    Hart, Genevra; Harris, Justin A.; Westbrook, R. Frederick

    2010-01-01

    A series of experiments used rats to study the effect of a systemic or intra-amygdala infusion of the benzodiazepine, midazolam, on learning and re-learning to inhibit context conditioned fear (freezing) responses. Rats were subjected to two context-conditioning episodes followed by extinction under drug or vehicle, or to two cycles of context…

  4. Discovery of an imidazopyridine-containing 1,4-benzodiazepine nonpeptide vitronectin receptor (alpha v beta 3) antagonist with efficacy in a restenosis model.

    Science.gov (United States)

    Keenan, R M; Lago, M A; Miller, W H; Ali, F E; Cousins, R D; Hall, L B; Hwang, S M; Jakas, D R; Kwon, C; Louden, C; Nguyen, T T; Ohlstein, E H; Rieman, D J; Ross, S T; Samanen, J M; Smith, B R; Stadel, J; Takata, D T; Vickery, L; Yuan, C C; Yue, T L

    1998-11-17

    In the 3-oxo-1,4-benzodiazepine-2-acetic acid series of vitronectin receptor (alpha v beta 3) antagonists, a compound containing an imidazopyridine arginine mimetic was discovered which had sufficient potency and i.v. pharmacokinetics for demonstration of efficacy in a rat restenosis model.

  5. Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication--A Systematic Review with Meta-Analyses of Randomised Trials

    DEFF Research Database (Denmark)

    Penninga, Elisabeth I; Graudal, Niels; Ladekarl, Morten Baekbo

    2016-01-01

    Flumazenil is used for the reversal of benzodiazepine overdose. Serious adverse events (SAEs) including seizures and cardiac arrhythmias have been reported in patients treated with flumazenil, and the clinical advantage of flumazenil treatment has been questioned. The objective was to assess...

  6. Reliability of self-reported use of amphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, and opiates among acutely hospitalized elderly medical patients

    DEFF Research Database (Denmark)

    Glintborg, B.; Olsen, L.; Poulsen, H.

    2008-01-01

    Undisclosed use of illicit drugs and prescription controlled substances is frequent in some settings. The aim of the present study was to estimate the reliability of self-reported use of amphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, and opiates among acutely...

  7. Benzodiazepine receptor equilibrium constants for flumazenil and midazolam determined in humans with the single photon emission computer tomography tracer [123I]iomazenil

    DEFF Research Database (Denmark)

    Videbaek, C; Friberg, L; Holm, S

    1993-01-01

    twice, once without receptor blockade and once with a constant degree of partial blockade of the benzodiazepine receptors by infusion of nonradioactive flumazenil (Lanexat) or midazolam (Dormicum). Single photon emission computer tomography and blood sampling were performed intermittently for 6 h after...

  8. Pharmacologically induced long QT type 2 can be rescued by activation of IKs with benzodiazepine R-L3 in isolated guinea pig cardiomyocytes

    DEFF Research Database (Denmark)

    Nissen, Jakob Dahl; Diness, Jonas Goldin; Diness, Thomas Goldin

    2009-01-01

    of this study was to evaluate potential antiarrhythmic effects of compound induced IKs activation using the benzodiazepine L-364,373 (R-L3). Ventricular myocytes from guinea pigs were isolated and whole-cell current clamping was performed at 35 degrees C. It was found that 1 microM R-L3 significantly reduced...

  9. 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

    Science.gov (United States)

    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

  10. Functional characterization of the 1,5-benzodiazepine clobazam and its major active metabolite N-desmethylclobazam at human GABA(A receptors expressed in Xenopus laevis oocytes.

    Directory of Open Access Journals (Sweden)

    Harriet Hammer

    Full Text Available The 1,5-benzodiazepine clobazam is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older in the United States, and for treatment of anxiety and various forms of epilepsy elsewhere. Clobazam has been reported to exhibit different in vivo adverse effects and addiction liability profile than the classic 1,4-benzodiazepines. In this study, it was investigated whether the in vitro pharmacological properties of clobazam and its major active metabolite N-desmethylclobazam could explain some of these clinical differences. The functional properties of the two 1,5-benzodiazepines were characterized at the human γ-aminobutyric acid type A receptor (GABA(AR subtypes α1β2γ(2S, α2β2γ(2S, α3β2γ(2S, α5β2γ(2S and α6β2δ expressed in Xenopus laevis oocytes by use of two-electrode voltage-clamp electrophysiology and compared to those exhibited by the 1,4-benzodiazepine clonazepam. All three compounds potentiated GABA EC20-evoked responses through the α(1,2,3,5β2γ(2S GABA(ARs in a reversible and concentration-dependent manner, with each displaying similar EC50 values at the four subtypes. Furthermore, the degrees of potentiation of the GABA EC20 currents through the four receptors mediated by saturating modulator concentrations did not differ substantially for any of the three benzodiazepines. The three compounds were substantially less potent (200-3900 fold as positive allosteric modulators at the α6β2δ GABA(AR than at the α(1,2,3,5β2γ(2S receptors. Interestingly, however, clobazam and especially N-desmethylclobazam were highly efficacious potentiators of α6β2δ receptor signaling. Although this activity component is unlikely to contribute to the in vivo effects of clobazam/N-desmethylclobazam, the 1,5-benzodiazepine could constitute an interesting lead for novel modulators targeting this low-affinity binding site in GABAARs. In conclusion, the non

  11. Reaction of diazepam and related benzodiazepines with chlorine. Kinetics, transformation products and in-silico toxicological assessment.

    Science.gov (United States)

    Carpinteiro, Inmaculada; Rodil, Rosario; Quintana, José Benito; Cela, Rafael

    2017-09-01

    In this work, the reaction of four benzodiazepines (diazepam, oxazepam, nordazepam and temazepam) during water chlorination was studied by means of liquid chromatography-quadrupole-time of flight-mass spectrometry (LC-QTOF-MS). For those compounds that showed a significant degradation, i.e. diazepam, oxazepam and nordazepam, parameters affecting to the reaction kinetics (pH, chlorine and bromide level) were studied in detail and transformation products were tentatively identified. The oxidation reactions followed pseudofirst-order kinetics with rate constants in the range of 1.8-42.5 M -1  s -1 , 0.13-1.16 M -1  s -1 and 0.04-20.4 M -1  s -1 corresponding to half-life values in the range of 1.9-146 min, 1.8-87 h and 2.5-637 h for oxazepam, nordazepam and diazepam, respectively, depending of the levels of studied parameters. Chlorine and pH affected significantly the reaction kinetics, where an increase of the pH resulted into a decrease of the reaction rate, whereas higher chlorine dosages led to faster kinetics, as expected in this case. The transformation of the studied benzodiazepines occurs mainly at the 1,4-diazepine 7-membered-ring, resulting in ring opening to form benzophenone derivatives or the formation of a 6-membered pyrimidine ring, leading to quinazoline derivatives. The formation of these by-products was also tested in real surface water samples observing kinetics of oxazepam degradation slower in river than in creek water, while the degradation of the two other benzodiazepines occurred only in the simpler sample (creek water). Finally, the acute and chronical toxicity and mutagenicity of precursors and transformation products were estimated using quantitative structure-activity relationship (QSAR) software tools: Ecological Structure Activity Relationships (ECOSAR) and Toxicity Estimation Software Tool (TEST), finding that some transformation products could be more toxic/mutagenic than the precursor drug, but additional test would be needed

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

    Science.gov (United States)

    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.

  13. External adjustment of unmeasured confounders in a case-control study of benzodiazepine use and cancer risk

    DEFF Research Database (Denmark)

    Thygesen, Lau Caspar; Pottegård, Anton; Ersbøll, Annette Kjaer

    2017-01-01

    AIMS: Previous studies have reported diverging results on the association between benzodiazepine use and cancer risk. METHODS: We investigated this association in a matched case-control study including incident cancer cases during 2002-2009 in the Danish Cancer Registry (n = 94 923) and age......% confidence interval 1.00-1.19) and for smoking-related cancers from 1.20 to 1.10 (95% confidence interval 1.00-1.21). CONCLUSION: We conclude that the increased risk observed in the solely register-based study could partly be attributed to unmeasured confounding....... PSs were used: The error-prone PS using register-based confounders and the calibrated PS based on both register- and survey-based confounders, retrieved from the Health Interview Survey. RESULTS: Register-based data showed that cancer cases had more diagnoses, higher comorbidity score and more co...

  14. In vivo labelling in several rat tissues of 'peripheral type' benzodiazepine binding sites

    Energy Technology Data Exchange (ETDEWEB)

    Benavides, J.; Guilloux, F.; Rufat, P.; Uzan, A.; Renault, C.; Dubroeucq, M.C.; Gueremy, C.; Le Fur, G. (Pharmuka Laboratoires, 92 - Gennevilliers (France))

    1984-03-16

    'Peripheral type' benzodiazepine binding sites in several rat tissues were labelled by intravenous injection of (/sup 3/H)PK 11195 and (/sup 3/H)RO5-4864. Binding was saturable in all tissues studied and regional distribution paralleled the in vitro binding. A similar potency order of displacing compounds was found in vivo and in vitro PK 11195 > PK 11211 > RO5-4864 > diazepam > dipyridamole > clonazepam. These results demonstrate the feasibility of using this technique to examine the effects of pharmacological manipulation on the binding sites in their native state. However, some properties (broader maximum during time course, higher percentage of particulate binding in the brain and independence of temperature) make (/sup 3/H)PK 11195 the most suitable ligand for this kind of studies.

  15. A rapid fluorimetric screening method for the 1,4-benzodiazepines: Determination of their metabolite oxazepam in urine

    Energy Technology Data Exchange (ETDEWEB)

    Gil Tejedor, A.M. [Departamento de Ciencias Analiticas, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia, c/Senda del Rey 9, 28040 Madrid (Spain); Fernandez Hernando, P. [Departamento de Ciencias Analiticas, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia, c/Senda del Rey 9, 28040 Madrid (Spain)]. E-mail: pfhernando@ccia.uned.es; Durand Alegria, J.S. [Departamento de Ciencias Analiticas, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia, c/Senda del Rey 9, 28040 Madrid (Spain)

    2007-05-15

    Oxazepam is the major metabolite screened in urine samples for the evidence of the use of benzodiazepine drugs. The methods currently used, however, are laborious and time consuming. This paper proposes an oxazepam detection method based on its hydrolysis and cyclization - a reaction catalysed by cerium (IV) in an ortho-phosphoric acid-containing medium - to form 2-chloro-9(10H)-acridinone, a strongly fluorescent molecule. The variables involved in the hydrolysis and cyclization stages were optimised. Oxazepam was detectable in the 5-900 ng mL{sup -1} range, with a detection limit of 4.15 ng mL{sup -1} for k = 3. The method was successfully used for the determination of oxazepam in urine samples collected at different times after the oral administration of Valium[reg] and Tranxilium[reg].

  16. A rapid fluorimetric screening method for the 1,4-benzodiazepines: Determination of their metabolite oxazepam in urine

    International Nuclear Information System (INIS)

    Gil Tejedor, A.M.; Fernandez Hernando, P.; Durand Alegria, J.S.

    2007-01-01

    Oxazepam is the major metabolite screened in urine samples for the evidence of the use of benzodiazepine drugs. The methods currently used, however, are laborious and time consuming. This paper proposes an oxazepam detection method based on its hydrolysis and cyclization - a reaction catalysed by cerium (IV) in an ortho-phosphoric acid-containing medium - to form 2-chloro-9(10H)-acridinone, a strongly fluorescent molecule. The variables involved in the hydrolysis and cyclization stages were optimised. Oxazepam was detectable in the 5-900 ng mL -1 range, with a detection limit of 4.15 ng mL -1 for k = 3. The method was successfully used for the determination of oxazepam in urine samples collected at different times after the oral administration of Valium[reg] and Tranxilium[reg

  17. Comparison of Alcohol Withdrawal Outcomes in Patients Treated with Benzodiazepines Alone versus Adjunctive Phenobarbital: a Retrospective Cohort Study

    Directory of Open Access Journals (Sweden)

    Lauren Z. Gashlin

    2015-03-01

    Full Text Available Background: For treatment of severe alcohol withdrawal syndrome, high dose benzodiazepines (BZDs may cause delirium and over-sedation. Phenobarbital (PBT is a long-acting barbiturate effective for the treatment of alcohol withdrawal. Given the potential benefits of PBT, we sought to investigate the effectiveness of PBT as adjunctive treatment for alcohol withdrawal. Methods: This was a retrospective cohort study on patients with a diagnosis of alcohol withdrawal who had a CIWA-Ar score > 10 treated with either BZDs alone (BZD alone group or BZDs with adjunctive PBT (PBT-adjunct group. The patients received at least one dose of PBT in addition to BZDs (variable doses in the PBT-adjunct group, and three doses of 20 mg diazepam equivalents within 6 hours in the BZD alone group. The primary endpoint was the proportion of patients with a CIWA-Ar score < 10 at 24 hours after initial treatment. Duration of withdrawal and cumulative dose of BZDs were also assessed. Results: Seven subjects in the adjunctive phenobarbital and 21 in the benzodiazepine group were included in the final analysis. Two patients (28.6% in the PBT-adjunct group and 5 patients (23.8% in the BZD only group achieved the primary endpoint, though the difference between the two groups was not statistically significant (P = 0.588. The median (IQR duration of withdrawal symptoms was 44 (12-62 hours in the PBT-adjunct group compared to 53 (37-87 hours in the BZD only group, with no significant difference between the groups (P = 0.249. The median (IQR cumulative BZD dose requirement (diazepam equivalent in the PBT-adjunct group was significantly lower than BZD alone group (25 (20-226 vs. 326 (160-550 mg, P = 0.02. Conclusion: PBT appears to be a safe and effective alternative to BZDs for the treatment of alcohol withdrawal in non-critically ill patients and may be BZD sparing.

  18. The GABAA receptor complex in hepatic encephalopathy. Autoradiographic evidence for the presence of elevated levels of a benzodiazepine receptor ligand

    Energy Technology Data Exchange (ETDEWEB)

    Basile, A.S.; Ostrowski, N.L.; Gammal, S.H.; Jones, E.A.; Skolnick, P. (National Institutes of Health, Bethesda, MD (USA))

    1990-02-01

    Autoradiographic analysis was used to examine radioligand binding to benzodiazepine (BZ) and GABAA receptors in the brains of rabbits with hepatic encephalopathy (HE). Thin sections of whole brain from normal rabbits and rabbits with HE were mounted on slides and subdivided into two groups. One group was washed before incubation with radioligand, while the second group was not prewashed. (3H)Flunitrazepam binding to BZ receptors was decreased by 22% to 42% (p less than 0.05) in the cerebral cortex, superior and inferior colliculi, and cerebellum of unwashed sections from rabbits with HE compared to all other groups. The binding of (3H)Ro 15-1788 to unwashed sections from rabbits with HE was reduced by a similar degree (18% to 37%, p less than 0.05) in the cerebral cortex, hippocampus, superior colliculus, and cerebellar cortex. Incubation of sections with the GABA-mimetic muscimol and NaCl produced an additional decrease in (3H)flunitrazepam binding to the cortex and hippocampus (25% to 31%, p less than 0.05) in unwashed HE rabbit brain, but increased radioligand binding (27% to 71%, p less than 0.05) to several regions in control rabbits. No changes in radioligand binding to either GABAA or peripheral benzodiazepine receptors was observed between HE and control rabbit sections. These findings are consistent with previous electrophysiologic and neurochemical observations indicating no significant changes in either the function or density of GABAA or BZ receptors in this model of HE. Further, they indicate that a reversible BZ receptor ligand with agonist properties is present in the brain in HE. This substance may contribute to the enhancement of GABAergic tone observed in this syndrome.

  19. gamma-Aminobutyric acid- and benzodiazepine-induced modulation of [35S]-t-butylbicyclophosphorothionate binding to cerebellar granule cells

    International Nuclear Information System (INIS)

    Gallo, V.; Wise, B.C.; Vaccarino, F.; Guidotti, A.

    1985-01-01

    t-Butylbicyclophosphorothionate (TBPS) is a bicyclophosphate derivative with potent picrotoxin-like convulsant activity that binds with high affinity and specificity to a Cl- channel-modulatory site of the gamma-aminobutyric acid (GABA)/benzodiazepine receptor complex. Using intact cerebellar granule cells maintained in primary culture, the authors have studied the modifications induced by GABA and diazepam on the ion channel-modulatory binding site labeled by [ 35 S]TBPS. At 25 degrees C, and in a modified Locke solution, the [ 35 S]TBPS specific binding, determined by displacing the radioligand with an excess (10(-4) M) of picrotoxin, was approximately 70% of the total radioactivity bound to the cells. [ 35 S]TBPS specific binding was saturable with a Kd of approximately 100 nM, a Bmax of approximately 440 fmol/mg of protein, and a Hill coefficient of 1.18. Neither cerebellar astrocytes maintained in culture for 2 weeks nor a neuroblastoma cell line (NB-2A) exhibited any specific [ 35 S]TBPS binding. Muscimol (0.3 to 5 microM) enhanced and bicuculline (0.1 to 5 microM) inhibited [ 35 S]TBPS specific binding to intact cerebellar granule cells. The effect of muscimol and bicuculline on [ 35 S]TBPS binding was noncompetitive. Muscimol (0.1 to 5 microM) reversed bicuculline inhibition in a dose-dependent fashion but failed to reverse picrotoxin-induced inhibition. [ 35 S]TBPS binding was also modulated by benzodiazepine receptor ligands. The binding was increased by diazepam and decreased by 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methylester. Muscimol (0.05 microM) failed to reverse bicuculline inhibition in the absence of diazepam, but it became effective in the presence of 0.1 to 1 microM diazepam

  20. Honokiol promotes non-rapid eye movement sleep via the benzodiazepine site of the GABA(A) receptor in mice.

    Science.gov (United States)

    Qu, Wei-Min; Yue, Xiao-Fang; Sun, Yu; Fan, Kun; Chen, Chang-Rui; Hou, Yi-Ping; Urade, Yoshihiro; Huang, Zhi-Li

    2012-10-01

    Decoctions of the Chinese herb houpu contain honokiol and are used to treat a variety of mental disorders, including depression. Depression commonly presents alongside sleep disorders and sleep disturbances, which appear to be a major risk factor for depression. Here, we have evaluated the somnogenic effect of honokiol and the mechanisms involved. Honokiol was administered i.p. at 20:00 h in mice. Flumazenil, an antagonist at the benzodiazepine site of the GABA(A) receptor, was administered i.p. 15 min before honokiol. The effects of honokiol were measured by EEG and electromyogram (EMG), c-Fos expression and in vitro electrophysiology. Honokiol (10 and 20 mg·kg⁻¹) significantly shortened the sleep latency to non-rapid eye movement (non-REM, NREM) sleep and increased the amount of NREM sleep. Honokiol increased the number of state transitions from wakefulness to NREM sleep and, subsequently, from NREM sleep to wakefulness. However, honokiol had no effect on either the amount of REM sleep or EEG power density of both NREM and REM sleep. Honokiol increased c-Fos expression in ventrolateral preoptic area (VLPO) neurons, as examined by immunostaining, and excited sleep-promoting neurons in the VLPO by whole-cell patch clamping in the brain slice. Pretreatment with flumazenil abolished the somnogenic effects and activation of the VLPO neurons by honokiol. Honokiol promoted NREM sleep by modulating the benzodiazepine site of the GABA(A) receptor, suggesting potential applications in the treatment of insomnia, especially for patients who experience difficulty in falling and staying asleep. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  1. Modulation of cholinephosphotransferase activity in breast cancer cell lines by Ro5-4864, a peripheral benzodiazepine receptor agonist

    International Nuclear Information System (INIS)

    Akech, Jacqueline; Roy, Somdutta Sinha; Das, Salil K.

    2005-01-01

    Changes in phospholipid and fatty acid profile are hallmarks of cancer progression. Increase in peripheral benzodiazepine receptor expression has been implicated in breast cancer. The benzodiazepine, Ro5-4864, increases cell proliferation in some breast cancer cell lines. Biosynthesis of phosphatidylcholine (PC) has been identified as a marker for cells proliferating at high rates. Cholinephosphotransferase (CPT) is the terminal enzyme for the de novo biosynthesis of PC. We have addressed here whether Ro5-4864 facilitates some cancer causing mechanisms in breast cancer. We report that cell proliferation increases exponentially in aggressive breast cancer cell lines 11-9-1-4 and BT-549 when treated with nanomolar concentrations of Ro5-4864. This increase is seen within 24 h of treatment, consistent with the cell doubling time in these cells. Ro5-4864 also upregulates c-fos expression in breast cancer cell lines 11-9-1-4 and BT-549, while expression in non-tumorigenic cell line MCF-12A was either basal or slightly downregulated. We further examined the expression of the CPT gene in breast cancer (11-9-1-4, BT-549) and non-tumorigenic cell lines (MCF-12A, MCF-12F). We found that the CPT gene is overexpressed in breast cancer cell lines compared to the non-tumorigenic cell lines. Furthermore, the activity of CPT in forming PC is increased in the breast cancer cell lines cultured for 24 h. Additionally, we examined the CPT activity in the presence of nanomolar concentrations of Ro5-4864. Biosynthesis of PC was increased in breast cancer cell lines upon treatment. We therefore propose that Ro5-4864 facilitates PC formation, a process important in membrane biogenesis for proliferating cells

  2. Affinities and densities of high-affinity [3H]muscimol (GABA-A) binding sites and of central benzodiazepine receptors are unchanged in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy

    International Nuclear Information System (INIS)

    Butterworth, R.F.; Lavoie, J.; Giguere, J.F.; Pomier-Layrargues, G.

    1988-01-01

    The integrity of GABA-A receptors and of central benzodiazepine receptors was evaluated in membrane preparations from prefrontal cortex and caudate nuclei obtained at autopsy from nine cirrhotic patients who died in hepatic coma and an equal number of age-matched control subjects. Histopathological studies revealed Alzheimer Type II astrocytosis in all cases in the cirrhotic group; controls were free from neurological, psychiatric or hepatic diseases. Binding to GABA-A receptors was studied using [ 3 H]muscimol as radioligand. The integrity of central benzodiazepine receptors was evaluated using [ 3 H]flunitrazepam and [ 3 H]Ro15-1788. Data from saturation binding assays was analyzed by Scatchard plot. No modifications of either affinities (Kd) or densities (Bmax) of [ 3 H]muscimol of central benzodiazepine binding sites were observed. These findings do not support recent suggestions that alterations of either high-affinity GABA or benzodiazepine receptors play a significant role in the pathogenesis of hepatic encephalopathy

  3. Microwave assisted facile one pot synthesis of novel 5-carboxamido substituted analogues of 1,4-benzodiazepin-2-one of medicinal interest

    Directory of Open Access Journals (Sweden)

    R. Sirohi

    2013-05-01

    Full Text Available A novel synthetic approach developed by the use of a microwave (MW assisted one pot protocol to the synthesis of methyl-1,4-benzodiazepin-2-one-5-carboxylate (2 derivatives for which N-chloroacetylisatin was employed with an elegant success to afford the formation of 5-methyl carboxylate derivatives of 1,4-benzodiazepines from its reaction with methanolic hexamine. We have utilized MW technique in the present work in conducting the reaction of carboxylate ester derivative (2 with several selected primary and secondary amines 3, 4, 5, 6, 7, and 8 which had the previous history of being biologically active in the literature, to generate the corresponding carboxamide derivatives (9-14.

  4. Synthesis of iodine-123 labelled analogues of the partial agonist (S)-and (R)-bretazenil for the study of CNS benzodiazepine receptors using SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Katsifis, Andrew; Mattner, Filomena; McPhee, Meredith; Kassiou, Michael; Najdovski, Ljubco; Dikic, Branko [Australian Nuclear Science and Technology Organisation, Radiopharmaceutical Div., Menai, Sydney, NSW (Australia)

    1996-09-01

    The (S) and (R)-[{sup 123}I]iodinated analogues of the benzodiazepine receptor partial agonist bretazenil have been synthesized for study of the central benzodiazepine receptor using SPECT, (S)- and (R)-[{sup 123}I]iodobretazenil were prepared from the appropriate tin precursors by electrophilic iododestannylation with Na[{sup 123}I] in the presence of Chloramine-T. The products were purified by semi-preparative reverse-phase HPLC with radiochemical yields of 80% in a total synthesis time of 50 minutes. The specific activity was determined to be greater than 2500 Ci/mmol. The radiochemical and chemical purity assessed by radio-TLC and HPLC were found to be 98%. The enantiomeric purity of the (S) and (R) isomers were greater than 97% as assessed by analytical chiral HPLC analysis. (author).

  5. Different effects of long-term haloperidol administration on GABA/sub A/ and benzodiazepine receptors in various parts of the brain

    International Nuclear Information System (INIS)

    Vasar, Oe.Oe.; Nurk, A.M.; Maimets, M.O.; Soosaar, A.H.; Allikmets, L.H.

    1986-01-01

    The data described in this paper are evidence that long-term administration of haloperidol has an opposite effect on the density of GABA/sub A/ and benzodiazepine receptors in the fore- and hindbrain. These changes are reflected at the molecular level as reversal of behavioral effect of the GABA/sub A/ agonist muscimol and the benzodiazepine agonist Ro15-1788. By means of parallel behavioral tests, binding of 3 H-muscimol in the fore- and hindbrain of rats was investigated in experiments in vitro. 3 H-flunitrazepam binding experiments were carried out in vivo on mice. Parallel with reversal of the behavioral effects of muscimol and Ro15-1788, the number of binding sites both for 3 H-muscimol and for 3 H-flunitrazepam in the forebrain was reduced; in the hindbrain the opposite process took place

  6. Exploiting the acylating nature of the imide-Ugi intermediate: a straightforward synthesis of tetrahydro-1,4-benzodiazepin-2-ones.

    Science.gov (United States)

    Mossetti, Riccardo; Saggiorato, Dèsirèe; Tron, Gian Cesare

    2011-12-16

    We describe a simple and novel protocol for the synthesis of tetrahydro-1,4-benzodiazepin-2-ones with three points of diversity, exploiting the acylating properties of the recently rediscovered Ugi-imide. The final compounds can be easily prepared in three synthetic steps using a multicomponent reaction, a Staudinger reduction, and an acylative protocol, with good to excellent yields for each synthetic step.

  7. Sex and estrous cycle-dependent changes in neurosteroid and benzodiazepine effects on food consumption and plus-maze learning behaviors in rats.

    Science.gov (United States)

    Reddy, D S; Kulkarni, S K

    1999-01-01

    Experiments were designed to investigate the influence of estrous cycle and gender of the rat on the effects of a gamma-aminobutyric acid type A (GABA(A)) receptor active neurosteroid, 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone), the benzodiazepine, triazolam, and a GABA(A) receptor antagonistic neurosteroid, delta5-androsten-3beta-ol-17-one sulfate (dehydroepiandrosterone sulfate), on food intake and elevated plus-maze learning behaviors. Allopregnanolone (0.25 mg/kg, s.c.) and triazolam (0.25 mg/kg, i.p.) produced a hyperphagic effect, while dehydroepiandrosterone sulfate (5 mg/kg, s.c.) elicited an anorectic effect. However, allopregnanolone was more potent in diestrous females, whereas triazolam exhibited significantly higher hyperphagic potency in estrus females. The extent of anorexia following dehydroepiandrosterone sulfate was alike in male and female rats. The triazolam- and allopregnanolone-induced hyperphagic effect was blocked by bicuculline (1 mg/kg, i.p.), a selective GABA(A) receptor antagonist. In contrast to triazolam, the hyperphagic effect of allopregnanolone was insensitive to flumazenil (5 mg/kg, i.p.), a benzodiazepine antagonist. Vehicle-treated diestrous rats displayed moderately higher latencies in the elevated plus-maze learning task than estrus or proestrus females. Although allopregnanolone and triazolam elicited equipotent learning deficits in plus-maze learning in male and female rats, the magnitude of impairment-induced by triazolam was significantly higher in diestrous females than proestrus females. Dehydroepiandrosterone sulfate enhanced memory performance only in male rats. Although the use of the elevated plus-maze as a learning paradigm with benzodiazepines and neurosteroids may be sensitive to changes in anxiety, the differential data suggest that neurosteroid-induced effects are at least partly specific to learning behavior. These results confirm the role of estrous cycle and sex of rats in modifying the potency of

  8. Decrease in benzodiazepine receptor binding in a patient with Angelman syndrome detected by iodine-123 iomazenil and single-photon emission tomography

    International Nuclear Information System (INIS)

    Odano, Ikuo; Anezaki, Toshiharu; Ohkubo, Masaki; Yonekura, Yoshiharu; Onishi, Yoshihiro; Inuzuka, Takashi; Takahashi, Makoto; Tsuji, Shoji

    1996-01-01

    A receptor mapping technique using iodine-123 iomazenil and single-photon emission tomography (SPET) was employed to examine benzodiazepine receptor binding in a patient with Angelman syndrome (AS). AS is characterized by developmental delay, seizures, inappropriate laughter and ataxic movement. In this entity there is a cytogenic deletion of the proximal long arm of chromosome 15q11-q13, where the gene encoding the GABA A receptor β3 subunit (GABRB3) is located. Since the benzodiazepine receptor is constructed as a receptor-ionophore complex that contains the GABA A receptor, it is a suitable marker for GABA-ergic synapsis. To determine whether benzodiazepine receptor density, which indirectly indicates changes in GABA A receptor density, is altered in the brain in patients with AS, we investigated a 27-year-old woman with AS using 123 I-iomazenil and SPET. Receptor density was quantitatively assessed by measuring the binding potential using a simplified method. Regional cerebral blood flow was also measured with N-isopropyl-p- 123 iodoamphetamine. We demonstrated that benzodiazepiine receptor density is severely decreased in the cerebellum, and mildly decreased in the frontal and temporal cortices and basal ganglia, a result which is considered to indicate decreased GABA A receptor density in these regions. Although the deletion of GABRB3 was not observed in the present study, we indirectly demonstrated the disturbance of inhibitory neurotransmission mediated by the GABA A receptor in the investigated patient. 123 I-iomazenil with SPET was useful to map benzodiazepine receptors, which indicate GABA A receptor distribution and their density. (orig.)

  9. Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array (MEA) recording study"

    OpenAIRE

    Giulia ePuia; Francesca eGULLO; Elena eDossi; Marzia eLecchi; Enzo eWanke

    2012-01-01

    The balance between glutamate- and GABA-mediated neurotransmission in the brain is fundamental in the nervous system, but it is regulated by the ‘tonic’ release of a variety of endogenous factors. One such important group of molecules are the neurosteroids (NSs) which, similarly to benzodiazepines (BDZs), enhance GABAergic neurotransmission. The purpose of our work was to investigate, at in-vivo physiologically relevant concentrations, the effects of NSs and BDZs as GABA modulators on dissoc...

  10. Rapid determination of benzodiazepines, zolpidem and their metabolites in urine using direct injection liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Jeong, Yu-Dong; Kim, Min Kyung; Suh, Sung Ill; In, Moon Kyo; Kim, Jin Young; Paeng, Ki-Jung

    2015-12-01

    Benzodiazepines and zolpidem are generally prescribed as sedative, hypnotics, anxiolytics or anticonvulsants. These drugs, however, are frequently misused in drug-facilitated crime. Therefore, a rapid and simple liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for identification and quantification of benzodiazepines, zolpidem and their metabolites in urine using deuterium labeled internal standards (IS). Urine samples (120 μL) mixed with 80 μL of the IS solution were centrifuged. An aliquot (5 μL) of the sample solution was directly injected into the LC-MS/MS system for analysis. The mobile phases consisted of water and acetonitrile containing 2mM ammonium trifluoroacetate and 0.2% acetic acid. The analytical column was a Zorbax SB-C18 (100 mm × 2.1 mm i.d., 3.5 μm, Agilent). The separation and detection of 18 analytes were achieved within 10 min. Calibration curves were linear over the concentration ranges of 0.5-20 ng/mL (zolpidem), 1.0-40 ng/mL (flurazepam and temazepam), 2.5-100 ng/mL (7-aminoclonazepam, 1-hydroxymidazolam, midazolam, flunitrazepam and alprazolam), 5.0-200 ng/mL (zolpidem phenyl-4-carboxylic acid, α-hydroxyalprazolam, oxazepam, nordiazepam, triazolam, diazepam and α-hydroxytriazolam), 10-400 ng/mL (lorazepam and desalkylflurazepam) and 10-100 ng/mL (N-desmethylflunitrazepam) with the coefficients of determination (r(2)) above 0.9971. The dilution integrity of the analytes was examined for supplementation of short linear range. Dilution precision and accuracy were tested using two, four and ten-folds dilutions and they ranged from 3.7 to 14.4% and -12.8 to 12.5%, respectively. The process efficiency for this method was 63.0-104.6%. Intra- and inter-day precisions were less than 11.8% and 9.1%, while intra- and inter-day accuracies were less than -10.0 to 8.2%, respectively. The lower limits of quantification were lower than 10 ng/mL for each analyte. The applicability of the developed method was successfully

  11. An analytic study of central benzodiazepine receptor in the surgically resected tissues of patients with intractable localization-related epilepsy. Quantitative analysis using 125I-iomazenil autoradiography

    International Nuclear Information System (INIS)

    Doi, Toshiaki; Matsuda, Kazumi; Mihara, Tadahiro; Yagi, Kazuichi; Seino, Masakazu

    1998-01-01

    The authors report a quantitative autoradiographic analysis of benzodiazepine receptors using the partial inverse agonist 125 I-iomazenil in surgically resected tissues of 27 patients with intractable partial epilepsies. Pathological diagnosis of these tissues was; 14 mesial temporal sclerosis (MTS), 8 dysembryoplastic neuroepithelial tumor (DNT), 4 cortical dysplasia (CD) and 1 angioma. In MTS patients, the density of benzodiazepine receptors decreased in CA1, CA3 and CA4. The layers of gyrus dentatus were displaced with a thick and high density band. These findings were similar to simultaneous GABA-A stain findings. The decrease of receptor in each hippocampal structure highly correlated to the degree of cell loss in CA1, CA3 and CA4. The receptors were almost absent in the main lesions of DNT and angioma, and showed irregular distributions in the cortex around these lesions. The receptor densities of CD were parallel to Palmini's pathological grading. Nine cases were analyzed using 123 I-iomazenil SPECT before surgery after obtaining informed consent. Eight of them revealed marked low accumulations in the areas corresponding to the epileptogenic foci. We conclude that our results support histochemically the clinical availability of 123 I-iomazenil SPECT as a non-invasive technique for detecting the changes in benzodiazepine receptor densities in patients with partial epilepsies. (author)

  12. Solid-phase extraction and on-disc derivatization of the major benzodiazepines in urine using enzyme hydrolysis and Toxi-Lab VC MP3 column.

    Science.gov (United States)

    King, J W; King, L J

    1996-01-01

    Because of the increase in use of the newer benzodiazepines, we explored the opportunity to develop a gas chromatographic-mass spectrometric (GC-MS) method that encompasses most of the widely prescribed benzodiazepines in use today. The benzodiazepines included in our study are nordiazepam, oxazepam, temazepam, lorazepam, alpha-hydroxyalprazolam, alpha-hydroxytriazolam, desalkylflurazepam, and 2-hydroxyethylflurazepam. Using 1.0 mL of urine as the matrix, we added the enzyme Glusulase and incubated the specimens for 2 h to obtain the free drugs. The hydrolyzed samples were then loaded onto a Toxi-Lab Spec VC MP3 column containing a 15-mg disc. On-disc derivatization was accomplished by adding N-methyl-N-(t-butyldimethylsilyl) trifluroacetamide (MTBSTFA) with 1% TBDMSCI to the disc. The derivatives were then placed in a GC vial and analyzed by GC-MS in the selected ion monitoring mode. These results were then compared to confirmed positives by the traditional acid hydrolysis GC-MS method.

  13. Radiosynthesis and in vivo evaluation of N-[11C]methylated imidazopyridineacetamides as PET tracers for peripheral benzodiazepine receptors

    International Nuclear Information System (INIS)

    Sekimata, Katsuhiko; Hatano, Kentaro; Ogawa, Mikako; Abe, Junichiro; Magata, Yasuhiro; Biggio, Giovanni; Serra, Mariangela; Laquintana, Valentino; Denora, Nunzio; Latrofa, Andrea; Trapani, Giuseppe; Liso, Gaetano; Ito, Kengo

    2008-01-01

    Imidazopyridineacetoamide 5-8, a series of novel and potentially selective peripheral benzodiazepine receptor (PBR) ligands with affinities comparable to those of known PBR ligands, was investigated. Radiosyntheses of [ 11 C]5, 6, 7 or 8 was accomplished by N-methylation of the corresponding desmethyl precursors with [ 11 C]methyl iodide in the presence of NaH in dimethylformamide (DMF), resulting in 25% to 77% radiochemical yield and specific activitiy of 20 to 150 MBq/nmol. Each of the labeled compounds was injected in ddY mice, and the radioactivity and weight of dissected peripheral organs and brain regions were measured. Organ distribution of [ 11 C]7 was consistent with the known PBR distribution. Moreover, [ 11 C]7 showed the best combination of brain uptake and PBR binding, leading to its high retention in the olfactory bulb and cerebellum, areas where PBR density is high in mouse brain. Coinjection of PK11195 or unlabeled 7 significantly reduced the brain uptake of [ 11 C]7. These results suggest that [ 11 C]7 could be a useful radioligand for positron emission tomography imaging of PBRs

  14. Alterations of benzodiazepine receptor binding potential in anxiety and somatoform disorders measured by 123I-iomazenil SPECT

    International Nuclear Information System (INIS)

    Tokunaga, Mari; Ida, Ituro; Mikuni, Masahiko; Higuchi, Teruhiko.

    1997-01-01

    123 I-iomazenil (IMZ), a newly developed radioligand which acts on benzodiazepine receptors (BZR) as a partial inverse agonist, made it possible to evaluate the function of central BZR by single photon emission tomography (SPECT). To examine the alterations of the binding potential (BP) in the anxiety state, 123 I-IMZ SPECT was performed in five patients with anxiety and somatoform disorders, and five epileptic patients without anxiety symptoms served as a reference. The BP of BZR was determined by using a table look-up procedure based on a three-compartment, two-parameter model in the bilateral superior frontal, inferior frontal, temporal, parietal, occipital, and cerebellar cortex. The mean BP of patients with anxiety and somatoform disorders was significantly decreased in the superior frontal, temporal, and parietal cortex, in comparison with that of epileptic patients. A significant correlation was observed between the anxiety levels scored on the Hamilton anxiety scale and BP in the right temporal cortex and left superior frontal cortex. These changes in BZR revealed by SPECT suggest the usefulness of 123 I-IMZ SPECT to objectively evaluate anxiety levels in patients with anxiety symptoms. (author)

  15. Regular Benzodiazepine and Z-Substance Use and Risk of Dementia: An Analysis of German Claims Data.

    Science.gov (United States)

    Gomm, Willy; von Holt, Klaus; Thomé, Friederike; Broich, Karl; Maier, Wolfgang; Weckbecker, Klaus; Fink, Anne; Doblhammer, Gabriele; Haenisch, Britta

    2016-09-06

    While acute detrimental effects of benzodiazepine (BDZ), and BDZ and related z-substance (BDZR) use on cognition and memory are known, the association of BDZR use and risk of dementia in the elderly is controversially discussed. Previous studies on cohort or claims data mostly show an increased risk for dementia with the use of BDZs or BDZRs. For Germany, analyses on large population-based data sets are missing. To evaluate the association between regular BDZR use and incident any dementia in a large German claims data set. Using longitudinal German public health insurance data from 2004 to 2011 we analyzed the association between regular BDZR use (versus no BDZR use) and incident dementia in a case-control design. We examined patient samples aged≥60 years that were free of dementia at baseline. To address potential protopathic bias we introduced a lag time between BDZR prescription and dementia diagnosis. Odds ratios were calculated applying conditional logistic regression, adjusted for potential confounding factors such as comorbidities and polypharmacy. The regular use of BDZRs was associated with a significant increased risk of incident dementia for patients aged≥60 years (adjusted odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13-1.29). The association was slightly stronger for long-acting substances than for short-acting ones. A trend for increased risk for dementia with higher exposure was observed. The restricted use of BDZRs may contribute to dementia prevention in the elderly.

  16. Stabilization study on a wet-granule tableting method for a compression-sensitive benzodiazepine receptor agonist.

    Science.gov (United States)

    Fujita, Megumi; Himi, Satoshi; Iwata, Motokazu

    2010-03-01

    SX-3228, 6-benzyl-3-(5-methoxy-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one, is a newly-synthesized benzodiazepine receptor agonist intended to be developed as a tablet preparation. This compound, however, becomes chemically unstable due to decreased crystallinity when it undergoes mechanical treatments such as grinding and compression. A wet-granule tableting method, where wet granules are compressed before being dried, was therefore investigated as it has the advantage of producing tablets of sufficient hardness at quite low compression pressures. The results of the stability testing showed that the drug substance was chemically considerably more stable in wet-granule compression tablets compared to conventional tablets. Furthermore, the drug substance was found to be relatively chemically stable in wet-granule compression tablets even when high compression pressure was used and the effect of this pressure was small. After investigating the reason for this excellent stability, it became evident that near-isotropic pressure was exerted on the crystals of the drug substance because almost all the empty spaces in the tablets were occupied with water during the wet-granule compression process. Decreases in crystallinity of the drug substance were thus small, making the drug substance chemically stable in the wet-granule compression tablets. We believe that this novel approach could be useful for many other compounds that are destabilized by mechanical treatments.

  17. Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis.

    Science.gov (United States)

    Tokuda, Kazuhiro; O'Dell, Kazuko A; Izumi, Yukitoshi; Zorumski, Charles F

    2010-12-15

    Benzodiazepines (BDZs) enhance GABA(A) receptor inhibition by direct actions on central BDZ receptors (CBRs). Although some BDZs also bind mitochondrial receptors [translocator protein (18 kDa) (TSPO)] and promote the synthesis of GABA-enhancing neurosteroids, the role of neurosteroids in the clinical effects of BDZs is unknown. In rat hippocampal slices, we compared midazolam, an anesthetic BDZ, with clonazepam, an anticonvulsant/anxiolytic BDZ that activates CBRs selectively. Midazolam, but not clonazepam, increased neurosteroid levels in CA1 pyramidal neurons without changing TSPO immunostaining. Midazolam, but not clonazepam, also augmented a form of spike inhibition after stimulation adjacent to the pyramidal cell layer and inhibited induction of long-term potentiation. These effects were prevented by finasteride, an inhibitor of neurosteroid synthesis, or 17PA [17-phenyl-(3α,5α)-androst-16-en-3-ol], a blocker of neurosteroid effects on GABA(A) receptors. Moreover, the synaptic effects were mimicked by a combination of clonazepam with FGIN (2-[2-(4-fluorophenyl)-1H-indol-3-yl]-N,N-dihexylacetamide), a selective TSPO agonist, or a combination of clonazepam with exogenous allopregnanolone. Consistent with these in vitro results, finasteride abolished the effects of midazolam on contextual fear learning when administrated 1 d before midazolam injection. Thus, dual activation of CBRs and TSPO appears to result in unique actions of clinically important BDZs. Furthermore, endogenous neurosteroids are shown to be important regulators of pyramidal neuron function and synaptic plasticity.

  18. Transcranial Random Noise Stimulation-induced plasticity is NMDA-receptor independent but sodium-channel blocker and benzodiazepines sensitive

    Directory of Open Access Journals (Sweden)

    Leila eChaieb

    2015-04-01

    Full Text Available Background: Application of transcranial random noise stimulation (tRNS between 0.1 and 640 Hz of the primary motor cortex (M1 for 10 minutes induces a persistent excitability increase lasting for at least 60 minutes. However, the mechanism of tRNS-induced cortical excitability alterations is not yet fully understood. Objective: The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. Methods: Single-pulse transcranial magnetic stimulation (TMS was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1mA for 10mins stimulation duration and a pharmacological agent (or sham on 8 healthy male participants. Results: The sodium channel blocker carbamazepine showed a tendency towards inhibiting MEPs 5-60 mins poststimulation. The GABAA agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0-20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS.Conclusions: In contrast to transcranial direct current stimulation (tDCS, aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms.

  19. Effect of variations in treatment regimen and liver cirrhosis on exposure to benzodiazepines during treatment of alcohol withdrawal syndrome

    Directory of Open Access Journals (Sweden)

    Pavel Gershokovich

    2015-08-01

    Full Text Available Purpose: Benzodiazepines (BDZs are the drugs of choice to prevent the symptoms of alcohol withdrawal syndrome (AWS. Various treatment protocols are published and have been shown to be effective in both office-managed and facility-managed treatment of AWS. The aim of this scientific commentary is to demonstrate the differences in the expected exposure to BDZs during AWS treatment using different treatment regimens available in the literature, in patients with or without alcoholic liver cirrhosis. Methods: Diazepam and lorazepam AWS protocols were examined and reviewed in the literature, and blood plasma levels were examined and compared, respectively. Results: Considerable variation in the blood levels with the different dosing schedules was found. Because the drugs are metabolized differently, we have also shown that liver disease affects the blood levels of diazepam, but not of lorazepam. Conclusions: Differences in treatment regimens, the choice of BDZ, as well as the presence of liver cirrhosis can substantially alter the exposure of patients to drugs used for AWS treatment. Outpatient treatment of AWS has been shown to be relatively safe and effective for the treatment of AWS but patients should be carefully monitored.

  20. Benzodiazepine use among employees of a private company Consumo de benzodiazepinas en trabajadores de una empresa privada Consumo de benzodiazepinas por trabalhadores de uma empresa privada

    Directory of Open Access Journals (Sweden)

    Alide Salazar Molina

    2008-08-01

    Full Text Available This study aimed to identify variables associated to the consumption of benzodiazepine among workers of a private company in the VIII Region, Chile. This is a cross-sectional and correlative study. Study population: 40 employees of a private company. The instruments included a questionnaire on socio-demographic variables and a benzodiazepine questionnaire. There was no record of benzodiazepine consumption at the moment of the study. Twenty percent (20% of the interviewees had already used benzodiazepine in the past, whereas, half of them (10% in the last year. The bivariate analysis of the last year consumption of benzodiazepine with work hours variables showed no significant relation (p=0.073. No association was found between benzodiazepine consumption and socio-demographic variables among the study participants.El propósito de este estudio fue identificar las variables asociadas al consumo de benzodiazepinas en población trabajadora de una institución privada de la VIII Región, Chile. Diseño cuantitativo, transversal y correlacional. Población del estudio: 40 trabajadores de una empresa privada de la VIII Región, Chile. Instrumentos recolectores de datos. Cuestionario de variables biosociodemográficas y Cuestionario de benzodiazepinas. No se registró consumo de benzodiazepinas al momento del estudio. 20% de los entrevistados tenía antecedentes de consumo de benzodiazepinas en el pasado, de ellos la mitad (10% en el último año. El análisis bivariado del consumo de benzodiazepinas en el último año con variables del trabajo sólo mostró una relación débilmente significativa (p= 0,073 con la jornada de trabajo. No se encontró asociación entre el consumo de benzodiazepines y las variables sociodemográficas entre los participantes del estudio.O propósito deste estudo foi avaliar as variáveis associadas ao consumo de benzodiazepínicos em população trabalhadora de uma instituição privada da VIII Região, Chile. Este é um

  1. Effect of mirtazapine versus selective serotonin reuptake inhibitors on benzodiazepine use in patients with major depressive disorder: a pragmatic, multicenter, open-label, randomized, active-controlled, 24-week trial.

    Science.gov (United States)

    Hashimoto, Tasuku; Shiina, Akihiro; Hasegawa, Tadashi; Kimura, Hiroshi; Oda, Yasunori; Niitsu, Tomihisa; Ishikawa, Masatomo; Tachibana, Masumi; Muneoka, Katsumasa; Matsuki, Satoshi; Nakazato, Michiko; Iyo, Masaomi

    2016-01-01

    This study aimed to evaluate whether selecting mirtazapine as the first choice for current depressive episode instead of selective serotonin reuptake inhibitors (SSRIs) reduces benzodiazepine use in patients with major depressive disorder (MDD). We concurrently examined the relationship between clinical responses and serum mature brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF. We conducted an open-label randomized trial in routine psychiatric practice settings. Seventy-seven MDD outpatients were randomly assigned to the mirtazapine or predetermined SSRIs groups, and investigators arbitrarily selected sertraline or paroxetine. The primary outcome was the proportion of benzodiazepine users at weeks 6, 12, and 24 between the groups. We defined patients showing a ≥50 % reduction in Hamilton depression rating scale (HDRS) scores from baseline as responders. Blood samples were collected at baseline, weeks 6, 12, and 24. Sixty-five patients prescribed benzodiazepines from prescription day 1 were analyzed for the primary outcome. The percentage of benzodiazepine users was significantly lower in the mirtazapine than in the SSRIs group at weeks 6, 12, and 24 (21.4 vs. 81.8 %; 11.1 vs. 85.7 %, both P  depressive episodes may reduce benzodiazepine use in patients with MDD. Trial registration UMIN000004144. Registered 2nd September 2010. The date of enrolment of the first participant to the trial was 24th August 2010. This study was retrospectively registered 9 days after the first participant was enrolled.

  2. Benzodiazepine Use During Hospitalization: Automated Identification of Potential Medication Errors and Systematic Assessment of Preventable Adverse Events.

    Directory of Open Access Journals (Sweden)

    David Franklin Niedrig

    Full Text Available Benzodiazepines and "Z-drug" GABA-receptor modulators (BDZ are among the most frequently used drugs in hospitals. Adverse drug events (ADE associated with BDZ can be the result of preventable medication errors (ME related to dosing, drug interactions and comorbidities. The present study evaluated inpatient use of BDZ and related ME and ADE.We conducted an observational study within a pharmacoepidemiological database derived from the clinical information system of a tertiary care hospital. We developed algorithms that identified dosing errors and interacting comedication for all administered BDZ. Associated ADE and risk factors were validated in medical records.Among 53,081 patients contributing 495,813 patient-days BDZ were administered to 25,626 patients (48.3% on 115,150 patient-days (23.2%. We identified 3,372 patient-days (2.9% with comedication that inhibits BDZ metabolism, and 1,197 (1.0% with lorazepam administration in severe renal impairment. After validation we classified 134, 56, 12, and 3 cases involving lorazepam, zolpidem, midazolam and triazolam, respectively, as clinically relevant ME. Among those there were 23 cases with associated adverse drug events, including severe CNS-depression, falls with subsequent injuries and severe dyspnea. Causality for BDZ was formally assessed as 'possible' or 'probable' in 20 of those cases. Four cases with ME and associated severe ADE required administration of the BDZ antagonist flumazenil.BDZ use was remarkably high in the studied setting, frequently involved potential ME related to dosing, co-medication and comorbidities, and rarely cases with associated ADE. We propose the implementation of automated ME screening and validation for the prevention of BDZ-related ADE.

  3. Radiosynthesis and initial evaluation of [{sup 18}F]-FEPPA for PET imaging of peripheral benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Alan A. [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8 (Canada)], E-mail: alan.wilson@camhpet.ca; Garcia, Armando; Parkes, Jun [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); McCormick, Patrick [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Institute of Medical Science, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); Stephenson, Karin A. [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Houle, Sylvain; Vasdev, Neil [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8 (Canada)

    2008-04-15

    Introduction: A novel [{sup 18}F]-radiolabelled phenoxyanilide, [{sup 18}F]-FEPPA, has been synthesized and evaluated, in vitro and ex vivo, as a potential positron emission tomography imaging agent for the peripheral benzodiazepine receptor (PBR). Methods: [{sup 18}F]-FEPPA and two other radiotracers for imaging PBR, namely [{sup 11}C]-PBR28 and [{sup 11}C]-PBR28-d3, were synthesised and evaluated in vitro and ex vivo as potential PBR imaging agents. Results: [{sup 18}F]-FEPPA is efficiently prepared in one step from its tosylate precursor and [{sup 18}F]-fluoride in high radiochemical yields and at high specific activity. FEPPA displayed a K{sub i} of 0.07 nM for PBR in rat mitochondrial membrane preparations and a suitable lipophilicity for brain penetration (log P of 2.99 at pH 7.4). Upon intravenous injection into rats, [{sup 18}F]-FEPPA showed moderate brain uptake [standard uptake value (SUV) of 0.6 at 5 min] and a slow washout (SUV of 0.35 after 60 min). Highest uptake of radioactivity was seen in the hypothalamus and olfactory bulb, regions previously reported to be enriched in PBR in rat brain. Analysis of plasma and brain extracts demonstrated that [{sup 18}F]-FEPPA was rapidly metabolized, but no lipophilic metabolites were observed in either preparation and only 5% radioactive metabolites were present in brain tissue extracts. Blocking studies to determine the extent of specific binding of [{sup 18}F]-FEPPA in rat brain were problematic due to large perturbations in circulating radiotracer and the lack of a reference region. Conclusions: Further evaluation of the potential of [{sup 18}F]-FEPPA will require the employment of rigorous kinetic models and/or appropriate animal models.

  4. Amygdala Lesions Reduce Anxiety-like Behavior in a Human Benzodiazepine-Sensitive Approach-Avoidance Conflict Test.

    Science.gov (United States)

    Korn, Christoph W; Vunder, Johanna; Miró, Júlia; Fuentemilla, Lluís; Hurlemann, Rene; Bach, Dominik R

    2017-10-01

    Rodent approach-avoidance conflict tests are common preclinical models of human anxiety disorder. Their translational validity mainly rests on the observation that anxiolytic drugs reduce rodent anxiety-like behavior. Here, we capitalized on a recently developed approach-avoidance conflict computer game to investigate the impact of benzodiazepines and of amygdala lesions on putative human anxiety-like behavior. In successive epochs of this game, participants collect monetary tokens on a spatial grid while under threat of virtual predation. In a preregistered, randomized, double-blind, placebo-controlled trial, we tested the effect of a single dose (1 mg) of lorazepam (n = 59). We then compared 2 patients with bilateral amygdala lesions due to Urbach-Wiethe syndrome with age- and gender-matched control participants (n = 17). Based on a previous report, the primary outcome measure was the effect of intra-epoch time (i.e., an adaptation to increasing potential loss) on presence in the safe quadrant of the spatial grid. We hypothesized reduced loss adaptation in this measure under lorazepam and in patients with amygdala lesions. Lorazepam and amygdala lesions reduced loss adaptation in the primary outcome measure. We found similar results in several secondary outcome measures. The relative reduction of anxiety-like behavior in patients with amygdala lesions was qualitatively and quantitatively indistinguishable from an impact of anterior hippocampus lesions found in a previous report. Our results establish the translational validity of human approach-avoidance conflict tests in terms of anxiolytic drug action. We identified the amygdala, in addition to the hippocampus, as a critical structure in human anxiety-like behavior. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Alterations in brain-derived neurotrophic factor in the mouse hippocampus following acute but not repeated benzodiazepine treatment.

    Directory of Open Access Journals (Sweden)

    Stephanie C Licata

    Full Text Available Benzodiazepines (BZs are safe drugs for treating anxiety, sleep, and seizure disorders, but their use also results in unwanted effects including memory impairment, abuse, and dependence. The present study aimed to reveal the molecular mechanisms that may contribute to the effects of BZs in the hippocampus (HIP, an area involved in drug-related plasticity, by investigating the regulation of immediate early genes following BZ administration. Previous studies have demonstrated that both brain derived neurotrophic factor (BDNF and c-Fos contribute to memory- and abuse-related processes that occur within the HIP, and their expression is altered in response to BZ exposure. In the current study, mice received acute or repeated administration of BZs and HIP tissue was analyzed for alterations in BDNF and c-Fos expression. Although no significant changes in BDNF or c-Fos were observed in response to twice-daily intraperitoneal (i.p. injections of diazepam (10 mg/kg + 5 mg/kg or zolpidem (ZP; 2.5 mg/kg + 2.5 mg/kg, acute i.p. administration of both triazolam (0.03 mg/kg and ZP (1.0 mg/kg decreased BDNF protein levels within the HIP relative to vehicle, without any effect on c-Fos. ZP specifically reduced exon IV-containing BDNF transcripts with a concomitant increase in the association of methyl-CpG binding protein 2 (MeCP2 with BDNF promoter IV, suggesting that MeCP2 activity at this promoter may represent a ZP-specific mechanism for reducing BDNF expression. ZP also increased the association of phosphorylated cAMP response element binding protein (pCREB with BDNF promoter I. Future work should examine the interaction between ZP and DNA as the cause for altered gene expression in the HIP, given that BZs can enter the nucleus and intercalate into DNA directly.

  6. Long-term benzodiazepine treatment in patients with psychotic disorders attending a mental health service in rural Greece

    Directory of Open Access Journals (Sweden)

    Vaios Peritogiannis

    2016-01-01

    Full Text Available Introduction: Long-term benzodiazepine (BZD treatment in patients with mental disorders is widespread in clinical practice, and this is also the case of patients with schizophrenia, although the evidence is weak and BZD prescription is discouraged by guidelines and medical authorities. Data on BZD prescription are usually derived from national or regional databases whereas information on the use of BZD by patients with schizophrenia and related psychoses in general population-based samples is limited. Materials and Methods: Information for 77 patients with psychotic disorders who were regularly attending follow-up appointments with the multidisciplinary Mobile Mental Health Unit of the prefectures of Ioannina and Thesprotia, Northwest Greece, during 1-year period (2015 was obtained from our database. Results: From the total of 77 engaged patients, 30 (39% were regularly prescribed BZDs in the long term, as part of their treatment regimen. Prescribed BZDs were mostly diazepam and lorazepam, in 43.3% of cases each. The mean daily dose of these compounds was 13 mg and 3.77 mg, respectively. Statistical analysis showed a correlation of long-term BZD use with the history of alcohol/substance abuse. Most patients were receiving BZD continuously for several years, and the mean dose was steady within this interval. Conclusions: A large proportion of patients with psychotic disorders were regularly prescribed BZD in long term. It appears that when BZDs are prescribed for some period in the course of a psychotic disorder, their use commonly exceeds the recommended interval and then becomes a regular part of the chronic treatment regimen. Future research should address the factors that may be related to the long-term BZD use by patients with psychotic disorders. Interventions for the reduction of regular BZD prescription should target the primary care setting and all those who treat first episode patients.

  7. Effects of protein restriction, melatonin administration, and short daylength on brain benzodiazepine receptors in prepubertal male rats

    International Nuclear Information System (INIS)

    Kennaway, D.J.; Royles, P.; Webb, H.; Carbone, F.

    1988-01-01

    The possibility that there are changes in brain benzodiazepine binding sites controlled by photoperiod was investigated in two strains of male rats. The hypothesis was tested by 3H-diazepam binding studies in various brain regions of prepubertal rats maintained in 14 or 10 h of light or treated with late-afternoon injections of melatonin (50 micrograms/day). Protein restriction was applied during the experiment to sensitize the animals to the treatments. Under the conditions employed, rats kept in short daylength throughout or kept on long photoperiod and given late-afternoon melatonin injections showed evidence of delayed puberty (seminal vesicle, ventral prostate, and testis weight decreased by 45%, 55%, and 60% respectively, compared to control rats). Binding measurements were made 1 h before and 2 and 5 h after the onset of darkness in the pubertal (42-day-old) or experimentally prepubertal rats. In the rats of the Porton strain (for which protein restriction was obligatory for the gonadal response) there was no consistent treatment or time effects on specific binding of 3H-diazepam to washed membranes of the hypothalamus, midbrain, or striatum. Similarly, there were no differences in the stimulation of 3H-diazepam binding by 100 microM GABA or the inhibition of binding by 50 microM N-acetyl 5 methoxy kynurenamine. By contrast, in Wistar rats, specific binding to midbrain membranes was reduced 5 h after dark compared to 2 h (37% saline; 20% melatonin) and the extent of stimulation by GABA in the hypothalamus was increased 5 h after darkness (35.6% to 46.7% saline; 37.4% to 50% melatonin). Melatonin treatment resulted in significantly higher specific binding in the hypothalamus 2 h after dark (10%, control fed; 20%, protein restricted) but reduced the GABA induced stimulation of binding in the midbrain (35.5% to 25%, control fed; 33.7% to 23.5%, protein restricted)

  8. Topology characterization of a benzodiazepine-binding beta-rich domain of the GABAA receptor alpha1 subunit.

    Science.gov (United States)

    Xu, Zhiwen; Fang, Shisong; Shi, Haifeng; Li, Hoiming; Deng, Yiqun; Liao, Yinglei; Wu, Jiun-Ming; Zheng, Hui; Zhu, Huaimin; Chen, Hueih-Min; Tsang, Shui Ying; Xue, Hong

    2005-10-01

    Structural investigation of GABAA receptors has been limited by difficulties imposed by its trans-membrane-complex nature. In the present study, the topology of a membrane-proximal beta-rich (MPB) domain in the C139-L269 segment of the receptor alpha1 subunit was probed by mapping the benzodiazepine (BZ)-binding and epitopic sites, as well as fluorescence resonance energy transfer (FRET) analysis. Ala-scanning and semiconservative substitutions within this segment revealed the contribution of the phenyl rings of Y160 and Y210, the hydroxy group of S186 and the positive charge on R187 to BZ-binding. FRET with the bound BZ ligand indicated the proximity of Y160, S186, R187, and S206 to the BZ-binding site. On the other hand, epitope-mapping using the monoclonal antibodies (mAbs) against the MPB domain established a clustering of T172, R173, E174, Q196, and T197. Based on the lack of FRET between Trp substitutionally placed at R173 or V198 and bound BZ, this epitope-mapped cluster is located on a separate end of the folded protein from the BZ-binding site. Mutations of the five conserved Cys and Trp residues in the MPB domain gave rise to synergistic and rescuing effects on protein secondary structures and unfolding stability that point to a CCWCW-pentad, reminiscent to the CWC-triad "pin" of immunoglobulin (Ig)-like domains, important for the structural maintenance. These findings, together with secondary structure and fold predictions suggest an anti-parallel beta-strand topology with resemblance to Ig-like fold, having the BZ-binding and the epitopic residues being clustered at two different ends of the fold.

  9. A simple method for the quantification of benzodiazepine receptors using iodine-123 iomazenil and single-photon emission tomography

    International Nuclear Information System (INIS)

    Ito, Hiroshi; Goto, Ryoui; Koyama, Masamichi; Kawashima, Ryuta; Ono, Shuichi; Sato, Kazunori; Fukuda, Hiroshi

    1996-01-01

    Iodine-123 iomazenil (Iomazenil) is a ligand for central type benzodiazepine receptors that is suitable for single-photon emission tomography (SPET). The purpose of this study was to develop a simple method for the quantification of its binding potential (BP). The method is based on a two-compartment model (K 1 , influx rate constant; k 2 ', efflux rate constant; V T '(=K 1 /k 2 '), the total distribution volumes relative to the total arterial tracer concentration), and requires two SPET scans and one blood sampling. For a given input function, the radioactivity ratio of the early to delayed scans can be considered to tabulate as a function of k 2 ', and a table lookup procedure provides the corresponding k 2 ' value, from which K 1 and V t ' values are then calculated. The arterial input function is obtained by calibration of the standard input function by the single blood sampling. SPET studies were performed on 14 patients with cerebrovascular diseases, dementia or brain tumours (mean age ±SD, 56.0±12.2). None of the patients had any heart, renal or liver disease. A dynamic SPET scan was performed following intravenous bolus injection of Iomazenil. A static SPET scan was performed at 180 min after injection. Frequent blood sampling from the brachial artery was performed on all subjects for determination of the arterial input function. Two-compartment model analysis was validated for calculation of the V T ' value of Iomazenil. Good correlations were observed between V T ' values calculated by three-compartment model analysis and those calculated by the present method, in which the scan time combinations (early scan/delayed scan) used were 15/180 min, 30/180 min or 45/180 min (all combinations: r=0.92), supporting the validity of this method. The present method is simple and applicable for clinical use. (orig.)

  10. High-Dose Benzodiazepine Dependence: A Qualitative Study of Patients' Perceptions on Initiation, Reasons for Use, and Obtainment.

    Directory of Open Access Journals (Sweden)

    Michael Liebrenz

    Full Text Available High-dose benzodiazepine (BZD dependence is associated with a wide variety of negative health consequences. Affected individuals are reported to suffer from severe mental disorders and are often unable to achieve long-term abstinence via recommended discontinuation strategies. Although it is increasingly understood that treatment interventions should take subjective experiences and beliefs into account, the perceptions of this group of individuals remain under-investigated.We conducted an exploratory qualitative study with 41 adult subjects meeting criteria for (high-dose BZD-dependence, as defined by ICD-10. One-on-one in-depth interviews allowed for an exploration of this group's views on the reasons behind their initial and then continued use of BZDs, as well as their procurement strategies. Mayring's qualitative content analysis was used to evaluate our data.In this sample, all participants had developed explanatory models for why they began using BZDs. We identified a multitude of reasons that we grouped into four broad categories, as explaining continued BZD use: (1 to cope with symptoms of psychological distress or mental disorder other than substance use, (2 to manage symptoms of physical or psychological discomfort associated with somatic disorder, (3 to alleviate symptoms of substance-related disorders, and (4 for recreational purposes, that is, sensation-seeking and other social reasons. Subjects often considered BZDs less dangerous than other substances and associated their use more often with harm reduction than as recreational. Specific obtainment strategies varied widely: the majority of participants oscillated between legal and illegal methods, often relying on the black market when faced with treatment termination.Irrespective of comorbidity, participants expressed a clear preference for medically related explanatory models for their BZD use. We therefore suggest that clinicians consider patients' motives for long-term, high

  11. Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice

    Science.gov (United States)

    Smith, Kiersten S.; Engin, Elif; Meloni, Edward G.; Rudolph, Uwe

    2012-01-01

    GABAA receptor modulating drugs such as benzodiazepines (BZs) have been used to treat anxiety disorders for over five decades. In order to determine whether the same or different GABAA receptor subtypes are necessary for the anxiolytic-like action of BZs in unconditioned anxiety and conditioned fear models, we investigated the role of different GABAA receptor subtypes by challenging wild type, α1(H101R), α2(H101R) and α3(H126R) mice bred on the C57BL/6J background with diazepam or chlordiazepoxide in the elevated plus maze and the fear-potentiated startle paradigms. Both drugs significantly increased open arm exploration in the elevated plus maze in wild type, α1(H101R) and α3(H126R), but this effect was abolished in α2(H101R) mice; these were expected results based on previous published results. In contrast, while administration of diazepam and chlordiazepoxide significantly attenuated fear-potentiated startle (FPS) in wild type mice and α3(H126R) mice, the fear-reducing effects of these drugs were absent in both α1(H101R) and α2(H101R) point mutants, indicating that both α1- and α2-containing GABAA receptors are necessary for BZs to exert their effects on conditioned fear responses.. Our findings illustrate both an overlap and a divergence between the GABAA receptor subtype requirements for the impact of BZs, specifically that both α1- and α2-containing GABAA receptors are necessary for BZs to reduce conditioned fear whereas only α2-containing GABAA receptors are needed for BZ-induced anxiolysis in unconditioned tests of anxiety. This raises the possibility that GABAergic pharmacological interventions for specific anxiety disorders can be differentially tailored. PMID:22465203

  12. Alterations in in-vivo benzodiazepine-receptor binding of C-11-Ro15-1788 (flumazepil)

    International Nuclear Information System (INIS)

    Yamasaki, T.; Inoue, O.; Shinoto, H.; Ito, T.; Hashimoto, K.; Suzuki, K.; Tateno, Y.

    1985-01-01

    Alterations of the central benzodiazepine - receptor function caused by the change of physiological or psychological conditions, were recognized in both animal and human studies. Before the human study, animal experiments using tritiated Ro15-1788 were carried out. The stress was produced by forcing the mice to swim in a water-basin at 16 0 C for 5 min. Within 3 min after the forced swimming, the tracer was injected. Brain radioactivities in stress-loaded mice increased over a period of 15 min after the intra-venous injection of tracers, while brain activities of carrier-added tracer decreased. In human study, approximately 5 mCi of C-11-Ro15-1788, which specific activity is 0.3-1.0 Ci/μmol, were intravenously injected to each case. Measurements of the brain activity were performed using positron-CT, with blood sample collection. 31 human studies were performed on. Cerebral cortex time activity curves in several volunteers in nervous and stressful state, showed the same pattern to that in the stress-loaded animal experiment. It is important that the significant different time course of cerebral activity after the injection of labelled Ro15-1788, was observed in stressful state, compared with control, in both human and animal study. From these results, it will be concluded the positron CT study using /sup 11/C-Ro15-1788 will become a new technic to detect the change of psychological conditions in human brain and to diagnose some kind of neuropsychiatric disease

  13. Silexan, an essential oil from flowers of Lavandula angustifolia, is not recognized as benzodiazepine-like in rats trained to discriminate a diazepam cue.

    Science.gov (United States)

    Silenieks, Leo B; Koch, Egon; Higgins, Guy A

    2013-01-15

    Recently, an essential oil of selected quality produced from the flowering tops of Lavandula angustifolia Mill. by steam distillation (Silexan) has been approved in Germany for the treatment of restlessness in case of anxious mood. Based on the observed clinical effects, it has been speculated that lavender oil may exert benzodiazepine-like action including the known dependence and abuse potential of this class of drugs. Although no evidence for such an activity was generated during the long-standing medicinal use of lavender oil, further preclinical investigations were now conducted to evaluate this potential side effect in more detail. Twelve adult, male, Sprague-Dawley rats were trained to discriminate the benzodiazepine drug diazepam (2 mg/kg i.p.) from saline using a two-lever operant procedure. After approximately 40 training sessions the majority of rats learned the discrimination and pre-treatment with ascending doses of diazepam (0.3-2 mg/kg i.p.) produced a dose related generalization to the diazepam cue. In these same animals Silexan was administered to see if animals recognized the drug as "diazepam-like" i.e. generalized to diazepam or "saline-like". Silexan tested at doses 3-30 mg/kg i.p. produced almost exclusively (>90%) saline-like responding. Also there was no effect of Silexan on response rate, i.e. rate of lever pressing, at any dose suggesting that the test article is well tolerated and does not exert a sedating effect. In sum, Silexan has no diazepam-like interoceptive property in adult, male rats. This suggests that Silexan does not share the potential of benzodiazepines to induce the development of tolerance, dependence and addiction. Copyright © 2012 Elsevier GmbH. All rights reserved.

  14. The ultrastructural changes in the liver cells induced by high doses of Benzodiazepine Tranquilizing drugs: An experimental transmission electron microscopic study on male guinea pigs

    International Nuclear Information System (INIS)

    Bisher, Ameen S. Ahmad

    2008-01-01

    Benzodiazepines are tranquilizing psychotropic drugs. Unfortunately, despite their therapeutic benefits, they are illegally consumed in high doses by some addicts to reach a sedative, exhilarative and euphoria state similar to that produced by narcotic substances. The present study, using transmission electron microscope on male guinea pigs, aims to investigate the potential ultrastructural changes in the liver cells induced by the high doses of Benzodiazepines. Animals in three treated groups administrated a daily combined dose consisted of (10mg Alprazolam with 10mg Diazepam/day/animal) for three different treatment periods: 7, 15, and 25 days. The ultrastructural examination of the hepatocytes of the animals treated for 15 days showed limited changes in the form of marginal heterochromatine accompanied with marginal nucleoli enlargement. On the other hand, severe ultrastructural damages are observed in the animals treated for 25 days, which appeared in the following various patterns: fatty degeneration of the hepatocytes as indicated by the accumulation of large number of lipid droplets in the cytoplasm, marked nuclear atrophy in some necrotic hepatocytes, massive nuclear degeneration in other hepatocytes, mitochondrial damages in the form of cristea destruction accompanied with abnormal oval shape, massive lysis of the cytoplasmic organelles with severe plasma membrane rupture. In conclusion, the observed ultrastructural damages in the present study may refer to the potential hepatotoxic effects of the high dose of Benzodiazepins. It is recommended that much more official restrictions should be applied on the pharmacies sector to prevent any illegal selling of these drugs in order to prevent abusers from obtaining them, as unfortunately in some developing countries the illegal selling of these drugs is known to occur due to the absence of official control. (author)

  15. A captive solvent method for rapid N-[11C]methylation of secondary amides: application to the benzodiazepine, 4'-chlorodiazepam (RO5-4864)

    International Nuclear Information System (INIS)

    Watkins, G.L.; Jewett, D.M.; Mulholland, G.K.; Kilbourn, M.R.; Toorongian, S.A.

    1988-01-01

    [ 11 C]4'-Chlorodiazepam (RO5-4864), for PET studies of peripheral benzodiazepine receptors, was synthesized by alkylation of 1-desmethyl-4'-chlorodiazepam, in a small volume of acetone adsorbed on acrylic yarn, with [ 11 C]methyl iodide in the injection loop of a liquid chromatograph. The reaction mixture was introduced directly onto a small, disposable alumina chromatographic column. Elution with pentane: ethanol gave a product of high chemical and radiochemical purity. A simple heating and cooling device for the injection loop is described. (author)

  16. Contextos e padrões do uso indevido de benzodiazepínicos entre mulheres Contexts and patterns of undue use benzodiazepine among women

    Directory of Open Access Journals (Sweden)

    Ana Rosa Lins de Souza

    2013-04-01

    Full Text Available O uso indevido de benzodiazepínicos, especialmente entre mulheres, tem despertado preocupação na área de saúde pública. Este estudo objetivou compreender qualitativamente crenças e valores associados ao consumo indevido dessa substância por mulheres. Foram entrevistadas trinta e três mulheres (18-60 anos com histórico de uso indevido de benzodiazepínicos no último ano, selecionadas intencionalmente e por critérios. Os discursos foram transcritos e submetidos à análise de conteúdo com auxílio do software NVivo. A maioria das entrevistadas referiu tempo de uso bem superior ao recomendado (mediana: 7 anos e compra com receita médica. Os motivos de uso mais citados foram diminuição da ansiedade, problemas de insônia e fuga dos problemas. Apesar de reconhecerem a possibilidade de dependência, esta não motivou a interrupção do uso. O acompanhamento médico não pareceu, necessariamente, estimular a percepção de risco dos benzodiazepínicos, sendo um fator que favoreceu a manutenção do uso prolongado.The undue use of benzodiazepines particularly among women has raised concern in the public health area. This qualitative study aimed at understanding the beliefs and values associated with undue use of benzodiazepines among women. Thirty-three participants (aged between 18 and 60 with a history of undue use of benzodiazepines in the past year were selected intentionally using specific criteria. The interviews were fully transcribed and subjected to content analysis using NVivo software. The majority of respondents reported use for longer than the recommended duration (median 7 years and they purchased the drug with a medical prescription. Reasons for use most given were to deal with anxiety, to improve sleep and to "flee from problems." Even those who acknowledged the possibility of being addicted were not motivated to stop taking the drug. Medical supervision did not necessarily seem to influence the perception of risk of

  17. Ring rearrangements and reactivity of 3-((4-oxo-4H-chromen-3-ylmethylene-4-phenyl-1H-[1,5]benzodiazepin-2(3H-one toward some nucleophiles

    Directory of Open Access Journals (Sweden)

    Hanan Salah

    2017-05-01

    Full Text Available Condensation of 4-phenyl-1H-[1,5]benzodiazepin-2(3H-one (1 with 3-formylchromone (2 afforded a mixture of 3-(chromenylmethylene[1,5]benzodiazepinone 3 and 14-chromenylbenzodiazepino[2,3:6,5]pyrano[2,3-b]benzodiazepine 4. Ring rearrangements of compound 3 with different nucleophilic reagents, such as potassium hydroxide and/or ammonium acetate led to rearrangement into pyranobenzodiazepine 5 and pyridobenzodiazepine 6, respectively. Treatment of compound 3 with hydrazine hydrate, hydroxylamine hydrochloride, malononitrile, cyanothioacetamide, 2-cyano-3,3-disufanylacrylonitrile, and/or 2-cyano-3-phenylamino-3-sufanylacrylonitrile, has been carried out at different conditions, leading to versatile heterocyclic substituted benzodiazepines at position 3, viz. pyrazole 8, isoxazole 9, pyridines 10 and 11, 1,3-dithiine 12, and 1,3-thiazine 13 derivatives.

  18. Functional modulation of cerebral gamma-aminobutyric acidA receptor/benzodiazepine receptor/chloride ion channel complex with ethyl beta-carboline-3-carboxylate: Presence of independent binding site for ethyl beta-carboline-3-carboxylate

    Energy Technology Data Exchange (ETDEWEB)

    Taguchi, J.; Kuriyama, K. (Kyoto Prefectural Univ. of Medicine (Japan))

    1990-05-01

    Effect of ethyl beta-carboline-3-carboxylate (beta-CCE) on the function of gamma-aminobutyric acid (GABA)A receptor/benzodiazepine receptor/chloride ion channel complex was studied. Beta-CCE noncompetitively and competitively inhibited (3H)flunitrazepam binding to benzodiazepine receptor, but not (3H)muscimol binding to GABAA receptor as well as t-(3H)butylbicycloorthobenzoate (( 3H) TBOB) binding to chloride ion channel, in particulate fraction of the mouse brain. Ro15-1788 also inhibited competitively (3H) flunitrazepam binding. On the other hand, the binding of beta-(3H)CCE was inhibited noncompetitively and competitively by clonazepam and competitively by Ro15-1788. In agreement with these results, benzodiazepines-stimulated (3H)muscimol binding was antagonized by beta-CCE and Ro15-1788. Gel column chromatography for the solubilized fraction from cerebral particulate fraction by 0.2% sodium deoxycholate (DOC-Na) in the presence of 1 M KCl indicated that beta-(3H)CCE binding site was eluted in the same fraction (molecular weight, 250,000) as the binding sites for (3H)flunitrazepam, (3H)muscimol and (3H)TBOB. GABA-stimulated 36Cl- influx into membrane vesicles prepared from the bovine cerebral cortex was stimulated and attenuated by flunitrazepam and beta-CCE, respectively. These effects of flunitrazepam and beta-CCE on the GABA-stimulated 36Cl- influx were antagonized by Ro15-1788. The present results suggest that the binding site for beta-CCE, which resides on GABAA receptor/benzodiazepine receptor/chloride ion channel complex, may be different from that for benzodiazepine. Possible roles of beta-CCE binding site in the allosteric inhibitions on benzodiazepine binding site as well as on the functional coupling between chloride ion channel and GABAA receptor are also suggested.

  19. Expedient Protocols for the Installation of Pyrimidine Based Privileged Templates on 2-Position of Pyrrolo[2,1-c][1,4]-benzodiazepine Nucleus Linked Through a p-phenoxyl Spacer

    Directory of Open Access Journals (Sweden)

    Anshu Agarwal

    2012-01-01

    Full Text Available Exceedingly facile single step expedient protocols based on the versatility and reactivity of corresponding intermediates : [2-(dimethylaminomethylene ketone] (5 and chalcone (6, derived from 2-(p-acetyl phenoxyl substituted analogue of pyrrolo[2,1-c][1,4]-benzodiazepine (4, have been developed to provide an easy installation of the pyrimidine based privileged templates at 2-position of pyrrolo[2,1-c][1,4]-benzodiazepine through a p-phenoxyl spacer, by utilizing the synthetic strategy depicted in schemes-1 and 2.

  20. [11C]Flumazenil metabolite measurement in plasma is not necessary for accurate brain benzodiazepine receptor quantification

    International Nuclear Information System (INIS)

    Sanabria-Bohorquez, S.M.; Veraart, C.; Labar, D.; Bol, A.; Volder, A.G. de; Michel, C.; Leveque, P.

    2000-01-01

    In this work, a mathematical correction for metabolites has been validated which estimates the relative amount of [ 11 C]flumazenil ([ 11 C]FMZ) in the total plasma curve from the tissue kinetic data without the need for direct metabolite measurement in blood plasma samples. Kinetic data were obtained using a 90-min three-injection protocol on five normal volunteers. First, the relative amount of [ 11 C]FMZ in plasma was modelled by a two-parameter exponential function. The parameters were estimated either directly by fitting this model to the blood plasma metabolite measurements, or indirectly from the simultaneous fitting of tissue time activity curves from several brain regions with a non-linear FMZ kinetic model. Second, the direct and indirect metabolite corrections were fixed and the FMZ compartmental parameters were determined on a regional basis in the brain. The validation was performed by comparing the regional values of benzodiazepine receptor density B max and equilibrium dissociation constant K d obtained with the direct metabolite correction with those values obtained with the indirect correction. For B max , the correlation coefficient r 2 was above 0.97 for all subjects and the slope values of the linear regression were within the interval [0.97, 1.2]. For K d , r 2 was above 0.96, and the slope values of the linear regression were within the interval [0.99, 1.1]. Simulation studies were performed in order to evaluate whether this metabolite correction method could be used in a clinical protocol where only a single [ 11 C]FMZ injection and a linear compartmental model are used. The resulting [ 11 C]FMZ distribution volume estimates were found to be linearly correlated with the true values, with r 2 =1.0 and a slope value of 1.1. The mathematical metabolite correction proved to be a feasible and reliable method to estimate the relative amount of [ 11 C]FMZ in plasma and the compartmental model parameters for three-injection protocols. Although

  1. PET and SPECT in medically non-refractory complex partial seizures. Temporal asymmetries of glucose consumption, Benzodiazepine receptor density

    International Nuclear Information System (INIS)

    Matheja, P.; Kuwert, T.; Wolf, K.; Schober, O.; Stodieck, S.R.G.; Diehl, B.; Ringelstein, E.B.; Schuierer, G.

    1998-01-01

    Aim: In contrast to medically refractory complex partial seizures (CPS), only limited knowledge exists on cerebral perfusion and metabolism in medically non-refractory CPS. The aim of this study was to investigate the frequency of temporal asymmetries in regional cerebral glucose consumption (rCMRGlc), regional cerebral blood flow (rCBF), and regional cerebral benzodiazepine receptor density (BRD) in this group of patients. Methods: The study included 49 patients with medically non-refractory cryptogenic CPS (age: 36.0±16.1 years). rCMRGlc was studied with F-18-FDG-PET (FDG), rCBF with Tc-99m-ECD-SPECT (ECD), and BRD with I-123-iomazenil-SPECT (IMZ). All studies were performed interictally and within four weeks in each patient. Duration of epilepsy ranged from 0.1 to 42 years (median 4.0 years). SPECT was performed with the triple-headed SPECT camera Multispect 3, PET with the PET camera ECAT EXACT 47. Using linear profiles, glucose consumption, as well as uptake of ECD and IMZ, were measured in four temporal regions of interest (ROIs), and asymmetry indices were calculated (ASY). The results were compared to 95% confidence intervals determined in control subjects. Results: Thirty-five of the 49 (71%) patients had at least one significantly elevated ASY; temporal rCMRGlc was asymmetrical in 41% of the patients, temporal BRD in 29%, and temporal rCBF in 24%. One patient had an asymmetry of all three variables, two of temporal rCMRGlc and BRD, three of temporal rCMRGlc and rCBF, and another four of rCBF and BRD. Fourteen patients had an isolated temporal asymmetry in rCMRGlc, seven in BRD, and four in rCBF. A discrepancy in lateralization between the three modalities was not observed. Conclusion: The majority of patients with medically non-refractory CPS have focal abnormalities of blood flow and metabolism in their temporal lobe. In this group of patients, FDG-PET demonstrates abnormalities with the highest frequency of the three modalities studied, followed by IMZ

  2. Interactions between 2,4-bis-pteridine-1,5-benzodiazepine and group 12 dihalides: synthesis, spectral and XRD structural studies and theoretical calculations.

    Science.gov (United States)

    Illán-Cabeza, Nuria A; Jiménez-Pulido, Sonia B; Hueso-Ureña, Francisco; Peña-Ruiz, Tomás; Quirós-Olozábal, Miguel; Moreno-Carretero, Miguel N

    2016-11-28

    2,4-Bis(1,3,7-trimethyl-pteridine-2,4(1H,3H)-dione-6-yl)-2,3-dihydro-2-methyl-1H-1,5-benzodiazepine (DLMBZD) has been prepared and its molecular and crystal structures have been determined from spectral and XRD data. The benzodiazepine ligand was reacted with zinc(ii), cadmium(ii) and mercury(ii) chloride, bromide and iodide to give complexes with general formula [M(DLMBZD)X 2 ]. The complexes have been synthesized and characterized by IR, NMR and elemental analysis. The structure of seven complexes has been obtained by single crystal X-ray diffraction. In all the cases, the metal is (2 + 2 + 1)-five-coordinated by two halide ligands, two nitrogen atoms from pyrazine and diazepine rings and a carbonyl oxygen from a pteridine ring. The coordinated-metal environment is a square-based pyramid, with increasing trigonality from Hg(ii) to Zn(ii) complexes. To coordinate the metals, the ligand folds itself, establishing four intramolecular σ-π interactions with the pyrimidine and pyrazine rings. A topological analysis of the electron density using the Quantum Theory of Atoms in Molecules and the complexes stability has been performed.

  3. Regional specific binding of [11C]RO 15 1788 to central type benzodiazepine receptors in human brain: quantitative evaluation by PET

    International Nuclear Information System (INIS)

    Pappata, S.; Samson, Y.; Chavoix, C.; Prenant, C.; Maziere, M.; Baron, J.C.

    1988-01-01

    The central type benzodiazepine receptors were studied in 17 healthy human subjects with 11 C-RO 15 1788 and positron emission tomography (PET). The brain regional distribution of the tracer in eight control studies performed after injection of trace doses of 11 C-RO 15 1788 was consistent with that of benzodiazepine receptors. Saturation studies with co-injected cold RO 15 1788 in the remaining subjects showed a dose-dependent decrease of brain radiotracer until full inhibition of specific binding was achieved with doses above 0.1 mg/kg (four studies). Based on the results, a simple method to estimate the specifically bound 11 C-RO 15 1788 regionally in a single PET study is proposed, using the data from the full-saturation studies as a stable estimate of the nondisplaceable radioligand concentration. Using this method, it was found that quasiequilibrium between the estimated specifically bound and nondisplaceable components was achieved at times equal to or longer than 20 min after tracer administration. The validity of this method was partly supported by further results, showing a good agreement between the regional specific binding so calculated and postmortem data of receptor density

  4. Synthesis of [123I]iodine labelled imidazo[1,2-b] pyridazines as potential probes for the study of peripheral benzodiazepine receptors using SPECT

    International Nuclear Information System (INIS)

    Katsifis, A.; Mattner, F.; Dikic, B.; Barlin, G.

    2004-01-01

    The pyridazines 3-acetamidomethyl-6-chloro-2-(4'-iodophenyl)imidazo[1,2-b]pyridazine 1 (IC 50 = 1.6 nM) and 3-benzamidomethyl-6-iodo-2-(4'-t-butylphenyl)imidazo[1,2-b] pyridazine 2 (IC 50 = 4.2 nM), are high affinity and selective ligands for the peripheral benzodiazepine receptors (PBR) compared to the central benzodiazepine counterparts. The [ 123 I]1 and [ 123 I]2 labelled analogues of these compounds were subsequently synthesised for the potential study of the PBR in vivo using SPECT. Radioiodination of [ 123 I]1 was achieved by iododestannylation of the corresponding tributyl tin precursor with Na[ 123 I] in the presence of peracetic acid or chloramine-T and the product isolated by C-18 RP HPLC. Radioiodination of [ 123 I]2 was achieved by copper assisted bromine [ 123 I]iodine exchange of the corresponding bromo precursor in the presence of acetic acid and sodium bisulfate as reducing agent at 200 C. Purification of the crude products were achieved by semi-preparative C-18 RP HPLC to give the products in radiochemical yields > 90%. The products were obtained in > 97% chemical and radiochemical purity and with specific activities > 180 GBq/μmol. (orig.)

  5. Synthesis of [{sup 123}I]iodine labelled imidazo[1,2-b] pyridazines as potential probes for the study of peripheral benzodiazepine receptors using SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Katsifis, A.; Mattner, F.; Dikic, B. [Radiopharmaceuticals Div. ANSTO, Menai, NSW (Australia); Barlin, G. [Div. of Neurosciences, John Curtin School of Medical Research, Australian National Univ., Canberra (Australia)

    2004-07-01

    The pyridazines 3-acetamidomethyl-6-chloro-2-(4'-iodophenyl)imidazo[1,2-b]pyridazine 1 (IC{sub 50} = 1.6 nM) and 3-benzamidomethyl-6-iodo-2-(4'-t-butylphenyl)imidazo[1,2-b] pyridazine 2 (IC{sub 50} = 4.2 nM), are high affinity and selective ligands for the peripheral benzodiazepine receptors (PBR) compared to the central benzodiazepine counterparts. The [{sup 123}I]1 and [{sup 123}I]2 labelled analogues of these compounds were subsequently synthesised for the potential study of the PBR in vivo using SPECT. Radioiodination of [{sup 123}I]1 was achieved by iododestannylation of the corresponding tributyl tin precursor with Na[{sup 123}I] in the presence of peracetic acid or chloramine-T and the product isolated by C-18 RP HPLC. Radioiodination of [{sup 123}I]2 was achieved by copper assisted bromine [{sup 123}I]iodine exchange of the corresponding bromo precursor in the presence of acetic acid and sodium bisulfate as reducing agent at 200 C. Purification of the crude products were achieved by semi-preparative C-18 RP HPLC to give the products in radiochemical yields > 90%. The products were obtained in > 97% chemical and radiochemical purity and with specific activities > 180 GBq/{mu}mol. (orig.)

  6. Benzodiazepine receptor and cerebral blood flow in early Alzheimer's disease. SPECT study using 123I-Iomazenil and 123I-IMP

    International Nuclear Information System (INIS)

    Kitamura, Shin; Koshi, Yasuhiko; Komiyama, Tasuku; Sakayori, Osamu; Komaba, Yuichi; Ohyama, Masashi; Mishina, Masahiro; Tsuganesawa, Toshikazu; Terashi, Akiro

    1996-01-01

    This study was designed to investigate benzodiazepine receptors (BZR) and cerebral blood flow (CBF) in patients with early Alzheimer's disease. Imaging of BZR and measurement of CBF were performed by SPECT using 123 I-Iomazenil (IMZ) and 123 I-IMP respectively, in seven patients with early Alzheimer's disease and five patients with unilateral left cerebral infarction as controls. The values for the normal cerebral hemisphere (ratio to the contralateral cerebellum) in patients with cerebral infarction were adopted as control values. In patients with Alzheimer's disease, the CBF (ratio to cerebellum) decreased significantly in the frontal cortex and the parietal cortex compared with the control values. There was no significant difference in late IMZ SPECT counts (ratio to cerebellum) and washout (the ratio of late-to-early IMZ SPECT counts) between patients with Alzheimer's disease and the controls. However, the late IMZ SPECT counts and washout decreased in one patient with moderate dementia. There was a significant correlation between the severity of dementia and the late IMZ SPECT counts in the temporal cortex and the parietal cortex. These results suggest that benzodiazepine binding sites are relatively well preserved in patients with early Alzheimer's disease, and reduction of the CBF is caused by neuronal dysfunction rather than by neuronal loss. IMZ SPECT study is useful and necessary for clarifying the pathophysiological state in Alzheimer's disease. (author)

  7. Experiment K-6-18. Study of muscarinic and gaba (benzodiazepine) receptors in the sensory-motor cortex, hippcampus and spinal code

    Science.gov (United States)

    Daunton, N.; Damelio, F.; Krasnov, I.

    1990-01-01

    Frontal lobe samples of rat brains flown aboard Cosmos 1887 were processed for the study of muscarinic (cholinergic) and GABA (benzodiazepine) receptors and for immunocytochemical localization of the neurotransmitter gamma-aminobutyric acid (GABA) and glial fibrillary acidic protein (GFAP). Although radioactive labeling of both muscarinic cholinergic and GABA (benzodiazepine) receptors proved to be successful with the techniques employed, distinct receptor localization of individual laminae of the frontal neocortex was not possible since the sampling of the area was different in the various groups of animals. In spite of efforts made for proper orientation and regional identification of laminae, it was found that a densitometric (quantitation of autoradiograms) analysis of the tissue did not contribute to the final interpretation of the effects of weightlessness on these receptors. As to the immunocytochemical studies the use of both markers, GFAP and GABA antiserum, confirmed the suitability of the techniques for use in frozen material. However, similar problems to those encountered in the receptor studies prevented an adequate interpretation of the effects of micro-G exposure on the localization and distribution of GABA and GFAP. This study did, however, confirm the feasibility of investigating neurotransmitters and their receptors in future space flight experiments.

  8. Pregabalin versus SSRIs and SNRIs in benzodiazepine-refractory outpatients with generalized anxiety disorder: a post hoc cost-effectiveness analysis in usual medical practice in Spain

    Directory of Open Access Journals (Sweden)

    De Salas-Cansado M

    2012-06-01

    Full Text Available Marina De Salas-Cansado,1 José M Olivares,2 Enrique Álvarez,3 Jose L Carrasco,4 Andoni Barrueta,5 Javier Rejas,51Trial Form Support Spain, Madrid; 2Department of Psychiatry, Hospital Meixoeiro, Complejo Hospitalario Universitario, Vigo; 3Department of Psychiatry, Hospital de la Santa Creu i San Pau, Barcelona; 4Department of Psychiatry, Hospital Clínico San Carlos, Madrid; 5Health Outcomes Research Department, Medical Unit, Pfizer Spain, Alcobendas, Madrid, SpainBackground: Generalized anxiety disorder (GAD is a prevalent health condition which seriously affects both patient quality of life and the National Health System. The aim of this research was to carry out a post hoc cost-effectiveness analysis of the effect of pregabalin versus selective serotonin reuptake inhibitors (SSRIs/serotonin norepinephrine reuptake inhibitors (SNRIs in treated benzodiazepine-refractory outpatients with GAD.Methods: This post hoc cost-effectiveness analysis used secondary data extracted from the 6-month cohort, prospective, noninterventional ADAN study, which was conducted to ascertain the cost of illness in GAD subjects diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Benzodiazepine-refractory subjects were those who claimed persistent symptoms of anxiety and showed a suboptimal response (Hamilton Anxiety Rating Scale ≥16 to benzodiazepines, alone or in combination, over 6 months. Patients could switch to pregabalin (as monotherapy or addon or to an SSRI or SNRI, alone or in combination. Effectiveness was expressed as quality-adjusted life years gained, and the perspective was that of the National Health System in the year 2008. A sensitivity analysis was performed using bootstrapping techniques (10,000 resamples were obtained in order to obtain a cost-effectiveness plane and a corresponding acceptability curve.Results: A total of 282 subjects (mean Hamilton Anxiety Rating Scale score 25.8 were

  9. Prescription of anorectic and benzodiazepine drugs through notification B prescriptions in Natal, Rio Grande do Norte, Brazil

    Directory of Open Access Journals (Sweden)

    Solange Aparecida Nappo

    2010-06-01

    Full Text Available A study was conducted on 22,158 special B prescriptions (notificações B containing amphetamine-type anorectic drugs or benzodiazepines, obtained from compounding pharmacies or drugstores located in the city of Natal, RN, Brazil. The data obtained were compared with those from other Brazilian cities. Results showed that compounding pharmacies dispensed 85.4% of the prescriptions, indicating that these pharmacies filled out nearly 10 times more of these prescriptions than did the drugstores. The majority (83.5% of B prescriptions issued for the compounding pharmacies were for women, where the female/male patient ratio ranged from 7.1/1.0 for mazindol to 10.3/1.0 for amfepramone. Similar results were obtained for the benzodiazepines with ratios of 1.9/1.0 for clonazepam to 15.6/1.0 for oxazepam. Omissions and mistakes were present in the B prescriptions, including missing information about the patient (in 49.6% of the documents or about the pharmacies or drugstores (50.4%. There were cases where the name and/or CRM of the physician was lacking. It was noted that one medical doctor made out 1855 B prescriptions within one year. The same patient's name appeared on 138 prescriptions, and the same RG (identification card number was present in 125 others. Comparison of Natal's data with those of several other Brazilian cities disclosed a striking similarity throughout Brazil, from Pelotas - Rio Grande do Sul State to Belem-Para State, revealing a practically identical medical/pharmaceutical behavior. This pattern of prescription/dispensation of amphetamine-type substances mostly to women for weight loss is therefore for cosmetic reasons. Consequently, there is an urgent need for an ethical review of this behavior.Foram examinadas 22.158 notificações B contendo substâncias anoréticas tipo-anfetamina ou de benzodiazepínicos, obtidas de drogarias e de farmácias de manipulação. Os dados foram comparados com os de outras cidades do Brasil, obtendo

  10. Benzodiazepines and Opioid

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  11. Effect of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of calcium channel blockers

    Directory of Open Access Journals (Sweden)

    P. A. Virych

    2017-05-01

    Full Text Available The development of modern organic chemistry and molecular modeling technologies simplify the search for potential inhibitors of various receptor systems and biological processes. The one of the directions is the development of analgesics of broad spectrum and low toxicity. It is important to search for inhibitors of the kinin-kallikrein system that regulates many functions: inflammation, pain, carcinogenesis, vascular tone, smooth muscle contraction and other. Derivatives of 3-substituted 1,4-benzodiazepine-2-ones have a unique spatial conformation that allows one to simulate β-structures of bioactive peptides. The functional activity of compounds is determined by properties of their peripheral chemical radicals. We analyzed the effect of 3-substituted 1,4-benzodiazepin-2-ones derivatives on the normalized maximal rate of bradykinin-induced smooth muscle contraction and relaxation of the stomach in the presence of calcium channel blockers: verapamil (1 μM, gadolinium (300 μM and 2-aminoethyl diphenylborinate (0.1 μM. The levels of bradykinin and 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones in incubation solution were 10–6 M. Data processing on dynamics of contraction was performed according to the method of Burdyha and Kosterin. Compounds MX-1775 and MX-1925 reduced maximal normalized rate (Vn of bradykinin-induced smooth muscle contraction in the presence of Gd3+ by 21.2% and 31.0% respectively. Compound MX-1925 increased Vn of relaxation by 11.6%. A similar effect is typical for MX-2011, where there is an increase by 34.6%. In the presence of verapamil this compound additionally decreased Vn contraction by 20.5%. Substances MX-1775, MX-2004 and MX-1925 restored maximal normalized rate of relaxation to original values of bradykinin-induced contraction. In the presence of 2-aminoethyldiphenylborinate MX-1775 additionally reduced Vn of contractions by 7.5%. 3-substituted 1,4-benzo­diazepine-2-ones did not change the maximal

  12. The effects of benzodiazepine (triazolam), cyclopyrrolone (zopiclone) and imidazopyridine (zolpidem) hypnotics on the frequency of hippocampal theta activity and sleep structure in rats.

    Science.gov (United States)

    Yoshimoto, M; Higuchi, H; Kamata, M; Yoshida, K; Shimizu, T; Hishikawa, Y

    1999-01-01

    In order to investigate the relative efficacy and safety of zopiclone and zolpidem, we compared the effects of higher doses of zopiclone and zolpidem on the frequency of hippocampal theta activity and sleep structure with that of triazolam. Rats were divided into triazolam treatment group (1 mg/kg, 5 mg/kg), zopiclone treatment group (20 mg/kg, 100 mg/kg) and zolpidem treatment group (20 mg/kg, 100 mg/kg). Rats were injected intraperitoneally with these drugs or their vehicle. Polygraphic sleep recording and visual frequency analysis of the hippocampal EEG activity in REM sleep were carried out for 6 h after each injection. Zolpidem, unlike triazolam and zopiclone, had a much milder reducing-effect on the frequency of hippocampal theta activity and suppressing-effect on REM sleep. These results suggest that zolpidem may prove to be a safer hypnotic drug which has fewer or milder side effects than are benzodiazepine and cyclopyrrolone hypnotics.

  13. PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Vowinckel, E; Reutens, D; Becher, B

    1997-01-01

    Activated glial cells are implicated in regulating and effecting the immune response that occurs within the CNS as part of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). The peripheral benzodiazepine receptor (PBR) is expressed in glial cells. We...... examined the utility of using in vitro and in vivo ligand binding to the PBR as a measure of lesion activity in autoimmune CNS demyelinating diseases. Applying a combined autoradiography and immunohistochemical approach to spinal cord and brain tissues from mice with EAE, we found a correlation at sites...... of inflammatory lesions between [3H]-PK11195 binding and immunoreactivity for the activated microglial/macrophage marker Mac-1/CD11b. In MS tissues, [3H]-PK11195 binding correlated with sites of immunoreactivity for the microglial/macrophage marker CD68, at the edges of chronic active plaques. Positron emission...

  14. Detection of viable cortical neurons using benzodiazepine receptor imaging after reversible focal ischaemia in rats: comparison with regional cerebral blood flow

    International Nuclear Information System (INIS)

    Watanabe, Yoshiyuki; Nakano, Takayuki; Yutani, Kenji; Nishimura, Hiroshi; Nishimura, Tsunehiko; Kusuoka, Hideo; Nakamura, Hironobu

    2000-01-01

    To elucidate the utility of benzodiazepine receptor imaging for the detection of viable cortical neurons, dual-tracer autoradiography using iodine-125 iomazenil (IMZ) and iodine-123 N-isopropyl-4-iodoamphetamine (IMP) was performed in a model of reversible focal ischaemia during the acute and subacute phases. The right middle cerebral artery of anaesthetized rats was occluded for 60 min using an intraluminal filament and reperfused. In the acute phase study, 125 I-IMZ (370 kBq) was injected via the femoral vein at 2 h after reperfusion, and 123 I-IMP (37 MBq) was injected at 50 min post-injection. Rats were sacrificed 10 min after the injection of 123 I-IMP. In the subacute phase study, the same procedure was performed at 5 days after reperfusion. In the acute phase, the IMP uptake was significantly decreased in almost all areas of the lesioned hemisphere, an exception being the cerebellum; however, the IMZ uptake was significantly decreased only in ischaemic cores. The discrepancy between IMZ and IMP uptake was observed in the lateral neocortex and the lateral caudate putamen (CPu), which were most frequently damaged in this ischaemic model. In the subacute phase, the IMZ uptake in lesioned rats was significantly decreased only in the parietal lobe and hippocampus, though the IMP uptake was decreased in many regions of lesioned hemispheres (the frontal, parietal cortex, CPu, hippocampus and thalamus). Histopathological findings indicated that both the IMP and the IMZ uptake was markedly decreased in necrotic areas. Although the IMP uptake was significantly decreased in the ischaemic areas, the IMZ uptake was maintained in these areas. These results suggest that benzodiazepine receptor imaging is superior to regional cerebral blood flow imaging for the detection of viable cortical neurons in both the acute and subacute phases of ischaemia. (orig.)

  15. Evaluation of anti-hyperalgesic and analgesic effects of two benzodiazepines in human experimental pain: a randomized placebo-controlled study.

    Directory of Open Access Journals (Sweden)

    Pascal H Vuilleumier

    Full Text Available Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain.In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo. The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation, and pain during cuff algometry.For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001, but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed.Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental

  16. Detection of viable cortical neurons using benzodiazepine receptor imaging after reversible focal ischaemia in rats: comparison with regional cerebral blood flow

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, Yoshiyuki [Dept. of Radiology, Osaka National Hospital (Japan); Nakano, Takayuki; Yutani, Kenji; Nishimura, Hiroshi; Nishimura, Tsunehiko [Div. of Tracer Kinetics, Osaka University Medical School (Japan); Kusuoka, Hideo [Clinical Research Institute, Osaka National Hospital (Japan); Nakamura, Hironobu [Dept. of Radiology, Osaka University Medical School (Japan)

    2000-03-01

    To elucidate the utility of benzodiazepine receptor imaging for the detection of viable cortical neurons, dual-tracer autoradiography using iodine-125 iomazenil (IMZ) and iodine-123 N-isopropyl-4-iodoamphetamine (IMP) was performed in a model of reversible focal ischaemia during the acute and subacute phases. The right middle cerebral artery of anaesthetized rats was occluded for 60 min using an intraluminal filament and reperfused. In the acute phase study, {sup 125}I-IMZ (370 kBq) was injected via the femoral vein at 2 h after reperfusion, and {sup 123}I-IMP (37 MBq) was injected at 50 min post-injection. Rats were sacrificed 10 min after the injection of {sup 123}I-IMP. In the subacute phase study, the same procedure was performed at 5 days after reperfusion. In the acute phase, the IMP uptake was significantly decreased in almost all areas of the lesioned hemisphere, an exception being the cerebellum; however, the IMZ uptake was significantly decreased only in ischaemic cores. The discrepancy between IMZ and IMP uptake was observed in the lateral neocortex and the lateral caudate putamen (CPu), which were most frequently damaged in this ischaemic model. In the subacute phase, the IMZ uptake in lesioned rats was significantly decreased only in the parietal lobe and hippocampus, though the IMP uptake was decreased in many regions of lesioned hemispheres (the frontal, parietal cortex, CPu, hippocampus and thalamus). Histopathological findings indicated that both the IMP and the IMZ uptake was markedly decreased in necrotic areas. Although the IMP uptake was significantly decreased in the ischaemic areas, the IMZ uptake was maintained in these areas. These results suggest that benzodiazepine receptor imaging is superior to regional cerebral blood flow imaging for the detection of viable cortical neurons in both the acute and subacute phases of ischaemia. (orig.)

  17. A fast liquid chromatography-tandem mass spectrometry method for determining benzodiazepines and analogues in urine. Validation and application to real cases of forensic interest.

    Science.gov (United States)

    Salomone, Alberto; Gerace, Enrico; Brizio, Paola; Gennaro, M Carla; Vincenti, Marco

    2011-11-01

    A fast liquid chromatographic/tandem mass spectrometric method was developed for the simultaneous determination in human urine of seventeen benzodiazepines, four relevant metabolites together plus zolpidem and zopiclone. The sample preparation, optimized to take into account the matrix effect, was based on enzymatic hydrolysis and liquid-liquid extraction. The separation of the twenty-three analytes was achieved in less than eight minutes. The whole methodology was fully validated according to UNI EN ISO/IEC 17025:2005 rules and 2006 SOFT/AAFS guidelines. Selectivity, linearity range, identification (LOD) and quantitation (LOQ) limits, precision, accuracy and recovery were evaluated. For all the species the signal/concentration linearity was satisfactory in the 50-1000 ng/mL concentration range. The limits of detection ranged from 0.5 to 30 ng/mL and LOQs from 1.7 to 100.0 ng/mL. Precisions were in the ranges 5.0-11.8%, 1.5-11.0% and 1.1-4.4% for low (100 ng/mL), medium (300 ng/mL) and high (1000 ng/mL) concentration, respectively. The accuracy, expressed as bias% was within ± 25 % for all the analytes. The recovery values, evaluated at 300 ng/mL concentration, ranged from 56.2% to 98.8%. The present method for the determination of several benzodiazepines, zolpidem and zopiclone in human urine proved to be simple, fast, specific and sensitive. The quantification by LC-MS/MS was successfully applied to 329 forensic cases among driving re-licensing, car accidents and alleged sexual violence cases. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Effects of the benzodiazepine antagonists RO 15-1788, CGS-8216 and PK-11195 on amygdaloid kindled seizures and the anticonvulsant efficacy of diazepam.

    Science.gov (United States)

    Albertson, T E; Walby, W F

    1986-11-01

    The anticonvulsant effectiveness of the benzodiazepine antagonists RO 15-1788, CGS-8216 and PK-11195 were evaluated against threshold and suprathreshold (400 microA) stimulation in fully amygdaloid-kindled rats. Pretreatment with either RO 15-1788 (3, 10 and 30 mg/kg), CGS-8216 (3, 10 and 30 mg/kg) or PK-11195 (10 and 60 mg/kg) failed in this study to modify consistently either the afterdischarge thresholds or elicited suprathreshold seizures or duration of afterdischarge. Using a double injection paradigm, the effectiveness of these three benzodiazepine antagonists to reverse the anti-convulsant and behavioral effects of diazepam were studied. When diazepam (3 mg/kg) was injected 15 min before or after a second injection of the vehicle control DMSO (0.25 ml/kg), a significant reduction in the duration of afterdischarge and seizure rank, elicited by a suprathreshold stimulation in amygdaloid-kindled rats, occurred. When either CGS 8216 (10 mg/kg) or RO 15-1788 (10 mg/kg) were given 15 min before diazepam (3 mg/kg) prior to stimulation, the anticonvulsant properties of diazepam were blocked. When RO 15-1788 (10 mg/kg) was given 15 min after diazepam, antagonism of the anticonvulsant effects on diazepam was shown. However, when either CGS-8216 (10 mg/kg) or PK-11195 (10 and 60 mg/kg) were given 15 min after diazepam (3 mg/kg), the anticonvulsant properties of diazepam were not blocked. The anticonvulsant effects of diazepam were reversed when CGS-8216 (10 mg/kg) was given 5 min after diazepam (3 mg/kg) or when a larger dose (30 mg/kg) was given at the same 15 min interval.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Synthesis of [[sup 123]I]tert-Butyl 8-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiaze pine 3-carboxylate, a potential SPECT imaging agent for diazepam-intensive (DI) benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    He, Xiaoshu; Matecka, Dorota; Gu, Ziqiang; Rice, K C; Costa, B.R. de [National Inst. of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (United States); Lee, K S [National Inst. of Mental Health, Washington, DC (United States); Wong, Garry; Skolnick, Phil [National Inst. of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (United States). Lab. of Neuroscience

    1994-01-01

    [[sup 123]I]tert-Butyl 8-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4]benzodiazepine 3-carboxylate ([[sup 123]I]3), a high affinity and selective radioligand for the diazepam insensitive (DI) benzodiazepine receptor was synthesized in 2 steps from tert-butyl 8-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiaz epine 3-carboxylate. (Author).

  20. A validated method for simultaneous screening and quantification of twenty-three benzodiazepines and metabolites plus zopiclone and zaleplone in whole blood by liquid-liquid extraction and ultra-performance liquid chromatography- tandem mass spectrometry

    DEFF Research Database (Denmark)

    Simonsen, Kirsten Wiese; Hermansson, Sigurd; Steentoft, Anni

    2010-01-01

    , oxazepam, temazepam, triazolam, zaleplon, and zopiclone. Whole blood from drug-free volunteers was used for all experiments. Blood samples (0.200 g) were extracted with ethyl acetate at pH 9. Target drugs were quantified using a Waters ACQUITY UPLC system coupled to a Waters Quattro Premier XE triple......An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method for detection of 23 benzodiazepines and related compounds in whole blood was developed and validated. The method is used for screening and quantitation of benzodiazepines in whole blood received from autopsy...... quadrupole in positive electrospray ionization, multiple reaction monitoring mode. The use of deuterated internal standards for most compounds verified that the accuracy of the method was not influenced by matrix effects. Extraction recoveries were 73-108% for all analytes. Lower limits of quantification...

  1. Effect of 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones on the bradykinin-induced smooth muscle contraction

    Directory of Open Access Journals (Sweden)

    P. A. Virych

    2017-01-01

    Full Text Available Damage to tissue, inflammation and disruption of normal functioning of organs are often accompanied by pain. In pain perceptions, the kinin-kallikrein system with bradykinin as mediator is very important. Regulatory activity of the kinin-kallikrein system permits the control of inflammation, pain, vascular tone and other functions. A new group of substances that may used for this purpose are 3-substituted 1,4-benzdiazepinones. We analyzed the effect of 3-aryl amino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones derivatives on the normalized maximal rate of bradykinin-induced smooth muscle contraction of the stomach in the presence of calcium channel blockers verapamil (1 μM and gadolinium (300 μM. The levels of bradykinin and 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones in the incubation solution were 10–6 M. Data processing on the dynamics of contraction was performed according to the method of T. Burdyha and S. Kosterin. Statistically significant changes were found for MX-1828. This compound reduced the maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of Gd3+ and verapamil by 19.3% and 32.0%, respectively. Also, MX-1828 demonstrated effects similar to those of the competitive inhibitor bradykinin B2-receptor – des-Arg9-bradykinin-acetate, which is possible evidence of its interaction with the receptor or signal transduction pathways. MX-1828 additionally reduced the maximum normalized rate of relaxation by 6.2% in the presence of Gd3+. This effect was demonstrated for MX-1906 in the presence of verapamil with additional reduction of the maximal normalized rate of relaxation, which was 26.4%. The results suggest the presence of inhibitory interaction between MX-1828 and kinin-kallikrein system receptors or signal transduction pathways. The effects which were found for MX-1906 require further studies to clarify the mechanisms of influence on bradykinin-induced smooth muscle contraction.

  2. Different sensitivities to competitive inhibition of benzodiazepine receptor binding of {sup 11}C-iomazenil and {sup 11}C-flumazenil in rhesus monkey brain

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Osamu; Hosoi, Rie; Kobayashi, Kaoru [Osaka Univ., Suita (Japan). Medical School; Itoh, Takashi; Gee, A.; Suzuki, Kazutoshi

    2001-04-01

    The in vivo binding kinetics of {sup 11}C-iomazenil were compared with those of {sup 11}C-flumazenil binding in rhesus monkey brain. The monkey was anesthetized with ketamine and intravenously injected with either {sup 11}C-iomazenil or {sup 11}C-flumazenil in combination with the coadministration of different doses of non-radioactive flumazenil (0, 5 and 20 {mu}g/kg). The regional distribution of {sup 11}C-iomazenil in the brain was similar to that of {sup 11}C-flumazenil, but the sensitivity of {sup 11}C-iomazenil binding to competitive inhibition by non-radioactive flumazenil was much less than that of {sup 11}C-flumazenil binding. A significant reduction in {sup 11}C-flumazenil binding in the cerebral cortex was observed with 20 {mu}g/kg of flumazenil, whereas a relatively smaller inhibition of {sup 11}C-iomazenil binding in the same region was observed with the same dose of flumazenil. These results suggest that {sup 11}C-flumazenil may be a superior radiotracer for estimating benzodiazepine receptor occupancy in the intact brain. (author)

  3. Radiosynthesis and in vivo evaluation of N-[{sup 11}C]methylated imidazopyridineacetamides as PET tracers for peripheral benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Sekimata, Katsuhiko [Department of Brain Sciences and Molecular Imaging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522 (Japan); Hatano, Kentaro [Department of Brain Sciences and Molecular Imaging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522 (Japan)], E-mail: hatanok@nils.go.jp; Ogawa, Mikako [Photon Medical Research Center, Hamamatsu University School of Medicine, Shizuoka 431-3192 Japan (Japan); Abe, Junichiro [Department of Brain Sciences and Molecular Imaging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522 (Japan); Magata, Yasuhiro [Photon Medical Research Center, Hamamatsu University School of Medicine, Shizuoka 431-3192 Japan (Japan); Biggio, Giovanni; Serra, Mariangela [Department of Experimental Biology, University of Cagliari, Cagliari 09100 (Italy); Laquintana, Valentino; Denora, Nunzio; Latrofa, Andrea; Trapani, Giuseppe; Liso, Gaetano [Pharmaco-Chemistry Department, University of Bari, Bari 70125 (Italy); Ito, Kengo [Department of Brain Sciences and Molecular Imaging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522 (Japan)

    2008-04-15

    Imidazopyridineacetoamide 5-8, a series of novel and potentially selective peripheral benzodiazepine receptor (PBR) ligands with affinities comparable to those of known PBR ligands, was investigated. Radiosyntheses of [{sup 11}C]5, 6, 7 or 8 was accomplished by N-methylation of the corresponding desmethyl precursors with [{sup 11}C]methyl iodide in the presence of NaH in dimethylformamide (DMF), resulting in 25% to 77% radiochemical yield and specific activitiy of 20 to 150 MBq/nmol. Each of the labeled compounds was injected in ddY mice, and the radioactivity and weight of dissected peripheral organs and brain regions were measured. Organ distribution of [{sup 11}C]7 was consistent with the known PBR distribution. Moreover, [{sup 11}C]7 showed the best combination of brain uptake and PBR binding, leading to its high retention in the olfactory bulb and cerebellum, areas where PBR density is high in mouse brain. Coinjection of PK11195 or unlabeled 7 significantly reduced the brain uptake of [{sup 11}C]7. These results suggest that [{sup 11}C]7 could be a useful radioligand for positron emission tomography imaging of PBRs.

  4. The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: a pilot [(11)C]Ro15-4513 positron emission tomography study.

    Science.gov (United States)

    Mendez, Maria Andreina; Horder, Jamie; Myers, Jim; Coghlan, Suzanne; Stokes, Paul; Erritzoe, David; Howes, Oliver; Lingford-Hughes, Anne; Murphy, Declan; Nutt, David

    2013-05-01

    GABA (gamma-amino-butyric-acid) is the primary inhibitory neurotransmitter in the human brain. It has been proposed that the symptoms of autism spectrum disorders (ASDs) are the result of deficient GABA neurotransmission, possibly including reduced expression of GABAA receptors. However, this hypothesis has not been directly tested in living adults with ASD. In this preliminary investigation, we used Positron Emission Tomography (PET) with the benzodiazepine receptor PET ligand [(11)C]Ro15-4513 to measure α1 and α5 subtypes of the GABAA receptor levels in the brain of three adult males with well-characterized high-functioning ASD compared with three healthy matched volunteers. We found significantly lower [(11)C]Ro15-4513 binding throughout the brain of participants with ASD (p < 0.0001) compared with controls. Planned region of interest analyses also revealed significant reductions in two limbic brain regions, namely the amygdala and nucleus accumbens bilaterally. Further analysis suggested that these results were driven by lower levels of the GABAA α5 subtype. These results provide initial evidence of a GABAA α5 deficit in ASD and support further investigations of the GABA system in this disorder. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Differential effect of detergents on [3H]Ro 5-4864 and [3H]PK 11195 binding to peripheral-type benzodiazepine-binding sites

    International Nuclear Information System (INIS)

    Awad, M.; Gavish, M.

    1988-01-01

    The present study demonstrates a differential effect of various detergent treatments on [ 3 H]Ro 5-4864 and [ 3 H]PK 11195 binding to peripheral benzodiazepine binding sites (PBS). Triton X-100 caused a decrease of about 70% in [ 3 H]Ro 5-4864 binding to membranes from various peripheral tissues of rat, but had only a negligible effect on [ 3 H]PK 11195 binding. A similar effect of Triton X-100 was observed on guinea pig and rabbit kidney membranes. The decrease in [ 3 H]Ro 5-4864 binding after treatment with Triton X-100 was apparently due to a decrease in the density of PBS, since the affinity remained unaltered. The detergents 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate (CHAPS), Tween 20, deoxycholic acid, or digitonin (0.0125%) caused only a minor change in [ 3 H]Ro 5-4864 and [ 3 H]PK 11195 binding to rat kidney membranes; but when concentrations were substantially increased (0.1%), all detergents caused a decrease of at least 50% in [ 3 H]Ro 5-4864 binding, while [ 3 H]PK 11195 binding to rat kidney membranes remained unaffected by the first three detergents, with only a minor decrease (15%) after treatment with digitonin

  6. Assessment of cerebral benzodiazepine receptor distribution in anxiety disorders by 123I-iomazenil-SPECT. Comparison to cerebral perfusion scintigraphy by 123I-IMP

    International Nuclear Information System (INIS)

    Uchiyama, Mayuki; Sue, Hironari; Fukumitsu, Nobuyoshi; Mori, Yutaka; Kawakami, Kenji

    1997-01-01

    123 I-Iomazenil ( 123 I-IMZ) and 123 I-IMP imaging were performed in 5 patients with anxiety disorder (PAD) and 6 normal volunteers (NV). On 123 I-IMZ delayed imaging, the 2 PAD showed abnormally decreased findings. In anxiety disorder, decreased accumulation on 123 I-IMZ delayed images was seen in left hippocampus and parahippocampal gyrus in one patient, in right frontal and temporal lobe and left occipital pole in the other. Compared with NV, PAD had lower 123 I-IMZ uptake on delayed image in right upper and left lower frontal cortices, indicating the involvement of the benzodiazepine receptor complex in anxiety disorder. Compared with grading for anxiety disorder with Hamilton anxiety scale (HAS) and delayed to early count ratios of 123 I-IMZ, negative correlation (R 123 I-IMP image, positive correlation (R>0.7) was recognized in the hippocampus, the parahippocampal gyrus, the lower outer temporal cortex and the lower frontal cortex. (author)

  7. Structural basis for ligand recognition at the benzodiazepine binding site of GABAA alpha 3 receptor, and pharmacophore-based virtual screening approach.

    Science.gov (United States)

    Vijayan, R S K; Ghoshal, Nanda

    2008-10-01

    Given the heterogeneity of GABA(A) receptor, the pharmacological significance of identifying subtype selective modulators is increasingly being recognized. Thus, drugs selective for GABA(A) alpha(3) receptors are expected to display fewer side effects than the drugs presently in clinical use. Hence we carried out 3D QSAR (three-dimensional quantitative structure-activity relationship) studies on a series of novel GABA(A) alpha(3) subtype selective modulators to gain more insight into subtype affinity. To identify the 3D functional attributes required for subtype selectivity, a chemical feature-based pharmacophore, primarily based on selective ligands representing diverse structural classes was generated. The obtained pseudo receptor model of the benzodiazepine binding site revealed a binding mode akin to "Message-Address" concept. Scaffold hopping was carried out across multi-conformational May Bridge database for the identification of novel chemotypes. Further a focused data reduction approach was employed to choose a subset of enriched compounds based on "Drug likeness" and "Similarity-based" methods. These results taken together could provide impetus for rational design and optimization of more selective and high affinity leads with a potential to have decreased adverse effects.

  8. Rapid and efficient radiosynthesis of [{sup 123}I]I-PK11195, a single photon emission computed tomography tracer for peripheral benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Pimlott, Sally L. [Department of Clinical Physics, West of Scotland Radionuclide Dispensary, Western Infirmary, G11 6NT Glasgow (United Kingdom)], E-mail: s.pimlott@clinmed.gla.ac.uk; Stevenson, Louise [Department of Chemistry, WestCHEM, University of Glasgow, G12 8QQ Glasgow (United Kingdom); Wyper, David J. [Institute of Neurological Sciences, Southern General Hospital, G51 4TF Glasgow (United Kingdom); Sutherland, Andrew [Department of Chemistry, WestCHEM, University of Glasgow, G12 8QQ Glasgow (United Kingdom)

    2008-07-15

    Introduction: [{sup 123}I]I-PK11195 is a high-affinity single photon emission computed tomography radiotracer for peripheral benzodiazepine receptors that has previously been used to measure activated microglia and to assess neuroinflammation in the living human brain. This study investigates the radiosynthesis of [{sup 123}I]I-PK11195 in order to develop a rapid and efficient method that obtains [{sup 123}I]I-PK11195 with a high specific activity for in vivo animal and human imaging studies. Methods: The synthesis of [{sup 123}I]I-PK11195 was evaluated using a solid-state interhalogen exchange method and an electrophilic iododestannylation method, where bromine and trimethylstannyl derivatives were used as precursors, respectively. In the electrophilic iododestannylation method, the oxidants peracetic acid and chloramine-T were both investigated. Results: Electrophilic iododestannylation produced [{sup 123}I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than achievable using the halogen exchange method investigated. Using chloramine-T as oxidant provided a rapid and efficient method of choice for the synthesis of [{sup 123}I]I-PK11195. Conclusions: [{sup 123}I]I-PK11195 has been successfully synthesized via a rapid and efficient electrophilic iododestannylation method, producing [{sup 123}I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than previously achieved.

  9. Rapid and efficient radiosynthesis of [123I]I-PK11195, a single photon emission computed tomography tracer for peripheral benzodiazepine receptors

    International Nuclear Information System (INIS)

    Pimlott, Sally L.; Stevenson, Louise; Wyper, David J.; Sutherland, Andrew

    2008-01-01

    Introduction: [ 123 I]I-PK11195 is a high-affinity single photon emission computed tomography radiotracer for peripheral benzodiazepine receptors that has previously been used to measure activated microglia and to assess neuroinflammation in the living human brain. This study investigates the radiosynthesis of [ 123 I]I-PK11195 in order to develop a rapid and efficient method that obtains [ 123 I]I-PK11195 with a high specific activity for in vivo animal and human imaging studies. Methods: The synthesis of [ 123 I]I-PK11195 was evaluated using a solid-state interhalogen exchange method and an electrophilic iododestannylation method, where bromine and trimethylstannyl derivatives were used as precursors, respectively. In the electrophilic iododestannylation method, the oxidants peracetic acid and chloramine-T were both investigated. Results: Electrophilic iododestannylation produced [ 123 I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than achievable using the halogen exchange method investigated. Using chloramine-T as oxidant provided a rapid and efficient method of choice for the synthesis of [ 123 I]I-PK11195. Conclusions: [ 123 I]I-PK11195 has been successfully synthesized via a rapid and efficient electrophilic iododestannylation method, producing [ 123 I]I-PK11195 with a higher isolated radiochemical yield and a higher specific activity than previously achieved

  10. Preserved benzodiazepine receptors in Alzheimer's disease measured with C-11 flumazenil PET and I-123 iomazenil SPECT in comparison with CBF

    International Nuclear Information System (INIS)

    Ohyama, Masashi; Kitamura, Shin; Mishina, Masahiro; Katayama, Yasuo; Senda, Michio; Ishiwata, Kiichi; Ishii, Kenji; Toyama, Hinako; Oda, Keiichi

    1999-01-01

    This study evaluates the regional cerebral blood flow (CBF) with H 2 15 O-PET and the distribution of central benzodiazepine receptor (BZR) with C-11 flumazenil (FMZ) by PET and I-123 iomazenil (IMZ) by SPECT in Alzheimer's disease (AD). In AD, whereas the CBF was diminished in the frontal, temporal, parietal, and occipital cortex, the distribution volume of FMZ and delayed activity of IMZ were relatively preserved in these cortices, suggesting that the BZR reduction, reflecting neuronal loss, is less prominent than the CBF suppression. The mini-mental state examination score (MMS) was weakly correlated with the CBF in the parietal cortex but not with BZR. It is speculated that the neuronal density reflected by BZR is less impaired than the neuronal function assessed with blood flow in the association cortex of AD. High correlation was found between the uptake of FMZ and the delayed activity of IMZ. The delayed image of IMZ-SPECT is clinically useful to evaluate the preservation of neuronal density in the affected temoporoparietal association cortex in AD. (author)

  11. Assessment of cerebral benzodiazepine receptor distribution in anxiety disorders by {sup 123}I-iomazenil-SPECT. Comparison to cerebral perfusion scintigraphy by {sup 123}I-IMP

    Energy Technology Data Exchange (ETDEWEB)

    Uchiyama, Mayuki; Sue, Hironari; Fukumitsu, Nobuyoshi; Mori, Yutaka; Kawakami, Kenji [Jikei Univ., Tokyo (Japan). School of Medicine

    1997-01-01

    {sup 123}I-Iomazenil ({sup 123}I-IMZ) and {sup 123}I-IMP imaging were performed in 5 patients with anxiety disorder (PAD) and 6 normal volunteers (NV). On {sup 123}I-IMZ delayed imaging, the 2 PAD showed abnormally decreased findings. In anxiety disorder, decreased accumulation on {sup 123}I-IMZ delayed images was seen in left hippocampus and parahippocampal gyrus in one patient, in right frontal and temporal lobe and left occipital pole in the other. Compared with NV, PAD had lower {sup 123}I-IMZ uptake on delayed image in right upper and left lower frontal cortices, indicating the involvement of the benzodiazepine receptor complex in anxiety disorder. Compared with grading for anxiety disorder with Hamilton anxiety scale (HAS) and delayed to early count ratios of {sup 123}I-IMZ, negative correlation (R<-0.7) was recognized hippocampus and parahippocampal gyrus, frontal and occipital cortices. Compared between HAS and the count ratio to the cerebellum on {sup 123}I-IMP image, positive correlation (R>0.7) was recognized in the hippocampus, the parahippocampal gyrus, the lower outer temporal cortex and the lower frontal cortex. (author)

  12. Reduced binding potential of GABA-A/benzodiazepine receptors in individuals at ultra-high risk for psychosis: an [18F]-fluoroflumazenil positron emission tomography study.

    Science.gov (United States)

    Kang, Jee In; Park, Hae-Jeong; Kim, Se Joo; Kim, Kyung Ran; Lee, Su Young; Lee, Eun; An, Suk Kyoon; Kwon, Jun Soo; Lee, Jong Doo

    2014-05-01

    Altered transmission of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter, may contribute to the development of schizophrenia. The purpose of the present study was to investigate the presence of GABA-A/benzodiazepine (BZ) receptor binding abnormalities in individuals at ultra-high risk (UHR) for psychosis in comparison with normal controls using [(18)F]-fluoroflumazenil (FFMZ) positron emission tomography (PET). In particular, we set regions of interest in the striatum (caudate, putamen, and nucleus accumbens) and medial temporal area (hippocampus and parahippocampal gyrus). Eleven BZ-naive people at UHR and 15 normal controls underwent PET scanning using [(18)F]-FFMZ to measure GABA-A/BZ receptor binding potential. The regional group differences between UHR individuals and normal controls were analyzed using Statistical Parametric Mapping 8 software. Participants were evaluated using the structured interview for prodromal syndromes and neurocognitive function tasks. People at UHR demonstrated significantly reduced binding potential of GABA-A/BZ receptors in the right caudate. Altered GABAergic transmission and/or the imbalance of inhibitory and excitatory systems in the striatum may be present at the putative prodromal stage and play a pivotal role in the pathophysiology of psychosis.

  13. Design and combinatorial library generation of 1H 1,4 benzodiazepine 2,5 diones as photosystem-II inhibitors: A public QSAR approach

    Directory of Open Access Journals (Sweden)

    Purusottam Banjare

    2017-09-01

    Full Text Available Exponential rise in the population around the word increased the demand of food grains/crops with limited expansion of the agricultural land. To meet the demand, generation of new herbicidal agents is of primary need for the manufacturing firm. In silico tool like QSAR is one of the regularly used in designing newer compounds along with wet experiment. Photosystem-II (PS-II regarded as one of the major target for the herbicidal agents. With this aim in the present study a series of 1H, 1,4 benzodiazepine 2,5-dione analogues as herbicidal (PS-II inhibitors agents were subjected to QSAR analysis using 2D PaDEL descriptors (open source. Two different splitting techniques namely, kennard stone based and k-means clustering splitting were used to divide the whole data set and GFA based on MAE criteria was used a statistical method to develop a model to investigate the physicochemical and structural requirement of potential PS-II inhibitors. All the models are statistically robust both internally and externally (Q2: 0.540–0.693, R2pred: 0.722–0.810. The activity is mostly affected by polarizabilities, electro negativities as well as substituents at the phenyl ring. Based on the results, a library of compounds was generated using SmiLib v2.0 tool (open source and better predicted inside applicability domain compounds were identified by applying three different applicability domain (AD approaches. Therefore the developed public QSAR models may be helpful for the scientific community for the further research.

  14. Evaluation of a radiolabelled peripheral benzodiazepine receptor ligand in the central nervous system inflammation of experimental autoimmune encephalomyelitis: a possible probe for imaging multiple sclerosis

    International Nuclear Information System (INIS)

    Mattner, F.; Katsifis, A.; Ballantyne, P.; Staykova, M.; Willenborg, D.O.

    2005-01-01

    Peripheral benzodiazepine receptors (PBRs) are upregulated on macrophages and activated microglia, and radioligands for the PBRs can be used to detect in vivo neuroinflammatory changes in a variety of neurological insults, including multiple sclerosis. Substituted 2-phenyl imidazopyridine-3-acetamides with high affinity and selectivity for PBRs have been prepared that are suitable for radiolabelling with a number of positron emission tomography and single-photon emission computed tomography (SPECT) isotopes. In this investigation, the newly developed high-affinity PBR ligand 6-chloro-2-(4'-iodophenyl)-3-(N,N-diethyl)imidazo [1,2-a]pyridine-3-acetamide, or CLINDE, was radiolabelled with 123 I and its biodistribution in the central nervous system (CNS) of rats with experimental autoimmune encephalomyelitis (EAE) evaluated. EAE was induced in male Lewis rats by injection of an emulsion of myelin basic protein and incomplete Freund's adjuvant containing Mycobacterium butyricum. Biodistribution studies with 123 I-CLINDE were undertaken on EAE rats exhibiting different clinical disease severity and compared with results in controls. Disease severity was confirmed by histopathology in the spinal cord of rats. The relationship between inflammatory lesions and PBR ligand binding was investigated using ex vivo autoradiography and immunohistochemistry on rats with various clinical scores. 123 I-CLINDE uptake was enhanced in the CNS of all rats exhibiting EAE when compared to controls. Binding reflected the ascending nature of EAE inflammation, with lumbar/sacral cord > thoracic cord > cervical cord > medulla. The amount of ligand binding also reflected the clinical severity of disease. Ex vivo autoradiography and immunohistochemistry revealed a good spatial correspondence between radioligand signal and foci of inflammation and in particular ED-1 + cells representing macrophages and microglia. These results demonstrate the ability of 123 I-CLINDE to measure in vivo

  15. Omega 3 (peripheral type benzodiazepine binding) site distribution in the rat immune system: an autoradiographic study with the photoaffinity ligand [3H]PK 14105

    International Nuclear Information System (INIS)

    Benavides, J.; Dubois, A.; Dennis, T.; Hamel, E.; Scatton, B.

    1989-01-01

    The anatomical distribution of omega 3 (peripheral type benzodiazepine binding) sites in the immune system organs of the rat has been studied autoradiographically at both macroscopic and microscopic levels of resolution using either reversible or irreversible (UV irradiation) labeling with [ 3 H]PK 14105. In thymus sections, [ 3 H]PK 14105 labeled with high affinity (Kd, derived from saturation experiments = 10.8 nM) a single population of sites which possessed the pharmacological characteristics of omega 3 sites. In the thymus gland, higher omega 3 site densities were detected in the cortex than in the medulla; in these subregions, silver grains were associated to small (10-18 microns diameter) cells. In the spleen, omega 3 sites were more abundant in the white than in the red pulp. In the white pulp, silver grains were denser in the marginal zone than in the vicinity of the central artery and labeling was, as in the thymus, associated to small cytoplasm-poor cells. In the red pulp, omega 3 site associated silver grains were observed mainly in the Bilroth cords. In the lymph nodes, the medullary region showed a higher labeling than the surrounding follicles and paracortex. A significant accumulation of silver grains was observed in the lymph node medullary cords. In the intestine, Peyer patches were particularly enriched in omega 3 sites (especially in the periphery of the follicles). The distribution of omega 3 sites in the immune system organs suggests a preferential labeling of cells of T and monocytic lineages. This is consistent with the proposed immunoregulatory properties of some omega 3 site ligands

  16. Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array (MEA recording study"

    Directory of Open Access Journals (Sweden)

    Giulia ePuia

    2012-11-01

    Full Text Available The balance between glutamate- and GABA-mediated neurotransmission in the brain is fundamental in the nervous system, but it is regulated by the ‘tonic’ release of a variety of endogenous factors. One such important group of molecules are the neurosteroids (NSs which, similarly to benzodiazepines (BDZs, enhance GABAergic neurotransmission. The purpose of our work was to investigate, at in-vivo physiologically relevant concentrations, the effects of NSs and BDZs as GABA modulators on dissociated neocortical neuron networks grown in long-term culture. We used a multi-electrode array (MEA recording technique and a novel analysis that was able to both identify the action potentials of engaged excitatory and inhibitory neurons and to detect drug-induced network up-states (burst. We found that the NSs tetrahydrodeoxycorticosterone (THDOC and allopregnanolone (ALLO applied at low nM concentrations, produced different modulatory effects on the two neuronal clusters. Conversely, at high concentrations (1 µM, both NSs, decreased excitatory and inhibitory neuron cluster excitability; however, even several hours after washout, the excitability of inhibitory neurons continued to be depressed, leading to a network long term depression (LTD. The BDZs clonazepam (CLZ and midazolam (MDZ also decreased the network excitability, but only MDZ caused LTD of inhibitory neuron cluster. To investigate the origin of the LTD after MDZ application, we tested finasteride (FIN, an inhibitor of endogenous NSs synthesis. FIN did not prevent the LTD induced by MDZ, but surprisingly induced it after application of CLZ. The significance and possible mechanisms underlying these LTD effects of NSs and BDZs are discussed. Taken together, our results not only demonstrate that ex-vivo networks show a sensitivity to NSs and BDZs comparable to that expressed in vivo, but also provide a new global in-vitro description that can help in understanding their activity in more complex

  17. Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticity and depression-like behavior in mice.

    Science.gov (United States)

    Zhao, Yunan; Wang, Zhongli; Dai, Jianguo; Chen, Lin; Huang, Yufang; Zhan, Zhen

    2012-03-17

    Whether benzodiazepines (BZDs) have beneficial effects on the progress of chronic stress-induced impairment of hippocampal structural plasticity and major depression is uncertain. The present study designed four preclinical experiments to determine the effects of BZDs using chronic unpredictable stress model. In Experiment 1, several time course studies on behavior and hippocampus response to stress were conducted using the forced swim and tail suspension tests (FST and TST) as well as hippocampal structural plasticity markers. Chronic stress induced depression-like behavior in the FST and TST as well as decreased hippocampal structural plasticity that returned to normal within 3 wk. In Experiment 2, mice received p.o. administration of three diazepam dosages prior to each variate stress session for 4 wk. This treatment significantly antagonized the elevation of stress-induced corticosterone levels. Only low- (0.5mg/kg) and medium-dose (1mg/kg) diazepam blocked the detrimental effects of chronic stress. In Experiment 3, after 7 wk of stress sessions, daily p.o. diazepam administration during 1 wk recovery phase dose-dependently accelerated the recovery of stressed mice. In Experiment 4, 1 wk diazepam administration to control mice enhanced significantly hippocampal structural plasticity and induced an antidepressant-like behavioral effect, whereas 4 wk diazepam administration produced opposite effects. Hence, diazepam can slow the progress of chronic stress-induced detrimental consequences by normalizing glucocorticoid hormones. Considering the adverse effect of long-term diazepam administration on hippocampal plasticity, the preventive effects of diazepam may depend on the proper dose. Short-term diazepam treatment enhances hippocampal structural plasticity and is beneficial to recovery following chronic stress. Copyright © 2011 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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

  19. Targeted deletion of the GABRA2 gene encoding alpha2-subunits of GABA(A) receptors facilitates performance of a conditioned emotional response, and abolishes anxiolytic effects of benzodiazepines and barbiturates.

    Science.gov (United States)

    Dixon, C I; Rosahl, T W; Stephens, D N

    2008-07-01

    Mice with point-mutated alpha2 GABA(A) receptor subunits (rendering them diazepam insensitive) are resistant to the anxiolytic-like effects of benzodiazepines (BZs) in the conditioned emotional response (CER) test, but show normal anxiolytic effects of a barbiturate. We investigated the consequence of deleting the alpha2-subunit on acquisition of the CER with increasing intensity of footshock, and on the anxiolytic efficacy of a benzodiazepine, diazepam, and a barbiturate, pentobarbital. alpha2 knockout (KO) and wildtype (WT) mice were trained in a conditioned emotional response (CER) task, in which lever pressing for food on a variable interval (VI) schedule was suppressed during the presentation of a compound light/tone conditioned stimulus (CS+) that predicted footshock. The ability of diazepam and of pentobarbital to reduce suppression during the CS+ was interpreted as an anxiolytic response. There were no differences between the genotypes in shock sensitivity, as assessed by their flinch responses to increasing levels of shock. However, alpha2 KO mice showed a greater suppression of lever pressing than WT littermates in the presence of a compound cue signalling footshock. Diazepam (0, 0.5, 1 and 2 mg/kg) induced a dose-dependent anxiolytic-like effect in WT mice but no such effect was seen in KO mice. Similarly, although pentobarbital (20 mg/kg) reduced the ability of the CS+ to reduce lever pressing rates in WT mice, this effect was not seen in the KO. These findings suggest that alpha2-containing GABA(A) receptors mediate the anxiolytic effects of barbiturates, as well as benzodiazepines, and that they may be involved in neuronal circuits underlying conditioned anxiety.

  20. Ethyl 2-{4-[(1,5-dibenzyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-ylmethyl]-1H-1,2,3-triazol-1-yl}acetate

    Directory of Open Access Journals (Sweden)

    Hind Jabli

    2010-01-01

    Full Text Available The reaction of 1,5-dibenzyl-3-propargyl-1,5-benzodiazepine-2,4-dione with ethyl azidoacetate in the presence of copper sulfate pentahydrate and sodium ascorbate leads to the formation of the title regioisomer, C30H29N5O4, which features a phenylene ring fused with a seven-membered diazepinyl ring. The latter ring adopts a boat conformation (with the methyltriazolylacetate-bearing C atom as the prow and the fused-ring C atoms as the stern. The benzyl groups connected to the diazepinyl ring jprotrude from the sides; the methyltriazolylacetate substituent occupies an axial position.

  1. Comparison of benzodiazepine receptor SPECT and 18F-FDG PET using a coincidence detection camera in patients with temporal lobe epilepsy: preliminary results

    International Nuclear Information System (INIS)

    Wissmeyer, M.; Geiger, L.; Luescher, D.; Krause, T.; Loevblad, K.; Donati, F.; Wielepp, J.P.

    2002-01-01

    Full text: The aim of this preliminary study was to compare the results of benzodiazepine receptor (BDR) SPECT using 123 I-Iomazenil with those of 18 F-FDG (FDG) PET obtained on a double-headed gamma camera with a coincidence detection system in patients with temporal lobe epilepsy (TLE). We evaluated 6 patients (4 female, 2 male; age range 26-54 years, average 43.5 years) with therapy-refractory TLE due to mesiotemporal sclerosis or other focal brain anomalies. To delineate the epileptogenic zone, clinical evaluation, ictal and interictal surface EEG using the international 10-20 system, brain MRI, interictal CBF SPECT using 99m Tc-ECD, BDR SPECT and FDG coincidence PET were performed. The CBF SPECT, BDR SPECT and coincidence PET scans were viewed independently by 2 observers considering the regional cerebral blood flow, BDR density and FDG uptake asymmetry in the temporal lobe visually as none (0), low (1), moderate (2) and high (3). Ictal and interictal EEG recordings located the epileptogenic focus in all patients in the temporal region. Both the BDR SPECT and the FDG coincidence PET located the epileptogenic focus correctly in circumscribed areas of the temporal lobe in all patients, whereas brain MRI revealed focal anomalies only in 5 of 6 cases . The lateralization to the right (n=4) and left hemisphere (n=2) by interictal CBF SPECT, BDR SPECT and FDG coincidence PET corresponded to the EEG findings in all patients. The visual consideration of the asymmetry revealed a slightly but not statistically significant higher value for the FDG coincidence PET (observer 1: mean 2.333, SD 0.516; observer 2: mean 2.000, SD 0.632) than for the BDR SPECT (observer 1: mean 1.667, SD 1.033; observer 2: mean 1.833, SD 0.753). Visual consideration of the interictal CBF SPECT revealed mean values of 2.000 for both observers. The inter-observer variability was higher in the BDR SPECT than in the FDG coincidence PET and the interictal CBF SPECT, but the difference was not

  2. Pharmacological evaluation of [123I]-CLINDE: a radioiodinated imidazopyridine-3-acetamide for the study of peripheral benzodiazepine binding sites (PBBS).

    Science.gov (United States)

    Mattner, Filomena; Mardon, Karine; Katsifis, Andrew

    2008-04-01

    The study aims to evaluate the iodinated imidazopyridine, N',N'-diethyl-6-Chloro-(4'-[(123)I]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide ([(123)I]-CLINDE) as a tracer for the study of peripheral benzodiazepine binding sites (PBBS). In vitro studies were performed using membrane homogenates and sections from kidney, adrenals, and brain cortex of Sprague-Dawley (SD) rats and incubated with [(123)I]-CLINDE. For in vivo studies, the rats were injected with [(123)I]-CLINDE. In competition studies, PBBS-specific drugs PK11195 and Ro 5-4864 and the CBR specific drug Flumazenil were injected before the radiotracer. In vitro binding studies in adrenal, kidney, and cortex mitochondrial membranes indicated that [(123)I]-CLINDE binds with high affinity to PBBS, K(d) = 12.6, 0.20, and 3.84 nM, respectively. The density of binding sites was 163, 5.3, and 0.34 pmol/mg protein, respectively. In vivo biodistribution indicated high uptake in adrenals (5.4), heart (1.5), lungs (1.5), kidney (1.5) %ID/g at 6 h p.i. In the central nervous system (CNS), the olfactory bulbs displayed the highest uptake; up to six times the activity in blood. Pre-administration of unlabeled CLINDE, PK11195 and Ro 5-4864 (1 mg/kg) reduced the uptake of [(123)I]-CLINDE by 70-55% in olfactory bulbs. In the kidney and heart, a reduction of 60-80% ID/g was observed, while an increase was observed in the adrenals requiring 10 mg/kg for significant displacement. Flumazenil had no effect on uptake in peripheral organs and brain. Metabolite analysis indicated >90% of the radioactivity in the above tissues was intact [(123)I]-CLINDE. [(123)I]-CLINDE displays high and selective uptake for the PBBS and warrants further development as a probe for imaging PBBS using single photon emission computed tomography (SPECT).

  3. Pharmacological evaluation of [{sup 123}I]-CLINDE: a radioiodinated imidazopyridine-3-acetamide for the study of peripheral benzodiazepine binding sites (PBBS)

    Energy Technology Data Exchange (ETDEWEB)

    Mattner, Filomena; Katsifis, Andrew [Australian Nuclear Science and Technology Organisation, Radiopharmaceuticals Research Institute, PMB 1 Menai, N.S.W., Sydney (Australia); Mardon, Karine [The University of Queensland, Centre for Studies in Drug Disposition, Brisbane (Australia)

    2008-04-15

    The study aims to evaluate the iodinated imidazopyridine, N',N'-diethyl-6-Chloro-(4'-[{sup 123}I]iodophenyl)imidazo[1,2-a]pyridine-3-acetamide ([{sup 123}I]-CLINDE) as a tracer for the study of peripheral benzodiazepine binding sites (PBBS). In vitro studies were performed using membrane homogenates and sections from kidney, adrenals, and brain cortex of Sprague-Dawley (SD) rats and incubated with [{sup 123}I]-CLINDE. For in vivo studies, the rats were injected with [{sup 123}I]-CLINDE. In competition studies, PBBS-specific drugs PK11195 and Ro 5-4864 and the CBR specific drug Flumazenil were injected before the radiotracer. In vitro binding studies in adrenal, kidney, and cortex mitochondrial membranes indicated that [{sup 123}I]-CLINDE binds with high affinity to PBBS, K{sub d} = 12.6, 0.20, and 3.84 nM, respectively. The density of binding sites was 163, 5.3, and 0.34 pmol/mg protein, respectively. In vivo biodistribution indicated high uptake in adrenals (5.4), heart (1.5), lungs (1.5), kidney (1.5) %ID/g at 6 h p.i. In the central nervous system (CNS), the olfactory bulbs displayed the highest uptake; up to six times the activity in blood. Pre-administration of unlabeled CLINDE, PK11195 and Ro 5-4864 (1 mg/kg) reduced the uptake of [{sup 123}I]-CLINDE by 70-55% in olfactory bulbs. In the kidney and heart, a reduction of 60-80% ID/g was observed, while an increase was observed in the adrenals requiring 10 mg/kg for significant displacement. Flumazenil had no effect on uptake in peripheral organs and brain. Metabolite analysis indicated >90% of the radioactivity in the above tissues was intact [{sup 123}I]-CLINDE. [{sup 123}I]-CLINDE displays high and selective uptake for the PBBS and warrants further development as a probe for imaging PBBS using single photon emission computed tomography (SPECT). (orig.)

  4. Pharmacological evaluation of [123I]-CLINDE: a radioiodinated imidazopyridine-3-acetamide for the study of peripheral benzodiazepine binding sites (PBBS)

    International Nuclear Information System (INIS)

    Mattner, Filomena; Katsifis, Andrew; Mardon, Karine

    2008-01-01

    The study aims to evaluate the iodinated imidazopyridine, N',N'-diethyl-6-Chloro-(4'-[ 123 I]iodophenyl)imidazo [1,2-a]pyridine-3-acetamid e ([ 123 I]-CLINDE) as a tracer for the study of peripheral benzodiazepine binding sites (PBBS). In vitro studies were performed using membrane homogenates and sections from kidney, adrenals, and brain cortex of Sprague-Dawley (SD) rats and incubated with [ 123 I]-CLINDE. For in vivo studies, the rats were injected with [ 123 I]-CLINDE. In competition studies, PBBS-specific drugs PK11195 and Ro 5-4864 and the CBR specific drug Flumazenil were injected before the radiotracer. In vitro binding studies in adrenal, kidney, and cortex mitochondrial membranes indicated that [ 123 I]-CLINDE binds with high affinity to PBBS, K d = 12.6, 0.20, and 3.84 nM, respectively. The density of binding sites was 163, 5.3, and 0.34 pmol/mg protein, respectively. In vivo biodistribution indicated high uptake in adrenals (5.4), heart (1.5), lungs (1.5), kidney (1.5) %ID/g at 6 h p.i. In the central nervous system (CNS), the olfactory bulbs displayed the highest uptake; up to six times the activity in blood. Pre-administration of unlabeled CLINDE, PK11195 and Ro 5-4864 (1 mg/kg) reduced the uptake of [ 123 I]-CLINDE by 70-55% in olfactory bulbs. In the kidney and heart, a reduction of 60-80% ID/g was observed, while an increase was observed in the adrenals requiring 10 mg/kg for significant displacement. Flumazenil had no effect on uptake in peripheral organs and brain. Metabolite analysis indicated >90% of the radioactivity in the above tissues was intact [ 123 I]-CLINDE. [ 123 I]-CLINDE displays high and selective uptake for the PBBS and warrants further development as a probe for imaging PBBS using single photon emission computed tomography (SPECT). (orig.)

  5. Benzodiazepine and Z-drug use and risk of pneumonia in patients with chronic kidney disease: A population-based nested case-control study.

    Science.gov (United States)

    Wang, Meng-Ting; Wang, Yun-Han; Chang, Hsin-An; Tsai, Chen-Liang; Yang, Ya-Sung; Lin, Chen Wei; Kuo, Cheng-Chin; Hsu, Yu-Juei

    2017-01-01

    Concerns were raised about pneumonia development from benzodiazepines (BZDs) and Z-drugs, but direct evidence is limited, conflicting and without examining the highly susceptible patients with chronic kidney disease (CKD) nor specifying the risk for different drug utilizations. This study aimed to investigate whether use of BZDs and Z-drugs was each associated with an increased risk of pneumonia in a CKD population. We performed a nested case-control study of 36,880 CKD patients analyzing the Taiwan National Health Insurance Database between 01/1/2000 and 12/31/2011. Among the study cohort, we identified 4,533 cases of pneumonia based on validated disease codes, chest x-ray examination, and prescriptions of respiratory antibiotics, and randomly selected 16,388 controls from risk sets, matched by sex, age, and number of CKD-related hospitalizations. All prescription filling records of BZDs and Z-drugs in the year before the event/index date were analyzed for cases and controls. Conditional logistic regressions were performed to estimate the odds ratios (ORs). Current use of BZDs was associated with a 1.31-fold (95% CI, 1.18-1.26) increased risk of pneumonia compared to nonuse, but not for recent and past use. The risk from current BZD use was confined to new initiation (adjusted OR, 2.47; 95% CI, 2.02-3.03) or use for ≤ 30 days, and elevated to 2.88-fold (95% CI, 1.87-4.42) with parenteral administration. New initiation and current short-term use of Z-drugs was associated with a 2.94-fold (95% CI, 1.65-5.26) and 1.75-fold (95% CI, 1.13-2.72) increased risk of pneumonia, respectively. The findings were robust to adoption of a case-crossover study that analyzed cases only. Use of BZRAs is associated with an increased risk of pneumonia in CKD patients, especially for patients newly initiating BZDs or Z-drugs or those injected with BZDs. Physicians should exercise cautions for signs of pneumonia when prescribing BZDs or Z-drugs to CKD patients.

  6. Strategy for improved [11C]DAA1106 radiosynthesis and in vivo peripheral benzodiazepine receptor imaging using microPET, evaluation of [11C]DAA1106

    International Nuclear Information System (INIS)

    Probst, Katrin C.; Izquierdo, David; Bird, Joseph L.E.; Brichard, Laurent; Franck, Dominic; Davies, John R.; Fryer, Tim D.; Richards, Hugh K.; Clark, John C.; Davenport, Anthony P.; Weissberg, Peter L.; Warburton, Elizabeth A.

    2007-01-01

    Introduction: The peripheral benzodiazepine receptor (PBR) has shown considerable potential as a clinical marker of neuroinflammation and tumour progression. [ 11 C]DAA1106 ([ 11 C]N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)-acetamide) is a promising positron emission tomography (PET) radioligand for imaging PBRs. Methods: A four-step synthetic route was devised to prepare DAA1123, the precursor for [ 11 C]DAA1106. Two robust, high yielding methods for radiosynthesis based on [ 11 C]-O-methylation of DAA1123 were developed and implemented on a nuclear interface methylation module, producing [ 11 C]DAA1106 with up to 25% radiochemical yields at end-of-synthesis based on [ 11 C]CH 3 I trapped. Evaluation of [ 11 C]DAA1106 for in vivo imaging was performed in a rabbit model with microPET, and the presence of PBR receptor in the target organ was further corroborated by immunohistochemistry. Results: The standard solution method produced 2.6-5.2 GBq (n=19) of [ 11 C]DAA1106, whilst the captive solvent method produced 1.6-6.3 GBq (n=10) of [ 11 C]DAA1106. Radiochemical purities obtained were 99% and specific radioactivity at end-of-synthesis was up to 200 GBq/μmol for both methods. Based on radiochemical product, shorter preparation times and simplicity of synthesis, the captive solvent method was chosen for routine productions of [ 11 C]DAA1106. In vivo microPET [ 11 C]DAA1106 scans of rabbit kidney demonstrated high levels of binding in the cortex. The subsequent introduction of nonradioactive DAA1106 (0.2 μmol) produced considerable displacement of the radioactive signal in this region. The presence of PBR in kidney cortex was further corroborated by immunohistochemistry. Conclusions: A robust, high yielding captive solvent method of [ 11 C]DAA1106 production was developed which enabled efficacious in vivo imaging of PBR expressing tissues in an animal model

  7. Evaluation of C.L.I.N.D.E. as potent peripheral-type benzodiazepine receptor tracer in a rat model of micro-glial activation

    Energy Technology Data Exchange (ETDEWEB)

    Arlicot, N.; Guilloteau, D.; Chalon, S. [Institut National de la Sante et de la Recherche Medicale (INSERM), U619, 37 - Tours (France); Universite Francois Rabelais de Tours, 37 (France); Katsifis, A.; Mattner, F. [ANSTO, Sydney (Australia)

    2008-02-15

    The peripheral-type benzodiazepine receptors (P.B.R.) are localized in mitochondria of glial cells and are very low expressed in normal brain. Their expression rises after micro-glial activation consecutive to brain injury. Accordingly, P.B.R. are potential targets to evaluate neuro inflammatory changes in a variety of C.N.S. disorders. To date no effective tool is available to explore P.B.R. by SPECT. We characterized here 6-chloro-2-(4 iodophenyl)-3-(N,N-diethyl)-imidazo[1,2-a]pyridine- 3-acetamide, C.L.I.N.D.E., in a rat model of excitotoxic lesion. Excitotoxicity was induced in male Wistar rats by unilateral intra striatal injection of different amounts of quinolinic acid (Q.A.: 75, 150 or 300 nmol). One week later, 2 groups of rats (n = 5-6/group) were i.v. injected with [{sup 125}I]-C.L.I.N.D.E. (0.4 MBq), one group being pre-injected with P.K.11195 (5 mg/kg). Brains were removed 30 min after tracer injection and the radioactivity of cerebral areas measured. Complementary ex vivo autoradiography and immunohistochemical studies using O.X.-42 were performed on brain sections In the control group, [{sup 125}I]-C.L.I.N.D.E. binding was significantly higher ( p < 0.001) in lesioned than that in intact side (striatum: 0.552 {+-} 0.109 vs. 0.123 {+-} 0.012% I.D./g tissue; cortex: 0.385 {+-} 0.126 vs. 0.131 {+-} 0.007% with 300 nmol Q.A.). This binding disappeared in rats pretreated with P.K.11195 ( p < 0.001), showing specific binding of C.L.I.N.D.E. to P.B.R.. Ex vivo autoradiography and immunohistochemistry were consistent with this, revealing a spatial correspondence between radioactivity signal and activated micro-glia. Regression analysis yielded a significant correlation ( p < 0.001) between the ligand binding and the dose of Q.A.. These results demonstrate that C.L.I.N.D.E. is suitable for P.B.R. in vivo SPECT imaging to explore their involvement in neuro degenerative disorders associated with micro-glial activation. (authors)

  8. Memory function in opioid-dependent patients treated with methadone or buprenorphine along with benzodiazepine: longitudinal change in comparison to healthy individuals

    Directory of Open Access Journals (Sweden)

    Rapeli Pekka

    2009-04-01

    Full Text Available Abstract Background Opioid-substitution treatment (OST for opioid dependence (OD has proven effective in retaining patients in treatment and reducing illegal opiate abuse and crime. Consequently, the World Health Organization (WHO has listed the opioid agonists methadone and buprenorphine as essential drugs for OD that should be available worldwide. In many areas of the world, OD is often associated with concomitant benzodiazepine (BZD dependence and abuse, which complicates treatment. However, possible changes in the cognitive functioning of these patients are not well-known. The present study is the first to examine longitudinal stability of memory function in OST patients with BZD use, thus providing a new tool for health policy authorities in evaluating the usefulness of OST. Methods Within the first two months (T1 and between 6–9 months (T2 after OST admission, we followed the working memory, immediate verbal memory, and memory consolidation of 13 methadone- and 15 buprenorphine- or buprenorphine/naloxone-treated patients with BZD dependence or abuse disorder. The results were compared to those of fifteen normal comparison participants. All participants also completed a self-reported memory complaint questionnaire on both occasions. Results Both patient groups performed statistically significantly worse than normal comparison participants in working memory at time points T1 and T2. In immediate verbal memory, as measured by list learning at T1, patients scored lower than normal comparison participants. Both patient groups reported significantly more subjective memory problems than normal comparison participants. Patients with more memory complaints recalled fewer items at T2 from the verbal list they had learned at T1 than those patients with fewer memory complaints. The significance of the main analyses remained nearly the same when the statistical tests were performed without buprenorphine-only patients leaving 12 patients to

  9. Teaching young GPs to cope with psychosocial consultations without prescribing: a durable impact of an e-module on determinants of benzodiazepines prescribing.

    Science.gov (United States)

    Creupelandt, Hanne; Anthierens, Sibyl; Habraken, Hilde; Declercq, Tom; Sirdifield, Coral; Siriwardena, Aloysius Niroshan; Christiaens, Thierry

    2017-12-19

    Despite guidelines and campaigns to change prescribing behavior, General Practitioners (GPs) continue to overprescribe benzodiazepines (BZDs). New approaches to improve prescribing are needed. Using behavior change techniques and tailoring interventions to user characteristics are vital to promote behavior change. This study evaluated the impact of an e-module on factors known to determine BZD prescribing practice. A tailored e-module that focuses on avoiding initial BZD prescriptions (and using psychological interventions as an alternative) was developed and offered to GPs in vocational training. Three self-report assessments took place: at baseline, immediately after the module (short term) and at least six months after completion (long term). Assessed determinants include GPs' attitudes concerning treatment options, perceptions of the patient and self-efficacy beliefs. Readiness to adhere to prescribing guidelines was evaluated through assessing motivation, self-efficacy and implementability of non-pharmacological interventions. Changes in determinants were analyzed using the Wilcoxon signed-rank test. Changes in readiness to adhere to guidelines was analyzed using the nonparametric McNemar Bowker test. A desirable, significant and durable impact on determinants of BZD prescribing was observed. GPs (n = 121) underwent desirable changes in their attitudes, perceptions and self-efficacy beliefs and these changes remained significant months after the intervention. Barriers to using a non-pharmacological approach often cited in literature remained absent and were not highlighted by the intervention. Furthermore a significant impact on GPs' readiness to adhere to guidelines was observed. Participants reported change in their ability to cope with psychosocial consultations and to have tried using non-pharmacological interventions. Tailoring an e-intervention to target group (GPs) characteristics appears to be successful in promoting behavioral change in GPs

  10. International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: VI. Trends in recommendations for the pharmacotherapy of anxiety disorders, 1992-1997.

    Science.gov (United States)

    Uhlenhuth, E H; Balter, M B; Ban, T A; Yang, K

    1999-01-01

    To assemble expert clinical experience and judgment regarding the treatment of anxiety disorders in a systematic, quantitative manner, particularly with respect to changes during the preceding five years. A panel of 73 internationally recognized experts in the pharmacotherapy of anxiety and depression was constituted by multistage peer nomination. Sixty-six completed a questionnaire in 1992, and 51 of those completed a follow-up questionnaire in 1997. This report focuses on the experts' responses to questions about therapeutic options relevant to seven vignettes describing typical cases of different anxiety disorders. The preferred initial treatment strategy in 1992 was a combination of medication with a psychological therapy for all vignettes except simple phobia, where a psychological procedure alone was favored. There was little change in 1997, primarily some decrease in the choice of psychological therapy and some increase in the choice of medication for social phobia. Experts recommending a medication in 1992 most often chose as first-line treatment a benzodiazepine anxiolytic (BZ) for panic disorder (PD), generalized anxiety disorder (GAD), simple phobia, and adjustment disorder. They recommended a beta-blocker most often for social phobia and a tricyclic anti-depressant (TCA) for agoraphobia and obsessive-compulsive disorder (OCD). Nearly a fourth chose a combination of medications, usually a TCA plus a BZ. In 1997, the expert panel's most frequent recommendation for agoraphobia, PD, and OCD changed to a specific serotonin reuptake inhibitor (SSRI); and they also recommended these compounds more often for GAD, social phobia, and simple phobia. Fewer experts chose BZs or TCAs. However, in 1997 many again chose a combination of medications, often a BZ plus a SSRI, so that, overall, there was only a small decline in recommendations for BZs. As second-line medications (1997 only), the experts recommended SSRIs most often for most vignettes, but a TCA for PD and

  11. Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage

    Energy Technology Data Exchange (ETDEWEB)

    Kadriu, Bashkim; Guidotti, Alessandro; Costa, Erminio [Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612 (United States); Auta, James [Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor St., Chicago, IL 60612 (United States)

    2009-02-27

    Organophosphate (OP)-nerve agent poisoning may lead to prolonged epileptiform seizure activity, which can result in irreversible neuronal brain damage. A timely and effective control of seizures with pharmacological agents can minimize the secondary and long-term neuropathology that may result from this damage. Diazepam, the current anticonvulsant of choice in the management of OP poisoning, is associated with unwanted effects such as sedation, amnesia, cardio-respiratory depression, anticonvulsant tolerance, and dependence liabilities. In search for an efficacious and safer anticonvulsant benzodiazepine, we studied imidazenil, a potent anticonvulsant that is devoid of sedative action and has a low intrinsic efficacy at {alpha}1- but is a high efficacy positive allosteric modulator at {alpha}5-containing GABA{sub A} receptors. We compared the potency of a combination of 2 mg/kg, i.p. atropine with: (a) imidazenil 0.05-0.5 mg/kg i.p. or (b) equipotent anti-bicuculline doses of diazepam (0.5-5 mg/kg, i.p.), against diisopropyl fluorophosphate (DFP; 1.5 mg/kg, s.c.)-induced status epilepticus and its associated neuronal damage. The severity and frequency of seizure activities were determined by continuous radio telemetry recordings while the extent of neuronal damage and neuronal degeneration were assessed using the TUNEL-based cleaved DNA end-labeling technique or neuron-specific nuclear protein (NeuN)-immunolabeling and Fluoro-Jade B (FJB) staining, respectively. We report here that the combination of atropine and imidazenil is at least 10-fold more potent and longer lasting than the combination with diazepam at protecting rats from DFP-induced seizures and the associated neuronal damage or ongoing degeneration in the anterior cingulate cortex, CA1 hippocampus, and dentate gyrus. While 0.5 mg/kg imidazenil effectively attenuated DFP-induced neuronal damage and the ongoing neuronal degeneration in the anterior cingulate cortex, dentate gyrus, and CA1 hippocampus, 5

  12. Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage

    International Nuclear Information System (INIS)

    Kadriu, Bashkim; Guidotti, Alessandro; Costa, Erminio; Auta, James

    2009-01-01

    Organophosphate (OP)-nerve agent poisoning may lead to prolonged epileptiform seizure activity, which can result in irreversible neuronal brain damage. A timely and effective control of seizures with pharmacological agents can minimize the secondary and long-term neuropathology that may result from this damage. Diazepam, the current anticonvulsant of choice in the management of OP poisoning, is associated with unwanted effects such as sedation, amnesia, cardio-respiratory depression, anticonvulsant tolerance, and dependence liabilities. In search for an efficacious and safer anticonvulsant benzodiazepine, we studied imidazenil, a potent anticonvulsant that is devoid of sedative action and has a low intrinsic efficacy at α1- but is a high efficacy positive allosteric modulator at α5-containing GABA A receptors. We compared the potency of a combination of 2 mg/kg, i.p. atropine with: (a) imidazenil 0.05-0.5 mg/kg i.p. or (b) equipotent anti-bicuculline doses of diazepam (0.5-5 mg/kg, i.p.), against diisopropyl fluorophosphate (DFP; 1.5 mg/kg, s.c.)-induced status epilepticus and its associated neuronal damage. The severity and frequency of seizure activities were determined by continuous radio telemetry recordings while the extent of neuronal damage and neuronal degeneration were assessed using the TUNEL-based cleaved DNA end-labeling technique or neuron-specific nuclear protein (NeuN)-immunolabeling and Fluoro-Jade B (FJB) staining, respectively. We report here that the combination of atropine and imidazenil is at least 10-fold more potent and longer lasting than the combination with diazepam at protecting rats from DFP-induced seizures and the associated neuronal damage or ongoing degeneration in the anterior cingulate cortex, CA1 hippocampus, and dentate gyrus. While 0.5 mg/kg imidazenil effectively attenuated DFP-induced neuronal damage and the ongoing neuronal degeneration in the anterior cingulate cortex, dentate gyrus, and CA1 hippocampus, 5 mg/kg or a

  13. Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users

    DEFF Research Database (Denmark)

    Baandrup, Lone; Ebdrup, Bjørn H; Rasmussen, Jesper Ø

    2018-01-01

    .13 points, 95% CI -4.03 to 3.77; very low-quality evidence).The following pharmacological interventions reduced symptoms of anxiety at end of intervention: carbamazepine (1 study, 36 participants; MD -6.00 points, 95% CI -9.58 to -2.42; very low-quality evidence), pregabalin (1 study, 106 participants; MD...

  14. Avaliação da orientação médica sobre os efeitos colaterais de benzodiazepínicos Evaluation of the medical orientation for the benzodiazepine side effects

    Directory of Open Access Journals (Sweden)

    Luciana Auchewski

    2004-03-01

    Full Text Available OBJETIVOS: Os benzodiazepínicos, pelos seus empregos como ansiolítico, hipnótico, miorrelaxante e anticonvulsivante, são muito prescritos. Os efeitos colaterais que comprometem o paciente são: diminuição da atividade psicomotora, interação com outras drogas, como o álcool, e o desenvolvimento de dependência. Neste estudo, avaliou-se a qualidade da orientação médica sobre esses efeitos colaterais. MÉTODOS: Foram entrevistados 120 pacientes (39 homens e 81 mulheres com idade média de 48 anos que procuraram as farmácias de Curitiba, Paraná, para comprar benzodiazepínicos. Para avaliar as orientações médicas recebidas sobre os efeitos colaterais dos medicamentos, aplicou-se um questionário com perguntas abertas e estimuladas. RESULTADOS: Treze por cento dos pacientes relataram ter sido orientados sobre os três tipos principais de efeitos colaterais, 27% a respeito de pelo menos dois e 40% sobre pelo menos um, enquanto que 19% não recebeu nenhuma orientação. A qualidade da orientação não foi influenciada pelo grau de instrução do paciente, pela especialidade do médico prescritor e pelo tipo de atendimento (particular ou público. Houve predomínio da orientação ''não beber'' (85%, seguida do cuidado para operar máquinas e dirigir veículos (46%, e por último, a orientação sobre o desenvolvimento de dependência (31%. CONCLUSÃO: Os resultados sugerem que os médicos estavam mais preocupados com o risco de interação com o álcool, que pode ser fatal. O elevado número de pacientes que usavam a medicação de modo contínuo por mais de um ano (61%, o insucesso na interrupção da medicação (94% e a pouca orientação sobre o tempo de uso do medicamento (22% podem indicar a falta de preocupação do médico com a possível dependência induzida pelos benzodiazepínicos.OBJECTIVES: Benzodiazepines are among the most prescribed drugs indicated as anxiolytics, hypnotics, myorrelaxants or antiepileptics. Their

  15. Concordance with a STOPP (Screening Tool of Older Persons' Potentially Inappropriate Prescriptions) Criterion in Nova Scotia, Canada: Benzodiazepine and Zoplicone Prescription Claims by Older Adults with Fall-related Hospitalizaions.

    Science.gov (United States)

    Hill-Taylor, B; Sketris, I S; Gardner, D M; Thompson, K

    2016-01-01

    Optimization of prescribing in older adults is needed. The STOPP criteria provide a systematic way of identifying potentially inappropriate prescribing in this population. Previous research indicates poor concordance between benzodiazepine prescribing and STOPP. To determine the extent and predictors of benzodiazepine and zopiclone (BZD-Z) pharmacy dispensations in older adults with a history of a recent fall, in concordance with STOPP. Prescription claims data from the Nova Scotia Seniors' Phamacare Program were linked with fall-related injury data from the CIHI Discharge Abstract Database. Adults aged ≥ 66 years making a claim for a BZD-Z in the 100 days prior to fall-related hospitalization were identified. Their BZD-Z claims in the 100 days following discharge were also identified. Descriptive statistics, trend tests and logistical regression modelling were performed to examine predictors for continued use of BZD-Z post-fall. Over 5 years, from a pool of 8,271 older adults discharged following a fall-related hospitalization, 1,789 (21.6%) had made a claim for a BZD-Z in the 100 days prior to admission. Of these, 82% were women. Younger age and female sex were predictors of continuing BZD-Z dispensations post-fall. In the 100 days following discharge, 74.2% (n=1327) made a claim for at least one BZD-Z. BZD-Z use continued in 74% of patients following discharge from a fall-related hospitalization, representing limited concordance with the STOPP criterion. Such hospitalizations and follow-up care present an opportunity to address an ongoing modifiable risk factor.

  16. Association of benzodiazepine and Z-drug use with the risk of hospitalisation for fall-related injuries among older people: a nationwide nested case-control study in Taiwan.

    Science.gov (United States)

    Yu, Nan-Wen; Chen, Pei-Jung; Tsai, Hui-Ju; Huang, Chih-Wan; Chiu, Yu-Wen; Tsay, Wen-Ing; Hsu, Jui; Chang, Chia-Ming

    2017-07-11

    Non-benzodiazepine hypnotics (Z-drugs) are advocated to be safer than benzodiazepines (BZDs). This study comprehensively investigated the association of BZD and Z-drug usage with the risk of hospitalisation for fall-related injuries in older people. This study used the Taiwan National Health Insurance Database with a nested matched case-control design. We identified 2238 elderly patients who had been hospitalised for fall-related injuries between 2003 and 2012. They were individually matched (1:4) with a comparison group by age, sex, and index year. Conditional logistic regression was used to determine independent effects of drug characteristics (type of exposure, dosage, half-life, and polypharmacy) on older people. Older people hospitalisation for fall-related injuries were significantly associated with current use of BZDs (adjusted odds ratio [AOR] = 1.32, 95% confidential interval [CI] = 1.17-1.50) and Z-drugs (AOR = 1.24, 95%CI = 1.05-1.48). At all dose levels of BZDs, high dose levels of Z-drugs, long-acting BZD, and short-acting BZD use were all significantly increased the risk of fall-related injuries requiring hospitalisation. Polypharmacy, the use of two or more kinds of BZDs, one kind of BZD plus Z-drugs and two or more kinds of BZDs plus Z-drugs, also significantly increased the risk (AOR = 1.61, 95% CI = 1.38-1.89; AOR = 1.65, 95% CI = 1.08-2.50, and AOR = 1.58, 95% CI = 1.21-2.07). Different dose levels and half-lives of BZDs, a high dose of Z-drugs, and polypharmacy with BZDs and Z-drugs were associated with an increased risk of fall-related injury requiring hospitalisation in older people. Physicians should balance the risks and benefits when prescribing these drug regimens to older people considering the risk of falls.

  17. FT-IR, FT-Raman spectra and ab initio HF and DFT calculations of 7-chloro-5-(2-chlorophenyl)-3-hydroxy-2,3-dihydro-1H-1,4-benzodiazepin-2-one.

    Science.gov (United States)

    Muthu, S; Prasath, M; Paulraj, E Isac; Balaji, R Arun

    2014-01-01

    The Fourier Transform infrared and Fourier Transform Raman spectra of 7-chloro-5 (2-chlorophenyl)-3-hydroxy-2,3-dihydro-1H-1,4-benzodiazepin-2-one (7C3D4B) were recorded in the regions 4000-400 and 4000-100 cm(-1), respectively. The appropriate theoretical spectrograms for the IR and Raman spectra of the title molecule were also constructed. The calculated results show that the predicted geometry can well reproduce the structural parameters. Predicted vibrational frequencies have been assigned and compared with experimental IR spectra and they supported each other. Stability of the molecule arising from hyperconjugative interactions, charge delocalization and intramolecular hydrogen bond-like weak interaction has been analyzed using natural bond orbital (NBO) analysis by using B3LYP/6-31G(d,p) method. The results show that electron density (ED) in the σ* and π* antibonding orbitals and second-order delocalization energies E(2) confirm the occurrence of intramolecular charge transfer (ICT) within the molecule. The first order hyperpolarizability (βtotal) of this molecular system and related properties (β, μ, and Δα) are calculated using HF/6-31G(d,p) and B3LYP/6-31G(d,p) methods based on the finite-field approach. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. The GABA-A benzodiazepine receptor complex: Role of pet and spect in neurology and psychiatry; Der GABA-A-benzodiazepinrezeptorkomplex: Rolle von PET und SPECT in Neurologie und Psychiatrie

    Energy Technology Data Exchange (ETDEWEB)

    Juengling, F.D. [Abt. fuer Nuklearmedizin, Radiologie III, Universitaetsklinik Ulm (Germany); Schaefer, M.; Heinz, A. [Klinik fuer Psychiatrie und Psychotherapie, Charite, Humboldt-Univ. zu Berlin (Germany)

    2002-09-01

    Nuclear medicine imaging techniques such as positron emission tomography (PET) and single photon emission tomography (SPECT) for selective depiction of GABA-A-benzodiazepine receptor (GBZR) binding are complementary investigations in the diagnostic process of neurological and psychiatric disorders. This review summarizes the current knowledge about options and limitations of PET and SPECT for in vivo diagnostics in neurology and psychiatry. The growing importance of GBZR-imaging for the understanding of pathophysiology and pharmacological treatment in different psychiatric syndromes is discussed. (orig.) [German] Mit der Entwicklung selektiver Liganden fuer den GABA-A-Benzodiazepinrezeptorkomplex (GBZR) hat die nuklearmedizinische Bildgebung mittels positronen-emissionstomographie (PET) und single-photon-emissionscomputertomographie (SPECT) einen festen Stellenwert fuer Klinik und Forschung in der Neurologie und Psychiatrie erlangt. Die vorliegende Ueberblicksarbeit fasst den aktuellen Wissensstand von Anwendungsmoeglichkeiten und -grenzen der nuklearmedizinischen Bildgebung der GBZR in vivo zusammen und beleuchtet ihren klinischen Nutzen. Die wachsende Bedeutung fuer das Verstaendnis der Pathophysiologie und pharmakotherapeutischer Konzepte unterschiedlicher psychiatrischer Erkrankungen wird herausgestellt. (orig.)

  19. Hip/femur fractures associated with the use of benzodiazepines (anxiolytics, hypnotics and related drugs): a methodological approach to assess consistencies across databases from the PROTECT-EU project.

    Science.gov (United States)

    Requena, Gema; Huerta, Consuelo; Gardarsdottir, Helga; Logie, John; González-González, Rocío; Abbing-Karahagopian, Victoria; Miret, Montserrat; Schneider, Cornelia; Souverein, Patrick C; Webb, Dave; Afonso, Ana; Boudiaf, Nada; Martin, Elisa; Oliva, Belén; Alvarez, Arturo; De Groot, Mark C H; Bate, Andrew; Johansson, Saga; Schlienger, Raymond; Reynolds, Robert; Klungel, Olaf H; de Abajo, Francisco J

    2016-03-01

    Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs. Copyright © 2015 John Wiley & Sons, Ltd.

  20. Ethyl 2-{4-[(1,5-dibenzyl-2,4-dioxo-2,3,4,5-tetra-hydro-1H-1,5-benzo-diazepin-3-yl)meth-yl]-1H-1,2,3-triazol-1-yl}acetate.

    Science.gov (United States)

    Jabli, Hind; Kandri Rodi, Y; Ladeira, Sonia; Essassi, El Mokhtar; Ng, Seik Weng

    2009-12-12

    The reaction of 1,5-dibenzyl-3-propargyl-1,5-benzodiazepine-2,4-dione with ethyl azido-acetate in the presence of copper sulfate pentahydrate and sodium ascorbate leads to the formation of the title regioisomer, C(30)H(29)N(5)O(4), which features a phenyl-ene ring fused with a seven-membered diazepinyl ring. The latter ring adopts a boat conformation (with the methyl-triazolylacetate-bearing C atom as the prow and the fused-ring C atoms as the stern). The benzyl groups connected to the diazepinyl ring jprotrude from the sides; the methyl-triazolylacetate substituent occupies an axial position.

  1. The synthesis of 1,2,7,11b-Tetrahydroisoxazolo[2,3-d][1,4]benzodiazepin-6(5H)-ones and 1,3,3a,9b-tetrahydroisoxazolo[4,3-c]quinolin-4(5H)-ones

    OpenAIRE

    Heaney, Frances; Bourke, Sharon

    1995-01-01

    The reaction of various ethyl 3-[[2-(1-hydroxyiminoalkyl)phenyl]carbamoyl]acrylates (2) with electron deficient olefins proceeds via a sequential dipole formation, dipolar cycloaddition sequence to furnish the tetrahydroisoxazolo[2,3-d][1,4]benzodiazepin-6(5H)-ones and tetrahydroisoxazolo[4,3-c]quinolin-4(5H)-ones (4) and (6). The product distribution reflects the nature of the reacting olefin and the position and extent of substitution on the acrylate moiety.

  2. Radiosynthesis of [11C]D.P.A.-713, [11C]D.P.A.-715 and [11C]clinme, selected carbon-11-labelled novel potential radioligands for imaging the peripheral benzodiazepine receptors with PET

    International Nuclear Information System (INIS)

    Dolle, F.; Thominiaux, C.; Hinnen, F.; Demphel, S.; Le helleix, S.; Chauveau, F.; Boutin, H.; Herard, A.S.; Hantraye, P.; Tavitian, B.; Kassiou, M.; James, M.; Creelman, A.; Fulton, R.; Kassiou, M.; Katsifis, A.; Greguric, I.; Mattner, F.; Loch, C.; Selleri, S.

    2008-01-01

    11 C P.K.11195 is not only the oldest, but also the most widely used PET radiotracer for in vivo imaging of the peripheral benzodiazepine receptors (P.B.R. or translocator protein (18 kDa, T.S.P.O.). With the aim of developing a new PET imaging probe for the in vivo study of the P.B.R., two pyrazol [1,5-a]pyrimidineacetamides (D.P.A.-713 and D.P.A.-715) and one imidazol[1,2-a]pyridine-acetamide (C.L.I.N.M.E.) were radiolabelled with the positron emitters carbon 11 (half life: 20.38 min) [1-5]. Briefly, C.L.I.N.M.E. (2-[6-chloro-2(4-iodophenyl)-imidazol[1,2-a]pyridin-3-yl] -N-ethyl-N-methyl-acetamide) was labelled at its methyl-acetamide moity chain from the corresponding nor-analogue using[ 11 C]methyl iodide (in D.M.S.O./D.M.F (100/200 μL) containing powdered K.O.H. (3-5 mg) at 110 degrees C for 3 min. D.P.A.-713 (N,N-diethyl-2-[2-(4-methoxy-phenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin -3-yl]acetamide) and D.P.A.-715 (N,N-diethyl-2-[2-(4-methoxy-phenyl)-5,7-bis-tri-fluoro-methyl-pyrazolo [1,5-a]pyrimidin-3-yl]acetamide) were labelled at their aromatic methoxy groups from the corresponding nor-derivatives using [ 11 C]methyl triflate (in acetone (300μL) containing aq. 3 M NaOH (4μL) at 110 degrees C for 1 min). All radioligands were purified using semi preparative Zorbax reverse phase H.P.L.C., were adequately formulated for in vivo injection within 30 min and were found to be > 95% chemically and radiochemically pure. (N.C.)

  3. [{sup 18}F]D.P.A.-714: a novel fluorine-18-labelled pyrazolo[1,5-a]pyrimidine acetamide for imaging the peripheral benzodiazepine receptors with PET - radiosynthesis on a zymate-xp robotic system

    Energy Technology Data Exchange (ETDEWEB)

    Dolle, F.; Damont, A.; Hinnen, F.; Kuhnast, B.; Chauveau, F.; Van camp, N.; Hantraye, P.; Tavitian, B. [Servvice Hospitalier Frederic Joliot, I2BM/DSV, 91 - Orsay (France); James, M.; Creelman, A.; Fulton, R.; Kassiou, M. [Sydney Univ., Brain and Mind Research Institute, NSW (Australia); Vercouillie, J.; Guilloteau, D. [Universite Francois Rabelais de Tours, 37 (France); Vercouillie, J.; Guilloteau, D. [Centre Hospitalier Regional Universitaire, 37 - Tours (France); Selleri, S.; Kassiou, M. [Sydney Univ., Discipline of Medical Radiations, Sciences and School of Chemistry, NSW (Australia)

    2008-02-15

    {sup 11}C D.P.A.-713 (N,N-diethyl-2-[2-(4-[{sup 11}C]methoxy-phenyl)-5,7-dimethyl-pyrazolo [1,5-a]pyrimidin-3-yl]acetamide) is a recently developed carbon-11-labelled (half life: 20.4 min)pyrazolo[1,5-a]pyrimidine acetamide for the in vivo imaging of the peripheral benzodiazepine receptors (P.B.R. or translocator protein (18 kDa, T.S.P.O.)). Preliminary results obtained in a rodent-model demonstrates that {sup 11}C D.P.A.-713 showed a high potential to in vivo image neuro-inflammation and additionally, this radioligand allowed a higher contrast between the lesioned area and the corresponding area in the intact contralateral hemisphere when compared to the radioligand of reference. D.P.A-714 (N,N-diethyl-2-[2-[4-(2-fluoro-ethoxy)phenyl] -5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]acetamide), a chemically closely related derivative of D.P.A.-713, had been designed with a fluorine atom in its structure, allowing ultimate labelling with fluorine-18, a longer-lived positron-emitter (half life:109.8 min) and today one of the most attractive PET isotopes for radiopharmaceutical chemistry. D.P.A.-714 as well as its corresponding tosylated derivative have been re-synthesized in 2 chemicals steps from D.P.A.-713. D.P.A.-714 has then been labelled at its aromatic fluoro-ethoxy group from the corresponding tosyl-derivative using the K{sup 18}FF-kryptofix{sub 222} (in CH{sub 3}CN (3 mL) at 85 degrees C for 5 min or D.M.S.O. (600 {mu}L) at 130 degrees C for 5 min). {sup 18}FD.P.A.-714 was then purified using semi preparative X terra reverse phase H.P.L.C., adequately formulated for i.v. injection and was found to be > 95% chemically and radiochemically pure. The total synthesis time was less than 90 min and the specific radioactivities at the end of the radiosynthesis ranged from 1 to 3 Ci/micro-mole. (N.C.)

  4. Radiosynthesis of [{sup 11}C]D.P.A.-713, [{sup 11}C]D.P.A.-715 and [{sup 11}C]clinme, selected carbon-11-labelled novel potential radioligands for imaging the peripheral benzodiazepine receptors with PET

    Energy Technology Data Exchange (ETDEWEB)

    Dolle, F.; Thominiaux, C.; Hinnen, F.; Demphel, S.; Le helleix, S.; Chauveau, F.; Boutin, H.; Herard, A.S.; Hantraye, P.; Tavitian, B. [Service Hospitalier Frederic Joliot, I2BM/DSV, 91 - Orsay (France); Kassiou, M.; James, M.; Creelman, A.; Fulton, R. [Sydney Univ., Brain and Mind Research Institute, NSW (Australia); Kassiou, M. [Sydney Univ., Discipline of Medical Radiations, Sciences and School of Chemistry, NSW (Australia); Katsifis, A.; Greguric, I.; Mattner, F.; Loch, C. [Radiopharmaceuticals Research Institute, ANSTO, NSW (Australia); Selleri, S. [Degli Studi di Firenze Univ., Dipt. di Scienze Farmaceutiche (Italy)

    2008-02-15

    {sup 11}C P.K.11195 is not only the oldest, but also the most widely used PET radiotracer for in vivo imaging of the peripheral benzodiazepine receptors (P.B.R. or translocator protein (18 kDa, T.S.P.O.). With the aim of developing a new PET imaging probe for the in vivo study of the P.B.R., two pyrazol [1,5-a]pyrimidineacetamides (D.P.A.-713 and D.P.A.-715) and one imidazol[1,2-a]pyridine-acetamide (C.L.I.N.M.E.) were radiolabelled with the positron emitters carbon{sup 11} (half life: 20.38 min) [1-5]. Briefly, C.L.I.N.M.E. (2-[6-chloro-2(4-iodophenyl)-imidazol[1,2-a]pyridin-3-yl] -N-ethyl-N-methyl-acetamide) was labelled at its methyl-acetamide moity chain from the corresponding nor-analogue using[{sup 11}C]methyl iodide (in D.M.S.O./D.M.F (100/200 {mu}L) containing powdered K.O.H. (3-5 mg) at 110 degrees C for 3 min. D.P.A.-713 (N,N-diethyl-2-[2-(4-methoxy-phenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin -3-yl]acetamide) and D.P.A.-715 (N,N-diethyl-2-[2-(4-methoxy-phenyl)-5,7-bis-tri-fluoro-methyl-pyrazolo [1,5-a]pyrimidin-3-yl]acetamide) were labelled at their aromatic methoxy groups from the corresponding nor-derivatives using [{sup 11}C]methyl triflate (in acetone (300{mu}L) containing aq. 3 M NaOH (4{mu}L) at 110 degrees C for 1 min). All radioligands were purified using semi preparative Zorbax reverse phase H.P.L.C., were adequately formulated for in vivo injection within 30 min and were found to be > 95% chemically and radiochemically pure. (N.C.)

  5. Synthesis and carbon-11-labeling of p-MeO-SSR180575, a novel indoleacetamide-based candidate for PET imaging of the peripheral benzodiazepine receptor (TSPO 18 kDa)

    International Nuclear Information System (INIS)

    Damont, A.L.; Le Helleix, St.; Kuhnast, B.; Boisgard, R.; Tavitian, B.; Dolle, F.; Marguet, F.; Puech, F.

    2011-01-01

    Complete text of publication follows: Objectives: The 3-iso-quinolinecarboxamide [ 11 C]PK11195, despite its low brain uptake and high level of nonspecific binding, is still the most widely used PET-radioligand for the in vivo imaging of the peripheral benzodiazepine receptor (PBR or TSPO 18 kDa). Several new PBR radioligands are currently developed to replace [ 11 C]PK11195 [1], e.g the pyrazolo[1, 5-a]pyrimidine-acetamides [ 11 C]DPA-713 and [ 18 F]DPA-714, the imidazo[1, 2-a]pyridine-acetamides [ 11 C]CLINME and [ 18 F]PBR111 and the N-benzyl-N-(2-phenoxy-aryl)- acetamides [ 11 C]PBR28 and [ 18 F]FEDAA1106. Another attractive newly identified chemical class of structures are the indole-acetamides and notably compounds derived from the lead compound SSR180575 [2]. Herein are reported the synthesis and the labelling with the positron-emitter carbon-11 (half-life: 20.38 min) of a novel derivative of SSR180575, bearing a para methoxy function on its phenyl ring. Methods: p-MeO-SSR180575 (1) was synthesized from commercially available 4-chloro-2-nitrotoluene in 10 steps. O-demethylation, performed with a boron tribromide solution in dichloromethane at low temperature, afforded the free phenol derivative 2. Carbon-11 labeling of p-MeO-SSR180575 (1) was performed using a TRACERLab FX-C Pro synthesizer (GEMS) and comprised (1) trapping of [ 11 C]MeOTf at -10 C in acetone (0.3 mL) containing the nor-derivative 2 (O-demethylated, 0.6-0.9 mg) and aq. 3N NaOH (8 μL); (2) heating at 110 C for 2 min; (3) concentration to dryness and taking up the residue in 1.0 mL of the HPLC mobile phase; (4) purification using semi-preparative reversed-phase HPLC (Waters Symmetry R C-18 - eluent: CH 3 CN / H 2 O / TFA: 50 / 50 / 0.1 (v:v:v) - flow rate: 5 mL/min - detection at 254 nm) and (5) SepPak Plus R C-18-based formulation for i.v. injection approach was the pyridazine ring formation reaction that proceeded partially: the maximum conversion of the intermediate diester-indole reacting

  6. Synthesis and carbon-11-labeling of p-MeO-SSR180575, a novel indoleacetamide-based candidate for PET imaging of the peripheral benzodiazepine receptor (TSPO 18 kDa)

    International Nuclear Information System (INIS)

    Damont, A.; Le Helleix, St.; Kuhnast, B.; Boisgard, R.; Tavitian, B.; Dolle, F.; Marguet, F.; Puech, F.

    2011-01-01

    Complete text of publication follows: Objectives: The 3-iso-quinolinecarboxamide [ 11 C]PK11195, despite its low brain uptake and high level of nonspecific binding, is still the most widely used PET-radioligand for the in vivo imaging of the peripheral benzodiazepine receptor (PBR or TSPO 18 kDa). Several new PBR radioligands are currently developed to replace [ 11 C]PK11195, e.g the pyrazolo[1, 5-a]pyrimidine-acetamides [ 11 C]DPA-713 and [ 18 F]DPA-714, the imidazo[1, 2-a]pyridine-acetamides [ 11 C]CLINME and [ 18 F]PBR111 and the N-benzyl-N-(2-phenoxy-aryl)- acetamides [ 11 C]PBR28 and [ 18 F]FEDAA1106. Another attractive newly identified chemical class of structures are the indole-acetamides and notably compounds derived from the lead compound SSR180575. Herein are reported the synthesis and the labelling with the positron-emitter carbon-11 (half-life: 20.38 min) of a novel derivative of SSR180575, bearing a para methoxy function on its phenyl ring. Methods: p-MeO-SSR180575 (1) was synthesized from commercially available 4-chloro-2-nitrotoluene in 10 steps. O-demethylation, performed with a boron tribromide solution in dichloromethane at low temperature, afforded the free phenol derivative 2. Carbon-11 labeling of p-MeO-SSR180575 (1) was performed using a TRACERLab FX-C Pro synthesizer (GEMS) and comprised (1) trapping of [ 11 C]MeOTf at -10 C in acetone (0.3 mL) containing the nor-derivative 2 (O-demethylated, 0.6-0.9 mg) and aq. 3N NaOH (8 μL); (2) heating at 110 C for 2 min; (3) concentration to dryness and taking up the residue in 1.0 mL of the HPLC mobile phase; (4) purification using semi-preparative reversed-phase HPLC (Waters Symmetry C-18 - eluent: CH 3 CN / H 2 O / TFA: 50 / 50 / 0.1 (v:v:v) - flow rate: 5 mL/min - detection at 254 nm) and (5) SepPak R Plus C-18-based formulation for i.v. injection. Results: p-MeO-SSR180575 (1) was obtained in 10% overall yield. The tricky and low-yielding step in our approach was the pyridazine ring formation

  7. Crystal strucutre of rac-methyl (11aR*,12S*,13R*,15aS*,15bS*-11-oxo-11,11a,12,13-tetrahydro-9H,15bH-13,15a-epoxyisoindolo[1,2-c]pyrrolo[1,2-a][1,4]benzodiazepine-12-carboxylate

    Directory of Open Access Journals (Sweden)

    Vladimir P. Zaytsev

    2014-12-01

    Full Text Available The title compound, C21H18N2O4, obtained as a racemate, contains a novel heterocyclic system, viz. isoindolo[1,2-c]pyrrolo[1,2-a][1,4]benzodiazepine. The central diazepane ring has a distorted boat conformation with two phenylene-fused and one methine C atom deviating by 0.931 (1, 0.887 (1 and 0.561 (1 Å, respectively, from the mean plane of the rest of the ring. The γ-lactone ring has an envelope conformation, with the C atom opposite to amide bond deviating by 0.355 (1 Å from its plane. In the crystal, molecules form centrosymmetric dimers through pairs of C—H...O hydrogen bonds.

  8. Utilização de benzodiazepínicos no Serviço Municipal de Saúde de Coronel Fabriciano, Minas Gerais Use of benzodiazepines in local public health services in Coronel Fabriciano in the State of Minas Gerais

    Directory of Open Access Journals (Sweden)

    Karleyla Fassarelo Firmino

    2012-01-01

    Full Text Available Neste estudo foram avaliadas as indicações de benzodiazepínicos no Serviço Municipal de Saúde de Coronel FabricianoMG, verificando sua conformidade com o preconizado pela literatura. O estudo avaliou todas as receitas desses medicamentos provenientes das Unidades Municipais de Saúde no período de Setembro a Outubro de 2006, os formulários de indicação clínica preenchidos pelo prescritor e cadastros informatizados do serviço. Analisaram-se 1.866 receitas, sendo 59,7% do Diazepam e o restante do Clonazepam. A Dose Diária Definida por mil habitantes por dia foi de 24,69 para o Diazepam e de 3,58 para o Clonazepam. Cerca de 50% das indicações relatadas pelos médicos foram como hipnótico ou ansiolítico, 21,9% para "uso crônico/dependência" e o restante para outras indicações. Das receitas que atenderam aos critérios de inclusão para análise da adequação da indicação (1618, cerca de 70% foram consideradas não adequadas, tendo em vista a indicação e o tempo de tratamento. Houve um alto percentual de inadequação na utilização de benzodiazepínicos, principalmente pelo uso prolongado e para atender a casos considerados pelos prescritores como uso crônico/dependência. Assim, há responsabilidade do serviço de saúde na manutenção da dependência.In this study, indications for benzodiazepines in the healthcare services of the city of Coronel Fabriciano (State of Minas Gerais, Brazil were analyzed in terms of compliance with the indications established in the literature. The study was carried out using all prescriptions for benzodiazepines in municipal healthcare units between September and October 2006, as well as the prescription form filled out by the prescriber and computer files. A total of 1866 prescriptions were analyzed; 59.7% were for diazepam and the rest were for clonazepam. The mean daily dose per 1000 inhabitants/day was 24.69 for diazepam and 3.58 for clonazepam. Approximately 50% of the indications

  9. Heterocycles [h]-Fused Onto 4-Oxoquinoline-3-Carboxylic Acid, Part VIII [1]. Convenient Synthesis and Antimicrobial Properties of Substituted Hexahydro[1,4]diazepino[2,3-h]quinoline-9-carboxylic acid and Its Tetrahydroquino[7,8-b]benzodiazepine Analog

    Directory of Open Access Journals (Sweden)

    Yusuf M. Al-Hiari

    2008-11-01

    Full Text Available [1,4]Diazepino[2,3-h]quinolone carboxylic acid 3 and its benzo-homolog tetrahydroquino[7,8-b]benzodiazepine-3-carboxylic acid 5 were prepared via PPAcatalyzed thermal lactamization of the respective 8-amino-7-substituted-1,4-dihydroquinoline-3-carboxylic acid derivatives 8, 10. The latter compounds were obtained by reduction of their 8-nitro-7-substituted-1,4-dihydroquinoline-3-carboxylic acid precursors 7, 9 which, in turn, were prepared by reaction of 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-1,4-dihydroquinoline-3-carboxylic acid (6 with each of β-alanine and anthranilic acid. All intermediates and target compounds were characterized using elemental analysis, NMR, IR and MS spectral data. The prepared targets and the intermediates have shown interesting antibacterial activity mainly against Gram positive strains. In particular, compound 8 showed good activity against S. aureus (MIC = 0.39 μg/mL and B. subtilis (MIC = 0.78 μg/mL. Compounds 5a and 9 have also displayed good antifungal activity against C. albicans (MIC = 1.56 μg/mL and 0.78 μg/mL, respectively. None of the compounds tested showed any anticancer activity against solid breast cancer cell line MCF-7 cells or a human breast adenocarcinoma cell line.

  10. Radiosynthesis of 7-chloro-N, N-dimethyl-5-[11C] methyl-4-oxo-3-phenyl-3, 5-dihydro-4H pyridazino [4, 5-b]indole-1-acetamide, [11C]SSR180575, a novel radioligand for imaging the TSPO (peripheral benzodiazepine receptor) with PET

    International Nuclear Information System (INIS)

    Thominiaux, C.; Damont, A.L.; Kuhnast, B.; Demphel, St.; Le Helleix, St.; Chauveau, F.; Boutin, H.; Van Camp, N.; Boisgard, R.; Tavitian, B.; Dolle, F.; Boisnard, S.; Rivron, L.; Roy, S.; Allen, J.; Chauveau, F.; Boutin, H.; Van Camp, N.; Boisgard, R.; Tavitian, B.; Rooney, T.; Benavides, J.; Hantraye, Ph.

    2010-01-01

    SSR180575 (7-chloro-N, N, 5-trimethyl-4-oxo-3-phenyl-3, 5-dihydro-4H-pyridazino [4, 5-b]indole-1-acetamide) is the lead compound of an original pyridazino-indole series of potent and highly selective TSPO (peripheral benzodiazepine receptor) ligands. Isotopic labeling of SSR180575 with the short-lived positron-emitter carbon-11 (T1/2: 20.38 min) at its 5-methyl-pyridazino[4, 5-b]indole moiety as well as at its N, N-dimethylacetamide function by methylation of the corresponding nor-analogues was investigated. Best results in terms of radiochemical yields and purities were obtained for the preparation of [indole-N-methyl- 11 C]SSR180575, where routine production batches of 4.5-5.0 GBq of radiochemically pure (499%) i.v. injectable solutions (specific radioactivities: 50-90 GBq/μmol) could be prepared within a total synthesis time of 25 min (HPLC purification included) starting from a 55 GBq [ 11 C]CO 2 cyclotron production batch (non decay-corrected overall radiochemical yields: 8-9%). The process comprises (1) trapping at -10 C of [ 11 C]methyl triflate in DMF (300 μl) containing 0.2-0.3 mg of the indole precursor for labeling and 4 mg of K 2 CO 3 (excess); (2) heating at 120 C for 3 min; (3) dilution of the residue with 0.5 ml of the HPLC mobile phase and (4) purification using semi-preparative reversed phase HPLC (Zorbax R SB-C-18). In vivo pharmacological properties of [indole-N-methyl- 11 C]SSR180575 as a candidate for imaging neuro-inflammation with positron emission tomography are currently evaluated. (authors)

  11. Benzodiazepines still play a role in modern psychiatric therapy

    DEFF Research Database (Denmark)

    Jørgensen, Martin Balslev; Videbech, Poul; Osler, Merete

    2017-01-01

    , and that BZ cause traffic accidents, increased mortality and dementia. In Denmark, the use of BZ has been substantially reduced. In this article it is argued, that not all patients habituate, that most of the epidemiological findings are hampered by confounding, and that there still is a role for long...

  12. In vivo study of drug interaction with brain benzodiazepine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, O.; Shinotoh, H.; Ito, T.; Suzuki, K.; Hashimoto, K.; Yamasaki, T.

    1985-05-01

    The possibility of direct estimation of in vivo Bz receptor occupancy in brain was evaluated using C-11, or H-3-flumazepil (Ro15-1788). In animal experiments, 1 ..mu..Ci of H-3-Ro15-1788 was injected at 0.5 or 20 hr after i.v. injection of various dosage of clonazepam. Then radioactivity in cerebral cortex, cerebellum and blood at 5 min. after injection of the tracer was compared. Competitive inhibition of in vivo binding was clearly observed when clonazepam was pretreated at 0.5 hr before injection of the tracer. On the other hand, brain radioactivity was increased when clonazepam was administered at 20 hr before injection of the tracer. This increase in binding of H-3-Ro15-1788 might be caused by rebound of Bz receptor function by treatment with Bz agonist, and this rebound may have an important role in physiological function. Clinical investigation concerning drug interaction with brain Bz receptor was performed in normal volunteer and patients with neurological disorders. The distribution of C-11-Ro15-1788 in the brain of patients chronically treated with clonazepam were significantly heterogeneous. However, cerebral blood flow estimated with N-13 NH3 of these patients were normal.

  13. Consumption of benzodiazepines without prescription among first-year nursing students at the University of Guayaquil, school of nursing, Ecuador Consumo de benzodiacepinas sin prescripción médica en los/as estudiantes de primer año de la escuela de enfermería de la Universidad de Guayaquil, Ecuador Consumo de benzodiazepinos sem prescrição médica entre estudantes do primeiro ano da escola de enfermagem da Universidade de Guayaquil, Equador

    Directory of Open Access Journals (Sweden)

    Nivia Pinos Paredes

    2008-08-01

    Full Text Available This study aimed to determine the consumption of benzodiazepines without prescription among first-year students from a nursing school of a public University in Ecuador. This is a descriptive, transversal and explanatory study with a quantitative approach. A questionnaire was used for data collection. The population studied was of 181 students. The results showed that 10.5% of the students had consumed benzodiazepine without prescription once in their lives. Of these, 6.1% consumed benzodiazepine in the last year, and 3.9% are currently consuming it. The diazepam was the most consumed BZD without prescription and pharmacies, were the place of higher access. The main reasons for the benzodiazepine consumption were: insomnia, anxiety, stress, depression, family and economical problems. The use of benzodiazepines with non-medicinal purposes is related to problems such as memory loss, retirement syndrome and sedation. When benzodiazepines are consumed jointly with alcohol or other drugs they can lead to coma or death. This study shows the serious consequences benzodiazepines cause when used by nursing students in Ecuador.La finalidad de este estudio fue determinar el consumo de benzodiacepinas sin prescripción en estudiantes del primer año de enfermería de una universidad pública de Ecuador. Se trata de un estudio transversal, descriptivo y exploratorio, con aproximación cuantitativa. Un cuestionario fue usado para la recolecta de los datos. La población estudiada fue compuesta por 181 estudiantes. Los resultados muestran que el 10,5% de los estudiantes consumió benzodiacepinas sin prescripción médica alguna vez en la vida. Del total, el 6,1% consumió en el último año y el 3,9% usan actualmente. El Diazepan fue la BZD más usada sin prescripción médica, siendo la farmacia el local de mayor acceso. Entre los principales motivos para el consumo de benzodiacepinas se encuentran: insomnio, ansiedad, estrés, depresión y problemas

  14. Utilização de benzodiazepínicos por idosos de umaestratégia de saúde da família: implicações para enfermagem Utilización de benzodiazepinas en ancianos de una estrategia de salud familiar: implicaciones para enfermería The use of benzodiazepines in the elderly in a family health strategy: implications in

    Directory of Open Access Journals (Sweden)

    Paulo Celso Prado Telles Filho

    2011-09-01

    propicia la adecuación de las prescripciones y seguimiento optimizado de las mismas. Palabras clave: Sistemas de Medicación. Utilización de Medicamentos. AncianoBenzodiazepines are drugs that may cause risks to the elderly. The purpose of this study was to verify and analyze the prevalence of the use of benzodiazepines among elderly patients enrolled in a Family Health Strategy in Diamantina, Minas Gerais, Brazil. This descriptive study was performed with 27 elderly individuals, from May to July 2010, using a semi-structured questionnaire. A descriptive analysis of the data was performed. Results show that most participants were between 71 and 75 years old (25.92%, female (88.88% and had incomplete primary education (66.66%. The most common drugs were: Diazepam (37.03%, Clonazepam (25.92%, Bromazepam (18.51% and Alprazolam (11.11%. Of all participants, 88.90% had prescriptions for their medication and 11.10% did not. Among those with prescriptions, 33.33% did not comply with recommendations. There is a need to reorganize the working process at the studied institution to promote an adaptation of the prescriptions and a more effective compliance.

  15. Changes of seizure susceptibility during benzodiazepine withdrawal in immature rats: comparison of clonazepam and partial benzodiazepine agonist Ro 19-8022

    Czech Academy of Sciences Publication Activity Database

    Kubová, Hana

    2006-01-01

    Roč. 47, č. S4 (2006), s. 221-221 ISSN 0013-9580. [Annual Meeting of the American Epilepsy Society and Canadian League against Epilepsy. 01.12.2006-05.12.2006, San Diego, CA] R&D Projects: GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50110509 Keywords : PTZ-induced seizures * clonazepam * agonist Ro 19-8022 Subject RIV: ED - Physiology

  16. Is Peripheral Benzodiazepine Receptor (PBR) Gene Expression Involved in Breast Cancer Suppression by Dietary Soybean Protein?

    National Research Council Canada - National Science Library

    Das, Salil

    2006-01-01

    .... It has been established that women in Asian countries consume more soy protein than women in the United States and that the incidence of breast cancer in women in Asian countries is generally lower...

  17. How to face a patient with benzodiazepine dependence in primary health care? Strategies for withdrawal

    OpenAIRE

    Josefina Aguiluz; Matías Álvarez; Eduardo Pimentel; Carolina Abarca; Philippa Moore

    2018-01-01

    Resumen Las benzodiacepinas son fármacos ampliamente utilizados en atención primaria de salud. Su uso prolongado se ha convertido en un problema relevante dadas las consecuencias médicas que ocasionan, especialmente en adultos mayores. Entre otras, estas son: dependencia, deterioro cognitivo y riesgo de caídas. Además, los médicos que trabajan en atención primaria cuentan con pocas herramientas para ayudar al paciente en su deshabituación. Se realizó una búsqueda y revisión de la mejor evi...

  18. How to face a patient with benzodiazepine dependence in primary health care? Strategies for withdrawal

    Directory of Open Access Journals (Sweden)

    Josefina Aguiluz

    2018-01-01

    Full Text Available Resumen Las benzodiacepinas son fármacos ampliamente utilizados en atención primaria de salud. Su uso prolongado se ha convertido en un problema relevante dadas las consecuencias médicas que ocasionan, especialmente en adultos mayores. Entre otras, estas son: dependencia, deterioro cognitivo y riesgo de caídas. Además, los médicos que trabajan en atención primaria cuentan con pocas herramientas para ayudar al paciente en su deshabituación. Se realizó una búsqueda y revisión de la mejor evidencia disponible sobre estrategias prácticas para el médico no especialista en adicciones, para evitar la dependencia al momento de la prescripción inicial y en el paciente con uso prolongado y probablemente dependiente. Se encontraron 10 revisiones sistemáticas relevantes que mostraron evidencia a favor del uso de estrategias multifacéticas en la prescripción, disminución progresiva, cartas y consejería estandarizadas, farmacoterapia y psicoterapia cognitiva conductual. Una estrategia sencilla, eficaz y duradera para prescribir benzodiacepinas es informar al paciente de la necesidad de reducir su consumo, dándole por escrito la pauta de retirada, señalando sus posibles efectos y su solución. Debido a la evidencia disponible, se propone un modelo integrado y escalonado para el manejo del paciente usuario de benzodiacepinas, desde su prescripción hasta su descontinuación.

  19. Consequences of early postnatal benzodiazepines exposure in rats. I. Cognitive-like behavior

    Directory of Open Access Journals (Sweden)

    Anna eMikulecka

    2014-03-01

    Full Text Available Clinical and experimental studies suggest possible risks associated with the repeated administration of BZDS during the prenatal or early postnatal period on further development and behavior. In the present study, we assess short- and long-term effects of early exposure to clonazepam (CZP on cognitive tasks. CZP (0.5 or 1.0 mg/kg/day was administered from postnatal day (P7 until P11, and animals were exposed to the following behavioral tests at different developmental stages: (1 a homing response test, which exploits the motivation of a rat pup to reach its home nest, was administered on P12, P15, P18 and P23 rats; (2 passive avoidance was tested in three trials (at 0 h, 2 h and 24 h intervals on P12, P15, P18, P25 and P32 rats; (3 within- and between-session habituation was tested in an open field (OF at P70; and (4 a long-term memory version of the Morris water maze (MWM was tested at P80. A 1.0 mg/kg dose of CZP extended latency in the homing response and decreased the number of correct responses when tested at P12 and P23. In the first trial of the passive avoidance test, latency to enter a dark compartment was shorter in the CZP-exposed rats. Both treated and control animals older than P15 learned the passive-avoidance response at the same rate. Irrespective of the treatments, all adult animals showed within-session habituation. Between-session habituation, however, was found only in the controls. With respect to the MWM test, all animals learned to reach the platform, but animals exposed to higher doses of CZP spent more time swimming in the first acquisition test. No difference between groups was found in a repeated acquisition test (10 and 40 days after the first acquisition test. The results of the present study show that even short-term exposure to CZP alters behavioral responsiveness in pre-weaning, juvenile and adult animals. Not only were changes observed on conventional cognitive tests in our study, but the changes also seem to be related to

  20. Is Peripheral Benzodiazepine Receptor (PBR) Gene Expression Involved in Breast Cancer Suppression by Dietary Soybean Protein

    National Research Council Canada - National Science Library

    Das, Salil

    2004-01-01

    ...% casein and those of groups 3 and 4 received same diet containing 20% soybean protein. Animals of groups 2 and 4 received DMBA in sesame oil by gavage (15 mg per animal). Control animals (groups 1 and 3...

  1. Evidence of a role for GABA in benzodiazepine effects on food preference in rats.

    Science.gov (United States)

    Hodges, H M; Green, S E

    1981-01-01

    It has previously been shown that chronic treatment with the GABA-transaminase inhibitor ethanolamine-O-sulphate (EOS), which elevates brain GABA levels by around 200%, selectivity enhances novel food consumption in rats treated with chlordiazepoxide (CDP) and given a food preference test. To replicate and extend these findings, the effects of two doses of CDP with and without EOS pretreatment were compared with those of EOS or saline alone. EOS alone had no significant effects except to decrease eating rate but, in combination with 2.5 mg/kg CDP, it antagonised the increase in weight of familiar food eaten found with CDP alone and marginally increased weight eaten and duration of novel foot eating episodes. EOS magnified the effects of 5.0 mg/kg CDP to increase markedly the weight eaten and duration of episodes for novel chocolate drops. As no additive effects of EOS and CDP on rate of eating were found, the results are consistent with a facilitation of novel food consumption by an anxiolytic action of the two drugs, rather than by a rate-retarding action which might bias animals toward novel food. Finally, that EOS alone did not mimic the effects of CDP suggests that the role of GABA in the anxiolytic action of CDP may be indirect.

  2. Atuoradiographic detection of multiple sclerosis plaques with an ω3 (peripheral type benzodiazepine) binding site radiogland

    International Nuclear Information System (INIS)

    HAUW, J.J.; Sazdovitch, V.; Cornu, P.; Dubois, A.; Benavides, J.; Mac Kenzie, E.; Scatton, B.

    1989-01-01

    In Multiple Sclerosis (MS), the presence of monocyte-macrophages and microglial cells in active plaques is a constant feature. They are numerous at the border of active lesions where they constiture, with other cell types such as lymphocytes and oligodendrocytes the so-called flial wall. Monocyte-macrophages and microglial cells are thought to be directly involved in the process of demyelination. Some macrophages laden with meylin degradation products are also seen in the center of the plaqie, often located in the perivascular cuffs. In addition, astrocytic gliosis occurs in the center of the plaques. As all these cell types are richly endowed with ω3 sites, the feasibility of using ω3 site autoradiagraphy to detect the demyelination plaques in the brain of post-mortem cases of Multiple Sclerosis has been investigated. (Author). 8 refs

  3. (11-Methylpyrido[2,3-b][1,4]benzodiazepin-6-yl(phenylmethanone

    Directory of Open Access Journals (Sweden)

    Fuqiang Shi

    2010-09-01

    Full Text Available In the title compound, C20H15N3O, the diazepine ring adopts a boat conformation. The dihedral angle between pyridine and benzene rings is 55.2 (1°. The benzoyl phenyl ring forms dihedral angles of 49.4 (1 and 75.9 (1°, respectively, with the pyridine and benzene rings. In the crystal, molecules are linked into centrosymmetric dimers by pairs of C—H...N hydrogen bonds.

  4. Degradation of benzodiazepines using water falling film dielectric barrier discharge reactor

    Directory of Open Access Journals (Sweden)

    Radulović Vesna M.

    2017-01-01

    Full Text Available Classical methods of wastewater treatment are often not suitable for the treatment of pharmaceutical waste. The previous studies have shown that the use of the advanced oxidation procedures (AOP can lead to a more efficient degradation of various biologically active compounds, which are active pharmaceutical ingredients of applied drugs. The aim of this paper is the application of the plasma technology on the degradation of a two active pharmaceutical ingredients (APIs, diazepam and alprazolam and the finished products (Bensedin® and Ksalol® using the dielectric barrier discharge (DBD reactor for AOP. We studied the degradation rate of these pharmaceuticals, depending on the number of passes through the reactor. This degradation method was efficient 61 % for diazepam and 95 % alprazolam. We also examined the influence of the pH adjustment between the passes of APIs through the DBD reactor. The degradation rate of APIs and the finished products was monitored by the high performance liquid chromatography (HPLC technique, using a photodiode array detector. The concentration of the dissolved ozone was determined using the iodometric procedure. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 172030

  5. Use of the glyceryl guaiacolate alone and associated with levomepromazine and benzodiazepines in gelding of horses

    Directory of Open Access Journals (Sweden)

    Flavio Massone

    1990-12-01

    caracterizar-se por valores maiores de freqüência respiratória que os demais grupos. As três técnicas anestésicas mostraram-se satisfatórias, pela estabilidade de parâmetros fisiológicos e indução e recuperação suaves, sendo que a associação da levomepromazina com o flunitrazepan ou midazolam proporcionou prostração mais eficaz, bem como maior miorrelaxamento, sedação e hipoalgesia.

  6. Differential effects of benzodiazepines on phospholipid methylation in hippocampus and cerebellum of rats

    Energy Technology Data Exchange (ETDEWEB)

    Tacconi, M.T.; Salmona, M.

    1988-01-01

    To elucidate the relationship between the occupancy of BDZ binding sites and phospholipid methylation in brain, the authors examined phosphatidylethanolamine-N-methyltransferase (PEMT) activity in synaptosomes of rat hippocampi and cerebella in the presence of BDZ ligands with different modes of action. We found that Ro 5-4864, a specific ligand for peripheral type receptors, increased PL methylation in hippocampal and cerebellar synaptosomes. This effect was directly related to receptor occupancy, since the specific antagonist PK11195 inhibited the rise in PEMT activity induced by Ro 5-4864. Clonazepam, on the other hand, tended to reduce PL production in cerebellum and hippocampus except for hiccocampal (/sup 3/H)-phosphatidyl-N-monomethylethanolamine which was elevated by 40 to 70% at doses ranging from 10/sup -9/ to 10/sup -6/M. When equimolar concentrations of the antagonist Ro 15-1788 were given in association the clonazepam-induced phosphatidyl-N-monomethylethanolamine increase was reduced by 70%. These data support the involvement of structural and functional membrane alterations in the action of BDZ. 20 references, 2 figures, 2 tables.

  7. Consequences of early postnatal benzodiazepines exposure in rats. II. Social behavior

    Directory of Open Access Journals (Sweden)

    Anna eMikulecka

    2014-05-01

    Full Text Available Social behavior represents an integral part of behavioral repertoire of rats particularly sensitive to pharmacological and environmental influences. The aim of the present study was to investigate whether early postnatal clonazepam (CZP exposure can induce age-dependent changes related to expression of social behavior. The drug was administered from postnatal day (P 7 until P11 at daily doses of 0.1, 0.5 and 1.0 mg/kg i.p. We designed three experiments to assess whether exposure to CZP affects social behavior in respect to the age of rats and the test circumstances, specifically their familiarity with test conditions during adolescence (P32, social behavior in juveniles and adolescents (P18-P42 and social behavior in a resident-intruder paradigm. The frequency and duration of a various patterns of social behavior related to play and social investigation not related to play were evaluated. The results showed that CZP postnatal exposure decreased social play behavior regardless of age and familiarity or unfamiliarity of experimental environment but did not affect the social investigation per se. When rats were confronted with an intruder in their home cages intense wrestling and inhibition of genital investigation were found. In conclusion, these findings show that short-term CZP postnatal exposure inhibits social play behavior and alters specific patterns of social behavior in an age and environment related manner

  8. Current issues in the use of benzodiazepines for the treatment of ...

    African Journals Online (AJOL)

    QuickSilver

    SA Psych Rev 2003;6:4-6. South African ... BZ2 receptors are believed to be involved in cognition, memory and motor ... tors has fewer adverse cognitive effects (e.g. zolpidem). ..... Vaughn McCall W. A psychiatric perspective of Insomnia.

  9. The benzodiazepine brotizolam reduces fear in calves exposed to a novel object test

    NARCIS (Netherlands)

    Reenen, van C.G.; Hopster, H.; Werf, van der J.T.N.; Engel, B.; Buist, W.G.; Jones, R.B.; Blokhuis, H.J.; Korte, S.M.

    2009-01-01

    The present study examined the effects of the intravenous administration of the anxiolytic drug brotizolam on the behavioral and physiological responsiveness of calves to novelty in a dose response fashion. Holstein Friesian heifer calves (39¿41 weeks of age; body weight 200¿300 kg) received an

  10. Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA(A) receptors

    DEFF Research Database (Denmark)

    Nilsson, Jakob; Gidlöf, Ritha; Nielsen, Elsebet Østergaard

    2011-01-01

    in an overall yield of approximately 40%, and a library of 9-substituted analogues was prepared by cross-coupling reactions. Compound 8e, 21, 22, and 24 were tested on recombinant rat a(1)ß(3)¿(2), a(2)ß(3)¿(2), a(3)ß(3)¿(2), and a(5)ß(3)¿(2) subtypes, and displayed selectivity for the a(1)ß(3)¿(2) isoform....

  11. Role of interleukin-1 receptor signaling in the behavioral effects of ethanol and benzodiazepines.

    Science.gov (United States)

    Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy; Mayfield, Jody; Harris, R Adron

    2015-08-01

    Gene expression studies identified the interleukin-1 receptor type I (IL-1R1) as part of a pathway associated with a genetic predisposition to high alcohol consumption, and lack of the endogenous IL-1 receptor antagonist (IL-1ra) strongly reduced ethanol intake in mice. Here, we compared ethanol-mediated behaviors in mice lacking Il1rn or Il1r1. Deletion of Il1rn (the gene encoding IL-1ra) increases sensitivity to the sedative/hypnotic effects of ethanol and flurazepam and reduces severity of acute ethanol withdrawal. Conversely, deletion of Il1r1 (the gene encoding the IL-1 receptor type I, IL-1R1) reduces sensitivity to the sedative effects of ethanol and flurazepam and increases the severity of acute ethanol withdrawal. The sedative effects of ketamine and pentobarbital were not altered in the knockout (KO) strains. Ethanol intake and preference were not changed in mice lacking Il1r1 in three different tests of ethanol consumption. Recovery from ethanol-induced motor incoordination was only altered in female mice lacking Il1r1. Mice lacking Il1rn (but not Il1r1) showed increased ethanol clearance and decreased ethanol-induced conditioned taste aversion. The increased ethanol- and flurazepam-induced sedation in Il1rn KO mice was decreased by administration of IL-1ra (Kineret), and pre-treatment with Kineret also restored the severity of acute ethanol withdrawal. Ethanol-induced sedation and withdrawal severity were changed in opposite directions in the null mutants, indicating that these responses are likely regulated by IL-1R1 signaling, whereas ethanol intake and preference do not appear to be solely regulated by this pathway. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. The effect of the benzodiazepine antagonist flumazenil on regional cerebral blood flow in human volunteers

    DEFF Research Database (Denmark)

    Wolf, J; Friberg, L; Jensen, J

    1990-01-01

    computerized tomography, SPECT, immediately before, and 5 and 35 min after intravenous injection of flumazenil 1.0 mg or placebo. In addition, mean arterial blood pressures or PaCO2, rCBF were analysed for changes in various regions of interest (RoI). No alterations were found either in the global CBF or in r......CBF in RoI after flumazenil injection. The results showed that a clinically active dose of flumazenil did not directly affect the cerebral circulation in the normal brain and indicated absence of significant intrinsic activity of the drug....

  13. Benzodiazepine receptor quantification in vivo in humans using [11C]flumazenil and PET

    DEFF Research Database (Denmark)

    Lassen, N A; Bartenstein, P A; Lammertsma, A A

    1995-01-01

    (60 min instead of 120 min) it was preferred. The five subjects had a mean KD value of 12 nM/L of water and Bmax values of the grey matter ranging from 39 +/- 11 in thalamus to 120 +/- 14 nM/L of brain in occipital cortex. Most previous studies have been based on the pseudoequilibrium approach using...

  14. Stability of benzodiazepines and cocaine in blood spots stored on filter paper.

    Science.gov (United States)

    Alfazil, Abdulkareem A; Anderson, Robert A

    2008-09-01

    Previous studies have shown that drug concentrations in blood can change during storage, especially at room temperature, but even labile drugs such as cocaine may be stable in dried blood spots (DBS). A new method has been developed for the analysis of hydrolytically labile drugs in blood spots on filter paper in order to assess their degradation during a storage period of one month. The drugs selected included flunitrazepam, temazepam, oxazepam, lorazepam, nitrazepam, diazepam, and cocaine. A Guthrie card 903 was spotted with 100 microL of blood containing the drugs at concentrations of 1000 ng/mL and left overnight to dry at room temperature. The filter paper was suspended in extraction buffer for 1 h with ultrasonication. Drugs were then extracted from the buffer by solid-phase extraction using Clean Screen((R)) columns and analyzed by liquid chromatography-tandem mass spectrometry. Method validation showed that all calibration curves were linear over the concentration range 5-200 ng/spot with correlation coefficients of 0.994-0.999. Interday and intraday precisions at three concentrations (10, 50, and 100 ng/spot) were 1.6-18.3% and 2.8-14.7%, respectively. Limits of detection were 0.29-0.74 ng/spot, and lower limits of quantitation were 0.99-2.46 ng/spot. Recoveries of all analytes were in the range 81-106%. DBS were stored in duplicate at room temperature, 4 degrees C, and -20 degrees C for up to one month. Degradation of the drugs in DBS at all storage conditions was less than for the corresponding liquid blood samples stored under similar conditions and more than 80% of each analyte could be recovered from the samples.

  15. Screening for drugs of abuse (II): Cannabinoids, lysergic acid diethylamide, buprenorphine, methadone, barbiturates, benzodiazepines and other drugs.

    Science.gov (United States)

    Simpson, D; Braithwaite, R A; Jarvie, D R; Stewart, M J; Walker, S; Watson, I W; Widdop, B

    1997-09-01

    Requirements for the provision of an efficient and reliable service for drugs of abuse screening in urine have been summarized in Part I of this review. The requirements included rapid turn-around times, good communications between requesting clinicians and the laboratory, and participation in quality assessment schemes. In addition, the need for checking/confirmation of positive results obtained for preliminary screening methods was stressed. This aspect of the service has assumed even greater importance with widespread use of dip-stick technology and the increasing number of reasons for which drug screening is performed. Many of these additional uses of drug screening have possible serious legal implications, for example, screening school pupils, professional footballers, parents involved in child custody cases, persons applying for renewal of a driving licence after disqualification for a drug-related offence, doctors seeking re-registration after removal for drug abuse, and checking for compliance with terms of probation orders; as well as pre-employment screening and work-place testing. In many cases these requests will be received from a general practitioner or drug clinic with no indication of the reason for which testing has been requested. This also raises the serious problems of a chain of custody, provision of two samples, stability of samples, and secure and lengthy storage of samples in the laboratory-samples may be requested by legal authorities several months after the initial testing. The need for confirmation of positive results is now widely accepted but it may be equally important to confirm unexpected negative results. Failure to detect the presence of maintenance drugs may lead to the patient being discharged from a drug treatment clinic and, if attendance at the clinic is one of the terms of continued employment, to dismissal. It seems likely that increasing abuse of drugs and the efforts of regulatory authorities to control this, will lead to the manufacture of more designer drugs. Production of substituted phenethylamines was facilitated by the drug makers' cook book, 'PIHKAL' (Phenethylamines I Have Known And Loved) by Dr Alexander Shulgin and Ann Shulgin, and production of substituted tryptamines is promised in their next book, TIHKAL. Looking to the future, laboratories will need to ensure that they can detect and quantitate an ever-increasing number of drugs and related substances. The question of confidence in results of drugs of abuse testing raised in 1993 by Watson has assumed even greater importance as a result of attention focused on the OJ Simpson trial in Los Angeles. Toxicological investigations are likely to be challenged more frequently in the future. Even if analyses have been performed by GC-MS, there is a need to establish the level of match between the spectrum of the unknown substance and a library spectrum which is considered acceptable for legal purposes. It will also be essential to ensure that computer libraries contain spectra for all substances likely to be encountered in drugs of abuse screening.

  16. Sex differences in concomitant medication with benzodiazepines or antidepressants in first-break schizophrenic patients treated with antipsychotic medication

    NARCIS (Netherlands)

    Rijcken, C.A.W.; Knegtering, H; Bruggeman, R; Tobi, H; de Jong-van den Berg, Lolkje Theodora Wilhelmina

    2005-01-01

    During a first episode of psychosis, treatment with antipsychotic drugs can improve both positive and negative symptoms. If sufficient amelioration does not occur, adding psychotropic comedication may result in a favorable outcome. To establish sex differences in psychotropic comedication use, we

  17. Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Alvarado, M.; Budinger, T.F.; Grossman, R.; Hensley, K.; West, M.S.; Kotake, Y.; Ono, M.; Floyd, R.A.

    2001-12-10

    Following induction of acute neuroinflammation by intracisternal injection of endotoxin (lipopolysaccharide) in rats, quantitative autoradiography was used to assess the regional level of microglial activation and glutamate (NMDA) receptor binding. The possible protective action of the antioxidant phenyl-tert-butyl nitrone in this model was tested by administering the drug in the drinking water for 6 days starting 24 hours after endotoxin injection. Animals were killed 7 days post-injection and consecutive cryostat brain sections labeled with [3H]PK11195 as a marker of activated microglia and [125I]iodoMK801 as a marker of the open-channel, activated state of NMDA receptors. Lipopolysaccharide increased [3H]PK11195 binding in the brain, with the largest increases (2-3 fold) in temporal and entorhinal cortex, hippocampus, and substantia innominata. A significant (>50 percent) decrease in [125I]iodoMK801 binding was found in the same brain regions. Phenyl-tert-butyl nitrone treatment resulted in a partial inhibition ({approx}25 percent decrease) of the lipopolysaccharide-induced increase in [3H]PK11195 binding but completely reversed the lipopolysaccharide-induced decrease in [125I]iodoMK80 binding in the entorhinal cortex, hippocampus, and substantia innominata. Loss of NMDA receptor function in cortical and hippocampal regions may contribute to the cognitive deficits observed in diseases with a neuroinflammatory component, such as meningitis or Alzheimer's disease.

  18. The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: Synergism with the benzodiazepine diazepam

    International Nuclear Information System (INIS)

    Schultz, M.K.; Wright, L.K.M.; Stone, M.F.; Schwartz, J.E.; Kelley, N.R.; Moffett, M.C.; Lee, R.B.; Lumley, L.A.

    2012-01-01

    Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of γ-aminobutyric acid A (GABA A ) receptors. However, seizure activity itself causes the endocytosis of GABA A receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-D-aspartic acid (NMDA) receptor antagonist prevents this reduction in GABAergic inhibition. We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate (CED; 20 mg/kg, im) and DZP (10 mg/kg, sc), administered both separately and in combination, at 10, 20 or 30 min following seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD 50 ; 132 μg/kg, sc) in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase (AChE) activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine (PHY; 0.2 mg/kg, im) as a therapy for GD exposure. We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20–30 min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or DZP treatment. We conclude that: 1) CED and DZP treatment offers considerable protection against the effects of GD and 2) PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity. -- Highlights: ► Soman (GD) produced seizure activity resulting in neuropathology in rats. ► Tx: caramiphen (CED) and/or diazepam (DZP) @ 10, 20 or 30 min after seizure onset. ► CED/DZP showed superior anticonvulsant and neuroprotective capacity. ► Physostigmine (PHY) was examined as an adjunct post-exposure therapy. ► PHY attenuated GD-induced seizure development, but not seizure duration.

  19. The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: Synergism with the benzodiazepine diazepam

    Energy Technology Data Exchange (ETDEWEB)

    Schultz, M.K.; Wright, L.K.M.; Stone, M.F.; Schwartz, J.E.; Kelley, N.R.; Moffett, M.C.; Lee, R.B.; Lumley, L.A., E-mail: lucille.a.lange@us.army.mil

    2012-03-15

    Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of γ-aminobutyric acid A (GABA{sub A}) receptors. However, seizure activity itself causes the endocytosis of GABA{sub A} receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-D-aspartic acid (NMDA) receptor antagonist prevents this reduction in GABAergic inhibition. We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate (CED; 20 mg/kg, im) and DZP (10 mg/kg, sc), administered both separately and in combination, at 10, 20 or 30 min following seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD{sub 50}; 132 μg/kg, sc) in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase (AChE) activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine (PHY; 0.2 mg/kg, im) as a therapy for GD exposure. We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20–30 min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or DZP treatment. We conclude that: 1) CED and DZP treatment offers considerable protection against the effects of GD and 2) PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity. -- Highlights: ► Soman (GD) produced seizure activity resulting in neuropathology in rats. ► Tx: caramiphen (CED) and/or diazepam (DZP) @ 10, 20 or 30 min after seizure onset. ► CED/DZP showed superior anticonvulsant and neuroprotective capacity. ► Physostigmine (PHY) was examined as an adjunct post-exposure therapy. ► PHY attenuated GD-induced seizure development, but not seizure duration.

  20. Triton X-100 inhibits agonist-induced currents and suppresses benzodiazepine modulation of GABA(A) receptors in Xenopus oocytes

    DEFF Research Database (Denmark)

    Søgaard, Rikke; Ebert, Bjarke; Klaerke, Dan

    2009-01-01

    Changes in lipid bilayer elastic properties have been proposed to underlie the modulation of voltage-gated Na(+) and L-type Ca(2+) channels and GABA(A) receptors by amphiphiles. The amphiphile Triton X-100 increases the elasticity of lipid bilayers at micromolar concentrations, assessed from its...... by flunitrazepam at alpha(1)beta(3)gamma(2S) receptors. All effects were independent of the presence of a gamma(2S) subunit in the GABA(A) receptor complex. The present study suggests that Triton X-100 may stabilize open and desensitized states of the GABA(A) receptor through changes in lipid bilayer elasticity....

  1. Partial agonist of benzodiazepine receptors Ro 19-2088 elicits withdrawal symptoms after short-term administration in immature rats

    Czech Academy of Sciences Publication Activity Database

    Kubová, Hana; Mareš, Pavel

    2012-01-01

    Roč. 61, č. 3 (2012), s. 319-323 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GA305/09/0846; GA ČR(CZ) GBP304/12/G069 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : Ro 19-2088 * iatrogenic withdrawal * pentylentetrazol-induced seizures * immature rats Subject RIV: FH - Neurology Impact factor: 1.531, year: 2012

  2. The Anticholinergic and Antiglutamatergic Drug Caramiphen Reduces Seizure Duration in Soman-Exposed Rats: Synergism with the Benzodiazepine Diazepam

    Science.gov (United States)

    2012-01-01

    progress to self-sustained seizures ( status epilepticus , SE) and result in extensive neuropathology as seen in rats (de Araujo Furtado et al., 2009, 2010...physostigmineOP organophosphorus BuChE butyrylcholinesterase ChE cholinesterase SE status epilepticus ATR atropine sulfate 2-PAM 2-pralidoxime NMDA N...L.C., Lichtenstein, S., Yourick, D.L., 2010. Spontaneous recurrent seizures after status epilepticus induced by soman in Sprague-Dawley rats

  3. Objective and subjective sleep quality

    DEFF Research Database (Denmark)

    Baandrup, Lone; Glenthøj, Birte Yding; Jennum, Poul Jørgen

    2016-01-01

    and subjective sleep quality during benzodiazepine discontinuation and whether sleep variables were associated with benzodiazepine withdrawal. Eligible patients included adults with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder and long-term use of benzodiazepines in combination...

  4. Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project.

    Science.gov (United States)

    Huerta, Consuelo; Abbing-Karahagopian, Victoria; Requena, Gema; Oliva, Belén; Alvarez, Yolanda; Gardarsdottir, Helga; Miret, Montserrat; Schneider, Cornelia; Gil, Miguel; Souverein, Patrick C; De Bruin, Marie L; Slattery, Jim; De Groot, Mark C H; Hesse, Ulrik; Rottenkolber, Marietta; Schmiedl, Sven; Montero, Dolores; Bate, Andrew; Ruigomez, Ana; García-Rodríguez, Luis Alberto; Johansson, Saga; de Vries, Frank; Schlienger, Raymond G; Reynolds, Robert F; Klungel, Olaf H; de Abajo, Francisco José

    2016-03-01

    Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10,000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences. Copyright © 2015 John Wiley & Sons, Ltd.

  5. Septal co-infusions of glucose with the benzodiazepine agonist chlordiazepoxide impair memory, but co-infusions of glucose with the opiate morphine do not.

    Science.gov (United States)

    Krebs-Kraft, Desiree L; Parent, Marise B

    2010-03-30

    We have found repeatedly that medial septal (MS) infusions of glucose impair memory when co-infused with the gamma-amino butyric acid (GABA) agonist muscimol. The present experiments sought to determine whether the memory-impairing effects of this concentration of glucose would generalize to another GABA(A) receptor agonist and to an agonist from another neurotransmitter system that is known to impair memory. Specifically, we determined whether the dose of glucose that produces memory deficits when combined with muscimol in the MS would also impair memory when co-infused with the GABA(A) receptor modulator chlordiazepoxide (CDP) or the opiate morphine. Male Sprague-Dawley rats were given MS co-infusions and then 15 min later tested for spontaneous alternation or given shock avoidance training (retention tested 48 h later). The results showed that MS infusions of the higher dose of glucose with morphine did not produce memory deficits, whereas, the performance of rats given MS co-infusions of CDP with glucose was impaired. These findings suggest that the memory-impairing effects of brain glucose administration may involve an interaction with the GABA(A) receptor. (c) 2009 Elsevier Inc. All rights reserved.

  6. Use of Medicines from the Group of Benzodiazepines in the Period of 2003-2013 Year in the Republic of Macedonia

    Directory of Open Access Journals (Sweden)

    Tatjana Petrushevska

    2014-12-01

    CONCLUSIONS: The analysis shows that the use of BZD in MKD is particularly high. Limited number of studies was performed for this kind of drugs relating to their effects; differences in use between genders; adult population. There is need for additional focused research that will contribute to developing a full picture of the situation.

  7. Stress Sensitization of Ethanol Withdrawal-Induced Reduction in Social Interaction: Inhibition by CRF-1 and Benzodiazepine Receptor Antagonists and a 5-HT1A-Receptor Agonist

    OpenAIRE

    Breese, George R; Knapp, Darin J; Overstreet, David H

    2004-01-01

    Repeated withdrawals from chronic ethanol sensitize the withdrawal-induced reduction in social interaction behaviors. This study determined whether stress might substitute for repeated withdrawals to facilitate withdrawal-induced anxiety-like behavior. When two 1-h periods of restraint stress were applied at 1-week intervals to rats fed control diet, social interaction was reduced upon withdrawal from a subsequent 5-day exposure to ethanol diet. Neither this ethanol exposure alone nor exposur...

  8. The synthesis of 7-chloro-5-pentadeuteriophenyl-1-methyl-1H-1, 5-benzodiazepine-2,4(3H, 5H)dione ([2H5]clobazam)

    International Nuclear Information System (INIS)

    Borel, A.G.; Abbott, F.S.

    1990-01-01

    Pentadeuteriophenyl clobazam was synthesized in essentially quantitative isotopic purity, and characterized by 1 H-NMR and mass spectroscopy. The title compound was found to be >98% pure by HPLC, and its retention time (t R 6.17 min) was less than that of an authentic clobazam standard (t R 6.32 min). Of the five steps in the synthesis of clobazam, the most susceptible to deuterium exchange was the nucleophilic substitution of 2,4-dichloronitrobenzene by aniline-d 7 to form N-(5-chloro-2-nitrophenyl)penta-deuteriophenylamine. In this step, the isotopic impurity aniline-2,3,4,5-d 5 introduced protons from nitrogen into the ortho and para positions of the deuteriophenyl ring of N-(5-chloro-2-nitrophenyl)pentadeuteriophenylamine. (author)

  9. Synthesis of substituted [{sup 123}I]imidazo[1,2-a]pyridines as potential probes for the study of the peripheral benzodiazepine receptors using SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Katsifis, A.; Mattner, F.; Dikic, B.; Papazian, V. [Radiopharmaceuticals Div. R and D, ANSTO, Menai, NSW (Australia)

    2000-07-01

    The imidazo[1,2-a]pyridines N,N'-dimethyl-6-chloro-(4'-iodophenyl)imidazo[1,2-a]pyridine-3-acetamide 1. N,N'-diethyl-6-chloro-(4'-iodophenyl)imidazo[1,2-a]pyridine-3-acetamide 2, and N-methyl-6-chloro-(4'-iodophenyl)imidazo[1,2-a]pyridine-3-acetamide 3, are high affinity and selective ligands for the peripheral benzodiazepineodiazepine receptors (PBR). The [{sup 123}I]1-3 labelled analogues of these compounds were subsequently synthesised for the potential study of the PBR in vivo using SPECT. Radioiodination was achieved by iododestannylation reactions of the corresponding tributyl tin precursors with Na[{sup 123}I] in the presence of peracetic acid, chloramine-T or Iodogen. Purification of the crude product was achieved by semipreparative C-18 RP HPLC to give the products in radiochemical yields of 40-85%. The products were obtained in >97% chemical and radiochemical purity and with specific activities >80 GBq/{mu}mol. (orig.)

  10. Synthesis of substituted [123I]imidazo[1,2-a]pyridines as potential probes for the study of the peripheral benzodiazepine receptors using SPECT

    International Nuclear Information System (INIS)

    Katsifis, A.; Mattner, F.; Dikic, B.; Papazian, V.

    2000-01-01

    The imidazo[1,2-a]pyridines N,N'-dimethyl-6-chloro-(4'-iodophenyl)imidazo[1,2-a]pyridine-3-acetamide 1. N,N'-diethyl-6-chloro-(4'-iodophenyl)imidazo[1,2-a]pyridine-3-acetamide 2, and N-methyl-6-chloro-(4'-iodophenyl)imidazo[1,2-a]pyridine-3-acetamide 3, are high affinity and selective ligands for the peripheral benzodiazepineodiazepine receptors (PBR). The [ 123 I]1-3 labelled analogues of these compounds were subsequently synthesised for the potential study of the PBR in vivo using SPECT. Radioiodination was achieved by iododestannylation reactions of the corresponding tributyl tin precursors with Na[ 123 I] in the presence of peracetic acid, chloramine-T or Iodogen. Purification of the crude product was achieved by semipreparative C-18 RP HPLC to give the products in radiochemical yields of 40-85%. The products were obtained in >97% chemical and radiochemical purity and with specific activities >80 GBq/μmol. (orig.)

  11. A monoclinic modification of (4Z-1-benzyl-4-(2-oxopropylidene-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

    Directory of Open Access Journals (Sweden)

    Mohamed Samba

    2018-02-01

    Full Text Available In the title molecule, C19H18N2O2, the orientation of the oxopropylidene substituent is largely determined by an intramolecular N—H...O hydrogen bond. In the crystal, C—H...O hydrogen bonds form zigzag chains, which are elaborated into sheets lying parallel to (101 by complementary C—H...π interactions. Comparisons to the structure of the triclinic modification are made.

  12. (3R,4Z-1,3-Diethyl-4-(2-oxopropylidene-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one

    Directory of Open Access Journals (Sweden)

    Laila El Foujji

    2018-04-01

    Full Text Available In the title compound, C16H20N2O2, the seven-membered ring adopts a bowl-shaped conformation while the orientation of the 2-oxopropylidene substituent is determined by an intramolecular N—H...O hydrogen bond, which generates an S(6 ring. In the crystal, inversion dimers linked by pairs of very weak C—H...O interactions occur, which generate R22(8 loops.

  13. Anxiolytic-like actions of the hexane extract from leaves of Annona cherimolia in two anxiety paradigms: possible involvement of the GABA/benzodiazepine receptor complex.

    Science.gov (United States)

    López-Rubalcava, C; Piña-Medina, B; Estrada-Reyes, R; Heinze, G; Martínez-Vázquez, M

    2006-01-11

    A hexane extract of leaves of Annona cherimolia produced anxiolytic-like actions when administered to mice and tested in two animal models of anxiety: the mouse avoidance exploratory behavior and the burying behavior tests. In order to discard unspecific drug-actions on general activity, all treatments studied in the anxiety paradigms were also analyzed in the open field test. Results showed that A. cherimolia induced anxiolytic-like actions at the doses of 6.25, 12.5, 25.0 and 50.0 mg/kg. Picrotoxin (0.25 mg/kg), a GABA-gated chloride ion channel blocker, antagonized the anxiolytic-like actions of A. cherimolia, while a sub-effective dose of muscimol (0.5 mg/kg), a selective GABA(A) receptor agonist, facilitated the effects of a sub-optimal dose of A. cherimolia (3.12 mg/kg). Thus, the involvement of the GABA(A) receptor complex in the anxiolytic-like actions of A. cherimolia hexane extract is suggested. In addition the extract was also able to enhance the duration of sodium pentobarbital induced sleeping time. Taken together, results indicate that the hexane extract of A. cherimolia has depressant activity on the Central Nervous System and could interact with the GABA(A) receptor complex. On the other hand, the chromatographic separation of this extract led to the isolation of palmitone, and beta-sitosterol as major constituents. In addition a GC-MS study of some fractions revealed the presence of several compounds such beta-cariophyllene, beta-selinene, alpha-cubebene, and linalool that have been reported to show effects on behavior that could explain some of the extract effects.

  14. Synthesis, DNA binding ability and anticancer activity of 2-heteroaryl substituted benzimidazoles linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates.

    Science.gov (United States)

    Kamal, Ahmed; Pogula, Praveen Kumar; Khan, Mohammed Naseer Ahmed; Seshadri, Bobburi Naga; Sreekanth, Kokkonda

    2013-08-01

    As a continuation of our efforts to develop the benzimidazole-PBD conjugates as potential anticancer agents, a series of heteroaryl substituted benzimidazole linked PBD conjugates has been synthesized and evaluated for their anticancer potential in 60 human cancer cell lines. Most of the compounds exhibited promising anticancer activity and interestingly, compounds 4c and 4d displayed significant activity in most of the cell lines tested. Whereas, compound 4e showed selectivity in renal cancer cells with GI50 values of <10 and 70 nM against RXF 393 and UO-31 cell lines, respectively. Further, these compounds also showed significant DNA-binding affinity by thermal denaturation study using duplex form of calf thymus (CT) DNA.

  15. An update on the pharmacological treatment of anxiety and related ...

    African Journals Online (AJOL)

    requiring long-term treatment.1 In the past anxiety disorders specific disorder, generalised .... therapeutic dose. The short term ad hoc use of benzodiazepines .... associated with sedation, memory problems and dependence. Benzodiazepine ...

  16. Clinical practice guidelines for insomnia disorder

    African Journals Online (AJOL)

    Keywords: insomnia, benzodiazepines, cognitive behavioural therapy, sleep wake cycle, pharmacologic treatment .... events which occur just before bedtime, such as physical activity, food and .... benzodiazepines in women and in geriatrics.

  17. Benzodiazepinordinationer i almen praksis. En analyse of forbrugsmønstret for førstegangsbrugere

    DEFF Research Database (Denmark)

    Bjerrum, L; Andersen, U A

    1996-01-01

    ceased their use of benzodiazepines. Most of the patients ceased benzodiazepine medication on their own initiative. The doctor stopped the medication in 11% of the cases. The risk of a "repeat prescription syndrome" in continuation of the first prescription of a benzodiazepine seemed to be negligible...

  18. A rapid solid-phase extraction method for measurement of non-metabolised peripheral benzodiazepine receptor ligands, [18F]PBR102 and [18F]PBR111, in rat and primate plasma

    International Nuclear Information System (INIS)

    Katsifis, Andrew; Loc'h, Christian; Henderson, David; Bourdier, Thomas; Pham, Tien; Greguric, Ivan; Lam, Peter; Callaghan, Paul; Mattner, Filomena; Eberl, Stefan; Fulham, Michael

    2011-01-01

    Objectives: To develop a rapid and reliable method for estimating non-metabolised PBR ligands fluoroethoxy ([ 18 F]PBR102)- and fluoropropoxy ([ 18 F]PBR111)-substituted 2-(6-chloro-2-phenyl)imidazo[1,2-a]pyridine-3-yl)-N,N-diethylacetamides in plasma. Methods: Rats and baboons were imaged with PET up to 2 h postinjection of [ 18 F]PBR102 and [ 18 F]PBR111 under baseline conditions, after pre-blocking or displacement with PK11195. Arterial plasma samples were directly analysed by reverse-phase solid-phase extraction (RP-SPE) and RP-HPLC and by normal-phase TLC. SPE cartridges were successively washed with acetonitrile/water mixtures. SPE eluant radioactivity was measured in a γ-counter to determine the parent compound fraction and then analysed by HPLC and TLC for validation. Results: In SPE, hydrophilic and lipophilic radiolabelled metabolites were eluted in water and 20% acetonitrile/water. All non-metabolised [ 18 F]PBR102 and [ 18 F]PBR111 were in SPE acetonitrile fraction as confirmed by HPLC and TLC analysis. Unchanged (%) [ 18 F]PBR102 and [ 18 F]PBR111 from SPE analysis in rat and baboon plasma agreed with those from HPLC and TLC analysis. In rats and baboons, the fraction of unchanged tracer followed a bi-exponential decrease, with half-lives of 7 to 10 min for the fast component and >80 min for the slow component for both tracers. Conclusions: Direct plasma SPE analysis of [ 18 F]PBR102 and [ 18 F]PBR111 can reliably estimate parent compound fraction. SPE was superior to HPLC for samples with low activity; it allows rapid and accurate metabolite analysis of a large number of plasma samples for improved estimation of metabolite-corrected input function during quantitative PET imaging studies.

  19. Non-Classical Transformation of Benzendiazonium Hydrogen Sulfates. Access to 1,3-Dimethylisochromeno[4,3-c]pyrazol-5(1H-one, a Potential Benzodiazepine Receptor Ligand

    Directory of Open Access Journals (Sweden)

    Giuseppe Daidone

    2013-10-01

    Full Text Available The compound 2-((1,3-dimethyl-1H-pyrazol-5-yl(methylcarbamoylbenzene-diazonium hydrogen sulfate (10 was reacted with copper sulfate and sodium chloride, in the presence of ascorbic acid as reducing agent, to afford a mixture of the chlorinated epimers 4′-chloro-2,2′,5′-trimethyl-2′,4′-dihydrospiro[isoindoline-1,3′-pyrazol]-3-one (18 and (19, the epimers 4′-hydroxy-2,2′,5′-trimethyl-2′,4′-dihydrospiro[isoindoline-1,3′-pyrazol]-3-one (20 and (21, and N-(1,3-dimethyl-1H-pyrazol-5-ylbenzamide (22. Under the foregoing conditions, diazonium salt 10 affords neither the 2-chloro-N-(1,3-dimethyl-1H-pyrazol-5-yl-N-methylbenzamide (23 nor the tricyclic derivative 24, the classical products of the Sandmeyer and Pschorr reactions, respectively. Finally, by heating 20 at 210 °C the compound 1,3-dimethylisochromeno[4,3-c]pyrazol-5(1H-one (24 was obtained. The transformation under the above conditions of 2-((4-chloro-3-methyl-1-phenyl- 1H-pyrazol-5-yl(methylcarbamoylbenzendiazonium hydrogen sulphate (11 afforded 4′,4′-dichloro-2,5′-dimethyl-2′-phenyl-2′,4′-dihydrospiro[isoindoline-1,3′-pyrazol]-3-one (29 as the sole reaction product.

  20. The synthesis of 7-chloro-5-pentadeuteriophenyl-1-methyl-1H-1, 5-benzodiazepine-2,4(3H, 5H)dione (( sup 2 H sub 5 )clobazam)

    Energy Technology Data Exchange (ETDEWEB)

    Borel, A.G.; Abbott, F.S. (British Columbia Univ., Vancouver, BC (Canada). Dept. of Pharmaceutical Sciences)

    1990-07-01

    Pentadeuteriophenyl clobazam was synthesized in essentially quantitative isotopic purity, and characterized by {sup 1}H-NMR and mass spectroscopy. The title compound was found to be >98% pure by HPLC, and its retention time (t{sub R} 6.17 min) was less than that of an authentic clobazam standard (t{sub R} 6.32 min). Of the five steps in the synthesis of clobazam, the most susceptible to deuterium exchange was the nucleophilic substitution of 2,4-dichloronitrobenzene by aniline-d{sub 7} to form N-(5-chloro-2-nitrophenyl)penta-deuteriophenylamine. In this step, the isotopic impurity aniline-2,3,4,5-d{sub 5} introduced protons from nitrogen into the ortho and para positions of the deuteriophenyl ring of N-(5-chloro-2-nitrophenyl)pentadeuteriophenylamine. (author).