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Sample records for brain peripheral benzodiazepine

  1. Central and peripheral benzodiazepine receptors in rat brain and platelets: effects of treatment with diazepam and clobazam.

    Science.gov (United States)

    Larkin, J G; Thompson, G G; Scobie, G; Brodie, M J

    1992-09-01

    Tolerance to the effects of benzodiazepines (BZ) may be mediated by changes in benzodiazepine receptors (BZRs). Peripheral BZRs (in brain and platelets) and central BZRs (in brain) were measured in rats following intraperitoneal administration of diazepam and clobazam each for 4 and 12 days. BZRs were measured by binding assays using [3H] PK 11195 (peripheral) and [3H] flunitrazepam (central) as radioligands. Diazepam, but not clobazam, increased peripheral BZR numbers in platelets (both P < 0.005), but not in brain, after 4 and 12 days' treatment compared with appropriate controls. Neither drug altered central BZR affinities or numbers in rat brain. BZ effects on peripheral BZRs in platelets cannot be extrapolated to predict changes in brain receptors, either peripheral or central.

  2. Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy.

    Science.gov (United States)

    Lavoie, J; Layrargues, G P; Butterworth, R F

    1990-05-01

    Peripheral-type benzodiazepine receptors were evaluated using the specific ligand [3H]-PK 11195 in brain homogenates from nine cirrhotic patients who died in hepatic coma and from an equal number of age-matched control subjects. Histopathological studies showed evidence of severe Alzheimer type II astrocytosis in the brains of all cirrhotic patients. Saturation-binding assays revealed a single saturable binding site for [3H]-PK 11195 in brain, with affinities in the 2- to 3-nmol/L range. Diazepam was found to be a relatively potent inhibitor of 3H-PK 11195 binding (IC50 = 253 nmol/L), whereas the central benzodiazepine antagonist Ro 15-1788 displaced 3H-PK 11195 binding with low affinity (IC50 greater than 40 mumols/L). Densities of [3H]-PK 11195 binding sites were found to be increased by 48% (p less than 0.01) and 25% (p less than 0.05) in frontal cortex and caudate nuclei, respectively, from cirrhotic patients. Densities of [3H]-PK 11195 binding sites in frontal cortex from two nonencephalopathic cirrhotic patients were not significantly different from control values. No concomitant changes of affinities of these binding sites were observed. Because it has been suggested that peripheral-type benzodiazepine receptors may be localized on mitochondrial membranes and may therefore be involved in cerebral oxidative metabolism, the alterations observed in this study could be of pathophysiological significance in hepatic encephalopathy.

  3. 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.)

  4. [{sup 11}C]DAA1106: radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain

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    Zhang Mingrong E-mail: zhang@nirs.go.jp; Kida, Takayo; Noguchi, Junko; Furutsuka, Kenji; Maeda, Jun; Suhara, Tetsuya; Suzuki, Kazutoshi

    2003-05-01

    DAA1106 (N-(2,5-Dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide), is a potent and selective ligand for peripheral benzodiazepine receptors (PBR) in mitochondrial fractions of rat (K{sub i}=0.043 nM) and monkey (K{sub i}=0.188 nM) brains. This compound was labeled by [{sup 11}C]methylation of a corresponding desmethyl precursor (DAA1123) with [{sup 11}C]CH{sub 3}I in the presence of NaH, with a 72{+-}16% (corrected for decay) incorporation yield of radioactivity. After HPLC purification, [{sup 11}C]DAA1106 was obtained with {>=}98% radiochemical purity and specific activity of 90-156 GBq/{mu}mol at the end of synthesis. After iv injection of [{sup 11}C]DAA1106 into mice, high accumulations of radioactivity were found in the olfactory bulb and cerebellum, the high PBR density regions in the brain. Coinjection of [{sup 11}C]DAA1106 with unlabeled DAA1106 and PBR-selective PK11195 displayed a significant reduction of radioactivity, suggesting a high specific binding of [{sup 11}C]DAA1106 to PBR. Although this tracer was rapidly metabolized in the plasma, only [{sup 11}C]DAA1106 was detected in the brain tissues, suggesting the specific binding in the brain due to the tracer itself. These findings revealed that [{sup 11}C]DAA1106 is a potential and selective positron emitting radioligand for PBR.

  5. Fluorescence microscopy studies of a peripheral-benzodiazepine-receptor-targeted molecular probe for brain tumor imaging

    Science.gov (United States)

    Marcu, Laura; Vernier, P. Thomas; Manning, H. Charles; Salemi, Sarah; Li, Aimin; Craft, Cheryl M.; Gundersen, Martin A.; Bornhop, Darryl J.

    2003-10-01

    This study investigates the potential of a new multi-modal lanthanide chelate complex for specifically targeting brain tumor cells. We report here results from ongoing studies of up-take, sub-cellular localization and binding specificity of this new molecular imaging probe. Fluorescence microscopy investigations in living rat C6 glioma tumor cells demonstrate that the new imaging agent has affinity for glioma cells and binds to mitochondria.

  6. Effects of peripheral-type benzodiazepine receptor ligands on Ehrlich tumor cell proliferation.

    Science.gov (United States)

    Sakai, Mônica; Fonseca, Evelise Souza Monteiro; Oloris, Silvia Catarina Salgado; Matsuzaki, Patrícia; Otake, Andréia Hanada; Leite, Kátia Ramos Moura; Massoco, Cristina Oliveira; Dagli, Maria Lúcia Zaidan; Palermo-Neto, João

    2006-11-21

    Peripheral-type benzodiazepine receptors have been found throughout the body, and particularly, in high numbers, in neoplastic tissues such as the ovary, liver, colon, breast, prostate and brain cancer. Peripheral-type benzodiazepine receptor expression has been associated with tumor malignity, and its subcellular localization is important to define its function in tumor cells. We investigated the presence of peripheral-type benzodiazepine receptors in Ehrlich tumor cells, and the in vitro effects of peripheral-type benzodiazepine receptors ligands on tumor cell proliferation. Our results demonstrate the presence of peripheral-type benzodiazepine receptor in the nucleus of Ehrlich tumor cells (85.53+/-12.60%). They also show that diazepam and Ro5-4864 (peripheral-type benzodiazepine receptor agonists) but not clonazepam (a molecule with low affinity for the peripheral-type benzodiazepine receptor) decreased the percentage of tumor cells in G0-G1 phases and increased that of cells in S-G2-M phases. The effects of those agonists were prevented by PK11195 (a peripheral-type benzodiazepine receptor antagonist) that did not produce effects by itself. Altogether, these data suggest that the presence of peripheral-type benzodiazepine receptor within the nucleus of Ehrlich tumor cells is associated with tumor malignity and proliferation capacity.

  7. Imaging brain inflammation with [(11)C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats.

    Science.gov (United States)

    Rojas, Santiago; Martín, Abraham; Arranz, Maria J; Pareto, Deborah; Purroy, Jesús; Verdaguer, Esther; Llop, Jordi; Gómez, Vanessa; Gispert, Joan D; Millán, Olga; Chamorro, Angel; Planas, Anna M

    2007-12-01

    [(11)C]PK11195 is used in positron emission tomography (PET) studies for imaging brain inflammation in vivo as it binds to the peripheral-type benzodiazepine receptor (PBR) expressed by reactive glia and macrophages. However, features of the cellular reaction required to induce a positive [(11)C]PK11195 signal are not well characterized. We performed [(11)C]PK11195 PET and autoradiography in rats after transient focal cerebral ischemia. We determined [(3)H]PK11195 binding and PBR expression in brain tissue and examined the lesion with several markers. [(11)C]PK11195 standard uptake value increased at day 4 and grew further at day 7 within the ischemic core. Accordingly, ex vivo [(3)H]PK11195 binding increased at day 4, and increases further at day 7. The PET signal also augmented in peripheral regions, but to a lesser extent than in the core. Binding in the region surrounding infarction was supported by [(11)C]PK11195 autoradiography at day 7 showing that the radioactive signal extended beyond the infarcted core. Enhanced binding was preceded by increases in PBR mRNA expression in the ipsilateral hemisphere, and a 18-kDa band corresponding to PBR protein was detected. Peripheral-type benzodiazepine receptor immunohistochemistry showed subsets of ameboid microglia/macrophages within the infarcted core showing a distinctive strong PBR expression from day 4. These cells were often located surrounding microhemorrhages. Reactive astrocytes forming a rim surrounding infarction at day 7 also showed some PBR immunostaining. These results show cellular heterogeneity in the level of PBR expression, supporting that PBR is not a simple marker of inflammation, and that the extent of [(11)C]PK11195 binding depends on intrinsic features of the inflammatory cells.

  8. Peripheral benzodiazepine binding sites on striated muscles of the rat: Properties and effect of denervation

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, W.E.; Ickstadt, A. (Mainz Univ. (Germany, F.R.). Pharmakologisches Inst.); Hopf, H.Ch. (Mainz Univ. (Germany, F.R.))

    1985-01-01

    In order to test the hypothesis that peripheral benzodiazepine binding sites mediate some direct effects of benzodiazepines on striated muscles, the properties of specific /sup 3/H-Ro 5-4864 binding to rat biceps and rat diaphragm homogenates were investigated. In both tissues a single population of sites was found with a Ksub(D) value of 3 nmol/l. The density of these sites in both muscles was higher than the density in rat brain, but was considerably lower than in rat kidney. Competition experiments indicate a substrate specificity of specific /sup 3/H-Ro 5-4864 binding similar to the properties already demonstrated for the specific binding of this ligand to peripheral benzodiazepine binding sites in many other tissues. The properties of these sites in the rat diaphragm are not changed after motoric denervation by phrenicectomy. It is concluded that peripheral benzodiazepine binding sites are not involved in direct effects of benzodiazepines on striated muscles.

  9. Peripheral-type benzodiazepine receptor in neurosteroid biosynthesis, neuropathology and neurological disorders.

    Science.gov (United States)

    Papadopoulos, V; Lecanu, L; Brown, R C; Han, Z; Yao, Z-X

    2006-01-01

    The peripheral-type benzodiazepine receptor is a mitochondrial protein expressed at high levels in steroid synthesizing tissues, including the glial cells of the brain. Peripheral-type benzodiazepine receptor binds cholesterol with high affinity and is a key element of the cholesterol mitochondrial import machinery responsible for supplying the substrate cholesterol to the first steroidogenic enzyme, thus initiating and maintaining neurosteroid biosynthesis. Neurosteroid formation and metabolism of steroid intermediates are critical components of normal brain function. Peripheral-type benzodiazepine receptor also binds with high affinity various classes of compounds. Upon ligand activation peripheral-type benzodiazepine receptor-dependent cholesterol transport into mitochondria is accelerated leading in increased formation of neuroactive steroids. These steroids, such as allopregnanolone, have been shown to be involved in various neurological disorders, such as anxiety and mood disorders. Thus, peripheral-type benzodiazepine receptor drug ligand-induced neuroactive steroid formation offers a means to regulate brain dysfunction. Peripheral-type benzodiazepine receptor basal expression is upregulated in a number of neuropathologies, including gliomas and neurodegenerative disorders, as well as in various forms of brain injury and inflammation. In Alzheimer's disease pathology neurosteroid biosynthesis is altered and a decrease in the intermediate 22R-hydroxycholesterol levels is observed. This steroid was found to exert neuroprotective properties against beta-amyloid neurotoxicity. Based on this observation, a stable spirostenol derivative showing to display neuroprotective properties was identified, suggesting that compounds developed based on critical intermediates of neurosteroid biosynthesis could offer novel means for neuroprotection. In conclusion, changes in peripheral-type benzodiazepine receptor and neurosteroid levels are part of the phenotype seen in

  10. 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.

  11. The bovine peripheral-type benzodiazepine receptor: A receptor with low affinity for benzodiazepines

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    Parola, A.L.; Laird, H.E. II (Univ. of Arizona, Tucson (USA))

    1991-01-01

    The density of bovine peripheral-type benzodiazepine receptors (PBR) in four tissues was highest in adrenal cortex. The adrenal cortex PBR cofractionated with a mitochondrial membrane marker enzyme and could be solubilized with intact ligand binding properties using digitonin. The membrane bound and soluble mitochondrial receptors were pharmacologically characterized and showed the rank order of potency to inhibit ({sup 3}H)PK 11195 binding was PK 11195 > protoporphyrin IX > benzodiazepines. ({sup 3}H)PK 11195 binding to bovine adrenal mitochondria was unaffected by diethylpyrocarbonate, a histidine residue modifying reagent that decreased binding to rat liver mitochondria by 70%. ({sup 3}H)PK 14105 photolabeled the bovine PBR and the Mr was estimated under nondenaturing and denaturing conditions. These results demonstrate the bovine peripheral-type benzodiazepine receptor is pharmacologically and biochemically distinct from the rat receptor, but the receptor component photolabeled by an isoquinoline ligand has a similar molecular weight.

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

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

    1987-10-01

    The peripheral-type benzodiazepine receptor is a site identified by its nanomolar affinity for (/sup 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 (/sup 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. A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) system.

    Science.gov (United States)

    Gulyás, Balázs; Makkai, Boglárka; Kása, Péter; Gulya, Károly; Bakota, Lidia; Várszegi, Szilvia; Beliczai, Zsuzsa; Andersson, Jan; Csiba, László; Thiele, Andrea; Dyrks, Thomas; Suhara, Tetsua; Suzuki, Kazutoshi; Higuchi, Makato; Halldin, Christer

    2009-01-01

    The binding of two radiolabelled analogues (N-(5-[125I]Iodo-2-phenoxyphenyl)-N-(2,5-dimethoxybenzyl)acetamide ([125I]desfluoro-DAA1106) and N-(5-[125I]Fluoro-2-phenoxyphenyl)-N-(2-[125I]Iodo-5-methoxybenzyl)acetamide ([125I]desmethoxy-DAA1106) of the peripheral benzodiazepine receptor (PBR) (or TSPO, 18kDa translocator protein) ligand DAA1106 was examined by in vitro autoradiography on human post mortem whole hemisphere brain slices obtained from Alzheimer's disease (AD) patients and age-matched controls. Both [(125)I]desfluoro-IDAA1106 and [(125)I]desmethoxy-IDAA1106 were effectively binding to various brain structures. The binding could be blocked by the unlabelled ligand as well as by other PBR specific ligands. With both radiolabelled compounds, the binding showed regional inhomogeneity and the specific binding values proved to be the highest in the hippocampus, temporal and parietal cortex, the basal ganglia and thalamus in the AD brains. Compared with age-matched control brains, specific binding in several brain structures (temporal and parietal lobes, thalamus and white matter) in Alzheimer brains was significantly higher, indicating that the radioligands can effectively label-activated microglia and the up-regulated PBR/TSPO system in AD. Complementary immunohistochemical studies demonstrated reactive microglia activation in the AD brain tissue and indicated that increased ligand binding coincides with increased regional microglia activation due to neuroinflammation. These investigations yield further support to the PBR/TSPO binding capacity of DAA1106 in human brain tissue, demonstrate the effective usefulness of its radio-iodinated analogues as imaging biomarkers in post mortem human studies, and indicate that its radiolabelled analogues, labelled with short half-time bioisotopes, can serve as prospective in vivo imaging biomarkers of activated microglia and the up-regulated PBR/TSPO system in the human brain.

  14. Development of a new radioligand, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoroethyl-5-methoxybenzyl)acetamide, for pet imaging of peripheral benzodiazepine receptor in primate brain.

    Science.gov (United States)

    Zhang, Ming-Rong; Maeda, Jun; Ogawa, Masanao; Noguchi, Junko; Ito, Takehito; Yoshida, Yuichiro; Okauchi, Takashi; Obayashi, Shigeru; Suhara, Tetsuya; Suzuki, Kazutoshi

    2004-04-22

    To develop a positron emission tomography (PET) ligand for imaging the 'peripheral benzodiazepine receptor' (PBR) in brain and elucidating the relationship between PBR and brain diseases, four analogues (4-7) of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (2) were synthesized and evaluated as ligands for PBR. Of these compounds, fluoromethyl (4) and fluoroethyl (5) analogues had similar or higher affinities for PBR than the parent compound 2 (K(i) = 0.16 nM for PBR in rat brain sections). Iodomethyl analogue 6 displayed a moderate affinity, whereas tosyloxyethyl analogue 7 had weak affinity. Radiolabeling was performed for the fluoroalkyl analogues 4 and 5 using fluorine-18 ((18)F, beta(+); 96.7%, T(1/2) = 109.8 min). Ligands [(18)F]4 and [(18)F]5 were respectively synthesized by the alkylation of desmethyl precursor 3 with [(18)F]fluoromethyl iodide ([(18)F]8) and 2-[(18)F]fluoroethyl bromide ([(18)F]9). The distribution patterns of [(18)F]4 and [(18)F]5 in mice were consistent with the known distribution of PBR. However, compared with [(18)F]5, [(18)F]4 displayed a high uptake in the bone of mice. The PET image of [(18)F]4 for monkey brain also showed significant radioactivity in the bone, suggesting that this ligand was unstable for in vivo defluorination and was not a useful PET ligand. Ligand [(18)F]5 displayed a high uptake in monkey brain especially in the occipital cortex, a region with richer PBR than the other regions in the brain. The radioactivity level of [(18)F]5 in monkey brain was 1.5 times higher than that of [(11)C]2, and 6 times higher than that of (R)-(1-(2-chlorophenyl)-N-[(11)C]methyl,N-(1-methylpropyl)isoquinoline ([(11)C]1). Moreover, the in vivo binding of [(18)F]5 was significantly inhibited by PBR-selective 2 or 1, indicating that the binding of [(18)F]5 in the monkey brain was mainly due to PBR. Metabolite analysis revealed that [(18)F]4 was rapidly metabolized by defluorination to [(18)F]F(-) in the plasma and brain of

  15. Regulation of renal peripheral benzodiazepine receptors by anion transport inhibitors

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    Basile, A.S.; Lueddens, W.M.; Skolnick, P.

    1988-01-01

    The in vitro and in vivo regulation of (/sup 3/H)Ro 5-4864 binding to peripheral benzodiazepine receptors (PBR) by ion transport/exchange inhibitors was studied in the kidney. The potencies of 9-anthroic acid, furosemide, bumetanide, hydrochlorothiazide and SITS as inhibitors of (/sup 3/H)Ro 5-4864 binding to renal membranes were consistent with their actions as anion transport inhibitors (Ki approx. = 30 - 130 ..mu..M). In contrast, spironolactone, amiloride, acetazolamide, and ouabain were less potent (Ki=100-1000 ..mu..M). Administration of furosemide to rats for five days resulted in a profound diuresis accompanied by a significant increase in PBR density (43%) that was apparent by the fifth day of treatment. Administration of hydrochlorothiazide or Ro 5-4864 for five days also caused diuresis and increased renal PBR density. Both the diuresis and increased density of PBR produced by Ro 5-4864 were blocked by coadministration of PK 11195, which alone had no effect on either PBR density or urine volume. The equilibrium binding constants of (/sup 3/H)Ro 5-4864 to cardiac membranes were unaffected by administration of any of these drugs. These findings suggest that renal PBR may be selectively modulated in vivo and in vitro by administration of ion transport/exchange inhibitors. 36 references, 4 tables.

  16. The "peripheral-type" benzodiazepine (omega 3) receptor in hyperammonemic disorders.

    Science.gov (United States)

    Desjardins, Paul; Butterworth, Roger F

    2002-01-01

    Increased levels of brain ammonia occur in both congenital and acquired hyperammonemic syndromes including hepatic encephalopathy, fulminant hepatic failure, Reye's syndrome and congenital urea cycle disorders. In addition to its effect on neurotransmission and energy metabolism, ammonia modulates the expression of various genes including the astrocytic "peripheral-type" benzodiazepine (or omega 3) receptor (PTBR). Increased expression of the isoquinoline carboxamide binding protein (IBP), one of the components of the PTBR complex, is observed in brain and peripheral tissues following chronic liver failure as well as in cultured astrocytes exposed to ammonia. Increased densities of binding sites for the PTBR ligand [3H]-PK11195 are also observed in these conditions as well as in brains of animals with acute liver failure, congenital urea cycle disorders and in patients who died in hepatic coma. The precise role of PTBR in brain function has not yet fully elucidated, but among other functions, PTBR mediates the transport of cholesterol across the mitochondrial membrane and thus plays a key role in the biosynthesis of neurosteroids some of which modulate major neurotransmitter systems such as the gamma-aminobutyric acid (GABA(A)) and glutamate (N-methyl-D-aspartate (NMDA)) receptors. Activation of PTBR in chronic and acute hyperammonemia results in increased synthesis of neurosteroids which could lead to an imbalance between excitatory and inhibitory neurotransmission in the CNS. Preliminary reports suggest that positron emission tomography (PET) studies using [11C]-PK11195 may be useful for the assessment of the neurological consequences of chronic liver failure.

  17. Extraction and purification from Ceratonia siliqua of compounds acting on central and peripheral benzodiazepine receptors.

    Science.gov (United States)

    Avallone, R; Cosenza, F; Farina, F; Baraldi, C; Baraldi, M

    2002-08-01

    The presence of molecules with high affinity for central and peripheral benzodiazepine receptors was determined in the pod and leaves of Ceratonia siliqua (carob). The amount of the substances able to selectively bind the central benzodiazepine receptor recovered from carob pods and leaves was respectively 12.17 and 18.7 ng diazepam equivalent/g. The amount of compounds active on peripheral benzodiazepine receptor in both pods and leaves was higher in comparison with the central one, being 49.83 and 40.00 PK 11195 equivalent/g, respectively. In particular the compounds acting on peripheral benzodiazepine receptors were found to be extremely concentrated in the young leaves (2572.57 ng PK 11195 equivalent/g). The presence of substances with central benzodiazepine activity in carob extracts seems of great importance in view of the possibility to use carob extract as potential natural products with anxiolytic-sedative effects. Moreover, the prevalence in leaves of substances acting on peripheral benzodiazepine receptor suggests the possible utilisation of leave extracts as chemopreventive agents.

  18. Determinants of benzodiazepine brain uptake: lipophilicity versus binding affinity.

    Science.gov (United States)

    Arendt, R M; Greenblatt, D J; Liebisch, D C; Luu, M D; Paul, S M

    1987-01-01

    Factors influencing brain uptake of benzodiazepine derivatives were evaluated in adult Sprague Dawley rats (n = 8-10 per drug). Animals received single intraperitoneal doses of alprazolam, triazolam, lorazepam, flunitrazepam, diazepam, midazolam, desmethyldiazepam, or clobazam. Concentrations of each drug (and metabolites) in whole brain and serum 1 h after dosage were determined by gas chromatography. Serum free fraction was measured by equilibrium dialysis. In vitro binding affinity (apparent Ki) of each compound was estimated based on displacement of tritiated flunitrazepam in washed membrane preparations from rat cerebral cortex. Lipid solubility of each benzodiazepine was estimated using the reverse-phase liquid chromatographic (HPLC) retention index at physiologic pH. There was no significant relation between brain:total serum concentration ratio and either HPLC retention (r = 0.18) or binding Ki (r = -0.34). Correction of uptake ratios for free as opposed to total serum concentration yielded a highly significant correlation with HPLC retention (r = 0.78, P less than 0.005). However, even the corrected ratio was not correlated with binding Ki (r = -0.22). Thus a benzodiazepine's capacity to diffuse from systemic blood into brain tissue is much more closely associated with the physicochemical property of lipid solubility than with specific affinity. Unbound rather than total serum or plasma concentration most accurately reflects the quantity of drug available for diffusion.

  19. 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.

  20. Peripheral benzodiazepine receptors and cerebral ischemia%外周型苯二氮革受体与脑缺血

    Institute of Scientific and Technical Information of China (English)

    程超; 陈春富

    2009-01-01

    1he increased peripheral benzodiazepine receptors are more significant than normal ones after cerebral ischemia. Its main reactions are the multiple pathological changes,including microglial activation, participating in neuroinflammation response, and regulation of mitochondrial function. Using radionuclide-laheled specific ligands of the peripheral benzodiaz-epine receptor (such as PK11195) for in vivo imaging contribute to the location and quantitative detection for brain injury and the study of the pathophysiological changes after cerebral ischemi-a. In addition, this receptor is promising to become a new target of neuroprotective treatment.This article reviews the recent progress in research on peripheral benzodiazepine receptors and cerebral ischemia.%脑缺血后,外周型苯二氮革受体较正常时有明显增加,主要反应为小胶质细胞的活化、参与神经炎症反应以及线粒体功能调节等多途径病理学变化.应用放射性核素标记的特异性外周型苯二氮革受体配体(如PK11195)进行体内成像,有助于对脑损伤进行定位和定量检测以及研究脑缺血后病理生理学改变.另外,该受体还有望成为神经保护治疗的新靶点.文章就外周型苯二氮革受体与脑缺血的研究进展做一综述.

  1. In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution.

    Science.gov (United States)

    Arendt, R M; Greenblatt, D J; deJong, R H; Bonin, J D; Abernethy, D R; Ehrenberg, B L; Giles, H G; Sellers, E M; Shader, R I

    1983-10-01

    Factors influencing the rate and extent of benzodiazepine uptake into cerebrospinal fluid (CSF), peripheral tissue distribution and electroencephalographic (EEG) effects were evaluated in a model utilizing anesthetized male cats. A single (0.25-10 mg/kg) dose of the following eight benzodiazepines was administered i.v.: diazepam, desmethyldiazepam, midazolam, lorazepam, alprazolam, triazolam, flunitrazepam and clobazam. Multiple samples were simultaneously drawn from arterial blood and cisternal CSF over the next 4 hr and the EEG was continuously monitored. Concentrations of benzodiazepines in plasma and CSF samples were measured by electron-capture gas-liquid chromatography and plasma protein binding determined by equilibrium dialysis. Physicochemical properties of lipophilicity of each benzodiazepine were determined by measurement of the octanol/buffer partition ratio at physiologic pH and by the high-pressure liquid chromatographic (HPLC) retention on a reverse-phase C18 column at neutral pH. Disappearance of all benzodiazepines from plasma was consistent with a linear sum of two or three exponential terms. After correction for individual differences in protein binding, volume of distribution (Vd) of unbound drug was highly correlated with HPLC retention (r = 0.91), but not significantly related to octanol/buffer partition coefficient. Diazepam and midazolam, having the longest HPLC retention also had the largest unbound Vd. All benzodiazepines rapidly entered CSF, with peak concentrations usually attained within 15 min of dosage. More lipophilic drugs tended to enter CSF most rapidly, but associations of entry rate and in vitro lipophilicity were not significant. After distribution equilibrium was attained, disappearance of benzodiazepines from both plasma and CSF occurred in parallel. Equilibrium CSF/total plasma concentration ratios of all drugs were much less than unity.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Interactions of pyrethroid insecticides with GABA sub A and peripheral-type benzodiazepine receptors

    Energy Technology Data Exchange (ETDEWEB)

    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 1R{alpha}S, cis cypermethrin having an ED{sub 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 ({sup 3}H)Ro5-4864 to rat brain membranes with a significant correlation between the log EC{sub 50} values for their activities as proconvulsants and the log IC{sub 50} values for their inhibition of ({sup 3}H)Ro5-4864 binding. Both Ro5-4864 and pyrethroid insecticides were found to influence specific ({sup 35}S)TBPS binding in a GABA-dependent manner. PK 11195 and the Type II pyrethroid, deltamethrin antagonized the Ro5-4864-induced modulation of ({sup 35}S)TBPS binding. Pyrethroid insecticides, Ro5-4864 and veratridine influenced GABA-gated {sup 36}Chloride influx. Moreover, the Type II pyrethroids elicited an increase in {sup 36}chloride influx in the absence of GABA-stimulation. Both of these actions were antagonized by PK 11195 and tetrodotoxin.

  3. 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.

  4. Enhanced regional brain metabolic responses to benzodiazepines in cocaine abusers

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.J.; Fowler, J.S. [Brookhaven National Lab., Upton, NY (United States)] [and others

    1997-05-01

    While dopamine (DA) appears to be crucial for cocaine reinforcement, its involvement in cocaine addiction is much less clear. Using PET we have shown persistent reductions in striatal DA D2 receptors (which arc predominantly located on GABA cells) in cocaine abusers. This finding coupled to GABA`s role as an effector for DA led us to investigate if there were GABAergic abnormalities in cocaine abusers. In this study we measured regional brain metabolic responses to lorazepam, to indirectly assess GABA function (benzodiazepines facilitate GABAergic neurotransmission). Methods: The experimental subjects consisted of 12 active cocaine abusers and 32 age matched controls. Each subject underwent two PET FDG scans obtained within 1 week of each other. The first FDG scan was obtained after administration of placebo (3 cc of saline solution) given 40-50 minutes prior to FDG; and the second after administration of lorazepam (30 {mu}g/kg) given 40-50 minutes prior to FDG. The subjects were blind to the drugs received. Results: Lorazepam-induced sleepiness was significantly greater in abusers than in controls (p<0.001). Lorazepam-induced decreases in brain glucose metabolism were significantly larger in cocaine abusers than in controls. Whereas in controls whole brain metabolism decreased 13{+-}7 %, in cocaine abusers it decreased 21{+-}13 % (p < 0.05). Lorazepam-induced decrements in regional metabolism were significantly larger in striatum (p < 0.0 1), thalamus (p < 0.01) and cerebellum (p < 0.005) of cocaine abusers than of controls (ANOVA diagnosis by condition (placebo versus lorazepam) interaction effect). The only brain region for which the absolute metabolic changes-induced by lorazepam in cocaine abusers were equivalent to those in controls was the orbitofrontal cortex. These results document an accentuated sensitivity to benzodiazepines in cocaine abusers which is compatible with disrupted GABAergic function in these patients.

  5. Increased densities of binding sites for the peripheral-type benzodiazepine receptor ligand [3H]PK 11195 in congenital ornithine transcarbamylase-deficient sparse fur mouse.

    Science.gov (United States)

    Rao, V L; Qureshi, I A; Butterworth, R F

    1993-12-01

    Peripheral-type (mitochondrial) benzodiazepine receptors (PTBR) were studied in the brain and peripheral organs (kidney, liver, and testis) of normal male mice (CD-1/Y) and the congenitally hyperammonemic sparse fur (spf/Y) mouse. Radioligand binding assays were performed with [3H]PK 11195, a ligand with high selectivity and affinity for PTBR. Densities (maximal number of binding sites) of [3H]PK 11195 binding sites were greatest in kidney, followed by liver, testis, and brain. Densities of [3H]PK 11195 binding sites were significantly increased in all tissues of spf mice compared with control animals. In view of the localization of PTBR on the outer mitochondrial membrane, changes in PTBR in spf mouse tissues may modulate the altered mitochondrial function and oxidative metabolism, in brain and peripheral tissues, in congenital OTC deficiency. The positron emission tomography ligand 11C-PK 11195 could find an application in the assessment of end organ dysfunction in this disorder.

  6. 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.

  7. Purification of high affinity benzodiazepine receptor binding site fragments from rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Klotz, K.L.

    1984-01-01

    In central nervous system benzodiazepine recognition sites occur on neuronal cell surfaces as one member of a multireceptor complex, including recognition sites for benzodiazepines, gamma aminobutyric acid (GABA), barbiturates and a chloride ionophore. During photoaffinity labelling, the benzodiazepine agonist, /sup 3/H-flunitrazepam, is irreversibly bound to central benzodiazepine high affinity recognition sites in the presence of ultraviolet light. In these studies a /sup 3/H-flunitrazepam radiolabel was used to track the isolation and purification of high affinity agonist binding site fragments from membrane-bound benzodiazepine receptor in rat brain. The authors present a method for limited proteolysis of /sup 3/H-flunitrazepam photoaffinity labeled rat brain membranes, generating photolabeled benzodiazepine receptor fragments containing the agonist binding site. Using trypsin chymotrypsin A/sub 4/, or a combination of these two proteases, they have demonstrated the extent and time course for partial digestion of benzodiazepine receptor, yielding photolabeled receptor binding site fragments. These photolabeled receptor fragments have been further purified on the basis of size, using ultrafiltration, gel permeation chromatography, and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) as well as on the basis of hydrophobicity, using a high performance liquid chromatography (HPLC) precolumn, several HPLC elution schemes, and two different HPLC column types. Using these procedures, they have purified three photolabeled benzodiazepine receptor fragments containing the agonist binding site which appear to have a molecular weight of less than 2000 daltons each.

  8. PET study of carbon-11-PK 11195 binding to peripheral type benzodiazepine sites in glioblastoma: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Pappata, S.; Cornu, P.; Samson, Y.; Prenant, C.; Benavides, J.; Scatton, B.; Crouzel, C.; Hauw, J.J.; Syrota, A. (INSERM U. 334 Service Hospitalier Frederic Joliot, Paris (France))

    1991-08-01

    The utility of the peripheral type benzodiazepine site ligand 11C-PK 11195, for imaging human glioma in conjunction with Positron Emission Tomography, relies on a high specific binding of the tracer to tumoral peripheral type benzodiazepines sites. In a patient with glioblastoma, the authors found that 11C-PK 11195 binding was two-fold higher in the tumor than in normal gray matter and that 30% of tumoral binding could be displaced by a large excess of unlabeled drug. These findings suggest that tumoral retention of the ligand is due, in part, to specific binding.

  9. Differential expression of the peripheral benzodiazepine receptor and gremlin during adipogenesis.

    Science.gov (United States)

    Wade, F Marlene; Wakade, Chandramohan; Mahesh, Virendra B; Brann, Darrell W

    2005-05-01

    This study used the mRNA differential display technique to identify differentially expressed genes during the process of adipogenesis in the preadipocyte cell line, 3T3-L1. 3T3-L1 cells were treated with dexamethasone, isobutyl-1-methylxanthine, and insulin to induce differentiation into mature adipocytes. Cells were collected at three time-points during differentiation: Day 0 (d0), or nondifferentiated; Day 3 (d3), during differentiation; and Day 10 (d10), >90% of the cells had differentiated into mature adipocytes. Initial studies yielded 18 potentially differentially regulated cDNA candidates (8 down-regulated and 10 up-regulated). Reverse Northern and Northern blots confirmed differential expression of six of the candidates. Four of the candidates up-regulated on d3 and d10 were identified by sequence analysis to be lipoprotein lipase, a well-known marker of adipocyte differentiation. A fifth candidate that was expressed in d0, but not d3 or d10, was identified as DRM/gremlin, a bone morphogenetic protein antagonist. Finally, a sixth candidate that was increased at d3 and d10 was identified as the peripheral benzodiazepine receptor, which has been implicated in proliferation, differentiation, and cholesterol transport in cells. This study is the first to show that peripheral benzodiazepine receptor and DRM/gremlin are expressed in preadipocyte cell lines and that they are differentially regulated during adipogenesis.

  10. 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.

  11. Effects of PhD examination stress on allopregnanolone and cortisol plasma levels and peripheral benzodiazepine receptor density.

    NARCIS (Netherlands)

    Droogleever Fortuyn, H.A.; Broekhoven, F. van; Span, P.N.; Backstrom, T.; Zitman, F.G.; Verkes, R.J.

    2004-01-01

    Peripheral benzodiazepine receptor (PBR) density in blood platelets and plasma allopregnanolone concentration in humans were determined following acute stress as represented by PhD examination. Fifteen healthy PhD students participated. Heart rate, blood pressure, plasma allopregnanolone, plasma cor

  12. The benzodiazepine receptor in rat brain and its interaction with ethyl beta-carboline-3-carboxylate

    Energy Technology Data Exchange (ETDEWEB)

    Martin, I.L.; Doble, A.

    1983-06-01

    (3H)Ethyl beta-carboline-3-carboxylate ((3H) beta-CCE) binds to a homogeneous population of recognition sites in rat whole brain membranes with high affinity. The (3H)beta-CCE binding is completely displaceable by low concentrations of a number of benzodiazepines with similar potencies found when using a 3H-benzodiazepine as the ligand. This suggests that the recognition sites for beta-CCE and the benzodiazepines are identical or that they are involved in a close interaction. The binding of (3H)beta-CCE does not obey simple mass-action kinetics. (3H)Flunitrazepam dissociation from its receptor population is biphasic, and different methods of initiation of this dissociation indicate that cooperative interactions take place within the receptor population. We conclude that the benzodiazepine receptor is a single entity that can exist in two conformations, the equilibrium between which may be controlled by some as yet unidentified factor.

  13. Relation of cell proliferation to expression of peripheral benzodiazepine receptors in human breast cancer cell lines.

    Science.gov (United States)

    Beinlich, A; Strohmeier, R; Kaufmann, M; Kuhl, H

    2000-08-01

    Peripheral benzodiazepine receptor (PBR) agonist [(3)H]Ro5-4864 has been shown to bind with high affinity to the human breast cancer cell line BT-20. Therefore, we investigated different human breast cancer cell lines with regard to binding to [(3)H]Ro5-4864 and staining with the PBR-specific monoclonal antibody 8D7. Results were correlated with cell proliferation characteristics. In flow cytometric analysis, the estrogen receptor (ER)-negative breast cancer cell lines BT-20, MDA-MB-435-S, and SK-BR-3 showed significantly higher PBR expression (relative fluorescence intensity) than the ER-positive cells T47-D, MCF-7 and BT-474 (Pdiazepam-binding inhibitor are possibly involved in the regulation of cell proliferation of human breast cancer cell lines.

  14. Wavelet denoising for voxel-based compartmental analysis of peripheral benzodiazepine receptors with {sup 18}F-FEDAA1106

    Energy Technology Data Exchange (ETDEWEB)

    Shidahara, Miho; Ikoma, Yoko; Seki, Chie; Kanno, Iwao; Kimura, Yuichi [National Institute of Radiological Sciences, Biophysics Group, Molecular Imaging Center, Chiba (Japan); Fujimura, Yota; Ito, Hiroshi; Suhara, Tetsuya [National Institute of Radiological Sciences, Molecular Neuroimaging Group, Molecular Imaging Center, Chiba (Japan); Naganawa, Mika [National Institute of Radiological Sciences, Biophysics Group, Molecular Imaging Center, Chiba (Japan); Japan Society for the Promotion of Science, Tokyo (Japan)

    2008-02-15

    We evaluated the noise reduction capability of wavelet denoising for estimated binding potential (BP) images (k{sub 3}/k{sub 4}) of the peripheral benzodiazepine receptor using {sup 18}F-FEDAA1106 and nonlinear least-square fitting. Wavelet denoising within a three-dimensional discrete dual-tree complex wavelet transform was applied to simulate data and clinical dynamic positron emission tomography images of {sup 18}F-FEDAA1106. To eliminate noise components in wavelet coefficients, real and imaginary coefficients for each subband were thresholded individually using NormalShrink. A simulated dynamic brain image of {sup 18}F-FEDAA1106 was generated and Gaussian noise was added to mimic PET dynamic scan. The derived BP images were compared with true images using 156 rectangular regions of interest. Wavelet denoising was also applied to data derived from seven young normal volunteers. In the simulations, estimated BP by denoised image showed better correlation with the true BP values (Y = 0.83X + 0.94, r = 0.80), although no correlation was observed in the estimates between noise-added and true images (Y = 1.2X + 0.78, r = 0.49). For clinical data, there were visual improvements in the signal-to-noise ratio for estimated BP images. Wavelet denoising improved the bias and reduced the variation of pharmacokinetic parameters for BP. (orig.)

  15. Molecular size of benzodiazepine receptor in rat brain in situ: evidence for a functional dimer?

    Science.gov (United States)

    Doble, A.; Iversen, L. L.

    1982-02-01

    Benzodiazepine tranquillizers such as diazepam and chlordiazepoxide interact with high-affinity binding sites in nervous tissue1,2. The correlation between the affinities of various benzodiazepines for these sites with their clinical potencies and activity in behavioural and electrophysiological tests in animals suggests that the sites represent the functional `receptor' whereby benzodiazepines exert their effects3. The intimate involvement of benzodiazepines with γ-aminobutyric acid (GABA) and chloride channels raised the possibility that the benzodiazepine binding site (BDZ-R) may be a protein in the GABA receptor-effector complex4,5. GABA agonists enhance the affinity of BDZ-R for benzodiazepines6, although BDZ-R is distinct from the GABA receptor itself3. However, electrophysiological evidence suggests that the action of benzodiazepines is chloride channel, rather than receptor, directed7-10. Several attempts have been made to measure the molecular weight (Mr) of BDZ-R after solubilization from brain membranes: treatment with 1% Triton X-100 followed by assay of binding activity in solute fractions separated according to molecular weight suggested11 a value of ~200,000, photoaffinity labelling of BDZ-R with 3H-flunitrazepam (3H-FNZ) followed by more rigorous solubilization and gel chromatography indicated12,13 an apparent Mr of ~55,000 and a third approach14 a value of ~100,000. The measured molecular weight seems to depend critically on the solubilization procedure used. Chang et al.15 recently described the use of radiation inactivation to determine the size of BDZ-R in situ in calf brain membranes, and estimated a Mr, of 216,000. We have also used this approach; the results reported here indicate a Mr of between 90,000 and 100,000, but this is reduced to 60,000-63,000 in membranes pretreated with GABA, suggesting the disaggregation of a normally dimeric form.

  16. Quantitative autoradiographic determination of binding sites for a peripheral benzodiazepine ligand ((/sup 3/H)PK 11195) in human iris

    Energy Technology Data Exchange (ETDEWEB)

    Valtier, D.; Malgouris, C.; Uzan, A.

    1987-01-01

    Specific binding sites of peripheral-type benzodiazepines were investigated in human iris/ciliary body (8 eyes). Examination of color-coded prints and densitometric quantification of autoradiograms were performed on slides (20 ..mu..m) labelled with (/sup 3/H)PK 11195 (1 nM) at 25 deg C. Nonspecific binding was determined with PK 11211 (5 ..mu..M) or Ro 5-4864 (5 ..mu..M). Binding sites were present on all the slides, with equivalent density in the 3 regions of the preparation (ciliary body, iris and pupil margin). The numbers of binding sites in ciliary body, iris, and pupil margin, respectively were: 42.7 +- 0.2, 30.1 +- 0.5 and 37.4 +- 0.4 femtomol/mg protein. Labelling on the pupil margin seemed to coincide with the iris sphincter muscle. The presence of peripheral benzodiazepine binding sites in iris muscular tissue, and particularly in the pupil margin, suggests that the iris preparation may be a valuable tool to detect putative physiological effects of peripheral benzodiazepines on muscular motility.

  17. In Vivo Imaging of Peripheral Benzodiazepine Receptors in Mouse Lungs: A Biomarker of Inflammation

    Directory of Open Access Journals (Sweden)

    Matthew J. Hardwick

    2005-10-01

    Full Text Available The ability to visualize the immune response with radioligands targeted to immune cells will enhance our understanding of cellular responses in inflammatory diseases. Peripheral benzodiazepine receptors (PBR are present in monocytes and neutrophils as well as in lung tissue. We used lipopolysaccharide (LPS as a model of inflammation to assess whether the PBR could be used as a noninvasive marker of inflammation in the lungs. Planar imaging of mice administrated 10 or 30 mg/kg LPS showed increased [123I]-(R-PK11195 radioactivity in the thorax 2 days after LPS treatment relative to control. Following imaging, lungs from control and LPS-treated mice were harvested for ex vivo gamma counting and showed significantly increased radioactivity above control levels. The specificity of the PBR response was determined using a blocking dose of nonradioactive PK11195 given 30 min prior to radiotracer injection. Static planar images of the thorax of nonradioactive PK11195 pretreated animals showed a significantly lower level of radiotracer accumulation in control and in LPS-treated animals (p < .05. These data show that LPS induces specific increases in PBR ligand binding in the lungs. We also used in vivo small-animal PET studies to demonstrate increased [11C]-(R-PK11195 accumulation in the lungs of LPS-treated mice. This study suggests that measuring PBR expression using in vivo imaging techniques may be a useful biomarker to image lung inflammation.

  18. Blood flow dependence of the intratumoral distribution of peripheral benzodiazepine receptor binding in intact mouse fibrosarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Amitani, Misato [Radiochemistry Section, Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan) and Course of Allied Health Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871 (Japan)]. E-mail: amitani@sahs.med.osaka-u.ac.jp; Zhang, Ming-Rong [Radiochemistry Section, Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan); Noguchi, Junko [Radiochemistry Section, Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan); SHI Accelerator Service, Shinagawa-ku, Tokyo 141-8686 (Japan); Kumata, Katsushi [Radiochemistry Section, Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan); Ito, Takehito [Radiochemistry Section, Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan); SHI Accelerator Service, Shinagawa-ku, Tokyo 141-8686 (Japan); Takai, Nobuhiko [Radiochemistry Section, Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan); Suzuki, Kazutoshi [Radiochemistry Section, Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555 (Japan); Hosoi, Rie [Course of Allied Health Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871 (Japan); Inoue, Osamu [Course of Allied Health Sciences, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871 (Japan)

    2006-11-15

    The intratumoral distribution of [{sup 11}C]AC-5216 binding, a novel peripheral benzodiazepine receptor (PBR) ligand, was examined by autoradiography both in vitro and in vivo using a murine fibrosarcoma model. The regional distribution of [{sup 11}C]AC-5216 in a tumor in vivo was significantly heterogeneous; the uptake of [{sup 11}C]AC-5216 was comparatively higher in the outer rim of the tumor and was lower in the central area. In contrast, the images obtained following the injection of [{sup 11}C]AC-5216 with a large amount of nonlabeled PK11195 showed a relatively homogeneous distribution, suggesting that [{sup 11}C]AC-5216 uptake represented specific binding to PBRs. In vitro autoradiograms of [{sup 11}C]AC-5216 binding were also obtained using the section of the fibrosarcoma that was the same as that used to examine in vivo binding. In vitro autoradiographic binding images showed homogeneous distribution, and significant discrepancies of the intratumoral distribution of [{sup 11}C]AC-5216 were observed between in vivo and in vitro images. The in vivo images of [{sup 11}C]AC-5216 uptake, compared with those of [{sup 14}C]iodoantipyrine uptake, obtained by dual autoradiography to evaluate the influence of blood flow revealed the similar intratumoral distributions of both tracers. These results indicate that the delivery process from the plasma to the tumor might be the rate-limiting step for the intratumoral distribution of PBR binding in vivo in a fibrosarcoma model.

  19. Development of a unique 3D interaction model of endogenous and synthetic peripheral benzodiazepine receptor ligands

    Science.gov (United States)

    Cinone, Nunzia; Höltje, Hans-Dieter; Carotti, Angelo

    2000-11-01

    Different classes of Peripheral-type Benzodiazepine Receptor (PBR) ligands were examined and common structural elements were detected and used to develop a rational binding model based on energetically allowed ligand conformations. Two lipophilic regions and one electrostatic interaction site are essential features for high affinity ligand binding, while a further lipophilic region plays an important modulator role. A comparative molecular field analysis, performed over 130 PBR ligands by means of the GRID/GOLPE methodology, led to a PLS model with both high fitting and predictive values (r2 = 0.898, Q2 = 0.761). The outcome from the 3D QSAR model and the GRID interaction fields computed on the putative endogenous PBR ligands DBI (Diazepam Binding Inhibitor) and TTN (Tetracontatetraneuropeptide) was used to identify the amino acids most probably involved in PBR binding. Three amino acids, bearing lipophilic side chains, were detected in DBI (Phe49, Leu47 and Met46) and in TTN (Phe33, Leu31 and Met30) as likely residues underlying receptor binding. Moreover, a qualitative comparison of the molecular electrostatic potentials of DBI, TTN and selected synthetic ligands indicated also similar electronic properties. Convergent results from the modeling studies of synthetic and endogenous ligands suggest a common binding mode to PBRs. This may help the rational design of new high affinity PBR ligands.

  20. Effects of peripheral benzodiazepine receptor ligands on proliferation and differentiation of human mesenchymal stem cells.

    Science.gov (United States)

    Lee, D H; Kang, S K; Lee, R H; Ryu, J M; Park, H Y; Choi, H S; Bae, Y C; Suh, K T; Kim, Y K; Jung, Jin Sup

    2004-01-01

    The peripheral benzodiazepine receptor (PBR) has been known to have many functions such as a role in cell proliferation, cell differentiation, steroidogenesis, calcium flow, cellular respiration, cellular immunity, malignancy, and apoptosis. However, the presence of PBR has not been examined in mesenchymal stem cells. In this study, we demonstrated the expression of PBR in human bone marrow stromal cells (hBMSCs) and human adipose stromal cells (hATSCs) by RT-PCR and immunocytochemistry. To determine the roles of PBR in cellular functions of human mesenchymal stem cells (hMSCs), effects of diazepam, PK11195, and Ro5-4864 were examined. Adipose differentiation of hMSCs was decreased by high concentration of PBR ligands (50 microM), whereas it was increased by low concentrations of PBR ligands (<10 microM). PBR ligands showed a biphasic effect on glycerol-3-phosphate dehydrogenase (GPDH) activity. High concentration of PBR ligands (from 25 to 75 microM) inhibited proliferation of hMSCs. However, clonazepam, which does not have an affinity to PBR, did not affect adipose differentiation and proliferation of hMSCs. The PBR ligands did not induce cell death in hMSCs. PK11195 (50 microM) and Ro5-5864 (50 microM) induced cell cycle arrest in the G(2)/M phase. These results indicate that PBR ligands play roles in adipose differentiation and proliferation of hMSCs.

  1. 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.

  2. Study on measurement of free ligand concentration in blood and quantitative analysis of brain benzodiazepine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Kenji; Goromaru, Tsuyoshi; Inoue, Osamu; Itoh, Takashi; Yamasaki, Toshiro.

    1988-11-01

    We developed the method to determine rapidly the free ligand concentration in the blood as an input function for the purpose of quantitative analysis of binding potential (B/sub max//K/sub d/) of brain benzodiazepine receptor in vivo. It was found that the unmetabolized radioligand in the blood after intravenous administration of /sup 3/H-Ro 15 - 1788 could be extracted by chloroform, whereas the radioactive metabolites could not be extracted. And the plasma protein binding of /sup 3/H-Ro 15 - 1788 was determined using an ultrafiltration method. The biodistribution of /sup 3/H-Ro 15 - 1788 in the cerebral cortex, cerebellum and pons-medulla after intravenous administration of the radiotracer in the control and forced-swimmed mice was examined. And the time course of the free ligand concentration in the blood was determined as described above. Further, the binding potential of benzodiazepine receptor in the mouse brain was analyzed using a simple mathematical model. It was suggested that the binding potential of benzodiazepine receptor in the mouse brain was significantly decreased by forced-swimming. In conclusion, it was found that these methods would be useful for quantitative analysis of clinical data in the human brain using /sup 11/C-Ro 15 - 1788 and positron emission tomography (PET).

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

    Energy Technology Data Exchange (ETDEWEB)

    Branley, Howard M. [Imperial College London, Hammersmith Campus, W12 OHS London (United Kingdom)]. E-mail: howard.branley@whittington.nhs.uk; Bois, Roland M. du [Royal Brompton Hospital, SW3 6NP London (United Kingdom); Wells, Athol U. [Royal Brompton Hospital, SW3 6NP London (United Kingdom); Jones, Hazel A. [Imperial College London, Hammersmith Campus, W12 OHS London (United Kingdom)

    2007-07-15

    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 [{sup 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 {sub 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Basile, A.S.; Pannell, L.; Jaouni, T.; Gammal, S.H.; Fales, H.M.; Jones, E.A.; Skolnick, P. (National Institutes of Health, Bethesda, MD (USA))

    1990-07-01

    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.

  5. 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.

  6. Synthesis and evaluation of sup 11 C-PK 11195 for in vivo study of peripheral-type benzodiazepine receptors using positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Kenji (Fukuyama Univ., Hiroshima (Japan). Faculty of Pharmacy and Pharmaceutical Sciences); Inoue, Osamu; Suzuki, Kazutoshi; Yamasaki, Toshiro; Kojima, Masaharu

    1989-07-01

    The biodistribution of {sup 3}H-PK 11195, an antagonist of the peripheral-type benzodiazepine receptors, was studied in mice. High accumulations of radioactivity in the heart, lung, spleen, kidney and adrenal were observed after intravenous injection of tracer amounts of {sup 3}H-PK 11195 into the mice. The radioactivity in the heart, lung, spleen, kidney and adrenal was significantly decreased by the coadministration of carrier PK 11195, which indicated that PK 11195 specifically binds to the receptors. No radioactive metabolites were observed in the heart, lung and brain 20 min after intravenous administration of {sup 3}H-PK 11195. The accumulation of {sup 3}H-PK 11195 in the lung was not affected by pretreatment with either {alpha}-methyl benzylamine or imipramine, suggesting that {sup 3}H-PK 11195 specifically binds to the receptors. The ratios of radioactivity of the kidney, adrenal and spleen to blood increased as a function of time, whereas that of the lung and heart rapidly reached to a steady state. {sup 11}C-PK 11195 was synthesized by the N-methylation of desmethyl precursor yielding more than 100 mCi with high specific activity (more than 1.4 Ci/{mu}mol). The lebeling and purification procedure was completed within 23 min after the end of bombardment (EOB). The {sup 11}C-PK 11195 solution for injection seems to have a high potential for the in vivo study of the peripheral-type benzodiazepine receptors in the living human by means of positron emission tomography (PET). (author).

  7. Diazepam binding inhibitor gene expression: Location in brain and peripheral tissues of rate

    Energy Technology Data Exchange (ETDEWEB)

    Alho, H.; Fremeau, R.T. Jr.; Tiedge, H.; Wilcox, J.; Bovolin, P.; Brosius, J.; Roberts, J.L.; Costa, E.

    1988-09-01

    Diazepam binding inhibitor (DBI), an endogenous 10-kDa polypeptide was isolated from rat and human brain by monitoring displacement of radioactive diazepam bound to specific recognition sites in brain synaptic and mitochondrial membranes. The cellular location of DBI mRNA was studied in rat brain and selected peripheral tissues by in situ hybridization histochemistry with a /sup 35/S-labeled single-stranded complementary RNA probe. DBI mRNA was heterogeneously distributed in rat brain, with particularly high levels in the area postrema, the cerebellar cortex, and ependyma of the third ventricle. Intermediate levels were found in the olfactory bulb, pontine nuclei, inferior colliculi, arcuate nucleus, and pineal gland. Relatively low but significant levels of silver grains were observed overlying many mesencephalic and telencephalic areas that have previously been shown to contain numerous DBI-immunoreactive neurons and a high density of central benzodiazepine receptors. In situ hybridizations also revealed high levels of DBI mRNA in the posterior lobe of the pituitary gland, liver, and germinal center of the white pulp of spleen, all tissues that are rich in peripheral benzodiazepine binding sites. The tissue-specific pattern of DBI gene expression described here could be exploited to further understand the physiological function of DBI in the brain and periphery.

  8. Downregulation of (3H)Ro5-4864 binding sites after exposure to peripheral-type benzodiazepines in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, M.D.; Wang, J.K.; Morgan, J.I.; Spector, S.

    1986-09-01

    Peripheral-type benzodiazepine (BZD) binding sites undergo a rapid and pronounced downregulation after exposure to these compounds in vitro. Friend erythroleukemia cells were incubated with micromolar concentrations of BZD after which they were washed thoroughly and the binding of the specific peripheral-type BZD radioligand (/sup 3/H)Ro5-4864 was determined. Exposure to the peripheral-type BZD Ro7-3351 decreased the number of (/sup 3/H)Ro5-4864 binding sites from 324 to 41 fmol/10(6) cells with no change in affinity. Downregulation appears to require active cellular processes because it is blocked when exposure to BZD is at 4/sup 0/C rather than at 37/sup 0/C. Furthermore, whereas (/sup 3/H)Ro5-4864 binding is decreased substantially in membrane preparations made from downregulated cells, it is not altered when membrane preparations from control cells are exposed to BZD. The time course of downregulation is quite rapid, as it occurs within minutes. In contrast, the return of sites requires days and there is a close relationship between return of sites and growth of new cells. The ability of BZDs to downregulate correlates more closely with affinity for the peripheral-type site than with biological activity. The ability to undergo downregulation is characteristic of receptors and its occurrence suggests that peripheral-type BZD binding sites are functional receptors.

  9. 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...

  10. Tissue-specific alterations of binding sites for peripheral-type benzodiazepine receptor ligand [3H]PK11195 in rats following portacaval anastomosis.

    Science.gov (United States)

    Rao, V L; Audet, R; Therrien, G; Butterworth, R F

    1994-05-01

    Kinetics of binding of [3H]PK11195, an antagonist ligand with high selectivity for the peripheral-type (mitochondrial) benzodiazepine receptor (PTBR), was studied in homogenates of cerebral cortex, kidney, heart, and testis of portacaval shunted rats and sham-operated controls. Portacaval anastomosis resulted in a significant two- to threefold increase in the number of [3H]PK11195 binding sites in cerebral cortex and kidney. A reduction in the number of [3H]PK11195 binding sites was observed in testis preparations, while the number of binding sites in the heart remained unaltered. These differences in the response of PTBRs to portacaval anastomosis, in different organs suggest that the physiological function of these receptors and the factors regulating them are modulated by distinct mechanisms. The finding of increased densities of [3H]PK11195 binding sites in brain and kidney following portacaval anastomosis parallels the cellular hypertrophy in these tissues and, together with previous observations of similar increases of these binding sites in brain and kidney in congenital hyperammonemia, suggest a pathophysiologic role for ammonia in these changes. In contrast, the significant loss of [3H]PK11195 binding sites in testicular preparations following portacaval anastomosis together with the known effects of steroid hormones on these sites suggests a role for PTBRs in the pathogenesis of testicular atrophy in chronic liver disease.

  11. Expression of peripheral benzodiazepine receptor (PBR) in human tumors: relationship to breast, colorectal, and prostate tumor progression.

    Science.gov (United States)

    Han, Zeqiu; Slack, Rebecca S; Li, Wenping; Papadopoulos, Vassilios

    2003-01-01

    High levels of peripheral-type benzodiazepine receptor (PBR), the alternative-binding site for diazepam, are part of the aggressive human breast cancer cell phenotype in vitro. We examined PBR levels and distribution in normal tissue and tumors from multiple cancer types by immunohistochemistry. Among normal breast tissues, fibroadenomas, primary and metastatic adenocarcinomas, there is a progressive increase in PBR levels parallel to the invasive and metastatic ability of the tumor (p cancers, such as those of breast, colon-rectum and prostate tissues, where elevated PBR expression is associated with tumor progression. Thus, we propose that PBR overexpression could serve as a novel prognostic indicator of an aggressive phenotype in breast, colorectal and prostate cancers.

  12. 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.

  13. The radiosynthesis of ( sup 18 F)PK 14105 as an alternative radioligand for peripheral type benzodiazepine binding sites

    Energy Technology Data Exchange (ETDEWEB)

    Pascali, C.; Luthra, S.K.; Pike, V.W.; Price, G.W.; Ahier, R.G.; Hume, S.P.; Myers, R.; Manjil, L.; Cremer, J.E. (Hammersmith Hospital, London (UK). M.R.C. Cyclotron Unit)

    1990-01-01

    A method has been developed for labelling PK 14105 (N-methyl-N-(1-methyl-propyl)-1(2-fluoro-5-nitrophenyl)isoquinoline-3-carboxamide ), a ligand that has high affinity and selectivity for peripheral type benzodiazepine binding sites (PBBS), with NCA fluorine-18 (t{sub 1/2}=109.8 min, {beta}{sup +} = 96.9%). The method involves treating the 2-chloro-analogue with cyclotron-produced NCA ({sup 18}F)fluoride in dimethyl sulphoxide, with rubidium carbonate as base, at 140{sup 0}C for 20 min. Purification is achieved by separation on a reverse phase Sep-Pak followed by HPLC on a silica gel column, to give chemically and radiochemically pure product with a specific activity of ca 7.4 GBq/{mu}mol (200 mCi{mu}mol), decay-corrected to the end of radionuclide production (EOB). The radiosynthesis requires 210 min, giving a radiochemical yield of 10-20%, decay-corrected to EOB. ({sup 18}F)PK 14105 was found to bind avidly to sites associated with kainic acid-induced unilateral lesions of rat striata. Such binding was blocked by pre-dosing the rat with PK 11195, so providing evidence for specific binding to PBBS. These results suggest that ({sup 18}F)PK 14105 has potential for studying phenomena associated with PBBS in man by PET. (author).

  14. 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)

  15. 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.)

  16. Effects of vitamin B-6 nutrition on benzodiazepine (BDZ) receptor binding in the developing rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Borek, J.P.; Guilarte, T.R. (Johns Hopkins Univ., Baltimore, MD (United States))

    1990-02-26

    A dietary deficiency of vitamin B-6 promotes seizure activity in neonatal animals and human infants. Previous studied have shown that neonatal vitamin B-6 deprivation results in reduced levels of brain gamma-aminobutyric acid (GABA) and increased binding at the GABA site of the GABA/BDZ receptor complex. Since the GABA and BDZ receptors are allosterically linked, this study was undertaken to determine if vitamin B-6 deprivation had an effect on BDZ receptor binding. Benzodiazepine receptor binding isotherms using {sup 3}H-flunitrazepam as ligand were performed in the presence and absence of 10 {mu}M GABA. The results indicate a significant increase in the binding affinity (Kd) in the presence of GABA in cerebellar membranes from deficient rat pups at 14 days of age with no effect on receptor number (Bmax). By 28 days of age, the increase in Kd was no longer present. No change in Kd or Bmax was observed in cortical tissue from deficient animals at 14 or 28 days of age. Preliminary studies of GABA-enhancement of {sup 3}H-flunitrazepam binding indicate that vitamin B-6 deficiency also induces alterations in the ability of GABA to enhance BZD receptor binding. In summary, these results indicate that the effects of vitamin B-6 deprivation on BDZ receptor binding are region specific and age related.

  17. In vivo molecular imaging of the GABA/benzodiazepine receptor complex in the aged rat brain.

    Science.gov (United States)

    Hoekzema, Elseline; Rojas, Santiago; Herance, Raúl; Pareto, Deborah; Abad, Sergio; Jiménez, Xavier; Figueiras, Francisca P; Popota, Foteini; Ruiz, Alba; Flotats, Núria; Fernández, Francisco J; Rocha, Milagros; Rovira, Mariana; Víctor, Víctor M; Gispert, Juan D

    2012-07-01

    The GABA-ergic system, known to regulate neural tissue genesis during cortical development, has been postulated to play a role in cerebral aging processes. Using in vivo molecular imaging and voxel-wise quantification, we aimed to assess the effects of aging on the benzodiazepine (BDZ) recognition site of the GABA(A) receptor. To visualize BDZ site availability, [(11)C]-flumazenil microPET acquisitions were conducted in young and old rats. The data were analyzed and region of interest analyses were applied to validate the voxel-wise approach. We observed decreased [(11)C]-flumazenil binding in the aged rat brains in comparison with the young control group. More specifically, clusters of reduced radioligand uptake were detected in the bilateral hippocampus, cerebellum, midbrain, and bilateral frontal and parieto-occipital cortex. Our results support the pertinence of voxel-wise quantification in the analysis of microPET data. Moreover, these findings indicate that the aging process involves declines in neural BDZ recognition site availability, proposed to reflect alterations in GABA(A) receptor subunit polypeptide expression.

  18. Azaflavones compared to flavones as ligands to the benzodiazepine binding site of brain GABAA receptors

    DEFF Research Database (Denmark)

    Nilsson, Jakob; Nielsen, Elsebet Østergaard; Liljefors, Tommy

    2008-01-01

    A series of azaflavone derivatives and analogues were prepared and evaluated for their affinity to the benzodiazepine binding site of the GABA(A) receptor, and compared to their flavone counterparts. Three of the compounds, the azaflavones 9 and 12 as well as the new flavone 13, were also assayed...

  19. The human peripheral benzodiazepine receptor gene: cloning and characterization of alternative splicing in normal tissues and in a patient with congenital lipoid adrenal hyperplasia.

    Science.gov (United States)

    Lin, D; Chang, Y J; Strauss, J F; Miller, W L

    1993-12-01

    The mitochondrial benzodiazepine receptor (mBzR) appears to be a key factor in the flow of cholesterol into mitochondria to permit the initiation of steroid hormone synthesis. The mBzR consists of three components; the 18-kDa component on the outer mitochondrial membrane appears to contain the benzodiazepine binding site, and is hence often termed the peripheral benzodiazepine receptor (PBR). Using a cloned human PBR cDNA as probe, we have cloned the human PBR gene. The 13-kb gene is divided into four exons, with exon 1 encoding only a short 5' untranslated segment. The 5' flanking DNA lacks TATA and CAAT boxes but contains a cluster of SP-1 binding sites, typical of "house-keeping" genes. The encoded PBR mRNA is alternately spliced into two forms: "authentic" PBR mRNA retains all four exons, while a short form termed PBR-S lacks exon 2. While PBR-S contains a 102-codon open reading frame with a typical initiator sequence, the reading frame differs from that of PBR, so that the encoded protein is unrelated to PBR. RT-PCR and RNase protection experiments confirm that both PBR and PBR-S are expressed in all tissues examined and that expression PBR-S is about 10 times the level of PBR. Expression of PBR cDNA in pCMV5 vectors transfected into COS-1 cells resulted in increased binding of [3H]PK11195, but expression of PBR-S did not. It has been speculated that patients with congenital lipoid adrenal hyperplasia, who cannot make any steroids, might have a genetic lesion in mBzR. RT-PCR analysis of testicular RNA from such a patient, sequencing of the cDNA, and blotting analysis of genomic DNA all indicate that the gene and mRNA for the PBR component of mBzR are normal in this disease.

  20. 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.)

  1. Rate of entrance of benzodiazepines into the brain determined by eye movement recording.

    OpenAIRE

    1983-01-01

    1 Peak saccadic velocity of horizontal eye movements, saccade duration at 30 degrees of amplitude and saccade reaction time were measured in six drug free male subjects. 2 In two separate experiments, intravenous doses of diazepam (5 mg), lorazepam (2 mg), chlordiazepoxide (25 mg) and placebo were given, and eye movement recordings were made before and at frequent intervals after drug administration. 3 All the benzodiazepines produced a significant impairment of peak saccadic velocity and sac...

  2. Preferential affinity of /sup 3/H-2-oxo-quazepam for type I benzodiazepine recognition sites in the human brain

    Energy Technology Data Exchange (ETDEWEB)

    Corda, M.G.; Giorgi, O.; Longoni, B.; Ongini, E.; Montaldo, S.; Biggio, G.

    1988-01-01

    The hypnotic drug quazepam and its active metabolite 2-oxo-quazepam (2-oxo-quaz) are two benzodiazepines (BZ) containing a trifluoroethyl moiety on the ring nitrogen at position 1, characterized by their preferential affinity for Type I BZ recognition sites. In the present study we characterized the binding of /sup 3/H-2-oxo-quaz in discrete areas of the human brain. Saturation analysis demonstrated specific and saturable binding of /sup 3/H-2-oxo-quaz to membrane preparations from human cerebellum. Hill plot analysis of displacement curves of /sup 3/H-flunitrazepam binding by 2-oxo-quaz yielded Hill coefficients of approximately 1 in the cerebellum and significantly less than 1 in the cerebral cortex, hippocampus, caudate nucleus, thalamus and pons. Self and cross displacement curves for /sup 3/H-FNT and /sup 3/H-2-oxo-quaz binding in these brain areas indicated that 2-oxo-quaz binds with different affinities to two populations of binding sites. High affinity binding sites were more abundant in the cerebellum, cerebral cortex, hippocampus and thalamus, whereas low affinity sites were predominant in the caudate nucleus and pons. Competition studies of /sup 3/H-2-oxo-quaz and /sup 3/H-FNT using unlabelled ligands indicated that compounds which preferentially bind to Type I sites are more potent at displacing /sup 3/H-2-oxo-quaz than /sup 3/H-FNT from cerebral cortex membrane preparations. 26 references, 2 figures, 3 tables.

  3. Imaging of peripheral-type benzodiazepine receptor in tumor: carbon ion irradiation reduced the uptake of a positron emission tomography ligand [11C]DAC in tumor.

    Science.gov (United States)

    Yamasaki, Tomoteru; Koike, Sachiko; Hatori, Akiko; Yanamoto, Kazuhiko; Kawamura, Kazunori; Yui, Joji; Kumata, Katsushi; Ando, Koichi; Zhang, Ming-Rong

    2010-01-01

    We aimed to determine the effect of carbon ion irradiation on the uptake of N-benzyl-N-11C-methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([(11)C]DAC), a positron emission tomography (PET) ligand for the peripheral-type benzodiazepine receptor (PBR), in tumor cells and tumor-bearing mice. Spontaneous murine fibrosarcoma (NFSa) cells were implanted into the right hind legs of syngeneic C3H male mice. Conditioning irradiation with 290 MeV/u carbon ions was delivered to the 7- to 8-mm tumors In vitro uptake of [(11)C]DAC was measured in single NFSa cells isolated from NFSa-bearing mice after irradiation. In vivo biodistribution of [(11)C]DAC in NFSa-bearing mice was determined by small animal PET scanning and dissection. In vitro autoradiography was performed using tumor sections prepared from mice after PET scanning. In vitro and in vivo uptake of [(11)C]DAC in single NFSa cells and NFSa-bearing mice was significantly reduced by carbon ion irradiation. The decrease in [(11)C]DAC uptake in the tumor sections was mainly due to the change in PBR expression. In conclusion, [(11)C]DAC PET responded to the change in PBR expression in tumors caused by carbon ion irradiation in this study. Thus, [(11)C]DAC is a promising predictor for evaluating the effect of carbon ion radiotherapy.

  4. Peripheral-type benzodiazepine receptor levels correlate with the ability of human breast cancer MDA-MB-231 cell line to grow in SCID mice.

    Science.gov (United States)

    Hardwick, M; Rone, J; Han, Z; Haddad, B; Papadopoulos, V

    2001-11-01

    MDA-MB-231 (MDA-231) human breast cancer cells have a high proliferation rate, lack the estrogen receptor, express the intermediate filament vimentin, the hyaluronan receptor CD44, and are able to form tumors in nude mice. The MDA-231 cell line has been used in our laboratory to examine the role of the peripheral-type benzodiazepine receptor (PBR) in the progression of cancer. During these studies 2 populations of MDA-231 cells were subcloned based on the levels of PBR. The subclones proliferated at approximately the same rate, lacked the estrogen receptor, expressed vimentin and CD44, and had the same in vitro chemoinvasive and chemotactic potential. Both restriction fragment length polymorphism and comparative genomic hybridization analyses of genomic DNA from these cells indicated that both subclones are of the same genetic lineage. Only the subclone with high PBR levels, however, was able to form tumors when injected in SCID mice. These data suggest that the ability of MDA-231 cells to form tumors in vivo may depend on the amount of PBR present in the cells.

  5. Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [¹¹C]DAA1106.

    Science.gov (United States)

    Yasuno, Fumihiko; Kosaka, Jun; Ota, Miho; Higuchi, Makoto; Ito, Hiroshi; Fujimura, Yota; Nozaki, Shoko; Takahashi, Sho; Mizukami, Katsuyoshi; Asada, Takashi; Suhara, Tetsuya

    2012-07-30

    Subjects with mild cognitive impairment (MCI) have "prodromal or incipient" dementia with neuropathological changes. Peripheral benzodiazepine receptor (PBR) binding was shown to reflect activated microglia, one of the predictive biomarkers of conversion to dementia. We sought to evaluate PBR binding in MCI subjects using positron emission tomography (PET). PET scans with [¹¹C]DAA1106, a potent and selective ligand for PBR, were performed on seven MCI subjects, 10 patients with Alzheimer's disease (AD) and 10 age-matched control subjects. PBR binding in the regions of interest was quantified by binding potential (BP). Five MCI subjects were clinically followed for 5 years after their initial PET scans. [¹¹C]DAA1106 binding to PBR was significantly increased in widespread areas in MCI subjects when compared to healthy controls. We found no significant difference in BP between MCI and AD patients. MCI subjects with [¹¹C]DAA1106 binding values higher than the control mean +0.5 standard deviation (S.D.) developed dementia within 5 years. Our finding of higher DAA binding in MCI subjects indicated that microglial activation may occur before the onset of dementia. In vivo detection of microglial activation may provide useful prognostic information with respect to stratifying MCI subjects at increased risk of dementia.

  6. Improved synthesis of the peripheral benzodiazepine receptor ligand [{sup 11}C]DPA-713 using [{sup 11}C]methyl triflate

    Energy Technology Data Exchange (ETDEWEB)

    Thominiaux, C. [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); Dolle, F. [Service Hospitalier Frederic Joliot, Departement de Recherche Medicale, CEA/DSV, 4 place du General Leclerc, F-91401 Orsay (France); James, M.L. [Department of Pharmacology, University of Sydney, NSW 2006 (Australia)] (and others)

    2006-05-15

    Recently, the pyrazolopyrimidine, [{sup 11}C] N,N-Diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo [1,5-a]pyrimidin-3-yl]acetamide (DPA-713) has been reported as a new promising marker for the study of peripheral benzodiazepine receptors with positron emission tomography. In the present study, DPA-713 has been labelled from the corresponding nor-analogue using [{sup 11}C]methyl triflate (CH{sub 3}OTf). Conditions for HPLC were also modified to include physiological saline (aq. 0.9% NaCl)/ethanol:60/40 as mobile phase making it suitable for injection. The total time of radiosynthesis, including HPLC purification, was 18-20 min. This reported synthesis of [{sup 11}C]DPA-713, using [{sup 11}C]CH{sub 3}OTf, resulted in an improved radiochemical yield (30-38%) compared to [{sup 11}C]methyl iodide (CH{sub 3}I) (9) with a simpler purification method. This ultimately enhances the potential of [{sup 11}C]DPA-713 for further pharmacological and clinical evaluation. These improvements make this radioligand more suitable for automated synthesis which is of benefit where multi-dose preparations and repeated syntheses of radioligand are required.

  7. Quantification of human brain benzodiazepine receptors using [{sup 18}F]fluoroethylflumazenil: a first report in volunteers and epileptic patients

    Energy Technology Data Exchange (ETDEWEB)

    Leveque, Philippe [Unite de Tomographie par Positrons, Universite Catholique de Louvain, Louvain-la-Neuve (Belgium); Unite de Chimie Pharmaceutique et de Radiopharmacie, CMFA/REMA, Universite Catholique de Louvain, 73-40 Avenue Mounier, 1200, Bruxelles (Belgium); Sanabria-Bohorquez, Sandra [Imaging Research, Merck Research Laboratories, West Point, Philadelphia (United States); Bol, Anne; Volder, Anne de; Labar, Daniel [Unite de Tomographie par Positrons, Universite Catholique de Louvain, Louvain-la-Neuve (Belgium); Rijckevorsel, K. van [Service de Neurologie, Cliniques Universitaires Saint-Luc, Bruxelles (Belgium); Gallez, Bernard [Unite de Chimie Pharmaceutique et de Radiopharmacie, CMFA/REMA, Universite Catholique de Louvain, 73-40 Avenue Mounier, 1200, Bruxelles (Belgium); Unite de Resonance Magnetique Biomedicale, Universite Catholique de Louvain, Bruxelles (Belgium)

    2003-12-01

    Fluorine-18 fluoroethylflumazenil ([{sup 18}F]FEF) is a tracer for central benzodiazepine (BZ) receptors which is proposed as an alternative to carbon-11 flumazenil for in vivo imaging using positron emission tomography (PET) in humans. In this study, [{sup 18}F]FEF kinetic data were acquired using a 60-min two-injection protocol on three normal subjects and two patients suffering from mesiotemporal epilepsy as demonstrated by abnormal magnetic resonance imaging and [{sup 18}F]fluorodeoxyglucose positron emission tomography. First, a tracer bolus injection was performed and [{sup 18}F]FEF rapidly distributed in the brain according to the known BZ receptor distribution. Thirty minutes later a displacement injection of 0.01 mg/kg of unlabelled flumazenil was performed. Activity was rapidly displaced from all BZ receptor regions demonstrating the specific binding of [{sup 18}F]FEF. No displacement was observed in the pons. Plasma input function was obtained from arterial blood sampling, and metabolite analysis was performed by high-performance liquid chromatography. Metabolite quantification revealed a fast decrease in tracer plasma concentration, such that at 5 min post injection about 70% of the total radioactivity in plasma corresponded to [{sup 18}F]FEF, reaching 24% at 30 min post injection. The interactions between [{sup 18}F]FEF and BZ receptors were described using linear compartmental models with plasma input and reference tissue approaches. Binding potential values were in agreement with the known distribution of BZ receptors in human brain. Finally, in two patients with mesiotemporal sclerosis, reduced uptake of [{sup 18}F]FEF was clearly observed in the implicated left hippocampus. (orig.)

  8. Synthesis and evaluation of N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide: a deuterium-substituted radioligand for peripheral benzodiazepine receptor.

    Science.gov (United States)

    Zhang, Ming-Rong; Maeda, Jun; Ito, Takehito; Okauchi, Takashi; Ogawa, Masanao; Noguchi, Junko; Suhara, Tetsuya; Halldin, Christer; Suzuki, Kazutoshi

    2005-03-01

    N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide ([(18)F]2) is a potent ligand (IC(50): 1.71 nM) for peripheral benzodiazepine receptor (PBR). However, in vivo evaluation on rodents and primates showed that this ligand was unstable and rapidly metabolized to [(18)F]F(-) by defluorination of the [(18)F]fluoromethyl moiety. In this study, we designed a deuterium-substituted analogue, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide ([(18)F]5) as a radioligand for PBR to reduce the in vivo metabolic rate of the non-deuterated [(18)F]2. The design principle was based on the hypothesis that the deuterium substitution may reduce the rate of defluorination initiated by cleavage of the C-H bond without altering the binding affinity for PBR. The non-radioactive 5 was prepared by reacting diiodomethane-d(2) (CD(2)I(2), 6) with a phenol precursor 7, followed by treatment with tetrabutylammonium fluoride. The ligand [(18)F]5 was synthesized by the alkylation of 7 with [(18)F]fluoromethyl iodide-d(2) ([(18)F]FCD(2)I, [(18)F]9). Compound 5 displayed a similar in vitro affinity to PBR (IC(50): 1.90 nM) with 2. In vivo evaluation demonstrated that [(18)F]5 was metabolized by defluorination to [(18)F]F(-) as a main radioactive component, but its metabolic rate was slower than that of [(18)F]2 in the brain of mice. The deuterium substitution decreased the radioactivity level of [(18)F]5 in the bone of mouse, augmented by the percentage of specific binding to PBR in the rat brain determined by ex vivo autoradiography. However, the PET image of [(18)F]5 for monkey brain showed high radioactivity in the brain and skull, suggesting a possible species difference between rodents and primates.

  9. Biodistribution and dosimetry of [{sup 123}I]iodo-Pk 11195: a potential agent for SPET imaging of the peripheral benzodiazepine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Versijpt, J. [Groningen Univ. Hospital (Netherlands). Dept. of Biological Psychiatry; Div. of Nuclear Medicine, Ghent Univ. Hospital (Belgium); Dumont, F.; Vos, F. de; Slegers, G. [Dept. of Radiopharmacy, Ghent Univ. (Belgium); Thierens, H. [Dept. of Biomedical Physics and Radiation Protection, Ghent Univ. (Belgium); Jansen, H.; Dierckx, R.A. [Div. of Nuclear Medicine, Ghent Univ. Hospital (Belgium); Santens, P. [Dept. of Neurology, Ghent Univ. Hospital (Belgium); Korf, J. [Groningen Univ. Hospital (Netherlands). Dept. of Biological Psychiatry

    2000-09-01

    The highest concentrations of the peripheral benzodiazepine receptor (PBR) are found in the kidneys and heart. In addition, the PBR has been reported to reflect neuro-inflammatory damage by co-localisation with activated microglia. PK 11195 is a high-affinity ligand for the PBR. The aim of this study was to investigate in humans the biodistribution and dosimetry of [{sup 123}I]iodo-PK 11195, a potential single-photon emission tomography tracer for the PBR. Five healthy volunteers were injected with 112 MBq of [{sup 123}I]iodo-PK 11195. Sequential whole-body scans were performed up to 72 h post injection. Multiple blood samples were taken, and urine was collected to measure the fraction voided by the renal system. Decay-corrected regions of interest of the whole-body images were analysed, and geometric mean count rates were used to determine organ activity. Organ absorbed doses and effective dose were calculated using the MIRD method. [{sup 123}I]iodo-PK 11195 was rapidly cleared from the blood, mainly by the hepatobiliary system. Approximately 22% was voided in urine after 48 h. Average organ residence times were 0.74, 0.44 and 0.29 h for the liver, upper large intestine and lower large intestine, respectively. The testes received the highest dose, 109.4 {mu}Gy/MBq. All other organs investigated received doses of less than 50 {mu}Gy/MBq. The effective dose was 40.3 {mu}Sv/MBq. In conclusion, [{sup 123}I]iodo-PK 11195 is a suitable agent for the visualisation of the PBR and indirectly for the imaging of neuro-inflammatory lesions. Taking into account the radiation burden of 7.46 mSv following an administration of 185 MBq, a [{sup 123}I]iodo-PK 11195 investigation has to be considered an ICRP risk category IIb investigation. (orig.)

  10. Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies.

    Science.gov (United States)

    Ji, Bin; Maeda, Jun; Sawada, Makoto; Ono, Maiko; Okauchi, Takashi; Inaji, Motoki; Zhang, Ming-Rong; Suzuki, Kazutoshi; Ando, Kiyoshi; Staufenbiel, Matthias; Trojanowski, John Q; Lee, Virginia M Y; Higuchi, Makoto; Suhara, Tetsuya

    2008-11-19

    We demonstrate the significance of peripheral benzodiazepine receptor (PBR) imaging in living mouse models of Alzheimer's disease (AD) as biomarkers and functional signatures of glial activation. By radiochemically and immunohistochemically analyzing murine models of the two pathological hallmarks of AD, we found that AD-like Abeta deposition is concurrent with astrocyte-dominant PBR expression, in striking contrast with nonastroglial PBR upregulation in accumulations of AD-like phosphorylated tau. Because tau-induced massive neuronal loss was distinct from the marginal neurodegeneration associated with Abeta plaques in these models, cellular localization of PBR reflected deleterious and beneficial glial reactions to tau versus Abeta pathologies, respectively. This notion was subsequently examined in models of various non-AD neuropathologies, revealing the following reactive glial dynamics underlying differential PBR upregulation: (1) PBR(-) astrogliosis uncoupled with microgliosis or coupled with PBR(+) microgliosis associated with irreversible neuronal insults; and (2) PBR(+) astrogliosis coupled with PBR(- or +/-) microgliosis associated with minimal or reversible neuronal toxicity. Intracranial transplantation of microglia also indicated that nontoxic microglia drives astroglial PBR expression. Moreover, levels of glial cell line-derived neurotrophic factor (GDNF) in astrocytes were correlated with astroglial PBR, except for increased GDNF in PBR(-) astrocytes in the model of AD-like tau pathology, thereby suggesting that PBR upregulation in astrocytes is an indicator of neurotrophic support. Together, PBR expressions in astrocytes and microglia reflect beneficial and deleterious glial reactions, respectively, in diverse neurodegenerative disorders including AD, pointing to new applications of PBR imaging for monitoring the impact of gliosis on the pathogenesis and treatment of AD.

  11. Omega 3 (peripheral type benzodiazepine binding) site distribution in the rat immune system: an autoradiographic study with the photoaffinity ligand (/sup 3/H)PK 14105

    Energy Technology Data Exchange (ETDEWEB)

    Benavides, J.; Dubois, A.; Dennis, T.; Hamel, E.; Scatton, B.

    1989-04-01

    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 (/sup 3/H)PK 14105. In thymus sections, (/sup 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.

  12. The 18 kDa translocator protein (peripheral benzodiazepine receptor) expression in the bone of normal, osteoprotegerin or low calcium diet treated mice.

    Science.gov (United States)

    Kam, Winnie Wai-Ying; Meikle, Steven R; Zhou, Hong; Zheng, Yu; Blair, Julie M; Seibel, Marcus; Dunstan, Colin R; Banati, Richard B

    2012-01-01

    The presence of the translocator protein (TSPO), previously named as the mitochondrial or peripheral benzodiazepine receptor, in bone cells was studied in vitro and in situ using RT-qPCR, and receptor autoradiography using the selective TSPO ligand PK11195.In vitro, the TSPO is highly expressed in osteoblastic and osteoclastic cells.In situ, constitutive expression of TSPO is found in bone marrow and trabecular bone, e.g., spongiosa. Mice with a reduction of bone turnover induced by a 4-day treatment of osteoprotegerin reduces [(3)H]PK11195 binding in the spongiosa (320±128 Bq x mg(-1), 499±106 Bq x mg(-1) in saline-treated controls). In contrast, mice with an increase in bone turnover caused by a 4-day low calcium diet increases [(3)H]PK11195 binding in the spongiosa (615±90 Bq x mg(-1)). Further, our study includes technical feasibility data on [(18)F]fluoride microPET imaging of rodent bone with altered turnover. Despite [(18)F]fluoride having high uptake, the in vivo signal differences were small. Using a phantom model, we describe the spillover effect and partial volume loss that affect the quantitative microPET imaging of the small bone structures in experimental mouse models. In summary, we demonstrate the expression of TSPO in small rodent bone tissues, including osteoblasts and osteoclasts. A trend increase in TSPO expression was observed in the spongiosa from low to high bone turnover conditions. However, despite the potential utility of TSPO expression as an in vivo biomarker of bone turnover in experimental rodent models, our small animal PET imaging data using [(18)F]fluoride show that even under the condition of a good biological signal-to-noise ratio and high tracer uptake, the currently achievable instrument sensitivity and spatial resolution is unlikely to be sufficient to detect subtle differences in small structures, such as mouse bone.

  13. The 18 kDa translocator protein (peripheral benzodiazepine receptor expression in the bone of normal, osteoprotegerin or low calcium diet treated mice.

    Directory of Open Access Journals (Sweden)

    Winnie Wai-Ying Kam

    Full Text Available The presence of the translocator protein (TSPO, previously named as the mitochondrial or peripheral benzodiazepine receptor, in bone cells was studied in vitro and in situ using RT-qPCR, and receptor autoradiography using the selective TSPO ligand PK11195.In vitro, the TSPO is highly expressed in osteoblastic and osteoclastic cells.In situ, constitutive expression of TSPO is found in bone marrow and trabecular bone, e.g., spongiosa. Mice with a reduction of bone turnover induced by a 4-day treatment of osteoprotegerin reduces [(3H]PK11195 binding in the spongiosa (320±128 Bq x mg(-1, 499±106 Bq x mg(-1 in saline-treated controls. In contrast, mice with an increase in bone turnover caused by a 4-day low calcium diet increases [(3H]PK11195 binding in the spongiosa (615±90 Bq x mg(-1. Further, our study includes technical feasibility data on [(18F]fluoride microPET imaging of rodent bone with altered turnover. Despite [(18F]fluoride having high uptake, the in vivo signal differences were small. Using a phantom model, we describe the spillover effect and partial volume loss that affect the quantitative microPET imaging of the small bone structures in experimental mouse models. In summary, we demonstrate the expression of TSPO in small rodent bone tissues, including osteoblasts and osteoclasts. A trend increase in TSPO expression was observed in the spongiosa from low to high bone turnover conditions. However, despite the potential utility of TSPO expression as an in vivo biomarker of bone turnover in experimental rodent models, our small animal PET imaging data using [(18F]fluoride show that even under the condition of a good biological signal-to-noise ratio and high tracer uptake, the currently achievable instrument sensitivity and spatial resolution is unlikely to be sufficient to detect subtle differences in small structures, such as mouse bone.

  14. 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.

  15. Peripheral nerve injury induces adult brain neurogenesis and remodelling.

    Science.gov (United States)

    Rusanescu, Gabriel; Mao, Jianren

    2017-02-01

    Unilateral peripheral nerve chronic constriction injury (CCI) has been widely used as a research model of human neuropathic pain. Recently, CCI has been shown to induce spinal cord adult neurogenesis, which may contribute to the chronic increase in nociceptive sensitivity. Here, we show that CCI also induces rapid and profound asymmetrical anatomical rearrangements in the adult rodent cerebellum and pons. This remodelling occurs throughout the hindbrain, and in addition to regions involved in pain processing, also affects other sensory modalities. We demonstrate that these anatomical changes, partially reversible in the long term, result from adult neurogenesis. Neurogenic markers Mash1, Ngn2, doublecortin and Notch3 are widely expressed in the rodent cerebellum and pons, both under normal and injured conditions. CCI-induced hindbrain structural plasticity is absent in Notch3 knockout mice, a strain with impaired neuronal differentiation, demonstrating its dependence on adult neurogenesis. Grey matter and white matter structural changes in human brain, as a result of pain, injury or learned behaviours have been previously detected using non-invasive neuroimaging techniques. Because neurogenesis-mediated structural plasticity is thought to be restricted to the hippocampus and the subventricular zone, such anatomical rearrangements in other parts of the brain have been thought to result from neuronal plasticity or glial hypertrophy. Our findings suggest the presence of extensive neurogenesis-based structural plasticity in the adult mammalian brain, which may maintain a memory of basal sensory levels, and act as an adaptive mechanism to changes in sensory inputs.

  16. Binding of (/sup 3/H)ethyl-. beta. -carboline-3-carboxylate to brain benzodiazepine receptors. Effect of drugs and anions

    Energy Technology Data Exchange (ETDEWEB)

    Williams, E.F.; Paul, S.M.; Rice, K.C.; Skolnick, P. (National Institutes of Health, Bethesda, MD (USA)); Cain, M. (Wisconsin Univ., Milwaukee (USA). Dept. of Chemistry)

    1981-09-28

    It is reported that in contrast to the changes in affinity of (/sup 3/H)benzodiazepines elicited by halide ions, barbiturates, and pyrazolopyridines, the apparent affinity of ..beta..-(/sup 3/H)CCE (ethyl-..beta..-carboline-3-carboxylate) is unaffected by these agents. Furthermore, Scatchard analysis of ..beta..-(/sup 3/H)CCE binding to cerebral cortical and cerebellar membranes revealed a significantly greater number of binding sites than was observed with either (/sup 3/H)diazepam or (/sup 3/H)flunitazepam, suggesting that at low concentrations benzodiazepines selectively label a subpopulation of the receptors labelled with ..beta..-(/sup 3/H)CCE. Alternatively, ..beta..-(/sup 3/H)CCE may bind to sites that are distinct from those labelled with (/sup 3/H)-benzodiazepines.

  17. Resveratrol attenuates peripheral and brain inflammation and reduces ischemic brain injury in aged female mice.

    Science.gov (United States)

    Jeong, Sae Im; Shin, Jin A; Cho, Sunghee; Kim, Hye Won; Lee, Ji Yoon; Kang, Jihee Lee; Park, Eun-Mi

    2016-08-01

    Resveratrol is known to improve metabolic dysfunction associated with obesity. Visceral obesity is a sign of aging and is considered a risk factor for ischemic stroke. In this study, we investigated the effects of resveratrol on inflammation in visceral adipose tissue and the brain and its effects on ischemic brain injury in aged female mice. Mice treated with resveratrol (0.1 mg/kg, p.o.) for 10 days showed reduced levels of interleukin-1β and tumor necrosis factor-α, as well as a reduction in the size of adipocytes in visceral adipose tissue. Resveratrol also reduced interleukin-1β and tumor necrosis factor-α protein levels and immunoglobulin G extravasation in the brain. Mice treated with resveratrol demonstrated smaller infarct size, improved neurological function, and blunted peripheral inflammation at 3 days postischemic stroke. These results showed that resveratrol counteracted inflammation in visceral adipose tissue and in the brain and reduced stroke-induced brain injury and peripheral inflammation in aged female mice. Therefore, resveratrol administration can be a valuable strategy for the prevention of age-associated and disease-provoked inflammation in postmenopausal women.

  18. 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

    Energy Technology Data Exchange (ETDEWEB)

    Mattner, F.; Katsifis, A.; Ballantyne, P. [ANSTO, Radiopharmaceuticals Division, Lucas Heights (Australia); Staykova, M.; Willenborg, D.O. [Australian National University Medical School, The Canberra Hospital, Neurosciences Research Unit, Woden, Canberra (Australia)

    2005-04-01

    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{sup 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{sup 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. {sup 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{sup +} cells representing macrophages and microglia. These results demonstrate the ability of {sup 123}I

  19. Enhancement of peripheral benzodiazepine receptor ligand-induced apoptosis and cell cycle arrest of esophageal cancer cells by simultaneous inhibition of MAPK/ERK kinase.

    Science.gov (United States)

    Sutter, Andreas P; Maaser, Kerstin; Gerst, Bastian; Krahn, Antje; Zeitz, Martin; Scherübl, Hans

    2004-05-01

    Specific ligands of the peripheral benzodiazepine receptor (PBR) activate pro-apoptotic and anti-proliferative signaling pathways. Previously, we found that PBR ligands activated the p38 mitogen-activated protein kinase (MAPK) pathway in esophageal cancer cells, and that the activation of p38MAPK contributed to tumor cell apoptosis and cell cycle arrest. Here, we report that PBR ligands also activate the pro-survival MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway in esophageal cancer cells, which might compromise the efficacy of PBR ligands. Hence, a combination treatment of PBR ligands and MEK inhibitors, which are emerging as promising anticancer agents, was pursued to determine whether this treatment could lead to enhanced apoptosis and cell cycle arrest. Using Western blotting we demonstrated a time- and dose-dependent phosphorylation of ERK1/2 in response to PBR ligands. Apoptosis was investigated by assessment of mitochondrial alterations and caspase-3 activity. Cell cycle arrest was measured by flow cytometric analysis of stained isolated nuclei. The inhibition of MEK/ERK with a pharmacologic inhibitor, 2'-amino-3'-methoxyflavone (PD 98059), resulted in a synergistic enhancement of PBR-ligand-induced growth inhibition, apoptosis and cell cycle arrest. Specifity of the pharmacologic inhibitor was confirmed by the use of 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U 0126), a second MEK/ERK inhibitor, and 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U 0124), a structural analogue of it which does not display any affinity to MEK. Enhanced pro-apoptotic and anti-proliferative effects were observed both in KYSE-140 esophageal squamous cancer and OE-33 adenocarcinoma cells, suggesting that this effect was not cell-type specific. In addition, the PBR-mediated overexpression of the stress response gene (growth arrest and DNA-damage-inducible gene gadd153) was synergistically enhanced by MEK inhibition. This is the

  20. Radioiodinated benzodiazepines: agents for mapping glial tumors

    Energy Technology Data Exchange (ETDEWEB)

    Van Dort, M.E.; Ciliax, B.J.; Gildersleeve, D.L.; Sherman, P.S.; Rosenspire, K.C.; Young, A.B.; Junck, L.; Wieland, D.M.

    1988-11-01

    Two isomeric iodinated analogues of the peripheral benzodiazepine binding site (PBS) ligand Ro5-4864 have been synthesized and labeled in high specific activity with iodine-125. Competitive binding assays conducted with the unlabeled analogues indicate high affinity for PBS. Tissue biodistribution studies in rats with these /sup 125/I-labeled ligands indicate high uptake of radioactivity in the adrenals, heart, and kidney--tissues known to have high concentrations of PBS. Preadministration of the potent PBS antagonist PK 11195 blocked in vivo uptake in adrenal tissue by over 75%, but to a lesser degree in other normal tissues. In vivo binding autoradiography in brain conducted in C6 glioma bearing rats showed dense, PBS-mediated accumulation of radioactivity in the tumor. Ligand 6 labeled with /sup 123/I may have potential for scintigraphic localization of intracranial glioma.

  1. Traumatic Brain Injury and Peripheral Immune Suppression: Primer and Prospectus.

    Science.gov (United States)

    Hazeldine, Jon; Lord, Janet M; Belli, Antonio

    2015-01-01

    Nosocomial infections are a common occurrence in patients following traumatic brain injury (TBI) and are associated with an increased risk of mortality, longer length of hospital stay, and poor neurological outcome. Systemic immune suppression arising as a direct result of injury to the central nervous system (CNS) is considered to be primarily responsible for this increased incidence of infection, a view strengthened by recent studies that have reported novel changes in the composition and function of the innate and adaptive arms of the immune system post-TBI. However, our knowledge of the mechanisms that underlie TBI-induced immune suppression is equivocal at best. Here, after summarizing our current understanding of the impact of TBI on peripheral immunity and discussing CNS-mediated regulation of immune function, we propose roles for a series of novel mechanisms in driving the immune suppression that is observed post-TBI. These mechanisms, which have never been considered before in the context of TBI-induced immune paresis, include the CNS-driven emergence into the circulation of myeloid-derived suppressor cells and suppressive neutrophil subsets, and the release from injured tissue of nuclear and mitochondria-derived damage associated molecular patterns. Moreover, in an effort to further our understanding of the mechanisms that underlie TBI-induced changes in immunity, we pose throughout the review a series of questions, which if answered would address a number of key issues, such as establishing whether manipulating peripheral immune function has potential as a future therapeutic strategy by which to treat and/or prevent infections in the hospitalized TBI patient.

  2. 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.

  3. 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....

  4. Interaction of pyracetam with specific /sup 3/H-imipramine binding sites and GABA-benzodiazepine receptor complex of brain membranes

    Energy Technology Data Exchange (ETDEWEB)

    Rozhanets, V.V.; Chakhbra, K.K.; Danchev, N.D.; Malin, K.M.; Rusakov, D.Yu.; Val' dman, A.V.

    1986-06-01

    This paper studies the effect of pyracetam on parameters of specific binding of tritium-imipramine and GABA-activated binding of tritium-flunitrazepam with rat brain membranes. The experimental method is described and it is shown that pyracetam and mebicar in experiments in vivo on normal animals can exert their anxiolytic action without the participation of bensodiazepine receptors. Either the interaction of pyracetam and mebicar with benzodiazeprine receptors has a different interpretation than competition of these compounds with specific binding sites of tritium-flunitrazepam, or in experiments on normal animals in vivo GABA-benzodiazepine receptor complex does not accept pyracetam and mebicar, for it contains endogenous inhibitors of GABA-modulating action.

  5. 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)

  6. Receptor binding characterization of the benzodiazepine radioligand sup 125 I-Ro16-0154: Potential probe for SPECT (Single Photon Emission Computed Tomography) brain imaging

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, E.W.; Woods, S.W.; Zoghbi, S.; Baldwin, R.M.; Innis, R.B. (Yale Univ., West Haven, CT (USA)); McBride, B.J. (Medi-Physics, Inc., Emeryville, CA (USA))

    1990-01-01

    The binding of an iodinated benzodiazepine (BZ) radioligand has been characterized, particularly in regard to its potential use as a neuroreceptor brain imaging agent with SPECT (Single Photon Emission Computed Tomography). Ro16-0154 is an iodine-containing BZ antagonist and a close analog of Ro15-1788. In tissue homogenates prepared from human and monkey brain, the binding of {sup 125}I-labeled Ro16-0154 was saturable, of high affinity, and had high ratios of specific to non-specific binding. Physiological concentrations of NaCl enhanced specific binding approximately 15% compared to buffer without this salt. Kinetic studies of association and dissociation demonstrated a temperature dependent decrease in affinity with increasing temperature. Drug displacement studies confirmed that {sup 125}I-Ro16-0154 binds to the central type BZ receptor: binding is virtually identical to that of {sup 3}H-Ro15-1788 except that {sup 125}I-Ro16-0154 shows an almost 10 fold higher affinity at 37{degree}C. These in vitro results suggest that {sup 123}I-labeled Ro16-0154 shows promise as a selective, high affinity SPECT probe of the brain's BZ receptor.

  7. Benzodiazepines and Pregnancy

    Science.gov (United States)

    Benzodiazepines and Pregnancy In every pregnancy, a woman starts out with a 3-5% chance of having ... risk. This sheet talks about whether exposure to benzodiazepines may increase the risk for birth defects over ...

  8. [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.

  9. The history of benzodiazepines.

    Science.gov (United States)

    Wick, Jeannette Y

    2013-09-01

    After more than 50 years of experience with benzodiazepines, the American health care system has a love-hate relationship with them. In 1955, Hoffmann-La Roche chemist Leo Sternbach serendipitously identified the first benzodiazepine, chlordiazepoxide (Librium). By 1960, Hoffmann-La Roche marketed it as Librium, and it pursued molecular modifications for enhanced activity. Valium (diazepam) followed in 1963. Hoffmann-La Roche's competitors also began looking for analogues. Initially, benzodiazepines appeared to be less toxic and less likely to cause dependence than older drugs. A specific improvement was their lack of respiratory depression, a safety concern with barbiturates. Medical professionals greeted benzodiazepines enthusiastically at first, skyrocketing their popularity and patient demand. In the mid-to-late 1970s, benzodiazepines topped all "most frequently prescribed" lists. It took 15 years for researchers to associate benzodiazepines and their effect on gamma-aminobutyric acid as a mechanism of action. By the 1980s, clinicians' earlier enthusiasm and propensity to prescribe created a new concern: the specter of abuse and dependence. As information about benzodiazepines, both raising and damning, accumulated, medical leaders and legislators began to take action. The result: individual benzodiazepines and the entire class began to appear on guidelines and in legislation giving guidance on their use. Concurrently, clinicians began to raise concerns about benzodiazepine use by elderly patients, indicating that elders'lesser therapeutic response and heightened sensitivity to side effects demanded prescriber caution. The benzodiazepine story continues to evolve and includes modern-day issues and concerns beyond those ever anticipated.

  10. Fluctuations in Brain Temperature Induced by Lypopolysaccharides: Central and Peripheral Contributions

    Directory of Open Access Journals (Sweden)

    Jeremy S. Tang

    2010-01-01

    Full Text Available In this study, we examined changes in central (anterior-preoptic hypothalamus and peripheral (temporal muscle and facial skin temperatures in freely moving rats following intravenous administration of bacterial lipopolysaccharides (LPS at low doses (1 and 10 μg/kg at thermoneutral conditions (28˚C. Recordings were made with high temporal resolution (5-s bin and the effects of LPS were compared with those induced by a tail-pinch, a standard arousing somato-sensory stimulus. At each dose, LPS moderately elevated brain, muscle and skin temperatures. In contrast to rapid, monophasic and relatively short hyperthermic responses induced by a tail-pinch, LPS-induced increases in brain and muscle temperatures occurred with ~40 min onset latencies, showed three not clearly defined phases, were slightly larger with the 10 μm/kg dose and maintained for the entire 4-hour post-injection recording duration. Based on dynamics of brain-muscle and skin-muscle temperature differentials, it appears that the hyperthermic response induced by LPS at the lowest dose originates from enhanced peripheral heat production, with no evidence of brain metabolic activation and skin vasoconstriction. While peripheral heat production also appears to determine the first phase of brain and body temperature elevation with LPS at 10 μg/kg, a further prolonged increase in brain-muscle differentials (onset at ~100 min suggests metabolic brain activation as a factor contributing to brain and body hyperthermia. At this dose, skin temperature increase was weaker than in temporal muscle, suggesting vasoconstriction as another contributor to brain/ body hyperthermia. Therefore, although both LPS at low doses and salient sensory stimuli moderately increase brain and body temperatures, these hyperthermic responses have important qualitative differences, reflecting unique underlying mechanisms.

  11. HIV-1 phylogenetic analysis shows HIV-1 transits through the meninges to brain and peripheral tissues.

    Science.gov (United States)

    Lamers, Susanna L; Gray, Rebecca R; Salemi, Marco; Huysentruyt, Leanne C; McGrath, Michael S

    2011-01-01

    Brain infection by the human immunodeficiency virus type 1 (HIV-1) has been investigated in many reports with a variety of conclusions concerning the time of entry and degree of viral compartmentalization. To address these diverse findings, we sequenced HIV-1 gp120 clones from a wide range of brain, peripheral and meningeal tissues from five patients who died from several HIV-1 associated disease pathologies. High-resolution phylogenetic analysis confirmed previous studies that showed a significant degree of compartmentalization in brain and peripheral tissue subpopulations. Some intermixing between the HIV-1 subpopulations was evident, especially in patients that died from pathologies other than HIV-associated dementia. Interestingly, the major tissue harboring virus from both the brain and peripheral tissues was the meninges. These results show that (1) HIV-1 is clearly capable of migrating out of the brain, (2) the meninges are the most likely primary transport tissues, and (3) infected brain macrophages comprise an important HIV reservoir during highly active antiretroviral therapy.

  12. Triple Peripheral Nerve Injury Accompanying to Traumatic Brain Injury: A Case Report

    Directory of Open Access Journals (Sweden)

    Ižlknur Can

    2014-02-01

    Full Text Available Secondary injuries especially extremity fractures may be seen concurrently with traumatic brain injury (TBI. Peripheral nerve damages may accompany to these fractures and may be missed out, especially in acute stage. In this case report; damage of radial, ulnar and median nerves which was developed secondarily to distal humerus fracture that could not be detected in acute stage, in a patient who had motor vehicle accident (MVA. 29-year-old male patient was admitted with weakness in the right upper extremity. 9 months ago, he had traumatic brain injury because of MVA, and fracture of distal humerus was detected in follow-ups. Upon the suspect of the peripheral nerve injury, the diagnosis was confirmed with ENMG. The patient responded well to the rehabilitation program treatment. In a TBI patient, it must be kept in mind that there might be a secondary trauma and therefore peripheral nerve lesions may accompany to TBI.

  13. Whole-body distribution and metabolism of [N-methyl-{sup 11}C](R)-1-(2-chlorophenyl)-N-(1-methylpropyl)-3-isoquinolinecarboxamide in humans; an imaging agent for in vivo assessment of peripheral benzodiazepine receptor activity with positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Roivainen, Anne; Hirvonen, Jussi; Oikonen, Vesa; Virsu, Pauliina; Tolvanen, Tuula [Turku University Hospital, Turku PET Centre, Turku (Finland); Naagren, Kjell [University of Turku, Radiopharmaceutical Chemistry Laboratory, Turku (Finland); Rinne, Juha O. [Turku University Hospital, Turku PET Centre, Turku (Finland); Turku Imanet, GE Healthcare Medical Diagnostics, Turku (Finland)

    2009-04-15

    {sup 11}C-PK11195 is a radiopharmaceutical for in vivo assessment of peripheral benzodiazepine receptor (PBR) activity using PET. We sought to clarify the metabolic fate of {sup 11}C-PK11195 in a test-retest setting using radio-HPLC in comparison with radio-TLC, and the whole-body distribution in humans. In order to evaluate the reproducibility of radio-HPLC metabolite analyses, ten patients with Alzheimer's disease (AD) underwent two successive {sup 11}C-PK11195 examinations on separate days. For comparison of different analytical methods, plasma samples from seven patients were also analysed by radio-TLC. In addition, we evaluated the whole-body distribution of {sup 11}C-PK11195 and its uptake in the brain. The level of unmetabolized {sup 11}C-PK11195 decreased slowly from 96.3 {+-} 1.6% (mean{+-}SD) at 5 min to 62.7 {+-} 8.3% at 40 min after injection. Large individual variation was observed in the amount of plasma {sup 11}C-PK11195 radiometabolites. The whole-body distribution of {sup 11}C-PK11195 showed the highest radioactivity levels in urinary bladder, adrenal gland, liver, salivary glands, heart, kidneys, and vertebral column. In addition, the hip bone and breast bone were clearly visualized by PET. In patients with AD, {sup 11}C-PK11195 uptake in the brain was the highest in the basal ganglia and thalamus, followed by the cortical grey matter regions and the cerebellum. Low {sup 11}C-PK11195 uptake was observed in the white matter. Our results indicate that {sup 11}C-PK11195 is eliminated both through the renal and hepatobiliary systems. Careful analysis of plasma metabolites is required to determine the accurate arterial input function for quantitative PET measurement. (orig.)

  14. Automated radiosynthesis of [{sup 18}F]PBR111 and [{sup 18}F]PBR102 using the Tracerlab FX{sub FN} and Tracerlab MX{sub FDG} module for imaging the peripheral benzodiazepine receptor with PET

    Energy Technology Data Exchange (ETDEWEB)

    Bourdier, Thomas, E-mail: thomas@nucmed.rpa.cs.nsw.gov.au [PET and Nuclear Medicine Department, Royal Prince Alfred Hospital, Missenden road, Camperdown NSW 2050, Sydney (Australia); Pham, Tien Q. [LifeSciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC NSW 2232, Sydney (Australia); Henderson, David [PET and Nuclear Medicine Department, Royal Prince Alfred Hospital, Missenden road, Camperdown NSW 2050, Sydney (Australia); Jackson, Timothy [LifeSciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC NSW 2232, Sydney (Australia); Lam, Peter [PET and Nuclear Medicine Department, Royal Prince Alfred Hospital, Missenden road, Camperdown NSW 2050, Sydney (Australia); Izard, Michael; Katsifis, Andrew [LifeSciences, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC NSW 2232, Sydney (Australia)

    2012-01-15

    [{sup 18}F]PBR111 and [{sup 18}F]PBR102 are selective radioligands for imaging of the Peripheral Benzodiazepine Receptor (PBR). We have developed a fully automated method for the radiosynthesis of [{sup 18}F]PBR111 and [{sup 18}F]PBR102 in the Tracerlab FX{sub FN} (30{+-}2% radiochemical yield non-decay-corrected for both tracers) and Tracerlab MX{sub FDG} (25{+-}2% radiochemical yield non-decay-corrected for both tracers) from the corresponding p-toluenesulfonyl precursors. For all tracers, radiochemical purity was >99% and specific activity was >150 GBq/{mu}mol after less than 60 min of preparation time. - Highlights: Black-Right-Pointing-Pointer Radiosynthesis of novel ligands PBR111 and PBR102 with fluorine-18. Black-Right-Pointing-Pointer Fully automated synthesis undertaken using the GE Tracerlab FX{sub FN} and MX{sub FDG} modules. Black-Right-Pointing-Pointer Reproducible high yields suitable for clinical applications. Black-Right-Pointing-Pointer Radiosynthesis and formulation achieved in less than 60 mins. Black-Right-Pointing-Pointer PBR111 and PBR102 prepared in high radiochemical yield and specific activity.

  15. Peripheral lipopolysaccharide administration transiently affects expression of brain-derived neurotrophic factor, corticotropin and proopiomelanocortin in mouse brain.

    Science.gov (United States)

    Schnydrig, Sabine; Korner, Lukas; Landweer, Svenja; Ernst, Beat; Walker, Gaby; Otten, Uwe; Kunz, Dieter

    2007-12-11

    Peripheral inflammation induced by intraperitoneal (i.p.) injection of Lipopolysaccharide (LPS) is known to cause functional impairments in the brain affecting memory and learning. One of mechanisms may be the interference with neurotrophin (NT) expression and function. In the current study we administered a single, high dose of LPS (3mg/kg, i.p.) into mice and investigated changes in brain-derived neurotrophic factor (BDNF) gene expression within 1-6 days after LPS injection. Crude synaptosomes were isolated from brain tissue and subjected to Western-blot analyses. We found transient reductions in synaptosomal proBDNF- and BDNF protein expression, with a maximal decrease at day 3 as compared to saline injected controls. The time course of reduction of BDNF mRNA in whole brain extracts parallels the decrease in protein levels in synaptosomes. LPS effects in the central nervous system (CNS) are known to crucially involve the activation of the hypothalamic-pituitary-adrenal (HPA) axis. We analysed the time course of corticotropin releasing hormone (CRH)- and proopiomelanocortin (POMC) mRNA expression. As observed for BDNF-, CRH- and POMC mRNA levels are also significantly reduced on day 3 indicating a comparable time course. These results suggest that peripheral inflammation causes a reduction of trophic supply in the brain, including BDNF at synaptic sites. The mechanisms involved could be a negative feedback of the activated HPA axis.

  16. Sharpening peripheral dose gradient via beam number enhancement from patient head tilt for stereotactic brain radiosurgery

    Science.gov (United States)

    Chiu, Joshua; Pierce, Marlon; Braunstein, Steve E.; Theodosopoulos, Philip V.; McDermott, Michael W.; Sneed, Penny K.; Ma, Lijun

    2016-10-01

    Sharp dose fall-off is the hallmark of brain radiosurgery for the purpose of delivering high dose radiation to the target while minimizing peripheral dose to regional normal brain tissue. In this study, a technique was developed to enhance the peripheral dose gradient by magnifying the total number of beams focused toward each isocenter through pre-programmed patient head tilting. This technique was tested in clinical settings on a dedicated brain radiosurgical system (GKPFX, Gamma Knife Perfexion, Elekta Oncology) by comparing dosimetry as well as delivery efficiency for 20 radiosurgical cases previously treated with the system. The 3-fold beam number enhancement (BNE) treatment plans were found to produce nearly identical target volume coverage (absolute value    0.2) and dose conformity (BNE CI  =  1.41  ±  0.22 versus 1.41  ±  0.11, P  >  0.99) as the original treatment plans. The total beam-on time for the 3-fold BNE treatment plans were also found to be comparable (peripheral dose gradient for brain radiosurgery. This work was presented in part at the 2015 ISRS Congress in Yokohama Japan.

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

    Energy Technology Data Exchange (ETDEWEB)

    Lummis, S.C.R.; Johnston, G.A.R. (Univ. of Sydney, New South Wales (Australia)); Nicoletti, G. (Royal Melbourne Inst. of Tech. (Australia)); Holan, G. (CSIRO, Melbourne (Australia))

    1991-01-01

    Benzodiazepine binding sites, which were once considered to exist only in higher vertebrates, are here demonstrated in the bacteria E. coli. The bacterial ({sup 3}H)diazepam binding sites are modulated by GABA; the modulation is dose dependent and is reduced at high concentrations. The most potent competitors of E.Coli ({sup 3}H)diazepam binding are those that are active in displacing ({sup 3}H)benzodiazepines from vertebrate peripheral benzodiazepine binding sites. These vertebrate sites are not modulated by GABA, in contrast to vertebrate neuronal benzodiazepine binding sites. The E.coli benzodiazepine binding sites therefore differ from both classes of vertebrate benzodiazepine binding sites; however the 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.

  18. 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.

  19. [Benzodiazepines in geriatrics].

    Science.gov (United States)

    Hofmann, W

    2013-12-01

    About 10 % of community dwelling elderly people are chronically consuming benzodiazepines. This proportion rises to 30 % in nursing homes or hospitals. Particularly in older patients, this usage leads to a higher risk of adverse drug reactions. Exposure contributes to delirium and falls with subsequent femoral neck fractures. The WHO has classified the risk potential of the new z-drugs to be the same as that associated with benzodiazepines. It is recommended that benzodiazepines should be discontinued step by step under supervision of a doctor or the dosage should be reduced.

  20. Benzodiazepines: Sedation and Agitation.

    Science.gov (United States)

    Gallagher, Catherine

    2016-01-01

    Dental anxiety is common and frequently poses a barrier to necessary dental treatment. The increasing availability of conscious sedation in dental practice has made treatment much more accessible for anxious patients. At present, benzodiazepines are the most commonly used drugs in sedation practice and provide a pleasant experience for most, but not all, patients. An understanding of the mechanism of action of benzodiazepines should inform our practice and deepen our understanding of why and how sedation may fail. CPD/CLINICAL RELEVANCE: As an increasing number of dentists provide sedation for their patients an update on benzodiazepines is timely.

  1. Autoradiographic localization of benzodiazepine receptor downregulation

    Energy Technology Data Exchange (ETDEWEB)

    Tietz, E.I.; Rosenberg, H.C.; Chiu, T.H.

    1986-01-01

    Regional differences in downregulation of brain benzodiazepine receptors were studied using a quantitative autoradiographic method. Rats were given a 4-week flurazepam treatment known to cause tolerance and receptor downregulation. A second group of rats was given a similar treatment, but for only 1 week. A third group was given a single acute dose of diazepam to produce a brain benzodiazepine-like activity equivalent to that found after the chronic treatment. Areas studied included hippocampal formation, cerebral cortex, superior colliculus, substantia nigra, dorsal geniculate nucleus, lateral amygdala and lateral hypothalamus. There was a regional variation in the degree of downregulation after 1 week of flurazepam treatment, ranging from 12% to 25%. Extending the flurazepam treatment to 4 weeks caused little further downregulation in those areas studied, except for the pars reticulata of the substantia nigra, which showed a 13% reduction in (/sup 3/H)flunitrazepam binding after 1 week and a 40% reduction after 4 weeks of treatment. In a few areas, such as the lateral hypothalamus, no significant change in binding was found after 4 weeks. Acute diazepam treatment caused no change in binding. This latter finding as well as results obtained during the development of the methodology show that downregulation was not an artifact due to residual drug content of brain slices. The regional variations in degree and rate of downregulation suggest areas that may be most important for benzodiazepine tolerance and dependence and may be related to the varying time courses for tolerance to different benzodiazepine actions.

  2. 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.)

  3. Association between Peripheral Oxidative Stress and White Matter Damage in Acute Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Wei-Ming Lin

    2014-01-01

    Full Text Available The oxidative stress is believed to be one of the mechanisms involved in the neuronal damage after acute traumatic brain injury (TBI. However, the disease severity correlation between oxidative stress biomarker level and deep brain microstructural changes in acute TBI remains unknown. In present study, twenty-four patients with acute TBI and 24 healthy volunteers underwent DTI. The peripheral blood oxidative biomarkers, like serum thiol and thiobarbituric acid-reactive substances (TBARS concentrations, were also obtained. The DTI metrics of the deep brain regions, as well as the fractional anisotropy (FA and apparent diffusion coefficient, were measured and correlated with disease severity, serum thiol, and TBARS levels. We found that patients with TBI displayed lower FAs in deep brain regions with abundant WMs and further correlated with increased serum TBARS level. Our study has shown a level of anatomic detail to the relationship between white matter (WM damage and increased systemic oxidative stress in TBI which suggests common inflammatory processes that covary in both the peripheral and central reactions after TBI.

  4. 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.

  5. Aging aggravates ischemic stroke-induced brain damage in mice with chronic peripheral infection.

    Science.gov (United States)

    Dhungana, Hiramani; Malm, Tarja; Denes, Adam; Valonen, Piia; Wojciechowski, Sara; Magga, Johanna; Savchenko, Ekaterina; Humphreys, Neil; Grencis, Richard; Rothwell, Nancy; Koistinaho, Jari

    2013-10-01

    Ischemic stroke is confounded by conditions such as atherosclerosis, diabetes, and infection, all of which alter peripheral inflammatory processes with concomitant impact on stroke outcome. The majority of the stroke patients are elderly, but the impact of interactions between aging and inflammation on stroke remains unknown. We thus investigated the influence of age on the outcome of stroke in animals predisposed to systemic chronic infection. Th1-polarized chronic systemic infection was induced in 18-22 month and 4-month-old C57BL/6j mice by administration of Trichuris muris (gut parasite). One month after infection, mice underwent permanent middle cerebral artery occlusion and infarct size, brain gliosis, and brain and plasma cytokine profiles were analyzed. Chronic infection increased the infarct size in aged but not in young mice at 24 h. Aged, ischemic mice showed altered plasma and brain cytokine responses, while the lesion size correlated with plasma prestroke levels of RANTES. Moreover, the old, infected mice exhibited significantly increased neutrophil recruitment and upregulation of both plasma interleukin-17α and tumor necrosis factor-α levels. Neither age nor infection status alone or in combination altered the ischemia-induced brain microgliosis. Our results show that chronic peripheral infection in aged animals renders the brain more vulnerable to ischemic insults, possibly by increasing the invasion of neutrophils and altering the inflammation status in the blood and brain. Understanding the interactions between age and infections is crucial for developing a better therapeutic regimen for ischemic stroke and when modeling it as a disease of the elderly.

  6. Wirelessly powered, fully internal optogenetics for brain, spinal and peripheral circuits in mice.

    Science.gov (United States)

    Montgomery, Kate L; Yeh, Alexander J; Ho, John S; Tsao, Vivien; Mohan Iyer, Shrivats; Grosenick, Logan; Ferenczi, Emily A; Tanabe, Yuji; Deisseroth, Karl; Delp, Scott L; Poon, Ada S Y

    2015-10-01

    To enable sophisticated optogenetic manipulation of neural circuits throughout the nervous system with limited disruption of animal behavior, light-delivery systems beyond fiber optic tethering and large, head-mounted wireless receivers are desirable. We report the development of an easy-to-construct, implantable wireless optogenetic device. Our smallest version (20 mg, 10 mm(3)) is two orders of magnitude smaller than previously reported wireless optogenetic systems, allowing the entire device to be implanted subcutaneously. With a radio-frequency (RF) power source and controller, this implant produces sufficient light power for optogenetic stimulation with minimal tissue heating (optogenetic control throughout the nervous system (brain, spinal cord and peripheral nerve endings) of behaving mice. This technology opens the door for optogenetic experiments in which animals are able to behave naturally with optogenetic manipulation of both central and peripheral targets.

  7. Androgen manipulation and vasopressin binding in the rat brain and peripheral organs

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Xin; Phillips, P.; Oldfield, B.; Trinder, D.; Risvanis, J.; Stephenson, J.; Johnston, C. (Univ. of Melbourne, Parkville, Victoria (Australia))

    1994-03-01

    It is now widely recognized that there is a sexual dimorphism in the development of arginine vasopressin (AVP) immunoreactivity in certain parts of the brain, and that changes in brain AVP immunoreactivity change with manipulation of androgen status. The aim of the present experiment was to determine specifically any AVP receptor changes in response to manipulation of androgen levels using a selective V[sub 1] antagonist radioligand. Following castration, plasma testosterone levels fell and AVP immunoreactivity was reduced in the lateral septum and bed nucleus of the stria terminalis. With testosterone supplementation in castrated animals, the immunoreactivity in these regions was restored to a higher degree than in sham-operated animals. Central and peripheral V[sub 1] AVP receptor binding (as determined using the selective AVP V)[sub 1] antagonist radioligand [[sup 125]I](d(CH[sub 2])[sub 5],sarcosine[sup 7]) AVP was not changed in any of the brain regions studied or in liver or kidney membranes from the three groups. The study demonstrates that there is no change in brain AVP receptor binding despite changes in regional AVP immunoreactivity in the brain, and excludes any confounding interaction with changes in oxytocin receptors. 23 refs., 1 fig., 2 tabs.

  8. Strategy for improved [{sup 11}C]DAA1106 radiosynthesis and in vivo peripheral benzodiazepine receptor imaging using microPET, evaluation of [{sup 11}C]DAA1106

    Energy Technology Data Exchange (ETDEWEB)

    Probst, Katrin C. [Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)]|[BHF Carotid Imaging Group, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)]. E-mail: kp296@wbic.cam.ac.uk; Izquierdo, David [Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)]|[BHF Carotid Imaging Group, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Bird, Joseph L.E. [BHF Carotid Imaging Group, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)]|[Department of Medicine, Cardiovascular Medicine Division, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Brichard, Laurent; Franck, Dominic; Fryer, Tim D.; Clark, John C. [Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Davies, John R. [Cardiovascular Medicine Division, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Richards, Hugh K. [Neurology Unit, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Davenport, Anthony P. [Clinical Pharmacology Unit, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Weissberg, Peter L. [Cardiovascular Medicine Division, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom); Warburton, Elizabeth A. [BHF Carotid Imaging Group, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)]|[Department of Clinical Neurosciences, University of Cambridge, Addenbrooke' s Hospital, CB2 2QQ Cambridge (United Kingdom)

    2007-05-15

    Introduction: The peripheral benzodiazepine receptor (PBR) has shown considerable potential as a clinical marker of neuroinflammation and tumour progression. [{sup 11}C]DAA1106 ([{sup 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 [{sup 11}C]DAA1106. Two robust, high yielding methods for radiosynthesis based on [{sup 11}C]-O-methylation of DAA1123 were developed and implemented on a nuclear interface methylation module, producing [{sup 11}C]DAA1106 with up to 25% radiochemical yields at end-of-synthesis based on [{sup 11}C]CH{sub 3}I trapped. Evaluation of [{sup 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 [{sup 11}C]DAA1106, whilst the captive solvent method produced 1.6-6.3 GBq (n=10) of [{sup 11}C]DAA1106. Radiochemical purities obtained were 99% and specific radioactivity at end-of-synthesis was up to 200 GBq/{mu}mol for both methods. Based on radiochemical product, shorter preparation times and simplicity of synthesis, the captive solvent method was chosen for routine productions of [{sup 11}C]DAA1106. In vivo microPET [{sup 11}C]DAA1106 scans of rabbit kidney demonstrated high levels of binding in the cortex. The subsequent introduction of nonradioactive DAA1106 (0.2 {mu}mol) 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 [{sup 11}C]DAA1106 production was developed which enabled efficacious in vivo imaging of PBR expressing tissues in an animal model.

  9. 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.)

  10. [{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.)

  11. [Benzodiazepine and nonbenzodiazepine hypnotics].

    Science.gov (United States)

    Nakamura, Masaki; Inoue, Yuichi

    2015-06-01

    The prevalence of insomnia shows an age-associated increase. Especially, persons with age over 60 years frequently suffer from arousal during sleep and early-morning awakening. The reason of this phenomenon can be explained by age-related change in sleepwake regulation, comorbid diseases and psycho-social status. Benzodiazepine derivatives and benzodiazepine agonists have been widely used for treatment of insomnia. These GABA-A receptor agonist hypnotics have sedative effect, possibly causing various adverse events, i.e. falls and hip fracture, anterograde amnesia, next morning hangover especially in the elderly. When making a choice of treatment drugs for the elderly, low dose benzodiazepine hypnotics with relatively high Ω1-selectivity, and newer hypnotics including melatonic receptor agonist or orexin receptor antagonist can become important candidates considering their comorbid diseases or drug interaction with other medications.

  12. GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution

    Directory of Open Access Journals (Sweden)

    Melis Karaca

    2015-10-01

    Full Text Available Glucose, the main energy substrate used in the CNS, is continuously supplied by the periphery. Glutamate, the major excitatory neurotransmitter, is foreseen as a complementary energy contributor in the brain. In particular, astrocytes actively take up glutamate and may use it through oxidative glutamate dehydrogenase (GDH activity. Here, we investigated the significance of glutamate as energy substrate for the brain. Upon glutamate exposure, astrocytes generated ATP in a GDH-dependent way. The observed lack of glutamate oxidation in brain-specific GDH null CnsGlud1−/− mice resulted in a central energy-deprivation state with increased ADP/ATP ratios and phospho-AMPK in the hypothalamus. This induced changes in the autonomous nervous system balance, with increased sympathetic activity promoting hepatic glucose production and mobilization of substrates reshaping peripheral energy stores. Our data reveal the importance of glutamate as necessary energy substrate for the brain and the role of central GDH in the regulation of whole-body energy homeostasis.

  13. Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain

    Science.gov (United States)

    Bachstetter, Adam D; Pabon, Mibel M; Cole, Michael J; Hudson, Charles E; Sanberg, Paul R; Willing, Alison E; Bickford, Paula C; Gemma, Carmelina

    2008-01-01

    Background Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation. Results We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis. Conclusion The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain. PMID:18275610

  14. Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain

    Directory of Open Access Journals (Sweden)

    Sanberg Paul R

    2008-02-01

    Full Text Available Abstract Background Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation. Results We determined that human umbilical cord blood mononuclear cells (UCBMC given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis. Conclusion The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

  15. The Benzodiazepine-Dementia Disorders Link: Current State of Knowledge.

    Science.gov (United States)

    Pariente, Antoine; de Gage, Sophie Billioti; Moore, Nicholas; Bégaud, Bernard

    2016-01-01

    The short-term effects of benzodiazepines on memory are well established and are suspected in the long term. Eleven studies have been published so far concerning benzodiazepine use and the risk of dementia disorders; nine of these studies concluded these drugs have a deleterious effect, one found a protective effect, and one (the most recently published) observed no effect. The positive association found in some studies could be due to a reverse causation bias since the main indications for benzodiazepines (e.g. sleep disorders, anxiety) can also be prodromes of dementia disorders. This bias is less likely for treatments started more than 10 years before the diagnosis. Among others, three mechanisms could underlie the potential influence of benzodiazepines on the development of dementia disorders. First, benzodiazepines can decrease beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) and γ-secretase activity and slow down the accumulation of Aβ oligomers in the brain. This potential positive effect has never been confirmed; the same is true for the prevention of excitotoxicity through benzodiazepine anti-glutamatergic action. Second, since astrocytes located in the area of amyloid plaques could have gamma-aminobutyric acid (GABA)-secreting activity, patients with pre-dementia lesions could be at increased risk of presenting with more pronounced deleterious cognitive effects of benzodiazepines. Finally, owing to the neural compensation and cognitive reserve concepts, some subjects could cope with initial lesions by using/developing alternative networks. By lowering the brain activation level, benzodiazepines could limit this capacity. In conclusion, it is essential that animal studies explore the mechanistic hypotheses of this association found by most of the pharmacoepidemiological studies conducted on this topic.

  16. Process for determining the concentration of benzodiazepines in a body fluid

    Energy Technology Data Exchange (ETDEWEB)

    Braestrup, C.; Squires, R.F.

    1981-07-28

    A process for determining the concentration of benzodiazepines in a body liquid comprising the steps of contacting freeze-dried brain tissue with tritium labelled flunitrazepam to bond labelled flunitrazepam to receptor sites of the brain tissue, determining the concentration of labelled flunitrazepam of the brain tissue, incubating the brain tissue containing labelled flunitrazepam with a sample of body liquid containing benzodiazepine, the concentration of which is to be determined, to induce displacement of labelled flunitrazepam from said brain tissue, determining the concentration of labelled flunitrazepam bonded to the brain tissue after establishing equilibrium conditions and determining the concentration of benzodiazepine in the body liquid based on the change of concentration of labelled flunitrazepam induced by benzodiazepine contained in the sample.

  17. [Drug dependence on benzodiazepines and antidepressants].

    Science.gov (United States)

    Verbanck, P

    2009-09-01

    Since years, the concepts of drug abuse and drug dependence changed, due to new knowledge coming from the neurosciences. Specifically, the role of a brain structure called "reward circuit" was emphasized. Therefore, the diagnosis criteria for abuse and dependence on drugs are presently defined mostly from a behavioral point of view: both in animal models and in clinical situations, it was stressed the importance of drug-seeking behavior and of the loss of control of the consumption. The occurrence of a pharmacological dependence is in fact of concern for only some of addictive drugs. According to these new criteria, dependence on benzodiazepines or antidepressants is certainly not frequent, even if withdrawal manifestations can occur after a long-term exposition. Furthermore, it is important to keep in mind the risk for non-medical use of benzodiazepines in persons with illicit drug use.

  18. Effect of low-dose methylprednisolone on peripheral blood endothelial progenitor cells and its significance in rats after brain injury

    Directory of Open Access Journals (Sweden)

    Bin ZHANG

    2011-05-01

    Full Text Available Objective To explore the effects of low-dose methylprednisolone(MP treatment after traumatic brain injury(TBI in rats on the number of peripheral blood endothelial progenitor cells(EPCs and injury area of the brain.Methods One hundred and fifty-four adult male Wistar rats were involved in the present study,and they were randomly divided into normal control group(n=18,TBI control group(n=38,MP control group(n=30,MP+TBI group(n=30 and TBI+MP group(n=38.The TBI model was reproduced by fluid percussion injury(FPI.MP(5mg/kg was intraperitoneally administered once a day for 4 days.Peripheral venous blood samples were taken on day 1,3,7 and 14,and the counts of EPCs were determined by flow cytometry.The rats were sacrificed on day 1 and 3,brain edema was estimated by dry-wet weight method,and the blood-brain barrier(BBB permeability was determined by Evans-blue extravasation.Results The counts of peripheral blood EPCs were significantly higher in MP control group,MP+TBI group and TBI+MP group on day 1,3 and 7 than that in normal control and TBI control group,and it returned to the level of normal control group on day 14.The BBB permeability was improved and brain edema alleviated in MP+TBI and TBI+MP group on day 3.Conclusion The administration of low-dose MP may increase the count of peripheral blood EPCs in rats,decrease BBB damage,and alleviate brain edema.

  19. Brain-derived neurotrophic factor modulates immune reaction in mice with peripheral nerve xenotransplantation

    Directory of Open Access Journals (Sweden)

    Yu X

    2016-03-01

    Full Text Available Xin Yu,1 Laijin Lu,1 Zhigang Liu,1 Teng Yang,2 Xu Gong,1 Yubo Ning,3 Yanfang Jiang4 1Department of Hand Surgery, 2Department of Orthopedics, The First Hospital of Jilin University, Changchun, 3Department of Orthopedics, Ningshi Orthopedics Hospital of Tonghua, Tonghua, 4Department of Central Laboratory, The First Hospital of Jilin University, Changchun, People’s Republic of China Background: Brain-derived neurotrophic factor (BDNF has been demonstrated to play an important role in survival, differentiation, and neurite outgrowth for many types of neurons. This study was designed to identify the role of BDNF during peripheral nerve xenotransplantation. Materials and methods: A peripheral nerve xenotransplantation from rats to mice was performed. Intracellular cytokines were stained for natural killer (NK cells, natural killer T (NKT cells, T cells, and B cells and analyzed by flow cytometry in the spleen of the recipient mouse. Serum levels of related cytokines were quantified by cytometric bead array. Results: Splenic NK cells significantly increased in the xenotransplanted mice (8.47±0.88×107 cells/mL compared to that in the control mice (4.66±0.78×107 cells/mL, P=0.0003, which significantly reduced in the presence of BDNF (4.85±0.87×107 cells/mL, P=0.0004. In contrast, splenic NKT cell number was significantly increased in the mice with xenotransplantation plus BDNF (XT + BDNF compared to that of control group or of mice receiving xenotransplantation only (XT only. Furthermore, the number of CD3+ T cells, CD3+CD4+ T cells, CD3+CD4- T cells, interferon-γ-producing CD3+CD4+ T cells, and interleukin (IL-17-producing CD3+CD4+ T cells, as well as CD3-CD19+ B cells, was significantly higher in the spleen of XT only mice compared to the control mice (P<0.05, which was significantly reduced by BDNF (P<0.05. The number of IL-4-producing CD3+CD4+ T cells and CD3+CD4+CD25+Foxp3+ T cells was significantly higher in the spleen of XT + BDNF

  20. Inflammation and activity augment brain-derived neurotrophic factor peripheral release.

    Science.gov (United States)

    Qiao, L Y; Shen, S; Liu, M; Xia, C; Kay, J C; Zhang, Q L

    2016-03-24

    Brain-derived neurotrophic factor (BDNF) release to nerve terminals in the central nervous system is crucial in synaptic transmission and neuronal plasticity. However, BDNF release peripherally from primary afferent neurons has not been investigated. In the present study, we show that BDNF is synthesized by primary afferent neurons located in the dorsal root ganglia (DRG) in rat, and releases to spinal nerve terminals in response to depolarization or visceral inflammation. In two-compartmented culture that separates DRG neuronal cell bodies and spinal nerve terminals, application of 50mM K(+) to either the nerve terminal or the cell body evokes BDNF release to the terminal compartment. Inflammatory stimulation of the visceral organ (e.g. the urinary bladder) also facilitates an increase in spontaneous BDNF release from the primary afferent neurons to the axonal terminals. In the inflamed viscera, we show that BDNF immunoreactivity is increased in nerve fibers that are immuno-positive to the neuronal marker PGP9.5. Both BDNF and pro-BDNF levels are increased, however, pro-BDNF immunoreactivity is not expressed in PGP9.5-positive nerve-fiber-like structures. Determination of receptor profiles in the inflamed bladder demonstrates that BDNF high affinity receptor TrkB and general receptor p75 expression levels are elevated, with an increased level of TrkB tyrosine phosphorylation/activity. These results suggest a possibility of pro-proliferative effect in the inflamed bladder. Consistently we show that the proliferation marker Ki67 expression levels are enhanced in the inflamed organ. Our results imply that in vivo BDNF release to the peripheral organ is an important event in neurogenic inflammatory state.

  1. Ethanol suppression of peripheral blood mononuclear cell trafficking across brain endothelial cells in immunodeficiency virus infection

    Directory of Open Access Journals (Sweden)

    Lola C Hudson

    2010-01-01

    Full Text Available Lola C Hudson1, Brenda A Colby1, Rick B Meeker21Department of Molecular Biosciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA; 2Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAAbstract: Earlier studies suggested that the combination of alcohol use and immunodeficiency virus infection resulted in more severe neurologic disease than either condition individually. These deleterious interactions could be due to increased immune cell and virus trafficking or may result from interactions between ethanol and human immunodeficiency virus (HIV-associated toxicity within the brain. To determine the extent to which increased trafficking played a role, we examined the effect of ethanol on the migration of different peripheral blood mononuclear cell (PBMCs subsets across a brain endothelial cell monolayer. We utilized combinations of feline brain endothelial cells with astrocytes, and/or microglia with either acute exposure to 0.08 g/dL ethanol, a combination of ethanol and feline immunodeficiency virus (FIV, or FIV alone. Adherence of PBMCs to endothelium was increased in all combinations of cells with the addition of ethanol. Despite increased PBMC adhesion with ethanol treatment, transmigration of B cells, monocytes, CD4 T cells and CD8 T cells was not increased and was actually decreased in the presence of astrocytes. Expression of three common adhesion molecules, intercellular adhesion molecule-1 (ICAM1, ICAM2, and vascular cell adhesion molecule, was unchanged or slightly decreased by ethanol. This indicated that although adherence is increased by ethanol it is not due to an increased expression of adhesion molecules. RANTES, MIP1α, MIP1β, and MCP-1 mRNA expression was also studied in brain endothelial cells, astrocytes and microglia by reverse transcriptase-polymerase chain reaction. Ethanol treatment of astrocytes resulted in modest changes of

  2. Genetic Deletion of Rheb1 in the Brain Reduces Food Intake and Causes Hypoglycemia with Altered Peripheral Metabolism

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    Wanchun Yang

    2014-01-01

    Full Text Available Excessive food/energy intake is linked to obesity and metabolic disorders, such as diabetes. The hypothalamus in the brain plays a critical role in the control of food intake and peripheral metabolism. The signaling pathways in hypothalamic neurons that regulate food intake and peripheral metabolism need to be better understood for developing pharmacological interventions to manage eating behavior and obesity. Mammalian target of rapamycin (mTOR, a serine/threonine kinase, is a master regulator of cellular metabolism in different cell types. Pharmacological manipulations of mTOR complex 1 (mTORC1 activity in hypothalamic neurons alter food intake and body weight. Our previous study identified Rheb1 (Ras homolog enriched in brain 1 as an essential activator of mTORC1 activity in the brain. Here we examine whether central Rheb1 regulates food intake and peripheral metabolism through mTORC1 signaling. We find that genetic deletion of Rheb1 in the brain causes a reduction in mTORC1 activity and impairs normal food intake. As a result, Rheb1 knockout mice exhibit hypoglycemia and increased lipid mobilization in adipose tissue and ketogenesis in the liver. Our work highlights the importance of central Rheb1 signaling in euglycemia and energy homeostasis in animals.

  3. Peripheral obestatin has no effect on feeding behavior and brain Fos expression in rodents

    Science.gov (United States)

    Kobelt, Peter; Wisser, Anna-Sophia; Stengel, Andreas; Goebel, Miriam; Bannert, Norbert; Gourcerol, Guillaume; Inhoff, Tobias; Noetzel, Steffen; Wiedenmann, Bertram; Klapp, Burghard F.; Taché, Yvette; Mönnikes, Hubert

    2009-01-01

    Obestatin is produced in the stomach from proghrelin by post-translational cleavage. The initial report claimed anorexigenic effects of obestatin in mice. Contrasting studies indicated no effect of obestatin on food intake (FI). We investigated influences of metabolic state (fed/fasted), environmental factors (dark/light phase) and brain Fos response to intraperitoneal (ip) obestatin in rats, and used the protocol from the original study assessing obestatin effects in mice. FI was determined in male rats injected ip before onset of dark or light phase, with obestatin (1 or 5 μmol/kg), CCK8S (3.5 nmol/kg) or 0.15 M NaCl, after fasting (16 h, n = 8/group) or ad libitum (n = 10-14/group) food intake. Fos expression in hypothalamic and brainstem nuclei was examined in freely fed rats 90 min after obestatin (5 μmol/kg), CCK8S (1.75 nmol/kg) or 0.15 M NaCl (n = 4/group). Additionally, fasted mice were injected ip with obestatin (1 μmol/kg) or urocortin 1 (2 nmol/kg) 15 min before food presentation. No effect on FI was observed after obestatin administration during the light and dark phase under both metabolic conditions while CCK8S reduced FI irrespectively of the conditions. The number of Fos positive neurons was not modified by obestatin while CCK8S increased Fos expression in selective brain nuclei. Obestatin did not influence the refeeding response to a fast in mice, while urocortin was effective. Therefore, peripheral obestatin has no effect on FI under various experimental conditions and did not induce Fos in relevant central neuronal circuitries modulating feeding in rodents. PMID:18342400

  4. Action of peripherally administered cholecystokinin on monoaminergic and GABAergic neurons in the rat brain.

    Directory of Open Access Journals (Sweden)

    Kaneyuki,Takao

    1989-06-01

    Full Text Available In an acute study, cholecystokinin octapeptide sulfate (CCK in doses of 1, 10 or 100 micrograms/kg body weight was injected intraperitoneally into rats just prior to the dark cycle. Rats were sacrificed two hours following the CCK injection. Norepinephrine levels were elevated in the dorsal amygdala of rats injected with 10 micrograms of CCK as well as in the septum of rats injected with 1 and 10 micrograms of CCK. The dopamine level in the septum of rats injected with 1 microgram of CCK as well as the gamma-aminobutyric acid (GABA level in the lateral hypothalamus of rats injected with 10 micrograms of CCK were also elevated. In a chronic study, CCK (1 microgram/kg body weight/h was subcutaneously infused into rats with Alzet osmotic minipump for seven consecutive days. The daily food consumption did not change during the 7 days of CCK infusion. The dopamine turnover in the striatum accelerated and the GABA level increased. On the contrary, dopamine metabolism in the substantia nigra and locus coeruleus decreased. Furthermore, the serotonin level in the substantia nigra decreased. Norepinephrine levels decreased in the nucleus paraventricularis, the locus coeruleus and the substantia nigra. The results suggest that peripherally administered CCK may act on the monoaminergic neurons and GABAergic neurons in the brain.

  5. 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...

  6. Is peripheral immunity regulated by blood-brain barrier permeability changes?

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    Erin Bargerstock

    Full Text Available S100B is a reporter of blood-brain barrier (BBB integrity which appears in blood when the BBB is breached. Circulating S100B derives from either extracranial sources or release into circulation by normal fluctuations in BBB integrity or pathologic BBB disruption (BBBD. Elevated S100B matches the clinical presence of indices of BBBD (gadolinium enhancement or albumin coefficient. After repeated sub-concussive episodes, serum S100B triggers an antigen-driven production of anti-S100B autoantibodies. We tested the hypothesis that the presence of S100B in extracranial tissue is due to peripheral cellular uptake of serum S100B by antigen presenting cells, which may induce the production of auto antibodies against S100B. To test this hypothesis, we used animal models of seizures, enrolled patients undergoing repeated BBBD, and collected serum samples from epileptic patients. We employed a broad array of techniques, including immunohistochemistry, RNA analysis, tracer injection and serum analysis. mRNA for S100B was segregated to barrier organs (testis, kidney and brain but S100B protein was detected in immunocompetent cells in spleen, thymus and lymph nodes, in resident immune cells (Langerhans, satellite cells in heart muscle, etc. and BBB endothelium. Uptake of labeled S100B by rat spleen CD4+ or CD8+ and CD86+ dendritic cells was exacerbated by pilocarpine-induced status epilepticus which is accompanied by BBBD. Clinical seizures were preceded by a surge of serum S100B. In patients undergoing repeated therapeutic BBBD, an autoimmune response against S100B was measured. In addition to its role in the central nervous system and its diagnostic value as a BBBD reporter, S100B may integrate blood-brain barrier disruption to the control of systemic immunity by a mechanism involving the activation of immune cells. We propose a scenario where extravasated S100B may trigger a pathologic autoimmune reaction linking systemic and CNS immune responses.

  7. Enhanced peripheral visual processing in congenitally deaf humans is supported by multiple brain regions, including primary auditory cortex.

    Science.gov (United States)

    Scott, Gregory D; Karns, Christina M; Dow, Mark W; Stevens, Courtney; Neville, Helen J

    2014-01-01

    Brain reorganization associated with altered sensory experience clarifies the critical role of neuroplasticity in development. An example is enhanced peripheral visual processing associated with congenital deafness, but the neural systems supporting this have not been fully characterized. A gap in our understanding of deafness-enhanced peripheral vision is the contribution of primary auditory cortex. Previous studies of auditory cortex that use anatomical normalization across participants were limited by inter-subject variability of Heschl's gyrus. In addition to reorganized auditory cortex (cross-modal plasticity), a second gap in our understanding is the contribution of altered modality-specific cortices (visual intramodal plasticity in this case), as well as supramodal and multisensory cortices, especially when target detection is required across contrasts. Here we address these gaps by comparing fMRI signal change for peripheral vs. perifoveal visual stimulation (11-15° vs. 2-7°) in congenitally deaf and hearing participants in a blocked experimental design with two analytical approaches: a Heschl's gyrus region of interest analysis and a whole brain analysis. Our results using individually-defined primary auditory cortex (Heschl's gyrus) indicate that fMRI signal change for more peripheral stimuli was greater than perifoveal in deaf but not in hearing participants. Whole-brain analyses revealed differences between deaf and hearing participants for peripheral vs. perifoveal visual processing in extrastriate visual cortex including primary auditory cortex, MT+/V5, superior-temporal auditory, and multisensory and/or supramodal regions, such as posterior parietal cortex (PPC), frontal eye fields, anterior cingulate, and supplementary eye fields. Overall, these data demonstrate the contribution of neuroplasticity in multiple systems including primary auditory cortex, supramodal, and multisensory regions, to altered visual processing in congenitally deaf adults.

  8. Benzodiazepine use, abuse, and dependence.

    Science.gov (United States)

    O'brien, Charles P

    2005-01-01

    Although benzodiazepines are invaluable in the treatment of anxiety disorders, they have some potential for abuse and may cause dependence or addiction. It is important to distinguish between addiction to and normal physical dependence on benzodiazepines. Intentional abusers of benzodiazepines usually have other substance abuse problems. Benzodiazepines are usually a secondary drug of abuse-used mainly to augment the high received from another drug or to offset the adverse effects of other drugs. Few cases of addiction arise from legitimate use of benzodiazepines. Pharmacologic dependence, a predictable and natural adaptation of a body system long accustomed to the presence of a drug, may occur in patients taking therapeutic doses of benzodiazepines. However, this dependence, which generally manifests itself in withdrawal symptoms upon the abrupt discontinuation of the medication, may be controlled and ended through dose tapering, medication switching, and/or medication augmentation. Due to the chronic nature of anxiety, long-term low-dose benzodiazepine treatment may be necessary for some patients; this continuation of treatment should not be considered abuse or addiction.

  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 gener

  10. Brain pyruvate recycling and peripheral metabolism: an NMR analysis ex vivo of acetate and glucose metabolism in the rat.

    Science.gov (United States)

    Serres, Sébastien; Bezancon, Eric; Franconi, Jean-Michel; Merle, Michel

    2007-06-01

    The occurrence of pyruvate recycling in the rat brain was studied in either pentobarbital anesthetized animals or awake animals receiving a light analgesic dose of morphine, which were infused with either [1-13C]glucose + acetate or glucose + [2-13C]acetate for various periods of time. Metabolite enrichments in the brain, blood and the liver were determined from NMR analyses of tissue extracts. They indicated that: (i) Pyruvate recycling was revealed in the brain of both the anesthetized and awake animals, as well as from lactate and alanine enrichments as from glutamate isotopomer composition, but only after infusion of glucose + [2-13C]acetate. (ii) Brain glucose was labelled from [2-13C]acetate at the same level in anaesthetized and awake rats (approximately 4%). Comparing its enrichment with that of blood and liver glucose indicated that brain glucose labelling resulted from hepatic gluconeogenesis. (iii) Analysing glucose 13C-13C coupling in the brain, blood and the liver confirmed that brain glucose could be labelled in the liver through the activities of both pyruvate recycling and gluconeogenesis. (iv) The rate of appearance and the amount of brain glutamate C4-C5 coupling, a marker of pyruvate recycling when starting from [2-13C]acetate, were lower than those of brain glucose labelling from hepatic metabolism. (v) The evaluation of the contributions of glucose and acetate to glutamate metabolism revealed that more than 60% of brain glutamate was synthesized from glucose whereas only 7% was from acetate and that glutamate C4-C5 coupling was mainly due to the metabolism of glucose labelled through hepatic gluconeogenesis. All these results indicate that, under the present conditions, the pyruvate recycling observed through the labelling of brain metabolites mainly originates from peripheral metabolism.

  11. The hunt for brain Aβ oligomers by peripherally circulating multi-functional nanoparticles: Potential therapeutic approach for Alzheimer disease.

    Science.gov (United States)

    Mancini, Simona; Minniti, Stefania; Gregori, Maria; Sancini, Giulio; Cagnotto, Alfredo; Couraud, Pierre-Olivier; Ordóñez-Gutiérrez, Lara; Wandosell, Francisco; Salmona, Mario; Re, Francesca

    2016-01-01

    We previously showed the ability of liposomes bi-functionalized with phosphatidic acid and an ApoE-derived peptide (mApoE-PA-LIP) to reduce brain Aβ in transgenic Alzheimer mice. Herein we investigated the efficacy of mApoE-PA-LIP to withdraw Aβ peptide in different aggregation forms from the brain, using a transwell cellular model of the blood-brain barrier and APP/PS1 mice. The spontaneous efflux of Aβ oligomers (Aβo), but not of Aβ fibrils, from the 'brain' side of the transwell was strongly enhanced (5-fold) in presence of mApoE-PA-LIP in the 'blood' compartment. This effect is due to a withdrawal of Aβo exerted by peripheral mApoE-PA-LIP by sink effect, because, when present in the brain side, they did not act as Aβo carrier and limit the oligomer efflux. In vivo peripheral administration of mApoE-PA-LIP significantly increased the plasma Aβ level, suggesting that Aβ-binding particles exploiting the sink effect can be used as a therapeutic strategy for Alzheimer disease. From the Clinical Editor: Alzheimer disease (AD) at present is an incurable disease, which is thought to be caused by an accumulation of amyloid-β (Aβ) peptides in the brain. Many strategies in combating this disease have been focused on either the prevention or dissolving these peptides. In this article, the authors showed the ability of liposomes bi-functionalized with phosphatidic acid and with an ApoE- derived peptide to withdraw amyloid peptides from the brain. The data would help the future design of more novel treatment for Alzheimer disease.

  12. Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood–brain barrier

    Directory of Open Access Journals (Sweden)

    Erickson Michelle A

    2012-06-01

    Full Text Available Abstract Background Defects in the low density lipoprotein receptor-related protein-1 (LRP-1 and p-glycoprotein (Pgp clearance of amyloid beta (Aβ from brain are thought to contribute to Alzheimer’s disease (AD. We have recently shown that induction of systemic inflammation by lipopolysaccharide (LPS results in impaired efflux of Aβ from the brain. The same treatment also impairs Pgp function. Here, our aim is to determine which physiological routes of Aβ clearance are affected following systemic inflammation, including those relying on LRP-1 and Pgp function at the blood–brain barrier. Methods CD-1 mice aged between 6 and 8 weeks were treated with 3 intraperitoneal injections of 3 mg/kg LPS at 0, 6, and 24 hours and studied at 28 hours. 125I-Aβ1-42 or 125I-alpha-2-macroglobulin injected into the lateral ventricle of the brain (intracerebroventricular (ICV or into the jugular vein (intravenous (IV was used to quantify LRP-1-dependent partitioning between the brain vasculature and parenchyma and peripheral clearance, respectively. Disappearance of ICV-injected 14 C-inulin from brain was measured to quantify bulk flow of cerebrospinal fluid (CSF. Brain microvascular protein expression of LRP-1 and Pgp was measured by immunoblotting. Endothelial cell localization of LRP-1 was measured by immunofluorescence microscopy. Oxidative modifications to LRP-1 at the brain microvasculature were measured by immunoprecipitation of LRP-1 followed by immunoblotting for 4-hydroxynonenal and 3-nitrotyrosine. Results We found that LPS: caused an LRP-1-dependent redistribution of ICV-injected Aβ from brain parenchyma to brain vasculature and decreased entry into blood; impaired peripheral clearance of IV-injected Aβ; inhibited reabsorption of CSF; did not significantly alter brain microvascular protein levels of LRP-1 or Pgp, or oxidative modifications to LRP-1; and downregulated LRP-1 protein levels and caused LRP-1 mislocalization in cultured brain

  13. Brain region-specific alterations in the gene expression of cytokines, immune cell markers and cholinergic system components during peripheral endotoxin-induced inflammation.

    Science.gov (United States)

    Silverman, Harold A; Dancho, Meghan; Regnier-Golanov, Angelique; Nasim, Mansoor; Ochani, Mahendar; Olofsson, Peder S; Ahmed, Mohamed; Miller, Edmund J; Chavan, Sangeeta S; Golanov, Eugene; Metz, Christine N; Tracey, Kevin J; Pavlov, Valentin A

    2015-03-11

    Inflammatory conditions characterized by excessive peripheral immune responses are associated with diverse alterations in brain function, and brain-derived neural pathways regulate peripheral inflammation. Important aspects of this bidirectional peripheral immune-brain communication, including the impact of peripheral inflammation on brain region-specific cytokine responses, and brain cholinergic signaling (which plays a role in controlling peripheral cytokine levels), remain unclear. To provide insight, we studied gene expression of cytokines, immune cell markers and brain cholinergic system components in the cortex, cerebellum, brainstem, hippocampus, hypothalamus, striatum and thalamus in mice after an intraperitoneal lipopolysaccharide injection. Endotoxemia was accompanied by elevated serum levels of interleukin (IL)-1β, IL-6 and other cytokines and brain region-specific increases in Il1b (the highest increase, relative to basal level, was in cortex; the lowest increase was in cerebellum) and Il6 (highest increase in cerebellum; lowest increase in striatum) mRNA expression. Gene expression of brain Gfap (astrocyte marker) was also differentially increased. However, Iba1 (microglia marker) mRNA expression was decreased in the cortex, hippocampus and other brain regions in parallel with morphological changes, indicating microglia activation. Brain choline acetyltransferase (Chat ) mRNA expression was decreased in the striatum, acetylcholinesterase (Ache) mRNA expression was decreased in the cortex and increased in the hippocampus, and M1 muscarinic acetylcholine receptor (Chrm1) mRNA expression was decreased in the cortex and the brainstem. These results reveal a previously unrecognized regional specificity in brain immunoregulatory and cholinergic system gene expression in the context of peripheral inflammation and are of interest for designing future antiinflammatory approaches.

  14. Critical role of peripheral vasoconstriction in fatal brain hyperthermia induced by MDMA (Ecstasy) under conditions that mimic human drug use.

    Science.gov (United States)

    Kiyatkin, Eugene A; Kim, Albert H; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2014-06-04

    MDMA (Ecstasy) is an illicit drug used by young adults at hot, crowed "rave" parties, yet the data on potential health hazards of its abuse remain controversial. Here, we examined the effect of MDMA on temperature homeostasis in male rats under standard laboratory conditions and under conditions that simulate drug use in humans. We chronically implanted thermocouple microsensors in the nucleus accumbens (a brain reward area), temporal muscle, and facial skin to measure temperature continuously from freely moving rats. While focusing on brain hyperthermia, temperature monitoring from the two peripheral locations allowed us to evaluate the physiological mechanisms (i.e., intracerebral heat production and heat loss via skin surfaces) that underlie MDMA-induced brain temperature responses. Our data confirm previous reports on high individual variability and relatively weak brain hyperthermic effects of MDMA under standard control conditions (quiet rest, 22-23°C), but demonstrate dramatic enhancements of drug-induced brain hyperthermia during social interaction (exposure to male conspecific) and in warm environments (29°C). Importantly, we identified peripheral vasoconstriction as a critical mechanism underlying the activity- and state-dependent potentiation of MDMA-induced brain hyperthermia. Through this mechanism, which prevents proper heat dissipation to the external environment, MDMA at a moderate nontoxic dose (9 mg/kg or ~1/5 of LD50 in rats) can cause fatal hyperthermia under environmental conditions commonly encountered by humans. Our results demonstrate that doses of MDMA that are nontoxic under cool, quiet conditions can become highly dangerous under conditions that mimic recreational use of MDMA at rave parties or other hot, crowded venues.

  15. [Benzodiazepines in the treatment of catatonia].

    Science.gov (United States)

    Van Dalfsen, A N; Van Den Eede, F; Van Den Bossche, B; Sabbe, B G C

    2006-01-01

    A patient who developed acute catatonia during benzodiazepine withdrawal is discussed. The case prompted us to review the literature on the role of benzodiazepines in the treatment of acute catatonia. Only retrospective and open studies were found which indicate that benzodiazepines do have a beneficial effect. Lorazepam is the most widely studied benzodiazepine and at present is the best treatment option. In the specific case of acute catatonia brought on by benzodiazepine withdrawal the recommended dosage is the same as for acute catatonia caused by something other than benzodiazepine withdrawal.

  16. A History of Mild Traumatic Brain Injury affects Peripheral Pulse Oximetry during Normobaric Hypoxia

    Directory of Open Access Journals (Sweden)

    Leonard Temme

    2016-09-01

    Full Text Available Introduction: Physiological and emotional stressors increase symptoms of concussion in recently injured individuals and both forms of stress induce symptoms in people recovering from mild traumatic brain injury (mTBI but who are asymptomatic when not stressed or are at rest. Methods: Healthy asymptomatic adults (25.0 ± 5.1 years with a history of mTBI (n = 36 and matched healthy controls (n = 36 with no mTBI history were exposed to three levels of normobaric hypoxic stress generated with the Reduced Oxygen Breathing Device (ROBD (Environics, Inc., Tollande, CT, which reduced the percent oxygen by mixing sea level air with nitrogen. The ROBD reduced the percent oxygen in the breathable air from the normal 21% to 15.5% O2, 14% O2, and 13% O2. Under these conditions: (a a standard pulse oximeter recorded peripheral oxygen saturation (SpO2 and pulse rate (beats per minute, and (b the FIT (PMI, Inc., Rockville, MD recorded saccadic velocity and pupillary response dynamics to a brief light flash. Results: For all three hypoxic stress conditions the mTBI group had significantly higher SpO2 during the final minute of exposure than did the controls F(2.17,151.8 = 5.29, p < .001, η2 = .852 and the rate of SpO2 change over time was significantly shallower for the mTBI than for the controls F(2.3,161.3 = 2.863, p < .001, η2 = .569, Greenhouse-Geisser corrected. Overall, mTBI had lower pulse rate but the difference was only significant for the 14% O2 condition. FIT oculomotor measures were not sensitive to group differences. When exposed to mild or moderate normobaric hypoxic stress (15% O2: (1 SpO2 differences emerged between the mTBI and matched healthy controls, (2 heart rate trended lower in the mTBI group, and (3 FIT measures were not sensitive to group differences. Conclusion: A relatively minor hypoxic challenge can reveal measurable differences in SpO2 and heart rate in otherwise asymptomatic individuals with a history of mTBI.

  17. Effects of aerobic exercise training on peripheral brain-derived neurotrophic factor and eotaxin-1 levels in obese young men

    OpenAIRE

    Cho, Su Youn; Roh, Hee Tae

    2016-01-01

    [Purpose] The aim of the present study was to investigate the effects of aerobic exercise training on the levels of peripheral brain-derived neurotrophic factor and eotaxin-1 in obese young men. [Subjects and Methods] The subjects included sixteen obese young men with a body mass index greater than 25 kg/m2. They were randomly divided between control and exercise groups (n = 8 in each group). The exercise group performed treadmill exercise for 40 min, 3 times a week for 8 weeks at the intensi...

  18. [Cellular and molecular mechanisms of radiation-induced brain injury: can peripheral markers be detected?].

    Science.gov (United States)

    Piskunov, A K; Nikitin, K V; Potapov, A A

    2015-01-01

    Investigation of the mechanisms of radiation-induced brain injury is a relevant fundamental objective of radiobiology and neuroradiology. Damage to the healthy brain tissue is the key factor limiting the application of radiation therapy in patients with nervous systems neoplasms. Furthermore, postradiation brain injury can be clinically indiscernible from continued tumor growth and requires differential diagnosis. Thus, there exists high demand for biomarkers of radiation effects on the brain in neurosurgery and radiobiology. These markers could be used for better understanding and quantifying the effects of ionizing radiation on brain tissues, as well as for elaborating personalized therapy. Despite the high demand, biomarkers of radiation-induced brain injury have not been identified thus far. The cellular and molecular mechanisms of the effect of ionizing radiation on the brain were analyzed in this review in order to identify potential biomarkers of radiation-induced injury to nervous tissue.

  19. Impairment of blood brain barrier is related with the neuroinflammation induced peripheral immune status in intracerebroventricular colchicine injected rats: An experimental study with mannitol.

    Science.gov (United States)

    Sil, Susmita; Ghosh, Arijit; Ghosh, Tusharkanti

    2016-09-01

    The neurodegeneration in AD patients may be associated with changes of peripheral immune responses. Some peripheral immune responses are altered due to neuroinflammation in colchicine induced AD (cAD) rats. The leaky blood brain barrier (BBB) in cAD-rats may be involved in inducing peripheral inflammation, though there is no report in this regard. Therefore, the present study was designed to investigate the role of BBB in cADrats by altering the BBB in a time dependent manner with injection (i.v.) of mannitol (BBB opener). The inflammatory markers in the brain and serum along with the peripheral immune responses were measured after 30 and 60min of mannitol injection in cAD rats. The results showed higher inflammatory markers in the hippocampus and serum along with alterations in peripheral immune parameters in cAD rats. Although the hippocampal inflammatory markers did not further change after mannitol injection in cAD rats, the serum inflammatory markers and peripheral immune responses were altered and these changes were greater after 60min than that of 30min of mannitol injection. The present study shows that the peripheral immune responses in cAD rats after 30 and 60min of mannitol injection are related to magnitude of impairment of BBB in these conditions. It can be concluded from this study that impairment of BBB in cAD rats is related to the changes of peripheral immune responses observed in that condition.

  20. Is recovery driven by central or peripheral factors? A role for the brain in recovery following intermittent-sprint exercise.

    Directory of Open Access Journals (Sweden)

    Geoffrey M Minett

    2014-02-01

    Full Text Available Prolonged intermittent-sprint exercise (i.e. team sports induce disturbances in skeletal muscle structure and function that are associated with reduced contractile function, a cascade of inflammatory responses, perceptual soreness and a delayed return to optimal physical performance. In this context, recovery from exercise-induced fatigue is traditionally treated from a peripheral viewpoint, with the regeneration of muscle physiology and other peripheral factors the target of recovery strategies. The direction of this research narrative on post-exercise recovery differs to the increasing emphasis on the complex interaction between both central and peripheral factors regulating exercise intensity during exercise performance. Given the role of the central nervous system (CNS in motor-unit recruitment during exercise, it too may have an integral role in post-exercise recovery. Indeed, this hypothesis is indirectly supported by an apparent disconnect in time-course changes in physiological and biochemical markers resultant from exercise and the ensuing recovery of exercise performance. Equally, improvements in perceptual recovery, even withstanding the physiological state of recovery, may interact with both feed-forward/feed-back mechanisms to influence subsequent efforts. Considering the research interest afforded to recovery methodologies designed to hasten the return of homeostasis within the muscle, the limited focus on contributors to post-exercise recovery from CNS origins is somewhat surprising. Based on this context, the current review aims to outline the potential contributions of the brain to performance recovery after strenuous exercise.

  1. Imaging of peripheral-type benzodiazepine receptor in tumor: in vitro binding and in vivo biodistribution of N-benzyl-N-[{sup 11}C]methyl-2- (7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide

    Energy Technology Data Exchange (ETDEWEB)

    Yamasaki, Tomoteru; Kumata, Katsushi; Yanamoto, Kazuhiko; Hatori, Akiko [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Takei, Makoto; Nakamura, Yukio [Tokyo Nuclear Service Co. Ltd., Tokyo 141-8686 (Japan); Koike, Sachiko; Ando, Koichi [Heavy-ion Radiobiology Research Group, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Suzuki, Kazutoshi [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Zhang, Ming-Rong [Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan)], E-mail: zhang@nirs.go.jp

    2009-10-15

    Introduction: The aim of this study was to evaluate N-benzyl-N-[{sup 11}C]methyl-2- (7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide ([{sup 11}C]DAC) as a novel peripheral-type benzodiazepine receptor (PBR) ligand for tumor imaging. Methods: [{sup 11}C]DAC was synthesized by the reaction of a desmethyl precursor with [{sup 11}C]CH{sub 3}I. In vitro uptake of [{sup 11}C]DAC was examined in PBR-expressing C6 glioma and intact murine fibrosarcoma (NFSa) cells. In vivo distribution of [{sup 11}C]DAC was determined using NFSa-bearing mice and small-animal positron emission tomography (PET). Results: [{sup 11}C]DAC showed specific binding to PBR in C6 glioma cells, a standard cell line with high PBR expression. Specific binding of [{sup 11}C]DAC was also confirmed in NFSa cells, a target tumor cell line in this study. Results of PET experiments using NFSa-bearing mice, showed that [{sup 11}C]DAC was taken up specifically into the tumor, and pretreatment with PK11195 abolished the uptake. Conclusions: [{sup 11}C]DAC was taken up into PBR-expressing NFSa. [{sup 11}C]DAC is a promising PET ligand that can be used for imaging PBR in tumor-bearing mice.

  2. Postmortem concentrations of gamma-hydroxybutyrate (GHB) in peripheral blood and brain tissue - Differentiating between postmortem formation and antemortem intake.

    Science.gov (United States)

    Thomsen, Ragnar; Rasmussen, Brian Schou; Johansen, Sys Stybe; Linnet, Kristian

    2017-03-01

    Gamma-hydroxybutyrate (GHB) is a recreational drug, a drug of abuse, as well as an endogenous molecule in mammals. The drug has become infamous as a tool for drug-facilitated sexual assault. GHB is found in low concentrations in living humans, while at postmortem the concentration of GHB rises due to fermentation processes. The endogenous nature of GHB leads to difficulty in interpretation of concentrations, as the source of GHB is not obvious. Postmortem brain and blood samples were collected from 221 individuals at autopsy. Of these, 218 were not suspected of having ingested GHB, while GHB intake was reported for the last three (cases A-C). Decomposition level was estimated and cases classified into no/minor and advanced decomposition. Brain samples were extracted from the frontal lobe; only gray matter from the cerebral cortex was used. Blood was drawn from the femoral vein. Brain samples were homogenized and diluted with water. Brain homogenates or femoral blood were then prepared using protein precipitation and GHB was quantified with UHPLC-MS/MS. For 189 cases where ingestion of GHB was not suspected and where no/minor decomposition had occurred the concentrations were in the range 4.8-45.4mg/kg (median 15.3mg/kg) in blood and not-detected to 9.8mg/kg (median 4.8mg/kg) in brain tissue. For case A, where intoxication with GHB was deemed to be the sole cause of death, the concentrations were 199 and 166mg/kg in blood and brain, respectively. For case B, where intoxication with GHB was a contributing factor of death, the respective concentrations were 142 and 78.4mg/kg. For case C, where GHB was ingested but the cause of death was opioid poisoning, the concentrations were 40.3 and 12.7mg/kg. The results demonstrate that postmortem-formed levels of GHB are much lower in brain than peripheral blood. Analysis of GHB in brain tissue thus provides for an improved capability to identify an exogenous source of GHB. By measuring GHB in brain tissue and employing a cut

  3. Postmortem concentrations of gamma-hydroxybutyrate (GHB) in peripheral blood and brain tissue - Differentiating between postmortem formation and antemortem intake

    DEFF Research Database (Denmark)

    Thomsen, Ragnar; Rasmussen, Brian Schou; Johansen, Sys Stybe

    2017-01-01

    /kg (median 15.3mg/kg) in blood and not-detected to 9.8mg/kg (median 4.8mg/kg) in brain tissue. For case A, where intoxication with GHB was deemed to be the sole cause of death, the concentrations were 199 and 166mg/kg in blood and brain, respectively. For case B, where intoxication with GHB...... was a contributing factor of death, the respective concentrations were 142 and 78.4mg/kg. For case C, where GHB was ingested but the cause of death was opioid poisoning, the concentrations were 40.3 and 12.7mg/kg. The results demonstrate that postmortem-formed levels of GHB are much lower in brain than peripheral...... to fermentation processes. The endogenous nature of GHB leads to difficulty in interpretation of concentrations, as the source of GHB is not obvious. Postmortem brain and blood samples were collected from 221 individuals at autopsy. Of these, 218 were not suspected of having ingested GHB, while GHB intake...

  4. Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders.

    Science.gov (United States)

    Bevan, Adam K; Duque, Sandra; Foust, Kevin D; Morales, Pablo R; Braun, Lyndsey; Schmelzer, Leah; Chan, Curtis M; McCrate, Mary; Chicoine, Louis G; Coley, Brian D; Porensky, Paul N; Kolb, Stephen J; Mendell, Jerry R; Burghes, Arthur H M; Kaspar, Brian K

    2011-11-01

    Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide a compelling case for advancing AAV9 to the clinic. An important translational step is to demonstrate efficient CNS targeting in large animals at various ages. In the present study, we tested systemically injected AAV9 in cynomolgus macaques, administered at birth through 3 years of age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at crossing the blood-brain barrier (BBB) at all time points investigated. Transgene expression was detected primarily in glial cells throughout the brain, dorsal root ganglia neurons and motor neurons within the spinal cord, providing confidence for translation to SMA patients. Systemic injection also efficiently targeted skeletal muscle and peripheral organs. To specifically target the CNS, we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients. Our findings support the use of AAV9 for gene transfer to the CNS for disorders in pediatric populations.

  5. The neural butterfly effect The injury to peripheral nerves changes the brain

    Institute of Scientific and Technical Information of China (English)

    Krzysztof Czaja

    2012-01-01

    @@ Regeneration of damaged innervations in the peripheral nervous system (PNS) has been well documented in both animals and human[1].After injury, the damaged neurite swells and undergoes retrograde degeneration.Once the debris is cleared, it begins to sprout and restore damaged connections.

  6. [Benzodiazepine dependence: causalities and treatment options].

    Science.gov (United States)

    Heberlein, A; Bleich, S; Kornhuber, J; Hillemacher, T

    2009-01-01

    Benzodiazepines are very often prescribed because of their anxiolytic, sedative and hypnotic properties. However, long term treatment is associated with development of benzodiazepine dependence. Besides development of physical dependence, which is linked to a typical benzodiazepine withdrawal syndrome when drug intake is discontinued, also behavioural addiction to benzodiazepines has been described. Benzodiazepines are known to enhance GABAergic neurotransmission. Counter regulation of enhanced GABAergic neurotransmission by enhancement of glutamatergic neurotransmission is thought to be one reason underlying the typical symptoms of benzodiazepine withdrawal. Also alterations in the expression of neuropeptides like Corticotropin Releasing Hormone and Neuropeptide Y are thought to be involved in the development of benzodiazepine dependence. However, until today the knowledge of neural mechanisms underlying the development of benzodiazepine dependence remains incomplete. Because even long term treatment with small doses of benzodiazepines is associated with adverse reactions like cognitive dysfunctions withdrawal from benzodiazepines should be aimed. Anticonvulsants and antidepressants seem to reduce the intensity of benzodiazepine withdrawal and to enhance long term prognosis of dependence.

  7. GDH-Dependent Glutamate Oxidation in the Brain Dictates Peripheral Energy Substrate Distribution

    DEFF Research Database (Denmark)

    Karaca, Melis; Frigerio, Francesca; Migrenne, Stephanie;

    2015-01-01

    Glucose, the main energy substrate used in the CNS, is continuously supplied by the periphery. Glutamate, the major excitatory neurotransmitter, is foreseen as a complementary energy contributor in the brain. In particular, astrocytes actively take up glutamate and may use it through oxidative...... glutamate dehydrogenase (GDH) activity. Here, we investigated the significance of glutamate as energy substrate for the brain. Upon glutamate exposure, astrocytes generated ATP in a GDH-dependent way. The observed lack of glutamate oxidation in brain-specific GDH null CnsGlud1(-/-) mice resulted....... Our data reveal the importance of glutamate as necessary energy substrate for the brain and the role of central GDH in the regulation of whole-body energy homeostasis....

  8. Epilepsia partialis continua triggered by traumatic hand injury: a peripheral tuning of brain excitability?

    Science.gov (United States)

    Paglioli, Eliseu; Martins, William Alves; Cruz, Walter De la; Andrade, Victor; Silva, Vinicius Duval da; Nunes, Rafael Menezes; Palmini, André

    2016-03-01

    Epilepsia partialis continua is often refractory to antiepileptic medication and its causal relation to peripheral sensory stimuli has only rarely been suggested. We report a man who received surgery for temporal lobe epilepsy 10 years ago, who presented "de novo" epilepsia partialis continua following mild traumatic injury of the left hand. Continuous myoclonus of the left upper limb started the day after injury and persisted unabated for several weeks. Non-invasive evaluation was inconclusive. Acute electrocorticography during surgery under local anaesthesia revealed continuous, rhythmic spiking over the right sensorimotor cortex. Tailored excision of the posterior bank of the motor and adjacent sensory cortex immediately stopped the continuous myoclonus. Histopathology showed abnormal radial lamination and was compatible with focal cortical dysplasia type IA. Epilepsia partialis continua did not recur for seven years. Afferent stimuli from peripheral injury can disinhibit hyperexcitable sensorimotor cortex leading to epilepsia partialis continua. [Published with video sequences online].

  9. Withdrawing benzodiazepines in primary care.

    Science.gov (United States)

    Lader, Malcolm; Tylee, Andre; Donoghue, John

    2009-01-01

    The use of benzodiazepine anxiolytics and hypnotics continues to excite controversy. Views differ from expert to expert and from country to country as to the extent of the problem, or even whether long-term benzodiazepine use actually constitutes a problem. The adverse effects of these drugs have been extensively documented and their effectiveness is being increasingly questioned. Discontinuation is usually beneficial as it is followed by improved psychomotor and cognitive functioning, particularly in the elderly. The potential for dependence and addiction have also become more apparent. The licensing of SSRIs for anxiety disorders has widened the prescribers' therapeutic choices (although this group of medications also have their own adverse effects). Melatonin agonists show promise in some forms of insomnia. Accordingly, it is now even more imperative that long-term benzodiazepine users be reviewed with respect to possible discontinuation. Strategies for discontinuation start with primary-care practitioners, who are still the main prescribers.This review sets out the stratagems that have been evaluated, concentrating on those of a pharmacological nature. Simple interventions include basic monitoring of repeat prescriptions and assessment by the doctor. Even a letter from the primary-care practitioner pointing out the continuing usage of benzodiazepines and questioning their need can result in reduction or cessation of use. Pharmacists also have a role to play in monitoring the use of benzodiazepines, although mobilizing their assistance is not yet routine. Such stratagems can avoid the use of specialist back-up services such as psychiatrists, home care, and addiction and alcohol misuse treatment facilities.Pharmacological interventions for benzodiazepine dependence have been reviewed in detail in a recent Cochrane review, but only eight studies proved adequate for analysis. Carbamazepine was the only drug that appeared to have any useful adjunctive properties for

  10. Effects of aerobic exercise training on peripheral brain-derived neurotrophic factor and eotaxin-1 levels in obese young men.

    Science.gov (United States)

    Cho, Su Youn; Roh, Hee Tae

    2016-04-01

    [Purpose] The aim of the present study was to investigate the effects of aerobic exercise training on the levels of peripheral brain-derived neurotrophic factor and eotaxin-1 in obese young men. [Subjects and Methods] The subjects included sixteen obese young men with a body mass index greater than 25 kg/m(2). They were randomly divided between control and exercise groups (n = 8 in each group). The exercise group performed treadmill exercise for 40 min, 3 times a week for 8 weeks at the intensity of 70% heart rate reserve. Blood collection was performed to examine the levels of serum glucose, plasma malonaldehyde, serum brain-derived neurotrophic factor, and plasma eotaxin-1 before and after the intervention (aerobic exercise training). [Results] Following the intervention, serum BDNF levels were significantly higher, while serum glucose, plasma MDA, and plasma eotaxin-1 levels were significantly lower than those prior to the intervention in the exercise group. [Conclusion] Aerobic exercise training can induce neurogenesis in obese individuals by increasing the levels of brain-derived neurotrophic factor and reducing the levels of eotaxin-1. Alleviation of oxidative stress is possibly responsible for such changes.

  11. Correlation between Peripheral Levels of Brain-Derived Neurotrophic Factor and Hippocampal Volume in Children and Adolescents with Bipolar Disorder

    Directory of Open Access Journals (Sweden)

    Tatiana Lauxen Peruzzolo

    2015-01-01

    Full Text Available Pediatric bipolar disorder (PBD is a serious mental disorder that affects the development and emotional growth of affected patients. The brain derived neurotrophic factor (BDNF is recognized as one of the possible markers of the framework and its evolution. Abnormalities in BDNF signaling in the hippocampus could explain the cognitive decline seen in patients with TB. Our aim with this study was to evaluate possible changes in hippocampal volume in children and adolescents with BD and associate them to serum BDNF. Subjects included 30 patients aged seven to seventeen years from the ProCAB (Program for Children and Adolescents with Bipolar Disorder. We observed mean right and left hippocampal volumes of 41910.55 and 41747.96 mm3, respectively. No statistically significant correlations between peripheral BDNF levels and hippocampal volumes were found. We believe that the lack of correlation observed in this study is due to the short time of evolution of BD in children and adolescents. Besides studies with larger sample sizes to confirm the present findings and longitudinal assessments, addressing brain development versus a control group and including drug-naive patients in different mood states may help clarify the role of BDNF in the brain changes consequent upon BD.

  12. Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier

    Directory of Open Access Journals (Sweden)

    Salter Michael W

    2010-11-01

    Full Text Available Abstract Background The blood-brain barrier (BBB plays the crucial role of limiting exposure of the central nervous system (CNS to damaging molecules and cells. Dysfunction of the BBB is critical in a broad range of CNS disorders including neurodegeneration, inflammatory or traumatic injury to the CNS, and stroke. In peripheral tissues, the vascular-tissue permeability is normally greater than BBB permeability, but vascular leakage can be induced by efferent discharge activity in primary sensory neurons leading to plasma extravasation into the extravascular space. Whether discharge activity of sensory afferents entering the CNS may open the BBB or blood-spinal cord barrier (BSCB remains an open question. Results Here we show that peripheral nerve injury (PNI produced by either sciatic nerve constriction or transecting two of its main branches causes an increase in BSCB permeability, as assessed by using Evans Blue dye or horseradish peroxidase. The increase in BSCB permeability was not observed 6 hours after the PNI but was apparent 24 hours after the injury. The increase in BSCB permeability was transient, peaking about 24-48 hrs after PNI with BSCB integrity returning to normal levels by 7 days. The increase in BSCB permeability was prevented by administering the local anaesthetic lidocaine at the site of the nerve injury. BSCB permeability was also increased 24 hours after electrical stimulation of the sciatic nerve at intensity sufficient to activate C-fibers, but not when A-fibers only were activated. Likewise, BSCB permeability increased following application of capsaicin to the nerve. The increase in permeability caused by C-fiber stimulation or by PNI was not anatomically limited to the site of central termination of primary afferents from the sciatic nerve in the lumbar cord, but rather extended throughout the spinal cord and into the brain. Conclusions We have discovered that injury to a peripheral nerve and electrical stimulation of C

  13. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves

    DEFF Research Database (Denmark)

    Rossini, P M; Burke, D; Chen, R

    2015-01-01

    in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non......These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some...... of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation...

  14. Blood borne hormones in a cross-talk between peripheral and brain mechanisms regulating blood pressure, the role of circumventricular organs.

    Science.gov (United States)

    Ufnal, Marcin; Skrzypecki, Janusz

    2014-04-01

    Accumulating evidence suggests that blood borne hormones modulate brain mechanisms regulating blood pressure. This appears to be mediated by the circumventricular organs which are located in the walls of the brain ventricular system and lack the blood-brain barrier. Recent evidence shows that neurons of the circumventricular organs express receptors for the majority of cardiovascular hormones. Intracerebroventricular infusions of hormones and their antagonists is one approach to evaluate the influence of blood borne hormones on the neural mechanisms regulating arterial blood pressure. Interestingly, there is no clear correlation between peripheral and central effects of cardiovascular hormones. For example, angiotensin II increases blood pressure acting peripherally and centrally, whereas peripherally acting pressor catecholamines decrease blood pressure when infused intracerebroventricularly. The physiological role of such dual hemodynamic responses has not yet been clarified. In the paper we review studies on hemodynamic effects of catecholamines, neuropeptide Y, angiotensin II, aldosterone, natriuretic peptides, endothelins, histamine and bradykinin in the context of their role in a cross-talk between peripheral and brain mechanisms involved in the regulation of arterial blood pressure.

  15. Benzodiazepine dependence: focus on withdrawal syndrome.

    Science.gov (United States)

    Authier, N; Balayssac, D; Sautereau, M; Zangarelli, A; Courty, P; Somogyi, A A; Vennat, B; Llorca, P-M; Eschalier, A

    2009-11-01

    Benzodiazepines are potentially addictive drugs: psychological and physical dependence can develop within a few weeks or years of regular or repeated use. The socioeconomic costs of the present high level of long-term benzodiazepine use are considerable. These consequences could be minimised if prescriptions for long-term benzodiazepines were decreased. However, many physicians continue to prescribe benzodiazepines and patients wishing to withdraw receive little advice or support. Particular care should be taken in prescribing benzodiazepines for vulnerable patients such as elderly persons, pregnant women, children, alcohol- or drug-dependent patients and patients with comorbid psychiatric disorders. The following update gives recent research results on the withdrawal pathophysiology and practical information in order to treat or prevent benzodiazepine withdrawal syndrome.

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

    Energy Technology Data Exchange (ETDEWEB)

    McCabe, R.T.; Mahan, D.R.; Smith, R.B.; Wamsley, J.K. (Neuropsychiatric Research Institute, Fargo, ND (USA))

    1990-10-01

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

  17. [The addicted patient in anaesthesia - benzodiazepine dependence].

    Science.gov (United States)

    Schneemilch, Christine; Brinkers, Michael

    2015-06-01

    As a result of the demographic change, the proportions of elderly patients undergoing operations and anesthesia are increasingly important. The consumption of benzodiazepines evidently rises with increasing age. Associated with the increasing consumption in the elderly is the risk of cognitive impairment, delirium, falls and fractures. Also long-term benzodiazepine use in low-dose may induce perioperative withdrawal syndrome. The following article will present characteristics and complications accompanied by critical benzodiazepine use especially in the elderly patients.

  18. Do benzodiazepines contribute to respiratory problems?

    Science.gov (United States)

    Vozoris, Nicholas T

    2014-12-01

    Non-selective benzodiazepines are a class of sedative and anxiolytic medication that are commonly prescribed. Physiology studies and animal studies suggest that non-selective benzodiazepines may adversely impact respiration through a variety of mechanisms. Several recent, well-designed, population-based observational studies confirm that benzodiazepine-related negative respiratory outcomes are a concern. In this article, the mechanisms and clinical evidence for non-selective benzodiazepine-related adverse respiratory outcomes, as well as the methodological issues relating to the evaluation of adverse drug effects are reviewed.

  19. Benzodiazepines and postoperative cognitive dysfunction in the elderly

    DEFF Research Database (Denmark)

    Rasmussen, L.S.; Steentoft, Anni; Rasmussen, H.

    1999-01-01

    hypnotics benzodiazepine,diazepam,age factor,anaesthesia,geriatric,psychological responses,postoperative......hypnotics benzodiazepine,diazepam,age factor,anaesthesia,geriatric,psychological responses,postoperative...

  20. Arterial baroreceptors and brain histamine contribute to bradycardia to peripheral hyperosmolality.

    Science.gov (United States)

    Kenney, M J; Bealer, S L

    1993-10-01

    The purpose of this study was to determine whether the bradycardic response to peripheral hyperosmolality in conscious rats is dependent on afferent baroreceptor mechanisms and whether central histamine H2 receptors play a role in baroreflex-mediated changes in heart rate (HR). Mean arterial pressure (MAP) and HR were recorded continuously during a 30-min infusion of 2.5 M NaCl (10 microliters.100 g-1.min-1) hypertonic saline (HTS). HTS infusion significantly increased MAP (21 +/- 4 mmHg) and reduced HR (-62 +/- 10 beats/min) in rats with intact arterial baroreceptors. In sinoaortic-denervated rats, HR remained unchanged from control despite a significant increase in MAP. After intracerebroventricular (lateral ventricle) administration of cimetidine or ranitidine (H2-receptor antagonists) in intact rats, HTS infusion significantly increased MAP (19 +/- 2 and 17 +/- 2 mmHg, respectively) but the bradycardia was abolished (-12 +/- 10 and -10 +/- 10 beats/min, respectively). In contrast, central H2-receptor blockade did not alter reflex HR responses to the intravenous administration of phenylephrine and nitroprusside or to the central administration of histamine or angiotensin II. These results indicate that the bradycardic response to HTS infusion is mediated through the arterial baroreceptor reflex and involves in part a selective histaminergic pathway.

  1. Peripheral vagus nerve stimulation significantly affects lipid composition and protein secondary structure within dopamine-related brain regions in rats.

    Science.gov (United States)

    Surowka, Artur Dawid; Krygowska-Wajs, Anna; Ziomber, Agata; Thor, Piotr; Chrobak, Adrian Andrzej; Szczerbowska-Boruchowska, Magdalena

    2015-06-01

    Recent immunohistochemical studies point to the dorsal motor nucleus of the vagus nerve as the point of departure of initial changes which are related to the gradual pathological developments in the dopaminergic system. In the light of current investigations, it is likely that biochemical changes within the peripheral nervous system may influence the physiology of the dopaminergic system, suggesting a putative role for it in the development of neurodegenerative disorders. By using Fourier transform infrared microspectroscopy, coupled with statistical analysis, we examined the effect of chronic, unilateral electrical vagus nerve stimulation on changes in lipid composition and in protein secondary structure within dopamine-related brain structures in rats. It was found that the chronic vagal nerve stimulation strongly affects the chain length of fatty acids within the ventral tegmental area, nucleus accumbens, substantia nigra, striatum, dorsal motor nucleus of vagus and the motor cortex. In particular, the level of lipid unsaturation was found significantly increasing in the ventral tegmental area, substantia nigra and motor cortex as a result of vagal nerve stimulation. When it comes to changes in protein secondary structure, we could see that the mesolimbic, mesocortical and nigrostriatal dopaminergic pathways are particularly affected by vagus nerve stimulation. This is due to the co-occurrence of statistically significant changes in the content of non-ordered structure components, alpha helices, beta sheets, and the total area of Amide I. Macromolecular changes caused by peripheral vagus nerve stimulation may highlight a potential connection between the gastrointestinal system and the central nervous system in rat during the development of neurodegenerative disorders.

  2. Unexpected effects of peripherally administered kynurenic acid on cortical spreading depression and related blood–brain barrier permeability

    Directory of Open Access Journals (Sweden)

    Oláh G

    2013-09-01

    Full Text Available Gáspár Oláh,1 Judit Herédi,1 Ákos Menyhárt,1 Zsolt Czinege,2 Dávid Nagy,1 János Fuzik,1 Kitti Kocsis,1 Levente Knapp,1 Erika Krucsó,1 Levente Gellért,1 Zsolt Kis,1 Tamás Farkas,1 Ferenc Fülöp,3 Árpád Párdutz,4 János Tajti,4 László Vécsei,4 József Toldi1 1Department of Physiology, Anatomy and Neuroscience, 2Department of Software Engineering, 3Institute of Pharmaceutical Chemistry and MTA-SZTE Research Group for Stereochemistry, 4Department of Neurology and MTA-SZTE Neuroscience Research Group, University of Szeged, Szeged, Hungary Abstract: Cortical spreading depression (CSD involves a slowly-propagating depolarization wave in the cortex, which can appear in numerous pathophysiological conditions, such as migraine with aura, stroke, and traumatic brain injury. Neurons and glial cells are also depolarized transiently during the phenomena. CSD is followed by a massive increase in glutamate release and by changes in the brain microcirculation. The aim of this study was to investigate the effects of two N-methyl-D-aspartate receptor antagonists, endogenous kynurenic acid (KYNA and dizocilpine, on CSD and the related blood–brain barrier (BBB permeability in rats. In intact animals, KYNA hardly crosses the BBB but has some positive features as compared with its precursor L-Kynurenine, which is frequently used in animal studies (KYNA cannot be metabolized to excitotoxic agents such as 3-hydroxy-L-kynurenine and quinolinic acid. We therefore investigated the possible effects of peripherally administered KYNA. Repetitive CSD waves were elicited by the application of 1 M KCl solution to the cortex. Direct current-electrocorticograms were measured for 1 hour. Four parameters of the waves were compared. Evans blue dye and fluorescent microscopy were used to study the possible changes in the permeability of the BBB. The results demonstrated that N-methyl-D-aspartate receptor antagonists can reduce the number of CSD waves and decrease

  3. Prescribing of benzodiazepines by casualty officers.

    OpenAIRE

    1989-01-01

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

  4. Peripheral brain-derived neurotrophic factor is related to cardiovascular risk factors in active and inactive elderly men

    Directory of Open Access Journals (Sweden)

    A. Zembron-Lacny

    2016-01-01

    Full Text Available Regular exercise plays an important preventive and therapeutic role in heart and vascular diseases, and beneficially affects brain function. In blood, the effects of exercise appear to be very complex and could include protection of vascular endothelial cells via neurotrophic factors and decreased oxidative stress. The purpose of this study was to identify the age-related changes in peripheral brain-derived neurotrophic factor (BDNF and its relationship to oxidative damage and conventional cardiovascular disease (CVD biomarkers, such as atherogenic index, C-reactive protein (hsCRP and oxidized LDL (oxLDL, in active and inactive men. Seventeen elderly males (61-80 years and 17 young males (20-24 years participated in this study. According to the 6-min Åstrand-Rhyming bike test, the subjects were classified into active and inactive groups. The young and elderly active men had a significantly better lipoprotein profile and antioxidant status, as well as reduced oxidative damage and inflammatory state. The active young and elderly men had significantly higher plasma BDNF levels compared to their inactive peers. BDNF was correlated with VO2max (r=0.765, P<0.001. In addition, we observed a significant inverse correlation of BDNF with atherogenic index (TC/HDL, hsCRP and oxLDL. The findings demonstrate that a high level of cardiorespiratory fitness reflected in VO2max was associated with a higher level of circulating BDNF, which in turn was related to common CVD risk factors and oxidative damage markers in young and elderly men.

  5. Management of benzodiazepine misuse and dependence.

    Science.gov (United States)

    Brett, Jonathan; Murnion, Bridin

    2015-10-01

    There are well-recognised harms from long-term use of benzodiazepines. These include dependency, cognitive decline and falls. It is important to prevent and recognise benzodiazepine dependence. A thorough risk assessment guides optimal management and the necessity for referral. The management of dependence involves either gradual benzodiazepine withdrawal or maintenance treatment. Prescribing interventions, substitution, psychotherapies and pharmacotherapies can all contribute. Unless the patient is elderly, it is helpful to switch to a long-acting benzodiazepine in both withdrawal and maintenance therapy. The dose should be gradually reduced over weeks to lower the risk of seizures. Harms from drugs such as zopiclone and zolpidem are less well characterised. Dependence is managed in the same manner as benzodiazepine dependence.

  6. Benzodiazepines: risks and benefits. A reconsideration.

    Science.gov (United States)

    Baldwin, David S; Aitchison, Katherine; Bateson, Alan; Curran, H Valerie; Davies, Simon; Leonard, Brian; Nutt, David J; Stephens, David N; Wilson, Sue

    2013-11-01

    Over the last decade there have been further developments in our knowledge of the risks and benefits of benzodiazepines, and of the risks and benefits of alternatives to benzodiazepines. Representatives drawn from the Psychopharmacology Special Interest Group of the Royal College of Psychiatrists and the British Association for Psychopharmacology together examined these developments, and have provided this joint statement with recommendations for clinical practice. The working group was mindful of widespread concerns about benzodiazepines and related anxiolytic and hypnotic drugs. The group believes that whenever benzodiazepines are prescribed, the potential for dependence or other harmful effects must be considered. However, the group also believes that the risks of dependence associated with long-term use should be balanced against the benefits that in many cases follow from the short or intermittent use of benzodiazepines and the risk of the underlying conditions for which treatment is being provided.

  7. 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

    Carbon-11-labeled flumazenil combined with positron emission tomography (PET) was used to measure the concentration (Bmax) of the benzodiazepine (Bz) receptor in the brain and its equilibrium dissociation constant (KD) for flumazenil in five normal subjects. The steady-state approach was used inj...

  8. 21 CFR 862.3170 - Benzodiazepine test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Benzodiazepine test system. 862.3170 Section 862....3170 Benzodiazepine test system. (a) Identification. A benzodiazepine test system is a device intended to measure any of the benzodiazepine compounds, sedative and hypnotic drugs, in blood, plasma,...

  9. Cerebral and peripheral changes occurring in nitric oxide (NO synthesis in a rat model of sleeping sickness: identification of brain iNOS expressing cells.

    Directory of Open Access Journals (Sweden)

    Donia Amrouni

    Full Text Available BACKGROUND: The implication of nitric oxide (NO in the development of human African trypanosomiasis (HAT using an animal model, was examined. The manner by which the trypanocidal activity of NO is impaired in the periphery and in the brain of rats infected with Trypanosoma brucei brucei (T. b. brucei was analyzed through: (i the changes occurring in NO concentration in both peripheral (blood and cerebral compartments; (ii the activity of nNOS and iNOS enzymes; (iii identification of the brain cell types in which the NO-pathways are particularly active during the time-course of the infection. METHODOLOGY/PRINCIPAL FINDINGS: NO concentration (direct measures by voltammetry was determined in central (brain and peripheral (blood compartments in healthy and infected animals at various days post-infection: D5, D10, D16 and D22. Opposite changes were observed in the two compartments. NO production increased in the brain (hypothalamus from D10 (+32% to D16 (+71%, but decreased in the blood from D10 (-22% to D16 (-46% and D22 (-60%. In parallel with NO measures, cerebral iNOS activity increased and peaked significantly at D16 (up to +700%. However, nNOS activity did not vary. Immunohistochemical staining confirmed iNOS activation in several brain regions, particularly in the hypothalamus. In peritoneal macrophages, iNOS activity decreased from D10 (-83% to D16 (-65% and D22 (-74% similarly to circulating NO. CONCLUSION/SIGNIFICANCE: The NO changes observed in our rat model were dependent on iNOS activity in both peripheral and central compartments. In the periphery, the NO production decrease may reflect an arginase-mediated synthesis of polyamines necessary to trypanosome growth. In the brain, the increased NO concentration may result from an enhanced activity of iNOS present in neurons and glial cells. It may be regarded as a marker of deleterious inflammatory reactions.

  10. AHR-11797: a novel benzodiazepine antagonist

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-03-01

    AHR-11797(5,6-dihydro-6-methyl-1-phenyl-/sup 3/H-pyrrolo(3,2,1-ij)quinazolin-3-one) displaced /sup 3/H-flunitrazepam (IC/sub 50/ = 82 nM) and /sup 3/H-Ro 15-1877 (IC/sub 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/sub 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/sub 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.

  11. Perceptions of Benzodiazepine Dependence Among Women Age 65 and Older

    OpenAIRE

    Canham, Sarah L.; Gallo, Joseph; Simoni-Wastila, Linda

    2014-01-01

    A phenomenological study explored whether older women who are chronic benzodiazepine users identified themselves as dependent, how dependence was perceived, and how meanings and understandings shaped experiences of benzodiazepine use. Self-reported benzodiazepine dependence was associated with being unable to reduce use or a desire to discontinue use and reliance on benzodiazepines to remain comfortable and able to handle daily life. Themes included: 1) benzodiazepine dependence is similar to...

  12. Benzodiazepines consumption: does dependence vary with age?

    Science.gov (United States)

    Gérardin, Marie; Victorri-Vigneau, Caroline; Guerlais, Marylène; Guillou-Landreat, Morgane; Grall-Bronnec, Marie; Jolliet, Pascale

    2014-09-01

    We have compared two groups of chronic benzodiazepines (or zolpidem/zopiclone) users: "Seniors," aged 65 years or more, and "Adults," aged less than 65 years. The study took place in the Pays de Loire region. The questionnaire assesses dependence based on items from the DSM-IV. The analysis was based on 176 Senior questionnaires and 212 Adult questionnaires. Whereas Senior patients take benzodiazepines routinely with little negative consequences, Adults suffer from underlying psychological trouble, mention a higher consumption than planned, which causes negative consequences. 35.2% of Seniors are dependent on benzodiazepines versus 49.8% of Adults.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-06-17

    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 /sup 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.

  14. Brain-derived neurotrophic factor from bone marrow-derived cells promotes post-injury repair of peripheral nerve.

    Directory of Open Access Journals (Sweden)

    Yoshinori Takemura

    Full Text Available Brain-derived neurotrophic factor (BDNF stimulates peripheral nerve regeneration. However, the origin of BNDF and its precise effect on nerve repair have not been clarified. In this study, we examined the role of BDNF from bone marrow-derived cells (BMDCs in post-injury nerve repair. Control and heterozygote BDNF knockout mice (BDNF+/- received a left sciatic nerve crush using a cerebral blood clip. Especially, for the evaluation of BDNF from BMDCs, studies with bone marrow transplantation (BMT were performed before the injury. We evaluated nerve function using a rotarod test, sciatic function index (SFI, and motor nerve conduction velocity (MNCV simultaneously with histological nerve analyses by immunohistochemistry before and after the nerve injury until 8 weeks. BDNF production was examined by immunohistochemistry and mRNA analyses. After the nerve crush, the controls showed severe nerve dysfunction evaluated at 1 week. However, nerve function was gradually restored and reached normal levels by 8 weeks. By immunohistochemistry, BDNF expression was very faint before injury, but was dramatically increased after injury at 1 week in the distal segment from the crush site. BDNF expression was mainly co-localized with CD45 in BMDCs, which was further confirmed by the appearance of GFP-positive cells in the BMT study. Variant analysis of BDNF mRNA also confirmed this finding. BDNF+/- mice showed a loss of function with delayed histological recovery and BDNF+/+→BDNF+/- BMT mice showed complete recovery both functionally and histologically. These results suggested that the attenuated recovery of the BDNF+/- mice was rescued by the transplantation of BMCs and that BDNF from BMDCs has an essential role in nerve repair.

  15. The use of benzodiazepines in the workplace.

    Science.gov (United States)

    Roy-Byrne, P P; Cowley, D S

    1990-01-01

    Benzodiazepines differ from many of the other abused substances in that there are legitimate medical indications for their use. Any prescription for benzodiazepines must be preceded by a careful risk-benefit analysis that considers the specifics of an individual's particular life situation, personality style, and psychiatric diagnosis. The risk of benzodiazepine abuse by chemically dependent individuals and the problems of cognitive and/or psychomotor impairment and dependence for all individuals have to be balanced against the therapeutic benefits of these drugs for patients who experience disabling anxiety disorders or anxiety that accompanies chronic medical illness. Problems of dependence can be minimized by utilizing a variety of pharmacologic and psychotherapeutic strategies to ameliorate withdrawal symptoms that might accompany the discontinuation of long-term benzodiazepine treatment.

  16. Peripheral physiological reactivity and brain activity in specific phobias - Reactividad fisiológica periférica y actividad cerebral en las fobias específicas

    Directory of Open Access Journals (Sweden)

    José María Martínez Selva

    2009-12-01

    Full Text Available Specific phobias are exaggerated and irrational fears caused by specific stimuli. These anxiety disorders can appear together with physiological reactions and fight or flight responses. At a peripheral level the phobic response is featured by an increase in somatic and autonomic reactivity as shown by different physiological indices (heart rate, electrodermal activity and a potentiation of defensive reflexes, such as the cardiac defense response and the blink reflex. At a central level it has been described a network of brain structures that are involved both in the processing of the phobic stimulus and in the reaction that it provokes. This brain network is composed by the amygdala, the orbitofrontal and cingulate cortices and the anterior insula. An increase in the activity of these brain regions occurs during the phobic reaction that can be associated with the somatic and autonomic changes, the subjective experience of intense fear and the avoidance behavior elicited by the phobic stimulus.

  17. [Why benzodiazepines are still in wide use?].

    Science.gov (United States)

    Vlastelica, Mirela; Jelaska, Marin

    2012-05-01

    The advent of benzodiazepines in the 1960s provided their wide use in neurology and psychiatry. They proved to be myorelaxant and anticonvulsive therapy in neurology; their anxiolytic and hypnotic properties have made them the treatment of choice for insomnia and anxiety problems; they have also been used in alcohol withdrawal and in anesthesia, and for a wide range of treatments in other clinical branches. However, reports giving rise to a prescription controversy including abuse, harmful effects, intoxication and dependence toward addiction appeared soon. On the other hand, the revolutionary appearance of selective serotonin reuptake inhibitors (SSRIs) overshadowed benzodiazepines. According to recommendations of many scientific and professional institutions, the use of benzodiazepines has been gradually excluded or reduced or limited to short-term use. However, clinical experience showed that benzodiazepines are frequently used for long-term treatment, and there are many reasons for this, e.g., prescribing tradition, patient preference, difficulties associated with benzodiazepine withdrawal (even in patients taking low doses) because they have a rapid clinical onset of action, and good efficacy with few initial adverse effects. Moreover, SSRIs as alternative drugs are associated with incomplete therapeutic response and more uncomfortable adverse effects. Some authors therefore point out that the rationale for the shift from benzodiazepines to SSRIs is inappropriate.

  18. Differential role of P-glycoprotein and breast cancer resistance protein in drug distribution into brain, CSF and peripheral nerve tissues in rats.

    Science.gov (United States)

    Huang, Liyue; Li, Xingwen; Roberts, Jonathan; Janosky, Brett; Lin, Min-Hwa Jasmine

    2015-01-01

    1. This study was designed to evaluate how the absence of P-glycoprotein (Pgp, Mdr1a), breast cancer-resistance protein (Bcrp, Abcg2) or both affects drug distribution into sciatic nerves, brain and cerebrospinal fluid (CSF) in rats. 2. Pgp substrate (loperamide), BCRP substrates (dantrolene and proprietary compound X) and dual substrates (imatinib and proprietary compound Y) were well distributed into sciatic nerves with comparable nerve to plasma concentration ratios between wild-type and knockout (KO) rats. 3. Brain exposure increased substantially in Mdr1a(-/-) rats for loperamide and in Mdr1a(-/-)/Abcg2(-/-) rats for imatinib and compound Y, but minimally to modestly in Abcg2(-/-) rats for dantrolene and compound X. The deletion of Mdr1a or Abcg2 alone had little effect on brain distribution of compound Y. 4. While CSF to unbound brain concentration ratio remained ≥3 in the KO animals for dantrolene, compounds X and Y, it was reduced to 1 in the Mdr1a(-/-)/Abcg2(-/-) rats for imatinib. 5. The data indicate that Pgp and Bcrp do not play significant roles in drug distribution into peripheral nerve tissues in rats, while working in concert to regulate brain penetration. Our results further support that CSF concentration may not be a good surrogate for unbound brain concentration of efflux substrates.

  19. Perceptions of benzodiazepine dependence among women age 65 and older.

    Science.gov (United States)

    Canham, Sarah L; Gallo, Joseph; Simoni-Wastila, Linda

    2014-01-01

    A phenomenological study explored whether older women who are chronic benzodiazepine users identified themselves as dependent, how dependence was perceived, and how meanings and understandings shaped experiences of benzodiazepine use. Self-reported benzodiazepine dependence was associated with being unable to reduce use or a desire to discontinue use and reliance on benzodiazepines to remain comfortable and able to handle daily life. Themes included: (a) benzodiazepine dependence is similar to dependence to diabetes or blood pressure medications; (b) dependence is distinctive from addiction/abuse; (c) addiction/abuse is perceived as worse than dependence; and (d) concerns of addiction/abuse result in low-dose benzodiazepine use.

  20. Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression.

    Directory of Open Access Journals (Sweden)

    Dongsha Wang

    Full Text Available The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET measures of brain serotonin (5-HT synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC. Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25 who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20 where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.

  1. Social-cognitive predictors of intended and actual benzodiazepine cessation among chronic benzodiazepine users

    NARCIS (Netherlands)

    Ten Wolde, Geeske B.; Dijkstra, Arie; Van Empelen, Pepijn; Neven, Arie Knuistingh; Zitman, Frans G.

    2008-01-01

    Long-term benzodiazepine use is associated with a variety of negative health consequences. Cessation of long-term use is therefore an important health goal. In a prospective study among chronic benzodiazepinc users (N=356) social-cognitive factors of benzodiazepine cessation were examined with a nin

  2. Cross-validation of the benzodiazepine dependence self-report questionnaire in outpatient benzodiazepine users.

    NARCIS (Netherlands)

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

    2001-01-01

    The aim of this study was to cross-validate the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ), which reflects the severity of benzodiazepine (BZD) dependence. The Bendep-SRQ, Symptom Checklist-90 (SCL-90) Schedules for Clinical Assessments in Neuropsychiatry (SCAN), and Addiction

  3. Cross-validation of the Benzodiazepine Dependence Self-Report Questionnaire in Outpatient Benzodiazepine Users

    NARCIS (Netherlands)

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

    2001-01-01

    The aim of this study was to cross-validate the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ), which reflects the severity of benzodiazepine (BZD) dependence. The Bendep-SRQ, Symptom Checklist-90 (SCL-90) Schedules for Clinical Assessments in Neuropsychiatry (SCAN), and Addiction

  4. A clinical observation of the influence of deep brain stimulation on peripheral blood lymphocytes in patients with Parkinson's disease

    Directory of Open Access Journals (Sweden)

    LIU Jing

    2013-07-01

    Full Text Available Objective To study the changing in number of peripheral blood lymphocyte (PBL of patients with Parkinson's disease (PD after deep brain stimulation (DBS, and to explore the mechanism of DBS in treating PD. Methods One hundred and thirty PD patients were divided into 2 groups, namely, non-DBS group [N = 105; 68 males and 37 females; mean age (61.54 ± 10.44 years; mean duration (7.29 ± 4.57 years], and DBS group [N = 25; 16 males and 9 females; mean age (59.20 ± 10.67 years; mean disease duration (12.16 ± 4.79 years]. There were 73 healthy subjects [37 males and 36 females; mean age (61.89 ± 12.20 years] in control group. The differences of the number of PBL among the 3 groups were analyzed. Spearman's rank correlation analysis was used to assess the relationship between PBL number and influenzing factors [gender, age, disease duration, Unified Parkinson's Disease Rating Scale (UPDRS Ⅲ score, Hoehn-Yahr (H-Y stage, and drug equivalent daily dose]. Results The number of PBL in non-DBS group was less than that in control group (P = 0.000. There was significant correlation between UPDRS Ⅲ and PBL number (rs = - 0.403, P = 0.031. No correlation was found between PBL number and gender, age, disease duration, H-Y stage or drug equivalent daily dose (P > 0.05, for all. No difference was shown between PBL number in control group and in DBS group (P = 0.137 and no correlations were found with clinical variables (P > 0.05. The PBL number in non-DBS group was less than that in DBS group (P = 0.006. With the same H-Y stage, PBL number in non-DBS group was also less than that in DBS group in Mann-Whitney U test (H-Y 2.5: Z = - 2.197, P = 0.043; H-Y 3: Z = - 1.875, P = 0.027; H-Y 4: Z = - 3.760, P = 0.016. Conclusion The changing in the number of PBL is the specific feature of PD and may be correlated with the immuno-inflammation of central nervous system, which may be relieved by DBS.

  5. Effect of glatiramer acetate on peripheral blood brain-derived neurotrophic factor and phosphorylated TrkB levels in relapsing-remitting multiple sclerosis.

    Science.gov (United States)

    Vacaras, Vitalie; Major, Zsigmond Z; Muresanu, Dafin F; Krausz, Tibor L; Marginean, Ioan; Buzoianu, Dana A

    2014-01-01

    Glatiramer acetate (GA) is one of the most widely used disease-modifying drugs for the treatment of relapsing-remitting multiple sclerosis; is assumed to have inductor effects on neurotrophic factor expression. One of these neurotrophic factor systems is the brain-derived neurotrophic factor (BDNF)/receptor tyrosine kinase B (TrkB) pathway. Peripheral blood is thought to contain soluble BDNF, and some blood cells express TrkB. We attempted to determine whether GA treatment leads to changes in plasma BDNF levels and TrkB activation. Such a phenomenon are relapsing-remitting multiple sclerosis patients is significantly reduced; GA treatment is not influencing peripheral BDNF levels, after one year of sustained therapy, not from the point of view of total free BDNF nor the phosphorylated TrkB.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-05-01

    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 ..mu..g/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 ..mu..g/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.

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

    Science.gov (United States)

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

    2010-03-01

    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 40-42 year old participants in Norwegian health surveys (year 1985-1989) linked to a prescription database (year 2004-2006), was used to describe risk of long-term use of benzodiazepines among disability pension recipients. The study population constituted benzodiazepine users at baseline. More than half of those on disability pensions, 57% of all men and 65% of all women, retrieved benzodiazepine prescriptions 20 years later, a span covering a large part of the potential active workforce period. Further, the observed amount of benzodiazepines dispensed over a three-year period indicated more than sporadic use e.g. half of the female disability pensioners were dispensed an amount of benzodiazepines corresponding to the use of a daily dose every second day over a three year period (median 450 daily doses). The majority of those who were dispensed benzodiazepines, were dispensed opioids as well: half of all men and 3 out of four women. And last, being on a disability pension was a predictor of benzodiazepine use 20 years later. Our study suggests that benzodiazepines are extensively and unfavourably used among disability pensioners, and that disability pension may have an independent effect on long-term use. Improved management of benzodiazepine use may be one alternative to get disability pensioners with the potential to work back into employment.

  8. 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.

  9. GABA systems, benzodiazepines, and substance dependence.

    Science.gov (United States)

    Malcolm, Robert J

    2003-01-01

    Alterations in the gamma-aminobutyric acid (GABA) receptor complex and GABA neurotransmission influence the reinforcing and intoxicating effects of alcohol and benzodiazepines. Chronic modulation of the GABA(A)-benzodiazepine receptor complex plays a major role in central nervous system dysregulation during alcohol abstinence. Withdrawal symptoms stem in part from a decreased GABAergic inhibitory function and an increase in glutamatergic excitatory function. GABA(A) receptors play a role in both reward and withdrawal phenomena from alcohol and sedative-hypnotics. Although less well understood, GABA(B) receptor complexes appear to play a role in inhibition of motivation and diminish relapse potential to reinforcing drugs. Evidence suggests that long-term alcohol use and concomitant serial withdrawals permanently alter GABAergic function, down-regulate benzodiazepine binding sites, and in preclinical models lead to cell death. Benzodiazepines have substantial drawbacks in the treatment of substance use-related disorders that include interactions with alcohol, rebound effects, alcohol priming, and the risk of supplanting alcohol dependency with addiction to both alcohol and benzodiazepines. Polysubstance-dependent individuals frequently self-medicate with benzodiazepines. Selective GABA agents with novel mechanisms of action have anxiolytic, anticonvulsant, and reward inhibition profiles that have potential in treating substance use and withdrawal and enhancing relapse prevention with less liability than benzodiazepines. The GABA(B) receptor agonist baclofen has promise in relapse prevention in a number of substance dependence disorders. The GABA(A) and GABA(B) pump reuptake inhibitor tiagabine has potential for managing alcohol and sedative-hypnotic withdrawal and also possibly a role in relapse prevention.

  10. Chronic use of benzodiazepines among older adults.

    Science.gov (United States)

    Alvarenga, Jussara Mendonça; Giacomin, Karla Cristina; Loyola Filho, Antônio Ignácio de; Uchoa, Elizabeth; Firmo, Josélia Oliveira Araújo

    2014-12-01

    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.

  11. Inhibition of Peripheral TNF-α and Downregulation of Microglial Activation by Alpha-Lipoic Acid and Etanercept Protect Rat Brain Against Ischemic Stroke.

    Science.gov (United States)

    Wu, Ming-Hsiu; Huang, Chao-Ching; Chio, Chung-Ching; Tsai, Kuen-Jer; Chang, Ching-Ping; Lin, Nan-Kai; Lin, Mao-Tsun

    2016-09-01

    Ischemic stroke, caused by obstruction of blood flow to the brain, would initiate microglia activation which contributes to neuronal damage. Therefore, inhibition of microglia-mediated neuroinflammation could be a therapeutic strategy for ischemic stroke. This study was aimed to elucidate the anti-inflammatory effects of alpha-lipoic acid and etanercept given either singly or in combination in rats subjected to middle cerebral artery occlusion. Both α-lipoic acid and etanercept markedly reduced cerebral infarct, blood-brain barrier disruption, and neurological motor deficits with the former drug being more effective with the dosage used. Furthermore, when used in combination, the reduction was more substantial. Remarkably, a greater diminution in the serum levels of tumor necrosis factor-alpha as well as the brain levels of microglial activation (e.g., microgliosis, amoeboid microglia, and microglial overexpression of tumor necrosis factor-α) was observed with the combined drug treatment as compared to the drugs given separately. We conclude that inhibition of peripheral tumor necrosis factor-alpha as well as downregulation of brain microglial activation by alpha-lipoic acid or etanercept protect rat brain against ischemic stroke. Moreover, when both drugs were used in combination, the stroke recovery was promoted more extensively.

  12. Increased expression of mitochondrial benzodiazepine receptors following low-level light treatment facilitates enhanced protoporphyrin IX production in glioma-derived cells in vitro

    Science.gov (United States)

    Bisland, S. K.; Hassanali, N. S.; Johnson, C.; Wilson, B. C.

    2007-02-01

    This study investigates whether low level light treatment (LLLT) can enhance the expression of Peripheral-type mitochondrial benzodiazepine receptors (PBRs) on the glioma-derived tumour cell line, CNS-1, and by doing so promote the synthesis of protoporphyrin IX (PpIX) and increase the photodynamic therapy (PDT)-induced cell kill using 5-aminolevulinic acid (ALA). The endogenous photosensitizer, (PpIX) and related metabolites including coproporphyrin III are known to traffic via the PBRs on the outer mitochondrial membrane on their passage into or out of the mitochondria. Astrocyte-derived cells within the brain express PBRs, while neurons express the central-type of benzodiazepine receptor. CNS-1 cells were exposed to a range of differing low-level light protocols immediately prior to PDT. LLLT involved using broad-spectrum light or monochromatic laser light specific to 635 or 905 nm wavelength. Cells (5μ10 5) were exposed to a range of LLLT doses (0, 1 or 5 J/cm2) using a fixed intensity of 10 mW/cm2 and subsequently harvested for cell viability, immunofluorescence or western blot analysis of PBR expression. The amount of PpIX within the cells was determined using chemical extraction techniques. Results confirm the induction of PBR following LLLT is dependent on the dose and wavelength of light used. Broadspectrum light provided the greatest cell kill following PDT, although LLLT with 635 nm or 905 nm also increased cell kill as compared to PDT alone. All LLLT regimens increased PBR expression compared to controls with corresponding increases in PpIX production. These data suggest that by selectively increasing PBR expression in tumour cells, LLLT may facilitate enhanced cell kill using ALA-PDT without damaging surrounding normal brain.

  13. Is there a way to curb benzodiazepine addiction?

    Science.gov (United States)

    Lalive, Arnaud L; Rudolph, Uwe; Lüscher, Christian; Tan, Kelly R

    2011-10-19

    Benzodiazepines are widely prescribed drugs used to treat anxiety and insomnia, induce muscle relaxation, control epileptic seizures, promote anaesthesia or produce amnesia. Benzodiazepines are also abused for recreational purposes and the number of benzodiazepine abusers is unfortunately increasing. Within weeks of chronic use, tolerance to the pharmacological effects can develop and withdrawal becomes apparent once the drug is no longer available, which are both conditions indicative of benzodiazepine dependence. Diagnosis of addiction (i.e. compulsive use despite negative consequences) may follow in vulnerable individuals. Here, we review the historical and current use of benzodiazepines from their original synthesis, discovery and commercialisation to the recent identification of the molecular mechanism by which benzodiazepines induce addiction. These results have identified the mechanisms underlying the activation of midbrain dopamine neurons by benzodiazepines, and how these drugs can hijack the mesocorticolimbic reward system. Such knowledge calls for future developments of new receptor subtype specific benzodiazepines with a reduced addiction liability.

  14. 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...

  15. Neural bases for addictive properties of benzodiazepines.

    Science.gov (United States)

    Tan, Kelly R; Brown, Matthew; Labouèbe, Gwenaël; Yvon, Cédric; Creton, Cyril; Fritschy, Jean-Marc; Rudolph, Uwe; Lüscher, Christian

    2010-02-11

    Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behaviour. The neural basis for the addictive nature of benzodiazepines, however, remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA(A) (gamma-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on alpha1-containing GABA(A) receptors expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell-type-specific expression of alpha1-containing GABA(A) receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing alpha1 may be devoid of addiction liability.

  16. Distribution of radiolabeled L-glutamate and D-aspartate from blood into peripheral tissues in naive rats: Significance for brain neuroprotection

    Energy Technology Data Exchange (ETDEWEB)

    Klin, Yael [Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100 (Israel); Zlotnik, Alexander; Boyko, Matthew; Ohayon, Sharon; Shapira, Yoram [The Division of Anesthesiology, Soroka Medical Center and Ben Gurion University of the Negev, Beer-Sheva (Israel); Teichberg, Vivian I., E-mail: Vivian.teichberg@weizmann.ac.il [Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100 (Israel)

    2010-09-03

    Research highlights: {yields} Blood glutamate has a half-life time of 2-3 min. {yields} Blood glutamate is submitted to rapid decarboxylation. {yields} Blood glutamate and its metabolites are mainly absorbed in skeletal muscle and liver. {yields} The skeletal muscle and liver are now targets for potential drugs affording brain neuroprotection. -- Abstract: Excess L-glutamate (glutamate) levels in brain interstitial and cerebrospinal fluids (ISF and CSF, respectively) are the hallmark of several neurodegenerative conditions such as stroke, traumatic brain injury or amyotrophic lateral sclerosis. Its removal could prevent the glutamate excitotoxicity that causes long-lasting neurological deficits. As in previous studies, we have established the role of blood glutamate levels in brain neuroprotection, we have now investigated the contribution of the peripheral organs to the homeostasis of glutamate in blood. We have administered naive rats with intravenous injections of either L-[1-{sup 14}C] Glutamic acid (L-[1-{sup 14}C] Glu), L-[G-{sup 3}H] Glutamic acid (L-[G-{sup 3}H] Glu) or D-[2,3-{sup 3}H] Aspartic acid (D-[2,3-{sup 3}H] Asp), a non-metabolized analog of glutamate, and have followed their distribution into peripheral organs. We have observed that the decay of the radioactivity associated with L-[1-{sup 14}C] Glu and L-[G-{sup 3}H] Glu was faster than that associated with glutamate non-metabolized analog, D-[2,3-{sup 3}H] Asp. L-[1-{sup 14}C] Glu was subjected in blood to a rapid decarboxylation with the loss of {sup 14}CO{sub 2}. The three major sequestrating organs, serving as depots for the eliminated glutamate and/or its metabolites were skeletal muscle, liver and gut, contributing together 92% or 87% of total L-[U-{sup 14}C] Glu or D-[2,3-{sup 3}H] Asp radioactivity capture. L-[U-{sup 14}C] Glu and D-[2,3-{sup 3}H] Asp showed a different organ sequestration pattern. We conclude that glutamate is rapidly eliminated from the blood into peripheral tissues

  17. Views of general practitioners and benzodiazepine users on benzodiazepines: a qualitative analysis.

    Science.gov (United States)

    Parr, Jannette M; Kavanagh, David J; Young, Ross McD; McCafferty, Kelly

    2006-03-01

    Effectively assisting benzodiazepine users to cease use requires a greater understanding of general practitioners' (GPs) and benzodiazepine users' views on using and ceasing benzodiazepines. This paper reports the findings from a qualitative study that examined the views of 28 GPs and 23 benzodiazepine users (BUs) in Cairns, Australia. A semi-structured interview was conducted with all participants and the information gained was analysed using the Consensual Qualitative Research Approach, which allowed comparisons to be made between the views of the two groups of interviewees. There was commonality between GPs and BUs on reasons for commencing benzodiazepines, the role of dependence in continued use, and the importance of lifestyle change in its cessation. However, several differences emerged regarding commencement of use and processes of cessation. In particular, users felt there was greater need for GPs to routinely advise patients about non-pharmacological management of their problems and potential adverse consequences of long-term use before commencing benzodiazepines. Cessation could be discussed with all patients who use benzodiazepines for longer than 3 months, strategies offered to assist in management of withdrawal and anxiety, and referral to other health service providers for additional support. Lifestyle change could receive greater focus at all stages of treatment.

  18. Influence of benzodiazepines on antiparkinsonian drug treatment in levodopa users

    NARCIS (Netherlands)

    van de Vijver, D A M C; Roos, R A C; Jansen, P A F; Porsius, A J; de Boer, A

    2002-01-01

    OBJECTIVES: Animal studies showed that benzodiazepines decrease the concentration of dopamine in the striatum. Benzodiazepines may therefore affect the treatment of Parkinson's disease. This study determined whether start of a benzodiazepine in patients on levodopa was followed by a faster increase

  19. 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.

  20. Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain

    Directory of Open Access Journals (Sweden)

    Schmitt Charlotte

    2012-08-01

    Full Text Available Abstract Background Cerebrospinal fluid (CSF has been considered as a preferential pathway of circulation for immune cells during neuroimmune surveillance. In order to evaluate the involvement of CSF-filled spaces in the pathogenesis of experimental autoimmune encephalomyelitis (EAE, a model of multiple sclerosis, we performed a time-course analysis of immune cell association with the CSF-containing ventricles, velae, and cisterns in two active models of this disease. Methods Guinea-pig spinal cord homogenate-induced EAE in rat and myelin oligodendrocyte glycoprotein-induced EAE in mouse were used. Leukocyte distribution and phenotypes were investigated by immunohistochemistry in serial sections of brain areas of interest, as well as in CSF withdrawn from rat. Immune cells associated with the choroid plexuses were quantified. Results Freund’s adjuvant-induced peripheral inflammation in the absence of brain antigen led to a subtle but definite increase in the number of myeloid cells in the extraventricular CSF spaces. In both rats and mice, EAE was characterized by a sustained and initial infiltration of lymphocytes and monocytes within forebrain/midbrain fluid-filled compartments such as the velum interpositum and ambient cisterns, and certain basal cisterns. Leukocytes further infiltrated periventricular and pericisternal parenchymal areas, along perivascular spaces or following a downward CSF-to-tissue gradient. Cells quantified in CSF sampled from rats included lymphocytes and neutrophils. The distinctive pattern of cell distribution suggests that both the choroid plexus and the vessels lying in the velae and cisterns are gates for early leukocyte entry in the central nervous system. B-cell infiltration observed in the mouse model was restricted to CSF-filled extraventricular compartments. Conclusion These results identified distinctive velae and cisterns of the forebrain and midbrain as preferential sites of immune cell homing following

  1. Predictors of benzodiazepine discontinuation in subjects manifesting complicated dependence.

    Science.gov (United States)

    Vorma, Helena; Naukkarinen, Hannu H; Sarna, Seppo J; Kuoppasalmi, Kimmo I

    2005-01-01

    We described characteristics of subjects with benzodiazepine dependence that was typically complicated by harmful and hazardous alcohol use or high benzodiazepine doses, and assessed predictors of successful discontinuation of benzodiazepines for this group. Seventy-six patients who participated in a randomized clinical trial of two different gradual withdrawal treatment approaches were assessed. The trial was conducted between February 1995 and July 1999. The mean age +/- SD of subjects was 40.0 +/- 9.6 years, 55% were male, 38% were married or cohabiting, and 70% had received more than nine years of education. The median benzodiazepine dose was 35 mg/day (range 2.5-180) in diazepam equivalents. The median duration of benzodiazepine use was 84 (range 8-360) months. Subjects with lower benzodiazepine doses and no previous withdrawal attempts were more successful at benzodiazepine discontinuation. Cluster B personality/borderline personality disorder was associated with an inability to stop benzodiazepine use and with "dropping out" of treatment. Alcohol use-related disorders or other psychiatric diagnoses were not associated with outcome. Further studies on predictors of successful benzodiazepine discontinuation in different populations are required. Patients manifesting cluster B personality/borderline personality disorder and benzodiazepine dependence may need concomitant treatment for their personality disorders to benefit from benzodiazepine discontinuation treatment.

  2. Benzodiazepines, benzodiazepine-like drugs, and typical antipsychotics impair manual dexterity in patients with schizophrenia.

    Science.gov (United States)

    Sasayama, Daimei; Hori, Hiroaki; Teraishi, Toshiya; Hattori, Kotaro; Ota, Miho; Matsuo, Junko; Kinoshita, Yukiko; Okazaki, Mitsutoshi; Arima, Kunimasa; Amano, Naoji; Higuchi, Teruhiko; Kunugi, Hiroshi

    2014-02-01

    Impaired dexterity is a major psychomotor deficit reported in patients with schizophrenia. In the present study, the Purdue pegboard test was used to compare the manual dexterity in patients with schizophrenia and healthy controls. We also examined the influence of antipsychotics, benzodiazepines, and benzodiazepine-like drugs on manual dexterity. Subjects were 93 patients with schizophrenia and 93 healthy controls, matched for sex and age distributions. Control subjects scored significantly higher on all scores of Purdue pegboard than patients with schizophrenia. Age, PANSS negative symptom scale, typical antipsychotic dose, and use of benzodiazepines and/or benzodiazepine-like drugs were negatively correlated with the pegboard scores in patients with schizophrenia. The present results indicate that patients with schizophrenia have impaired gross and fine fingertip dexterity compared to healthy controls. The use of typical antipsychotics and benzodiazepines and/or benzodiazepine-like drugs, but not atypical antipsychotics, had significant negative impact on dexterity in patients with schizophrenia. Psychiatrists should be aware that some psychotropic medications may enhance the disability caused by the impairment of dexterity in patients with schizophrenia.

  3. Benzodiazepine pathways in the chronically ill

    NARCIS (Netherlands)

    Van Hulten, Rolf; Heerdink, Eibert R.; Bakker, Albert; Leufkens, Hubert G.

    1999-01-01

    The association between patterns of use of benzodiazepines and chronic somatic morbidity was examined by applying the Chronic Disease Score (CDS). In the only pharmacy in a Dutch community, 6921 patients with data available covering a 10-year period (1983-1992) were included. In 1992, two-thirds of

  4. [Benzodiazepines in the treatment of epilepsy].

    Science.gov (United States)

    Nakken, Karl O; Rytter, Elisif M; Brockmeier, Frans

    2010-04-22

    In epilepsy benzodiazepines are mainly used to stop ongoing attacks. In hospitals intravenous diazepam is the drug of choice for status epilepticus. Outside of hospitals buccal midazolam is in the process of replacing rectal diazepam. Clonazepam, clobazam and nitrazepam (to children) are partially used as additional medication to prevent seizures.

  5. Catatonia in mixed alcohol and benzodiazepine withdrawal

    Directory of Open Access Journals (Sweden)

    Aniruddha Basu

    2014-01-01

    Full Text Available Catatonia is mostly caused by different neuropsychiatric conditions. We report a case of a 30 year old man suffering from both alcohol and benzodiazepine dependence who exhibited catatonic features soon after stopping the intake of substances. This case will help clinicians to recognize catatonic features within the varied symptomatology of substance withdrawal and thereby helping in its early diagnosis and management.

  6. Defining benzodiazepine dependence: The confusion persists

    NARCIS (Netherlands)

    Linsen, S.M.; Zitman, F.G.; Breteler, M.H.M.

    1995-01-01

    Little consensus exists on the risk of benzodiazepine (BZD) dependence. We investigated how often BZD dependence and related concepts have been defined in the literature on BZD effects in humans. In addition, the definitions of BZD dependence were compared in order to assess the similarity of conten

  7. Benzodiazepine use in Denmark 1997-2008

    DEFF Research Database (Denmark)

    Holm, E.; Pedersen, H.; Fosbol, E.

    2012-01-01

    Purpose: Analysis of the pattern of benzodiazepine (BZD) use over time in the period 1997-2008 in relation to age and comorbidity. Methods: All Danish citizens more than or equal to 10 years on January 1, 1997 were included in the study based on data from national databases. Main outcome measures...

  8. 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…

  9. PET in neuroscience. Dopaminergic, CABA/benzodiazepine, and opiate system; PET in den Neurowisssenschaften: dopaminerges, GABA/Benzodiazepin- und Opiatsystem

    Energy Technology Data Exchange (ETDEWEB)

    Bartenstein, P. [Mainz Univ. (Germany). Klinik und Poliklinik fuer Nuklearmedizin

    2004-02-01

    This article gives an overview on radiotracer imaging with positron emission tomography (PET) in measuring various aspects of neurotransmission. The review focusses on the dopaminergic system, the GABA/benzodiazepine system, and the opiate system. Besides dealing with the current clinical applications for brain PET studies with specific radiopharmaceuticals this article outlines an idea on potential future developments for the use of these methods in basic neuroscience. (orig.) [German] Diese Arbeit praesentiert eine Uebersicht zur aktuellen Forschung und klinischen Anwendung von PET-Untersuchungen mit Radiopharmaka, die verschiedene Komponenten der Neurotransmission erfassen. Ausserdem werden Perspektiven und Trend der Methodik gezeigt. Im Mittelpunkt stehen das dopaminerge System, das GABA/Benzodiazepinsystem, und das Opiatsystem. Ausfuehrlich dargestellt werden aktuelle klinische und kliniknahe Moeglichkeiten sowie methodische Aspekte der grundlagenorientierten Forschung, die fuer eine zukunftsorientierte Anwendung von PET-Studien mit Rezeptorliganden u.a. Radiopharmaka zur Bildgebung komplexer biochemischer Prozesse von Bedeutung sind. (orig.)

  10. Protracted treatment with diazepam increases the turnover of putative endogenous ligands for the benzodiazepine/. beta. -carboline recognition site

    Energy Technology Data Exchange (ETDEWEB)

    Miyata, M.; Mocchetti, I.; Ferrarese, C.; Guidotti, A.; Costa, E.

    1987-03-01

    DBI (diazepam-binding inhibitor) is a putative neuromodulatory peptide isolated from rat brain that acts on ..gamma..-aminobutyric acid-benzodiazepine-Cl/sup -/ ionosphore receptor complex inducing ..beta..-carboline-like effects. The authors used a cDNA probe complementary to DBI mRNA and a specific antibody for rat DBI to study in rat brain how the dynamic state of DBI can be affected after protected (three times a day for 10 days) treatment with diazepam and chlordiazepoxide by oral gavage. Both the content of DBI and DBI mRNA increased in the cerebellum and cerebral cortex but failed to change in the hippocampus and striatum of rats receiving this protracted benzodiazepine treatment. Acute treatment with diazepam did not affect the dynamic state of brain DBI. An antibody was raised against a biologically active octadecaneuropeptide derived from the tryptic digestion of DBI. The combined HPLC/RIA analysis of rat cerebellar extracts carried out with this antibody showed that multiple molecular forms of the octadecaneuropeptide-like reactivity are present and all of them are increased in rats receiving repeated daily injections of diazepam. It is inferred that tolerance to benzodiazepines in associated with an increase in the turnover rate of DBI, which may be responsible for the ..gamma..-aminobutyric acid receptor desensitization that occurs after protracted benzodiazepine administration.

  11. Ruta 6 selectively induces cell death in brain cancer cells but proliferation in normal peripheral blood lymphocytes: A novel treatment for human brain cancer.

    Science.gov (United States)

    Pathak, Sen; Multani, Asha S; Banerji, Pratip; Banerji, Prasanta

    2003-10-01

    Although conventional chemotherapies are used to treat patients with malignancies, damage to normal cells is problematic. Blood-forming bone marrow cells are the most adversely affected. It is therefore necessary to find alternative agents that can kill cancer cells but have minimal effects on normal cells. We investigated the brain cancer cell-killing activity of a homeopathic medicine, Ruta, isolated from a plant, Ruta graveolens. We treated human brain cancer and HL-60 leukemia cells, normal B-lymphoid cells, and murine melanoma cells in vitro with different concentrations of Ruta in combination with Ca3(PO4)2. Fifteen patients diagnosed with intracranial tumors were treated with Ruta 6 and Ca3(PO4)2. Of these 15 patients, 6 of the 7 glioma patients showed complete regression of tumors. Normal human blood lymphocytes, B-lymphoid cells, and brain cancer cells treated with Ruta in vitro were examined for telomere dynamics, mitotic catastrophe, and apoptosis to understand the possible mechanism of cell-killing, using conventional and molecular cytogenetic techniques. Both in vivo and in vitro results showed induction of survival-signaling pathways in normal lymphocytes and induction of death-signaling pathways in brain cancer cells. Cancer cell death was initiated by telomere erosion and completed through mitotic catastrophe events. We propose that Ruta in combination with Ca3(PO4)2 could be used for effective treatment of brain cancers, particularly glioma.

  12. PRO-2-PAM: The First Therapeutic Drug for Reactivation of Organo-Phosphate-Inhibited Central (Brain) and Peripheral Cholinesterases

    Science.gov (United States)

    2008-12-01

    the H&E and fluoro-jade stained slides, respectively. The middle lobe of the piriform cortex, a distinct brain region known to be sensitive to OP...U /m g Figure 8. H & E stain of guinea pig brain, 40x magnification of the piriform cortical neuron layer (“A”; see Methods section 2.5). (a...receiving DFP followed by the oxime 2-PAM. Black arrow points to piriform neurons. (a) ControlPiriform cortical neuron layer (b) DFP (c) DFP, then pro-2

  13. DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients

    Science.gov (United States)

    Lázaro-Ibáñez, Elisa; Peris-Celda, María; Alonso, Marta M.; Guzmán-De-Villoria, Juan; Fernández-Carballal, Carlos; de Mendivil, Ana Ortiz; García-Duque, Sara; Escobedo-Lucea, Carmen; Prat-Acín, Ricardo; Belda-Iniesta, Cristóbal; Ayuso-Sacido, Angel

    2017-01-01

    Tumor-cell-secreted extracellular vesicles (EVs) can cross the disrupted blood-brain barrier (BBB) into the bloodstream. However, in certain gliomas, the BBB remains intact, which might limit EVs release. To evaluate the ability of tumor-derived EVs to cross the BBB, we used an orthotopic xenotransplant mouse model of human glioma-cancer stem cells featuring an intact BBB. We demonstrated that all types of tumor cells-derived EVs−apoptotic bodies, shedding microvesicles and exosomes−cross the intact BBB and can be detected in the peripheral blood, which provides a minimally invasive method for their detection compared to liquid biopsies obtained from cerebrospinal fluid (CSF). Furthermore, these EVs can be readily distinguished from total murine EVs, since they carry human-specific DNA sequences relevant for GBM biology. In a small cohort of glioma patients, we finally demonstrated that peripheral blood EVs cargo can be successfully used to detect the presence of IDH1G395A, an essential biomarker in the current management of human glioma PMID:27902458

  14. Anticonvulsive Activity in Audiogenic DBA/2 Mice of 1,4-Benzodiazepines and 1,5-Benzodiazepines with Different Activities at Cerebellar Granule Cell GABAA Receptors.

    Science.gov (United States)

    Gatta, Elena; Cupello, Aroldo; Di Braccio, Mario; Grossi, Giancarlo; Robello, Mauro; Scicchitano, Francesca; Russo, Emilio; De Sarro, Giovambattista

    2016-12-01

    Herein, we tested in a model of generalized reflex epilepsy in mice different 1,4-benzodiazepines and 1,5-benzodiazepines with agonistic activity at the GABAA receptor population contributing to the peak component of the chloride current elicited by GABA in cerebellar granule cells (CGCs) in culture. The substances have all higher lipophilia than clobazam, an antiepileptic drug well known and used in human therapy. This ensures that they all can pass relatively easily the blood-brain barrier (BBB). The benzodiazepines were administered intraperitoneally (i.p.) and tested for their activity against sound-induced tonic and clonic seizures in a genetic model of experimental epilepsy, the DBA/2 mouse. Our data demonstrates an interesting inverse correlation between the ED50s and the efficacy (E %) of the drugs in increasing the peak chloride current elicited by GABA in cerebellar granule cells in culture. There is indication of the existence of a threshold of E % above which the increase of ED50 with increasing E % becomes linear. This is statistically significant for the clonic phase, whereas it is at the limit of significance for the tonic one. A possible interpretation of these results is that in this epilepsy model, projections from the cerebellum exert a convulsion prevention activity.

  15. Defining benzodiazepine dependence: The confusion persists

    OpenAIRE

    1995-01-01

    Little consensus exists on the risk of benzodiazepine (BZD) dependence. We investigated how often BZD dependence and related concepts have been defined in the literature on BZD effects in humans. In addition, the definitions of BZD dependence were compared in order to assess the similarity of contents. From a total of 250 papers (published between 1988 and 1991) 51 provided 126 dependence-related definitions. Six studies referred to the DSM definitions and one to the WHO definition. The obsol...

  16. Influence of benzodiazepines on antiparkinsonian drug treatment in levodopa users

    OpenAIRE

    2002-01-01

    OBJECTIVES: Animal studies showed that benzodiazepines decrease the concentration of dopamine in the striatum. Benzodiazepines may therefore affect the treatment of Parkinson's disease. This study determined whether start of a benzodiazepine in patients on levodopa was followed by a faster increase of antiparkinsonian drug treatment. METHODS: Data came from the PHARMO database, which includes information on drug dispensing for all residents of six Dutch cities. Selected were all patients aged...

  17. Benzodiazepine use among the elderly in the community.

    Science.gov (United States)

    Kirby, M; Denihan, A; Bruce, I; Radic, A; Coakley, D; Lawlor, B A

    1999-04-01

    Benzodiazepines are the most commonly prescribed psychotropic drug in the elderly. Benzodiazepines with a long duration of action can produce marked sedation and psychomotor impairment in older people, and are associated with an increased risk of hip fracture and of motor vehicle crash. One thousand seven hundred and one individuals of 65 years and over, identified from General Practitioner lists, were interviewed using the Geriatric Mental State-AGECAT package and current psychotropic drug use was recorded. Benzodiazepines were classified as having a short or long elimination half-life. Two hundred and ninety-five (17.3%) individuals were taking a benzodiazepine, with use in females being twice that in males. Of the 295, 152 (51.5%) were taking a long acting benzodiazepine and the use of long acting anxiolytic type benzodiazepines was particularly common. Fifty-two (17.6%) benzodiazepine users were taking one or more other psychotropic drugs. A benzodiazepine was used by eight of 18 (44.4%) subjects with an anxiety disorder, 62 of 180 (34.4%) individuals with depression, and seven of 71 (9.9%) people with dementia. Four-fifths of older people on a psychotropic drug were taking a benzodiazepine, highlighting the importance of this class of drug in the elderly population. The choice of a benzodiazepine with a long duration of action, which have been shown to be associated with serious adverse events in the elderly in over one half of benzodiazepine users, is of concern. The potential for adverse effects was further accentuated by polypharmacy practices. The choice of benzodiazepine for an older person has important consequences and should be addressed in greater detail with primary care.

  18. Benzodiazepines do not potentiate GABA responses in neonatal hippocampal neurons.

    Science.gov (United States)

    Rovira, C; Ben-Ari, Y

    1991-09-16

    Benzodiazepines (midazolam; flunitrazepam) and pentobarbital increase the response to exogenous gamma-aminobutyric acid (GABA) in adult hippocampal cells. We report in this paper that in contrast pentobarbital but not benzodiazepine potentiate the effects of exogenous (GABA) in neurons recorded from slices of less than two weeks old. This finding suggests that the functional association of benzodiazepine and GABAA receptors is changed during early postnatal life.

  19. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics.

    Science.gov (United States)

    Riss, J; Cloyd, J; Gates, J; Collins, S

    2008-08-01

    Benzodiazepines (BZDs) remain important agents in the management of epilepsy. They are drugs of first choice for status epilepticus and seizures associated with post-anoxic insult and are also frequently used in the treatment of febrile, acute repetitive and alcohol withdrawal seizures. Clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity. Benzodiazepines are used in a variety of clinical situations because they have a broad spectrum of clinical activity and can be administered via several routes. Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions. Benzodiazepines differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used. Among the approximately 35 BZDs available, a select few are used for the management of seizures and epilepsy: clobazam, clonazepam, clorazepate, diazepam, lorazepam and midazolam. Among these BZDs, clorazepate has a unique profile that includes a long half-life of its active metabolite and slow onset of tolerance. Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained-release formulation) could theoretically help minimize adverse events. However, larger, controlled studies of clorazepate are needed to further examine its role in the treatment of patients with epilepsy.

  20. Benzodiazepine dependence and its treatment with low dose flumazenil.

    Science.gov (United States)

    Hood, Sean David; Norman, Amanda; Hince, Dana Adelle; Melichar, Jan Krzysztof; Hulse, Gary Kenneth

    2014-02-01

    Globally benzodiazepines remain one of the most prescribed medication groups, especially in the primary care setting. With such high levels of prescribing it is not surprising that benzodiazepine dependence is common, cutting across all socioeconomic levels. Despite recognition of the potential for the development of iatrogenic dependence and the lack of any effective treatment, benzodiazepines continue to be widely prescribed in general practice. Conventional dependence management, benzodiazepine tapering, is commonly a protracted process over several weeks or months. It is often associated with significant withdrawal symptoms and craving leading to patient drop out and return to use. Accordingly, there is a worldwide need to find effective pharmacotherapeutic interventions for benzodiazepine dependence. One drug of increasing interest is the GABAA benzodiazepine receptor antagonist/partial agonist, flumazenil. Multiple bolus intravenous infusions of low dose flumazenil used either with or without benzodiazepine tapering can reduce withdrawal sequelae, and/or longer term symptoms in the months following withdrawal. Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for 4 days significantly reduces acute benzodiazepine withdrawal sequelae. The subcutaneous infusion was shown to be tissue compatible so the development of a longer acting (i.e. several weeks) depot flumazenil formulation has been explored. This could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae. Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future.

  1. Benzodiazepines and adequacy of initial antidepressant treatment for depression.

    Science.gov (United States)

    Pfeiffer, Paul N; Ganoczy, Dara; Zivin, Kara; Valenstein, Marcia

    2011-06-01

    In short-term efficacy studies, coprescription of a benzodiazepine improves first-month adherence and response to antidepressant treatment. We used Veterans Health Administration data to examine the impact of coprescribed benzodiazepines on initial antidepressant adherence in routine clinical practice and the risks of long-term benzodiazepine use, abuse, and dependence. Our study population was 43,915 Veterans Health Administration patients diagnosed with depression and started on an antidepressant between October 2006 and September 2007. Using logistic regression, adjusting for demographic and clinical covariates, we predicted the likelihood that patients received antidepressant treatment for an adequate duration (90 days), with our primary independent variable of interest being receipt of a benzodiazepine on the same day as the start of the antidepressant. We also assessed the frequency and characteristics of patients whose benzodiazepine use persisted for 1 year or who were diagnosed with anxiolytic abuse or dependence after receiving combined treatment. The adjusted probability of receiving antidepressant treatment of adequate duration was 42.4% for patients who received a benzodiazepine with their initial antidepressant compared with 39.3% for patients initially treated with an antidepressant alone (P benzodiazepines for at least 1 year, and 0.7% were diagnosed with anxiolytic abuse or dependence. Anxiolytic abuse or dependence, but not long-term benzodiazepine use, was associated with other substance use disorders. These findings should be considered by clinicians when assessing the individual risks and benefits of combining a benzodiazepine with antidepressant treatment.

  2. Mice chronically infected with chimeric HIV resist peripheral and brain superinfection: a model of protective immunity to HIV.

    Science.gov (United States)

    Kelschenbach, Jennifer L; Saini, Manisha; Hadas, Eran; Gu, Chao-Jiang; Chao, Wei; Bentsman, Galina; Hong, Jessie P; Hanke, Tomas; Sharer, Leroy R; Potash, Mary Jane; Volsky, David J

    2012-06-01

    Infection by some viruses induces immunity to reinfection, providing a means to identify protective epitopes. To investigate resistance to reinfection in an animal model of HIV disease and its control, we employed infection of mice with chimeric HIV, EcoHIV. When immunocompetent mice were infected by intraperitoneal (IP) injection of EcoHIV, they resisted subsequent secondary infection by IP injection, consistent with a systemic antiviral immune response. To investigate the potential role of these responses in restricting neurotropic HIV infection, we established a protocol for efficient EcoHIV expression in the brain following intracranial (IC) inoculation of virus. When mice were inoculated by IP injection and secondarily by IC injection, they also controlled EcoHIV replication in the brain. To investigate their role in EcoHIV antiviral responses, CD8+ T lymphocytes were isolated from spleens of EcoHIV infected and uninfected mice and adoptively transferred to isogenic recipients. Recipients of EcoHIV primed CD8+ cells resisted subsequent EcoHIV infection compared to recipients of cells from uninfected donors. CD8+ spleen cells from EcoHIV-infected mice also mounted modest but significant interferon-γ responses to two HIV Gag peptide pools. These findings suggest EcoHIV-infected mice may serve as a useful system to investigate the induction of anti-HIV protective immunity for eventual translation to human beings.

  3. Scalability, reliability and validity of the benzodiazepine dependence self report questionnaire in outpatient benzodiazepine users

    NARCIS (Netherlands)

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

    1999-01-01

    As there is no multidimensional instrument available which reflects the severity of BZD dependence comprehensively, the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ) was developed and investigated. The Bendep-SRQ, Symptom Checlist-90, Schedules for Clinical Assessments in Neuropsy

  4. Abnormal benzodiazepine and zinc modulation of GABAA receptors in an acquired absence epilepsy model.

    Science.gov (United States)

    Wu, Jie; Ellsworth, Kevin; Ellsworth, Marc; Schroeder, Katherine M; Smith, Kris; Fisher, Robert S

    2004-07-01

    Brain cholesterol synthesis inhibition (CSI) at a young age in rats has been shown to be a faithful model of acquired absence epilepsy, a devastating condition for which few therapies or models exist. We employed the CSI model to study cellular mechanisms of acquired absence epilepsy in Long-Evans Hooded rats. Patch-clamp, whole-cell recordings were compared from neurons acutely dissociated from the nucleus reticularis of thalamus (nRt) treated and untreated with a cholesterol synthesis inhibitor, U18666A. In U18666A-treated animals, 91% of rats developed EEG spike-waves (SWs). Patchclamp results revealed that although there was no remarkable change in GABAA receptor affinity, both a loss of ability of benzodiazepines to enhance GABAA-receptor responses and an increase of Zn2+ inhibition of GABAA-receptor responses of nRt neurons occurred in Long-Evans Hooded rats previously administered U18666A. This change was specific, since no significant changes were found in neurons exposed to the GABA allosteric modulator, pentobarbital. Taken collectively, these findings provide evidence for abnormalities in benzodiazepine and Zn2+ modulation of GABAA receptors in the CSI model, and suggest that decreased gamma2 subunit expression may underlie important aspects of generation of thalamocortical SWs in atypical absence seizures. The present results are also consistent with recent findings that mutation of the gamma2 subunit of the GABAA receptor changes benzodiazepine modulation in families with generalized epilepsy syndromes.

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

    Energy Technology Data Exchange (ETDEWEB)

    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 /sup 3/H-GABA binding sites is greater in SS cerebellar tissue and /sup 3/H-flunitrazepam binding is greater in the mid-brain region of LS mice. GABA enhancement of /sup 3/H-flunitrazepma binding is greater in SS mice. Ethanol also enhances /sup 3/H-flunitrazepam binding and increases the levels of /sup 3/H-flunitrazepam binding above those observed for GABA. Using correlational techniques on data from LS and SS mice and several inbred mouse strains, it was demonstrated that a positive relationship exists between the degree of receptor coupling within the GABA receptor complex and the degree of resistance to seizures.

  6. Aging and a peripheral immune challenge interact to reduce mature brain-derived neurotrophic factor and activation of TrkB, PLCgamma1, and ERK in hippocampal synaptoneurosomes.

    Science.gov (United States)

    Cortese, Giuseppe P; Barrientos, Ruth M; Maier, Steven F; Patterson, Susan L

    2011-03-16

    For reasons that are not well understood, aging significantly increases brain vulnerability to challenging life events. High-functioning older individuals often experience significant cognitive decline after an inflammatory event such as surgery, infection, or injury. We have modeled this phenomenon in rodents and have previously reported that a peripheral immune challenge (intraperitoneal injection of live Escherichia coli) selectively disrupts consolidation of hippocampus-dependent memory in aged (24-month-old), but not young (3-month-old), F344xBN rats. More recently, we have demonstrated that this infection-evoked memory deficit is mirrored by a selective deficit in long-lasting synaptic plasticity in the hippocampus. Interestingly, these deficits occur in forms of long-term memory and synaptic plasticity known to be strongly dependent on brain-derived neurotrophic factor (BDNF). Here, we begin to test the hypothesis that the combination of aging and an infection might disrupt production or processing of BDNF protein in the hippocampus, decreasing the availability of BDNF for plasticity-related processes at synaptic sites. We find that mature BDNF is markedly reduced in Western blots of hippocampal synaptoneurosomes prepared from aged animals following infection. This reduction is blocked by intra-cisterna magna administration of the anti-inflammatory cytokine IL-1Ra (interleukin 1-specific receptor antagonist). Levels of the pan-neurotrophin receptor p75(NTR) and the BDNF receptor TrkB (tropomyosin receptor kinase B) are not significantly altered in these synaptoneurosomes, but phosphorylation of TrkB and downstream activation of PLCγ1 (phospholipase Cγ1) and ERK (extracellular response kinase) are attenuated-observations consistent with reduced availability of mature BDNF to activate TrkB signaling. These data suggest that inflammation-evoked reductions in BDNF at synapses might contribute to inflammation-evoked disruptions in long-term memory and synaptic

  7. In Vivo Reactivation by Oximes of Inhibited Blood, Brain and Peripheral Tissue Cholinesterase Activity Following Exposure to Nerve Agents in Guinea Pigs

    Science.gov (United States)

    2010-01-01

    peripheral tissues and the blood components . A “+” sign was assigned for each of the peripheral tissues or blood com- ponents, when an oxime treatment...reactivation by oxime treatments in peripheral tissues and blood components following exposure to GB, GF, VR, and VXa. A. Peripheral tissues (diaphragm...tissues (A) or blood components (B), an oxime treatm ign. When an oxime treatment did not significantly reactivate a nerve agent-inhib ll four nerve

  8. Using Tutte polynomials to analyze the structure of the benzodiazepines

    Science.gov (United States)

    Cadavid Muñoz, Juan José

    2014-05-01

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

  9. Expression of GLUT4 mRNA of peripheral tissues and insulin resistance in rats with severe traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    CHEN Da-qing; ZHU Lie-lie; LI Yong-ling

    2007-01-01

    Objective: To evaluate the expression of glucose transporter-4 (GLUT4) mRNA in skeletal muscle and subcutaneous adipose tissues and investigate the mechanism of posttraumatic insulin resistance.Methods: Sixteen adult male Wistar rats were randomly divided into 2 group (n=8 in each group), i.e., severe traumatic brain injury (TBI) group due to falls from a height and normal control group. Blood glucose and serum insulin were measured at 0.5 h before trauma and 3 h, 24 h, 72 h, 7 d after trauma, respectively. And insulin sensitivity was calculated by insulin activity index (IAI) formula. Skeletal muscle and subcutaneous adipose tissue samples were collected at the same time when blood was sampled. The changes of expression of GLUT4 mRNA were observed using reverse transcription-polymerase chain reaction (RT-PCR).Results: Accompanied by the decrease of insulin sensitivity, the expression of GLUT4 mRNA was significantly decreased in adipose tissues at 24 h and 72 h after trauma (P<0.01), however, such phenomena did not appear in skeletal muscle samples.Conclusions: To some extent, the development of posttraumatic insulin resistance is related to the abnormality of transcription activity of GLUT4 gene. Adipose tissues show some difference in the transcriptional level of GLUT4 gene after trauma as compared with skeletal muscle tissues.

  10. [Leo Sternbach, an inventor of benzodiazepines].

    Science.gov (United States)

    Uchibayashi, Masao

    2007-01-01

    A biography of Leo Sternbach, an inventor of benzodiazepine tranquillizers, is presented. It consists of (1) a societal desire for lifestyle pills, (2) Leo's birth in 1908 and youth, (3) education, (4) in Vienna, (5) in Zurich, (6) at Hoffmann-La Roche, Basel, (7) to the New World, (8) at Roche, Nutley NJ, (9) invention of the new drugs, (10) revolution of people's lifestyle, and (11) reward, retirement and obituary in 2005. This paper may be the first comprehensive biography of this remarkable chemist written in Japanese.

  11. 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...

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

    NARCIS (Netherlands)

    Janssen, MJ; Hulst, R; Kellogg, RM; Hendriks, MMWB; Ensing, K; De Zeeuw, RA

    2000-01-01

    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 cou

  13. Withdrawing Benzodiazepines in Patients With Anxiety Disorders.

    Science.gov (United States)

    Lader, Malcolm; Kyriacou, Andri

    2016-01-01

    The large class of CNS-depressant medications-the benzodiazepines-have been extensively used for over 50 years, anxiety disorders being one of the main indications. A substantial proportion (perhaps up to 20-30 %) of long-term users becomes physically dependent on them. Problems with their use became manifest, and dependence, withdrawal difficulties and abuse were documented by the 1980s. Many such users experience physical and psychological withdrawal symptoms on attempted cessation and may develop clinically troublesome syndromes even during slow tapering. Few studies have been conducted to establish the optimal withdrawal schedules. The usual management comprises slow withdrawal over weeks or months together with psychotherapy of various modalities. Pharmacological aids include antidepressants such as the SSRIs especially if depressive symptoms supervene. Other pharmacological agents such as the benzodiazepine antagonist, flumazenil, and the hormonal agent, melatonin, remain largely experimental. The purpose of this review is to analyse the evidence for the efficacy of the usual withdrawal regimes and the newer agents. It is concluded that little evidence exists outside the usual principles of drug withdrawal but there are some promising leads.

  14. Benzodiazepine stability in postmortem samples stored at different temperatures.

    Science.gov (United States)

    Melo, Paula; Bastos, M Lourdes; Teixeira, Helena M

    2012-01-01

    Benzodiazepine (lorazepam, estazolam, chlordiazepoxide, and ketazolam) stability was studied in postmortem blood, bile, and vitreous humor stored at different temperatures over six months. The influence of NaF, in blood and bile samples, was also investigated. A solid-phase extraction technique was used on all the studied samples, and benzodiazepine quantification was performed by high-performance liquid chromatography-diode-array detection. Benzodiazepine concentration remained almost stable in all samples stored at -20°C and -80°C. Estazolam appeared to be a stable benzodiazepine during the six-month study, and ketazolam proved to be the most unstable benzodiazepine. A 100% loss of ketazolam occurred in all samples stored over 1 or 2 weeks at room temperature and over 8 or 12 weeks at 4°C, with the simultaneous detection of diazepam. Chlordiazepoxide suffered complete degradation in all samples, except preserved bile samples, stored at room temperature. Samples stored at 4°C for 6 months had a 29-100% decrease in chlordiazepoxide concentration. The data obtained suggest that results from samples with these benzodiazepines stored long-term should be cautiously interpreted. Bile and vitreous humor proved to be the most advantageous samples in cases where degradation of benzodiazepines by microorganisms may occur.

  15. Reduction of aggression during benzodiazepine withdrawal: effects of flumazenil.

    Science.gov (United States)

    Saxon, L; Borg, S; Hiltunen, A J

    2010-08-01

    Benzodiazepine withdrawal has been associated with hostile and aggressive behavior. The benzodiazepine antagonist flumazenil has reduced, increased or not affected hostility and aggression in animal and human studies. In the present study we analyzed data collected in a placebo-controlled study of the effects of the benzodiazepine antagonist flumazenil in patients previously treated for benzodiazepine dependency, and healthy controls. The aim was to analyze the effects of flumazenil on hostility and aggression. Ten patients and 10 controls received, on two separate occasions, cumulative doses of flumazenil (0.05, 0.1, 0.25, 0.5 and 1mg at 15min intervals) or placebo. Withdrawal symptoms were rated after each injection. Patients had been free from benzodiazepines for 47 (4-266) weeks on the first occasion. A three-way interaction (groupxtreatmentxdose) was found, and was explained by: 1) patients rating aggression and hostility higher than controls at all times during placebo, while 2) during the flumazenil provocation i) the initial significant difference between patients and controls was no longer significant above the 0.5mg dose, and ii) patients rated aggression and hostility significantly lower above the 0.5mg dose compared to base-line. The results suggest that self-rated aggression and hostility in patients treated for benzodiazepine dependency was reduced by the partial benzodiazepine agonist flumazenil.

  16. Opioid and benzodiazepine withdrawal symptoms in paediatric intensive care patients.

    Science.gov (United States)

    Franck, Linda S; Naughton, Ita; Winter, Ira

    2004-12-01

    The purposes of this prospective repeated measures study were to: (a) describe the occurrence of withdrawal symptoms with the use of a standardised protocol to slowly taper opioids and benzodiazepines; and (b) to test the predictive validity of an opioid and benzodiazepine withdrawal assessment scoring tool in critically ill infants and young children after prolonged opioid and benzodiazepine therapy. Fifteen children (6 weeks-28 months of age) with complex congenital heart disease and/or respiratory failure who received opioids and benzodiazepines for 4 days or greater were evaluated for withdrawal symptoms using a standardized assessment tool. Thirteen children showed moderate to severe withdrawal symptoms a median 3 days after commencement of tapering. Symptom intensity was not related to prior opioid or benzodiazepine exposure, extracorporeal membrane oxygenation (ECMO) therapy or length of tapering. Children who received fentanyl in addition to morphine more often exhibited signs of withdrawal. This study demonstrated that significant withdrawal symptoms occur in critically ill children even with the use of a standardised assessment tool and tapering management protocol. The predictive validity and utility of the Opioid and Benzodiazepine Withdrawal Score (OBWS) was adequate for clinical use, but areas for further improvement of the tool were identified. Problems with the clinical withdrawal prevention and management guidelines were also identified. More research is needed to establish the optimal methods for prevention and management of iatrogenic opioid and benzodiazepine withdrawal in paediatric critical care.

  17. 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.

  18. 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.

  19. Transfer in vitro of three benzodiazepines across the human placenta.

    Science.gov (United States)

    Guerre-Millo, M; Rey, E; Challier, J C; Turquais, J M; d'Athis, P; Olive, G

    1979-04-17

    A comparative study of the placental transfer to the foetus of three benzodiazepines was performed using a dual perfusion system of the human placental lobule. A transport fraction was calculated for each benzodiazepine and was compared with reference substances. Relative to antipyrine, the transport fraction of diazepam was 85%, and that of nordiazepam was 84%. The transport fraction of clorazepate represented only 20% of that of tritiated water. The relatively high transfer of diazepam and nordiazepam can be attributed to their high lipid solubility, and the lower transfer of clorazepate is due to its polar nature. It is suggested that in certain instances this benzodiazepine may be of especial value to obstetricians.

  20. Benzodiazepines misuse: The study community level Thailand

    Directory of Open Access Journals (Sweden)

    Puangkot Sukdepat

    2010-01-01

    Full Text Available Context: Benzodiazepines (BZD misuse, abuse, and dependence are becoming a new problem in medicine, in Thailand, and the pharmacoepidemiology knowledge is insufficient. The aim of this study is to estimate the prevalence of benzodiazepine use, misuse, abuse, and dependence in the general population of the Ubon Rachathani province, in Thailand. Aims: To estimate the prevalence of benzodiazepine use, misuse, abuse, and dependence in the general population. Settings and Design: The cross-sectional household survey research was conducted from October 2008 to June 2009, with a target population age of 15 years and above. This took place in Ubon Ratchathani Province, in Thailand. Materials and Methods: A total sample size of 2280 were selected from three-stage stratified random sampling. BZD were identified with an accuracy of generic name, trade name, and drug characteristics. The DSM-IV questionnaire was used to define misuse, abuse, and dependence. The accuracy of dependence was interpreted with the help of the judgment of a psychiatric nurse. Statistical analysis: For the statistical analyses, prevalence was estimated with weight adjustment, variances estimated by the Teylor Series Linearization method, and interpreted with 95% confidence interval (CI. Results: There were 46,805 current users [3.9% (95% CI: 2.2-6.4], 26,404 misusers [2.2% (95% CI: 1.6-6.2], 7,203 abusers [0.6% (95% CI: 0.1 - 4.1], and 2,402 with dependence [0.2% (0.1-9.2]. When considering the group of current users in this study, 57.2% misusers, 16.6% abusers, and 5.9% with dependence were found, respectively. Conclusions: All prevalence of use was higher than previously reported, in Thailand, while more than half of the current users had a behavior of misuse. Surveillance of misuse should be undertaken in the current use. The medical professional should counsel the patient on the harm of misuse and limit the amount of medicine, with necessary dispensing.

  1. [Dependence on benzodiazepines. Clinical and biological aspects].

    Science.gov (United States)

    Pelissolo, A; Bisserbe, J C

    1994-01-01

    The high rate of benzodiazepines (BZD) consumption has been repeatedly confirmed by epidemiological surveys in most major western world countries. In a recent french survey 7% of chronic users of BZD (use in 5/7 days for the last 12 months) were found the general population (17% in the population aged above 65). It has been suggested that the high BZD consumption rate could be related to dependence. The existence of BZD dependence was described in the early sixties with very high dose of chlordiazepoxide but it has become a real concern for the medical community since the late seventies with increasing number of reports of withdrawal symptoms. The extend of the actual rate of withdrawal symptoms at BZD tapering is still very controversial and according to the different studies it varies from 39 to 90%. The between studies difference in parameters such as: the patient populations (psychopathology, treatment duration), the type of tapering employed (duration, nature of the medical and psychological support) and the used operational criteria for withdrawal definition most likely explain this wide variation in the rate of occurrence of withdrawal manifestations. According to the American Psychiatric Association Task Force on Benzodiazepine Dependence, Toxicity and Abuse three type of pathological events can happen after treatment discontinuation: rebound, withdrawal syndrome and recurrence. The rebound consists in the early and transitory reappearance of the anxiety symptoms pre-existing to the treatment but in an exacerbated from; the withdrawal syndrome associates the resurgence of the pre-existing anxiety symptoms and new symptoms as sensory disturbances (metallic taste, hyperosmia, cutaneous exacerbated sensitivity, photophobia...) nausea, headache, motor disturbance in some rare cases depersonalization, paranoid reaction, confusion, convulsion. Rebound or withdrawal syndrome appearance delay varies from hours to few days according mostly to compounds elimination

  2. Specific binding of benzodiazepines to human breast cancer cell lines.

    Science.gov (United States)

    Beinlich, A; Strohmeier, R; Kaufmann, M; Kuhl, H

    1999-01-01

    Binding of [3H]Ro5-4864, a peripheral benzodiazepine receptor (PBR) agonist, to BT-20 human, estrogen- (ER) and progesterone- (PR) receptor negative breast cancer cells was characterized. It was found to be specific, dose-dependent and saturable with a single population of binding sites. Dissociation constant (K(D)) was 8.5 nM, maximal binding capacity (Bmax) 339 fM/10(6) cells. Ro5-4864 (IC50 17.3 nM) and PK 11195 (IC50 12.3 nM) were able to compete with [3H]Ro5-4864 for binding, indicating specificity of interaction with PBR. Diazepam was able to displace [3H]Ro5-4864 from binding only at high concentrations (>1 microM), while ODN did not compete for PBR binding. Thymidine-uptake assay showed a biphasic response of cell proliferation. While low concentrations (100 nM) of Ro5-4864, PK 11195 and diazepam increased cell growth by 10 to 20%, higher concentrations (10-100 microM) significantly inhibited cell proliferation. PK 11195, a potent PBR ligand, was able to attenuate growth of BT-20 cells stimulated by 100 nM Ro5-4864 and to reverse growth reduction caused by 1 and 10 microM Ro5-4864, but not by 50 microM and 100 microM. This indicates that the antimitotic activity of higher concentrations of Ro5-4864 is independent of PBR binding. It is suggested, that PBR are involved in growth regulation of certain human breast cancer cell lines, possibly by supplying proliferating cells with energy, as their endogenous ligand is a polypeptide transporting Acyl-CoA.

  3. Terahertz spectroscopic study of benzodiazepine sedative hypnotics

    Science.gov (United States)

    Deng, Fusheng; Shen, Jingling; Wang, Xianfeng

    2011-08-01

    Terahertz time domain spectroscopy (THz-TDS) is used to the pure active ingredient of three benzodiazepine sedative hypnotics with similar molecular structure. The absorption spectra of them are studied in the range of 0.2~2.6THz. Based on the experiment, the theoretical simulation results of diazepam, nitrazepam and clonazepam are got by the Gaussian03 package of DFT/B3LYP/6-31G* method in single-molecule models. The experimental results show that even if the molecular structure and medicine property of them are similar, the accurate identification of them can still be done with their characteristic absorption spectra. Theoretical simulation results are well consistent with the experimental results. It demonstrates that absorption peaks of them in THz range mainly come from intra-molecular forces and are less affected by the intermolecular interaction and crystal effects.ô

  4. Eight principles for safer opioid prescribing and cautions with benzodiazepines.

    Science.gov (United States)

    Webster, Lynn R; Reisfield, Gary M; Dasgupta, Nabarun

    2015-01-01

    The provision of long-term opioid analgesic therapy for chronic pain requires a careful risk/benefit analysis followed by clinical safety measures to identify and reduce misuse, abuse, and addiction and their associated morbidity and mortality. Multiple data sources show that benzodiazepines, prescribed for comorbid insomnia, anxiety, and mood disorders, heighten the risk of respiratory depression and other adverse outcomes when combined with opioid therapy. Evidence is presented for hazards associated with coadministration of opioids and benzodiazepines and the need for caution when initiating opioid therapy for chronic pain. Clinical recommendations follow, as drawn from 2 previously published literature reviews, one of which proffers 8 principles for safer opioid prescribing; the other review presents risks associated with benzodiazepines, suggests alternatives for co-prescribing benzodiazepines and opioids, and outlines recommendations regarding co-prescribing if alternative therapies are ineffective.

  5. Benzodiazepine absetzen im Alter. Wann und, wenn ja, wie?

    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...... disorder treated? 2. To what extent do the patient and other key persons consider discontinuation to be reasonable and will they support discontinuation? 3. Is the target complete withdrawal, a dose reduction or shift to another benzodiazepine drug which is more suitable in old age for pharmacokinetic...... reasons? This article provides assistance in answering these questions and some guidelines for the practical management of discontinuation. It is mandatory 1) to periodically address the problem of long-term benzodiazepine use when counseling the patient and key persons and 2) to be aware that several...

  6. [Should we continue to use benzodiazepines in clinical practice?].

    Science.gov (United States)

    Sampogna, Gaia; Del Vecchio, Valeria; Luciano, Mario; De Rosa, Corrado; Albert, Umberto; Dell'Osso, Bernardo; Fiorillo, Andrea

    2015-06-01

    The discovery of benzodiazepines has represented a milestone in the history of pharmacological treatments and in relation to the management of anxiety, sleep and other psychiatric disorders. After several decades, these agents still represent one of the largest and most widely prescribed groups of medications, not only in the psychiatric clinical practice, but also in the whole medical field. Over the last decade, however, multiple concerns have been raised on the risks related to the prescription of benzodiazepines, for their addictive potential and for cognitive side-effects. Therefore, benzodiazepines are today considered as a double-edge sword, which should be carefully handled and preferentially prescribed by specialists (or at least under their supervision), after an adequate training. Unfortunately, this is not the case in many situations, and the need to improve training on benzodiazepines management has been recently emphasized.

  7. Comparison of urine and oral fluid as matrices for screening of thirty-three benzodiazepines and benzodiazepine-like substances using immunoassay and LC–MS(–MS).

    NARCIS (Netherlands)

    Smink, B.E. Mathijssen, M.P.M. Lusthof, K.J. Gier, J.J. de Egberts, A.C.G. & Uges, D.R.A.

    2006-01-01

    Benzodiazepines are the most frequently detected medicinal drugs in drivers. The use of benzodiazepines is associated with an increased road accident risk. In this study, the presence of benzodiazepines detected by liquid chromatography–(tandem) mass spectrometry [LC–MS(–MS)] in oral fluid and urine

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

    Energy Technology Data Exchange (ETDEWEB)

    Churchill, L.; Pazdernik, T.L.; Cross, R.S.; Nelson, S.R.; Samson, F.E. (Univ. of Kansas Medical Center, Kansas City (USA))

    (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.

  9. The proapoptotic benzodiazepine Bz-423 affects the growth and survival of malignant B cells.

    Science.gov (United States)

    Boitano, Anthony; Ellman, Jonathan A; Glick, Gary D; Opipari, Anthony W

    2003-10-15

    Bz-423 is a novel proapoptotic 1,4-benzodiazepine that induces cell death via a superoxide signal. Previous work has shown that Bz-423 ameliorates disease in animal models of systemic lupus erythematosus that also have features of lymphoproliferative disease. Here we describe the effects of Bz-423 against a group of malignant B-cell lines derived from Burkitt's lymphoma. These experiments demonstrate that Bz-423 has cytotoxic activity against all B-cell lines tested, regardless of EBV status or Bcl-2 and Bcl-x(L) expression levels. In addition to its cytotoxic properties, we found that Bz-423 is also a potent antiproliferative agent that induces a G(1)-phase arrest independent of p53. Mechanistically, both the cytotoxicity and growth arrest are mediated by increased reactive oxygen species levels and appear independent of binding to the peripheral benzodiazepine receptor. This work further defines the biological activities of Bz-423 that are consistent with those of other compounds in clinical development for antineoplastic therapies.

  10. 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.

  11. Effects of exposure to benzodiazepine during fetal life.

    Science.gov (United States)

    Bergman, U; Rosa, F W; Baum, C; Wiholm, B E; Faich, G A

    1992-09-19

    Dysmorphism and mental retardation have been reported in 7 Swedish children born of mothers who had taken high doses of benzodiazepines regularly during pregnancy. To explore this association further, we examined benzodiazepine use during pregnancy in 104,000 women whose deliveries were registered by the US public health insurance system, Medicaid, during 1980-83. Fetal outcomes were assessed from the health claims profiles of their offspring, up to 6-9 years after delivery. 80 pregnant women had received 10 or more benzodiazepine prescriptions during the 4 years. Their records showed heavy general use of health care and frequent alcohol and substance abuse, and other disorders that could confound any effect of the benzodiazepines. For the 80 pregnancies, 3 intrauterine deaths were identified as well as 2 infants with congenital abnormalities whose curtailed records suggested neonatal death. Records of 64 surviving children could be linked to these 80 pregnancies whilst records for 11 apparent survivors could not be located. 6 of the 64 survivors had diagnoses consistent with teratogenic abnormalities. The high rate of teratogenicity after heavy maternal benzodiazepine use occurs with multiple alcohol and substance exposure and thus may not be due to benzodiazepine exposure.

  12. 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.

  13. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee.

    Science.gov (United States)

    Rossini, P M; Burke, D; Chen, R; Cohen, L G; Daskalakis, Z; Di Iorio, R; Di Lazzaro, V; Ferreri, F; Fitzgerald, P B; George, M S; Hallett, M; Lefaucheur, J P; Langguth, B; Matsumoto, H; Miniussi, C; Nitsche, M A; Pascual-Leone, A; Paulus, W; Rossi, S; Rothwell, J C; Siebner, H R; Ugawa, Y; Walsh, V; Ziemann, U

    2015-06-01

    These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments.

  14. Peripheral Neuropathy

    Science.gov (United States)

    ... can be associated with peripheral neuropathy. Metabolic and endocrine disorders impair the body’s ability to transform nutrients into ... to neuropathies as a result of chemical imbalances. Endocrine disorders that lead to hormonal imbalances can disturb normal ...

  15. Do benzodiazepines mimic reverse-turn structures?

    Science.gov (United States)

    Hata, Masayuki; Marshall, Garland R.

    2006-05-01

    The role of benzodiazepine derivatives (BZD) as a privileged scaffold that mimics β-turn structures (Ripka et al. (1993) Tetrahedron 49:3593-3608) in peptide/protein recognition was reexamined in detail. Stable BZD ring conformers were determined with MM3, and experimental reverse-turn structures were extracted from the basis set of protein crystal structures previously defined by Ripka et al. Ideal β-turns were also modeled and similarly compared with BZD conformers. Huge numbers of conformers were generated by systematically scanning the torsional degrees of freedom for BZDs, as well as those of ideal β-turns for comparison. Using these structures, conformers of BZDs were fit to experimental structures as suggested by Ripka et al., or modeled classical β-turn conformers, and the root-mean-square deviation (RMSD) values were calculated for each pairwise comparison. Pairs of conformers with the smallest RMSD values for overlap of the four α-β side-chain orientations were selected. All overlaps of BZD conformers with experimental β-turns yielded one or more comparisons where the least RMSD was significantly small, 0.48-0.86 Å, as previously suggested. Utilizing a different methodology, the overall conclusion that benzodiazepines could serve as reverse-turn mimetics of Ripka et al. is justified. The least RMSD values for the overlap of BZDs and modeled classical β-turns were also less than 1 Å. When comparing BZDs with experimental or classical β-turns, the set of experimental β-turns selected by Ripka et al. fit the BZD scaffolds better than modeled classical β-turns; however, all the experimental β-turns did not fit a particular BZD scaffold better. A single BZD ring conformation, and/or chiral orientation, can mimic some, but not all, of the experimental β-turn structures. BZD has two central ring conformations and one chiral center that explains why the four variations of the BZD scaffold can mimic all types of β-turn structure examined. It was

  16. High-affinity benzodiazepine receptor ligands among benzodiazepines and betacarbolines with different intrinsic activity

    Energy Technology Data Exchange (ETDEWEB)

    Yliniemelae, A.; Gynther, J. (Univ. of Kuopio (Finland)); Konschin, H.; Tylli, H. (Univ. of Helsinki (Finland)); Rouvinen, J. (Univ. of Joensuu (Finland))

    1989-01-01

    Structural and electrostatic features of diazepam, flumazenil, and methyl betacarboline-3-carboxylate (BCCM) have been investigated using the molecular superimposition method. These high-affinity benzodiazepine (BZ) receptor ligands are structurally unrelated and they have different intrinsic activity. These ligands are superimposed in such a way that common structural and electrostatic features essential for the high receptor binding affinity overlap. In addition to this binding pharmacophore, there are roughly three separate binding zones in the BZ receptor, one for each class of ligands. The intrinsic activity of BZ receptor ligands depends on the molecular structures and the way the ligand approaches the receptor.

  17. Are febrile seizures an indication for intermittent benzodiazepine treatment, and if so, in which cases?

    Science.gov (United States)

    Camfield, Peter; Camfield, Carol

    2014-10-09

    Febrile seizures occur in ∼4% of children. After a first febrile seizure, the risk of recurrence is ∼40%, but excellent studies document that febrile seizures do not cause brain damage or deficits in cognition or behaviour. The risk of subsequent epilepsy is 2-4%. Prolonged febrile seizures are of concern because a child may later develop mesial temporal sclerosis and intractable epilepsy in rare cases. Most prolonged febrile seizures represent the first febrile seizure and cannot be anticipated. A first prolonged febrile seizure does not increase the risk of recurrence, but if there is a recurrence, it is more likely to be prolonged. Prevention of recurrent febrile seizures is difficult. Antipyretics are ineffective. Daily AED treatment is not often justified. Intermittent oral diazepam at the time of illness is not very successful and has significant side effects. The most optimistic study found that the number of subjects required to treat in order to prevent one recurrence was 14. Intermittent clobazam has fewer side effects than diazepam and may be somewhat effective. Rescue benzodiazepines given outside health care facilities may be effective in selected patients to prevent prolonged recurrences, although this has not been proven with rectal diazepam which has been more extensively studied than buccal or nasal midazolam. Currently, we suggest that, for children with febrile seizures, candidates for consideration for rescue benzodiazepines are those with a prolonged febrile seizure or poor access to medical care. It is possible that the use of a rescue benzodiazepine may alleviate severe parental anxiety, but this remains to be established.

  18. Allosteric modulation by benzodiazepine receptor ligands of the GABAA receptor channel expressed in Xenopus oocytes.

    Science.gov (United States)

    Sigel, E; Baur, R

    1988-01-01

    Chick brain mRNA was isolated and injected into Xenopus oocytes. This led to the expression in the surface membrane of functional GABA-activated channels with properties reminiscent of vertebrate GABAA channels. The GABA-induced current was analyzed quantitatively under voltage-clamp conditions. Picrotoxin inhibited this current in a concentration-dependent manner with IC50 = 0.6 microM. The allosteric modulation of GABA currents by a number of drugs acting at the benzodiazepine binding site was characterized quantitatively. In the presence of the benzodiazepine receptor ligands diazepam and clorazepate, GABA responses were enhanced, and in the presence of the convulsant beta-carboline compound methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), they were depressed. Maximal stimulation of the response elicited by 10 microM GABA was 160% with diazepam and 90% with clorazepate, and maximal inhibition was 42% with DMCM, 30% with methyl beta-carboline-3-carboxylate (beta-CCM), 15% with ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a][1,4]benzodiazepine-3-carboxylate (Ro 15-1788), and 12% with ethyl beta-carboline-3-carboxylate (beta-CCE). Half-maximal stimulation was observed with 20 nM diazepam and 390 nM clorazepate, respectively, and half-maximal inhibition with 6 nM DMCM. beta-CCM had a similar effect to DMCM, whereas beta-CCE and Ro 15-1788 showed only small inhibition at low concentrations (less than 1 microM). All the tested carboline compounds and Ro 15-1788 showed a biphasic action and stimulated GABA current at concentrations higher than 1 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Benzodiazepine harm: how can it be reduced?

    Science.gov (United States)

    Lader, Malcolm

    2014-02-01

    The benzodiazepines (BZDs) are anxiolytics, hypnotics, anticonvulsants, muscle-relaxants and induce anaesthesia. Adverse effects comprise sedation subjectively and cognitive and psychomotor impairment objectively. Complex skills such as driving can be compromised. Paradoxical excitement can have forensic implications. Long term use beyond the licensed durations is common but both efficacy and adverse effects associated with this have been poorly documented. Withdrawal and dependence have excited particular concern, and even polemic. Perhaps a third of long term (beyond 6  months) users experience symptoms and signs on attempting to withdraw - anxiety, insomnia, muscle spasms and tension and perceptual hypersensitivity. Uncommonly, fits or a psychosis may supervene. The patterns following withdrawal vary widely. The usual method of withdrawal is slow tapering but it may not obviate the problems completely. BZDs are also drugs of abuse either on their own or in conjunction with opioids and stimulants. Claims have been made that the use of BZDs is associated with increased mortality. This is a concern in view of the widespread usage of these drugs, particularly in the elderly. All of these factors impinge on the risk : benefit ratio and the severity of the indications. Harm reduction should focus on choice of alternative treatments both psychological and pharmacological. Guidelines emphasise that BZDs are not drugs of first choice and should only be used short term. Schedules are available to educate about methods of withdrawal in current users, emphasising the slow rate of taper. General principles of harm minimization in the addiction field are appropriate to BZD abuse.

  20. Is benzodiazepine use during pregnancy really teratogenic?

    Science.gov (United States)

    Ornoy, A; Arnon, J; Shechtman, S; Moerman, L; Lukashova, I

    1998-01-01

    Benzodiazepines (BDs) have a widespread use among people suffering from anxiety. These drugs easily cross the placenta and may affect the developing embryo and fetus. The literature is divided as to whether BD may cause an increase in spontaneous abortions or congenital anomalies. From the years 1988 to 1996, 756 women called the Israeli TIS concerning exposures to BD prior to or during pregnancy. Of 599 women who called us during pregnancy, we have follow-up information on 460 pregnancies (76.6%). The incidence of congenital anomalies (3.1%) was not different from that found in 424 control pregnancies (2.6%). There was a significantly higher incidence of induced abortions (14.1% vs. 4.7%, P = 0.00) and of spontaneous abortions (8.7% vs. 5.2%, P = 0.01). From an examination of our results, it does not appear that BD during pregnancy caused an increase in the incidence of birth defects. There was no specific defect in the offspring. The increase in the rate of induced abortions is probably related to the counseling of the callers, and the increase in spontaneous abortions seems to be a result of the lower gestational age at the time of counseling in the women exposed to BD. It is unknown whether BD could be responsible for developmental or behavioral problems, which are observed only at a later stage.

  1. [Knowledge regarding Proper Use Guidelines for Benzodiazepines].

    Science.gov (United States)

    Inada, Ken

    2016-01-01

      Benzodiazepines (BZs) work by agonising gamma-aminobutyric acid (GABA)-BZ-receptor complex and thereby produce sedation and anti-anxiety effects. BZs are commonly used in several clinical areas as hypnotics or anti-anxiety drugs. However, these drugs once supplied by medical institutions often lead to abuse and dependence. Thus it is important for institutions to supply and manage BZs properly. At Tokyo Women's Medical University Hospital educational activities about proper use of BZs are performed by not only medical doctors but also pharmacists. We coordinate distribution of leaflets and run an educational workshop. As a result of these activities, the number of patients receiving BZ prescriptions was reduced. Performing these activities, pharmacists were required to work for patients, doctors, and nurses; they acquired knowledge about BZs such as action mechanisms, efficacy, adverse effects, problems about co-prescription, and methods of discontinuing BZs, as well as information on coping techniques other than medication. The most important point to attend the patients is to answer their anxieties.

  2. A fluorescent receptor assay for benzodiazepines using coumarin labeled desethylflumazenil as ligand

    NARCIS (Netherlands)

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

    2001-01-01

    This article describes a novel nonisotopic receptor assay for benzodiazepines with fluorescence detection, As labeled ljgand (coumarin-labeled desethylflumazenil, CLDEF), a metabolite of the benzodiazepine antagonist flumazenil (desetheylflumazenil, Ro15-3890) has been coupled to a coumarin fluoroph

  3. Flumazenil-sensitive dose-related physical dependence in planarians produced by two benzodiazepine and one non-benzodiazepine benzodiazepine-receptor agonists.

    Science.gov (United States)

    Raffa, Robert B; Cavallo, Federica; Capasso, Anna

    2007-06-14

    Two benzodiazepine (midazolam and clorazepate) and one non-benzodiazepine (zolpidem) benzodiazepine-receptor agonists produced dose-related physical dependence, as evidenced by abstinence-induced decrease in planarian locomotor velocity (pLMV) when drug-exposed planarians were placed into drug-free water, but not when they were placed into drug-containing water (i.e., an abstinence-induced withdrawal, since the effect was only obtained in the removal of drug and not in the continued presence of drug). We have previously shown that the decrease in pLMV is associated with specific and transient withdrawal signs. In the present study, the selective benzodiazepine-receptor antagonist flumazenil significantly antagonized (Pbenzodiazepine-receptor agonists, for two different chemical categories, produce dose-related physical dependence manifested as abstinence-induced withdrawal in this simple and convenient model, and (2) in the absence of cloning or radioligand binding literature, suggest a possible specific interaction site (receptor?) for these compounds in planarians.

  4. Electrophoretic fingerprinting of benzodiazepine tablets in spike drinks.

    Science.gov (United States)

    Sáiz, Jorge; Ortega-Ojeda, Fernando; López-Melero, Lucía; Montalvo, Gema; García-Ruiz, Carmen

    2014-11-01

    Over the last few years, there has been an increase in the reports of drug-facilitated crimes. The list of drugs associated with these crimes is extensive and benzodiazepines constitute one of the groups of substances more commonly used. The sedative properties, which characterize benzodiazepines, are enhanced when such drugs are combined with alcohol, being more attractive for committing these types of crimes. In this work, a capillary electrophoresis method was applied to the analysis of 63 different samples of club drinks spiked with benzodiazepine tablets. The resulting electropherograms were processed and analyzed with the chemometric multivariate techniques: principal component analysis (PCA) and soft independent modeling of class analogies (SIMCA) classification. The PCA results allowed a clear differentiation of each drug class in a 3D plot. In addition, the SIMCA classification model (5% significance level) showed that eight out of nine test samples were automatically assigned by software to their proper sample class. The conflicting sample was correctly classified in the Coomans' plot (95% confidence). This novel approach based on the comparison of electrophoretic profiles of spiked drinks by chemometric tools allows determining the benzodiazepine used for drink spiking without the use of drug standards. Moreover, it provides an opportunity for the forensic laboratories to incorporate the identification capability provided by the electrophoretic fingerprinting of benzodiazepine solutions in existing or new databases.

  5. High affinity ligands for 'diazepam-insensitive' benzodiazepine receptors.

    Science.gov (United States)

    Wong, G; Skolnick, P

    1992-01-14

    Structurally diverse compounds have been shown to possess high affinities for benzodiazepine receptors in their 'diazepam-sensitive' (DS) conformations. In contrast, only the imidazobenzodiazepinone Ro 15-4513 has been shown to exhibit a high affinity for the 'diazepam-insensitive' (DI) conformation of benzodiazepine receptors. We examined a series of 1,4-diazepines containing one or more annelated ring systems for their affinities at DI and DS benzodiazepine receptors, several 1,4-diazepinone carboxylates including Ro 19-4603, Ro 16-6028 and Ro 15-3505 were found to possess high affinities (Ki approximately 2.6-20 nM) for DI. Nonetheless, among the ligands examined, Ro 15-4513 was the only substance with a DI/DS potency ratio approximately 1; other substances had ratios ranging from 13 to greater than 1000. Ligands with high to moderate affinities at DI were previously classified as partial agonists, antagonists, or partial inverse agonists at DS benzodiazepine receptors, but behaved as 'GABA neutral' (antagonist) substances at DI. The identification of several additional high affinity ligands at DI benzodiazepine receptors may be helpful in elucidating the pharmacological and physiological importance of these sites.

  6. Withdrawal-induced delirium associated with a benzodiazepine switch: a case report

    Directory of Open Access Journals (Sweden)

    Bosshart Herbert

    2011-05-01

    Full Text Available Abstract Introduction Introduced in the early 1960s, diazepam remains among the most frequently prescribed benzodiazepine-type sedatives and hypnotics. Patients with chronic use of short-acting benzodiazepines are frequently switched to diazepam because the accumulating, long-acting metabolite, N-desmethyl-diazepam, prevents benzodiazepine-associated withdrawal symptoms, which can occur during trough plasma levels of short-acting benzodiazepines. Although mild to moderate withdrawal symptoms are frequently observed during benzodiazepine switching to diazepam, severe medical complications associated with this treatment approach have thus far not been reported. Case presentation A 64-year-old female Caucasian with major depression, alcohol dependence and benzodiazepine dependence was successfully treated for depression and, after lorazepam-assisted alcohol detoxification, was switched from lorazepam to diazepam to facilitate benzodiazepine discontinuation. Subsequent to the benzodiazepine switch, our patient unexpectedly developed an acute delirious state, which quickly remitted after re-administration of lorazepam. A newly diagnosed early form of mixed dementia, combining both vascular and Alzheimer-type lesions, was found as a likely contributing factor for the observed vulnerability to benzodiazepine-induced withdrawal symptoms. Conclusion Chronic use of benzodiazepines is common in the elderly and a switch to diazepam often precedes benzodiazepine discontinuation trials. However, contrary to common clinical practice, benzodiazepine switching to diazepam may require cross-titration with slow tapering of the first benzodiazepine to allow for the build-up of N-desmethyl-diazepam, in order to safely prevent severe withdrawal symptoms. Alternatively, long-term treatment with low doses of benzodiazepines may be considered, especially in elderly patients with chronic use of benzodiazepines and proven vulnerability to benzodiazepine

  7. Substance misuse in young people in Ireland - a focus on benzodiazepines

    OpenAIRE

    2014-01-01

    Benzodiazepines are a class of drugs that are prescribed for the treatment of anxiety and insomnia. Due to the powerful tolerance that can develop as a result of sustained use, benzodiazepines can also be dependence-forming. Benzodiazepine dependence can occur from prescribed and from recreational use, and is a significant issue for young people. The consequences of benzodiazepine dependence include cognitive and learning impairment, depressive symptoms, and increased suicide risk. Despite th...

  8. Withdrawal-induced delirium associated with a benzodiazepine switch: a case report

    OpenAIRE

    2011-01-01

    Abstract Introduction Introduced in the early 1960s, diazepam remains among the most frequently prescribed benzodiazepine-type sedatives and hypnotics. Patients with chronic use of short-acting benzodiazepines are frequently switched to diazepam because the accumulating, long-acting metabolite, N-desmethyl-diazepam, prevents benzodiazepine-associated withdrawal symptoms, which can occur during trough plasma levels of short-acting benzodiazepines. Although mild to moderate withdrawal symptoms ...

  9. Benzodiazepines should still be first-line treatment for alcohol withdrawal

    DEFF Research Database (Denmark)

    Askgaard, Gro; Pottegård, Anton; Fink-Jensen, Anders

    2017-01-01

    In this review, we summarize the evidence for benzodiazepines and barbiturates as alcohol withdrawal treatment and outline a treatment guideline. A number of randomized controlled trials (RCTs) indicate that benzodiazepine treatment decreases alcohol withdrawal seizures and is safe....... For barbiturates, only a few RCTs have been undertaken, and barbiturates were not found to be superior to benzodiazepines. Consequently, we suggest that benzodiazepines should still be first-line treatment for alcohol withdrawal....

  10. Is long-term use of benzodiazepine a risk for cancer?

    Science.gov (United States)

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

    2015-02-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  12. Comparison of anticonvulsant tolerance, crosstolerance, and benzodiazepine receptor binding following chronic treatment with diazepam or midazolam.

    Science.gov (United States)

    Ramsey-Williams, V A; Wu, Y; Rosenberg, H C

    1994-07-01

    In a previous study, rats treated chronically with flurazepam were tolerant to the anticonvulsant action of some benzodiazepines (BZs), but not others (34). To determine if this differential crosstolerance was unique to flurazepam, rats were treated chronically with diazepam or midazolam, and tested for tolerance to the anticonvulsant actions of diazepam, midazolam, clonazepam, and clobazam. Regional benzodiazepine receptor binding in brain was also studied. In contrast to previous findings with flurazepam, 1 week treatment with diazepam or with midazolam did not cause tolerance. Rats treated with diazepam for 3 weeks were tolerant to diazepam, clonazepam, clobazam, and midazolam. In contrast, rats treated 3 weeks with midazolam were tolerant to diazepam and midazolam, but not clobazam or clonazepam. Neither diazepam nor midazolam treatment for 3 weeks altered BZ binding in cerebral cortex, cerebellum, or hippocampus. The effects of chronic BZ treatment depended not only on the BZ given chronically, but also on the BZ used to evaluate these effects, suggesting drug-specific interactions of different BZs with their receptors.

  13. Subchronic treatment with antiepileptic drugs modifies pentylenetetrazol-induced seizures in mice: Its correlation with benzodiazepine receptor binding

    Directory of Open Access Journals (Sweden)

    Luisa Rocha

    2008-06-01

    Full Text Available Luisa RochaPharmacobiology Department, Center for Research and Advanced Studies, Calz, Tenorios, MéxicoAbstract: Experiments using male CD1 mice were carried out to investigate the effects of subchronic (daily administration for 8 days pretreatments with drugs enhancing GABAergic transmission (diazepam, 10 mg/kg, ip; gabapentin, 100 mg/kg, po; or vigabatrin, 500 mg/kg, po on pentylenetetrazol (PTZ-induced seizures, 24 h after the last injection. Subchronic administration of diazepam reduced latencies to clonus, tonic extension and death induced by PTZ. Subchronic vigabatrin produced enhanced latency to the first clonus but faster occurrence of tonic extension and death induced by PTZ. Subchronic gabapentin did not modify PTZ-induced seizures. Autoradiography experiments revealed reduced benzodiazepine receptor binding in several brain areas after subchronic treatment with diazepam or gabapentin, whereas subchronic vigabatrin did not induce significant receptor changes. The present results indicate differential effects induced by the subchronic administration of diazepam, vigabatrin, and gabapentin on the susceptibility to PTZ-induced seizures, benzodiazepine receptor binding, or both.Keywords: diazepam, gabapentin, vigabatrin, pentylenetetrazol, benzodiazepine receptors

  14. Initial benzodiazepine use and improved health-related quality of life.

    NARCIS (Netherlands)

    van Hulten, Rolf; Teeuw, Bart; Bakker, Albert; Leufkens, Hubert G

    2005-01-01

    OBJECTIVE: The health-related quality of life (HRQOL) of initial benzodiazepine users was measured over time. Furthermore, benzodiazepine usage characteristics as determinants of change in mental and physical health status of the benzodiazepine users were examined. METHODS: In the only pharmacy of a

  15. 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 commun

  16. Biological properties of 2'-[18F]fluoroflumazenil for central benzodiazepine receptor imaging.

    Science.gov (United States)

    Chang, Young Soo; Jeong, Jae Min; Yoon, Young Hyun; Kang, Won Jun; Lee, Seung Jin; Lee, Dong Soo; Chung, June-Key; Lee, Myung Chul

    2005-04-01

    A novel positron emitting agent, 2'-[18F]fluoroflumazenil (fluoroethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate, FFMZ), has been reported for benzodiazepine imaging. In the present study, biological properties of [18F]FFMZ were investigated. Stability tests of [18F]FFMZ in human and rat sera were performed. Biodistribution was investigated in mice and phosphorimages of brains were obtained from rats. A receptor binding assay was performed using rat brain (mixture of cortex and cerebellum) homogenate. A static positron emission tomography (PET) image was obtained from a normal human volunteer. Although [18F]FFMZ was stable in human serum, it was rapidly hydrolyzed in rat serum. The hydrolysis was 39%, 63% and 92% at 10, 30 and 60 min, respectively. According to the biodistribution study in mice, somewhat even distribution (between 2 approximately 3% ID/g) was observed in most organs. Intestinal uptake increased up to 6% ID/g at 1 h due to biliary excretion. Bone uptake slowly increased from 1.5% to 3.5% ID/g at 1 h. High uptakes in the cortex, thalamus and cerebellum, which could be completely blocked by coinjection of cold FMZ, were observed by phosphorimaging study using rats. Determination of Kd value and Bmax using rat brain tissue was performed by Scatchard plotting and found 1.45+/-0.26 nM and 1.08+/-0.03 pmol/mg protein, respectively. The PET image of the normal human volunteer showed high uptake in the following decreasing order: frontal cortex, temporal cortex, occipital cortex, cerebellum, parietal cortex and thalamus. In conclusion, the new FMZ derivative, [18F]FFMZ appears to be a promising PET agent for central benzodiazepine receptor imaging with a convenient labeling procedure and a specific binding property.

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

    Science.gov (United States)

    Peng, Teng J; Patchett, Nicholas D; Bernard, Sheilah A

    2016-01-01

    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.

  18. 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.

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

    Science.gov (United States)

    Peng, Teng J.

    2016-01-01

    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. PMID:27547472

  20. Benzodiazepines may have protective effects against Alzheimer disease.

    Science.gov (United States)

    Fastbom, J; Forsell, Y; Winblad, B

    1998-03-01

    In this study, we examined the association between benzodiazepine use and the occurrence of Alzheimer disease and vascular dementia. The study was based on longitudinal data from a case-control study of 668 individuals aged 75 and older. The elderly were examined extensively by physicians, and family interviews were assessed. Dementia diagnosis was made by using DSM-III-R criteria. Individuals with a history of continuous use of benzodiazepines (BDZ+) were compared with nonusers (BDZ-), with respect to the incidence of Alzheimer disease or vascular dementia at follow-up 3 years later. It was found that there was a significantly lower incidence of Alzheimer disease in the BDZ+ group than in the BDZ- group. This negative association remained significant when controlling for age, gender, level of education, use of nonsteriodal antiinflammatory drugs, and estrogens. These results suggest that benzodiazepines may have protective effects against the disease.

  1. UV-guided screening of benzodiazepine producing species in Penicillium

    DEFF Research Database (Denmark)

    Larsen, Thomas Ostenfeld; Frydenvang, K.; Frisvad, Jens Christian

    2000-01-01

    The benzodiazepine sclerotigenin (auranthine B) recently described as a metabolite of Penicillium sclerotigenum, has been isolated as the major metabolite from an isolate of P. commune. The structure of sclerotigenin was established by a single-crystal X-ray diffraction study and by NMR spectrosc......The benzodiazepine sclerotigenin (auranthine B) recently described as a metabolite of Penicillium sclerotigenum, has been isolated as the major metabolite from an isolate of P. commune. The structure of sclerotigenin was established by a single-crystal X-ray diffraction study and by NMR...... spectroscopy, UV-guided screening for benzodiazepine production by other penicillia revealed that sclerotigenin was also produced by isolates of P. clavigerum, P. lanosum, P. melanoconidium, P. sclerotigenum and P. verrucosum. Sclerotigenin was detected both intra- and extracellularly, Apparently, P...

  2. UV-guided screening of benzodiazepine producing species in Penicillium

    DEFF Research Database (Denmark)

    Ostenfeld Larsen T; Frydenvang, Karla Andrea; Christian Frisvad J

    2000-01-01

    The benzodiazepine sclerotigenin (auranthine B) recently described as a metabolite of Penicillium sclerotigenum, has been isolated as the major metabolite from an isolate of P. commune. The structure of sclerotigenin was established by a single-crystal X-ray diffraction study and by NMR spectrosc......The benzodiazepine sclerotigenin (auranthine B) recently described as a metabolite of Penicillium sclerotigenum, has been isolated as the major metabolite from an isolate of P. commune. The structure of sclerotigenin was established by a single-crystal X-ray diffraction study and by NMR...... spectroscopy. UV-guided screening for benzodiazepine production by other penicillia revealed that sclerotigenin was also produced by isolates of P. clavigerum, P. lanosum, P. melanoconidium, P. sclerotigenum and P. verrucosum. Sclerotigenin was detected both intra- and extracellularly. Apparently, P...

  3. 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...

  4. A Quantum of Solace: molecular electronics of benzodiazepines

    Science.gov (United States)

    Turin, Luca; Horsfield, Andrew; Stoneham, Marshall

    2011-03-01

    Benzodiazepines and related drugs modulate the activity of GABA-A receptors, the main inhibitory receptor of the central nervous system. The prevailing view is that these drugs bind at the interface between two receptor subunits and allosterically modulate the response to GABA. In this talk I shall present evidence that benzodiazepines work instead by facilitating electron transport from the cytoplasm to a crucial redox-sensitive group in the gamma subunit. If this idea is correct, benzodiazepines should not only be regarded as keys fitting into a lock, but also as one-electron chemical field-effect transistors fitting into an electronic circuit. Supported by DARPA Grant N66001-10-1-4062.

  5. Benzodiazepines and risk of dementia: true association or reverse causation?

    Science.gov (United States)

    Barbui, C; Gastaldon, C; Cipriani, A

    2013-12-01

    According to a recently published population study conducted in France, exposure to benzodiazepines may be associated with an approximately 50% increase in the risk of dementia in the elderly. However, the clinical interpretation of this finding raised some concerns. A causal link between benzodiazepine use and diagnosis of dementia may be real, but it is nevertheless possible that the increased risk might be due to other confounding factors. In this article, the main strengths and weaknesses of this study are briefly analysed, including the possibility of reverse causation. Implications for research and current practice are discussed.

  6. Peripheral markers of thyroid function

    DEFF Research Database (Denmark)

    Schmidt, Ulla; Nygaard, Birte; Winther Jensen, Ebbe;

    2013-01-01

    the combination therapy. HYPOTHESIS: Peripheral tissue might also be stimulated during T4/T3 combination therapy compared with T4 monotherapy. METHODS: Serum levels of sex hormone-binding globulin (SHBG), pro-collagen-1-N-terminal peptide (PINP), and N-terminal pro-brain natriuretic peptide (NT...

  7. Positron emission tomography assessment of effects of benzodiazepines on regional glucose metabolic rate in patients with anxiety disorder

    Energy Technology Data Exchange (ETDEWEB)

    Buchsbaum, M.S.; Wu, J.; Haier, R.; Hazlett, E.; Ball, R.; Katz, M.; Sokolski, K.; Lagunas-Solar, M.; Langer, D.

    1987-06-22

    Patients with generalized anxiety disorder (n = 18) entered a 21-day, double-blind, placebo-controlled random assignment trial of clorazepate. Positron emission tomography with YF-deoxyglucose was carried out before and after treatment. Decreases in glucose metabolic rate in visual cortex and relative increases in the basal ganglia and thalamus were found. A correlation between regional changes in metabolic rate and regional benzodiazepine receptor binding density from other human autopsy studies was observed; brain regions highest in receptor density showed the greatest decrease in rate.

  8. Bromine-76 and carbon-11 labelled NNC 13-8199, metabolically stable benzodiazepine receptor agonists as radioligands for positron emission tomography (PET)

    Energy Technology Data Exchange (ETDEWEB)

    Foged, C. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, Stockholm (Sweden)]|[Novo Nordisk A/S, Health Care Discovery and Development, Maaloev (Denmark); Halldin, C.; Pauli, S.; Suhara, T.; Swahn, C.G.; Karlsson, P.; Farde, L. [Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, Stockholm (Sweden); Loc`h, C.; Maziere, B.; Maziere, M. [Service Hospitalier Frederic Joliot, CEA, Orsay (France); Hansen, H.C. [Novo Nordisk A/S, Health Care Discovery and Development, Maaloev (Denmark)

    1997-10-01

    NNC 13-8241 has recently been labelled with iodine-123 and developed as a metabolically stable benzodiazepine receptor ligand for single-photon emission computed tomography (SPECT) in monkeys and man. NNC 13-8199 is a bromo-analogue of NNC 13-8241. This partial agonist binds selectively and with subnanomolar affinity to the benzodiazepine receptors. We prepared {sup 76}Br labelled NNC 13-8199 from the trimethyltin precursor by the chloramine-T method. Carbon-11 labelled NNC 13-8199 was synthesised by N-alkylation of the nitrogen of the amide group with [{sup 11}C]methyl iodide. Positron emission tomography (PET) examination with the two radioligands in monkeys demonstrated a high uptake of radioactivity in the occipital, temporal and frontal cortex. In the study with [{sup 76}Br]NNC 13-8199, the monkey brain uptake continued to increase until the time of displacement with flumazenil at 215 min after injection. For both radioligands the radioactivity in the cortical brain regions was markedly reduced after displacement with flumazenil. More than 98% of the radioactivity in monkey plasma represented unchanged radioligand 40 min after injection. The low degree of metabolism indicates that NNC 13-8199 is metabolically much more stable than hitherto developed PET radioligands for imaging of benzodiazepine receptors in the primate brain. [{sup 76}Br]NNC 13-8199 has potential as a radioligand in human PET studies using models where a slow metabolism is an advantage. (orig.) With 8 figs., 28 refs.

  9. Associations between Benzodiazepine Use and Neuropsychological Test Scores in Older Adults.

    Science.gov (United States)

    Helmes, Edward; Østbye, Truls

    2015-06-01

    Benzodiazepines are widely prescribed for anxiety, although use of this class of medications has been associated with dependency and cognitive changes. This article describes the study in which we investigated the relationship between the class of benzodiazepine available for use and associated performance on neuropsychological tests in a community sample of 1,754 older Canadians from the Canadian Study of Health and Aging. Benzodiazepines were classified as short-, intermediate-, and long-acting. Associations were calculated between each class of benzodiazepine and eight neuropsychological measures, using multiple regression analysis and controlling for demographic variables. Results showed different effects of the co-variates across the three drug classes, and short half-life benzodiazepines were not associated with any neuropsychological measure. Intermediate half-life and long half-life benzodiazepine use were each associated with two measures. Increased focus on specific domains of cognitive function is needed to improve our understanding of how benzodiazepine use influences cognition.

  10. 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...

  11. Peripheral neuromodulation in chronic migraine.

    Science.gov (United States)

    Perini, F; De Boni, A

    2012-05-01

    Patients with chronic migraines are often refractory to medical treatment. Therefore, they might need other strategies to modulate their pain, according to their level of disability. Neuromodulation can be achieved with several tools: meditation, biofeedback, physical therapy, drugs and electric neurostimulation (ENS). ENS can be applied to the central nervous system (brain and spinal cord), either invasively (cortical or deep brain) or non-invasively [cranial electrotherapy stimulation, transcranial direct current stimulation and transcranial magnetic stimulation]. Among chronic primary headaches, cluster headaches are most often treated either through deep brain stimulation or occipital nerve stimulation because there is a high level of disability related to this condition. ENS, employed through several modalities such as transcutaneous electrical nerve stimulation, interferential currents and pulsed radiofrequency, has been applied to the peripheral nervous system at several sites. We briefly review the indications for the use of peripheral ENS at the site of the occipital nerves for the treatment of chronic migraine.

  12. Benzodiazepine Administration Induces Exogenic Psychosis: A Case of Child Abuse.

    Science.gov (United States)

    Marcus, Alexander; And Others

    1995-01-01

    An 11-year-old boy with psychiatric symptoms (anxiety, panic reactions, rage, and disorientation) was brought to the pediatric clinic by his father. Purposeful administration by his mother of benzodiazepine, a prescription drug available in the household, was suspected as responsible for the psychotic symptoms. (DB)

  13. Reimbursement restriction moderately decreases Benzodiazepine use in general practice.

    NARCIS (Netherlands)

    Hoebert, J.M.; Souverein, P.C.; Mantel-Teeuwisse, A.K.; Leufkens, H.G.M.; Dijk, L. van

    2011-01-01

    Problem Statement: On January 1st 2009, benzodiazepines were excluded from the Dutch positive reimbursement list when used as anxiolytic, hypnotic or sedative, to limit misuse and for cost savings. Thus far, the (un)intended effects of this reimbursement restriction are unknown. Objective(s): To ass

  14. Reimbursement restriction moderately decreases benzodiazepine use in general practice.

    NARCIS (Netherlands)

    Hoebert, J.M.; Souverein, P.C.; Mantel, A.K.; Leufkens, B.G.M.; Dijk, L. van

    2011-01-01

    Background: On January 1st 2009, benzodiazepines were excluded from the Dutch positive reimbursement list when used as anxiolytic, hypnotic or sedative, to limit misuse and for cost savings. Thus far, the (un)intended effects of this reimbursement restriction are unknown. Objectives: To assess the i

  15. Prediction of benzodiazepines solubility using different cosolvency models.

    Science.gov (United States)

    Nokhodchi, A; Shokri, J; Barzegar-Jalali, M; Ghafourian, T

    2002-07-01

    The solubility of four benzodiazepines (BZPs) including diazepam (DIZ), lorazepam (LRZ) clonazepam (CLZ), and chlordiazepoxide (CHZ) in water-cosolvent (ethanol propylene glycol and polyethylene glycol 200) binary systems were studied. In general, increasing the volume fraction of cosolvents resulted in an increase in the solubility of benzodiazepines. The mole fraction solubilities were fitted to the various cosolvency models, namely extended Hildebrand approach (EHA), excess free energy (EFE), combined nearly ideal binary solvent/Redlich-Kister (CNIBS/R-K), general single model (GSM), mixture response surface (MR-S). double log-log (DL-L), and linear double log-log (LDL-L). The results showed that DL-L model was the best model in predicting the solubility of all drugs in all the water-cosolvent mixtures (OAE% = 4.71). The minimum and maximum errors were observed for benzodiazepine's solubility in water-propylene glycol and water-ethanol mixtures which were 2.67 and 11.78%, respectively. Three models (EFE, CNIBS/R-K and LDL-L) were chosen as general models for solubility descriptions of these structurally similar drugs in each of the solvent systems. Among these models, the EFE model was the best in predicting the solubility of benzodiazepines in binary solvent mixtures (OAE% = 11.19).

  16. Different study criteria affect the prevalence of benzodiazepine use.

    NARCIS (Netherlands)

    Zandstra, S.M.; Furer, J.W.; Lisdonk, E.H. van de; Hof, M.A. van 't; Bor, J.H.J.; Weel, C. van; Zitman, F.G.

    2002-01-01

    BACKGROUND: Different prevalences of benzodiazepine (BZ) use are described in the literature. The present study assessed the effects of employing various definitions of BZ use and various observation periods on the prevalence rate of BZ use in an open population aged 18-74 years. METHOD: In a litera

  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, a

  18. Multicomponent Synthesis of Diverse 1,4-Benzodiazepine Scaffolds

    NARCIS (Netherlands)

    Huang, Yijun; Khoury, Kareem; Chanas, Tyler; Domling, Alexander

    2012-01-01

    The 1,4-benzodiazepine (BDZ) scaffold is of particular interest in drug design due to a balanced ensemble of beneficial physicochemical properties including a semirigid and compact diazepine ring with spatial placements of several substituents, combined with low number of rotatable bonds, hydrogen b

  19. Association between Benzodiazepine Use and Dementia: A Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    GuoChao Zhong

    Full Text Available The association between long-term benzodiazepine use and risk of dementia remains controversial. Therefore, current study aimed to quantify this association, and to explore a potential dose-response pattern.We searched PubMed, Embase and the Cochrane Library through August 17, 2014. We included nested case-control or prospective cohort studies that provided risk estimates on the association of benzodiazepine use with risk of dementia, and a clear definition of status of benzodiazepine use. Overall effect size was calculated using a random-effects model.Six studies were eligible for inclusion, involving 11,891 dementia cases and 45,391 participants. Compared with never users, pooled adjusted risk ratios (RRs for dementia were 1.49 (95% confidence interval (CI 1.30-1.72 for ever users, 1.55 (95% CI 1.31-1.83 for recent users, and 1.55 (95% CI 1.17-2.03 for past users. The risk of dementia increased by 22% for every additional 20 defined daily dose per year (RR, 1.22, 95%CI 1.18-1.25. When we restricted our meta-analyses to unadjusted RRs, all initial significant associations persisted.Long-term benzodiazepine users have an increased risk of dementia compared with never users. However, findings from our study should be treated with caution due to limited studies and potential reverse causation. Large prospective cohort studies with long follow-up duration are warranted to confirm these findings.

  20. Patterns of chronic benzodiazepine use in the elderly

    Directory of Open Access Journals (Sweden)

    Vanessa Sgnaolin

    Full Text Available Abstract Background In several countries, prevalence studies demonstrate that chronic use of BZD in the elderly population is very high. This scenario has reached pandemic proportions for decades and is an important public health problem. Objectives To examine the independent association between chronic benzodiazepine use in depression, anxiety and bipolar disorder, as well as other clinical and sociodemographic factors. Methods This cross-sectional study was developed from a population-based survey and conducted from March, 2011 to December, 2012 using a random sample of 550 elderly people who were enrolled in the Family Health Strategy in Porto Alegre, Brazil. Data was collected from identifying epidemiological and health data (sociodemographic, self-perception health, self-reported diseases, smoking, alcohol and pharmacotherapeutic evaluation and from the diagnoses of mood and anxiety disorders. Results Elderly patients diagnosed with depression, anxiety, concomitant depression/anxiety and bipolar disorders, and those who were using antidepressants have a higher risk of benzodiazepine use. Individuals who self-reported drinking alcohol had a lower risk of benzodiazepine use. Discussion Benzodiazepines are often used by the elderly for long periods, which has a direct impact on the treatment of mood and anxiety disorders and on vulnerable groups such as the elderly, who may be unnecessarily taking these drugs.

  1. Benzodiazepine-associated delirium in critically ill adults

    NARCIS (Netherlands)

    Zaal, Irene J.; Devlin, John W.; Hazelbag, Marijn; Klein Klouwenberg, Peter M. C.; van der Kooi, Arendina W.; Ong, David S. Y.; Cremer, Olaf L.; Groenwold, Rolf H.; Slooter, Arjen J. C.

    2015-01-01

    PURPOSE: The association between benzodiazepine use and delirium risk in the ICU remains unclear. Prior investigations have failed to account for disease severity prior to delirium onset, competing events that may preclude delirium detection, other important delirium risk factors, and an adequate nu

  2. Lack of evidence of teratogenicity of benzodiazepine drugs in Hungary.

    Science.gov (United States)

    Czeizel, A

    In order to investigate possible teratogenic effects of commonly used benzodiazepines (diazepam, chlordiazepoxide, nitrazepam) in Hungary, four approaches were used: 1. A retrospective case-control study of 630 cases with isolated cleft lip +/- cleft palate, 179 cases with isolated cleft palate, 392 cases of multiple congenital anomalies including cleft lip and/or cleft palate, and their matched control cases; 2. The Case-Control Surveillance System of Congenital Anomalies in Hungary, 1980 to 1984, involving 355 cases with isolated cleft palate, 417 cases with multiple congenital anomalies, and 186 cases with Down's syndrome (as positive controls). Benzodiazepines were taken by 14.9% of 11,073 control pregnant women studied; 3. A prospective study of 33 pregnant women attending the Counselling Clinic following ingestion of benzodiazepines during the first trimester of pregnancy; 4. An observational study involving 12 pregnant women who attempted suicide and one with accidental overdosage with benzodiazepines during pregnancy. None of these four approaches gave any indication of an association between facial clefting and in utero exposure to these substances.

  3. 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 of cessat......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...... of cessation hazards among incident users of benzodiazepines, in particular with respect to potential changes after three months use. Methods: Follow-up on a 25% randomly selected cohort of all Danes (n = 1,612,171) in the period Jan 1, 1995, to Jul 1, 2007, identified through the Danish civil registration...... number (CRN), which is unique for each individual, holds information on gender and date of birth, and yields access to migration and date of death. All filled prescriptions within the cohort of a benzodiazepine (ATC codes N05BA, B03AE01, N05CD, and N05CF) were identified from the national Danish Product...

  4. A Way of Conceptualizing Benzodiazepines to Guide Clinical Use.

    Science.gov (United States)

    Preskorn, Sheldon H

    2015-11-01

    Benzodiazepines are medications that are widely used for a number of different therapeutic indications and in a wide range of patients in terms of age and health status. Presented here is a simple 2 by 2 way of classifying all of the most commonly used benzodiazepines. This conceptualization is based on the most clinically relevant ways of differentiating these drugs: (a) their affinity for their common and predominant mechanism of action, the benzodiazepine-binding site of the γ-aminobutyric acid (GABA)-A iontropic receptor (ie, the chloride ion channel); and (b) their pharmacokinetics (ie, their half-lives and metabolism). The science underlying this conceptualization is presented and then its clinical applicability is discussed. This system can help clinicians select the most appropriate benzodiazepine for their patients and better understand how to switch between these medications to minimize withdrawal symptoms; it also provides a rational basis for cautiously using these agents in combination when necessary, in a manner analogous to the combined use of short-acting and long-acting forms of insulin.

  5. 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

  6. Neighbourhood characteristics and use of benzodiazepines in The Netherlands.

    NARCIS (Netherlands)

    Groenewegen, P.P.; Leufkens, H.G.; Spreeuwenberg, P.; Worm, W.

    1999-01-01

    This paper analyses the relationship between individual and neighbourhood characteristics and the use of benzodiazepines within a Dutch city. It is hypothesized that the proportion of users is lower in more socially integrated and less deprived neighbourhoods. Hypotheses have been tested by using mu

  7. 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.

  8. Benzodiazepines and traffic safety : forensic, analytical-toxicological and epidemiological aspects of driving under the influence of benzodiazepines

    NARCIS (Netherlands)

    Smink, Beitske Eelkje

    2008-01-01

    Driving under the influence of alcohol, illicit and medicinal drugs (e.g. benzodiazepines) is under discussion world-wide because many studies have shown that its use is associated with impaired driving and increased accident risk despite sometimes conflicting results. In The Netherlands, the number

  9. GABAA receptor γ2 subunit knockdown mice have enhanced anxiety-like behavior but unaltered hypnotic response to benzodiazepines

    Directory of Open Access Journals (Sweden)

    De Blas Angel L

    2005-04-01

    Full Text Available Abstract Background Gamma-aminobutyric acid type A receptors (GABAA-Rs are the major inhibitory receptors in the mammalian brain and are modulated by a number of sedative/hypnotic drugs including benzodiazepines and anesthetics. The significance of specific GABAA-Rs subunits with respect to behavior and in vivo drug responses is incompletely understood. The γ2 subunit is highly expressed throughout the brain. Global γ2 knockout mice are insensitive to the hypnotic effects of diazepam and die perinatally. Heterozygous γ2 global knockout mice are viable and have increased anxiety-like behaviors. To further investigate the role of the γ2 subunit in behavior and whole animal drug action, we used gene targeting to create a novel mouse line with attenuated γ2 expression, i.e., γ2 knockdown mice. Results Knockdown mice were created by inserting a neomycin resistance cassette into intron 8 of the γ2 gene. Knockdown mice, on average, showed a 65% reduction of γ2 subunit mRNA compared to controls; however γ2 gene expression was highly variable in these mice, ranging from 10–95% of normal. Immunohistochemical studies demonstrated that γ2 protein levels were also variably reduced. Pharmacological studies using autoradiography on frozen brain sections demonstrated that binding of the benzodiazepine site ligand Ro15-4513 was decreased in mutant mice compared to controls. Behaviorally, knockdown mice displayed enhanced anxiety-like behaviors on the elevated plus maze and forced novelty exploration tests. Surprisingly, mutant mice had an unaltered response to hypnotic doses of the benzodiazepine site ligands diazepam, midazolam and zolpidem as well as ethanol and pentobarbital. Lastly, we demonstrated that the γ2 knockdown mouse line can be used to create γ2 global knockout mice by crossing to a general deleter cre-expressing mouse line. Conclusion We conclude that: 1 insertion of a neomycin resistance gene into intron 8 of the γ2 gene variably

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

    Energy Technology Data Exchange (ETDEWEB)

    Odano, Ikuo [Dept. of Radiology, Niigata Univ. School of Medicine, Niigata (Japan); Anezaki, Toshiharu [Dept. of Neurology, Brain Research Inst., Niigata Univ., Niigata (Japan); Ohkubo, Masaki [Dept. of Radiology, Niigata Univ. School of Medicine, Niigata (Japan); Yonekura, Yoshiharu [Nihon Medi-Physics Co. Ltd., Hyogo (Japan); Onishi, Yoshihiro [Biomedical Imaging Research Center, Fukui Medical School, Fukui (Japan); Inuzuka, Takashi [Dept. of Neurology, Brain Research Inst., Niigata Univ., Niigata (Japan); Takahashi, Makoto [Dept. of Radiology, Niigata Univ. School of Medicine, Niigata (Japan); Tsuji, Shoji [Dept. of Neurology, Brain Research Inst., Niigata Univ., Niigata (Japan)

    1996-05-01

    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{sub A} receptor {beta}3 subunit (GABRB3) is located. Since the benzodiazepine receptor is constructed as a receptor-ionophore complex that contains the GABA{sub A} receptor, it is a suitable marker for GABA-ergic synapsis. To determine whether benzodiazepine receptor density, which indirectly indicates changes in GABA{sub A} receptor density, is altered in the brain in patients with AS, we investigated a 27-year-old woman with AS using {sup 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-[{sup 123}]iodoamphetamine. We demonstrated that benzodiazepine 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{sub 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{sub A} receptor in the investigated patient. {sup 123}I-iomazenil with SPET was useful to map benzodiazepine receptors, which indicate GABA{sub A} receptor distribution and their density. (orig.)

  11. 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.

  12. Attention Span, Anxiety and Benzodiazepine Receptors

    Science.gov (United States)

    1991-02-26

    represent a new class of nootropic druos witn a s9intricant clinical potential. 2 FINAL TECHNICAL REPORT ON GRANT AFOSR-87-0364 ENTITLED "ATTENTION SPAN...acquisition and retention of novel aversively motivated goal-directed behavior. This nootropic action may be linked to the flumazenil enhanced brain...metabolism, as revealed by oxygen utilization in the rat forebrain [32]. The nootropic effect may also be linked to increased protein synthesis in the CNS, an

  13. Delayed image of iodine-123 iomazenil as a relative map of benzodiazepine receptor binding: the optimal scan time

    Energy Technology Data Exchange (ETDEWEB)

    Onishi, Yoshihiro [Nihon Medi-Physics Co. Ltd., Nishinomiya (Japan); Yonekura, Yoshiharu [Fukui Medical School, Fukui (Japan); Tanaka, Fumiko [Kyoto University School of Medicine, Kyoto (Japan); Nishizawa, Sadahiko [Kyoto University School of Medicine, Kyoto (Japan); Okazawa, Hidehiko [Kyoto University School of Medicine, Kyoto (Japan); Ishizu, Koichi [Kyoto University School of Medicine, Kyoto (Japan); Fujita, Toru [Kyoto University School of Medicine, Kyoto (Japan); Konishi, Junji [Kyoto University School of Medicine, Kyoto (Japan); Mukai, Takao [Kyoto College of Medical Technology, Kyoto (Japan)

    1996-11-01

    ``Delayed`` single-photon emission tomograpic (SPET) images after an intravenous bolus injection of iodine-123 iomazenil have been used as a relative map of benzodiazepine receptor binding. We determined the optimal scan time for obtaining such a map and assessed the errors of the map. SPET and blood data from six healthy volunteers and five patients were used. A three-compartment kinetic model was employed in simulation studies and analyses of actual data. The simulation studies suggested that, in the normal brain, the scan time at which a single SPET image best represented the relative receptor binding was 3.0-3.5 h post-injection. This finding was supported by actual data from the volunteers. The simulation studies also suggested that the optimal scan time was not greatly changed by the variability of the input functions, and that the error in the SPET image contrast in the vicinity of the optimal scan time was not increased by changes in the tracer kinetics in the entire brain. The SPET image contrast in the patients at 3.0 h post-injection agreed well with the reference receptor binding estimated by kinetic analysis, with a mean error of 3.6%. These findings support the use of a single SPET image after bolus injection of [{sup 123}I]iomazenil as a relative map of benzodiazepine receptor binding. For this purpose, a SPET scan time of 3.0-3.5 h post-injection is recommended. (orig.). With 5 figs., 1 tab.

  14. Limited in vivo bioassays on some benzodiazepines: lack of experimental initiating or promoting effect of the benzodiazepine tranquillizers diazepam, clorazepate, oxazepam and lorazepam.

    Science.gov (United States)

    Mazue, G; Remandet, B; Gouy, D; Berthe, J; Roncucci, R; Williams, G M

    1982-05-01

    Four benzodiazepine tranquillizers were tested for their ability to initiate or promote the development of preneoplastic and neoplastic rat liver lesions. In comparison with the liver carcinogen, N-2-fluorenylacetamide, the benzodiazepines exhibited no initiating activity during a 14-week period of daily administration by gavage. To study the promoting activity, N-2-fluorenylacetamide was used to initiate altered foci and neoplastic nodules in rat liver during 8 weeks and then the benzodiazepines were administered by daily gavage for a period of 12 weeks. The liver tumor promoter phenobarbital had a substantial enhancing effect upon the persistence of nodules but none of the benzodiazepines showed a similar effect. Thus, in the process model systems used, to detect initiating or promoting potential effect, the benzodiazepine tranquillizers failed to exhibit either an initiating or a promoting action.

  15. Subcellular localization and displacement by diuretics of the peripheral benzodiazepine binding site (PBS) from rat kidney

    Energy Technology Data Exchange (ETDEWEB)

    Lukeman, S.; Fanestil, D.

    1986-03-05

    Although the PBS has been identified in many organs, its function and cellular location are speculative. Using rapid filtration, binding of (/sup 3/H)RO 5-4864 (*RO) (.75 nM) was assessed in four subcellular fractions (.3 mg/ml) derived from depapillated rat kidney by differential centrifugation: N (450g x 2 min), O (13,000 x 10), P (105,000 x 30), and S. The binding distribution was: N-18%, O-74%, P-6%, and S-2%. Marker enzyme analysis revealed that O was enriched in mitochondria (M), lysosomes (L), peroxisomes (P), and endoplasmic reticulum (ER), but not plasma membrane, and that N contained small amounts (10-15%) of markers for the above. Repeated washing of O removed ER enzymes but preserved *RO binding. O was further fractionated with centrifugation (57,000g x 4 hr) on a linear sucrose gradient (18-65%); *RO binding then comigrated with M but not P and L markers. Centrifugation of isolated M (5500 x 10 min) on another linear sucrose gradient (37-65%) gave low and high density bands, which contained 65% and 35% of *RO binding activity, resp. *RO binding in O was specific, saturable, reversible, and inhibited by diuretics. Inhibitors with the highest potency were indacrinone (K/sub d/ = 35 ..mu..M), hydrochlorothiazide (100 ..mu..M), and ethacrynic acid (325 ..mu..M). Low potency inhibitors (K/sub d/ greater than or equal to 1 mM) included amiloride, triamterene, furosemide, bumetanide, and ozolinone.

  16. PET Imaging of the Peripheral Benzodiazepine Receptor : Monitoring Disease Progression and Therapy Response in Neurodegenerative Disorders

    NARCIS (Netherlands)

    Doorduin, Janine; de Vries, Erik F. J.; Dierckx, Rudi A.; Klein, Hans C.

    2008-01-01

    It is important to gain more insight into neurodegenerative diseases, because these debilitating diseases can not be cured. A common characteristic of many neurological diseases is neuroinflammation, which is accompanied by the presence of activated microglia cells. In activated microglia cells, an

  17. Development of new peripheral benzodiazepine receptor ligands for SPECT and PET imaging

    Energy Technology Data Exchange (ETDEWEB)

    Katsifis, A.; Fookes, C.; Pham, T.; Holmes, T.; Mattner, F.; Berghoffer, P.; Gregoire, M.C.; Loc' h, C.; Greguric, I. [Radiopharmaceuticas Research Institute, ANSTO, Menai, N.S.W. Sydney (Australia); Thominiaux, C.; Boutin, H.; Chauveau, F.; Gregoire, M.C.; Hantraye, Ph.; Tavitain, B.; Dolle, F. [Service Hospitalier Frederic Joliot, CEA/DSV, 91 - Orsay (France); Arlicot, N.; Chalon, S.; Guilloteau, D. [Universite Francois Rabelais, Inserm U619, 37 - Tours (France)

    2008-02-15

    This study aims to demonstrate that a number of radiolabelled ({sup 123}I,{sup 11}C, {sup 18}F) imidazo pyridines, imidazo pyridazines and indolglyoxylamides can be developed as potential tracers for SPECT and PET imaging. (N.C.)

  18. Is Peripheral Benzodiazepine Receptor (PBR) Gene Expression Involved in Breast Cancer Suppression by Dietary Soybean Protein?

    Science.gov (United States)

    2006-06-01

    Macromolecules, Jan 10-14, 2005, Puri, India. Ferguson M, Das SK and Mukherjee S. Role of Glyoxalase I and Glyoxalase II in Non- Tumorigenic and...dependent human breast carcinoma by soy and tea bioactive components in mice. Int J Cancer 108: 8-14, 2003. 9. Fotsis T, Pepper MS, Aktas E, et al

  19. Comparison of blood flow and distribution of benzodiazepine receptors in focal epilepsy: Preliminary results of a SPECT study. Vergleich von Blutfluss und Benzodiazepin-Rezeptorverteilung bei fokaler Epilepsie: Vorlaeufige Ergebnisse einer SPECT-Studie

    Energy Technology Data Exchange (ETDEWEB)

    Bartenstein, P.; Schober, O.; Lottes, G.; Boettger, I. (Muenster Univ. (Germany, F.R.). Klinik und Poliklinik fuer Nuklearmedizin); Ludolph, A. (Muenster Univ. (Germany, F.R.). Klinik und Poliklinik fuer Neurologie); Beer, H.F. (Paul Scherrer Inst., Wuerenlingen (Switzerland))

    1989-10-01

    {sup 99m}Tc-HMPAO-SPECT and SPECT with the {sup 123}I-labelled benzodiazepine (Bz) receptor ligand Ro 16-0154 were performed in 10 patients suffering from partial epilepsy, without cerebral lesion in MRT or CT.2 h p.i. of Ro 16-0154 the distribution of activity correlated with the known distribution of Bz-receptors in the human brain. Perfusion and receptor-binding were found decreased in 7 patients of each study in the suspicious brain-area. {sup 123}I-labelled Ro 16-0154 is suitable for Bz-receptor mapping by SPECT. The decrease of Bz-receptor binding in epileptic foci, as described in PET-studies, was also detected by SPECT in 7 of 10 patients. (orig.).

  20. Afferent Fiber Remodeling in the Somatosensory Thalamus of Mice as a Neural Basis of Somatotopic Reorganization in the Brain and Ectopic Mechanical Hypersensitivity after Peripheral Sensory Nerve Injury

    Science.gov (United States)

    Yagasaki, Yuki; Katayama, Yoko

    2017-01-01

    Abstract Plastic changes in the CNS in response to peripheral sensory nerve injury are a series of complex processes, ranging from local circuit remodeling to somatotopic reorganization. However, the link between circuit remodeling and somatotopic reorganization remains unclear. We have previously reported that transection of the primary whisker sensory nerve causes the abnormal rewiring of lemniscal fibers (sensory afferents) on a neuron in the mouse whisker sensory thalamus (V2 VPM). In the present study, using transgenic mice whose lemniscal fibers originate from the whisker sensory principle trigeminal nucleus (PrV2) are specifically labeled, we identified that the transection induced retraction of PrV2-originating lemniscal fibers and invasion of those not originating from PrV2 in the V2 VPM. This anatomical remodeling with somatotopic reorganization was highly correlated with the rewiring of lemniscal fibers. Origins of the non-PrV2-origin lemniscal fibers in the V2 VPM included the mandibular subregion of trigeminal nuclei and the dorsal column nuclei (DCNs), which normally represent body parts other than whiskers. The transection also resulted in ectopic receptive fields of V2 VPM neurons and extraterritorial pain behavior on the uninjured mandibular region of the face. The anatomical remodeling, emergence of ectopic receptive fields, and extraterritorial pain behavior all concomitantly developed within a week and lasted more than three months after the transection. Our findings, thus, indicate a strong linkage between these plastic changes after peripheral sensory nerve injury, which may provide a neural circuit basis underlying large-scale reorganization of somatotopic representation and abnormal ectopic sensations.

  1. 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.

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

    OpenAIRE

    Peng, Teng J; Patchett, Nicholas D.; Bernard, Sheilah A.

    2016-01-01

    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 m...

  3. Benzodiazepines for conscious sedation in the dental office

    OpenAIRE

    Theodoro Weissheimert; Alexandre da Silveira Gerzson; Henderson Eduarth Schwengber; Angelo Menuci Neto

    2016-01-01

    Conventional behavioral conditioning techniques are usually suf fi cient for management of patients with fear and anxiety during dental treatment. When such techniques do not produce the expected results, dental anxiety can be managed using drug-based treatments known as conscious sedation. Anxiety can complicate dental procedures because of effects such as increased blood pressure, hyperventilation, and fainting. Medications such as benzodiazepines can be used to avoid these complicat...

  4. Binding of several benzodiazepines to bovine serum albumin: Fluorescence study

    Science.gov (United States)

    Machicote, Roberta G.; Pacheco, María E.; Bruzzone, Liliana

    2010-10-01

    The interactions of lorazepam, oxazepam and bromazepam with bovine serum albumin (BSA) were studied by fluorescence spectrometry. The Stern-Volmer quenching constants and corresponding thermodynamic parameters Δ H, Δ G and Δ S were calculated. The binding constants and the number of binding sites were also investigated. The distances between the donor (BSA) and the acceptors (benzodiazepines) were obtained according to fluorescence resonance energy transfer and conformational changes of BSA were observed from synchronous fluorescence spectra.

  5. Association between risk factors for injurious falls and new benzodiazepine prescribing in elderly persons

    Directory of Open Access Journals (Sweden)

    Sylvestre Marie-Pierre

    2009-01-01

    Full Text Available Abstract Background Benzodiazepines are frequently prescribed to elderly patients' despite concerns about adverse effects leading to injurious falls. Previous studies have not investigated the extent to which patients with pre-existing risk factors for falls are prescribed benzodiazepines. The objective of this study is to assess if some of the risk factors for falls are associated with new benzodiazepine prescriptions in elderly persons. Methods Using provincial administrative databases, elderly Quebec residents were screened in 1989 for benzodiazepine use and non-users were followed for up to 5 years. Logistic regression models were used to evaluate potential predictors of new benzodiazepine use among patient baseline characteristics. Results In the 252,811 elderly patients who had no benzodiazepine prescription during the baseline year (1989, 174,444 (69% never filled a benzodiazepine prescription and 78,367 (31% filled at least one benzodiazepine prescription. In the adjusted analysis, several risk factors for falls were associated with statistically significant increases in the risk of receiving a new benzodiazepine prescription including the number of prescribing physicians seen at baseline (OR: 1.12; 95% CI 1.11–1.13, being female (OR: 1.20; 95% CI 1.18–1.22 or a diagnosis of arthritis (OR: 1.11; 95% CI 1.09–1.14, depression (OR: 1.42; 95% CI 1.35–1.49 or alcohol abuse (OR: 1.24; 95% CI 1.05–1.46. The strongest predictor for starting a benzodiazepine was the use of other medications, particularly anti-depressants (OR: 1.85; 95% CI 1.75–1.95. Conclusion Patients with pre-existing conditions that increase the risk of injurious falls are significantly more likely to receive a new prescription for a benzodiazepine. The strength of the association between previous medication use and new benzodiazepine prescriptions highlights an important medication safety issue.

  6. Contingent reinforcement for benzodiazepine-free urines: evaluation of a drug abuse treatment intervention.

    OpenAIRE

    Stitzer, M L; Bigelow, G E; Liebson, I A; Hawthorne, J W

    1982-01-01

    This study evaluated contingent reinforcement for benzodiazepine-free urines as a therapeutic intervention for promoting reduced use of supplemental benzodiazepine drugs among methadone maintenance outpatients. Ten methadone maintenance patients were selected for participation on the basis of positive urinalysis results. During a 12-week intervention period these patients were offered clinic privileges, including monetary payments or methadone take-home doses, contingent on benzodiazepine neg...

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

    OpenAIRE

    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 benzodiazepine users described in the literature are based on studies in which long-term users were compared with non-users. Thus these characteristics may be imprecise. AIM: To study the characteristi...

  8. Association between risk factors for injurious falls and new benzodiazepine prescribing in elderly persons

    OpenAIRE

    2009-01-01

    Abstract Background Benzodiazepines are frequently prescribed to elderly patients' despite concerns about adverse effects leading to injurious falls. Previous studies have not investigated the extent to which patients with pre-existing risk factors for falls are prescribed benzodiazepines. The objective of this study is to assess if some of the risk factors for falls are associated with new benzodiazepine prescriptions in elderly persons. Methods Using provincial administrative databases, eld...

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

    OpenAIRE

    2015-01-01

    Background: Benzodiazepines are frequently prescribed in patients with Alzheimer’s disease. Unfortunately, studies evaluating their benefits and risks in these patients are limited. Methods: Clinical trials focusing on the effect of benzodiazepines on cognitive functions, disease progression, behavioral symptoms, sleep disturbances, and the general frequency of benzodiazepine use were included in this review. Published articles from January 1983 to January 2015 were identified using specific ...

  10. Emission and absorption spectra of some bridged 1,5-benzodiazepines

    Science.gov (United States)

    Mellor, J. M.; Pathirana, R. N.; Stibbard, J. H. A.

    Absorption spectra in neutral and acidic media are reported for a series of bridged 1,5-benzodiazepines, which are unable to tautomerize. Comparison is made with non-bridged 1,5-benzodiazepines capable of tautomeric rearrangement. Both bridged and non-bridged 1,5-benzodiazepines are essentially non-fluorescent due to the "proximity effect" of interaction between singlet ηπ* and ππ* states of similar energy, a phenomenon previously recognised in six-membered nitrogen heterocycles.

  11. Identification of the gene encoding Brain Cell Membrane Protein 1 (BCMP1, a putative four-transmembrane protein distantly related to the Peripheral Myelin Protein 22 / Epithelial Membrane Proteins and the Claudins

    Directory of Open Access Journals (Sweden)

    Christophe Daniel

    2001-07-01

    Full Text Available Abstract Background A partial cDNA clone from dog thyroid presenting a very significant similarity with an uncharacterized mouse EST sequence was isolated fortuitously. We report here the identification of the complete mRNA and of the gene, the product of which was termed "brain cell membrane protein 1" (BCMP1. Results The 4 kb-long mRNA sequence exhibited an open-reading frame of only 543 b followed by a 3.2 kb-long 3' untranslated region containing several AUUUA instability motifs. Analysis of the encoded protein sequence identified the presence of four putative transmembrane domains. Similarity searches in protein domain databases identified partial sequence conservations with peripheral myelin protein 22 (PMP22/ epithelial membrane proteins (EMPs and Claudins, defining the encoded protein as representative of the existence of a novel subclass in this protein family. Northern-blot analysis of the expression of the corresponding mRNA in adult dog tissues revealed the presence of a huge amount of the 4 kb transcript in the brain. An EGFP-BCMP1 fusion protein expressed in transfected COS-7 cells exhibited a membranous localization as expected. The sequences encoding BCMP1 were assigned to chromosome X in dog, man and rat using radiation hybrid panels and were partly localized in the currently available human genome sequence. Conclusions We have identified the existence in several mammalian species of a gene encoding a putative four-transmembrane protein, BCMP1, wich defines a novel subclass in this family of proteins. In dog at least, the corresponding mRNA is highly present in brain cells. The chromosomal localization of the gene in man makes of it a likely candidate gene for X-linked mental retardation.

  12. Abuse and dependence liability of benzodiazepine-type drugs: GABA(A) receptor modulation and beyond.

    Science.gov (United States)

    Licata, Stephanie C; Rowlett, James K

    2008-07-01

    Over the past several decades, benzodiazepines and the newer non-benzodiazepines have become the anxiolytic/hypnotics of choice over the more readily abused barbiturates. While all drugs from this class act at the GABA(A) receptor, benzodiazepine-type drugs offer the clear advantage of being safer and better tolerated. However, there is still potential for these drugs to be abused, and significant evidence exists to suggest that this is a growing problem. This review examines the behavioral determinants of the abuse and dependence liability of benzodiazepine-type drugs. Moreover, the pharmacological and putative biochemical basis of the abuse-related behavior is discussed.

  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. Caffeine consumption among adults on benzodiazepine therapy: United States 1988-1994.

    Science.gov (United States)

    Cooper, Michael; Safran, Marc; Eberhardt, Mark

    2004-08-01

    The concomitant use of benzodiazepines and caffeine was studied to learn if caffeine consumption varied as a function of benzodiazepine use. Caffeine may antagonize the effects of benzodiazepine and even relatively small amounts can aggravate symptoms associated with anxiety disorders. In addition, caffeine can cause or aggravate insomnia, one of the main reasons cited for use by the subjects in this analysis. Given this, there would seem to be sufficient reason for at least some users of benzodiazepines to consider, with their physicians, avoiding or limiting caffeine consumption. Data from the Third National Health and Nutrition Examination Survey were analyzed to obtain a nationally representative sample of benzodiazepine users. Subjects included 253 individuals (64% women) whose median age was 54 yr. Approximately 88% of benzodiazepine users reported caffeine consumption in the 24-hr. Dietary Recall. 26% of benzodiazepine users and 23% of nonusers reported consuming greater than 250 mg of caffeine during the 24-hr. reference period. In regression analyses, no significant relationships were found between reported caffeine consumption and benzodiazepine use. This study suggests that users and nonusers of benzodiazepines ingest similar amounts of caffeine even though some users should probably avoid or limit caffeine use.

  15. Cyclosporine, a P-glycoprotein modulator, increases [{sup 18}F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies

    Energy Technology Data Exchange (ETDEWEB)

    Lacan, Goran; Way, Baldwin M. [UCLA, Department of Molecular and Medical Pharmacology, Los Angeles, CA (United States); Plenevaux, Alain; Defraiteur, Caroline; Lemaire, Christian; Aerts, Joel; Luxen, Andre [Liege University, Cyclotron Research Center, Liege (Belgium); Rubins, Daniel J. [Merck and Co., Inc, Merck Research Laboratories, West Point, PA (United States); Cherry, Simon R. [Cyclotron Research Center, Department of Biomedical Engineering, Davis, CA (United States); Melega, William P. [UCLA, Department of Molecular and Medical Pharmacology, Los Angeles, CA (United States); UCLA School of Medicine, Department of Molecular and Medical Pharmacology, Los Angeles, CA (United States)

    2008-12-15

    Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2''-pyridinyl)-p-[{sup 18}F]fluorobenzamido]ethylpiperazine ([{sup 18}F]MPPF) for binding to hydroxytryptamine{sub 1A} (5-HT{sub 1A}) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies. Each Sprague-Dawley rat (n=4) received a baseline [{sup 18}F]MPPF microPET scan followed by second scan 2-3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.p.). Maximum a posteriori reconstructed images and volumetric ROIs were used to generate dynamic radioactivity concentration measurements for hippocampus, striatum, and cerebellum, with simplified reference tissue method (SRTM) analysis. Western blots were used to semiquantify P-gp regional distribution in brain. MicroPET studies showed that hippocampus uptake of [{sup 18}F]MPPF was increased after cyclosporine; ex vivo studies showed similar increases in hippocampus and frontal cortex at 30 min, and for heart and kidney at 2.5 and 5 min, without concomitant increases in [{sup 18}F]MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex. These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [{sup 18}F]MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [{sup 18}F]MPPF binding to 5-HT{sub 1A} receptors can be imaged in rat hippocampus. The heterogeneous brain distribution of P-gp appeared to invalidate the use of cerebellum as a nonspecific reference region for SRTM modeling. Regional quantitation of P-gp may be necessary for accurate PET assessment of 5-HT{sub 1A} receptor density when based on tracer uptake sensitive to P-gp modulation. (orig.)

  16. Behavioral and neurophysiological signatures of benzodiazepine-related driving impairments

    Directory of Open Access Journals (Sweden)

    Bradly T Stone

    2015-11-01

    Full Text Available Impaired driving due to drug use is a growing problem, worldwide; estimates show that 18-23.5% of fatal accidents, and up to 34% of injury accidents may be caused by drivers under the influence of drugs (Drummer et al., 2003; NHTSA, 2010; Walsh et al., 2004. Furthermore, at any given time, up to 16% of drivers may be using drugs that can impair one’s driving abilities (NHTSA, 2009. Currently, drug recognition experts (law enforcement officers with specialized training to identify drugged driving, have the most difficult time with identifying drivers potentially impaired on central nervous system (CNS depressants (Smith, Hayes, Yolton, Rutledge, & Citek, 2002. The fact that the use of benzodiazepines, a type of CNS depressant, is also associated with the greatest likelihood of causing accidents (Dassanayake, Michie, Carter, & Jones, 2011, further emphasizes the need to improve research tools in this area which can facilitate the refinement of, or additions to, current assessments of impaired driving. Our laboratories collaborated to evaluate both the behavioral and neurophysiological effects of a benzodiazepine, alprazolam, in a driving simulation (miniSim™. This drive was combined with a neurocognitive assessment utilizing time synched neurophysiology (EEG, ECG. While the behavioral effects of benzodiazepines are well characterized (Rapoport et al., 2009, we hypothesized that, with the addition of real-time neurophysiology and the utilization of simulation and neurocognitive assessment, we could find objective assessments of drug impairment that could improve the detection capabilities of drug recognition experts. Our analyses revealed that 1 specific driving conditions were significantly more difficult for benzodiazepine impaired drivers and; 2 the neurocognitive tasks’ metrics were able to classify impaired vs. unimpaired with up to 80% accuracy based on lane position deviation and lane departures. While this work requires replication in

  17. Different Mode of Afferents Determines the Frequency Range of High Frequency Activities in the Human Brain: Direct Electrocorticographic Comparison between Peripheral Nerve and Direct Cortical Stimulation.

    Directory of Open Access Journals (Sweden)

    Katsuya Kobayashi

    Full Text Available Physiological high frequency activities (HFA are related to various brain functions. Factors, however, regulating its frequency have not been well elucidated in humans. To validate the hypothesis that different propagation modes (thalamo-cortical vs. cortico-coritcal projections, or different terminal layers (layer IV vs. layer II/III affect its frequency, we, in the primary somatosensory cortex (SI, compared HFAs induced by median nerve stimulation with those induced by electrical stimulation of the cortex connecting to SI. We employed 6 patients who underwent chronic subdural electrode implantation for presurgical evaluation. We evaluated the HFA power values in reference to the baseline overriding N20 (earliest cortical response and N80 (late response of somatosensory evoked potentials (HFA(SEP(N20 and HFA(SEP(N80 and compared those overriding N1 and N2 (first and second responses of cortico-cortical evoked potentials (HFA(CCEP(N1 and HFA(CCEP(N2. HFA(SEP(N20 showed the power peak in the frequency above 200 Hz, while HFA(CCEP(N1 had its power peak in the frequency below 200 Hz. Different propagation modes and/or different terminal layers seemed to determine HFA frequency. Since HFA(CCEP(N1 and HFA induced during various brain functions share a similar broadband profile of the power spectrum, cortico-coritcal horizontal propagation seems to represent common mode of neural transmission for processing these functions.

  18. Ultradian feeding in mice not only affects the peripheral clock in the liver, but also the master clock in the brain.

    Science.gov (United States)

    Sen, Satish; Raingard, Hélène; Dumont, Stéphanie; Kalsbeek, Andries; Vuillez, Patrick; Challet, Etienne

    2017-01-01

    Restricted feeding during the resting period causes pronounced shifts in a number of peripheral clocks, but not the central clock in the suprachiasmatic nucleus (SCN). By contrast, daily caloric restriction impacts also the light-entrained SCN clock, as indicated by shifted oscillations of clock (PER1) and clock-controlled (vasopressin) proteins. To determine if these SCN changes are due to the metabolic or timing cues of the restricted feeding, mice were challenged with an ultradian 6-meals schedule (1 food access every 4 h) to abolish the daily periodicity of feeding. Mice fed with ultradian feeding that lost feeding. Mice fed with ultradian feeding that lost >10% body mass (i.e. hypocaloric) became more diurnal, hypothermic in late night, and displayed larger (3.5 h) advance of body temperature rhythm, more reduced PER1 expression in the SCN, and further modified gene expression in the liver (e.g. larger phase-advance of Per2 and up-regulated levels of Pgc-1α). While glucose rhythmicity was lost under ultradian feeding, the phase of daily rhythms in liver glycogen and plasma corticosterone (albeit increased in amplitude) remained unchanged. In conclusion, the additional impact of hypocaloric conditions on the SCN are mainly due to the metabolic and not the timing effects of restricted daytime feeding.

  19. Comparison of the effects of central and peripheral aluminum administration on regional 2-deoxy-D-glucose incorporation in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Lipman, J.J.; Tolchard, S. (Vanderbilt Univ., Nashville, TN (USA))

    1989-01-01

    Intracerebroventricular (ICV) Injection of aluminum tartrate (ALT 205.7 mcg) in the rat induces a progressive encephalopathy characterized by neurobehavioral derangements. The condition is associated with a reduced ability of cerebral synaptosomes to incorporate radiolabeled 2-Deoxy-D-glucose (2DG) in vitro. The present study surveyed and compared the in vivo regional cerebral glucose uptake (rCGlu) capacity of rats injected with ALT 7 or 14 days previously either by the ICV or intraperitoneal routes. ICV injection produces transient rCGlu depression in caudate-putamen, geniculate bodies and periaquaeductal gray, resolving by day 14. Thalamic nuclei exhibit depressed rCGlu by the 7th day undergoing further depression by day 14. The rCGlu of occipitoparietal cortices, normal at day 7, was increased by day 14. In contrast, peripheral aluminum administration produced transient rCGlu depression in olfactory bulbs, frontal and occipitoparietal cortices, nucleus accumbens and cerebellum, and transiently increased rCGlu in the geniculate nuclei. These effects, present by day 7, had resolved by day 14 when rCGlu has increased in the previously normal pontine nuclei and decreased in the previously normal hippocampus.

  20. Circulating brain derived neurotrophic factor (BDNF) and frequency of BDNF positive T cells in peripheral blood in human ischemic stroke: Effect on outcome.

    Science.gov (United States)

    Chan, Adeline; Yan, Jun; Csurhes, Peter; Greer, Judith; McCombe, Pamela

    2015-09-15

    The aim of this study was to measure the levels of circulating BDNF and the frequency of BDNF-producing T cells after acute ischaemic stroke. Serum BDNF levels were measured by ELISA. Flow cytometry was used to enumerate peripheral blood leukocytes that were labelled with antibodies against markers of T cells, T regulatory cells (Tregs), and intracellular BDNF. There was a slight increase in serum BDNF levels after stroke. There was no overall difference between stroke patients and controls in the frequency of CD4(+) and CD8(+) BDNF(+) cells, although a subgroup of stroke patients showed high frequencies of these cells. However, there was an increase in the percentage of BDNF(+) Treg cells in the CD4(+) population in stroke patients compared to controls. Patients with high percentages of CD4(+) BDNF(+) Treg cells had a better outcome at 6months than those with lower levels. These groups did not differ in age, gender or initial stroke severity. Enhancement of BDNF production after stroke could be a useful means of improving neuroprotection and recovery after stroke.

  1. 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.

  2. Benzodiazepines and risk of death: Results from two large cohort studies in France and UK.

    Science.gov (United States)

    Palmaro, Aurore; Dupouy, Julie; Lapeyre-Mestre, Maryse

    2015-10-01

    Benzodiazepines are widely prescribed for the treatment of anxiety or insomnia, but their impact on mortality is still debated. This study investigated the impact of benzodiazepine use on short term mortality. Exposed-unexposed cohorts were constructed with the Clinical Practice Research Datalink (CPRD) in the UK and with the General Sample of Beneficiaries (EGB) in France. Benzodiazepine incident users were matched to incident users of antidepressants/non-benzodiazepine sedatives and to controls (non-users of antidepressants or anxiolytics/hypnotics) according to age and gender in both sources (and practice for the CPRD only). Survival at one year was studied using Cox regression model. In the CPRD, the final population comprised 94 123 patients per group (57 287 in the EGB). In the CPRD, adjusted HR was 3.73 in benzodiazepine users (95% CI, 3.43-4.06), and 1.61 (1.47-1.76) in antidepressant/non-benzodiazepine users compared to controls. When considering benzodiazepine use as a time-dependent covariate, adjusted HR for current use at 12 months was 1.70 (1.36-2.12). In the EGB, adjusted HR was 1.26 in benzodiazepine users (95% CI, 1.08-1.48), and 1.07 (95% CI, 0.91-1.27) in antidepressant/non-benzodiazepine users. When considering benzodiazepine use as a time-dependent covariate, adjusted HR for current use at 12 months was 1.03 (0.74-1.44). Using two nationally representative databases, we found a significant while moderate increase in all-cause mortality in relation to benzodiazepines, in a population of incident and mostly occasional users. This issue need to be monitored given the extensive use of these drugs.

  3. Classical activation of microglia in CD200-deficient mice is a consequence of blood brain barrier permeability and infiltration of peripheral cells.

    Science.gov (United States)

    Denieffe, Stephanie; Kelly, Ronan J; McDonald, Claire; Lyons, Anthony; Lynch, Marina A

    2013-11-01

    The interaction between CD200, expressed on several cell types, and its receptor CD200R, expressed on cells of the myeloid lineage, has been shown to be an important factor in modulating inflammation in macrophage function in several conditions including colitis and arthritis. More recently its modulatory effect on microglial activation has been identified and CD200-deficiency has been associated with increased microglial activation accompanied by increased production of inflammatory cytokines. The response of glia prepared from CD200-deficient mice to stimuli like lipopolysaccharide (LPS) is markedly greater than the response of cells prepared from wildtype mice and, consistent with this, is the recent observation that expression of Toll-like receptor (TLR)4 and signalling through NFκB are increased in microglia prepared from CD200-deficient mice. Here we show that glia from CD200-deficient mice are also more responsive to interferon-γ (IFNγ) which triggers classical activation of microglia. We investigated the effects of CD200-deficiency in vivo and report that there is an increase in expression of several markers of microglial activation including tumor necrosis factor (TNF)-α, which is a hallmark of classically-activated microglia. These changes are accompanied by increased IFNγ, and the evidence suggests that this is produced by infiltrating cells including T cells and macrophages. We propose that these cells enter the brain as a consequence of increased blood brain barrier (BBB) permeability in CD200-deficient mice and that infiltration is assisted by increased expression of the chemokines, monocyte chemotactic protein-1 (MCP-1), IFNγ-induced protein-10 (IP-10) and RANTES. This may have implications in neurodegenerative diseases where BBB permeability is compromised.

  4. Prescription of benzodiazepines in general practice in the context of a man-made disaster: a longitudinal study.

    OpenAIRE

    2007-01-01

    BACKGROUND: Mental health problems associated with benzodiazepine treatment are often highly prevalent in the aftermath of disasters. Nevertheless, not much is known about benzodiazepine use after disasters. Considering the negative effects associated with prolonged use and the adverse effects of benzodiazepines on recovery of patients with acute stress, the aim of the present study was to explore benzodiazepine use in the context of the Enschede fireworks disaster of 13 May 2000. METHODS: A ...

  5. Potential Impact of Benzodiazepine Use on the Rate of Hip Fractures in Five Large European Countries and the United States

    OpenAIRE

    2012-01-01

    Benzodiazepine use increases the risk of falls and has been associated with an increased risk of hip fractures. Our aim was to estimate the possible population impact of the use of benzodiazepines on the rate of hip fracture in France, Germany, Italy, Spain, the United Kingdom, and the United States. We conducted a literature review to estimate the pooled relative risk (RR) for hip fractures and use of benzodiazepines. Prevalence rates of benzodiazepine use in 2009 were calculated for each co...

  6. [Peripheral neuropathies associated with hereditary cerebellar ataxias].

    Science.gov (United States)

    Anheim, M; Tranchant, C

    2011-01-01

    Inherited cerebellar ataxias constitute a complicated and heterogeneous group of neurodegenerative disorders affecting the cerebellum and/or spinocerebellar tract, spinal cord and peripheral nerves. A peripheral neuropathy is frequently seen in inherited cerebellar ataxias although it rarely reveals the disease. Moreover, the peripheral neuropathy is helpful for the diagnostic procedure and contributes to the functional prognosis of the disease. Thus, electroneuromyography is essential in the algorithm for the diagnosis of inherited cerebellar ataxias, as well as brain MRI (looking especially for cerebellar atrophy) and the assessment of several biomarkers (alpha-foetoprotein, vitamin E, albumin, LDL cholesterol, lactic acid, phytanic acid).

  7. Benzodiazepine Discontinuation among Adults with GAD: A Randomized Trial of Cognitive-Behavioral Therapy

    Science.gov (United States)

    Gosselin, Patrick; Ladouceur, Robert; Morin, Charles M.; Dugas, Michel J.; Baillargeon, Lucie

    2006-01-01

    This study evaluated the specific effectiveness of cognitive-behavior therapy (CBT) combined with medication tapering for benzodiazepine discontinuation among generalized anxiety disorder (GAD) patients by using a nonspecific therapy control group. Sixty-one patients who had used benzodiazepines for more than 12 months were randomly assigned to…

  8. 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 evaluatio

  9. Assessment of Benzodiazepine dependence in alcohol and drug dependent outpatients: A research report

    NARCIS (Netherlands)

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

    2001-01-01

    In this study on 99 outpatients who were being treated for alcohol and/or drug dependence and also using benzodiazepines (BZDs), prevalence rates of DSM-III-R and ICD-10 substance dependence diagnoses were ascertained and scalability, reliability and validity of the scales of the Benzodiazepine Depe

  10. 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 benz

  11. Determinants of chronic benzodiazepine use in the elderly: A longitudinal study

    NARCIS (Netherlands)

    H.J. Luijendijk (Hendrika); H.W. Tiemeier (Henning); A. Hofman (Albert); J. Heeringa (Jan); B.H.Ch. Stricker (Bruno)

    2008-01-01

    textabstractAIMS: The risk of adverse events due to chronic benzodiazepine use is high in the elderly. Clinicians need to be able to identify those persons who are at risk of chronic benzodiazepine use, but little is known about the determinants. This study determined social and health related facto

  12. The Relationship between Benzodiazepine Use and Traffic Accidents A Systematic Literature Review

    NARCIS (Netherlands)

    Smink, Beitske E.; Egberts, Antoine C. G.; Lusthof, Klaas J.; Uges, Donald R. A.; de Gier, Johan I.

    2010-01-01

    In many countries, benzodiazepines are the most commonly used and misused psychoactive medicinal drugs. Results of epidemiological studies investigating the association between benzodiazepine use and traffic accidents seem to be inconclusive or inconsistent at first sight. However, the outcome of ep

  13. High affinity, bioavailable 3-amino-1,4-benzodiazepine-based gamma-secretase inhibitors.

    Science.gov (United States)

    Owens, Andrew P; Nadin, Alan; Talbot, Adam C; Clarke, Earl E; Harrison, Timothy; Lewis, Huw D; Reilly, Michael; Wrigley, Jonathan D J; Castro, José L

    2003-11-17

    In this paper, we describe the development of a novel series of high affinity, orally bioavailable 3-amino-1,4 benzodiazepine-based gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. We disclose structure-activity relationships based around the 1, 3 and 5 positions of the benzodiazepine core structure.

  14. 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 care

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

    NARCIS (Netherlands)

    Oude Voshaar, R.C.; Krabbe, P.F.M.; Gorgels, W.J.M.J.; Adang, E.M.M.; Balkom, A.J.L.M. van; Lisdonk, E.H. van de; Zitman, F.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 care

  16. Benzodiazepiner og cyclopyrroloner før, under og efter hospitalsindlaeggelse

    DEFF Research Database (Denmark)

    Andersen, Stig Ejdrup; Møller, Frederik Trier

    2010-01-01

    The aim was to describe the prescription patterns of benzodiazepines (BZD) and cyclopyrrolones (Z-drugs) in a population of medical and surgical patients prior to, during and after hospital admission.......The aim was to describe the prescription patterns of benzodiazepines (BZD) and cyclopyrrolones (Z-drugs) in a population of medical and surgical patients prior to, during and after hospital admission....

  17. Tolerance to benzodiazepines among long-term users in primary care

    NARCIS (Netherlands)

    Willems, Inge A. T.; Gorgels, Wim J. M. J.; Voshaar, Richard C. Oude; Mulder, Jan; Lucassen, Peter L. B. J.

    2013-01-01

    BACKGROUND: Tolerance towards the effects of benzodiazepines is observed in various animal and human studies. Therefore, it is assumed that patients who use benzodiazepines for a longer period of time need to increase their dose over time to experience the same effect. OBJECTIVE: To observe whether

  18. Childhood maternal care is associated with DNA methylation of the genes for brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) in peripheral blood cells in adult men and women.

    Science.gov (United States)

    Unternaehrer, Eva; Meyer, Andrea Hans; Burkhardt, Susan C A; Dempster, Emma; Staehli, Simon; Theill, Nathan; Lieb, Roselind; Meinlschmidt, Gunther

    2015-01-01

    In adults, reporting low and high maternal care in childhood, we compared DNA methylation in two stress-associated genes (two target sequences in the oxytocin receptor gene, OXTR; one in the brain-derived neurotrophic factor gene, BDNF) in peripheral whole blood, in a cross-sectional study (University of Basel, Switzerland) during 2007-2008. We recruited 89 participants scoring  33 (n = 42, 35 women) on the maternal care subscale of the Parental Bonding Instrument (PBI) at a previous assessment of a larger group (N = 709, range PBI maternal care = 0-36, age range = 19-66 years; median 24 years). 85 participants gave blood for DNA methylation analyses (Sequenom(R) EpiTYPER, San Diego, CA) and cell count (Sysmex PocH-100i™, Kobe, Japan). Mixed model statistical analysis showed greater DNA methylation in the low versus high maternal care group, in the BDNF target sequence [Likelihood-Ratio (1) = 4.47; p = 0.035] and in one OXTR target sequence Likelihood-Ratio (1) = 4.33; p = 0.037], but not the second OXTR target sequence [Likelihood-Ratio (1) BDNF (estimate = -0.005, 95% CI = -0.025 to 0.015; p = 0.626) or OXTR DNA methylation (estimate = -0.015, 95% CI = -0.038 to 0.008; p = 0.192). Hence, low maternal care in childhood was associated with greater DNA methylation in an OXTR and a BDNF target sequence in blood cells in adulthood. Although the study has limitations (cross-sectional, a wide age range, only three target sequences in two genes studied, small effects, uncertain relevance of changes in blood cells to gene methylation in brain), the findings may indicate components of the epiphenotype from early life stress.

  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. 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.

  1. Off-Label Use of Medications for Treatment of Benzodiazepine Use Disorder.

    Science.gov (United States)

    Sabioni, Pamela; Bertram, Jonathan; Le Foll, Bernard

    2015-01-01

    There is a high rate of benzodiazepine use in the population. Benzodiazepines are used for multiple indications (anxiety, seizures, alcohol withdrawal, muscular relaxation and anesthesia). Benzodiazepines are also addictive substances and a non-negligible fraction of regular users will develop dependence. There is currently no approved pharmacotherapy for benzodiazepine use disorder treatment and optimal strategies for treatment are unclear. In this review, we aimed to summarize the findings on off-label pharmacologic therapy that have been used for BZD dependence. One classical approach is to provide a slow taper associated with counseling. Anti-epileptic drugs appear also to alleviate symptoms of withdrawal. The long-term strategies of maintenance therapy (with benzodiazepine) or of blocking therapy (with a GABA antagonist such as flumazenil) could provide some clinical benefit but have not yet been tested appropriately. Pregabalin appears promising and deserves further investigation. There is a clear need for more clinical trials in this area to improve care.

  2. Recent development in [1,4]benzodiazepines as potent anticancer agents: a review.

    Science.gov (United States)

    Gill, Rupinder Kaur; Kaushik, Shiv Om; Chugh, Jasreen; Bansal, Sumit; Shah, Anamik; Bariwal, Jitender

    2014-01-01

    The [1,4]benzodiazepine is an important class of heterocyclic compounds and clinically used for many ailments in humans. The [1,4]benzodiazepine has unique structure that mimics the peptide linkage. This interesting observation completely shifted the interest of medicinal chemist for [1,4]benzodiazepine from CNS acting drugs to anticancer agents. During last few decades, a large number of reports have appeared in the literature highlighting the anticancer activity of [1,4]benzodiazepines. Here, in this article, we have discussed the brief synthesis, origin of [1,4]benzodiazepines as anticancer agent, their mechanism of action and latest developments in this field. We have compiled the most important literature reports from last few decades till date.

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

    OpenAIRE

    2012-01-01

    Background 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 ...

  4. [Benzodiazepines and limbic system. Anxiety and vigilance (author's transl)].

    Science.gov (United States)

    Gekiere, F; Allegre, G; Brindeau, F; Borenstein, P

    1980-01-01

    A neurophysiological study of 4 benzodiazepines in the free implanted cat serves as basis to a discussion concerning tranquilizers, anxiety and vigilance. The electrophysiological and behavioural effects of diazepam, nitrazepam, lorazepam and of clorazepate dipotassique are analysed and compared between them and other psychotropic drugs. Their mode of action on the behaviour, on the bioelectric cortical and hippocampal rhythms, is explained according to recent biochemical data. The relations with anxiety, vigilance and neuro-psycho-physiologic mechanisms which subtend them are discussed at the light of clinical effects provoked by substances called tranquillizers.

  5. Benzodiazepine receptor ligands: a patent review (2006 -- 2012)

    OpenAIRE

    2013-01-01

    Introduction: Ligands at the benzodiazepine site of the GABAA receptor (GABAA-R) act by modulating the effect of GABAA (g-aminobutyric acid). The selective modulator effects of such ligands are related to the a-subunits type (i.e., a1, a2, a3, and a5), being shown that the a1 subunit is associated with sedative, anticonvulsant and amnesic effects; whereas the a2 and a3 subunits mediate anxiolytic and myorelaxant effects. Recently it was shown the involvement of a5 subunit in...

  6. Application of radioreceptor assay of benzodiazepines for toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Aaltonen, L.; Scheinin, M. (Department of Pharmacology and the Department of Internal Medicine, University of Turku, Finland)

    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.

  7. Across-sectional survey on benzodiazepine use among older people in an Italian region

    Directory of Open Access Journals (Sweden)

    Francesco Donato

    2005-06-01

    Full Text Available

    Background. Benzodiazepines are among the most commonly prescribed drugs in Italy and they are often used inappropriately according to guidelines for their rational use.

    The aim of this study was to investigate the prevalence and pattern of use of benzodiazepine amongst the general population aged 65-84 years in the Friuli-Venezia Giulia Region, in North-East Italy.

    Methods. A total of 40 general practitioners participated in the study. Two data sources were used in the research. The first was the Health Search Database, the second was a short questionnaire administered by the general practitioners to the 65 to 84 year old patients attending their surgeries for any reason during the study period. Data on the use of benzodiazepines between 1st February and 31st July 2001 were extracted from both the Health Search Database using drug prescriptions and the questionnaires.

    Results. Of the 10,468 patients aged 65-84 years with complete demographical data in the general practitioners’ patient lists, 2,369 subjects used benzodiazepines, hypnotics and over the counter drugs. Overall prevalence of benzodiazepine use was 21.5% (95% confidence interval: 19.8-23.1%. Of the benzodiazepine users, 66.9% consumed a short-intermediate half-life and 33.1% a long half-life benzodiazepine. Most patients took benzodiazepines at night (68.2%, less frequently in the daytime and at night (23.7%, or in the daytime only (8.1%. Most users (89.2% said they had been taking benzodiazepine for years.

    Conclusions. Benzodiazepine use was associated with patient characteristics, such as being female, using analgesics or antidepressants and the presence of a chronic disease especially cancer or chronic heart failure.

  8. 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.

  9. The relationship between benzodiazepine use and traffic accidents: A systematic literature review.

    Science.gov (United States)

    Smink, Beitske E; Egberts, Antoine C G; Lusthof, Klaas J; Uges, Donald R A; de Gier, Johan J

    2010-08-01

    In many countries, benzodiazepines are the most commonly used and misused psychoactive medicinal drugs. Results of epidemiological studies investigating the association between benzodiazepine use and traffic accidents seem to be inconclusive or inconsistent at first sight. However, the outcome of epidemiological studies may be influenced by several methodological factors like study design, study population, exposure measurement, outcome definitions and possible confounders. Our objective was to conduct a systematic literature review of epidemiological studies that investigated the association between benzodiazepine use and traffic accidents, including related outcomes like culpability and injury or accident severity. We searched EMBASE, PubMed and Forensic Science Abstracts 3/0 (FORS) for references included in these databases at 1 June 2009 using the term 'benzodiazepines' in combination with 'driving performance' or 'accident risk' or 'traffic accident'. For inclusion in this review, the study design had to be comparative, include road users involved in accidents and provide specific data about benzodiazepines. Sixty-six studies were included in the review. The study populations varied from the general (driving) population, accident-involved road users with or without injury and persons admitted to a hospital to fatally injured accident-involved drivers. Exposure assessment was performed by using toxicological results, prescription data or questionnaires. The divergent study populations and comparison groups and the variety of methods used to express the outcome of interest hampered comparison between results. Evidence is growing that exposure to benzodiazepines is related to increased accident risk. The literature indicates that the greatest accident risk is associated with the use of long half-life benzodiazepines, increasing dosage and the first few weeks of use of benzodiazepines. Clear evidence of increased culpability associated with benzodiazepine use is

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

    Directory of Open Access Journals (Sweden)

    Tharani Ambreen

    2011-08-01

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

  11. Benzodiazepines and risk of hip fractures in older people: a review of the evidence.

    Science.gov (United States)

    Cumming, Robert G; Le Couteur, David G

    2003-01-01

    A hip fracture epidemic is occurring in developed countries in association with population aging. The increasing number of people with a hip fracture has major implications for clinicians and health service managers. More importantly, a hip fracture is a devastating event in the life of an older person, as it often leads to loss of independence and death. Identification of risk factors for hip fracture is an essential first step towards prevention. The use of psychotropic medications is an established risk factor for hip fracture. The purpose of this article is to systematically review epidemiological studies of the relationship between use of benzodiazepines and risk of hip fracture and, then, to see how the findings of these studies fit with what is known about the pharmacology of benzodiazepines. Eleven primary epidemiological studies were identified. The results of these studies were not consistent; however, the inconsistency appeared to be almost entirely explained by research design. The studies that did not show an association between increased hip fracture risk and benzodiazepine use were nearly all hospital-based case-control studies, a type of study that often lacks validity because of the difficulty of finding an appropriate control group. After excluding the hospital-based case-control studies, all but one of the remaining seven studies found that use of benzodiazepines was associated with an increased risk of hip fracture that varied between 50% and 110%. The only higher quality study that did not find an association between benzodiazepine use and hip fracture was also the only study conducted entirely in nursing homes. There was no evidence that the risk of hip fracture differed between short- and long-acting benzodiazepines. People using higher doses of benzodiazepines and those who had recently started using benzodiazepines were at the highest risk of hip fracture. In very old people, there was some preliminary evidence that benzodiazepines that

  12. Neuropharmacological profile of clobazam, a new 1',5'-benzodiazepine.

    Science.gov (United States)

    Gerhards, H J

    1978-06-15

    The effect of the new 1,5-benzodiazepine clobazam on visual evoked potentials (VEP) and spontaneous EEG in the conscious rabbit and on spinal polysynaptic reflexes in the decerebrated cat was studied in comparison to the 1,4-benzodiazepine diazepam. Clobazam was half as potent as diazepam in depressing the amplitude of visual evoked potentials in the nonanaesthetized rabbit, whereas the depressing effect on spinal polysynaptic reflexes in the decerebrated cat was only 1/7 --1/30 of the diazepam effect. The action of clobazam and diazepam on VEP also showed differences in time course, i.e., the peak effect of clobazam lasted from 1 to 6 h after application, whereas the effect of diazepam appeared after 10 min and declined already after 1 h. Both compounds had similar effects on computer-analyzed spontaneous EEG in the rabbit (power spectrum analysis), with an increase of power in the beta-band (13-39Hz) and a decrease in the alpha (8-13 Hz) and theta (4-8Hz) bands.

  13. A [11C]Ro15 4513 PET study suggests that alcohol dependence in man is associated with reduced α5 benzodiazepine receptors in limbic regions.

    Science.gov (United States)

    Lingford-Hughes, Anne; Reid, Alastair G; Myers, James; Feeney, Adrian; Hammers, Alexander; Taylor, Lindsay G; Rosso, Lula; Turkheimer, Federico; Brooks, David J; Grasby, Paul; Nutt, David J

    2012-02-01

    Preclinical evidence suggests the α5 subtype of the GABA-benzodiazepine receptor is involved in some of the actions of alcohol and in memory. The positron emission tomography (PET) tracer, [(11)C]Ro15 4513 shows relative selectivity in labelling the α5 subtype over the other GABA-benzodiazepine receptor subtypes in limbic regions of the brain. We used this tracer to investigate the distribution of α5 subtype availability in human alcohol dependence and its relationship to clinical variables. Abstinent (>6 weeks) alcohol-dependent men and healthy male controls underwent an [(11)C]Ro15 4513 PET scan. We report [(11)C]Ro15 4513 brain uptake for 8 alcohol-dependent men and 11 healthy controls. We found a significant reduction in [(11)C]Ro15 4513 binding in the nucleus accumbens, parahippocampal gyri, right hippocampus and amygdala in the alcohol-dependent compared with the healthy control group. Levels of [(11)C]Ro15 4513 binding in both hippocampi were significantly and positively associated with performance on a delayed verbal memory task in the alcohol-dependent but not the control group. We speculate that the reduced limbic [(11)C]Ro15 4513 binding seen here results from the effects of alcohol, though we cannot currently distinguish whether they are compensatory in nature or evidence of brain toxicity.

  14. Systematic review of modulators of benzodiazepine receptors in irritable bowel syndrome:Is there hope?

    Institute of Scientific and Technical Information of China (English)

    Pooneh Salari; Mohammad Abdollahi

    2011-01-01

    Several drugs are used in the treatment of irritable bowel syndrome (IBS) but all have side effects and variable efficacy.Considering the role of the gut-brain axis,immune,neural,and endocrine pathways in the patho-genesis of IBS and possible beneficial effects of ben-zodiazepines (BZD) in this axis,the present systematic review focuses on the efficacy of BZD receptor modulators in human IBS.For the years 1966 to February 2011,all literature was searched for any articles on the use of BZD receptor modulators and IBS.After thorough evaluation and omission of duplicate data,10 out of 69 articles were included.BZD receptor modulators can be helpful,especially in the diarrhea-dominant form of IBS,by affecting the inflammatory,neural,and psychologic pathways,however,controversies still exist.Recently,a new BZD receptor modulator,dextofisopam was synthesized and studied in human subjects,but the studies are limited to phase II b clinical trials.None of the existing trials considered the neuroimmunomodulatory effectof BZDs in IBS,but bearing in mind the concentration-dependent effect of BZDs on cytokines and cell proliferation,future studies using pharmacodynamic and pharmacokinetic approaches are highly recommended.

  15. Agonist substitution--a treatment alternative for high-dose benzodiazepine-dependent patients?

    Science.gov (United States)

    Liebrenz, Michael; Boesch, Lukas; Stohler, Rudolf; Caflisch, Carlo

    2010-11-01

    There is vast evidence for the superiority of agonist treatments (methadone, buprenorphine) over a withdrawal approach in opioid-dependent populations. Little research, however, has been conducted on the same approach for the treatment of high-dose benzodiazepine (BZD) dependence. Even large-scale reviews and meta-analyses discussing treatment strategies for benzodiazepine-dependent patients focus solely upon approaches that aim at achieving abstinence, namely on complete BZD withdrawal. While the types of interventions differ (e.g. gradual benzodiazepine taper with a long or a short half-life benzodiazepine, switching to non-benzodiazepine anxiolytics or prescribing adjunctive medications such as antidepressants or anticonvulsants on an in- or out-patient basis), the common aim of treatment still is total abstinence from benzodiazepines. However, the majority of patients suffering from high-dose BZD dependence do not succeed with long-term abstinence, irrespective of the procedure, and clinicians have been using BZD 'substitution' treatment in such cases for decades. Therefore, we suggest the evaluation of a substitution approach in this group, consisting of maintenance treatment with a slow-onset, long-acting BZD. Advantages of such a procedure may be improved health, less craving, fewer withdrawal complications, reduced anxiety, increased treatment retention, improvements in social functioning and less illegal activity. Cognitive impairments, the most problematic side effects of substitution treatment with benzodiazepines, could possibly be minimized by using an optimal agonist.

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

    Energy Technology Data Exchange (ETDEWEB)

    Sarter, M.; Schneider, H.H.

    1988-07-01

    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 (/sup 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.

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

    Science.gov (United States)

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

    2014-02-01

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

  18. Peripheral intravenous line (image)

    Science.gov (United States)

    A peripheral intravenous line is a small, short plastic catheter that is placed through the skin into a vein, ... or foot, but occasionally in the head. A peripheral intravenous line is used to give fluids and ...

  19. Peripheral arterial line (image)

    Science.gov (United States)

    A peripheral arterial line is a small, short plastic catheter placed through the skin into an artery of the arm or leg. The purpose of a peripheral arterial line is to allow continuous monitoring of ...

  20. Adjunctive benzodiazepine treatment of hospitalized schizophrenia patients in Asia from 2001 to 2008.

    Science.gov (United States)

    Tor, Phern-Chern; Ng, Tze Pin; Yong, Kian-Hui; Sim, Kang; Xiang, Yu-Tao; Wang, Chuan-Yue; Lee, Edwin Ho Ming; Fujii, Senta; Yang, Shu-Yu; Chong, Mian-Yoon; Ungvari, Gabor S; Si, Tianmei; He, Yan Ling; Chung, Eun Kee; Chee, Kok-Yoon; Trivedi, Jintendra; Udomratn, Pichet; Shinfuku, Naotaka; Kua, Ee Heok; Tan, Chay Hoon; Sartorius, Norman; Baldessarini, Ross J

    2011-07-01

    Benzodiazepines are commonly prescribed to patients with schizophrenia in many countries, but as little is known about such treatment in Asia, we evaluated their adjunctive use for 6761 in-patients diagnosed with schizophrenia in nine Asian countries using a cross-sectional study design in 2001, 2004 and 2008. Multivariate logistic regression and multivariate linear regression analyses were performed to assess predictors of benzodiazepine use and dose, respectively. Overall, 54% of the patients received adjunctive benzodiazepines at an average daily dose equivalent to 30.3 mg diazepam, with minor changes over the years sampled. Benzodiazepine use was highest in Taiwan and Japan, lowest in Thailand and China, and was associated with fewer years ill, presence of delusions (OR 1.24), hallucinations (OR 1.22), disorganized speech (OR 1.17), social or occupational dysfunction (OR 1.16), and use of mood stabilizers (OR 3.15), antiparkinsonian (OR 1.79) or antidepressant drugs (OR 1.33), and lower doses of antipsychotics (all p=0.016 to Benzodiazepine doses were highest in Taiwan and China, lowest in Korea and Singapore; higher doses were associated with being young, male, physically aggressive, receiving mood stabilizers, and having electroconvulsive treatment (all p=0.019 to Benzodiazepine use was associated with neurological and systemic adverse effects. In conclusion, benzodiazepine use was common in Asian patients with schizophrenia. Predictors of benzodiazepine use and dose differed in this population. Critical clinical guidelines should be developed specifically for Asian countries to address sound practices in regard to use of benzodiazepines for psychotic disorders.

  1. Selective peripheral denervation : comparison with pallidal stimulation and literature review

    NARCIS (Netherlands)

    Contarino, Maria Fiorella; Van den Munckhof, Pepijn; Tijssen, Marina A. J.; de Bie, Rob M. A.; Bosch, D. Andries; Schuurman, P. Richard; Speelman, Johannes D.

    2014-01-01

    Patients with cervical dystonia who are non-responders to Botulinum toxin qualify for surgery. Selective peripheral denervation (Bertrand's procedure, SPD) and deep brain stimulation of the globus pallidus (GPi-DBS) are available surgical options. Although peripheral denervation has potential advant

  2. Propylthiouracil and peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Valentina Van Boekel

    1992-06-01

    Full Text Available Peripheral neuropathy is a rare manifestation in hyperthyroidism. We describe the neurological manifestations of a 38 year old female with Graves' disease who developed peripheral neuropathy in the course of her treatment with propylthiouracil. After the drug was tapered off, the neurological signs disappeared. Therefore, we call attention for a possible toxic effect on peripheral nervous system caused by this drug.

  3. 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.

  4. 1,4-Benzodiazepine drugs adsorption on the Ag colloidal surface

    Science.gov (United States)

    Cîntã, S.; Iliescu, T.; Astilean, S.; David, L.; Cozar, O.; Kiefer, W.

    1999-05-01

    The adsorption behaviour in the SERS complex of diazepam (7-chloro-1-methyl-5-phenyl-3-dihydro-1,4-benzodiazepin-2-one) and nitrazepam (1,3-dihydro-7-nitro-5-phenyl-1,4-benzodiazepin-2-one) with the Ag colloidal particles is reported and discussed. In both cases, the CN bond vibration of the 1,4-benzodiazepine is strongly affected by adsorption and enhanced. The SERS system of Ag colloid with diazepam or nitrazepam allow the recognition of the drug sample at concentration of 10 -7 mol l -1.

  5. [Are z-hypnotics better and safer sleeping pills than benzodiazepines?].

    Science.gov (United States)

    Mellingsaeter, Trude C; Bramness, Jørgen G; Slørdal, Lars

    2006-11-16

    Benzodiazepines and the benzodiazepine-like z-hypnotics (zopiclone, zolpidem, and zaleplon) have the same mode of action and many of the same effects. The use of z-hypnotics has had a steady and large increase since their introduction in Norway, and sales data suggest extensive use among the elderly. The relatively short half-lives of these drugs may cause less hangover effects, but z-hypnotics are hardly more effective or safer than benzodiazepines. The two classes of drugs should be prescribed with similar caution.

  6. 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.

  7. Detection of benzodiazepines in different tissues, including bone, using a quantitative ELISA assay.

    Science.gov (United States)

    Gorczynski, L Y; Melbye, F J

    2001-07-01

    Benzodiazepines were analyzed in different tissue samples, including hone, by ELISA. The sensitivity of detection for different benzodiazepines was consistent with the manufacturer's reports of the cross reactivities of the antibodies used, with the greatest sensitivity for midazolam and the least for diazepam; in addition the pharmacokinetics was consistent with the known duration of action of the different benzodiazepines, with midazolam cleared rapidly, and diazepam slowly. Following intramuscular injection of 300 microg of midazolam at 16 h intervals for ten days, the drug was detectable in bone tissue samples obtained from skeletonized remains buried in soil at room temperature for three weeks.

  8. A New Method of Separation of Four Benzodiazepines by RP-CEC

    Institute of Scientific and Technical Information of China (English)

    Jin Lan ZHANG; Tong Hui ZHOU

    2004-01-01

    A new method to separate diazepam, nitrazepam, estazolam, alprazolam was established on both C18 and C8 CEC columns.The influence of separation voltage, Tris concentration, column temperature and the percentage of acetonitrile on the resolution and retention behavior of four benzodiazepines was investigated.The results showed that the percentage of acetonitrile had the largest effect on the resolution and retention behavior of the four benzodiazepines.Other separation conditions had also effects on the resolution and retention behavior, but smaller than the concentration of acetonitrile.Optimum separation conditions were obtained to separate four benzodiazepines on C18 and C8 CEC columns.

  9. Complexity of illness and adjunctive benzodiazepine use in outpatients with bipolar I or II disorder: results from the Bipolar CHOICE study.

    Science.gov (United States)

    Bobo, William V; Reilly-Harrington, Noreen A; Ketter, Terence A; Brody, Benjamin D; Kinrys, Gustavo; Kemp, David E; Shelton, Richard C; McElroy, Susan L; Sylvia, Louisa G; Kocsis, James H; McInnis, Melvin G; Friedman, Edward S; Singh, Vivek; Tohen, Mauricio; Bowden, Charles L; Deckersbach, Thilo; Calabrese, Joseph R; Thase, Michael E; Nierenberg, Andrew A; Rabideau, Dustin J; Schoenfeld, David A; Faraone, Stephen V; Kamali, Masoud

    2015-02-01

    Benzodiazepines are widely prescribed for patients with bipolar disorders in clinical practice, but very little is known about the subtypes of patients with bipolar disorder or aspects of bipolar illness that contribute most to benzodiazepine use. We examined the prevalence of and factors associated with benzodiazepine use among 482 patients with bipolar I or II disorder enrolled in the Bipolar CHOICE study. Eighty-one subjects were prescribed benzodiazepines at study entry and were considered benzodiazepine users. Stepwise logistic regression was used to model baseline benzodiazepine use versus nonuse, using entry and exit criteria of P benzodiazepine users were prescribed a significantly higher number of other psychotropic medications and were more likely to be prescribed lamotrigine or antidepressants as compared with benzodiazepine nonusers. Benzodiazepine users were more likely to have a diagnosis of bipolar I disorder and comorbid anxiety disorder, but not comorbid alcohol or substance use disorders. Benzodiazepine users also had experienced more anxiety and depressive symptoms and suicidality, but not irritability or manic symptoms, than did benzodiazepine nonusers. In the multivariate model, anxiety symptom level (regardless of diagnosis), lamotrigine use, number of concomitant psychotropic medications, college education, and high household income predicted benzodiazepine use. Benzodiazepine use in patients with bipolar disorders is associated with greater illness complexity as indicated by a higher number of concomitant psychotropic medications and higher anxiety symptom burden, regardless of a comorbid anxiety disorder diagnosis. Demographic factors were also important determinants of benzodiazepine use, which may be related to access to care and insurance coverage for benzodiazepines.

  10. Pharmacological properties of AC-3933, a novel benzodiazepine receptor partial inverse agonist.

    Science.gov (United States)

    Hashimoto, T; Kiyoshi, T; Kohayakawa, H; Iwamura, Y; Yoshida, N

    2014-01-01

    We investigated in this study the pharmacological properties of AC-3933 (5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1,6-naphthyridin-2(1H)-one), a novel benzodiazepine receptor (BzR) partial inverse agonist. AC-3933 potently inhibited [3H]-flumazenil binding to rat whole brain membrane with a Ki value of 5.15 ± 0.39 nM and a GABA ratio of 0.84 ± 0.03. AC-3933 exhibited almost no affinity for the other receptors, transporters and ion channels used in this study. In addition, AC-3933, in the presence of GABA (1 μM), gradually but significantly increased [³⁵S] tert-butylbicyclophosphorothionate binding to rat cortical membrane to 117.1% of the control (maximum increase ratio) at 3000 nM. However, this increase reached a plateau at 30 nM with hardly any change at a concentration range of 100-3000 nM (from 115.2% to 117.1%). AC-3933 (0.1-10 μM) significantly enhanced KCl-evoked acetylcholine (ACh) release from rat hippocampal slices in a concentration-dependent manner. Moreover, in vivo brain microdialysis showed that intragastric administration of AC-3933 at the dose of 10 mg/kg significantly increased extracellular ACh levels in the hippocampus of freely moving rats (area under the curve (AUC₀₋₂ h) of ACh level; 288.3% of baseline). These results indicate that AC-3933, a potent and selective BzR inverse agonist with low intrinsic activity, might be useful in the treatment of cognitive disorders associated with degeneration of the cholinergic system.

  11. Benzodiazepine whole blood concentrations in cases with positive oral fluid on-site screening test results using the DrugWipe(®) single for benzodiazepines.

    Science.gov (United States)

    Blencowe, Tom; Vimpari, Kari; Lillsunde, Pirjo

    2011-07-01

    Reliable on-site oral fluid screening devices are a useful and convenient means of policing traffic. In Finland, benzodiazepines represent a particular challenge to traffic safety. This study presents a retrospective examination of toxicological analysis results from whole blood in cases which gave a positive screening result for benzodiazepines in oral fluid using the DrugWipe Single device (Securetec). Use of oral fluid on-site screening tests and blood confirmation analyses reflects the real situation in many countries. The data were compiled from the databases of Alcohol and Drug Analytics Unit at the National Institute for Health and Welfare. Confirmation analysis results in whole blood were obtained using gas chromatography-mass spectrometry. Data were from 224 real cases in which the Finnish police had conducted a DrugWipe Single benzodiazepines test on drivers suspected of driving under the influence of drugs (DUID). The benzodiazepine concentrations encountered in positive oral fluid screening cases in this study indicate that the device is able to detect these substances even at relatively low levels. However, the DrugWipe device does not enable any distinction between therapeutic use and harmful use of benzodiazepines at higher doses.

  12. In vitro effect of benzodiazepines on polymorphonuclear leukocyte oxidative activity.

    Science.gov (United States)

    Goldfarb, G; Belghiti, J; Gautero, H; Boivin, P

    1984-01-01

    The effect of three benzodiazepine compounds, diazepam, flunitrazepam, and clorazepate, on oxidative activity of human polymorphonuclear leukocyte (PMN) was investigated. The oxidative activity of zymosan-stimulated PMN in the presence of three concentrations (10, 20, and 40 micrograms/ml) of these compounds was measured polarographically. In addition, zymosan-stimulated nitroblue tetrazolium (NBT) reduction was measured in the presence of various concentrations of flunitrazepam. All three compounds inhibited oxygen consumption of the PMN. The extent of inhibition was linear with respect to log-concentrations; oxygen consumption was reduced 50% for concentrations of diazepam, flunitrazepam, and clorazepate of 13 micrograms/ml, 56 micrograms/ml, and 285 micrograms/ml, respectively. In addition 30% and 100% inhibition of NBT reduction by flunitrazepam were observed at respective concentrations of 10 micrograms/ml and 60 micrograms/ml. The clinical relevance of these findings remains to be determined.

  13. Pregabalin in the treatment of alcohol and benzodiazepines dependence.

    Science.gov (United States)

    Oulis, Panagiotis; Konstantakopoulos, George

    2010-01-01

    We review all available studies on the use of the newer anticonvulsant drug pregabalin (PGB) in the treatment of both alcohol dependence (AD) and benzodiazepine dependence (BD). In AD, the available evidence includes one open-label and one double-blind randomized studies, whereas in BD, only a few case reports and one open-label study are as yet available. In both conditions, PGB was found efficacious with significant improvement in withdrawal symptoms at the dosage ranges of 150-450 mg/day (AD) and 225-900 mg/day (BD). Moreover, its side effects were mild and transient. Despite the limited quality of the studies design, their findings suggest that PGB might constitute a novel efficacious and safe option in the treatment of both AD and BD.

  14. Clinical observations in children after prenatal benzodiazepine exposure.

    Science.gov (United States)

    Laegreid, L

    1990-01-01

    Eight children excessively exposed to benzodiazepines (BZD) in utero are described. Five of the 8 mothers admitted regular use of BZD and in 3 mothers, stored serum from early pregnancy could be analysed and found positive for BZD and its metabolite. All the children had similar dysmorphic features, in addition, 1 child had aplasia of one kidney and 2 had cleft palate. At follow-up 2 children had become microcephalic. 2 were severely mentally retarded, 5 had a mild mental retardation and only 1 was of normal intelligence. In a case-control study, 4 neonatal diagnoses of congenital malformations, in our experience characteristic of fetal BZD exposure, were chosen as inclusion criteria. In 8 of 18 cases, blood samples from early pregnancy were positive for BZD as compared to 2 of 60 control samples. An association between BZD-positive serum tests and the particular diagnoses could be demonstrated (p = 0.00006).

  15. Correlates of (inappropriate) benzodiazepine use : the Netherlands Study of Depression and Anxiety (NESDA)

    NARCIS (Netherlands)

    Manthey, Leonie; van Veen, Tineke; Giltay, Erik J.; Stoop, Jose E.; Neven, Arie Knuistingh; Penninx, Brenda W. J. H.; Zitman, Frans G.

    2011-01-01

    AIM Results on determinants of benzodiazepine (BZD) use in general and inappropriate use were inconsistent and mostly univariate. The relative importance of sociodemographic, psychological and physical determinants has never been investigated in a comprehensive, multivariate model. METHODS We includ

  16. Central benzodiazepine receptor imaging and quantitation with single photon emission computerised tomography

    DEFF Research Database (Denmark)

    Okocha, C I; Kapczinski, F; Lassen, N

    1995-01-01

    This review discusses the current use of single photon emission computerised tomography (SPECT) for central benzodiazepine receptor imaging and quantitation. The general principles underlying SPECT imaging and receptor quantitation methods such as the kinetic, pseudo-equilibrium and steady...

  17. An efficient synthesis of 1,5-benzodiazepine derivatives catalyzed by boric acid

    Institute of Scientific and Technical Information of China (English)

    Xin Zhou; Mei Yue Zhang; Shu Tao Gao; Jing Jun Ma; Chun Wang; Chao Liu

    2009-01-01

    1,5-Benzodiazepine derivatives have been synthesized by the condensation of o-phenylenediamines and ketones in the presence of boric acid as catalyst under mild conditions. This method is simple, environmentally benign and high yielding.

  18. Sulfanilic acid catalyzed solvent-free synthesis of 1,5-benzodiazepine derivatives

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Sulfanilic acid has been found to be an efficient catalyst for the synthesis of 1,5-benzodiazepines from o-phenylenediamine and ketones. This method is simple, effective and environmentally friendly and gives better yields.

  19. 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.

  20. Robust brain-computer interfaces

    NARCIS (Netherlands)

    Reuderink, Boris

    2011-01-01

    A brain-computer interface (BCI) enables direct communication from the brain to devices, bypassing the traditional pathway of peripheral nerves and muscles. Current BCIs aimed at patients require that the user invests weeks, or even months, to learn the skill to intentionally modify their brain sign

  1. Positive Drug Screen for Benzodiazepine Due to a Chinese Herbal Product

    OpenAIRE

    Eachus, Patricia L.

    1996-01-01

    A female athlete tested positive for benzodiazepine on a random drug screen. She denied taking any illicit or prescription drugs. The positive screen was found to be caused by undeclared addiction of diazepam to a Chinese herbal product, “Miracle Herb.” Some foreign vitamins, health care products, or herbal tea may contain banned or dangerous additives unknown to the consumer. These additives may include ingredients such as benzodiazepine, mefenamic acid, or corticosteroids. Possible physical...

  2. Intramolecular azide to alkene cycloadditions for the construction of pyrrolobenzodiazepines and azetidino-benzodiazepines.

    Science.gov (United States)

    Hemming, Karl; Chambers, Christopher S; Jamshaid, Faisal; O'Gorman, Paul A

    2014-10-17

    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.

  3. 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.

  4. 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.

  5. Inappropriate benzodiazepine use in older adults and the risk of fracture

    OpenAIRE

    2008-01-01

    textabstractAIMS: The Beers criteria for prescribing in elderly are well known and used for many drug utilization studies. We investigated the clinical value of the Beers criteria for benzodiazepine use, notably the association between inappropriate use and risk of fracture. METHODS: We performed a nested case-control study within the Rotterdam Study, a population-based cohort study in 7983 elderly. The proportion of 'inappropriate' benzodiazepine use according to the Beers criteria was compa...

  6. [Benzodiazepine or non-benzodiazepine hypnotics withdrawal syndrome during hospitalization: A series of 22 cases].

    Science.gov (United States)

    Thorel, Marine; Fummi, Camille; Gras, Valérie; Masmoudi, Kamel

    2016-06-01

    Twenty-two cases related to benzodiazepine (BZD) withdrawal syndrome were identified and reported to Amiens's regional pharmacovigilance center between January 1st, 1995 and March 25th, 2014, all with a favourable outcome after reintroduction of a BZD. Despite being a very classical well-known side effect, physicians may underestimate this risk. Our series also confirms that the patient is misinformed about the consequences of an abrupt BZD discontinuation especially when the BZD has been consumed for many years. Interviewing patient and his family on the nature of the current medical treatments should be systematic and an early diagnostic step taken by physicians faced with a recent behavioral disorder. Moreover, this would prevent unnecessary, sometimes invasive, expensive investigations and a prolonged hospitalization.

  7. The distribution of radioactivity in brains of rats given (N-methyl- sup 11 C)PK 11195 in vivo after induction of a cortical ischaemic lesion

    Energy Technology Data Exchange (ETDEWEB)

    Cremer, J.E.; Hume, S.P.; Cullen, B.M.; Myers, R.; Manjil, L.G.; Turton, D.R.; Luthra, S.K.; Bateman, D.M.; Pike, V.W. (Hammersmith Hospital, London (United Kingdom). M.R.C. Cyclotron Unit)

    1992-02-01

    PK 11195 is a selective ligand for the peripheral-type benzodiazepine bindings site (PTBBS). There are few sites in normal brain but their number increases in association with tissue necrosis. The time-course of appearance of PTBBS around a focally induced ischaemic lesion in frontal cortex of rat brain was established by autoradiography using (N-methyl-{sup 3} H )PK 11195. Using this information and the same experimental model of ischaemia, the distribution of radioactivity after injection of carbon-11 labelled PK 11195 was studied. The purpose was to synthesize (N-methyl-{sup 11}C)PK 11195 and to test its suitability as a tracer for depicting the presence of PTBB in ischaemic lesions. The time-profiles of distribution of radioactivity in brain regions after intravenous injection of tracer and the ratio of radioactivity in lesioned compared with unlesioned cortex were determined. Data for the temporal (days after lesion induction) and for the regional retention of radioactivity were consistent with independent evidence (autoradiographic and immunohistochemical) for the occurence of increased numbers of PTBBS, predominantly in association with macrophages, in areas undergoing necrosis. (Author).

  8. Reduction of group II metabotropic glutamate receptors during development of benzodiazepine dependence.

    Science.gov (United States)

    Okamoto, Ritsuko; Itoh, Yoshinori; Murata, Yusuke; Kobayashi, Daisuke; Hosoi, Masako; Mine, Kazunori

    2013-01-01

    Prolonged use of benzodiazepines often leads to dependence and withdrawal syndrome. However, the cellular mechanisms underlying benzodiazepine dependence have not been fully clarified. Several investigators have shown an involvement of metabotropic glutamate receptors (mGluRs) in the pathophysiology of dependence or withdrawal. This study was performed to elucidate the role of mGluRs in benzodiazepine dependence. Withdrawal signs were precipitated in mice by flumazenil injection (25 mg/kg) after continuous subcutaneous infusion of benzodiazepines for 7 days, and the effects of several Gi-coupled receptor ligands on forskolin-stimulated cyclic AMP accumulation were examined in the cerebral cortex of mice. The mRNA expression for mGluRs was determined by RT-PCR. A single injection of flumazenil precipitated typical withdrawal signs such as tail elevation and tremor in mice treated with diazepam or alprazolam, but not quazepam. The inhibitory effect of nonselective mGluR ligands on adenylate cyclase activity was diminished in mice that showed signs of benzodiazepine withdrawal. The mRNA expression levels of mGluR2 and mGluR3 were lowered in the cerebral cortex of mice pretreated with diazepam or alprazolam. Our findings suggest that the reduction in the expression of group II mGluRs subunits may be involved in the development of benzodiazepine dependence.

  9. Benzodiazepine drug use and adverse respiratory outcomes among older adults with COPD.

    Science.gov (United States)

    Vozoris, Nicholas T; Fischer, Hadas D; Wang, Xuesong; Stephenson, Anne L; Gershon, Andrea S; Gruneir, Andrea; Austin, Peter C; Anderson, Geoffrey M; Bell, Chaim M; Gill, Sudeep S; Rochon, Paula A

    2014-08-01

    Our purpose was to evaluate the association of new benzodiazepine use relative to non-use with adverse clinical respiratory outcomes among older adults with chronic obstructive pulmonary disease (COPD). This was a retrospective population-based cohort study of Ontario, Canada, residents between 2003 and 2010. A validated algorithm was applied to health administrative data to identify adults aged 66 years and older with COPD. Relative risks (RRs) of several clinically important respiratory outcomes were examined within 30 days of incident benzodiazepine use compared with non-use, applying propensity score matching. New benzodiazepine users were at significantly higher risk for outpatient respiratory exacerbations (RR 1.45, 95% CI 1.36-1.54) and emergency room visits for COPD or pneumonia (RR 1.92, 95% CI 1.69-2.18) compared to non-users. Risk of hospitalisation for COPD or pneumonia was also increased in benzodiazepine users, but was nonsignificant (RR 1.09, 95% CI 1.00-1.20). There were no significant differences in intensive care unit admissions between the two groups and all-cause mortality was slightly lower among new versus non-users. Benzodiazepines were associated with increased risk for several serious adverse respiratory outcomes among older adults with COPD. The findings suggest that decisions to use benzodiazepines in older patients with COPD need to consider potential adverse respiratory outcomes.

  10. Benzodiazepine use and mortality of incident dialysis patients in the United States.

    Science.gov (United States)

    Winkelmayer, W C; Mehta, J; Wang, P S

    2007-12-01

    Benzodiazepines and other omega-receptor agonists are frequently used for sleep and anxiety disorders. We studied the rates, correlates, and safety of individual benzodiazepines and zolpidem use from the records of 3690 patients in a national cohort of Dialysis Morbidity and Mortality Study Wave 2 data. We assessed drug utilization and an association between drug use and all-cause mortality. Overall, 14% of incident dialysis patients used a benzodiazepine or zolpidem. Women, Caucasians, current smokers, and patients with chronic obstructive pulmonary disease were more likely to use these drugs, whereas patients with cerebrovascular disease were less likely to use these drugs. In adjusted analyses, benzodiazepine or zolpidem use was associated with a 15% higher mortality rate. Chronic obstructive pulmonary disease significantly modified this association, suggesting that these patients were at higher risk. No association was found between benzodiazepine use and greater risk for hip fracture. We conclude that benzodiazepine or zolpidem use is common in incident dialysis patients and may be associated with greater mortality. Further studies are needed to elucidate the safety of these drugs in the dialysis population, which may lead to cautious and restrictive utilization of omega-receptor agonists in dialysis patients.

  11. Benzodiazepines for insomnia in community-dwelling elderly: a review of benefit and risk.

    Science.gov (United States)

    Grad, R M

    1995-11-01

    To critically assess and summarize the beneficial effects of benzodiazepine therapy for insomnia in community-dwelling elders, a systematic search was undertaken to review all published clinical trials and sleep laboratory studies. The risk of injury for benzodiazepine users was also reviewed. Ten studies met inclusion criteria for assessing benefit. There are no studies regarding the long-term effectiveness of benzodiazepines for the treatment of sleep disorders in the elderly. In the sleep laboratory setting, triazolam 0.125 mg, flurazepam 15 mg, and estazolam 1 mg improved sleep latency by 27 to 30 minutes and increased total sleep time by 47 to 81 minutes for the first 2 to 3 nights of treatment, compared with baseline measurements taken while the patients were receiving placebo. In contrast to these modest short-term benefits, there is an association between the use of benzodiazepines with a long half-life, eg, flurazepam, diazepam, and chlordiazepoxide, and an increased risk of hip fracture in the elderly. Triazolam can cause rebound insomnia as well as anterograde amnesia. Clinicians should discontinue their prescribing of long-acting benzodiazepines for elderly patients with insomnia. More research is needed on the effects of nondrug interventions as well as on short- and intermediate-acting benzodiazepines, such as oxazepam and temazepam, to treat insomnia in community-dwelling elderly.

  12. 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.

  13. Cross-reactivities and structure-reactivity relationships of six benzodiazepines to EMIT(®) immunoassay.

    Science.gov (United States)

    Bertol, Elisabetta; Vaiano, Fabio; Furlanetto, Sandra; Mari, Francesco

    2013-10-01

    Benzodiazepines are among the most frequently prescribed drugs due to their sedative, hypnotic, anxiolytic, muscle relaxant and antiepileptic properties. Considering the high consumption of benzodiazepines worldwide, there is increased potential for addiction and abuse in cases of crime, driving under the influence of drugs, suicide and drug-facilitated sexual assault (DFSA). For these reasons, this class of drugs and their metabolites are frequently present in both clinical and forensic cases. In a forensic toxicology laboratory, typical screening analysis for benzodiazepine involves various immunoassay screening methods. The present study investigates the cross-reactivity profiles of six benzodiazepines not included in the manufacturer's instructions (3-hydroxy-flunitrazepam, 7-amino-nitrazepam, brotizolam, delorazepam, pinazepam, α-hydroxy-midazolam) to EMIT(®) II Plus Benzodiazepine Assay. Pinazepam, delorazepam and brotizolam are the most reactive molecules, while the other ones present a very low cross-reactivity. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to confirm the concentrations of the spiked urines for immunoassay test and to make a comparison between the quantitative results of the different methods. Structure-reactivity relationships to EMIT(®) II Plus Benzodiazepine Assay were also evaluated. This paper draws attention to the problem of careless use of immunoassay tests for forensic purposes as they may provide false positive and/or negative results.

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

    Science.gov (United States)

    Varvounis, George

    2016-01-28

    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.

  15. Synthesis, characterisation, stereochemistry and antimicrobial activity of 5 -piperazino- and 5-morpholinoacetyl-2,2,4-trimethyl-1, 5-benzodiazepines

    Indian Academy of Sciences (India)

    S Ponnuswamy; A Akila; D Deepa Rajakumari; V Shreevidhyaa Suressh; G Usha

    2015-11-01

    Three 1,5-benzodiazepines viz., 5-chloroacetyl-, 5-piperazinoacetyl- and N5 -morpholinoacetyl-2,2,4-trimethyl-1H-1,5-benzodiazepines have been synthesized. The structural characterisation and the conformational preferences of the compounds have been carried out using IR, 1D and 2D NMR spectral data. The NMR spectral data show that the -acetyltetrahydro-1,5-benzodiazepines prefer to exist in boat conformation with exo orientation of >C=O at 5 position in the solution state. The X-ray crystal structure of 5-morpholinoacetyl-2,2,4-trimethyl-1H-1,5-benzodiazepine also supports boat conformation in the solid state. The antimicrobial activity for -acetyltetrahydro-1,5-benzodiazepines have been carried out. -morpholinoacetyl-2,2,4-trimethyl-1H-1,5-benzodiazepine demonstrated better antibacterial and antifungal activities.

  16. Patients' and physicians' characteristics associated with the purchase of benzodiazepines by older primary care patients in Israel.

    Science.gov (United States)

    Ayalon, Liat; Gross, Revital; Yaari, Aviv; Feldhamer, Elan; Balicer, Ran D; Goldfracht, Margalit

    2013-03-01

    This study evaluated patients' and physicians' characteristics associated with the purchase of benzodiazepines by older primary care patients in Israel. The analytic sample consists of those 6,421 patients age 65 and older. We used multi-level analysis with whether or not benzodiazepines were purchased at least once between June 2005 and 2007 as an outcome. We also evaluated patients' and physicians' characteristics associated with the purchase of benzodiazepines for 6 months or longer. Almost half the sample (41.5%) purchased benzodiazepines at least once during the study period and more than half (54.5%) of those purchasing benzodiazepines had a continued purchase for 6 months or longer. Physicians' characteristics explained only a small portion of the variance associated with purchasing, whereas patients' demographic and clinical characteristics were associated with purchasing. Any intervention to improve the use of benzodiazepines should be directed at both patients and physicians.

  17. Scientific calculating peripheral

    Energy Technology Data Exchange (ETDEWEB)

    Ethridge, C.D.; Nickell, J.D. Jr.; Hanna, W.H.

    1979-09-01

    A scientific calculating peripheral for small intelligent data acquisition and instrumentation systems and for distributed-task processing systems is established with a number-oriented microprocessor controlled by a single component universal peripheral interface microcontroller. A MOS/LSI number-oriented microprocessor provides the scientific calculating capability with Reverse Polish Notation data format. Master processor task definition storage, input data sequencing, computation processing, result reporting, and interface protocol is managed by a single component universal peripheral interface microcontroller.

  18. Neurogenesis in the adult peripheral nervous system

    Institute of Scientific and Technical Information of China (English)

    Krzysztof Czaja; Michele Fornaro; Stefano Geuna

    2012-01-01

    Most researchers believe that neurogenesis in mature mammals is restricted only to the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle in the central nervous system. In the peripheral nervous system, neurogenesis is thought to be active only during prenatal development, with the exception of the olfactory neuroepithelium. However, sensory ganglia in the adult peripheral nervous system have been reported to contain precursor cells that can proliferate in vitro and be induced to differentiate into neurons. The occurrence of insult-induced neurogenesis, which has been reported by several investigators in the brain, is limited to a few recent reports for the peripheral nervous system. These reports suggest that damage to the adult nervous system induces mechanisms similar to those that control the generation of new neurons during prenatal development. Understanding conditions under which neurogenesis can be induced in physiologically non-neurogenic regions in adults is one of the major challenges for developing therapeutic strategies to repair neurological damage. However, the induced neurogenesis in the peripheral nervous system is still largely unexplored. This review presents the history of research on adult neurogenesis in the peripheral nervous system, which dates back more than 100 years and reveals the evidence on the under estimated potential for generation of new neurons in the adult peripheral nervous system.

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Benzodiazepine use in COPD: empirical evidence from Norway

    Directory of Open Access Journals (Sweden)

    Halvorsen T

    2015-08-01

    Full Text Available Thomas Halvorsen,1 Pål E Martinussen21SINTEF Technology and Society, Department for Health Research, 2Department of Sociology and Political Science, Norwegian University of Science and Technology, Trondheim, NorwayBackground: The common comorbidities associated with COPD include, among others, anxiety, depression, and insomnia, for which the typical treatment involves the use of benzodiazepines (BZD. However, these medicines should be used with extra caution among COPD patients, since treatment with traditional BZD may compromise respiratory function. Aims: This study investigated the use of BZD among persons suffering from COPD by analyzing three relevant indicators: 1 the sum of defined daily doses (DDD; 2 the number of prescribers involved; and 3 the number of different types of BZD used. Data and methods: The study builds on a linkage of national prescription data and patient–administrative data, which includes all Norwegian drug prescriptions to persons hospitalized with a COPD diagnosis during 2009, amounting to a total of 5,380 observations. Regression techniques were used to identify the patients and the clinical characteristics associated with BZD use. Results: Of the 5,380 COPD patients treated in hospital during 2009, 3,707 (69% were dispensed BZD during the following 12 months. Moreover, they were dispensed on average 197.08 DDD, had 1.22 prescribers, and used 0.98 types of BZD during the year. Women are more likely to use BZD for all levels of BZD use. Overnight planned care not only increases the risk of BZD use (DDD, but also the number of prescribers and the types of BZD in use.Conclusion: In light of the high levels of BZD prescription found in this study, especially among women, it is recommended that general practitioners, hospital specialists, and others treating COPD patients should aim to acquire a complete picture of their patients’ BZD medication before more is prescribed in order to keep the use to a minimum

  1. Assessing the efficacy of melatonin to curtail benzodiazepine/Z drug abuse.

    Science.gov (United States)

    Cardinali, Daniel P; Golombek, Diego A; Rosenstein, Ruth E; Brusco, Luis I; Vigo, Daniel E

    2016-07-01

    The abuse of benzodiazepine (BZP) and Z drugs has become, due to the tolerance and dependence they produce, a serious public health problem. Thirty years ago, we demonstrated in experimental animals the interaction of melatonin with central BZD receptors, and in 1997 we published the first series of elderly patients who reduced BZP consumption after melatonin treatment. Almost every single neuron in the hypothalamic suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system, contains γ-aminobutyric acid (GABA) and many results in animals point out to a melatonin interaction with GABA-containing neurons. In addition, central-type BZD antagonism, that obliterates GABAA receptor function, blunted most behavioral effects of melatonin including sleep. Melatonin is involved in the regulation of human sleep. This is supported by the temporal relationship between the rise of plasma melatonin levels and sleep propensity as well as by the sleep-promoting effects of exogenously administered melatonin. Both meta-analyses and consensus agreements give support to the therapeutic use of melatonin in sleep disorders. This action is attributed to MT1 and MT2 melatoninergic receptors localized in the SCN, as well as in other brain areas. This review discusses available data on the efficacy of melatonin to curtail chronic BZD/Z drug use in insomnia patients. A major advantage is that melatonin has a very safe profile, it is usually remarkably well tolerated and, in some studies, it has been administered to patients at very large doses and for long periods of time, without any potentiality of abuse. Further studies on this application of melatonin are warranted.

  2. Potentiation of muscimol-induced long-term depression by benzodiazepines but not zolpidem.

    Science.gov (United States)

    Akhondzadeh, Shahin; Mohammadi, Mohammad Reza; Kashani, Ladan

    2002-10-01

    Zolpidem is a rapid-onset, short-duration, quickly eliminated imidazopyridine hypnotic. It has been suggested that zolpidem may produce less memory and cognitive impairment than benzodiazepines (BZs) due to its low binding affinity for BZ receptor subtypes found in areas of the brain that are involved in learning and memory, in particular the hippocampus. A novel protocol for inducing long-term synaptic depression through activation of gamma-aminobutyric acid (GABA(A)) receptors in the hippocampal slices has been recently reported. The authors used the CA1 region of rat hippocampal slices to compare the effects of classic BZs, which bind equipotently to BZ1 and BZ2 sites, and of nonbenzodiazepine zolpidem, which binds preferentially to the BZ1 sites of GABA(A) receptors, on the GABA(A)-induced long-term depression (LTD), a possible cellular mechanism for their different cognition-impairment profile. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). It was observed that diazepam and cholordiazepoxide at concentrations of 10 and 20 microM, which did not have any effect themselves on the population spike, potentiate the ability of muscimol to induce LTD, whereas zolpidem at concentrations of 10 and 20 microM failed to potentiate muscimol-induced LTD. The results suggest that the potentiation of muscimol-induced LTD by diazepam or chlordiazepoxide and the lack of this effect by zolpidem may explain their different cognition impairment profiles.

  3. Peripheral Ossifying Fibroma

    Directory of Open Access Journals (Sweden)

    Sudhakar S

    2009-11-01

    Full Text Available Peripheral ossifying fibroma is a relatively uncommon gingival growth that is considered to be reactive in nature and postulated to appear secondary to irritation or trauma. They usually occur in young adults with a female predominance and are solitary in nature. We report a case of peripheral ossifying fibroma in a 55-year old female.

  4. Vasculitic peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Mona Amini

    2014-02-01

    Full Text Available Primary systemic vasculitis in pre-capillary arteries is associated with peripheral neuropathy. In some types of systematic vasculitis about 60 % of patients have peripheral nervous system (PNS involvement. In vasculitic peripheral neuropathies (VPN a necrotizing and inflammatory process leads to narrowing of vasa nervorum lumen and eventually the appearance of ischemic lesions in peripheral nerves. Some features might be suggestive of VPN, like: axonal nerve degeneration, wallerian-like degeneration, and diameter irregularity of nerve. Peripheral nervous system (PNS destruction during systemic vasculitides should be considered, due to its frequency and early occurrence in vasculitis progression. The first line treatment of non systematic VPNs is corticosteroid agents, but these drugs might worsen the VPNs or systemic vasculitis.

  5. Effects of Benzodiazepines on Acinar and Myoepithelial Cells

    Science.gov (United States)

    Mattioli, Tatiana M. F.; Alanis, Luciana R. A.; Sapelli, Silvana da Silva; de Lima, Antonio A. S.; de Noronha, Lucia; Rosa, Edvaldo A. R.; Althobaiti, Yusuf S.; Almalki, Atiah H.; Sari, Youssef; Ignacio, Sergio A.; Johann, Aline C. B. R.; Gregio, Ana M. T.

    2016-01-01

    Background: Benzodiazepines (BZDs), the most commonly prescribed psychotropic drugs with anxiolytic action, may cause hyposalivation. It has been previously shown that BZDs can cause hypertrophy and decrease the acini cell number. In this study, we investigated the effects of BZDs and pilocarpine on rat parotid glands, specifically on acinar, ductal, and myoepithelial cells. Methods: Ninety male Wistar rats were divided into nine groups. Control groups received a saline solution for 30 days (C30) and 60 days (C60), and pilocarpine (PILO) for 60 days. Experimental groups received lorazepam (L30) and midazolam (M30) for 30 days. Another group (LS60 or MS60) received lorazepam or midazolam for 30 days, respectively, and saline for additional 30 days. Finally, other groups (LP60 or MP60) received either lorazepam or midazolam for 30 days, respectively, and pilocarpine for additional 30 days. The expression of calponin in myoepithelial cells and the proliferating cell nuclear antigen (PCNA) in acinar and ductal cells were evaluated. Results: Animals treated with lorazepam showed an increase in the number of positive staining cells for calponin as compared to control animals (p acinar and ductal cells and a decrease in the positive staining cells for calponin as compared to midazolam administered with saline (MS60). Conclusion: We found that myoepithelial cells might be more sensitive to the effects of BZD than acinar and ductal cells in rat parotid glands. PMID:27445812

  6. Alterations in in-vivo benzodiazepine-receptor binding of C-11-Ro15-1788 (flumazepil)

    Energy Technology Data Exchange (ETDEWEB)

    Yamasaki, T.; Inoue, O.; Shinoto, H.; Ito, T.; Hashimoto, K.; Suzuki, K.; Tateno, Y.

    1985-05-01

    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/sup 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/..mu..mol, 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.

  7. Association between Benzodiazepine Use and Dementia: Data Mining of Different Medical Databases.

    Science.gov (United States)

    Takada, Mitsutaka; Fujimoto, Mai; Hosomi, Kouichi

    2016-01-01

    Purpose: Some studies have suggested that the use of benzodiazepines in the elderly is associated with an increased risk of dementia. However, this association might be due to confounding by indication and reverse causation. To examine the association between benzodiazepine anxiolytic drug use and the risk of dementia, we conducted data mining of a spontaneous reporting database and a large organized database of prescriptions. Methods: Data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) from the first quarter of 2004 through the end of 2013 and data from the Canada Vigilance Adverse Reaction Online Database from the first quarter of 1965 through the end of 2013 were used for the analyses. The reporting odds ratio (ROR) and information component (IC) were calculated. In addition, prescription sequence symmetry analysis (PSSA) was performed to identify the risk of dementia after using benzodiazepine anxiolytic drugs over the period of January 2006 to May 2014. Results: Benzodiazepine use was found to be associated with dementia in analyses using the FAERS database (ROR: 1.63, 95% CI: 1.61-1.64; IC: 0.66, 95% CI: 0.65-0.67) and the Canada Vigilance Adverse Reaction Online Database (ROR: 1.88, 95% CI: 1.83-1.94; IC: 0.85, 95% CI: 0.80-0.89). ROR and IC values increased with the duration of action of benzodiazepines. In the PSSA, a significant association was found, with adjusted sequence ratios of 1.24 (1.05-1.45), 1.20 (1.06-1.37), 1.23 (1.11-1.37), 1.34 (1.23-1.47), 1.41 (1.29-1.53), and 1.44 (1.33-1.56) at intervals of 3, 6, 12, 24, 36, and 48 months, respectively. Furthermore, the additional PSSA, in which patients who initiated a new treatment with benzodiazepines and anti-dementia drugs within 12- and 24-month periods were excluded from the analysis, demonstrated significant associations of benzodiazepine use with dementia risk. Conclusion: Multi-methodological approaches using different methods, algorithms, and databases suggest

  8. Association between Benzodiazepine Use and Dementia: Data Mining of Different Medical Databases

    Science.gov (United States)

    Takada, Mitsutaka; Fujimoto, Mai; Hosomi, Kouichi

    2016-01-01

    Purpose: Some studies have suggested that the use of benzodiazepines in the elderly is associated with an increased risk of dementia. However, this association might be due to confounding by indication and reverse causation. To examine the association between benzodiazepine anxiolytic drug use and the risk of dementia, we conducted data mining of a spontaneous reporting database and a large organized database of prescriptions. Methods: Data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) from the first quarter of 2004 through the end of 2013 and data from the Canada Vigilance Adverse Reaction Online Database from the first quarter of 1965 through the end of 2013 were used for the analyses. The reporting odds ratio (ROR) and information component (IC) were calculated. In addition, prescription sequence symmetry analysis (PSSA) was performed to identify the risk of dementia after using benzodiazepine anxiolytic drugs over the period of January 2006 to May 2014. Results: Benzodiazepine use was found to be associated with dementia in analyses using the FAERS database (ROR: 1.63, 95% CI: 1.61-1.64; IC: 0.66, 95% CI: 0.65-0.67) and the Canada Vigilance Adverse Reaction Online Database (ROR: 1.88, 95% CI: 1.83-1.94; IC: 0.85, 95% CI: 0.80-0.89). ROR and IC values increased with the duration of action of benzodiazepines. In the PSSA, a significant association was found, with adjusted sequence ratios of 1.24 (1.05-1.45), 1.20 (1.06-1.37), 1.23 (1.11-1.37), 1.34 (1.23-1.47), 1.41 (1.29-1.53), and 1.44 (1.33-1.56) at intervals of 3, 6, 12, 24, 36, and 48 months, respectively. Furthermore, the additional PSSA, in which patients who initiated a new treatment with benzodiazepines and anti-dementia drugs within 12- and 24-month periods were excluded from the analysis, demonstrated significant associations of benzodiazepine use with dementia risk. Conclusion: Multi-methodological approaches using different methods, algorithms, and databases suggest

  9. [New use of benzodiazepines and the risk of hip fracture: A case-crossover study].

    Science.gov (United States)

    Hoffmann, F; Glaeske, G

    2006-04-01

    Benzodiazepines appear to increase the incidence of hip fractures. Their role as a time-dependent risk factor remains unclear. We therefore conducted a case-crossover study to determine whether the new use of benzodiazepines is associated with a rise in hip fractures. We analysed 49 months of the statutory health insurance Gmünder Ersatzkasse (GEK) and enrolled all first hip fractures. The index date was the day of hospital admission. Exposure to new use of benzodiazepines was compared within the five periods preceding the index date. Out of 1630 subjects, 223 (13.7%) had at least one prescription of benzodiazepines in the preceding 150 days before the index date, 74 (4.5%) of them as a first prescription. The average age of the population was 79.8 years (SD: 7.7). Odds ratio (OR) of hip fracture was highest during the initial 5 days of new use (OR: 3.43; 95% CI 1.15-10.20) and then declined to a non-significant OR of 1.59 (95% CI 0.96-2.63) after 30 days. In conclusion, the start of a new benzodiazepine is associated with an increased risk of hip fractures. However, the population attributable risk (PAR) and, therefore, the percentage of preventable events is small (PAR: 0.55%; 95% CI 0.05-1.06%).

  10. The basic pharmacoepidemiology of benzodiazepine use in Norway 2004-9

    Directory of Open Access Journals (Sweden)

    Jørgen G. Bramness

    2011-12-01

    Full Text Available Objectives: Benzodiazepines are effective and safe drugs for treatment of insomnia, anxiety, epilepsy and muscle spasm, but there is also a potential for harmful use, abuse and addiction. Even though these drugs are used extensively, have been on the market for 50 years, and quite a few reports have been published on risk factors and patterns of use, the basic epidemiological parameters of use, such as incidence, prevalence, mean volume used and duration of use have not been documented in Norway. The aim of this study was to describe these basic pharmacoepidemiological parameters of benzodiazepine use.Methods: Data were drawn from the Norwegian prescription database with an observation period of 5 years and 10 months between January 2004 and October 2009.Results: Around 61 per 1000 Norwegians filled at least one prescription each year in the observation period. The annual incidence rate of new users was 15 per 1000 in 2007, falling to 12 per 1000 in 2009. Of the users of benzodiazepines 65% were female, and they used a lower mean volume than men did. The mean volume used was often very low and for the most part was quite stable. The average length of use was estimated to bebetween 9 and 15 years. In addition to fewer incident users, the mean volume used also seemed to be declining.Conclusion: Most benzodiazepine use in Norway lasted a short period or at a very low level. Some individuals, however, carried on using benzodiazepines for years

  11. The evaluation of the applicability of a high pH mobile phase in ultrahigh performance liquid chromatography tandem mass spectrometry analysis of benzodiazepines and benzodiazepine-like hypnotics in urine and blood

    OpenAIRE

    2012-01-01

    A sensitive liquid chromatography tandem mass spectrometry method was developed and validated for simultaneous detection of benzodiazepines, benzodiazepine-like hypnotics and some metabolites (7-aminoflunitrazepam, alprazolam, bromazepam, brotizolam, chlordiazepoxide, chlornordiazepam, clobazam, clonazepam, clotiazepam, cloxazolam, diazepam, ethylloflazepate, flunitrazepam, flurazepam, loprazolam, lorazepam, lormetazepam, midazolam, N-desmethylflunitrazepam, nitrazepam, N-methylclonazepam (in...

  12. 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....

  13. 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.

  14. Peripheral inflammation increases seizure susceptibility via the induction of neuroinflammation and oxidative stress in the hippocampus

    OpenAIRE

    Ho, Ying-Hao; Lin, Yu-Te; Wu, Chih-Wei J.; Chao, Yung-Mei; Alice Y W Chang; Chan, Julie Y H

    2015-01-01

    Background Neuroinflammation with activation of microglia and production of proinflammatory cytokines in the brain plays an active role in epileptic disorders. Brain oxidative stress has also been implicated in the pathogenesis of epilepsy. Damage in the hippocampus is associated with temporal lobe epilepsy, a common form of epilepsy in human. Peripheral inflammation may exacerbate neuroinflammation and brain oxidative stress. This study examined the impact of peripheral inflammation on seizu...

  15. 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.

  16. 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 importan

  17. Potential impact of benzodiazepine use on the rate of hip fractures in Denmark (DK), the Netherlands (NL) and Norway (NO)

    NARCIS (Netherlands)

    Khong, Phuong T.; De Vries, Frank; Goldenberg, Jennifer S.B.; Klungel, Olaf H.; Petri, Hans

    2011-01-01

    Background: Benzodiazepines can increase the risk of falls and have therefore often been associated with an increased risk of hip fractures. However, estimations of the potential impact of benzodiazepine use on the population rate of hip fractures are missing. Objectives: To estimate the possible po

  18. Prescription of benzodiazepines in general practice in the context of a man-made disaster: a longitudinal study.

    NARCIS (Netherlands)

    Fassaert, T.; Dorn, T.; Spreeuwenberg, P.M.M.; Dongen, M.C.J.M.; Gool, C. van; Yzermans, C.J.

    2007-01-01

    BACKGROUND: Mental health problems associated with benzodiazepine treatment are often highly prevalent in the aftermath of disasters. Nevertheless, not much is known about benzodiazepine use after disasters. Considering the negative effects associated with prolonged use and the adverse effects of be

  19. 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....

  20. Long-term effectiveness of computer-generated tailored patient education on benzodiazepines : a randomized controlled trial

    NARCIS (Netherlands)

    Ten Wolde, Geeske Brecht; Dijkstra, Arie; Van Empelen, Pepijn; van den Hout, Wilbert; Neven, Arie Knuistingh; Zitman, Frans

    2008-01-01

    Aims Chronic benzodiazepine use is highly prevalent and is associated with a variety of negative health consequences. The present study examined the long-term effectiveness of a tailored patient education intervention on benzodiazepine use. Participants A randomized controlled trial was conducted co

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

    Directory of Open Access Journals (Sweden)

    Dell’Osso B

    2015-07-01

    Full Text Available Bernardo Dell’Osso,1,2,* Umberto Albert,3,* Anna Rita Atti,4 Claudia Carmassi,5 Giuseppe Carrà,6 Fiammetta Cosci,7 Valeria Del Vecchio,8 Marco Di Nicola,9 Silvia Ferrari,10 Arianna Goracci,11 Felice Iasevoli,12 Mario Luciano,8 Giovanni Martinotti,13 Maria Giulia Nanni,14 Alessandra Nivoli,15,16 Federica Pinna,17 Nicola Poloni,18 Maurizio Pompili,19 Gaia Sampogna,8 Ilaria Tarricone,20 Sarah Tosato,21 Umberto Volpe,8 Andrea Fiorillo8 1Department of Psychiatry, University of Milan, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy; 2Bipolar Disorders Clinic, Stanford Medical School, Stanford University, CA, USA; 3Rita Levi Montalcini Department of Neuroscience, University of Turin, Torino, 4Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, 5Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 6Division of Psychiatry, Faculty of Brain Sciences, University College London, London, UK; 7Department of Health Sciences, University of Florence, Florence, 8Department of Psychiatry, University of Naples SUN, Naples, 9Institute of Psychiatry and Psychology, Catholic University of Sacred Heart, Rome, 10Department of Diagnostic-Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, 11Department of Molecular Medicine and Clinical Department of Mental Health, University of Siena, Siena, 12Department of Neuroscience, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples, 13Department of Neuroscience, Imaging, and Clinical Science, University G.d Annunzio, Chieti-Pescara, 14Section of Psychiatry, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, 15Psychiatric Institute, Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy; 16Bipolar Disorder Unit, CIBERSAM, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain; 17Department of

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

    Science.gov (United States)

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

    1987-07-01

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

  3. Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family

    Science.gov (United States)

    Filippakopoulos, Panagis; Picaud, Sarah; Fedorov, Oleg; Keller, Marco; Wrobel, Matthias; Morgenstern, Olaf; Bracher, Franz; Knapp, Stefan

    2012-01-01

    Benzodiazepines are psychoactive drugs with anxiolytic, sedative, skeletal muscle relaxant and amnestic properties. Recently triazolo-benzodiazepines have been also described as potent and highly selective protein interaction inhibitors of bromodomain and extra-terminal (BET) proteins, a family of transcriptional co-regulators that play a key role in cancer cell survival and proliferation, but the requirements for high affinity interaction of this compound class with bromodomains has not been described. Here we provide insight into the structure–activity relationship (SAR) and selectivity of this versatile scaffold. In addition, using high resolution crystal structures we compared the binding mode of a series of benzodiazepine (BzD) and related triazolo-benzotriazepines (BzT) derivatives including clinically approved drugs such as alprazolam and midazolam. Our analysis revealed the importance of the 1-methyl triazolo ring system for BET binding and suggests modifications for the development of further high affinity bromodomain inhibitors. PMID:22137933

  4. Evaluation of cytotoxicity and mutagenicity of the benzodiazepine flunitrazepam in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Igor Vivian de Almeida

    2014-04-01

    Full Text Available Flunitrazepam (FNZ is a sedative benzodiazepine prescribed for the short-term treatment of insomnia. However, there are concerns regarding possible carcinogenic or genotoxic effects of this medicine. Thus, the aim of this study was to evaluate the cytotoxic, clastogenic and aneugenic effects of FNZ in hepatoma cells from Rattus norvegicus (HTC in vitro and in bone marrow cells of Wistar rats in vivo. These effects were examined in vitro following treatment with 0.2, 1.0, 5.0 or 10 μg/mL FNZ using a micronucleus test with a cytokinesis block or in vivo using a chromosomal aberration test following treatment with 7, 15 or 30 μg/mL/kg body weight. The results showed that the benzodiazepine concentrations tested were not cytotoxic, aneugenic or clastogenic. However, considering the adverse effects of using this benzodiazepine, more studies are required.

  5. Overview of clinical efficacy and risk data of benzodiazepines for prolonged seizures.

    Science.gov (United States)

    Lagae, Lieven

    2014-10-01

    An historical overview is provided regarding the use of benzodiazepines for the treatment of acute prolonged convulsive seizures. It is clear that intravenous benzodiazepines remain a first step for the in-hospital treatment of prolonged seizures or status epilepticus. However, in the community, in a pre-hospital situation, intravenous administration is not possible. In recent years, it was shown that rectal, buccal, intranasal, and intramuscular administration of benzodiazepines is very effective as a first and safe treatment step. In many cases, rectal diazepam is not socially acceptable anymore, and therefore more emphasis is now put on buccal, intranasal, and intramuscular administration. At present, based on the available data, midazolam is the product of choice for the acute treatment of prolonged convulsive seizures.

  6. 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

    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...

  7. Bio-sample preparation and gas chromatographic determination of benzodiazepines--a review.

    Science.gov (United States)

    Uddin, Mohammad Nasir; Samanidou, Victoria F; Papadoyannis, Ioannis N

    2013-08-01

    Benzodiazepines have become commonly prescribed medicines worldwide in the therapy of anxiety, sleep disorders and convulsive attacks because they are relatively safe, with mild side effects. The availability of rapid, sensitive and selective analytical methods is essential for the determination of these drugs in clinical and forensic cases. Benzodiazepines are usually present at trace levels (μg/mL or ng/mL) in a complex biological matrix, and the potentially interfering compounds need to be removed before analysis. Therefore, a sample preparation technique is often mandatory, both to extract the drugs of interest from the matrices and to increase their concentration. An extended and comprehensive review is presented herein, focusing on bio-sample preparation (pretreatment, extraction and derivatization) and gas chromatographic methods applied for the quantification of 1,4-benzodiazepines.

  8. [Peripheral ulcerative keratitis].

    Science.gov (United States)

    Stamate, Alina-cristina; Avram, Corina Ioana; Malciolu, R; Oprea, S; Zemba, M

    2014-01-01

    Ulcerative keratitis is frequently associated with collagen vascular diseases and presents a predilection for peripheral corneal localization, due to the distinct morphologic and immunologic features of the limbal conjunctiva, which provides access for the circulating immune complexes to the peripheral cornea via the capillary network. Deposition of immune complexes in the terminal ends of limbal vessels initiates an immune-mediated vasculitis process, with inflammatory cells and mediators involvement by alteration of the vascular permeability. Peripheral ulcerative keratitis generally correlates with exacerbations of the background autoimmune systemic disease. Associated sceritis, specially the necrotizing form, is usually observed in severe cases, which may evolve in corneal perforation and loss of vision. Although the first-line of treatment in acute phases is represented by systemic administration of corticosteroids, immunosuppressive and cytotoxic agents are necessary for the treatment of peripheral ulcerative keratitis associated with systemic diseases.

  9. Therapeutic response to benzodiazepine in panic disorder subtypes

    Directory of Open Access Journals (Sweden)

    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.

  10. Benzodiazepine use in COPD: empirical evidence from Norway

    Science.gov (United States)

    Halvorsen, Thomas; Martinussen, Pål E

    2015-01-01

    Background The common comorbidities associated with COPD include, among others, anxiety, depression, and insomnia, for which the typical treatment involves the use of benzodiazepines (BZD). However, these medicines should be used with extra caution among COPD patients, since treatment with traditional BZD may compromise respiratory function. Aims This study investigated the use of BZD among persons suffering from COPD by analyzing three relevant indicators: 1) the sum of defined daily doses (DDD); 2) the number of prescribers involved; and 3) the number of different types of BZD used. Data and methods The study builds on a linkage of national prescription data and patient–administrative data, which includes all Norwegian drug prescriptions to persons hospitalized with a COPD diagnosis during 2009, amounting to a total of 5,380 observations. Regression techniques were used to identify the patients and the clinical characteristics associated with BZD use. Results Of the 5,380 COPD patients treated in hospital during 2009, 3,707 (69%) were dispensed BZD during the following 12 months. Moreover, they were dispensed on average 197.08 DDD, had 1.22 prescribers, and used 0.98 types of BZD during the year. Women are more likely to use BZD for all levels of BZD use. Overnight planned care not only increases the risk of BZD use (DDD), but also the number of prescribers and the types of BZD in use. Conclusion In light of the high levels of BZD prescription found in this study, especially among women, it is recommended that general practitioners, hospital specialists, and others treating COPD patients should aim to acquire a complete picture of their patients’ BZD medication before more is prescribed in order to keep the use to a minimum. PMID:26356249

  11. 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

    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...... with either prolonged-release melatonin or placebo in a 24-week, double-blind clinical trial. All participants gradually tapered usual benzodiazepine dosage in a closely monitored treatment setting. We used the Brief Assessment of Cognition in Schizophrenia (BACS) to assess neurocognitive performance...

  12. Electrodiagnosis of peripheral neuropathy.

    Science.gov (United States)

    Ross, Mark A

    2012-05-01

    Electrodiagnostic studies are an important component of the evaluation of patients with suspected peripheral nerve disorders. The pattern of findings and the features that are seen on the motor and sensory nerve conduction studies and needle electromyography can help to identify the type of neuropathy, define the underlying pathophysiology (axonal or demyelinating), and ultimately help to narrow the list of possible causes. This article reviews the electrodiagnostic approach to and interpretation of findings in patients with peripheral neuropathies.

  13. Characterization of the designer benzodiazepine diclazepam and preliminary data on its metabolism and pharmacokinetics.

    Science.gov (United States)

    Moosmann, Bjoern; Bisel, Philippe; Auwärter, Volker

    2014-01-01

    Designer benzodiazepines, first offered in online shops selling 'research chemicals' in 2012, provide an attractive alternative to prescription-only benzodiazepines as they are readily available over the Internet at a low price. However, as data regarding pharmacokinetic parameters, metabolism, and detectability in biological fluids are limited, they present a challenge for forensic laboratories. Most recently, diclazepam (other names: 2-chlorodiazepam, Ro 5-3448 or 7-chloro-5-(2-chlorophenyl)-1-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one) emerged as a new compound in this class of drugs. In this paper, this new designer benzodiazepine was characterized utilizing nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS) as well as liquid chromatography tandem mass spectrometry (LC-MS/MS) techniques. Furthermore, a self-experiment was performed to gain preliminary data on pharmacokinetic properties and to identify the main metabolites. For this purpose, one tablet of diclazepam (declared amount: 1 mg) was ingested by one of the authors, and serum as well as urine samples were collected for 14 and 21 days, respectively. Based on this study, diclazepam has an approximate elimination half-life of 42 h and is metabolized into the pharmacologically active benzodiazepines delorazepam, lorazepam, and lormetazepam which can be detected in urine for 6, 19, and 11 days, respectively, when applying the presented LC-MS/MS method. In serum, the consumption could be proven between 99 h post-intake targeting the parent compound and up to 10 days targeting the metabolite delorazepam. As immunochemical assays are applied for screening purposes quite often, detectability using this technique was assessed, especially since detection of low-dosed benzodiazepines can be sometimes problematic. However, only one of the utilized immunochemical assays was capable of detecting the intake of one tablet diclazepam, and the positive results were restricted to a few urine

  14. Pharmacological analysis of the effects of benzodiazepines on punished schedule-induced polydipsia in rats.

    Science.gov (United States)

    Pellón, Ricardo; Ruíz, Ana; Lamas, Esmeralda; Rodríguez, Cilia

    2007-02-01

    Food-deprived Wistar rats were exposed to a fixed-time 60-s food delivery schedule until they developed schedule-induced polydipsia. Every fifth lick was then followed by an electric shock during two, signalled, 5-min periods, which ran concurrently with the food delivery schedule. Shock intensities were adjusted to reduce licking to 60-70% of the unpunished licking rates. The benzodiazepine full agonists, diazepam (0.3-3.0 mg/kg), chlordiazepoxide (0.3-10.0 mg/kg), oxazepam (0.3-3.0 mg/kg) and the benzodiazepine partial agonist, RU-32698 (3.0-17.0 mg/kg), led to increases in punished responding at intermediate doses and decreases at the highest doses tested. All benzodiazepine agonists brought about dose-dependent decreases in unpunished schedule-induced polydipsia, with doses required to reduce drinking proving higher than doses required to increase punished schedule-induced polydipsia. The antipunishment effect of 0.3 mg/kg of diazepam was dose-dependently antagonized by flumazenil and the benzodiazepine inverse agonist, RU-34000. Flumazenil effects, however, could reflect actions of flumazenil as a partial inverse agonist at GABAA receptors. RU-32698 at 10.0 mg/kg further facilitated the rate-increasing effect of 0.3 mg/kg of diazepam, but at 17.0 mg/kg partially blocked such antipunishment effect. Overall, the present results extend the similarities of the effects of benzodiazepine compounds on adjunctive and operant patterns of behaviour by showing similar interactions within the benzodiazepine receptor complex.

  15. Comparison of aggregating agents for the surface-enhanced Raman analysis of benzodiazepines.

    Science.gov (United States)

    Doctor, Erika L; McCord, Bruce

    2013-10-21

    Benzodiazepines are among the most prescribed compounds and are commonly present in many toxicological screens. They are also of concern forensically in cases of drug facilitated sexual assault. Currently these compounds are predominantly analyzed using immunoassay techniques; however more specific screening methods are needed. This paper demonstrates the applicability of surface enhanced Raman spectroscopy as a method for the analysis and detection of benzodiazepines. The procedure involves mixing urine extracts with gold nanoparticles and appropriate aggregating agents for trace detection of these compounds and their metabolites. In this paper we will discuss the optimization of various parameters of this technique as well as its application to screening urine samples. Eleven different benzodiazepines and metabolites were examined, including 1,2-triazolo-benzodiazepines and 1,4-benzodiazpines. Experiments were performed using four different chloride salts, MgCl2, CaCl2, KCl, and NaCl, as aggregating agents for the colloidal gold nanoparticles. Overall it was found that each aggregating agent produced different levels of signal enhancement for each drug. MgCl2 provided the lowest limit of detection at 2.5 ng mL(-1), and linearity over a wide range of concentrations for a variety of drugs chosen. It was also determined that the optimum MgCl2 concentration was 1.67 M. This method has shown the applicability of SERS for the detection of trace quantities of benzodiazepines in aqueous solutions as well as the optimization of the technique over a wide range of compounds. This technique can be utilized in the detection of trace benzodiazepines in toxicological samples following extraction of the analyte.

  16. Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis.

    Science.gov (United States)

    Sun, Eric C; Dixit, Anjali; Humphreys, Keith; Darnall, Beth D; Baker, Laurence C; Mackey, Sean

    2017-03-14

    Objectives To identify trends in concurrent use of a benzodiazepine and an opioid and to identify the impact of these trends on admissions to hospital and emergency room visits for opioid overdose.Design Retrospective analysis of claims data, 2001-13.Setting Administrative health claims database.Participants 315 428 privately insured people aged 18-64 who were continuously enrolled in a health plan with medical and pharmacy benefits during the study period and who also filled at least one prescription for an opioid.Interventions Concurrent benzodiazepine/opioid use, defined as an overlap of at least one day in the time periods covered by prescriptions for each drug. Main outcome measures Annual percentage of opioid users with concurrent benzodiazepine use; annual incidence of visits to emergency room and inpatient admissions for opioid overdose.Results 9% of opioid users also used a benzodiazepine in 2001, increasing to 17% in 2013 (80% relative increase). This increase was driven mainly by increases among intermittent, as opposed to chronic, opioid users. Compared with opioid users who did not use benzodiazepines, concurrent use of both drugs was associated with an increased risk of an emergency room visit or inpatient admission for opioid overdose (adjusted odds ratio 2.14, 95% confidence interval 2.05 to 2.24; Pbenzodiazepine/opioid use could reduce the risk of emergency room visits related to opioid use and inpatient admissions for opioid overdose by an estimated 15% (95% confidence interval 14 to 16).Conclusions From 2001 to 2013, concurrent benzodiazepine/opioid use sharply increased in a large sample of privately insured patients in the US and significantly contributed to the overall population risk of opioid overdose.

  17. Pre-analytical stability of selected benzodiazepines on a polymeric oral fluid sampling device.

    Science.gov (United States)

    Kempf, Jürgen; Wuske, Thomas; Schubert, Rolf; Weinmann, Wolfgang

    2009-04-15

    Oral fluid field tests are designed to provide preliminary results with a high grade of reliability in order to meet analytical and forensic standards. Some test systems additionally offer the possibility of an independent confirmatory analysis of a test sample. The pre-analytical stability of 11 frequently abused benzodiazepines on an oral fluid collecting device (Dräger DCD 5000) has been investigated. The collection device was designed to complement a special mobile testing system (Dräger DrugTest 5000) to be sent to a laboratory for further confirmatory analysis. Blank oral fluid pool was spiked with a mixture of eleven frequently abused benzodiazepines and given onto a collection device. To simulate possible sample shipping, the collection devices were stored in the dark up to 14 days at ambient temperature in a plastic tube. The collection device was simultaneously stored without further treatment after oral fluid collection ('native') and with addition of 950muL of methanol, respectively. At different storage intervals repeat determination was carried out for every sample using a modified version of our standard LC-MS/MS method for the detection of benzodiazepines in serum. Different recoveries of benzodiazepines due to degradation and/or adsorption to the collection device during the 14 days of 'native' storage were found. Major loss of analytes was found for benzodiazepines containing a nitro-group such as flunitrazepam and clonazepam. This could be prevented almost completely by methanolic storage of the collection device after sampling. Therefore, we recommend the centrifugation of the collection device and separation from the polymer unit prior to sample shipping. If this should not be possible, addition of methanol immediately after sample collection can be used to avoid degradation of benzodiazepines during shipment.

  18. Peripheral nervous system topics

    NARCIS (Netherlands)

    Marani, E.; Lakke, E.A.J.F.; Mai, J.K.; Paxinos, G.

    2011-01-01

    *Adopts standard nomenclature following the new scheme by Paxinos, Watson, and Puelles and aligned with the Mai et al. Atlas of the Human Brain (new edition in 2007) * Provides essential reference information for users in conjunction with brain atlases for the identification of brain structures, the

  19. Sex differences in benzodiazepine use in the HIV-infected population.

    Science.gov (United States)

    Wixson, Sarah E; Brouwer, Emily S

    2014-01-01

    In the HIV-infected population there is a high prevalence of psychiatric disorders, conditions that often coexist with drug and alcohol dependence. Symptoms associated with psychiatric disorders are frequently managed with benzodiazepines, a class of medication often abused. We examined whether HIV-infected patients were more likely to fill a benzodiazepine prescription than their uninfected counterparts using a privately insured, nationally representative sample receiving clinical care between January 2007 and December 2009. Odds ratios (OR) and 95% confidence intervals (CI) to quantify the likelihood of receiving a benzodiazepine were calculated using multivariate logistic regression models. We examined the presence of interaction between HIV infection and sex using backwards elimination and by comparing stratum-specific OR to identify clinically meaningful differences. Overall, 323,796 beneficiaries were included in the sample, of which 723 were HIV infected. Bivariate analyses showed that compared to the uninfected sample, HIV-infected patients were more likely to have filled a benzodiazepine prescription (24% vs. 19%) during the study period. HIV-infected patients were also more likely to be male (80% vs. 44%), black (21% vs. 7%) and have a diagnosis of depression (12% vs. 8%) or insomnia (6% vs. 3%) than were uninfected patients. Adjusted for other covariates, HIV infection was associated with an increase (OR): 1.68, 95% CI: 1.39, 2.02) in the likelihood of filling a benzodiazepine prescription. When stratified by sex, HIV-infected males were more likely (OR: 1.68, 95% CI: 1.05, 2.67) than uninfected males to fill a benzodiazepine prescription while there was no observed difference in the likelihood of filling a benzodiazepine prescription between HIV-infected and uninfected females (OR: 1.12, 95% CI: 0.73, 1.70). Our findings suggest that HIV-infected patients, particularly HIV-infected males, are more likely to fill benzodiazepine prescriptions than their

  20. Clobazam: chemical aspects of the 1,4 and 1,5-benzodiazepines.

    Science.gov (United States)

    Kuch, H

    1979-01-01

    1 The structures and chemistry of the 1,4- and 1,5-benzodiazepines are compared. These two groups of drugs differ in respect to basicity, lipophilicity and electronic charge distribution. 2 The 1,4-benzodiazepine diazepam has a weakly basic imine group in contrast to the acid methylene protons of clobazam. 3 The imine function of diazepam is more lipophilic than the carboxamide group of clobazam with its rather hydrophilic character. 4 Diazepam and clobazam differ in electronic charge distribution and hence in the location of the chemically reactive centres, the imine partial structure in diazepam and the malonic acid portion of clobazam.

  1. Benzodiazepine-Like Hypnotics and the Associated Risk of Road Traffic Accidents

    OpenAIRE

    2011-01-01

    The aim of the study was to investigate the association between the use of benzodiazepine or benzodiazepine-like hypnotics and the risk of road traffic accidents. Data from three French national databases were matched: the health-care insurance database, police reports, and the police database of injury-related traffic accidents. A total of 72,685 drivers involved in injury-related road traffic accidents in France, from 2005 to 2008, were included in the study. The risk of being responsible f...

  2. Behavioural effects of the benzodiazepine receptor partial agonist RO 16-6028 in mice.

    Science.gov (United States)

    Belzung, C; Misslin, R; Vogel, E

    1989-01-01

    The imidazo-diazepinone RO 16-6028 is a benzodiazepine receptor partial agonist which exhibits some anti-conflict effects in the two-chambered light/dark test without significantly affecting the behaviour of mice confronted with the staircase test. In addition, this drug slightly reduced locomotion and more markedly rearing in a free exploration procedure. These results indicate that RO 16-6028 appears to produce some anxiolytic and sedative properties like full agonists, but with weaker magnitude. This could be related to the benzodiazepine partial agonistic profile of the compound.

  3. [Participation of GABA--benzodiazepine receptor complex in the anxiolytic effect of piracetam].

    Science.gov (United States)

    Moldavkin, G M; Voronina, T A; Neznamov, G G; Maletova, O K; Eliava, N V

    2006-01-01

    It is established that bicuculline, picrotoxin, and flumazenil (agents blocking different sites of GABA receptor) decrease the anxiolytic effect of piracetam as manifested in the conflict situation test. The most pronounced interaction was observed between piracetam and flumazenyl. On the background of antagonist action, piracetam inhibited the effects of flumazenil (but not those of bicuculline and picrotoxin). Based on these data, it is assumed that the anxiolytic effect of piracetam is mediated to some extent by benzodiazepine site of the GABA-benzodiazepine receptor complex.

  4. 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 fractionated by VLC on silica and preparative C18 HPLC. Each step was monitored with the GABA(A)-benzodiazepine bioassay. The fractionation led to the isolation of apigenin, which may be responsible for CNS-effects of T. parthenium extracts. Copyright (c) 2009 John Wiley & Sons, Ltd....

  5. Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors

    DEFF Research Database (Denmark)

    Lager, Erik; Nilsson, Jakob; Nielsen, Elsebet Østergaard

    2008-01-01

    The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxamide derivatives may be high-affinity ligands at the benzodiazepine binding site of the GABA(A) receptor, prompted a study of 3-acyl-1,4-dihydro-4-oxoquinoline (3-acyl-4-quinolones......). In general, the affinity of the 3-acyl derivatives was found to be comparable with the 3-carboxylate and the 3-carboxamide derivatives, and certain substituents (e.g., benzyl) in position 6 were again shown to be important. As it is believed that the benzodiazepine binding site is situated between an alpha...

  6. Synthesis of carbon-13 and carbon-14 labelled triazolo-1,4-benzodiazepines

    Energy Technology Data Exchange (ETDEWEB)

    Banks, W.R.; Hawi, A.A.; Digenis, G.A. (Kentucky Univ., Lexington, KY (USA). College of Pharmacy)

    1989-04-01

    An efficient two-step synthesis of 8-chloro-1-methyl-6-phenyl-(3H)-S-triazolo-(4,3-a)(1,4)-benzodiazepine (alprazolam) and 8-chloro-6-(2-chlorophenyl)-1-methyl-(3H)-S-triazolo-(4,3-a)(1,4)-benzodiazepine (triazolam) labelled with carbon-13 or carbon-14 from their corresponding hydrazines is reported. The method involved acylation of the appropriate hydrazine using the mixed carbonic anhydride of sodium ({sup 13}C) or ({sup 14}C) acetate and isobutylchloroformate under mild conditions. Thermolysis of the resulting acetylhydrazides gave the target carbon-14 and carbon-13 labelled compounds in good yields. (author).

  7. Operation Brain Trauma Therapy

    Science.gov (United States)

    2014-10-01

    positive reports. However, recent reviews from the field of cancer suggest that often the literature on pre-clinical work is over-inflated –even when...in microglia cells in the brain, although it is also present in macrophages in the peripheral compartments. Importantly Iba-1 is highly up- regulated... ultrastructural analyses were performed. These studies confirmed the diffuse nature of the axonal injury while also confirming that the brain regions assessed

  8. 小剂量甲泼尼龙对颅脑损伤后外周血内皮祖细胞的影响及其意义%Effect of low-dose methylprednisolone on peripheral blood endothelial progenitor cells and its significance in rats after brain iniury

    Institute of Scientific and Technical Information of China (English)

    张斌; 韩振营; 张建宁

    2011-01-01

    Objective To explore the effects of low-dose methylprednisolone (MP) treatment after traumatic brain injury (TBI) in rats on the number of peripheral blood endothelial progenitor cells (EPCs) and injury area of the brain. Methods One hundred and fiftyfour adult male Wistar rats were involved in the present study, and they were randomly divided into normal control group (n=18), TBI control group (n=38), MP control group (n=30), MP+TBI group (n=30) and TBI+MP group (n=38). The TBI model was reproduced by fluid percussion injury (FPI). MP (5mg/kg) was imraperitoneally administered once a day for 4 days. Peripheral venous blood samples were taken on day 1, 3, 7 and 14, and the counts of EPCs were determined by flow cytometry. The rats were sacrificed on day 1 and 3, brain edema was estimated by dry-wet weight method, and the blood-brain barrier (BBB) permeability was determined by Evans-blue extravasation. Results The counts of peripheral blood EPCs were significandy higher in MP control group, MP+TBI group and TBI+MP group on day 1, 3 and 7 than that in normal control and TBI control group, and it returned to the level of normal control group on day 14. The BBB perrreability was improved and brain edema alleviated in MP + TBI and TBI + MP group on day 3. Conclusion The administration of low-dose MP may increase the count of peripheral blood EPCs in rats, decrease BBB damage, and alleviate brain edema.%目的 探讨小剂量甲泼尼龙(MP)对大鼠创伤性颅脑损伤(TBI)后外周血内皮祖细胞(EPCs)数量及创伤区脑组织的影响.方法 成年雄性Wistar大鼠154只,随机分为正常对照组(18只)、TBI对照组(38只)、非创伤给药组(30只)、给药后TBI组(30只)和TBI后给药组(38只).采用液压打击法(打击压力2.14kPa)制作TBI模型.MP采用腹腔注射(5mg/kg),1次/d,连续4d(TBI后给药组打击后即刻开始给药,给药后TBI组于打击前7d开始给药).分别于1、3、7、14d时取静脉血,采用流式细胞术检测

  9. Cholesterol metabolism and homeostasis in the brain

    OpenAIRE

    Zhang, Juan; Qiang LIU

    2015-01-01

    Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to blood-brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD)...

  10. Benzodiazepine Use and Misuse Among Patients in a Methadone Program

    Directory of Open Access Journals (Sweden)

    D'Adamo Christopher

    2011-05-01

    Full Text Available Abstract Background Benzodiazepines (BZD misuse is a serious public health problem, especially among opiate-dependent patients with anxiety enrolled in methadone program because it puts patients at higher risk of life-threatening multiple drug overdoses. Both elevated anxiety and BZD misuse increase the risk for ex-addicts to relapse. However, there is no recent study to assess how serious the problem is and what factors are associated with BZD misuse. This study estimates the prevalence of BZD misuse in a methadone program, and provides information on the characteristics of BZD users compared to non-users. Methods An anonymous survey was carried out at a methadone program in Baltimore, MD, and all patients were invited to participate through group meetings and fliers around the clinic on a voluntary basis. Of the 205 returned questionnaires, 194 were complete and entered into final data analysis. Those who completed the questionnaire were offered a $5 gift card as an appreciation. Results 47% of the respondents had a history of BZD use, and 39.8% used BZD without a prescription. Half of the BZD users (54% started using BZD after entering the methadone program, and 61% of previous BZD users reported increased or resumed use after entering methadone program. Compared to the non-users, BZD users were more likely to be White, have prescribed medication for mental problems, have preexistent anxiety problems before opiate use, and had anxiety problems before entering methadone program. They reported more mental health problems in the past month, and had higher scores in anxiety state, depression and perceived stress (p Conclusions Important information on epidemiology of BZD misuse among methadone-maintenance patients suggests that most methadone programs do not address co-occurring anxiety problems, and methadone treatment may trigger onset or worsening of BZD misuse. Further study is needed to explore how to curb misuse and abuse of BZD in the

  11. Initial human studies with single-photon emission tomography using iodine-123 labelled 3-(5-cyclopropyl-1,2,4-oxadiazo-3-yl)-7-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine (NNC 13-8241)

    Energy Technology Data Exchange (ETDEWEB)

    Kuikka, J.T. [Dept. of Clinical Physiology, Kuopio Univ. Hospital (Finland); Hiltunen, J. [MAP Medical Technologies Oy, Tikkakoski (Finland); Foged, C. [NOVO Nordisk A/S, Maalov (Denmark); Bergstroem, K.A. [Dept. of Clinical Physiology, Kuopio Univ. Hospital (Finland)]|[Karolinska Inst., Dept. of Clinical Neuroscience, Psychiatry Section, Stockholm (Sweden); Halldin, C. [Karolinska Inst., Dept. of Clinical Neuroscience, Psychiatry Section, Stockholm (Sweden); Aakerman, K. [Dept. of Clinical Physiology, Kuopio Univ. Hospital (Finland); Tiihonen, J. [Niuvaniemi Hospital, Kuopio (Finland); Farde, L. [Karolinska Inst., Dept. of Clinical Neuroscience, Psychiatry Section, Stockholm (Sweden)

    1996-07-01

    The iodine-123 labelled ligand 3-(5-cyclopropyl-1,2,4-oxadiazo-3-yl)-7-iodo-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5-a][1,4]-benzodiazepine ([{sup 123}I]NNC 13-8241) was evaluated as a probe for in vivo imaging of benzodiazepine receptor sites in the human brain. Four healthy volunteers were imaged with a high-resolution single-photon emission tomography (SPET) scanner. The metabolism of [{sup 123}I]NNC 13-8241 in plasma was slow. The total brain uptake was about 1.5-fold higher than that of [{sup 123}I]iomazenil. The specific binding in the cortical areas was high and less intense in the thalamus. The most intense uptake was seen in the occipital cortex. The peak cortical uptake of [{sup 123}I]NNC 13-8241 was observed 6-10 h after the injection of tracer. The radiation burden to the patient was moderate, being 2.5 x 10{sup -2} mSv/MBq (effective dose equivalent). A slow metabolism together with favourable kinetics indicates that [{sup 123}I]NNC 13-8241 is a specific and promising SPET ligand for imaging benzodiazepine receptor sites in the living human brain. (orig.)

  12. How Body Affects Brain.

    Science.gov (United States)

    Suzuki, Wendy A

    2016-08-09

    Studies show that physical exercise can affect a range of brain and cognitive functions. However, little is known about the peripheral signals that initiate these central changes. Moon et al. (2016) provide exciting new evidence that a novel myokine, cathepsin B (CTSB), released with exercise is associated with improved memory.

  13. In vivo pharmacological characterization of AC-3933, a benzodiazepine receptor partial inverse agonist for the treatment of Alzheimer's disease.

    Science.gov (United States)

    Hatayama, Y; Hashimoto, T; Kohayakawa, H; Kiyoshi, T; Nakamichi, K; Kinoshita, T; Yoshida, N

    2014-04-18

    GABAergic neurons are known to inhibit neural transduction and therefore negatively affect excitatory neural circuits in the brain. We have previously reported that 5-(3-methoxyphenyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)-1,6-naphthyridin-2(1H)-one (AC-3933), a partial inverse agonist for the benzodiazepine receptor (BzR), reverses GABAergic inhibitory effect on cholinergic neurons, and thus enhances acetylcholine release from these neurons in rat hippocampal slices. In this study, we evaluated AC-3933 potential for the treatment of Alzheimer's disease, a disorder characterized by progressive decline mainly in cholinergic function. Oral administration of AC-3933 (0.01-0.03mg/kg) resulted in the amelioration of scopolamine-induced amnesia, as well as a shift in electroencephalogram (EEG) relative power characteristic of pro-cognitive cholinergic activators, such as donepezil. In addition, treatment with AC-3933 even at the high dose of 100mg/kg p.o. produced no seizure or anxiety, two major adverse effects of BzR inverse agonists developed in the past. These findings indicate that AC-3933 with its low risk for side effects may be useful in the treatment of Alzheimer's disease.

  14. 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.

  15. Consumption of benzodiazepines without prescription among first-year nursing students at the University of Guayaquil, school of nursing, Ecuador.

    Science.gov (United States)

    Paredes, Nivia Pinos; Miasso, Adriana Inocenti; Tirapelli, Carlos Renato

    2008-01-01

    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.

  16. Development and application of a multi-component LC-MS/MS method for determination of designer benzodiazepines in urine.

    Science.gov (United States)

    Pettersson Bergstrand, Madeleine; Helander, Anders; Beck, Olof

    2016-11-01

    New psychoactive substances (NPS) have become an increasing drug problem in the past decade. For detection of NPS, new analytical methods have to be developed, and the methods also have to be updated regularly. This study aimed at developing a multi-component LC-MS/MS method for detection and quantification of 11 NPS of the benzodiazepine sub-class ("designer benzodiazepines") in urine specimens. The method involves dilution of urine with internal standard and hydrolysis of any glucuronide conjugated forms. Separation of the compounds was achieved on a BEH Phenyl column, followed by MS/MS detection in positive electrospray mode. Method validation was performed following the EMA guideline. The method was applied to study the occurrence of designer benzodiazepines in Sweden in 2014-2015, by analysis of 390 samples retrieved from a routine drug testing laboratory. In 40% of these samples, selected based on a positive immunoassay benzodiazepine screening but a negative MS confirmation for the standard set of prescription benzodiazepines, intake of designer benzodiazepines was revealed. These results stress the importance of using and updating confirmation methods to include the increasing number of designer benzodiazepines appearing on the NPS market.

  17. Effects of a Short-Acting Benzodiazepine on Brain Electrical Activity during Sleep.

    Science.gov (United States)

    1980-12-01

    The sleep spindle: Effects of chlordiazepoxide ; effects of other conditions. Sleep Recearch, 1974, 3: 48. 7. Azumi, K. & S. Shirakawa. Characteristics...poor sleepers during repeated use of flurazepam. Psychopharmacology, 1979, 61: 309-316. 13 25. Sherwin, I. Differential action of diazepam on evoked

  18. Discontinuation of long-term benzodiazepine use : 10-year follow-up

    NARCIS (Netherlands)

    de Gier, N. A. H.; Gorgels, W. J. M. J.; Lucassen, P. L. B. J.; Voshaar, R. Oude; Mulder, J.; Zitman, F.

    2011-01-01

    Background. Several interventions aiming at discontinuation of long-term benzodiazepine use have been proven effective in the short term. However, data on the persistence of discontinuation are lacking. Objectives. To assess 10-year follow-up status in patients who succeeded in stopping benzodiazepi

  19. Benzodiazepine Behavioral Side Effects: Review and Implications for Individuals with Mental Retardation.

    Science.gov (United States)

    Kalachnik, John E.; Hanzel, Thomas E.; Sevenich, Robert; Harder, Stuart R.

    2002-01-01

    A literature review found behavioral side effects occurred for 13% of 446 individuals with mental retardation who were prescribed benzodiazepine for either behavioral or psychiatric conditions (n=138, 17.4%), epilepsy (n=20, 15.4%), or other medical conditions such as myoclonus or cerebral palsy (n=100, 2%). Implications of nonrecognition are…

  20. Late-Life Benzodiazepine Use among Russian-Speaking Immigrants in Israel

    Science.gov (United States)

    Isralowitz, Richard; Reznik, Alex; Borkin, Sofia

    2006-01-01

    Purpose: In this prospective study, we examine the reasons for benzodiazepine use among Russian-speaking elderly people in Israel, and we discuss issues related to immigrants. We provide information that can be applied to the improvement of age-related health and social services. Design and Methods: During a 6-month period, we interviewed…

  1. Evaluation of anxiolytic-like effects of some short-acting benzodiazepine hypnotics in mice.

    Science.gov (United States)

    Nishino, Tomomi; Takeuchi, Tomoko; Takechi, Kenshi; Kamei, Chiaki

    2008-07-01

    Anxiolytic-like effects of some short-acting benzodiazepine hypnotics were examined with experimental paradigms of anxiety using an elevated plus-maze in male ICR mice. Diazepam was used as a positive control. The drug at a dose of 1 mg/kg significantly increased the percentage of time spent in the open arms and percentage of the number of open arm entries in the elevated plus-maze. Triazolam, brotizolam, rilmazafone, and lormetazepam also showed an anxiolytic-like effect as indicated by the significant increase in the percentage of time spent in the open arms and percentage of the number of open arm entries. Effects of short-acting benzodiazepine hypnotics used in the study were more potent than those of diazepam. In addition, the doses affecting the elevated plus-maze by benzodiazepine hypnotics were much smaller than those that showed muscle-relaxant activity measured by the rotarod test, indicating that anxiolytic-like effects of benzodiazepine hypnotics had high specificity and selectivity.

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

    Science.gov (United States)

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

    2011-04-01

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

  3. Associations of benzodiazepine craving with other clinical variables in a population of general practice patients.

    NARCIS (Netherlands)

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

    2005-01-01

    BACKGROUND: The aim of this study was to (1) describe the characteristics of patients reporting craving for benzodiazepines (BZs) and (2) to search for associations between BZ craving and other clinical variables in a population of general practice (GP) patients who have made an attempt to discontin

  4. Benzodiazepine receptor-mediated behavioral effects of nitrous oxide in the rat social interaction test.

    Science.gov (United States)

    Quock, R M; Wetzel, P J; Maillefer, R H; Hodges, B L; Curtis, B A; Czech, D A

    1993-09-01

    The present study was conducted to ascertain whether an anxiolytic effect of nitrous oxide was demonstrable in rats using the social interaction test and whether this drug effect might be mediated by benzodiazepine receptors. Compared to behavior of vehicle-pretreated, room air-exposed rats, rat pairs exposed to nitrous oxide showed a generally inverted U-shaped dose-response curve with the maximum increase in social interaction encounters occurring at 25% and significant increase in time of active social interaction at 15-35%; higher concentrations produced a sedative effect that reduced social interaction. Treatment with 5.0 mg/kg of the anxiolytic benzodiazepine chlordiazepoxide also increased social interaction. Pretreatment with 10 mg/kg of the benzodiazepine receptor blocker flumazenil, which alone had no effect, significantly antagonized the social interaction-increasing effects of both nitrous oxide and chlordiazepoxide. In summary, these findings suggest that nitrous oxide produces a flumazenil-sensitive effect comparable to that of chlordiazepoxide and implicate central benzodiazepine mechanisms in mediation of the anxiolytic effect of nitrous oxide.

  5. 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 prac

  6. 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 prac

  7. Associations of benzodiazepine craving with other clinical variables in a population of general practice patients

    NARCIS (Netherlands)

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

    2005-01-01

    BACKGROUND: The aim of this study was to (1) describe the characteristics of patients reporting craving for benzodiazepines (BZs) and (2) to search for associations between BZ craving and other clinical variables in a population of general practice (GP) patients who have made an attempt to discontin

  8. Comparative Study of Intranasal Midazolam and Intravenous Benzodiazepines in Control of Seizures in Children

    Directory of Open Access Journals (Sweden)

    Janki Panchal

    2013-02-01

    Full Text Available Background: Seizures are very common in pediatric patients. As duration of seizures impacts morbidity and mortality to child’s life, control of seizures should be achieved as early as possible, preferably at home. Rectal diazepam and intranasal midazolam are available methods for control of seizures and can be learnt by parents. Methods: We assessed safety and efficacy of intranasal midazolam for control of seizures and also compared its effect with other benzodiazepines given by intravenous route. Results: Among 84 patients, success rate of treatment with Midazolam (intranasal was 45.5% and success rate with Benzodiazepines (intravenous was 90%. The difference is statistically significant. In present study, average time recorded to give drug after arrival at hospital in IN Midazolam group was 0.379 min, where as it was 1.598 min in IV Benzodiazepine group. Average time for cessation of seizures after giving drug was 3.001 min in IN Midazolam group, where as it was 1.009 min in IV Benzodiazepine group. Conclusion: Intra-venous route for control of seizures is most effective compare to Inta-nasal Midazolam. However intranasal Midazolam can be use full when IV access is not available at home or during transport of patient to health care centre. [Natl J of Med Res 2013; 3(1.000: 30-33

  9. Determinants of Initiated and Continued Benzodiazepine Use in the Netherlands Study of Depression and Anxiety

    NARCIS (Netherlands)

    Manthey, Leonie; Giltay, Erik J.; van Veen, Tineke; Neven, Arie Knuistingh; Zitman, Frans G.; Penninx, Brenda W. J. H.

    2011-01-01

    Background: Longitudinal research on determinants of initiated and continued benzodiazepine (BZD) use is inconsistent and has identified many possible determinants. It is unclear which of those are most important in the prediction of BZD use. We aimed to identify the most important predictors of ini

  10. Determination of the main risk factors for benzodiazepine dependence using a multivariate and multidimensional approach.

    NARCIS (Netherlands)

    Kan, C.C.; Hilberink, S.R.; Breteler, M.H.M.

    2004-01-01

    The aim of this study was to identify risk factors for benzodiazepine (BZD) dependence, such as sociodemographic variables, characteristics of BZD use, and psychiatric parameters, which to date have been found to relate inconsistently to indicators of BZD dependence such as chronic BZD use and BZD w

  11. Inappropriate benzodiazepine use in older adults and the risk of fracture

    NARCIS (Netherlands)

    C.S. van der Hooft (Cornelis); M.W.C.J. Schoofs (Marlette); G. Ziere; A. Hofman (Albert); H.A.P. Pols (Huib); M.C.J.M. Sturkenboom (Miriam); B.H.Ch. Stricker (Bruno)

    2008-01-01

    textabstractAIMS: The Beers criteria for prescribing in elderly are well known and used for many drug utilization studies. We investigated the clinical value of the Beers criteria for benzodiazepine use, notably the association between inappropriate use and risk of fracture. METHODS: We performed a

  12. Improved benzodiazepine radioreceptor assay using the MultiScreen (R) Assay System

    NARCIS (Netherlands)

    Janssen, MJ; Ensing, K; de Zeeuw, RA

    1999-01-01

    In this article, an improved benzodiazepine radioreceptor assay is described, which allows substantial reduction in assay time, The filtration in this method was performed by using the MultiScreen(R) Assay System. The latter consists of a 96-well plate with glass fibre filters sealed at the bottom,

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

    NARCIS (Netherlands)

    Manthey, Leonie; Lohbeck, Marijke; Giltay, Erik J.; van Veena, Tineke; Zitman, Frans G.; Penninx, Brenda 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 Neth

  14. Phenylboronic acid catalysed synthesis of 1,5-benzodiazepines via cyclocondensation of -phenylenediamine and ketones

    Indian Academy of Sciences (India)

    Santosh V Goswami; Prashant B Thorat; Sudhakar R Bhusare

    2013-07-01

    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 easy mild reaction condition, experimental work up and good to excellent yields of products.

  15. A tentative quantitative structure-toxicity relationship study of benzodiazepine drugs.

    Science.gov (United States)

    Funar-Timofei, Simona; Ionescu, Daniela; Suzuki, Takahiro

    2010-02-01

    Benzodiazepines belong to a large family of drugs, being used as hypnotics, anxiolytics, tranquillizers, anticonvulsants, in pre-medication and intravenous sedation. Several quantitative structure-toxicity (lethal oral dose for mouse) relationship (QSTR) models for 54 benzodiazepine derivatives have been developed. The molecular structure of these compounds was energetically optimized by molecular mechanics calculations. To the lowest energy conformations thus obtained, quantum chemical calculations (RM1 approach) were applied to finally optimize the structures. Several structural descriptors, volumes, molecular surface area, hydrophobicities and quantum chemical descriptors were calculated from the minimized structures. Multiple linear regression (MLR) combined with genetic algorithm for variable selection, artificial neural networks (ANNs), support vector machines (SVMs) and partial least squares (PLS) have been employed. Few satisfactory MLR models with predictive power were obtained. Nonlinear modelling methods of ANNs and SVMs gave somewhat better models than those obtained by MLR using same set of descriptors. Additional information on the factors which influence the benzodiazepine toxicity was given by PLS. The obtained models can be used for a rough evaluation of benzodiazepine toxicity.

  16. Psychotropic medications, including short acting benzodiazepines, strongly increase the frequency of falls in elderly

    NARCIS (Netherlands)

    van Strien, Astrid M.; Koek, Huiberdina L.; van Marum, Rob J.; Emmelot-Vonk, Marielle H.

    2013-01-01

    Objectives: Falls in the elderly are common and often serious. The aim of this study was to examine the association between the use of different classes of psychotropic medications, especially short acting benzodiazepines, and the frequency of falling in elderly. Study design This retrospective coho

  17. Convenient synthesis of some optically active 1,4-benzodiazepin-2,5-diones

    Institute of Scientific and Technical Information of China (English)

    M. Bakavoli; A. Davoodnia; R. Shahnaee

    2008-01-01

    Isatoic anhydride was reacted with several L-amino acids to give the corresponding (2S)-N-(o-aminobenzoyl)-2-alkyl-aminoacetic acids. The latter compounds were treated with phosphoryl chloride under reflux temperature to afford the eyclizedproducts, (3S)-3-alkyl-3,4-dihydro- 1H- 1,4-benzodiazepin-2,5-diones.

  18. 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.

  19. 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

    The influence of the benzodiazepine antagonist flumazenil on regional cerebral blood flow (rCBF) was investigated in ten healthy, alert volunteers. The design was a randomized, placebo-controlled, double-blind, cross-over study. rCBF was measured by 133-Xe inhalation and single photon emission...

  20. 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...