Sample records for chlordiazepoxide

  1. Chlordiazepoxide (United States)

    ... or any of the ingredients in tablets and capsules. Ask your pharmacist for a list of the ingredients.tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking ...

  2. Cardiovascular effects of diazepam and chlordiazepoxide. (United States)

    Daniell, H B


    In open-chest dog preparations i.v. administration of diazepam and chlordiazepoxide caused increases in coronary blood flow and cardiac output while reducing blood pressure, heart rate, and myocardial contractile force. The decrease in force was independent of the alteration in coronary flow. Arterial--coronary sinus oxygen difference narrowed and myocardial oxygen consumption decreased. These data show that both diazepam and chlordiazepoxide exert an oxygen conserving action along with an increase in myocardial oxygen delivery and suggest that these drugs may be of benefit to the patient with coronary insufficiency by a direct effect on the cardiovascular system as well as through CNS-mediated antianxiety effects.

  3. Chlordiazepoxide and diazepam induced mouse killing by rats. (United States)

    Leaf, R C; Wnek, D J; Gay, P E; Corcia, R M; Lamon, S


    Chlordiazepoxide HCl, at dose levels from 2.5 mg/kg to 80 mg/kg, significantly increased the low base rates of mouse killing (3-9%) observed in large samples (N = 100/dose) of Holtzman strain albino male rats. Maximal killing rates were obtained at doses from 7.5 mg/kg to 20 mg/kg. Diazepam was equally effective, and several times more potent than chlordiazepoxide. Pentobarbital did not increase killing. Killing induced by chlordiazepoxide was blocked by d-amphetamine SO4, but not by l-amphetamine, at dose levels similar to those that block undrugged killing in this strain (ED50 = 1.5 mg/kg). Unlike pilocarpine-induced killing, the effects of chlordiazepoxide were not increased or decreased significantly by either peripherally or centrally active anticholinergic drugs, over wide dose ranges of these agents; nor were the effects of chlordiazepoxide increased by repeated daily administration.

  4. Potentiation of ifosfamide toxicity by chlordiazepoxide, diazepam and oxazepam. (United States)

    Furusawa, S; Fujimura, T; Sasaki, K; Takayanagi, Y


    The effects of chlordiazepoxide, diazepam and oxazepam on the lethal toxicity and metabolic activation of ifosfamide were investigated in mice. Ifosfamide was administered 24 h after the final injection of chlordiazepoxide, diazepam or oxazepam (100 mg/kg/d for 3 d, i.p.). The prior administration of chlordiazepoxide, diazepam or oxazepam enhanced the toxicity of ifosfamide (778 mg/kg, i.p.) during observation for 6 d after the administration of ifosfamide. In chlordiazepoxide-, diazepam- or oxazepam-treated mice, a higher concentration of active metabolite in the plasma after the administration of ifosfamide (200 or 600 mg/kg, i.p.) was observed as compared with that in mice treated with ifosfamide alone. On the other hand, chlordizepoxide, diazepam or oxazepam markedly enhanced the activity of ifosfamide oxidase in the liver microsomes. These results suggest that the potentiation of ifosfamide toxicity is due to stimulation of the metabolic activation of ifosfamide by chlordizepoxide, diazepam and oxazepam.

  5. Simultaneous spectrophotometric estimation of imipramine hydrochloride and chlordiazepoxide in tablets

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    Patel Sejal


    Full Text Available A binary mixture of imipramine HCl and chlordiazepoxide was determined by three different spectrophotometric methods. The first method involved determination of imipramine HCl and chlordiazepoxide using the simultaneous equations and the second method involved absorbance ratio method. Imipramine has absorbance maxima at 251 nm, chlordiazepoxide has absorbance maxima at 264.5 nm and isoabsorptive point is at 220 nm in methanol. Linearity was obtained in the concentration ranges of 1-25 and 1-10 μg/ml for Imipramine HCL and Chlordiazepoxide, respectively. The third method involved determination of these two drugs using the first-derivative spectrophotometric technique at 219 and 231.5 nm over the concentration ranges of 1-20 and 2-24 μg/ml with mean accuracies 99.46±0.78 and 101.43±1.20%, respectively. These methods were successively applied to pharmaceutical formulations because no interferences from the tablet excipients were found. The suitability of these methods for the quantitative determination of the compounds was proved by validation.

  6. Determination of chlordiazepoxide, diazepam, and their major metabolites in blood or plasma by spectrophotodensitometry. (United States)

    Stronjny, N; Bratin, K; Brooks, M A; de Silva, J A


    An analytical procedure was developed for the determination of chlordiazepoxide, diazepam and their major metabolites in blood or plasma. Demoxepam, a metabolite of chlordiazepoxide, is determined by spectrofluorometry after extraction. The remaining compounds are determined by spectrophotodensitometry after thin-layer chromatographic separation. The sensitivity limit of the spectrofluorometric determination of demoxepam is 0.1 to 0.2 microgram while that of the spectrophotodensitometric determination of chlordiazepoxide, diazepam and their N-desmethyl metabolites is 0.05 to 0.2 microgram. The sensitivity and specificity of the assay renders it suitable for monitoring plasma levels of chlordiazepoxide and its major metabolites following single or chronic oral administration of chlordiazepoxide hydrochloride. The sensitivity limit for diazepam and nordiazepam, its major metabolite, renders the assay useful only for the determination of plasma concentrations resulting from high dosage of diazepam. The assay was used to determine chlordiazepoxide and its metabolites following oral administration of Librium. The data showed a significant correlation to those obtained on the same specimens by differential pulse polarography and by radioimmunoassay.

  7. Cost-effectiveness analysis of baclofen and chlordiazepoxide in uncomplicated alcohol-withdrawal syndrome

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    Vikram K Reddy


    Full Text Available Objectives: Benzodiazepines (BZDs are the first-line drugs in alcohol-withdrawal syndrome (AWS. Baclofen, a gamma-aminobutyric acid B (GABA B agonist, controls withdrawal symptoms without causing significant adverse effects. The objective of this study was to compare the cost-effectiveness of baclofen and chlordiazepoxide in the management of uncomplicated AWS. Materials and Methods : This was a randomized, open label, standard controlled, parallel group study of cost-effectiveness analysis (CEA of baclofen and chlordiazepoxide in 60 participants with uncomplicated AWS. Clinical efficacy was measured by the Clinical Institute Withdrawal Assessment for alcohol (CIWA-Ar scores. Lorazepam was used as supplement medication if withdrawal symptoms could not be controlled effectively by the study drugs alone. Both direct and indirect medical costs were considered and the CEA was analyzed in both patient′s perspective and third-party perspective. Results : The average cost-effectiveness ratio (ACER in patient′s perspective of baclofen and chlordiazepoxide was Rs. 5,308.61 and Rs. 2,951.95 per symptom-free day, respectively. The ACER in third-party perspective of baclofen and chlordiazepoxide was Rs. 895.01 and Rs. 476.29 per symptom-free day, respectively. Participants on chlordiazepoxide had more number of symptom-free days when compared with the baclofen group on analysis by Mann-Whitney test (U = 253.50, P = 0.03. Conclusion : Both study drugs provided relief of withdrawal symptoms. Chlordiazepoxide was more cost-effective than baclofen. Baclofen was relatively less effective and more expensive than chlordiazepoxide.

  8. Study and Application of Polarographic Catalytic Wave of Chlordiazepoxide in the Presence of Persulfate

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    GUO,Wei(过玮); LIN,Hong(林洪); LIU,Li-Min(刘利民); GUO,Zhi-An(郭治安); SONG,Jun-Feng(宋俊峰)


    Polarographic catalytic wave of chlordiazepoxide in the presence of K2S2O8 was studied in aqueous and DMF/H2O mixed solutions. The results showed that a single reduction wave in alkaline medium was the reduction of the N= C bond in 1,2-position of chlordiazepoxide via an intermediate free radical in two one-electron successive additions. When K2S2O8 was present,the free radical of the N = C bond was oxidized to regenerate the original, producing a parallel catalytic wave of chlordiazepoxide. It was determined that the apparent rate constant kfof the oxidation reaction was 3.2 × 103 mol-1@L@s-1. Using the catalytic wave the trace of chlordiazepoxide can be determined by linear-potential scan polarography. In NH3/NH4Cl (pH10.2 ± 0.1, 0.12 mol/L)/K2S2O8 (0.016 mot/L) supporting electrolyte, the second-order derivative peak current of the catalytic wave was rectilinear to chlordiazepoxide concentration in the range of 3.20 × 10-8-1.60 × 10-7, 1.60×10-7-1.44 × 10-6 and 1.44 × 10-6-1.44 × 10-5 mol/L, respectively. The limit of detection was 9.0× 10-9 mol/L.

  9. [Cardiovascular effects of diazepam and chlordiazepoxide in experiments on non-narcotized animals]. (United States)

    Rozonov, Iu B


    Tests staged on non-anesthetized cats demonstrated that the symptoms of the inhibited behaviour of the animals following introduction of diazepam and chlordiazepoxide are attended by hypertension, tachycardia and an increased intensity of pressor vasomotor reflexes. Urethan and chlorasole lessened the intensity of the activating effect of the tranquilizers on the central component of the sympathetic nervous system tonicity.

  10. Stimulatory effects of chlordiazepoxide, diazepam and oxazepam on the drug-metabolizing enzymes in microsomes. (United States)

    Jablońska, J K; Knobloch, K; Majka, J; Wiśniewska-Knypl, J M


    5 days' exposure of rats to daily doses of 400 mg/kg body wt. of chlordiazepoxide, diazepam and oxazepam stimulated the microsomal metabolism in the liver, as evidenced by acceleration of both p-hydroxylation of aniline and hydroxylation of benzene. The effect was accompanied by an increased concentration of liver microsomal protein and by the development of tolerance to the drugs. Similar effects were found after exposure of rats to lower doses of the drugs. The metabolism of aniline in vivo in rats treated with chlordiazepoxide was accelerated; this was correlated with development of tolerance to these drugs. It is suggested that both the stimulation of microsomal metabolism and the development of tolerance are associated with the induction of microsomal drug-metabolizing enzymes.

  11. Simultaneous spectrophotometric determination of chlordiazepoxide and clidinium using multivariate calibration techniques. (United States)

    Khoshayand, Mohammad Reza; Abdollahi, Hamid; Moeini, Ali; Shamsaie, Ali; Ghaffari, Alireza; Abbasian, Sepideh


    Three multivariate modelling approaches including partial least squares regression (PLS), genetic algorithm-partial least squares regression (GA-PLS), and principal components-artificial neural network (PC-ANN) analysis were investigated for their application to the simultaneous determination of chlordiazepoxide and clidinium levels in pharmaceuticals. A set of synthetic mixtures of drugs in ethanol and 0.1 M HCL was made, and the prediction abilities of the aforementioned methods were examined using RSE% (relative standard error of the prediction). The PLS and PC-ANN methods were found to be comparable, and GA-PLS produced slightly better results. The predictive models that we built were successfully applied to simultaneously determine the levels of chlordiazepoxide and clidinium in coated tablets.

  12. Continuous intravenous flumazenil infusion in a patient with chlordiazepoxide toxicity and hepatic encephalopathy

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    Moh′d Al-Halawani


    Full Text Available Flumazenil, a benzodiazepine receptor antagonist, is the drug of choice for the diagnosis and treatment of benzodiazepine overdose. We are presenting a patient with chronic alcoholism and alcoholic liver disease, who came with alcohol withdrawal symptoms and treated chlordiazepoxide. Subsequently he developed a prolonged change in mental status that required treatment for benzodiazepine overdose and hepatic encephalopathy with flumazenil infusion for 28 days.

  13. Mephenesin, methocarbamol, chlordiazepoxide and diazepam: actions on spinal reflexes and ventral root potentials. (United States)

    Crankshaw, D P; Raper, C


    1. Dose levels of mephenesin, methocarbamol, chlordiazepoxide and diazepam which abolished polysynaptic reflex contractions had no effect on monosynaptic knee-jerk reflexes in chloralose anaesthetized cats.2. Ventral root potentials were recorded following stimulation of the corresponding dorsal root (L7 or S1), and the areas of the mono- and polysynaptic components were measured by planimetry.3. Dose levels of the drugs which abolished polysynaptic reflex contractions reduced the areas of the polysynaptic component of the ventral root potentials by about 50%. Mephenesin and methocarbamol reduced the area of the monosynaptic component to a similar extent. Chlordiazepoxide was less potent in this respect while diazepam was without effect at this dose level.4. Linear regression lines were calculated for the reduction in the mono- and polysynaptic components of ventral root potentials with increasing doses of each of the four drugs. With methocarbamol and mephenesin the lines were parallel and coincident. With chlordiazepoxide and diazepam they were parallel but not coincident. Large doses of diazepam were required to reduce the area of the monosynaptic component, this drug being the only one of the four tested to have a differential action on the two components which was statistically significant.5. The results are discussed in terms of depressant actions of the drugs on alpha-motorneurones, effects of the drugs at higher centres concerned with motor function, and the lack of evidence that spinal interneurones represent a specific site of action for centrally acting skeletal muscle relaxants.

  14. [Effect of tranquilizers (diazepam and chlordiazepoxide) on the blood supply and activity of the heart]. (United States)

    Chichikanov, G G


    The effect of diazepam (0.15 and 0.5 mg/kg) and chlordiazepoxide (1.0 and 2.0 mg/kg) on the blood supply and cardiac action were investigated in experiments on cats anesthetized with urethan and chlorasol. Both these compounds were found to lower the vascular resistance to the blood flow, to bring down the coronary circulation rate and the oxygen intake of the heart. The preparations exert a marked influence on the work of the heart and the state of hemodynamics. Diazepam causes the development of an appreciable hypertension, bradycardia and reduces the cardiac ejection. Chlordiazepoxide produces a less pronounced fall of the arterial pressure, bradycardia and reduced the cardiac ejection. Unlike chlordiazepoxide diapezam reduces the contractibility of the myocardium, this being manifested in lessening the maximum acceleration of the blood flow in the aorta and in an increase of the systolic contraction time. Inhibition of the myocardium contractility occurring under the influence of diazepam may, to a certain degree, explain more pronounced hypotension observable on administration of this preparation.

  15. Buspirone, chlordiazepoxide and diazepam effects in a zebrafish model of anxiety. (United States)

    Bencan, Zachary; Sledge, Damiyon; Levin, Edward D


    Zebrafish are becoming more widely used to study neurobehavioral pharmacology. We have developed a method to assess novel environment diving behavior of zebrafish as a model of stress response and anxiolytic drug effects. In a novel tank, zebrafish dwell in the bottom of the tank initially and then increase their swimming exploration to higher levels over time. We previously found that nicotine, which has anxiolytic effects in rodents and humans, significantly lessens the novel tank diving response in zebrafish. The specificity of the diving effect was validated with a novel vs. non-novel test tank. The novel tank diving response of zebrafish was tested when given three anxiolytic drugs from two different chemical and pharmacological classes: buspirone, chlordiazepoxide and diazepam. When the test tank was novel the diving response was clearly seen whereas it was significantly reduced when the test tank was not novel. Buspirone, a serotonergic (5HT(1A) receptor agonist) anxiolytic drug with some D(2) dopaminergic effect, had a pronounced anxiolytic-like effect in the zebrafish diving model at doses that did not have sedative effects. In contrast, chlordiazepoxide, a benzodiazepine anxiolytic drug, which is an effective agonist at GABA-A receptors, did not produce signs of anxiolysis in zebrafish over a broad dose range up to those that caused sedation. Diazepam another benzodiazepine anxiolytic drug did produce an anxiolytic effect at doses that did not cause sedation. The zebrafish novel tank diving task can be useful in discriminating anxiolytic drugs of several classes (serotonergic, benzodiazepines and nicotinic).

  16. Olfactory repeated discrimination reversal in rats: effects of chlordiazepoxide, dizocilpine, and morphine. (United States)

    Galizio, Mark; Miller, Laurence; Ferguson, Adam; McKinney, Patrick; Pitts, Raymond C


    Effects of a benzodiazepine (chlordiazepoxide), an N-methyl-D-aspartate receptor antagonist (dizocilpine), and an opiate agonist (morphine) were studied with a procedure designed to assess effects of drugs and other manipulations on nonspatial learning in rats. In each session, rats were exposed to 2 different 2-choice odor-discrimination problems with food reinforcement for correct responses. One problem (performance discrimination) remained the same throughout the study. That is, 1 odor was always correct (S+) and the other was never correct (S-). For the other problem (reversal discrimination), stimuli changed every session. Six different odors were used to program the reversal discrimination; on any given session, S+ was a stimulus that had served as S- the last time it had appeared, S- was a stimulus that had been S+ on its last appearance. Thus, in each session, learning a discrimination reversal could be studied along with the performance of a comparable, but previously learned, discrimination. Chlordiazepoxide interfered with reversal learning at doses that had no effect on the performance discrimination. Morphine and dizocilpine also impaired reversal learning but only at doses that also affected performance of the well-learned performance discrimination.

  17. Chlordiazepoxide enhances the anxiogenic action of CGS 8216 in the social interaction test: evidence for benzodiazepine withdrawal? (United States)

    File, S E; Pellow, S


    The benzodiazepine receptor 'inverse agonist' CGS 8216 has a specific anxiogenic action in the social interaction test that cannot be reversed by other compounds acting at the benzodiazepine site: Ro 15-1788, FG 7142 or beta-CCE. We tried to reverse the anxiogenic effect with chlordiazepoxide, which is able to antagonise the anxiogenic effects of several other compounds acting at benzodiazepine or related sites. Chlordiazepoxide given acutely (10-20 mg/kg) was unable to antagonise the anxiogenic action of CGS 8216 (5-10 mg/kg); instead there was a tendency to enhance its effects. The effects of chlordiazepoxide after 5 days pretreatment were then assessed, since chronic treatment is necessary to reverse the anxiogenic actions of Ro 15-1788 and Ro 5-4864. At 5 mg/kg chronically, chlordiazepoxide was unable to antagonise the anxiogenic effect of CGS 8216, and at 20 mg/kg there was a significant enhancement of the effects of CGS 8216 on social interaction without an effect on locomotor activity. These results are discussed in terms of withdrawal from benzodiazepine treatment.

  18. Effects of chlordiazepoxide and diazepam on feeding performance in a food-preference test. (United States)

    Cooper, S J


    Chlordiazepoxide (5 and 10 mg/kg) and diazepam (2.5 mg/kg) reduced the latency to eat and enhanced feeding response to familiar food in a food-preference test. The increased feeding response resulted from an increased frequency of individual eating episodes (bouts) without significant change in the episode duration. Experiment II indicated that this facilitatory action of the two drugs was not dependent on the presence of principal novelty cues in the food-preference test. Diazepam (5 mg/kg), in contrast, enhanced the feeding responses to novel food in the food preference test. Experiment III demonstrated that although diazepam can counteract induced food neophobia, its facilitory action on the response to novel foods may be mediated by a mechanism which can operate independently of food neophobia.

  19. Conflict behavior in the squirrel monkey: effects of chlordiazepoxide, diazepam and N-desmethyldiazepam. (United States)

    Sepinwall, J; Grodsky, F S; Cook, L


    Dose-response profiles were determined for chlordiazepoxide, diazepam and N-desmethyldiazepam in a squirrel monkey punishment (conflict) procedure. The monkeys were trained to lever press under a food-maintained concurrent schedule consisting of an unpunished 6-minute variable interval (VI) schedule, and a 1.5-minute VI schedule, on which responses were punished intermittently (24 response variable ratio) with electric footshocks. The three benzodiazepines effectively increased responding that had been suppressed by punishment; they had inverted U-shaped dose-effect curves. The minimum effective doses for increasing punished responding were: diazepam less than or equal to 0.31 mg/kg p.o.; N-desmethyldiazepam = chlordiazepoxide = 0.62 mg/kg. As a model to assess potential antianxiety activity, this procedure possessed excellent sensitivity and reliability. The following observations were also made. 1) During initial training, as shock intensity was increased and punished responding became suppressed, some monkeys exhibited an increase in unpunished response rates. This may have represented "positive behavioral contrast," but response rate changes were associated with changes in the amount of time the monkeys allocated to each schedule. 2) At certain dose levels, all three compounds exerted antipunishment effects 24 hours after administration. 3) As was reported previously for rats, when the monkeys had no previous drug experience ("drug-naive") they were more sensitive to the depressant effects of the benzodiazepines. With repeated administration, there was a reduction in this sedation and a concomitant increase in the antipunishment effect. This phenomenon was dose- and animal-dependent.

  20. Facilitation of extinction and re-extinction of operant behavior in mice by chlordiazepoxide and D-cycloserine. (United States)

    Leslie, Julian C; Norwood, Kelly


    The aim was to compare operant extinction with re-extinction following re-acquisition and to investigate neuropharmacological mechanisms through administration of drugs potentiating GABAergic or glutamatergic systems. Groups of C57Bl/6 mice were trained to lever press for food on a fixed ratio schedule, then extinguished with or without pre-session chlordiazepoxide or post-session d-cycloserine administration (15mg/kg in each case), then retrained to lever press for food, then re-extinguished with or without pre-session chlordiazepoxide or post-session d-cycloserine. Under vehicle injections, extinction and re-extinction curves were indistinguishable, but drug treatments showed that there was less resistance to extinction in the re-extinction phase. Chlordiazepoxide facilitated extinction and re-extinction, with an earlier effect during re-extinction. d-Cycloserine also facilitated extinction and re-extinction, with some evidence of an earlier effect during re-extinction. These results replicate and extend earlier findings with operant extinction, but differ from some previous reports of d-cycloserine on re-extinction of Pavlovian conditioned fear. Implications for accounts of the similarities and differences between neural mechanisms of extinction following either Pavlovian or operant conditioning, and applications of these findings, are discussed.

  1. Effects of chlordiazepoxide, diazepam and oxazepam on the antitumor activity, the lethality and the blood level of active metabolites of cyclophosphamide and cyclophosphamide oxidase activity in mice. (United States)

    Sasaki, K; Furusawa, S; Takayanagi, G


    Effects of chlordiazepoxide, diazepam and oxazepam on the antitumor activity and acute toxicity of cyclophosphamide and the level of its active metabolites in the plasma were investigated in mice. Cyclophosphamide was administered 24 h after the final injection of chlordiazepoxide, diazepam or oxazepam (100 mg/kg/d for 3 d, i.p.). Pretreatment with these drugs increased the acute toxicity of cyclophosphamide (300 or 450 mg/kg, i.p.), whereas drugs had no effect on the antitumor activity of cyclophosphamide (100 mg/kg, i.p.) against Ehrlich solid carcinoma. A high level of active metabolites of cyclophosphamide in the plasma after the administration of cyclophosphamide (300 or 450 mg/kg, i.p.) was observed in chlordiazepoxide-, diazepam- or oxazepam-treated mice. On the other hand, chlordiazepoxide, diazepam or oxazepam enhanced significantly the activity of cyclophosphamide oxidase in hepatic microsomes. It is concluded that potentiation of the acute toxicity at a high dose of cyclophosphamide by chlordiazepoxide, diazepam and oxazepam is due to an induction of microsomal drug-metabolizing enzyme which are responsible for the in vivo activation of cyclophosphamide.

  2. Diazepam- and chlordiazepoxide-mediated increases in erythrocyte aldehyde dehydrogenase activity and its possible implications. (United States)

    Murthy, P; Guru, S C; Shetty, K T; Ray, R; Channabasavanna, S M


    Erythrocyte ALDH activity was assayed in alcoholic (n = 70) and nonalcoholic (n = 40) subjects. In general, alcoholics without any prior medications (n = 57) were found to have a decreased ALDH activity (mean +/- SD: 3.38 +/- 1.7 mU; p less than 0.001) as compared to control group (5.10 +/- 1.57 mU). However, a group of alcoholics who were detoxified with benzodiazepines (n = 13) prior to blood collection for enzyme assay were found to have higher ALDH activity (4.92 +/- 2.46 mU; p less than 0.05) as compared to alcoholics who were not detoxified. In vitro experiments demonstrated that both diazepam (DZM) and chlordiazepoxide (CDP) could activate the ALDH. The magnitude of enzyme activation by DZM and CDP appear to correlate with their relative potency of tranquilizing effect. Further, the observed ability of DZM to reverse the inhibition of ALDH mediated by disulfiram may explain the biochemical basis of the reported ability of benzodiazepines (BDZ) to reduce the intensity of disulfiram ethanol reaction (DER).

  3. Behavioral comparison of pentylenetetrazol, clonidine, chlordiazepoxide and diazepam in infant rats. (United States)

    Pappas, B A; Walsh, P


    The effects of various doses of pentylenetetrazol, clonidine, chlordiazepoxide and diazepam on limb and head movement and behavioral seizure signs were examined in 4-, 8- and 16-day old rats tested at ambient temperatures of either 25 or 35 degrees C. All 4 drugs produced intense behavioral activation at the 2 younger ages but there were marked differences among them in the effects of test temperature on this activation and in the relationship between age and their activating effect. A "paradoxical" and intense behavioral energization was observed after the administration of either of the 2 benzodiazepines at 4, 8 but not 16 days, particularly at the lower test temperature. Clonidine and pentylenetetrazol were activating at all 3 ages but while clonidine had greater effect at the low test temperature, the opposite was the case after pentylenetetrazol. The effects of the benzodiazepines and clonidine were clearly distinct from those of pentylenetetrazol and this was the only drug to substantially elicit seizure signs. It is uncertain whether or not the benzodiazepines cause brain seizures in young animals. If so, then their behavioral manifestation is clearly different from that observed after pentylenetetrazol.

  4. Acid-base properties and solubility of pindolol, diazepam and chlordiazepoxide in SDS micelles. (United States)

    de Castro, B; Domingues, V; Gameiro, P; Lima, J L; Oliveira, A; Reis, S


    The effect of sodium dodecyl sulphate (SDS) on the acid-base properties and on the solubility of a beta-blocker (pindolol) and of two benzodiazepines (diazepam and chlordiazepoxide) has been assessed. The study was performed by potentiometric and spectrophotometric determinations of the acidity constants and by spectrophotometric evaluation of the solubilities of the pharmaceutical drugs in aqueous solution and in solutions to which was added SDS with concentrations below and above the critical micelle concentration (cmc), at 25 degrees C and at an ionic strength 0.1 M (NaCl). The effect of the organized assemblies on the pKa values was quantified by the application of two theoretical models that differ in the inclusion of ionic exchange between positively charged species in solution. These models have allowed the determination of the binding constants for drug/micelle and yielded values in good agreement with those obtained by the solubility method, and in addition provide a more detailed picture of the effect of drug charge on its partition. The results can be taken to evidence different interaction modes of the drugs with the SDS micelles.

  5. Anti-anxiety self-medication in rats: oral consumption of chlordiazepoxide and ethanol after reward devaluation. (United States)

    Manzo, Lidia; Donaire, Rocío; Sabariego, Marta; Papini, Mauricio R; Torres, Carmen


    Rats increased preference for ethanol after sessions of appetitive extinction, but not after acquisition (reinforced) sessions (Manzo et al., 2014). Drinking was not influenced by appetitive extinction in control groups with postsession access to water, rather than ethanol. Because ethanol has anxiolytic properties in tasks involving reward loss, these results were interpreted as anti-anxiety self-medication. The present experiment tested the potential for self-medication with the prescription anxiolytic chlordiazepoxide, a benzodiazepine with an addictive profile used in the treatment of anxiety disorders. To test this hypothesis, Wistar rats exposed to a 32-to-4% sucrose devaluation received a two-bottle, 2-h preference test immediately after consummatory training. One bottle contained 1 mg/kg of chlordiazepoxide, 2% ethanol, or water for different groups (the second bottle contained water for all groups). Three additional groups received the same postsession preference tests, but were exposed to 4% sucrose during consummatory training. Rats showed suppression of consummatory behavior after reward devaluation relative to unshifted controls. This effect was accompanied by a selective increase in preference for chlordiazepoxide and ethanol. Downshifted animals with access to water or unshifted controls with access to the anxiolytics failed to exhibit postsession changes in preference. Similar results were observed in terms of absolute consumption and consumption relative to body weight. This study shows for the first time that a prescription anxiolytic supports enhanced voluntary consumption during periods of emotional distress triggered by reward loss. Such anti-anxiety self-medication provides insights into the early stages of addictive behavior.

  6. Flumazenil prevents the development of chlordiazepoxide withdrawal in rats tested in the social interaction test of anxiety. (United States)

    Baldwin, H A; File, S E


    Rats were chronically treated with chlordiazepoxide (CDP 10 mg/kg/day) or vehicle for 27 days. Twenty-four hours after their last dose, they received flumazenil (4 mg/kg) or vehicle and were tested in the social interaction test, in a low-light, familiar arena. CDP withdrawal significantly reduced the time spent in social interaction compared with controls, indicating an anxiogenic withdrawal response. This was completely reversed by flumazenil. A second group received CDP for 27 days and, in addition, received a single dose of flumazenil (4 mg/kg) 6 days before testing. Flumazenil prevented the development of the anxiogenic withdrawal response in these rats.

  7. Antagonism of the anxiolytic action of diazepam and chlordiazepoxide by the novel imidazopyridines, EMD 39593 and EMD 41717. (United States)

    Skolnick, P; Paul, S; Crawley, J; Lewin, E; Lippa, A; Clody, D; Irmscher, K; Saiko, O; Minck, K O


    The imidazopyridines EMD 35993 and EMD 41717 antagonized the anticonflict actions of diazepam and chlordiazepoxide in rodent models which are predictive for anxiolytic action in man. In contrast to other described benzodiazepine antagonists, these compounds did not antagonize either the anticonvulsant or muscle relaxant properties of either benzodiazepine. Both EMD 39593 and EMD 41717 competitively inhibit the binding of [3H]diazepam to brain membranes, but do not exhibit regional differences in potency. These observations suggest that both EMD 39593 and EMD 41717 display some selectivity in antagonizing the anxiolytic properties of benzodiazepines, and as such may be useful tools in identifying neuronal substrates of anxiety.

  8. Preconcentration and determination of chlordiazepoxide and diazepam drugs using dispersive nanomaterial-ultrasound assisted microextraction method followed by high performance liquid chromatography. (United States)

    Pebdani, A Amiri; Khodadoust, S; Talebianpoor, M S; Zargar, H R; Zarezade, V


    Benzodiazepines (BDs) are used widely in clinical practice, due to their multiple pharmacological functions. In this study a dispersive nanomaterial-ultrasound assisted- microextraction (DNUM) method followed by high performance liquid chromatography (HPLC) was used for the preconcentration and determination of chlordiazepoxide and diazepam drugs from urine and plasma samples. Various parameters such as amount of adsorbent (mg: ZnS-AC), pH and ionic strength of sample solution, vortex and ultrasonic time (min), and desorption volume (mL) were investigated by fractional factorial design (FFD) and central composite design (CCD). Regression models and desirability functions (DF) were applied to find the best experimental conditions for providing the maximum extraction recovery (ER). Under the optimal conditions a linear calibration curve were obtained in the range of 0.005-10μgmL(-1) and 0.006-10μgmL(-1) for chlordiazepoxide and diazepam, respectively. To demonstrate the analytical performance, figures of merits of the proposed method in urine and plasma spiked with chlordiazepoxide and diazepam were investigated. The limits of detection of chlordiazepoxide and diazepam in urine and plasma were ranged from 0.0012 to 0.0015μgmL(-1), respectively.

  9. Postmortem Brain and Blood Reference Concentrations of Alprazolam, Bromazepam, Chlordiazepoxide, Diazepam, and their Metabolites and a Review of the Literature

    DEFF Research Database (Denmark)

    Skov, Louise; Holm, Karen Marie Dollerup; Johansen, Sys Stybe


    blood and brain tissue in 104 cases. BZDs were judged to be unrelated to the cause of death in 88 cases and contributing to death in 16 cases. No cases were found with cause of death solely attributed to BZD poisoning. All BZDs investigated tended to have higher concentrations in brain than in blood......, the brain, might be considered. Here we present reference concentrations of femoral blood and brain tissue of selected benzodiazepines (BZDs). Using LC-MS/MS, we quantified alprazolam, bromazepam, chlordiazepoxide, diazepam, and the metabolites desmethyldiazepam, oxazepam and temazepam in postmortem femoral...... with median brain-blood ratios ranging from 1.1 to 2.3. A positive correlation between brain and blood concentrations was found with R(2) values from 0.51 to 0.95. Our reported femoral blood concentrations concur with literature values, but sparse information on brain concentration was available. Drug...

  10. Effect of active metabolites of chlordiazepoxide and diazepam, alone or in combination with alcohol, on psychomotor skills related to driving. (United States)

    Palva, E S; Linnoila, M; Mattila, M J


    The interaction of the main metabolites of diazepam and chlordiazepoxide with alcohol was measured in two double-blind crossover subacute experiments on 40 healthy young volunteers. The drugs were administered for 2 weeks each. The variables measured were choice reaction time and accuracy, eye-hand coordination, divided attention, flicker fusion, proprioception, and nystagmus. ChL, MO and O significantly enhanced the alcohol-induced impairment of psychomotor skills whereas DMD did so only exceptionally on some subjects in the choice reaction test. It is concluded that the diazepam-alcohol interaction on psychomotor skills is mainly due to the parent compound. No correlations between the serum levels of the agents and the changes of performance were found.

  11. Simultaneous assay of diazepam, chlordiazepoxide, N-desmethyldiazepam, N-desmethylchloridazepoxide, and demoxepam in serum by high performance, liquid chromatography. (United States)

    Foreman, J M; Griffiths, W C; Dextraze, P G; Diamond, I


    A method is presented for simultaneously determining diazepam and chlordiazepoxide along with their respective major active serum metabolites N-desmethyldiazepam, and N-desmethylchlordiazepoxide and demoxepam. The drugs are extracted from one ml of buffered serum using chloroform containing 5-(p-methylphenyl)-5-phenylhydantoin as an internal standard. The elution is accomplished using a reversed-phase column with a mobile phase consisting of an acetonitrile/methanol/acetate buffer pH 5.0 (200/225/500) at a flow rate of 2.0 ml/min. Absorbance is monitored at 240 nm using a variable wavelength detector. Each chromatographic separation requires approximately 15 minutes at ambient temperature. Of more than twenty drugs tested for possible interference with this procedure, only methaqualone interferes with the internal standard, and phenytoin with demoxepam.

  12. The anxiogenic action of FG 7142 in the social interaction test is reversed by chlordiazepoxide and Ro 15-1788 but not by CGS 8216. (United States)

    File, S E; Pellow, S


    The effects of FG 7142 were examined in the social interaction test, alone and in combination with chlordiazepoxide, Ro 15-1788 and CGS 8216. The anxiogenic action of FG 7142 (5 mg/kg) was reversed by chlordiazepoxide (5 mg/kg) and by Ro 15-1788 (10 mg/kg), but not by CGS 8216 (10 mg/kg). The profile of FG 7142 in this test and the pattern of its interactions with other compounds is similar to that of beta-CCE, but can be distinguished from that of Ro 15-1788 and CGS 8216. It is concluded that FG 7142, Ro 15-1788 and CGS 8216 may act via different sites to produce their anxiogenic effects.

  13. Immediate effects on human performance of a 1,5-genzodiazepine (clobazam) compared with the 1,4-benzodiazepines, chlordiazepoxide hydrochloride and diazepam. (United States)

    Borland, R G; Nicholson, A N


    1 The immediate effects on human performance of the 1,5-benzodiazepine, clobazam (20 mg), and the 1,4-benzodiazepines, chlordiazepoxide hydrochloride (20 mg) and diazepam (10 mg), were studied by adaptive tracking and measurement of reaction time. Each drug was ingested at 09.00 h and performance was measured at 09 h 30 min (0.5 h), 11 h 30 min (2.5 h), 14 h 30 min (5.5 h) and 18 h 30 min (9.5 h after ingestion). 2 With diazepam decrements in performance on adaptive tracking were observed at 0.5 h and 2.5 h and performance was enhanced at 9.5 h after ingestion. With clobazam performance at individual times did not differ significantly from control, but there was evidence of an improvement in performance during the day. There was no evidence of impaired performance on adaptive tracking after chlordiazepoxide hydrochloride. 3 Reaction time was slowed at 0.5 h and 2.5 h after diazepam and chlordiazepoxide hydrochloride. A decrease in reaction time was observed at 9.5 h after diazepam. No changes in reaction time were observed after clobazam. 4 The subjects as a group differentiated correctly between performance decrements on adaptive tracking after diazepam and the absence of performance decrements after clobazam and chlordiazepoxide hydrochloride. The persistence of the decrement in performance after diazepam was accurately assessed. 5 It is evident that the nature and persistence of impaired performance and the ability to appreciate impaired performance vary considerably between the benzodiazepines, and that the choice of a benzodiazepine should include careful consideration of performance sequelae.

  14. Postmortem Brain and Blood Reference Concentrations of Alprazolam, Bromazepam, Chlordiazepoxide, Diazepam, and their Metabolites and a Review of the Literature. (United States)

    Skov, Louise; Holm, Karen Marie Dollerup; Johansen, Sys Stybe; Linnet, Kristian


    To interpret postmortem toxicology results, reference concentrations for non-toxic and toxic levels are needed. Usually, measurements are performed in blood, but because of postmortem redistribution phenomena this may not be optimal. Rather, measurement in the target organ of psychoactive drugs, the brain, might be considered. Here we present reference concentrations of femoral blood and brain tissue of selected benzodiazepines (BZDs). Using LC-MS/MS, we quantified alprazolam, bromazepam, chlordiazepoxide, diazepam, and the metabolites desmethyldiazepam, oxazepam and temazepam in postmortem femoral blood and brain tissue in 104 cases. BZDs were judged to be unrelated to the cause of death in 88 cases and contributing to death in 16 cases. No cases were found with cause of death solely attributed to BZD poisoning. All BZDs investigated tended to have higher concentrations in brain than in blood with median brain-blood ratios ranging from 1.1 to 2.3. A positive correlation between brain and blood concentrations was found with R(2) values from 0.51 to 0.95. Our reported femoral blood concentrations concur with literature values, but sparse information on brain concentration was available. Drug-metabolite ratios were similar in brain and blood for most compounds. Duplicate measurements of brain samples showed that the pre-analytical variation in brain (5.9%) was relatively low, supporting the notion that brain tissue is a suitable postmortem specimen. The reported concentrations in both brain and blood can be used as reference values when evaluating postmortem cases.

  15. The inability of CCK to block (or CCK antagonists to substitute for) the stimulus effects of chlordiazepoxide. (United States)

    Fox, M A; Levine, E S; Riley, A L


    To further examine the relationship between cholecystokinin (CCK) and GABA, the present study assessed the ability of the CCK-A antagonist devazepide and the CCK-B antagonist L-365,260 to substitute for the stimulus effects of chlordiazepoxide (CDP), as well as the ability of CCK-8s to block these effects, in female Long-Evans rats within the conditioned taste aversion baseline of drug discrimination learning. Both devazepide and L-365,260 failed to substitute for the discriminative stimulus properties of CDP, and CCK-8s failed to block its stimulus effects. The benzodiazepine diazepam did substitute for, and the benzodiazepine antagonist flumazenil did block, the stimulus effects of CDP. This suggests that the lack of substitution for, or antagonism of, CDP by the CCK antagonists and CCK-8s, respectively, was not due to the inability of the present design to assess such effects. Possible bases for the current findings, e.g., necessity of an anxiogenic baseline, drug and receptor specificity, as well as the dose-response nature of the interaction, were discussed. Given that a relationship between CCK and GABA has been reported in other designs, the present results suggest that such a relationship may be preparation specific.

  16. Chlordiazepoxide-induced released responding in extinction and punishment-conflict procedures is not altered by neonatal forebrain norepinephrine depletion. (United States)

    Bialik, R J; Pappas, B A; Pusztay, W


    The effects of chlordiazepoxide (CDZ) in extinction and punishment-conflict tasks were examined in rats after neonatal systemic administration of 6-hydroxydopamine (6-OHDA) to deplete forebrain norepinephrine (NE). At about 70 days of age the rats were water deprived and trained for three days to drink in a novel apparatus. On the fourth day (test day) drinking was either extinguished by elimination of water from the drinking tube or punished by lick-contingent shock. Just prior to this test session half of the vehicle and half of the 6-OHDA treated rats were given an injection of CDZ (8 mg/kg IP). Both the injection of CDZ and forebrain NE depletion prolonged responding during extinction and reduced the suppressant effects of punishment in male rats, and these effects were of similar magnitude. Furthermore, CDZ was as effective in neonatal 6-OHDA treated male rats as in vehicle treated rats indicating that decreased transmission is ascending NE fibers caused by CDZ is not solely responsible for its behavioral effects in extinction and conflict tasks. Rather, these effects may involve cooperative mediation by both noradrenergic and serotonergic forebrain terminals. Unexpectedly, CDZ's anti-extinction effect was absent in female rats and its anti-conflict effect observed only in NE depleted females.

  17. Simultaneous HPLC Determination of Chlordiazepoxide and Mebeverine HCl in the Presence of Their Degradation Products and Impurities

    Directory of Open Access Journals (Sweden)

    Rania N. El-Shaheny


    Full Text Available A simple, rapid, and sensitive RP-HPLC method was developed and validated for the simultaneous determination of chlordiazepoxide (CDO and mebeverine HCl (MBV in the presence of CDO impurity (2-amino-5-chlorobenzophenone, ACB and MBV degradation product (veratric acid, VER. Separation was achieved within 9 min on a BDS Hypersil phenyl column (4.5 mm × 250 mm, 5 µm particle size using a mobile phase consisting of acetonitrile: 0.1 M potassium dihydrogen phosphate: triethylamine (35 : 65 : 0.2, v/v/v in an isocratic mode at a flow rate of 1 mL/min. The pH of the mobile phase was adjusted to 4.5 with orthophosphoric acid and UV detection was set at 260 nm. A complete validation procedure was conducted. The proposed method exhibited excellent linearity over the concentration ranges of 1.0–100.0, 10.0–200.0, 2.0–40.0, and 2.0–40.0 µg/mL for CDO, MBV, VER, and ACB, respectively. The proposed method was applied for the simultaneous determination of CDO and MBV in their coformulated tablets with mean percentage recoveries of 99.75 ± 0.62 and 98.61 ± 0.38, respectively. The results of the proposed method were favorably compared with those of a comparison HPLC method using Student t-test and the variance ratio F-test. The chemical structure of MBV degradation product was ascertained by mass spectrometry and IR studies.

  18. The anxiogenic action of RO 5-4864 in the social interaction test: effect of chlordiazepoxide, RO 15-1788 and CGS 8216. (United States)

    File, S E; Pellow, S


    RO 5-4864 (20 mg/kg), a benzodiazepine with high affinity for peripheral-type benzodiazepine binding sites in rat kidney and brain, but not for the "classical" CNS sites, reduced the time spent by pairs of rats in active social interaction, without reducing locomotor activity, possibly reflecting an anxiogenic action. This anxiogenic effect was not reversed by chlordiazepoxide (5 or 10 mg/kg) given acutely, but was reversed by chlordiazepoxide (5 mg/kg) given for 5 days prior to testing. RO 15-1788 (10 mg/kg), a drug that antagonises several effects of benzodiazepines but has little affinity for peripheral-type sites, had no action on the reduction in social interaction induced by RO 5-4864. However, CGS 8216 (10 mg/kg) which also antagonises the effects of benzodiazepines and has little affinity for RO 5-4864 recognition sites, significantly enhanced the reduction in social interaction caused by RO 5-4864, and the combination produced a significant decrease in locomotor activity. These results are discussed in terms of possible sites of action of RO 5-4864 on the GABA-benzodiazepine receptor complex.

  19. Beta-CCT, a selective BZ-omega1 receptor antagonist, blocks the anti-anxiety but not the amnesic action of chlordiazepoxide in mice. (United States)

    Belzung, C; Le Guisquet, A M; Griebel, G


    The aim of this study was to test further the hypothesis that different benzodiazepine (BZ-omega) receptor subtypes may mediate anxiolytic and amnesic effects of BZ agonists, using the selective BZ-omega1 receptor antagonist beta-CCT (beta-carboline-3-carboxylate t-butyl-ester). Experiments were performed in Swiss mice using the elevated plus-maze anxiety test and two learning tasks - passive avoidance and the radial arm maze. In the elevated plus-maze test, beta-CCT (30 mg/kg, i.p.) completely abolished the increase in open-arm entries induced by the BZ chlordiazepoxide (5mg/kg, i.p.). Chlordiazepoxide decreased retention latency in the passive avoidance step-through procedure, and increased the number of errors in the radial arm maze. These effects were not modified by beta-CCT. Except for a slight, albeit significant, amnesic effect in the passive avoidance test, beta-CCT was devoid of intrinsic activity when administered alone. These results are in agreement with previous studies using selective BZ-omega1 agonists, and thus provide further evidence that BZ-omega1 receptors may be involved in the anxiolytic but not in the amnesic effects of BZ agonists.

  20. Chlordiazepoxide and Clidinium (United States)

    ... to evaluate the evidence regarding combined use of benzodiazepines or other CNS depressants with medication-assisted therapy (MAT) drugs used to treat opioid addiction and dependence. FDA is also evaluating whether labeling changes are ...

  1. Use of a Sonogel-Carbon electrode modified with bentonite for the determination of diazepam and chlordiazepoxide hydrochloride in tablets and their metabolite oxazepam in urine. (United States)

    Naggar, Ahmed Hosny; Elkaoutit, Mohammed; Naranjo-Rodriguez, Ignacio; El-Sayed, Abd El-Aziz Yossef; de Cisneros, José Luis Hidalgo-Hidalgo


    Sonogel-Carbon electrode (SngCE) modified with bentonite (BENT) shows an interesting alternative electrode to be used in the determination of 1,4-benzodiazepines by square wave adsorptive cathodic stripping voltammetry (SWAdCSV). Diazepam (DZ) and chlordiazepoxide hydrochloride (CPZ), were determined using SngCE modified by 5% BENT. An electrochemical study of different parameters (such as pH, buffer type, ionic strength, accumulation potential, scan rate, and accumulation time) which affect the determination of DZ and CPZ is reported. Linear concentration ranges of 0.028-0.256 μg mL(-1) DZ (r=0.9997) and 0.034-0.302 μg mL(-1) CPZ (r=0.9997) are successfully obtained after an accumulation time of 60s. The quantification and detection limits were calculated to be 14.0 and 4.0 ng mL(-1) for DZ, and 16.0 and 5.0 ng mL(-1) for CPZ, respectively. The surface of the proposed electrode was characterized by scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDAX). The developed method was applied to the analysis of commercially available tablets and human urine real samples. Analysis was performed with better precision, very low detection limits, and faster than previously reported voltammetric techniques.

  2. A detailed ethological analysis of the mouse open field test: effects of diazepam, chlordiazepoxide and an extremely low frequency pulsed magnetic field. (United States)

    Choleris, E; Thomas, A W; Kavaliers, M; Prato, F S


    The open field test (OFT) is a widely used procedure for examining the behavioral effects of drugs and anxiety. Detailed ethological assessments of animal behavior are lacking. Here we present a detailed ethological assessment of the effects of acute treatment with the benzodiazepines, diazepam (DZ, 1.5mg/kg) and chlordiazepoxide (CDP, 5.0 and 10.0mg/kg), as well as exposure to a non-pharmacological agent, a specific pulsed extremely low frequency magnetic field (MAG) on open field behavior. We examined the duration, frequency and time course of various behaviors (i.e. exploration, walk, rear, stretch attend, return, groom, sit, spin turn, jump and sleep) exhibited by male mice in different regions of a novel open field. Both DZ and CDP consistently reduced the typical anxiety-like behaviors of stretch attend and wall-following (thigmotaxis), along with that of an additional new measure: 'returns', without producing any overall effects on total locomotion. The drugs also differed in their effects. CDP elicited a shift in the locomotor pattern from a 'high explore' to a 'high walk', while DZ mainly elicited alterations in sit and groom. The MAG treatment was repeated twice with both exposures reducing horizontal and vertical (rearing) activity and increasing grooming and spin turns. However, the anxiety-like behaviors of stretch attend and return were marginally reduced by only the first exposure. We conclude that a detailed ethological analysis of the OFT allows not only the detection of specific effects of drugs and non-pharmacological agents (i.e. pulsed magnetic field) on anxiety-like behaviors, but also permits the examination of non-specific effects, in particular those on general activity.

  3. Evidence for PTZ-like cues as a function of time following treatment with chlordiazepoxide: implications for understanding tolerance and withdrawal. (United States)

    Barrett, R J; Smith, R L


    The present study used a two-lever, drug-discrimination procedure to train rats to discriminate between the cues associated with 5 mg/kg of the anxiolytic, chlordiazepoxide (CDP) and 15 mg/kg of the anxiogenic, pentylenetetrazol (PTZ), to investigate the relationship between withdrawal and acute tolerance. Training doses of the two drugs were chosen so that rats responded about equally on both levers when tested on saline (SAL). Following acquisition of the discrimination, rats were injected with 10 mg/kg CDP and tested for lever choice at various intervals from 6 h to 192 h. These tests revealed that cues associated with CDP withdrawal lasted approximately three times longer than the cues associated with the drug's primary effects. At the shortest retest interval (6 h) after treatment with 10 mg/kg CDP, rats responded primarily on the CDP lever, followed by a shift to predominant responding on the PTZ lever at the 16 h and 24 h intervals before returning to predrug, baseline levels at the longer intervals (48-192 h). In order to investigate the relationship between tolerance and withdrawal to the cue properties of CDP, CDP dose-response curves were determined 24 h following treatment with SAL or 10 mg/kg CDP. Acute tolerance, as defined by a rightward, parallel shift in the dose-response function, was observed in the rats pretreated with CDP. Furthermore, it was evident that the baseline shift associated with CDP withdrawal, rather than a weaker drug cue, accounted for acute tolerance. The results from this study are relevant to evaluating the role positive and negative reinforcement play in motivating compulsive drug use.

  4. Anxiety- and activity-related effects of diazepam and chlordiazepoxide in the rat light/dark and dark/light tests. (United States)

    Chaouloff, F; Durand, M; Mormède, P


    We have investigated, through factor analysis, anxiety- and activity-related variables in rats placed in the light/dark box. Thus, vehicle-, diazepam (DZ)-, and chlordiazepoxide (CDP)-treated rats were submitted 30 min later to 5-min light/dark or dark/light tests (initial placements in light or dark, respectively). Following this test, the animals were tested for 5 min in an automated activity monitor. Doses of DZ (0.75-3.0 mg/kg) and CDP (2.5-10.0 mg/kg) were based on preliminary evidence for 1.5 mg/kg of DZ and 5 mg/kg of CDP being anxiolytic in the elevated plus-maze. In the light/dark test, DZ increased the number of visits to and duration in the light compartment, and locomotor activity in the dark compartment; moreover, DZ decreased the latency to enter the light compartment. These effects were, however, significant for the highest dose only. Although CDP yielded similar behavioural effects, only the highest dose had a significant effect, namely, on latency to enter the light side. Conversely, none of the other variables were benzodiazepine-sensitive. Locomotion in the activity cages was decreased by DZ and CDP, an effect significant for the highest doses of benzodiazepines (dark/light test condition only). In both tests, factor analyses revealed an anxiety-related factor (to which all variables related to the visits in the light and part of the locomotion in the dark contributed), and an activity-related factor (upon which the latency to enter the dark and part of the locomotion in the dark loaded) in the light/dark test only. It is suggested that although the light/dark and dark/light tests capture an approach/avoidance dimension, DZ and CDP are more effective in the former test. Compared to the light/dark test, however, the plus-maze may be more sensitive to the anxiolytic effects of DZ and CDP.

  5. Application of Ultrasound-Assisted Surfactant-Enhanced Emulsification Microextraction Based on Solidification of Floating Organic Droplets and High Performance Liquid Chromatography for Preconcentration and Determination of Alprazolam and Chlordiazepoxide in Human Serum Samples. (United States)

    Goudarzi, Nasser; Amirnavaee, Monavar; Arab Chamjangali, Mansour; Farsimadan, Sahar


    An improved microextraction method is proposed on the basis of ultrasound-assisted surfactant-enhanced emulsification and solidification of a floating organic droplet procedure combined with high performance liquid chromatography for the preconcentration and quantification of alprazolam (ALP) and chlordiazepoxide (CHL) present in a number of human serum samples. Several parameters affecting the extraction efficiency were investigated by the Plackett -Burman factorial design as the screening design. Then the response surface methodology based on the Box-Behnken design was used to optimize the effective parameters in the proposed procedure. The limits of detection for the proposed method were found to be 3.0 and 3.1 ng mL-1 for CHL and ALP, respectively. The calibration curves obtained for the method were linear in the ranges of 10.0-3,500.0 and 10.0-3,000.0 ng mL-1 for CHL and ALP, respectively, with a good determination coefficient. The recoveries of the drugs in the spiked human serum samples were above 93.0%. The developed method was successfully applied to the analysis of these studied drugs in human serum samples. The pre-treatment of the serum samples was performed using acetonitrile to remove the proteins. The proposed procedure was an accurate and reliable one for the determination and preconcentration of these drugs in blood samples.

  6. [Studies on the interactions of chlordiazepoxide, nitrazepam, and diazepam with phenprocoumon (author's transl)]. (United States)

    Kinawi, A; Baumgartl, I


    The interaction of benzodiazepine derivatives with phenprocoumon (Marcumar) was investigated after a single dose of the combination of phenprocoumon/diazepoxide (Librium), phenprocoumon/diazepam (Valium) and phenprocoumon/nitrazepam (Mogadan) had been applied to rats. By means of the high pressure liquid chromatography (HPLC) the change of concentration of these pharmaceutical agents per unit time in serum was determined and related to the corresponding change of prothrombin-time. Hence it can be concluded that the benzodiazepine derivatives influence the distribution of phenprocoumon in the organism.

  7. Buspirone, Chlordiazepoxide and Diazepam Effects in a Zebrafish Model of Anxiety



    Zebrafish are becoming more widely used to study neurobehavioral pharmacology. We have developed a method to assess novel environment diving behavior of zebrafish as a model of stress response and anxiolytic drug effects. In a novel tank, zebrafish dwell in the bottom of the tank initially and then increase their swimming exploration to higher levels as the session progresses. We previously found that nicotine, which has anxiolytic effects in rodents and humans, significantly lessens the nove...

  8. Comparison of effects of Idazoxan and 5-HTP on anxiety with Chlordiazepoxide

    Directory of Open Access Journals (Sweden)

    Alaiy H


    Full Text Available We studied the effect of the selective alha-2 adrenoceptor blocker idazoxan and precursor serotonin (5-HTP on anxiety-related behavior in rats. The conflict drinking test, and evaluator plus-maze were used as model. Idazoxan (2 mg/kg showed an anticonflict effect, having doses dependently increased the number of punished lickes. 5-HTP showed that anxiolytic-like effect in both models. This drug reversed action and produced anxiogenic-like effect at high doses. In contrast, arecholine which is a cholinergic muscarinic agonist drug, produced anxiogenic-like behavior. At 2 mg/kg increased number of entrance (OE and using time (OT in open arms in montgomery's test. Anxiolytic-like effect of this drug was less than of chlordizepoxide. These results showed that increase release of noradrenaline in synaptic nerve terminals of neurons produced anxiety-related behavior. While high release of serotonin in this area reduced behaviors disorder in rats.

  9. Comparison of effects of Idazoxan and 5-HTP on anxiety with Chlordiazepoxide


    Alaiy H; Hajiamiri R


    We studied the effect of the selective alha-2 adrenoceptor blocker idazoxan and precursor serotonin (5-HTP) on anxiety-related behavior in rats. The conflict drinking test, and evaluator plus-maze were used as model. Idazoxan (2 mg/kg) showed an anticonflict effect, having doses dependently increased the number of punished lickes. 5-HTP showed that anxiolytic-like effect in both models. This drug reversed action and produced anxiogenic-like effect at high doses. In contrast, arecholine which ...

  10. Effects of Reinforcement Schedule on Facilitation of Operant Extinction by Chlordiazepoxide (United States)

    Leslie, Julian C.; Shaw, David; Gregg, Gillian; McCormick, Nichola; Reynolds, David S.; Dawson, Gerard R.


    Learning and memory are central topics in behavioral neuroscience, and inbred mice strains are widely investigated. However, operant conditioning techniques are not as extensively used in this field as they should be, given the effectiveness of the methodology of the experimental analysis of behavior. In the present study, male C57Bl/6 mice,…

  11. Drug: D10247 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10247 Mixture, Drug Chlordiazepoxide hydrochloride - clidinium bromide mixt; Chlor...diazepoxide hydrochloride and clidinium buromide (TN) Chlordiazepoxide hydrochloride [DR:D00693], Clidinium bromide... with psycholeptics A03CA02 Clidinium and psycholeptics D10247 Chlordiazepoxide hydrochloride - clidinium bromide mixt PubChem: 163312278 ...

  12. Drug: D00267 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 9) GABAergic synapse map07030 Anxiolytics map07230 GABA-A receptor agonists/antag... N05BA02 Chlordiazepoxide D00267 Chlordiazepoxide (JP16/USP/INN) USP drug classification [BR:br08302] Anxiolytic

  13. Patterns of Benzodiazepine Usage in a Family Medicine Centre



    In a one year survey of the use of diazepam, chlordiazepoxide and flurazepam at a university family medicine centre, the per capita prescribing of the three drugs rose with the age of the patients. Diazepam was used approximately four times as frequently as chlordiazepoxide and for four times as many problems, even though it has similar pharmacological properties and a half-life nearly three times that of chlordiazepoxide. The over 65 age group received 36% of prescriptions for diazepam for m...

  14. Cimetidine (United States)

    ... nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil); chlordiazepoxide (Librium); clopidogrel (Plavix), diazepam (Valium); lidocaine (Xylocaine); metronidazole (Flagyl); nifedipine (Adalat, Procardia); ...

  15. 21 CFR 1308.14 - Schedule IV. (United States)


    ... (4)Camazepam 2749 (5)Chloral betaine 2460 (6)Chloral hydrate 2465 (7)Chlordiazepoxide 2744 (8...) Delorazepam 2754 (14) Diazepam 2765 (15) Dichloralphenazone 2467 (16) Estazolam 2756 (17) Ethchlorvynol...

  16. The Behavioral Toxicology of High-Peak, Low Average Power, Pulsed Microwave Irradiation (United States)


    chlordiazepoxide and diazepam combined with low-level microwaves. Neurobehavioral Toxicology, 2, 131-135. Thomas, J. R., Schrot, J.. and Banvard, R. A...229-272. Thomas, J. R., Burch, L. S., and Yeandle. S. S. (1979). Microwave radiation and chlordiazepoxide : Synergistic effects on fixed-interval

  17. Drug: D00693 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available n hsa04727(2554+2555+2556+2557+2558+2559+2560+2561+2562+2563+2564+2565+2566+2567+2568+55879) GABAergic synapse map07030 Anxiolytic... drug classification [BR:br08302] Anxiolytics Benzodiazepines Chlordiazepoxide D0

  18. Chemical structure and biological activity of the diazepines



    1 Since the introduction of chlordiazepoxide and diazepam many diazepines have been developed. Use of these drugs is increasing and considerable knowledge has accumulated about their mechanisms of action.

  19. Neurobehavioral and Immunological Toxicity of Pyridostigmine, Permethrin and DEET in Males and Females (United States)


    diazepam : Effects on performance in dostigmine bromide, DEET, and permethrin. J. Toxicol. Environ. the running rat. Life Sci. 42:1925-1931; 1988. Health to one of eight different ported that chlorpromazine and chlordiazepoxide impaired experimental conditions. The delay of reinforcement was ei...389-394, 1999. 19 31. van Haaren, F.; Katon, E.; Anderson, K. G. The effects of chlordiazepoxide on low-rate behavior are gender-dependent. Pharmacol

  20. Effect of heparin administration on plasma binding of benzodiazepines.



    1 The effect of intravenous administration of 100 units of heparin on plasma of diazepam, chlordiazepoxide, oxazepam and lorazepam was examined in fourteen normal subjects and five patients with cirrhosis. 2 In normal non-fasted subjects heparin caused a rapid 150--250% rise in the free fraction of diazepam, chlordiazepoxide and oxazepam but no change of lorazepam. The changes in free fraction were slightly smaller, but still significant, when the subjects were fasted. 3 These change in free ...

  1. Ultrasonic Vocalizations by Adult Rats (Rattus norvegicus) (United States)


    begun. Diazepam , chlordiazepoxide , morphine, or naloxone was administered I.P. prior to placing the rat in the tailshock apparatus. Four chlordiazepoxide and diazepam . Drug Dev. Res., 5, 185-193 (1985). Gardner, C.R., and Budhram, P. Effects of agents which interact with central... diazepam , and chlorpromazine, attenuate these vocalizations. Recent work by Kaltwasser (1990) examined the occurrence of vocalizations in response to

  2. Lack of interaction between the behavioral effects of ketamine and benzodiazepines in mice. (United States)

    Fidecka, Sylwia; Pirogowicz, Ewa


    The effect of co-administration of ketamine at the sub-effective dose with diazepam, chlordiazepoxide and clonazepam on their antinociceptive and protective efficacy against pentetrazole-induced seizures were studied in mice. Ketamine alone produces dose-dependent antinociception manifested as reduction in the number of writhing episodes evoked by acetic acid. In the writhing test, the antinociceptive effects of the threshold doses of diazepam, chlordiazepoxide or clonazepam were not changed by ketamine, whereas that of morphine was intensified by ketamine. In the hot plate test, slight antinociceptive effects of the threshold dose of diazepam, but not that of chlordiazepoxide (except the results at 120 min of observation), were significantly intensified by ketamine vs ketamine alone. Ketamine alone was able to protect mice, in the dose-related manner, against pentetrazole-induced seizures. The anticonvulsant effects of the threshold doses of diazepam, chlordiazepoxide and clonazepam were not changed by ketamine. These findings indicate that co-administration of ketamine (at the sub-effective dose) with diazepam, chlordiazepoxide and clonazepam (at non-effective doses) resulted in an intensification of neither antinociceptive nor protective effect against pentetrazole-induced seizures in mice. These data seem to indicate the lack of interaction between ketamine and benzodiazepines with respect to their antinociceptive and anticonvulsant efficacy.

  3. Outpatient Benzodiazepine Prescribing, Adverse Events, and Costs (United States)


    Chlordiazepoxide 10 1,977 3.36 Chlordiazepoxide 25 803 1.36 Clonazepam 0.5 3,168 5.38 Clonazepam 1 2,088 3.55 Diazepam 2 1,393 2.37 Advances in...Alprazolam 0.5 7,046 11.97 Alprazolam 1 2,283 3.88 Chorazepate 3.75 36 0.06 Chorazepate 7.5 43 0.07 Chlordiazepoxide 5 625 1.06... Diazepam 5 8,266 14.04 Diazepam 10 1,959 3.33 Lorazepam 0.5 242 0.41 Lorazepam 1 1,230 2.09 Lorazepam 2 194 0.33 Oxazepam 10 5,078 8.62

  4. Phenobarbital compared to benzodiazepines in alcohol withdrawal treatment

    DEFF Research Database (Denmark)

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


    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...

  5. Effects of a Short-Acting Benzodiazepine on Brain Electrical Activity during Sleep. (United States)


    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

  6. Effects of Clozapine and Alprazolam on Cognitive Deficits and Anxiety-Like Behaviors in a Ketamine-Induced Rat Model of Schizophrenia (United States)


    M., & Prato, F.S. (2001). A detailed ethological analysis of the mouse open field test: Effects of diazepam , chlordiazepoxide , and an extremely low...M., Fukuda, T., & Kawahara, M. (1998). Inhibition by diazepam of ketamine-induced hyperlocomotion and dopamine turnover in mice. Canadian Journal of

  7. Behavioral Studies on the Mechanism of Buspirone, an Atypical Anti-Anxiety Drug (United States)


    diazepam ; a benzodiazepine) , currently the most widely prescribed anxiolytic on the market (Goldberg & Finnerty, 1979; 1982); however, those of the benzodiazepine, chlordiazepoxide . However, unlike the benzodiazepines, effects of buspirone were not reversible by the...efficacy of buspirone and diazepam in the treatment of anxiety. Affierican Journal of Psychiatry, 1979, ~, 1184-1187. Goldberg, H. L. & Finnerty, R

  8. 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



    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...

  9. Prolonged Inhibition of Motor Activity Following Repeated Exposure to Low Levels of Chemical Warfare Agent VX (United States)


    Anxious mice tend to avoid the brightly lit center of the maze, and display thigmotaxis (wall following), in which they closely walk along the...analysis of the mouse open field test: effects of diazepam , chlordiazepoxide and an extremely low frequency pulsed magnetic field, Neurosci Biobehav

  10. Alcohol Withdrawal Syndrome: Symptom-Triggered versus Fixed-Schedule Treatment in an Outpatient Setting

    DEFF Research Database (Denmark)

    Elholm, B.; Larsen, Klaus; Hornnes, N.;


    , time to relapse and patient satisfaction were measured. Patients assessed their symptoms using the Short Alcohol Withdrawal Scale (SAWS). Patient satisfaction was monitored by the Diabetes Treatment Satisfaction Questionnaire. We used the Well-Being Index and the European addiction severity index......Aims: To investigate whether, in the treatment with chlordiazepoxide for outpatient alcohol withdrawal, there are advantages of symptom-triggered self-medication over a fixed-schedule regimen. Methods: A randomized controlled trial in outpatient clinics for people suffering from alcohol dependence...... (AD) and alcohol-related problems; 165 adult patients in an outpatient setting in a specialized alcohol treatment unit were randomized 1:1 to either a symptom-triggered self-medication or tapered dose, using chlordiazepoxide. Alcohol withdrawal symptoms, amount of medication, duration of symptoms...

  11. Assessing the relationship between latent inhibition and the partial reinforcement extinction effect in autoshaping with rats. (United States)

    Boughner, Robert L; Papini, Mauricio R


    Results from a variety of independently run experiments suggest that latent inhibition (LI) and the partial reinforcement extinction effect (PREE) share underlying mechanisms. Experiment 1 tested this LI=PREE hypothesis by training the same set of rats in situations involving both nonreinforced preexposure to the conditioned stimulus (LI stage) and partial reinforcement training (PREE stage). Control groups were also included to assess both LI and the PREE. The results demonstrated a significant, but negative correlation between the size of the LI effect and that of the PREE. Experiment 2 extended this analysis to the effects on LI and the PREE of the anxiolytic benzodiazepine chlordiazepoxide (5 mg/kg, i.p.). Whereas chlordiazepoxide had no effect on LI, it delayed the onset of the PREE. No evidence in support of the LI=PREE hypothesis was obtained when these two learning phenomena were compared within the same experiment and under the same general conditions of training.

  12. Attenuation of reperfusion hyperalgesia in the rat by systemic administration of benzodiazepines.



    1. An investigation into whether reperfusion hyperalgesia is modulated by prior systemic administration of two benzodiazepine agonists (diazepam and chlordiazepoxide), and an antagonist (flumazenil) was conducted. 2. Transient ischaemia was induced in conscious rats by applying an inflatable tourniquet to the base of the tail; when the rats exhibited a co-ordinated escape response, the tourniquet was deflated and reperfusion of the tail was allowed. Reperfusion hyperalgesia manifested as a de...

  13. Attenuation of alcohol withdrawal syndrome and blood cortisol level with forced exercise in comparison with diazepam.



    Relieving withdrawal and post-abstinence syndrome of alcoholism is one of the major strategies in the treatment of alcohol addicted patients. Diazepam, chlordiazepoxide, and topiramate are the approved medications that were used for this object. To assess the role of non-pharmacologic therapy in the management of alcohol withdrawal syndrome, we analyzed effects of forced exercise by treadmill on alcohol dependent mice as an animal model. A total of 60 adult male mice were divided into 5 group...

  14. Effects of some depressant drugs on synaptic responses to glutamate at the crayfish neuromuscular junction.



    Excitatory junction currents produced by glutamate were recorded with an extracellular electrode at the neuromuscular junction of the crayfish. Pentobarbitone, phenobarbitone, diazepam, chlordiazepoxide and procaine had only minimal effects on current decay at concentrations which are highly effective in other preparations. The glutamate synapse in the crayfish appears relatively resistant to these drugs. In contrast, ether and halothane increased the rate of decay of the currents at concentr...

  15. Rebound Insomnia: A Critical Review (United States)


    patients who had received benzodiazepine doses equivalent to approximately 14-16 mg diazepam for 72-75 months (12). Symptoms occurred earlier...who had been treated with diazepam for a week, by the administration of RO 15-1788, a specific Leceptor antagonist of benzodiazepines (13). 3 In the...Withdrawal reactions from chlordiazepoxide (Librium). Psychopharmacology 1961;2(1):63-8. 2. Hollister LE, Bennett JC, Kimbel L Jr, Savage C, Overall JE

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



    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...

  17. Benzodiazepine receptor-mediated behavioral effects of nitrous oxide in the rat social interaction test. (United States)

    Quock, R M; Wetzel, P J; Maillefer, R H; Hodges, B L; Curtis, B A; Czech, D A


    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.

  18. Development of differential tolerance to the sedative and anti-stress effects of benzodiazepines. (United States)

    Mediratta, P K; Sharma, K K; Rana, J


    Differential degree of tolerance has been reported to develop for anticonvulsant, sedative and skeletal muscle relaxant effects of benzodiazepines (BZDs). Acute treatment with BZDs reportedly reduces the formation of gastric stress ulcers and attenuates stress-induced immunosuppression. The present study investigates whether tolerance develops to these antistress effects of BZDs by using diazepam and chlordiazepoxide as representative drugs. A single dose of diazepam (5 mg/kg, i.p.) or chlordiazepoxide (20 mg/kg, i.p.) produced a significant reduction in locomotor activity, a measure of sedative effect and antagonized the effect of restraint stress (RS) on gastric mucosal lesions and anti-sheep red blood cell (SRBC) antibody titre. With chronic treatment (X 7 d), there was a marked tolerance to the sedative effect of both the studied BZD drugs, while much less tolerance developed to their ulcer protective action. However, no tolerance was observed to the attenuating effect of diazepam and chlordiazepoxide on RS-induced immunosuppression. Thus, the results of the present study indicate that different mechanisms may be involved in the development of tolerance to the sedative, antiulcer and immunomodulatory effects of BZDs.

  19. Benzodiazepine stability in postmortem samples stored at different temperatures. (United States)

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


    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.

  20. Are benzodiazepines really anxiolytic? Evidence from a 3D maze spatial navigation task. (United States)

    Ennaceur, A; Michalikova, S; van Rensburg, R; Chazot, P L


    The effects of diazepam and chlordiazepoxide were assessed in a 3D maze which is a modification of an 8-arm radial maze. Each arm of the maze is attached to a bridge radiating from a central platform. Animals exposed for the first time to the maze do not venture beyond the line that separate a bridge from an arm. The prime criteria set for an anxiolytic effect is whether mice would increase the frequency of entries onto arms and increase arm/bridge entries ratio. C57 mice readily cross the line on first exposure and make more than 8 arm visits onto arms on second exposure, while other strains (CD-1 and Balb/c) hold back and rarely cross the line on first exposure and require more sessions to make more than 8 arm entries. An anxiolytic drug is expected to encourage intermediate (CD-1) and high (Balb/c) anxiety mice to adventure onto the arms of the maze and make more visits to the arms to comparable levels seen with low anxiety c57 mice. In the present report, administration of different doses of diazepam (0.625, 1.25, 2.5 and 5 mg kg(-1) i.p.) and chlordiazepoxide (5, 10 and 15 mg kg(-1) i.p.) did not reduce anxiety in animals, with the lowest dose of diazepam increasing motor activity in Balb/c and increasing anxiety in c57 mice while the highest doses of both diazepam (2.5 and 5 mg kg(-1) i.p.) and chlordiazepoxide (15 mg kg(-1) i.p.) induced mild sedation. Our results raise some concerns about the methodological foundations in the current assessment of anxiety and anxiolytic compounds both in animal and human studies.

  1. Effect of the new antiepileptic drug retigabine in a rodent model of mania

    DEFF Research Database (Denmark)

    Dencker, Ditte; Dias, Rebecca; Pedersen, Mette Lund;


    Bipolar spectrum disorders are severe chronic mood disorders that are characterized by episodes of mania or hypomania and depression. Because patients with manic symptoms often experience clinical benefit from treatment with anticonvulsant drugs, it was hypothesized that retigabine, a novel...... compound with anticonvulsant efficacy, may also possess antimanic activity. The amphetamine (AMPH)+chlordiazepoxide (CDP)-induced hyperactivity model has been proposed as a suitable model for studying antimanic-like activity of novel compounds in mice and rats. The aims of the present study in rats were...

  2. Diazepam and Its Effects on Psychophysiological Measures of Performance. (United States)


    to the benzodoazepines. Chlordiazepoxide , nitrazepam, oxazepam, and diazepam have generally been found to impair psy- chomotor skills, depress critical...RFAML-TR-95-926 UNC LASIIE F365-E--011F 615 ML MENhhhhhh T .2 13 N 1. It. %MbIMW~dbdSb AFAMRL-TR-85-036 (0 DIAZEPAM AND ITS EFFECTS ON...Performance " Test Battery ° Diazepam / Evoked Response " Valium - Behavioral Measures ABSTRACT iContinue on reverse if necessary and identify by oI

  3. Fatty Acid Metabolism and Pulmonary Insufficiency Studies. (United States)


    179:43-66, 1971. 4. Greenblatt DJ, Koch-Weser J: Clinical toxicology of chlordiazepoxide and diazepam in relation to serum albumin concentration: A...of heparin 1000 U.S.P. units i.v. on the blood, * -". plasma and free conc.ntrationb of diazepam and its metabolite, "" N-desmethyldiazepam have been...investigated 3 hours after the oral administration of 10 mg diazepam to 5 normal voluntcers. The Z free diazepam and N-desmethyldiazepam increased at

  4. Development of a home cage locomotor tracking system capable of detecting the stimulant and sedative properties of drugs in rats. (United States)

    Dunne, Fergal; O'Halloran, Ambrose; Kelly, John P


    The advent of automated locomotor activity methodologies has been extremely useful in removing the subjectivity and bias out of measuring this parameter in rodents. However, many of these behavioural studies are still conducted in novel environments, rather than in ones that the animals are familiar with, such as their home cage. The purpose of the present series of experiments was to develop an automated home cage tracking (HCT) profile using EthoVision software and assessing the acute effects of stimulant (amphetamine and methamphetamine, 0-5 mg/kg, sc) and sedative (diazepam, 0-20 mg/kg, sc and chlordiazepoxide, 0-50 mg/kg sc) drugs in this apparatus. Young adult male Sprague-Dawley rats were used, and the home cage locomotor activity was recorded for 11-60 min following administration (n=4 per group). For amphetamine and methamphetamine, a dose-dependent increase in home cage activity was evident for both drugs, with a plateau, followed by reduction at higher doses. Methamphetamine was more potent, whereas amphetamine produced greater maximal responses. Both diazepam and chlordiazepoxide dose-dependently reduced locomotor activity, with diazepam exhibiting a greater potency and having stronger sedative effects than chlordiazepoxide. Three doses of each drug were selected at the 31-40 min time period following administration, and compared to open field responses. Diazepam, chlordiazepoxide and amphetamine did not produce significant changes in the open field, whilst methamphetamine produced a significant increase in the 2.5 mg/kg group. In conclusion, these studies have successfully developed a sensitive HCT methodology that has been validated using drugs with stimulant and sedative properties in the same test conditions, with relatively small numbers of animals required to produce statistically significant results. It has proven superior to the open field investigations in allowing dose-response effects to be observed over a relatively short observation period

  5. Pharmacological response of systemically derived focal epileptic lesions

    Energy Technology Data Exchange (ETDEWEB)

    Remler, M.P.; Sigvardt, K.; Marcussen, W.H.


    Focal epileptic lesions were made in rats by systemic focal epileptogenesis. In this method, a focal lesion of the blood-brain barrier (BBB) is produced by focal alpha irradiation followed by repeated systemic injection of a convulsant drug that cannot cross the normal BBB, resulting in a chronic epileptic focus. Changes in the spike frequency of these foci in response to various drugs was recorded. The controls, saline and chlorpromazine, produced no change. Phenytoin, phenobarbital, chlordiazepoxide, and valproic acid produced the expected decrease in spike frequency. Pentobarbital and diazepam produced a paradoxical increase in spike frequency.

  6. Effects of drugs on schedule-controlled running of mice in a circular runway. (United States)

    Lehr, E; Morse, W H; Dews, P B


    Partially food deprived mice ran in a 1-m circular runway. Every 30 circuits, diluted evaporated milk was delivered. Under control conditions mice averaged 0.18 circuits/s for 1 h. The rate was reduced to 0.11 circuits/s 1 h after gavage of Tylose (cellulose derivative) vehicle. Amphetamine, chlordiazepoxide and pentobarbital increased the rate of responding over some dose range, but chlorpromazine, clozapine, imipramine and morphine caused only decreases in responding at effective dose levels. The results are generally similar to reports of effects of the drugs on responses of much briefer duration occurring at similar rates.

  7. The pituitary mediates the anxiolytic-like effects of the vasopressin V1B receptor antagonist, SSR149415, in a social interaction test in rats. (United States)

    Shimazaki, Toshiharu; Iijima, Michihiko; Chaki, Shigeyuki


    A vasopressin V(1B) receptor antagonist has been shown to exhibit anxiolytic effects in a variety of animal models of anxiety. In the present study, we examined the involvement of the pituitary in the anxiolytic effects of a vasopressin V(1B) receptor antagonist by conducting a social interaction test in rats. In the sham-operated rats, both the vasopressin V(1B) receptor antagonist SSR149415 and the benzodiazepine chlordiazepoxide significantly increased the social behavior of a pair of unfamiliar rats, and the blood adrenocorticotropic hormone levels were markedly increased during the social interaction test. Hypophysectomy also increased the length of time that the animals engaged in social behavior to the same extent as that observed after treatment of the sham-operated rats with anxiolytics. However, while chlordiazepoxide further increased the duration of social interaction in the hypophysectomized rats, the anxiolytic effects of SSR149415 was no longer observed in these animals. These results suggest that the anxiolytic effects of the vasopressin V(1B) receptor antagonist in the social interaction test are mediated through blockade of the vasopressin V(1B) receptor in the pituitary.

  8. Use of the accelerating rotarod for assessment of motor performance decrement induced by potential anticonvulsant compounds in nerve agent poisoning. (Reannouncement with new availability information)

    Energy Technology Data Exchange (ETDEWEB)

    Capacio, B.R.; Harris, L.W.; Anderson, D.R.; Lennox, W.J.; Gales, V.


    The accelerating rotarod was used to assess motor performance decrement in rats after administration of candidate anticonvulsant compounds (acetazolamide, amitriptyline, chlordiazepoxide, diazepan, diazepam-lysine, lorazepam, loprazolam, midazolam, phenobarbital and scopolamine) against nerve agent poisoning. AH compounds were tested as the commercially available injectable preparation except for diazepam-lysine and loprazolam, which are not FDA approved. A peak effect time, as well as a dose to decrease performance time by 50% from control (PDD50), was determined. The calculated PDD50 (micrometer ol/kg) values and peak effect tunes were midazolam, 1.16 at 15 min; loprazolam, 1.17 at 15 min; diazepam-lysine, 4.17 at 30 min; lorazepwn, 4.98 at 15 min; diazepam, 5.27 at 15 min; phenobarbital, 101.49 at 45 min; chlordiazepoxide, 159.21 at 30 min; scopolamine, amitriptyline and acetazolamide did not demonstrate a performance decrement at any of the doses tested. The PDD50 values were compared with doses which have been utilized against nerve agent-induced convulsions or published ED50 values from standard anticonvulsant screening tests (maximal electroshock MES and subcutaneous pentylenetetrazol (scMET)). I serve agents, anticonvulsants, diazepam, accelerating rotarod, motor performance.

  9. Degradation of some benzodiazepines by a laccase-mediated system in aqueous solution. (United States)

    Ostadhadi-Dehkordi, Sattar; Tabatabaei-Sameni, Minoosadat; Forootanfar, Hamid; Kolahdouz, Shakiba; Ghazi-Khansari, Mahmoud; Faramarzi, Mohammad Ali


    Purified laccase from the soil ascomycete, Paraconiothyrium variabile was employed in the degradation of 7 benzodiazepine substances in the absence and presence of the enzyme mediators, 1-hydroxybenzotriazole (HBT), 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS), 2,6-dimethoxyphenol (DMP), and vanillic acid (VA). In the absence of a laccase mediator, the original concentrations of 10 μg mL(-1) of nitrazepam, alprazolam, diazepam, and oxazepam decreased by 27.3%, 45.6%, 18.6% and 18.7%, respectively, after 48 h treatment using the purified enzyme, whereas the removal percentages for clobazam, chlordiazepoxide, and lorazepam were only 5.6%, 3.6%, and 4.1%, respectively. Among the laccase mediators, HBT was the most efficient compound, increasing the degradation percentages of nitrazepam, alprazolam, diazepam, and oxazepam to 73%, 88.1%, 61.4%, and 71.2%, respectively. The removal percentages of clobazam, chlordiazepoxide, and lorazepam was increased to 8.2%, 4.7%, and 6.5%, respectively, when the laccase-HBT system was used. The data presented suggest that the laccase-mediated system has potential for the elimination of some benzodiazepines in aqueous solution.

  10. Anticonvulsive and convulsive effects of lidocaine: comparison with those of phenytoin, and implications for mechanism of action concepts. (United States)

    Stone, W E; Javid, M J


    The anticonvulsive action of lidocaine was tested in mice against a series of convulsants, and its profile of action compared with that of phenytoin. Both agents antagonized seizures induced by ouabain or glutamate (injected i.c.b.), effects attributable to reduction of the sodium conductance of neuronal membranes. Lidocaine and phenytoin were relatively ineffective against convulsants that act on synaptic chloride channels via the GABA-ionophore receptor complex. At higher dose levels, both lidocaine and phenytoin are excitatory within limited ranges. Lidocaine-induced seizures were potentiated by phenytoin, and antagonized by chlordiazepoxide, phenobarbital, valproate, trimethadione and muscimol, but not by ethosuximide. This profile of action is similar to that of bicuculline, suggesting that lidocaine may bind to the GABA recognition site and to another site in the GABA-ionophore receptor complex. Phenytoin-induced excitation was antagonized by chlordiazepoxide, less effectively by phenobarbital or trimethadione, only minimally by valproate, and not by trimethadione or muscimol. Phenytoin is known to bind to picrotoxin and benzodiazepine receptor sites; these findings suggest that it may be excitatory at one or both of these sites.

  11. Rapid ultraviolet monitoring of multiple psychotropic drugs with a renewable microfluidic device. (United States)

    Sheng, Jin; Lei, Jianping; Ju, Huangxian; Song, Chaojin; Zhang, Daming


    A rapid method for sensitive ultraviolet detection of multiple psychotropic drugs in human plasma was developed on a low-cost and expediently fabricated hybrid microfluidic device. The device was composed of one fused-silica capillary with a sampling fracture, a poly(methyl methacrylate) board with four reservoirs, and a printed circuit board. At the optimal separation and detection conditions, the baseline separation of three kinds of psychotropic drugs including barbiturates (phenobarbital and barbital), benzodiazepines (nitrazepam, clonazepam, chlordiazepoxide, alprazolam and diazepam) and tricyclic antidepressant drugs (amitriptyline) was achieved within 200 s with separation efficiency up to 3.80 × 10(5) plates m(-1). The linear ranges for ultraviolet detection were from 2.0 to 1000.0 μg mL(-1) for chlordiazepoxide and 1.0 to 1000.0 μg mL(-1) for other seven drugs. Combining with solid-phase extraction, this novel protocol could successfully be used to screen naturally existing psychotropic drugs in a known human plasma sample. The minimum detectable concentration was down to 27 ng mL(-1) for phenobarbital spiked in plasma. This work provided a promising way to initially screen different psychotropic drugs with high resolution, rapid separation and low-cost.

  12. Simultaneous Separation of Eight Benzodiazepines in Human Urine Using Field-Amplified Sample Stacking Micellar Electrokinetic Chromatography. (United States)

    Oledzka, Ilona; Kulińska, Zofia; Prahl, Adam; Baczek, Tomasz


    A novel approach for the simultaneous quantification of eight benzodiazepines (BZDs) using dispersive liquid-liquid microextraction (DLLME) and field-amplified sample stacking (FASS) combined with micellar electrokinetic chromatography (MEKC) was investigated and evaluated in the context of precision, accuracy, sensitivity, linearity, detection and limits of quantification (LOQ). The absolute recovery rates of BZDs were above 90.65%. The limits of detection (LOD) were 20 ng/mL for chlordiazepoxide, estazolam, temazepam and midazolam, and 30 ng/mL for clonazepam, lorazepam, lormetazepam and medazepam, while the LOQ was set at 50 ng/mL for chlordiazepoxide, estazolam, temazepam and midazolam, and 100 ng/mL for clonazepam, lorazepam, lormetazepam and medazepam. Linearity was confirmed in the range of 50-2,000 ng/mL for chlordiazepoxide, estazolam, temazepam and midazolam, and 100-2,000 ng/mL for clonazepam, lorazepam, lormetazepam and medazepam, with a correlation coefficient greater than 0.9987 for all analytes. The elaborated procedure meets all the requirements of analytical methods. During the extraction procedure, a mixture of 1 mL of ethanol and 500 µL of dichloromethane, used as the disperser and extraction solvent, respectively, was rapidly injected into 3 mL of a urine sample. A significant improvement in sensitivity was achieved when DLLME was used to extract BZDs from the urine sample and FASS as an on-line preconcentration technique was developed. For the best separation of analytes, the running buffer was composed of 30 mM SDS, 10 mM sodium tetraborate and 15% methanol (pH 8.8), whereas a sample buffer was composed of 10 mM SDS and 2 mM sodium tetraborate. Moreover, a fused-silica capillary [inner diameter (i.d.) of 75 µm and length of 50 cm], photodiode array detection, pneumatic injection for 15 s and a voltage of 23 kV were applied. The applicability of the method has been confirmed for the analysis of BZD in urine samples collected from patients who

  13. Corticotropin-releasing factor has an anxiogenic action in the social interaction test. (United States)

    Dunn, A J; File, S E


    The effects of intracerebroventricular (icv) injections of corticotropin-releasing factor (CRF, 100 and 300 ng) were investigated in the social interaction test of anxiety in rats. Both doses of CRF significantly decreased active social interaction without a concomitant decrease in locomotor activity. CRF also significantly increased self-grooming, an effect that was independent of the decrease in social interaction. These results indicate an anxiogenic action for CRF. Chlordiazepoxide (CDP, 5 mg/kg ip) pretreatment reversed the anxiogenic effects of icv CRF (100 ng), but CRF did not prevent the sedative effects of CDP. There were no statistically significant changes due to CRF in locomotor activity or rears or head dipping in the holeboard test. Both doses of CRF significantly increased plasma concentrations of corticosterone. The possible mechanisms of the behavioral effects of CRF are discussed.

  14. Altered response to benzodiazepine anxiolytics in mice lacking GABA B(1) receptors. (United States)

    Mombereau, Cedric; Kaupmann, Klemens; van der Putten, Herman; Cryan, John F


    Recently, we demonstrated that mice lacking the GABA(B(1)) subunit were more anxious than wild-type animals in several behavioural paradigms, most notably in the light-dark test. In an attempt to assess the effects of classical benzodiazepine anxiolytics on anxiety-like behaviour observed in these mice, animals were administered either chlordiazepoxide (10 mg/kg, p.o.) or diazepam (7.5 mg/kg, p.o.) prior to testing in the light-dark box. Surprisingly, in contrast with the wild-type mice, neither benzodiazepines decreased anxiety-like behaviour in GABA(B(1))(-/-) mice. These data suggest that targeted deletion of GABA(B(1)) subunit alters GABA(A) receptor function in vivo.

  15. Impact of pH value on the chromatography behavior of four kinds of Benzodiazepines by HPLC%流动相pH值对地西泮、艾司唑仑、氯氮卓、三唑仑HPLC色谱行为的影响

    Institute of Scientific and Technical Information of China (English)

    王蔚昕; 张春水; 黄星


    在其它HPLC分析条件不变的前提下,本实验考察了地西泮、艾司唑仑、氯氮卓、三唑仑4种苯二氮卓类药物保留时间、拖尾因子、峰面积3个指标随流动相水相PH值改变而变化的趋势,初步总结了流动相pH值对4种药物HPLC色谱行为的影响.%Fixing other parameters, the change of the diazepam,Estazolam,Chlordiazepoxide and triazolam in retention time,tailing factor and peak area with PH value were studied in reversed phase high performance liquid chromatography. And the impact of PH value on the chromatography behavior of the four drugs was summarized preliminarily.

  16. The liberal state and the rogue agency: FDA's regulation of drugs for mood disorders, 1950s-1970s. (United States)

    Shorter, Edward


    The theory of the liberal state does not generally contemplate the possibility that regulatory agencies will turn into "rogues," regulating against the interests of their clients and, indeed, the public interest. In the years between circa 1955 and 1975 this seems to have happened to one of the prime regulatory agencies of the US federal government: the Food and Drug Administration (FDA). Intent upon transforming itself from a traditional "cop" agency to a regulatory giant, the FDA campaigned systematically to bring down some safe and effective drugs. This article concentrates on hearings in the area of psychopharmacology regarding several antianxiety drugs, namely meprobamate (Miltown), chlordiazepoxide (Librium) and diazepam (Valium). In addition, from 1967 to 1973 this regulatory vengefulness occurred on a broad scale in the Drug Efficacy Study Implementation (DESI), an administrative exercise that removed from the market almost half of the psychopharmacopoeia. The article explores possible bureaucratic motives for these actions.

  17. Pharmacology of anti-anxiety drugs with special reference to clobazam. (United States)

    Fielding, S; Hoffmann, I


    1 In several studies clobazam exhibited a potency which ranges between that of chlordiazepoxide and diazepam. Its anxiolytic and anti-aggression effects are produced by doses usually ranging below those that cause disorders in motor activity. 2 This separation was demonstrable to an even greater degree with the desmethyl metabolite. The activity of the metabolite, however, was weaker than that of the original substance. 3 The advantage of clobazam compared with the 1.4 benzodiazepines lies mainly in the fact that motor activity is influenced only after very high doses, these doses being markedly above those required to induce tranquillizing and anti-agression activities. 4 Clobazam has no marked effect on the cardiovascular system, respiration of excretion.

  18. Use of psychotropics in the world. (United States)

    Itil, T M; Reisberg, B; Simeon, S


    A questionnaire regarding medication preferences for major categories of psychiatric disorders was sent to 1,059 psychiatric drug investigators in 53 countries. 264 questionnaires were returned, of which 165 were appropriate for this survey. A total of 87 different psychotropic drugs were selected. Chlorpromazine was the medication most frequently cited in the treatment of schizophrenia. Amitriptyline and imipramine together accounted for the vast majority of medication chosen for all varieties of depression. In the treatment of mania, chlorpromazine was chosen by almost one-third of our sample, lithium by only one-fifth. Chlordiazepoxide and diazepam were equally preferred in the treatment of alcoholism. Most psychiatrists preferred not to use any psychotropic medications consistently in treating patients with organic brain syndromes. The implications of this study are discussed and compared uith similar studies in more limited geographical regions and in children.

  19. Pediatric psychopharmacology outside the U.S.A. (United States)

    Simeon, J; Utech, C; Simeon, S; Itil, T M


    To obtain information on the use of psychotropic drugs children outside the U.S.A., 251 questionnaires were mailed to institutions in 53 countries. Seventy-three responses from 34 countries were analyzed. The percentage of patients receiving drugs under the care of these respondents ranged from 0 to 100% (mean 39%). A total of 56 different drugs were selected for eleven psychiatric disorders. No regional differences were apparent, except for infrequently used drugs. Respondents differed widely in the number of drugs selected and maximum dosages. The most popular drugs used in most disorders were diazepam, thioridazine, chlorpromazine, chlordiazepoxide, imipramine, amitriptyline, haloperidol and methylphenidate. Highest agreements among respondents were for imipramine in enuresis, diazepam in anxiety, chlorpromazine in psychosis and thioridazine in hyperkinesis. The results of this survey illustrate important problems in interpreting cross-cultural data in pediatric psychopharmacology, and recommendations for future research are made.

  20. A case-control study of breast cancer and psychotropic drug use. (United States)

    Wallace, R B; Sherman, B M; Bean, J A


    The relative risk of breast cancer incidence and tumor promotion associated with psychotropic drug consumption was evaluated in 151 patients with newly diagnosed neoplasms and 151 hospital controls. No significantly altered risk of breast cancer was found in association with the use of diazepam, chlordiazepoxide, antidepressants, major tranquillizers, sedatives or hypnotics, even after adjustment for known menstrual and reproductive risk factors. No substantial evidence of tumor promotion effects was found, as measured by altered age-at-onset of disease or altered clinical stage at presentation. Psychotropic drug use was inversely related to subject ponderosity (measured by the Quetelet Index) and while this did not confound risk estimates, it may be important in exploring biologic hypotheses of psychotropic drug use and breast cancer.


    Directory of Open Access Journals (Sweden)

    Wahlang JB


    Full Text Available Fixed drug eruption (FDE is common type of drug eruption seen in skin clinics. FDE usually occurs within hours of administration of the offending agent. Most commonly implicated are sulphonamides, salicylates, oxyphenbutazones, tetracycline, dapsone, chlordiazepoxide, barbiturates, phenolphthalein, morphine, codeine,quinine and derivatives, phenacetin, erythromycin, griseofulvin, mebendazole, meprobamate etc. We hereby report a case of fixed drug eruption on glans penis due to metronidazole, a nitroimidazole-derivative clinically indicated in trichomoniasis, amebiasis, giardiasis, anaerobic and mixed antibacterial infections. A patientadministered metronidazole IV developed erythematous superficial non-tender ulceration over the glans penis on the second day of treatment with Inj. Metronidazole. A provisional diagnosis of metronidazole induced fixed drug eruption was made, metronidazole inj. was stopped and the patient was managed with Tab. Prednisolone30mg/day tapered over 10 days and Fusidic acid+Betamethasone cream.

  2. Activation of 5-HT2B receptors in the medial amygdala causes anxiolysis in the social interaction test in the rat. (United States)

    Duxon, M S; Kennett, G A; Lightowler, S; Blackburn, T P; Fone, K C


    In a recent study, we reported the presence of neurones expressing 5-HT2B receptor protein in the medial amygdaloid nucleus of the adult rat brain. In the present study, bilateral micro-injection of the 5-HT2B receptor agonist 1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine hydrochloride (BW 723C86, 0.09 and 0.93 nmol, 5 min pretest) into the medial amygdaloid nuclei increased the total interaction time of a pair of male rats in the social interaction test, to a comparable extent to chlordiazepoxide (5 mg/kg p.o., 1 hr pretest) without altering locomotor activity; indicative of anxiolytic activity. The increase in social interaction was prevented by pretreatment with the 5-HT2C/2B receptor antagonist N-(1-methyl-5-indoyl)-N'-(3-pyridyl) urea hydrochloride (SB 200646A, at 2 but not 1 mg/kg p.o., 1 hr pretest), which did not alter behaviour when given alone. Intra-amygdala BW 723C86 (0.09, 0.31 and 0.93 nmol, 5 min pretest) did not significantly alter the number of punished responses made when the same rats were examined seven days later in a Vogel punished drinking test, although chlordiazepoxide (5 mg/kg p.o., 1 hr pretest) produced the expected anxiolytic profile. The results are consistent with the proposal that activation of 5-HT2B receptors in the medial amygdala induces anxiolysis in the social interaction model but has little effect on behaviour in a punished conflict model of anxiety. These data suggest that serotonergic neurotransmission in this nucleus may selectively affect specific kinds of anxiety generated by different animal models.

  3. Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice. (United States)

    Smith, Kiersten S; Engin, Elif; Meloni, Edward G; Rudolph, Uwe


    GABA(A) receptor modulating drugs such as benzodiazepines (BZs) have been used to treat anxiety disorders for over five decades. In order to determine whether the same or different GABA(A) receptor subtypes are necessary for the anxiolytic-like action of BZs in unconditioned anxiety and conditioned fear models, we investigated the role of different GABA(A) receptor subtypes by challenging wild type, α1(H101R), α2(H101R) and α3(H126R) mice bred on the C57BL/6J background with diazepam or chlordiazepoxide in the elevated plus maze and the fear-potentiated startle paradigms. Both drugs significantly increased open arm exploration in the elevated plus maze in wild type, α1(H101R) and α3(H126R), but this effect was abolished in α2(H101R) mice; these were expected results based on previous published results. In contrast, while administration of diazepam and chlordiazepoxide significantly attenuated fear-potentiated startle (FPS) in wild type mice and α3(H126R) mice, the fear-reducing effects of these drugs were absent in both α1(H101R) and α2(H101R) point mutants, indicating that both α1- and α2-containing GABA(A) receptors are necessary for BZs to exert their effects on conditioned fear responses. Our findings illustrate both an overlap and a divergence between the GABA(A) receptor subtype requirements for the impact of BZs, specifically that both α1- and α2-containing GABA(A) receptors are necessary for BZs to reduce conditioned fear whereas only α2-containing GABA(A) receptors are needed for BZ-induced anxiolysis in unconditioned tests of anxiety. This raises the possibility that GABAergic pharmacological interventions for specific anxiety disorders can be differentially tailored.

  4. Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY314582, MPEP and NKP608). (United States)

    Spooren, Will P J M; Schoeffter, Philippe; Gasparini, Fabrizio; Kuhn, Rainer; Gentsch, Conrad


    The stress-induced hyperthermia test is a paradigm developed several years ago to model the expression of autonomic hyperactivity in anxiety. Whereas in the classical stress-induced hyperthermia, cohort removal was used, in a recently described modification of the stress-induced hyperthermia model singly housed mice rather than groups of mice were used. The modification of this model can be summarized as follows: rectal temperature is recorded in singly housed animals at two consecutive time-points (T1 and T2) which are interspaced by a defined time-interval (15 min). Since the value at the second temperature-recording exceeds the value of the initial measure it is the difference between these two core-temperatures which reflects stress-induced hyperthermia. In the present study, the stress-induced hyperthermia paradigm, in its modified design, was evaluated in OF1/IC mice. By comparing the effect of various compounds in both the modified as well as the classical (cohort removal) stress-induced hyperthermia paradigm, a very high correlation was found for the pharmacological sensitivity of the two paradigms. Furthermore, it was demonstrated that other anxiolytics, all known to be active in the classical stress-induced hyperthermia paradigm, such as the benzodiazepines chlordiazepoxide (0.3, 1, 3, 10 mg/kg, p.o.), diazepam (0.1, 0.3, 1, 3 mg/kg, p.o.), clobazam (5 or 10 mg/kg, p.o.) and oxazepam (5 or 10 mg/kg, p.o.) as well as the non-benzodiazepines buspirone (7.5 or 15 mg/kg, p.o.) and ethanol (15% or 30%, 10 ml/kg, p.o.), showed a marked reduction in stress-induced hyperthermia in the modified design. New candidate anxiolytics, i.e. the metabotropic glutamate (mGlu) receptor group 2 agonist LY314582 (1 or 10 mg/kg, p.o.; racemic mixture of LY354740 ((2S,4S)-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-dioic acid), the metabotropic glutamate 5 receptor antagonist MPEP (1, 7.5, 15 or 30 mg/kg, p.o.; 2-methyl-6-(phenylethynyl)pyridine) and the neurokinin 1 (NK1

  5. A mixed MDPV and benzodiazepine intoxication in a chronic drug abuser: determination of MDPV metabolites by LC-HRMS and discussion of the case. (United States)

    Bertol, Elisabetta; Mari, Francesco; Boscolo Berto, Rafael; Mannaioni, Guido; Vaiano, Fabio; Favretto, Donata


    We report on a case of repeated MDPV consumptions that resulted in severe psychosis and agitation prompting the concomitant abuse of benzodiazepines. A 27-year-old man was found irresponsive in his apartment and was brought to the emergency department (ED) of a local hospital. When in ED, he rapidly recovered and self-reported to have recently injected some doses of MDPV that he had bought in the Internet. He left the hospital without medical cares. 15 days after, he was again admitted to the same ED due to severe agitation, delirium and hallucinations, and reported the use of MDPV and pharmaceutical drugs during the preceding week. He was sedated with diazepam and chlorpromazine. Urine samples collected in both occasions were sent for testing using liquid chromatography-high resolution mass spectrometry (LC-HRMS) and liquid chromatography-high resolution multiple mass spectrometry (LC-HRMS/MS) on an Orbitrap. The LC-HRMS analysis revealed the presence of MDPV and its phase I and phase II metabolites (demethylenyl-MDPV, demethylenyl-methyl-MDPV, demethylenyl-methyl-oxo-MDPV, demethylenyl-hydroxy-alkyl-MDPV, demethylenyl-methyl-hydroxy alkyl-MDPV, demethylenyl-oxo-MDPV and their corresponding glucuronides), alprazolam and alprazolam metabolite at the first ED admission; at the time of the second ED access, the same MDPV metabolites, alprazolam, temazepam, and chlordiazepoxide were detected together with diazepam and metabolites. LC-HRMS/MS was use to determine the following concentrations, respectively on his first and second admission: MDPV 55ng/mL, alprazolam 114ng/mL, α-hydroxyalprazolam 104ng/mL; MDPV 35ng/mL, alprazolam 10.4ng/mL, α -hydroxyalprazolam 13ng/mL; chlordiazepoxide 13ng/mL, temazepam 170ng/mL, diazepam 1.3ng/mL, nordiazepam 61.5, oxazepam 115ng/mL. The toxicological findings corroborated the referred concomitant use of multiple pharmaceutical drugs and benzodiazepines. Confirmation of previous hypothesis on human metabolism of MDPV could be

  6. 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. (United States)

    Verplaetse, Ruth; Cuypers, Eva; Tytgat, Jan


    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 (internal standard), nordiazepam, oxazepam, prazepam, temazepam, tetrazepam, triazolam, zaleplon, zolpidem, zopiclone) in urine and whole blood. Sample preparation was performed on a mixed-mode cation exchange solid phase extraction cartridge. Electrospray ionization was found to be more efficient than atmospheric pressure chemical ionization. The use of a mobile phase of high pH resulted in higher retention and higher electrospray ionization signals than the conventional low pH mobile phases. Considering the benefits of a high pH mobile phase on both chromatography and mass spectrometry, its use should be encouraged. In the final method, gradient elution with 10 mM ammonium bicarbonate (pH 9) and methanol was performed on a small particle column (Acquity C18, 1.7 μm, 2.1 mm × 50 mm). The optimized method was fully validated.

  7. Anxiolytic-like effect of paroxetine in a rat social interaction test. (United States)

    Lightowler, S; Kennett, G A; Williamson, I J; Blackburn, T P; Tulloch, I F


    The effects of short- and long-term administration of the selective serotonin reuptake inhibitor paroxetine were investigated in a rat social interaction test. A single administration of paroxetine at oral doses of 0.3, 1, 3 and 10 mg/kg had no effect on social interaction between pairs of male rats under bright light (high anxiety) conditions. After 21 days of daily administration, paroxetine given orally at 3 mg/kg significantly (p < 0.01) increased the time spent in social interaction by pairs of rats tested under the same conditions, with no effect on locomotor activity, indicating an anxiolytic-like effect. The magnitude of increase (+97%) was comparable to that seen after a single dose of chlordiazepoxide (4 mg/kg orally). Although there was also an increase in time spent in social interaction after 21 days of repeated oral administration of paroxetine at 0.3, 1, and 10 mg/kg (+44, +56, and +54% increases, respectively), statistical significance was not achieved. These results indicate that in the long term paroxetine has an anxiolytic action, and thus support the clinical evidence for its therapeutic use in the treatment of anxiety disorders in addition to its established role as an antidepressant.

  8. Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze. (United States)

    Dunn, R W; Corbett, R; Fielding, S


    The effects of several 5-HT1A agonists and excitatory amino acid antagonists were compared to the standard benzodiazepines, diazepam and chlordiazepoxide (CDP) in two assays predictive of anxiolytic activity, the social interaction and elevated plus maze procedures. Indicative of anxiolytic effects the 5-HT1A agonists, buspirone, gepirone and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) all significantly increased social interaction time and open arm exploration time in the social interaction and elevated plus maze procedures, respectively. Likewise, anxiolytic activity in these assays were also produced by the competitive N-methyl-D-aspartate (NMDA) antagonists, 2-amino-5-phosphonovaleric acid (AP-5), 2-amino-7-phosphonoheptanoic acid (AP-7), 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the non-competitive NMDA antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) while NMDA produced anxiogenic effects. Furthermore, the anxiolytic effects of these agents were of equal magnitude to the benzodiazepines. These two classes of compounds were differentiated in the yohimbine-induced seizure assay, with the NMDA antagonists dose dependently antagonizing seizures similar to the benzodiazepines while the 5-HT1A agonists were inactive. These results suggest that the 5-HT1A agonists and the NMDA antagonists may be potential non-classical anxiolytic agents with different mechanisms of action.

  9. The action of psychotropic drugs on DOPA induced behavioural responses in mice. (United States)

    Berendsen, H; Leonard, B E; Rigter, H


    The "DOPA potentiation" test in mice was investigated for its usefulness in the detection of compounds with antidepressant properties. It was found that the anti-depressant drugs imipramine, amitriptyline, 5-methylamino-acetyl-6-methyl-5,6-dihydro-phenanthridine-HCl (Org OI77) and 1,2,3,4,10,14b-hexahydro-2-methyl-dibenzo[c,f]pyrazino[1,2-a]azepine-HCl (mianserin, Org GB 94) potentiated the behavioural effect of DOPA in groups of mice which had been treated 17 h previously with the monoamine oxidase inhibitor (MAOI) iproniazid. However, the DOPA response was also potentiated by a variety of centrally acting drugs which do not have antidepressant properties (atropine, methysergide, chlordiazepoxide, apomorphine). The peptide hormones ACTH4-10 and desglycinamide lysine vasopressin had equivocal effects while melanocyte stimulating hormone release-inhibiting factor (MIF) had no effect on the DOPA response. The DOPA response was inhibited by the neuroleptics chlorpromazine and haloperidol. There appeared to be no correlation between the effects of the drugs on the behavioural responses elicited by DOPA and the changes found in the brain concentration of noradrenaline, dopamine, serotonin, gamma-aminobutyric acid, tryptophan and tyrosine. It is concluded that the "DOPA potentiation" test cannot be considered as a reliable test in the detection of anti-depressant compounds.

  10. Simultaneous determination and quantification of 12 benzodiazepines in serum or whole blood using UPLC/MS/MS. (United States)

    Gunn, Josh; Kriger, Scott; Terrell, Andrea R


    The benzodiazepines are a large, commonly prescribed family of psychoactive drugs. We describe a method permitting the simultaneous detection and quantification of 12 benzodiazepines in serum using ultra-performance liquid chromatography (UPLC) coupled with tandem mass spectrometry (MS/MS). Analytes included alprazolam, temazepam, oxazepam, nordiazepam, clonazepam, lorazepam, diazepam, chlordiazepoxide, midazolam, flunitrazepam, 7-aminoclonazepam, and 7-aminoflunitrazepam. Sample pretreatment is simple consisting of protein precipitation using cold acetonitrile (ACN) mixed with the deuterated internal standards. Samples were capped and vortexed for 5 min to ensure maximum precipitation. Following a 5-min centrifugation period, 400 microL of the supernatant was transferred to a clean tube and evaporated down under nitrogen. Samples were reconstituted in 200 microL of a deionized water:ACN (80:20) mixture and transferred to appropriate vials for analysis. Chromatographic run time was 7.5 min, and the 12 analytes were quantified using multiple reaction monitoring (MRM) and 6-point calibration curves constructed for each analyte at concentrations covering a clinically significant range.

  11. Anxiolytic effects of valproate and diazepam in mice are differentially sensitive to picrotoxin antagonism. (United States)

    Dalvi, A; Rodgers, R J


    Although it is widely believed that the anxiolytic effects of benzodiazepines are mediated through facilitation of GABA(A) receptor function, behavioural studies have to date provided rather weak support for this hypothesis. In particular, considerable inconsistency has been noted both for the effects of GABAergic manipulations in animal models of anxiety and the ability of GABA(A) receptor antagonists to block the anxiolytic effects of diazepam (DZ) and chlordiazepoxide. In view of the sensitivity of the murine plus-maze to the anxiety-modulating effects of GABAergic agents as well as classical benzodiazepines, the current study examined the extent to which the anxiolytic actions of valproic acid (VPA) and DZ in this test involve picrotoxin (PX)-sensitive receptor mechanisms. Subjects were male DBA/2 mice, test duration was 5 min, and ethological scoring methods were employed. Our results show that, while devoid of intrinsic behavioural effects under present test conditions, PX (0.25-0.5 mg/kg) selectively antagonised the anxiolytic-like (but not other) effects of VPA (400 mg/kg). In contrast, the same doses of PX failed to block any of the behavioural changes induced by DZ (1.5 mg/kg), including disinhibition of open arm exploration. These data suggest that the plus-maze anxiolytic effects of DZ in DBA/2 mice are not mediated through PX-sensitive GABA(A) receptors. Further studies will be required to assess the generality of present findings to other mouse strains, species and behavioural paradigms.

  12. Prediction of benzodiazepines solubility using different cosolvency models. (United States)

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


    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).

  13. Brainstem mediates diazepam enhancement of palatability and feeding: microinjections into fourth ventricle versus lateral ventricle. (United States)

    Peciña, S; Berridge, K C


    The hypothesis that benzodiazepine-induced hyperphagia is due to a specific enhancement of the palatability of foods has been supported by previous 'taste reactivity' studies of affective (hedonic and aversive) reactions to taste palatability. Diazepam and chlordiazepoxide enhance hedonic reactions of rats (rhythmic tongue protrusions, etc.) to sweet tastes in a receptor-specific fashion. A role for brainstem circuits has been indicated by a previous demonstration of the persistence of the taste reactivity enhancement by diazepam after midbrain decerebration. The present study examined whether benzodiazepine brainstem receptors are the chief substrates for palatability enhancement even in intact brains. We compared the effectiveness of benzodiazepine microinjections to elicit feeding and enhance hedonic reactions when delivered into either the lateral ventricle (forebrain) or the fourth ventricle (brainstem) of rats. The results show diazepam is reliably more effective at eliciting feeding and enhancing positive hedonic reactions to oral sucrose when microinjections are made in the fourth ventricle than in the lateral ventricle. We conclude that brainstem neural systems containing benzodiazepine-GABA receptors are likely to be the chief substrates for benzodiazepine-induced palatability enhancement.

  14. A validated method for simultaneous screening and quantification of twenty-three benzodiazepines and metabolites plus zopiclone and zaleplone in whole blood by liquid-liquid extraction and ultra-performance liquid chromatography- tandem mass spectrometry. (United States)

    Simonsen, Kirsten Wiese; Hermansson, Sigurd; Steentoft, Anni; Linnet, Kristian


    An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method for detection of 23 benzodiazepines and related compounds in whole blood was developed and validated. The method is used for screening and quantitation of benzodiazepines in whole blood received from autopsy cases and living persons. The detected compounds were alprazolam, bromazepam, brotizolam, chlordiazepoxide, demoxepam, clobazam, clonazepam, 7-aminoclonazepam, diazepam, nordiazepam, estazolam, flunitrazepam, 7-aminoflunitrazepam, lorazepam, lormetazepam, midazolam, nitrazepam, 7-aminonitrazepam, oxazepam, temazepam, triazolam, zaleplon, and zopiclone. Whole blood from drug-free volunteers was used for all experiments. Blood samples (0.200 g) were extracted with ethyl acetate at pH 9. Target drugs were quantified using a Waters ACQUITY UPLC system coupled to a Waters Quattro Premier XE triple quadrupole in positive electrospray ionization, multiple reaction monitoring mode. The use of deuterated internal standards for most compounds verified that the accuracy of the method was not influenced by matrix effects. Extraction recoveries were 73-108% for all analytes. Lower limits of quantification ranged from 0.002 to 0.005 mg/kg. Long-term imprecision (CV%) ranged from 6.0 to 18.7%. We present a fully validated UPLC-MS-MS method for 23 benzodiazepines in whole blood with a run-time of only 5 min and using only 0.200 g of whole blood.

  15. Simultaneous determination of benzodiazepines and their metabolites in human serum by liquid chromatography-tandem mass spectrometry using a high-resolution octadecyl silica column compatible with aqueous compounds. (United States)

    Nakamura, Mitsuhiro; Ohmori, Tomofumi; Itoh, Yoshinori; Terashita, Masato; Hirano, Kazuyuki


    A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using a high-resolution octadecyl silica column compatible with aqueous compounds was developed for the simultaneous determination of benzodiazepines and their metabolites in human serum. This method enabled us to determine multiple benzodiazepines, including flurazepam, bromazepam, chlordiazepoxide, nitrazepam, clonazepam, flunitrazepam, estazolam, clobazam, lorazepam, alprazolam, triazolam, brotizolam, fludiazepam, diazepam, quazepam, prazepam and their metabolites such as 7-aminonitrazepam, 7-aminoclonazepam, 7-acetamidonitrazepam, N-desmethylclobazam and N-desmethyldiazepam. The analytes spiked into human serum were subjected to solid-phase extraction followed by liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The running time was within 25 min for the measurement of 22 benzodiazepines and their metabolites. The recovery rates exceeded 58.1% for those compounds except for quazepam, which showed a recovery of 45.8%. The limit of detection ranged from 0.3 to 11.4 ng/mL. Linearity was satisfactory for all compounds. These data suggest that the present method can be applicable to routine assay for benzodiazepines in the clinical setting.

  16. The Rapid Measurement of Benzodiazepines in a Milk-Based Alcoholic Beverage Using QuEChERS Extraction and GC-MS Analysis. (United States)

    Famiglini, Giorgio; Capriotti, Fabiana; Palma, Pierangela; Termopoli, Veronica; Cappiello, Achille


    Benzodiazepines (BDZs) are widely used as tranquilizers and anti-depressive drugs in common clinical practice. However, their ready availability and their synergistic effects with alcohol make them attractive for criminal intentions. To prove criminal action for legal reasons, it is often necessary to analyze beverage residues from a crime scene. Milk-based alcoholic drinks (whiskey creams) are gaining popularity due to their lower alcohol content pleasant taste. However, the complexity of this sample, containing proteins and fatty acids, can mask the presence of drugs or other substances in standard analysis methods. These characteristics make whiskey creams highly suitable for illicit purposes. In this study, eight BDZs, including diazepam, chlordiazepoxide, clobazam, flunitrazepam, bromazepam, flurazepam, nitrazepam and clonazepam, were extracted from whiskey cream using the Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) method and analyzed using GC-MS. The QuEChERS protocol can efficiently separate most of the matrix from the target compounds while maintaining acceptable recoveries. The presented method is simple and rapid and has been validated in terms of precision, accuracy and recoveries. Limits of detection and limits of quantitation were in the range of 0.02-0.1 and 0.1-0.5 µg/mL, respectively. Whiskey cream beverages, fortified with commercial drugs at 20 µg/mL, were extracted and analyzed demonstrating the applicability of the method in forensic analysis.

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

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


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

  18. Some aspects of the effects of clobazam on human psychomotor performance. (United States)

    Hindmarch, I


    1 Three studies are described, the first being a comparison of the effects of acute night-time doses of clobazam 20 mg, amylobarbitone sodium 100 mg, nitrazepam 5 mg and placebo, on choice reaction time, critical flicker fusion (CFF) and stabilometer performance. Clobazam improved early morning performance on a choice reaction test, in contrast to the other two active drugs. 2 Repeated doses of clobazam 10 mg three times daily, chlordiazepoxide 10 mg three times daily and diazepam 5 mg three times daily were given for 5 days. Again clobazam did not produce any impairment of psychomotor performance, and noticeably increased CFF thresholds. 3 The effects of an acute night-time dose of clobazam 20 mg on psychomotor performance the morning after night-time medication were correlated with the neuroticism scores (on the EPI) of the subjects. Clobazam exerts a differential effect on psychomotor performance dependent on the basic personality trait. 4 Clobazam seems to differ significantly from the 1,4-benzodiazepines in that, although it reduces anxiety, it does so without any apparent impairment of psychomotor performance.

  19. Hepatotrophic activity of benzodiazepine drugs in adult rats of either sex. (United States)

    Gershbein, L L


    Adult rats with two-thirds of the liver removed were administered diets supplemented with benzodiazepine drugs over a period of 10 days and the mass of organ regenerated or the liver increment ascertained. For a number of the drugs, liver regeneration was stimulated; the effect was more consistent and reproducible in the adult female. On the basis of the lower sensitivity of the male, such animals provided an approach toward rating the hepatotrophic efficacy of the agents and in relation to structure. According to the current classification, hepatotrophic activity was higher with lorazepam, loprazolam, oxazepam and chlordiazepoxide; intermediate with nitrazepam, temazepam, quazepam, halazepam and triazepam and lower with diazepam, clorazepate dipotassium, clobazam and alprazolam. More reproducible responses in terms of g wet and dry liver per 100 g body weight were obtained with sham-operated or intact males. The antagonist, flumazenil, fed at 0.080% was not effective as such nor modified the responses in admixture with several drugs in partially hepatectomized or intact males. In vivo hepatic microsomal changes in protein, cytochrome P-450 or the enzymes, aminopyrine demethylase and benzo[a]pyrene hydroxylase with the various series were not remarkable or sporadic. Among other factors, the liver incremental changes noted currently are dependent on the metabolic intermediate benzodiazepines of varying elimination half-lives which may be distinct from that of the parent drug coupled with the alterations induced by partial ablation of the organ in rats of either sex.

  20. Inpatient management of acute alcohol withdrawal syndrome. (United States)

    Perry, Elizabeth C


    Alcohol withdrawal is a common condition encountered in the hospital setting after abrupt discontinuation of alcohol in an alcohol-dependent individual. Patients may present with mild symptoms of tremulousness and agitation or more severe symptoms including withdrawal seizures and delirium tremens. Management revolves around early identification of at-risk individuals and symptom assessment using a validated tool such as the revised Clinical Institute Withdrawal Assessment for Alcohol score. Benzodiazepines remain the mainstay of treatment and can be administered using a front-loading, fixed-dose, or symptom-triggered approach. Long-acting benzodiazepines such as chlordiazepoxide or diazepam are commonly used and may provide a smoother withdrawal than shorter-acting benzodiazepines, but there are no data to support superiority of one benzodiazepine over another. Elderly patients or those with significant liver disease may have increased accumulation and decreased clearance of the long-acting benzodiazepines, and lorazepam or oxazepam may be preferred in these patients. Patients with symptoms refractory to high doses of benzodiazepines may require addition of a rescue medication such as phenobarbital, propofol or dexmedetomidine. Anticonvulsants (carbamazepine, valproate, gabapentin) may have a role in the management of mild to moderate withdrawal. Other medications such as β-antagonists or neuroleptics may offer additional benefit in select patients but should not be used a monotherapy.

  1. Examination of reinforcement magnitude on the pharmacological disruption of fixed-ratio performance. (United States)

    Pinkston, Jonathan W; Ginsburg, Brett C; Lamb, R J


    Behavioral momentum theory proposes that operant behavior is the product of two separable processes: its rate of occurrence and its resistance to change. Generally speaking, operant situations providing more densely spaced or greater magnitudes of reinforcement should be more resistant to disruption. Attempts to disrupt ongoing behavior by manipulating the availability of food or deprivation level typically have supported the predictions of behavioral momentum. Tests with pharmacological disruptors, however, have yielded mixed results. Most investigations of pharmacological disruption of operant behavior have evaluated momentum across situations that differ in rate of reinforcement. The present experiment was an attempt to systematically replicate prior work, but under conditions of differing reinforcement magnitudes. Pigeons were trained to key peck on a multiple fixed-ratio 30 schedule of food presentation, where different components programmed 2-, 4-, or 8-s access to grain. Resistance to rate-decreasing effects of drugs was evaluated with several compounds drawn from distinct pharmacological classes: chlordiazepoxide, cocaine, clonidine, haloperidol, morphine, and ethanol were tested. Additionally, disruption by prefeeding and extinction was examined. Generally, resistance to change by drug administration was not modulated by reinforcement magnitude. Prefeeding and extinction tests, however, replicated previous work, indicating that our procedure was sensitive to more common disruptors. The results give additional support to the notion that pharmacological disruptors may not behave in the manner predicted by behavioral momentum theory.

  2. [Effect of liver cirrhosis on pharmacokinetics and pharmacodynamics of drugs]. (United States)

    Perlík, F


    Metabolic liver functions are significantly involved in the total clearance of a number of drugs. In liver cirrhosis the reduced drug elimination is a result of the blood flow through the liver, hepatocytes function and volume of hepatic tissue. Pharmacokinetic and pharmacodynamic changes depend on the nature and degree of hepatic impairment and on the characteristics of the dosed drug. Hepatocytes have a different extraction ability with respect to the individual drugs. The following are examples of drugs with high hepatic extraction: anodyne, propranolol, metoprolol, verapamil and lidocaine. These drugs are significantly dependent on the first passage through the liver. Intrahepatic and extrahepatic collateral blood flows significantly increase their bio-logical availability and reduce the clearance. The reduction in hepatic clearance of drugs with low extraction coefficient, such as chlordiazepoxide, diazepam or furosemide, is a result of its own limited functional capacity to eliminate the drug. Predicting a hepatic metabolic disorder based on a common bio-chemical assessment of enzyme activities is not sufficient. In advanced liver cirrhosis a higher risk is demonstrated for drugs with a narrow therapeutic width. It is always necessary to take into account whether the pharmacotherapy is necessary, use small doses and cautiously monitor the patient.

  3. 苯二氮(卓)类药物使用现状分析

    Institute of Scientific and Technical Information of China (English)

    朱正东; 肖水源


    苯二氮量类药物(benzodiazepines BZD)具有良好的镇静催眠抗焦虑作用,广泛应用于多种生理心理疾病的治疗,特别是焦虑和失眠.由于起效快、安全性好,从第一种BZD氯氮(卓)(chlordiazepoxide)于1960年上市以来,就迅速成为主要的抗焦虑药物[1-2].但由于存在滥用风险,长期使用可产生依赖性,骤停还会引起原有症状的复发、反跳,甚至恶化,即“真正的戒断症状群(the true abstinence symptoms)”[2-4],因此一般认为,较少滥用风险和毒副作用的抗抑郁剂和新型镇静催眠剂,如佐匹克隆(zopiclone)应当作为抗焦虑镇静催眠治疗的一线药物[3-5],并且在有些国家,这些药物的使用比例已经超过了BZD.

  4. Alcohol detoxification in Ysbyty Gwynedd: Two small sips or one big gulp? Two-step screening more reliable for identification of alcohol dependency syndrome at risk of delirium tremens for routine care. (United States)

    Salman, Muhammad; Subbe, Christian


    Compliance with pathways for hospitalised patients with alcohol dependency syndrome is often poor. A pathway for recognition and treatment of alcohol dependency was redesigned as part of a 12 month service improvement project in the acute medical unit using plan, do, study, act (PDSA) cycles. A needs assessment was undertaken: Audit data from 2013 showed over-prescription of chlordiazepoxide for detoxification treatment (DT) leading to prolonged hospital admissions with an average length of stay of 5.5 days in 2012/2013. Acceptability of screening tools was tested: Common screening tools (CEWA, AUDIT) were rejected by junior doctors due to the high number of questions as too cumbersome for routine practice. Compliance with usage in random samples over a three month period was persistently (n=10%. Testing of an abbreviated AUDIT questionnaire with only two questions and a specified threshold showed a AUROC of 1 (p<0.001 for correct identification). The screening tool was implemented in several PDSAs cycles. After the final cycle a random sample of 100 patients was reviewed for pathway compliance over a three months period. Eighty-six patients were screened with the two-question tool of these 18 were identified as possible risk. Of these 16 patients had the full AUDIT questionnaire, only eight with elevated values were started on DT. Overall compliance with the pathway increased to 84%.

  5. Differential genetic regulation of motor activity and anxiety-related behaviors in mice using an automated home cage task. (United States)

    Kas, Martien J H; de Mooij-van Malsen, Annetrude J G; Olivier, Berend; Spruijt, Berry M; van Ree, Jan M


    Traditional behavioral tests, such as the open field test, measure an animal's responsiveness to a novel environment. However, it is generally difficult to assess whether the behavioral response obtained from these tests relates to the expression level of motor activity and/or to avoidance of anxiogenic areas. Here, an automated home cage environment for mice was designed to obtain independent measures of motor activity levels and of sheltered feeding preference during three consecutive days. Chronic treatment with the anxiolytic drug chlordiazepoxide (5 and 10 mg/kg/day) in C57BL/6J mice reduced sheltered feeding preference without altering motor activity levels. Furthermore, two distinct chromosome substitution strains, derived from C57BL/6J (host strain) and A/J (donor strain) inbred strains, expressed either increased sheltering preference in females (chromosome 15) or reduced motor activity levels in females and males (chromosome 1) when compared to C57BL/6J. Longitudinal behavioral monitoring revealed that these phenotypic differences maintained after adaptation to the home cage. Thus, by using new automated behavioral phenotyping approaches, behavior can be dissociated into distinct behavioral domains (e.g., anxiety-related and motor activity domains) with different underlying genetic origin and pharmacological responsiveness.

  6. Drug Utilization Pattern In Psychiatry Outdoor Patients At Tertiary Care Teaching Hospital Of Bastar Region

    Directory of Open Access Journals (Sweden)

    Ahmed Tabish


    Full Text Available Background: Psychotropic drugs have had a remarkable impact in psychiatric practice. However, their utilization in actualClinical practice, effectiveness and safety in real life situation need continuous study.Aim: To evaluate the utilization pattern of antipsychotics drugs in the OPD of Psychiatry department.Materials and Methods: A prospective cross-sectional study was     undertaken for a period of three months.   The total number of prescriptions that were analyzed were 264. Patients of all ages and both sexes were included in the study while inpatients,Referred patients and patients of epilepsy were excluded.Results: Out of 264 patients, 180(68.18% were males and84 (31.81% were females. Depression (30.6% was the commonest psychotic ailment. Fluoxetine (34% was the most common antidepressant prescribed for its treatment.Anxiety comprised the second commonest category of psychotic disorder (24.4% followed by Schizophrenia (22%. Lorazepam (43.4% was the most prescribed anxiolytic whereas      Risperidone (46.6% was used to treat it.Conclusion:  Depression was the commonest psychotic ailment followed by anxiety and schizophrenia. Polypharmacy was found in 45% of prescriptions. Risperidone + Trihexyphenidyl was the commonest fixed dose combination used for Schizophrenia and Psychosis followed by amitriptyline+Chlordiazepoxide for anxiety and depression.

  7. Lack of evidence of teratogenicity of benzodiazepine drugs in Hungary. (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.

  8. Benzodiazepines for insomnia in community-dwelling elderly: a review of benefit and risk. (United States)

    Grad, R M


    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.

  9. Improvement of ketamine-induced social withdrawal in rats: the role of 5-HT7 receptors. (United States)

    Hołuj, Małgorzata; Popik, Piotr; Nikiforuk, Agnieszka


    Social withdrawal, one of the core negative symptoms of schizophrenia, can be modelled in the social interaction (SI) test in rats using N-methyl-D-aspartate receptor glutamate receptor antagonists. We have recently shown that amisulpride, an antipsychotic with a high affinity for serotonin 5-HT7 receptors, reversed ketamine-induced SI deficits in rats. The aim of the present study was to further elucidate the potential involvement of 5-HT7 receptors in the prosocial action of amisulpride. Acute administration of amisulpride (3 mg/kg) and SB-269970 (1 mg/kg), a 5-HT7 receptor antagonist, reversed ketamine-induced social withdrawal, whereas sulpiride (20 or 30 mg/kg) and haloperidol (0.2 mg/kg) were ineffective. The 5-HT7 receptor agonist AS19 (10 mg/kg) abolished the prosocial efficacy of amisulpride (3 mg/kg). The coadministration of an inactive dose of SB-269970 (0.2 mg/kg) showed the prosocial effects of inactive doses of amisulpride (1 mg/kg) and sulpiride (20 mg/kg). The anxiolytic chlordiazepoxide (2.5 mg/kg) and the antidepressant fluoxetine (2.5 mg/kg) were ineffective in reversing ketamine-induced SI deficits. The present study suggests that the antagonism of 5-HT7 receptors may contribute towards the mechanisms underlying the prosocial action of amisulpride. These results may have therapeutic implications for the treatment of negative symptoms in schizophrenia and other disorders characterized by social withdrawal.

  10. Kindling of the lateral septum and the amygdala: effects on anxiety in rats. (United States)

    Thomas, Earl; Gunton, Deborah J


    Long-term kindling of limbic system structures may produce substantial changes in emotional behavior in rats. This study examined long-term changes in two kindled structures that have opposite effects on anxiety, the lateral septum and the central nucleus of the amygdala. The purpose of the experiment was to examine the specificity of the emotional effects of kindling by employing a double dissociation design. Animals were tested in two common animal models of anxiety, the water-lick conflict test and the elevated plus-maze. In the conflict test amygdala-kindled animals demonstrated a significant anxiolytic effect when compared with sham-kindled animals. This effect was potentiated by chlordiazepoxide. Septally-kindled animals exhibited a significant anticonflict effect when compared to sham-kindled animals in the first session. Septally-kindled animals spent significantly more time on the open arms of the elevated plus-maze than did sham-kindled animals. Observed changes persisted 6weeks after the termination of 150 kindling sessions. The effects of long-term kindling were highly consistent with those of disruption rather than facilitation.

  11. A 'symptom-triggered' approach to alcohol withdrawal management. (United States)

    Murdoch, Jay; Marsden, Janet

    In acute hospital settings, alcohol withdrawal often causes significant management problems and complicates a wide variety of concurrent conditions, placing a huge burden on the NHS. A significant number of critical incidents around patients who were undergoing detoxification in a general hospital setting led to the need for a project to implement and evaluate an evidence-based approach to the management of alcohol detoxification-a project that included a pre-intervention case note audit, the implementation of an evidence-based symptom-triggered detoxification protocol, and a post-intervention case note audit. This change in practice resulted in an average reduction of almost 60% in length of hospital stay and a 66% reduction in the amount of chlordiazepoxide used in detoxification, as well as highlighting that 10% of the sample group did not display any signs of withdrawal and did not require any medication. Even with these reductions, no patient post-intervention developed any severe signs of withdrawal phenomena, such as seizures or delirium tremens. The savings to the trust (The Pennine Acute Hospital Trust) are obvious,but the development of a consistent, quality service will lead to fewer long-term negative effects for patients that can be caused by detoxification. This work is a project evaluation of a locally implemented strategy, which, it was hypothesised,would improve care by providing an individualised treatment plan for the management of alcohol withdrawal symptoms.

  12. AHR-11797: a novel benzodiazepine antagonist

    Energy Technology Data Exchange (ETDEWEB)

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


    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.

  13. 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.


    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.

  14. The history of benzodiazepines. (United States)

    Wick, Jeannette Y


    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.

  15. Simultaneous Determination of Six Benzodiazepines in Spiked Soft Drinks by High Performance Liquid Chromatography with Ultra Violet Detection (HPLC-UV) (United States)

    Soltaninejad, Kambiz; Karimi, Mohammad; Nateghi, Alireza; Daraei, Bahram


    A high performance liquid chromatographic method with ultra violet detection for simultaneous analysis of six benzodiazepines (BZDs) (chlordiazepoxide, diazepam, clonazepam, midazolam , flurazpam, and lorazepam) has been developed for forensic screening of adulterated non-alcoholic drinks. Samples were analyzed after a simple procedure for preparation using pH adjustment and filtering. Isocratic elution on a C18 column (250mm × 4.6 mm, 5μm) in the temperature 45ºC with a mobile phase consisting of 15mM phosphate buffer: methanol (50:50 v/v) at a flow rate 1.4 mL/min has been done. The column eluent was monitored with a UV detector at 245 nm. This allowed a rapid detection and identification as well as quantization of the eluting peaks. Calibration curves for all drugs in the range of 0.5- 10 µg/ mL that all the linear regression and has more than 0.996. Recovery rates for the BZDs were in the range 93.7- 108.7%. The limits of detection were calculated between 0.01- 0.02 µg/ mL. Also, the limits of quantification were 0.03- 0.05 µg/mL. Within-day and between -day coefficient of variation for all BZDs at all concentrations in the range of 0.45 - 7.69 % was calculated. The procedure can provide a simple, sensitive and fast method for the screening of six BZDs in adulterated soft drinks in forensic analysis. PMID:27642316

  16. Molecular size of benzodiazepine receptor in rat brain in situ: evidence for a functional dimer? (United States)

    Doble, A.; Iversen, L. L.


    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.

  17. Electrocardiographic Manifestations of Benzodiazepine Toxicity

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    Nahid Kazemzadeh


    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.

  18. Multiple Processes Underlie Benzodiazepine-Mediated Increases in the Consumption of Accepted and Avoided Stimuli (United States)

    McGinnis, M.R.; Richardson, L.M.; Miller, E.J.; Alimohamed, M.L.; Baird, J.P.


    Hyperphagia is a reported side effect of anxiolytic benzodiazepines such as chlordiazepoxide (CDP). Prior research has focused primarily on the ingestive responses to sweet or solid foods. We examined CDP effects on licking for normally accepted and avoided taste solutions across a range of concentrations. The effect of CDP (10 mg/kg) versus saline on the licking patterns of water-restricted rats for water and 3 concentrations of sucrose, saccharin, NaCl, monosodium glutamate (MSG), citric acid, and quinine (Q-HCl) solutions was evaluated during 1 h tests. CDP increased meal size for all tastants except citric acid. Analysis of licking microstructure revealed 3 dissociable effects of CDP. CDP affected oromotor coordination as indicated by a uniform increase in the modal interlick interval for all stimuli. CDP increased meal size as indicated by shorter pauses during consumption of water, MSG, and weaker saccharin concentrations, and by fewer long interlick intervals (250–2000 ms) for normally avoided tastants. CDP also increased meal size by increasing burst size, burst duration, and the initial rate of licking for most solutions, suggesting increased hedonic taste evaluation. CDP did not affect variables associated with postingestive feedback such as meal duration or number of bursts, and the results also suggest that CDP did not enhance the perceived taste intensity. We hypothesize that the reduction of pause duration is consistent with an increased motivation to sample the stimulus that synergizes with changes in taste-mediated responsiveness to some but not all stimuli to yield increases in the consumption of both normally accepted and avoided taste stimuli. PMID:22248457

  19. Attenuation of alcohol withdrawal syndrome and blood cortisol level with forced exercise in comparison with diazepam.

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    Majid Motaghinejad


    Full Text Available Relieving withdrawal and post-abstinence syndrome of alcoholism is one of the major strategies in the treatment of alcohol addicted patients. Diazepam, chlordiazepoxide, and topiramate are the approved medications that were used for this object. To assess the role of non-pharmacologic therapy in the management of alcohol withdrawal syndrome, we analyzed effects of forced exercise by treadmill on alcohol dependent mice as an animal model. A total of 60 adult male mice were divided into 5 groups, from which 4 groups became dependent to alcohol (2 g/kg/day for 15 days. From day 16, treatment groups were treated by diazepam (0.5mg/kg, forced exercise, and diazepam (0.5 mg/kg concurrent with forced exercise for two weeks; And the positive control group received same dose of alcohol (2 g/kg/day for two weeks. The negative control group received normal saline for four weeks. Finally, on day 31, all animals were observed for withdrawal signs, and Alcohol Total Withdrawal Score (ATWS was determined. Blood cortisol levels were measured in non-fasting situations as well. Present findings showed that ATWS significantly decrease in all treatment groups in comparison with positive control group (P<0.05 for groups received diazepam and treated by forced exercise and P<0.001 for group under treatment diazepam + forced exercise. Moreover, blood cortisol level significantly decreased in all treatment groups (P<0.001. This study suggested that forced exercise and physical activity can be useful as adjunct therapy in alcoholism and can ameliorate side effects and stress situation of withdrawal syndrome periods.

  20. Pharmacological analysis of the effects of benzodiazepines on punished schedule-induced polydipsia in rats. (United States)

    Pellón, Ricardo; Ruíz, Ana; Lamas, Esmeralda; Rodríguez, Cilia


    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.

  1. Attenuation of alcohol withdrawal syndrome and blood cortisol level with forced exercise in comparison with diazepam. (United States)

    Motaghinejad, Majid; Bangash, Mohammad Yasan; Motaghinejad, Ozra


    Relieving withdrawal and post-abstinence syndrome of alcoholism is one of the major strategies in the treatment of alcohol addicted patients. Diazepam, chlordiazepoxide, and topiramate are the approved medications that were used for this object. To assess the role of non-pharmacologic therapy in the management of alcohol withdrawal syndrome, we analyzed effects of forced exercise by treadmill on alcohol dependent mice as an animal model. A total of 60 adult male mice were divided into 5 groups, from which 4 groups became dependent to alcohol (2 g/kg/day) for 15 days. From day 16, treatment groups were treated by diazepam (0.5mg/kg), forced exercise, and diazepam (0.5 mg/kg) concurrent with forced exercise for two weeks; And the positive control group received same dose of alcohol (2 g/kg/day) for two weeks. The negative control group received normal saline for four weeks. Finally, on day 31, all animals were observed for withdrawal signs, and Alcohol Total Withdrawal Score (ATWS) was determined. Blood cortisol levels were measured in non-fasting situations as well. Present findings showed that ATWS significantly decrease in all treatment groups in comparison with positive control group (Pdiazepam and treated by forced exercise and Pdiazepam + forced exercise). Moreover, blood cortisol level significantly decreased in all treatment groups (P<0.001). This study suggested that forced exercise and physical activity can be useful as adjunct therapy in alcoholism and can ameliorate side effects and stress situation of withdrawal syndrome periods.

  2. Potentiation of muscimol-induced long-term depression by benzodiazepines but not zolpidem. (United States)

    Akhondzadeh, Shahin; Mohammadi, Mohammad Reza; Kashani, Ladan


    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. A novel operant conflict procedure using incrementing shock intensities to assess the anxiolytic and anxiogenic effects of drugs. (United States)

    Evenden, John; Ross, Laurie; Jonak, Gerald; Zhou, Jin


    There is a need for novel anxiolytics, which are effective, but do not cause sedation, tolerance, and rebound anxiety on discontinuation. To investigate a procedure that can be used to assess these characteristics preclinically, rats were initially trained to press a lever at a high rate to obtain food. Once trained, periods of punishment were introduced in which electric shocks were superimposed. The intensity of these electric shocks was increased every 90 s from very low (0.01 mA) to sufficiently high to stop most subjects responding (0.4 mA), so that a complete rate/intensity function was obtained during each punishment period. The benzodiazepine, chlordiazepoxide, and two novel subtype-selective gamma-aminobutyric acid-A agonists, TP003 and TPA023, significantly increased response rates mildly suppressed by intermediate levels of electric shock without any effect on unpunished response rate. Two clinically anxiogenic agents, yohimbine and flumazenil, reduced the rate of punished responding. Aripiprazole and amphetamine reduced both punished and unpunished responding. Repeated treatment with diazepam 2.5 mg/kg daily for 15 days, initially markedly reduced unpunished response rates, but also increased punished response rates, an effect which became greater with repeated treatment. Abrupt cessation of diazepam treatment produced a reduction in punished responding. Diazepam (5 mg/kg daily) produced a greater reduction in unpunished responding, a smaller increase in punished responding, and a larger and longer lasting reduction in punished rates on withdrawal. In conclusion, the procedure detected anxiolytic and anxiogenic effects of drugs, and the sedative side effects, development of tolerance, and rebound-anxiety on discontinuation of a benzodiazepine. This procedure should have utility in the characterization of novel treatments of anxiety.

  4. Anxiolytic-like effects of mGlu1 and mGlu5 receptor antagonists in rats. (United States)

    Pietraszek, Małgorzata; Sukhanov, Ilia; Maciejak, Piotr; Szyndler, Janusz; Gravius, Andreas; Wisłowska, Aleksandra; Płaźnik, Adam; Bespalov, Anton Y; Danysz, Wojciech


    The purpose of the present study was to compare anxiolytic activity of the metabotropic glutamate receptor 1 (mGlu) antagonist, EMQMCM ((3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and the mGlu5 receptor antagonist MTEP ([(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) and MPEP (2-methyl-6-(phenylethynyl)pyridine) in animal models of anxiety. In the elevated plus maze, diazepam (1 mg/kg), but not the mGlu1 or mGlu5 receptor antagonists induced anxiolytic-like effects. Meanwhile, MTEP (2.5 and 5 mg/kg), EMQMCM (5 mg/kg), and diazepam (2 mg/kg) all significantly inhibited fear potentiated startle. In the contextual fear conditioning test, MTEP (1.25 and 2.5 but not 5 mg/kg) and EMQMCM (0.6 to 5 mg/kg) attenuated freezing responding. In the Geller-Seifter conflict test, MPEP (1 and 3 mg/kg), MTEP (3 mg/kg), chlordiazepoxide (10 and 20 mg/kg) and midazolam (1 mg/kg) all facilitated punished responding, while ECMQCM failed to produce any significant effects up to 3 mg/kg dose. To summarise, the present data further support a significant anxiolytic potential of group I mGlu receptor antagonists, while suggesting the effects of mGlu1 receptor antagonists may depend on the experimental procedure and may be qualitatively different from those of mGlu5 receptor antagonists.

  5. Pharmacological evaluation of the stress-induced social avoidance model of anxiety. (United States)

    Leveleki, Cs; Sziray, N; Levay, G; Barsvári, B; Soproni, K; Mikics, E; Haller, J


    We have shown earlier that mild electric shocks induce a lasting social avoidance in male rats. Here we investigated whether shock-induced social avoidance can be developed into a laboratory model of stress-induced anxiety. The putative new model would assess sub-chronic, stress-induced anxiety (as opposed to tests based on natural fear) in a heterologous context (as opposed to classical fear conditioning). A single exposure to mild electric shocks induced a robust social avoidance that lasted more than 5 days. Low doses of chlordiazepoxide (0.5, 1 mg/kg), diazepam (0.5, 1, 5 mg/kg), buspirone (0.3, 1 mg/kg), and fluoxetine (1, 3, 5 mg/kg) abolished this effect, whereas the anxiogenic compound m-chlorophenylpiperazine (0.5-3 mg/kg) induced social avoidance in unshocked rats. These effects were produced at doses that did not affect locomotion in the open field. Haloperidol (0.05, 0.1, 1, 5 mg/kg) influenced social avoidance at sedative doses only. The sensitivity of the model to anxiolytic agents was compromised at high (sedating) doses. Taken conjointly, these data show that shock-induced social avoidance can be used to assess the anxiolytic potential of compounds. In addition to predictive validity, the model appears to show construct and face validity as well: stress is among the etiological factors of, whereas social avoidance simulates the social deficits seen in, a variety of anxiety disorders. The model may be used to study the effects of anxiolytics on sub-chronic states of stress-induced anxiety.

  6. Anxiolytic-induced attenuation of thigmotaxis in the Elevated Minus Maze. (United States)

    Pickles, A R; Hendrie, C A


    Findings using exploration models of anxiety such as the Elevated Plus Maze (EPM) and Elevated Zero Maze (EZM) are remarkably consistent given the differences in layout and number of walls used to describe their closed areas. These factors therefore do not appear to be critical. The present studies were conducted to determine if anxiolytic activity could be detected using an apparatus that presented animals with only one wall. Mice were pre-treated with either vehicle, diazepam (2-4 mg/kg) or 5-10 mg/kg chlordiazepoxide (CDP) and placed for 5 min onto a square platform containing a 12 cm × 14 cm wall. Measures were taken of frequency/duration of contacts with the wall and of general activity. Time spent in contact with the wall was selectively reduced by 4 mg/kg diazepam. 10 mg/kg CDP also decreased this measure but increased measures of general activity, indicating a possible mild stimulant effect. The closed areas of the EPM are described by 3 walls. The EZM uses 2. Current findings show that anxiolytic effects can also be detected in a model with just one wall. It could and these data provide further evidence that variations in the layout of these mazes are not critical for detecting anxiolytic action. Thigmotactic cues remain present regardless of the physical characteristics of these mazes or the local conditions they are employed under. Hence, it is suggested that thigmotactic cues may be the common source of motivation to behave in these models and that this may explain their robustness.

  7. [Behavioral and electroencephalographic study of 7-chloro-1-methyl-5-phenyl-1 H-1,5-benzodiazepine-2,4-(3H,5H)-dione (clobazam)]. (United States)

    Gomita, Y; Morii, M; Ichimaru, Y; Moriyama, M; Ueki, S


    Behavioral and electroencephalographic effects of clobazam (CBZ), a 1, 5 benzodiazepine, were investigated in mice, rats and rabbits and compared with the effects of diazepam (DZP) and chlordiazepoxide (CDP). In EEG studies of rabbits, CBZ, DZP and CDP at doses of 2-10 mg/kg, i.v., caused a drowsy pattern, i.e., high voltage slow waves in the frontal cortex and the desynchronization of hippocampal theta wave. EEG arousal responses induced not only by auditory stimulation but also by electric stimulation of the mesencephalic reticular formation were inhibited by CBZ; CBZ was less potent than DZP, but more potent than CDP. On hypothalamic self-stimulation behavior of rats, low rate responses induced by low current brain stimulation, VI or DRL procedure were increased by oral administration of the three drugs. CBZ was less potent than DZP in the above respondings, but the same potency as CDP in VI or DRL responding and more potent in low rate responding induced by low current stimulation. The preventive effect of CBZ on MES convulsion in mice was less potent than DZP, but 2.5 times as potent as CDP. The preventive effect of CBZ was 1.3 times as potent as DZP and 2.5 times as potent as CDP. CBZ reduced the hyperemotionality of olfactory bulbectomized rats, and this effect was less than DZP in suppressing muricide. The muscle relaxant effect of CBZ in inclined screen and rotarod tests of mice was less than that of DZP. CBZ was 2.2 times as potent as CDP in potentiating thiopental sleep in mice, but less than DZP. These results indicate that CBZ is qualitatively similar to 1, 4 benzodiazepines, DZP and CDP, and is more potent than CDP, but less potent than DZP.

  8. The mouse defense test battery: evaluation of the effects of non-selective and BZ-1 (omega1) selective, benzodiazepine receptor ligands. (United States)

    Griebel, G.; Sanger, D.J.; Perrault, G.


    The behavioral effects of several benzodiazepine (BZ) (omega) receptor ligands were compared using the Mouse Defense Test Battery which has been designed to assess defensive reactions of Swiss mice confronted with a natural threat (a rat) and situations associated with this threat. Primary measures taken before, during and after rat confrontation were escape attempts, flight, risk assessment and defensive threat and attack. The drugs used included non-selective BZ (omega) full (clonazepam, clorazepate, chlordiazepoxide and diazepam) and partial (bretazenil and imidazenil) agonists, and BZ-1 (omega1) selective (abecarnil, CL 218,872 and zolpidem) receptor ligands. With the exception of clonazepam, non-selective BZ (omega) receptor compounds only partially affected flight behaviors. The drugs reduced some but not all flight measures in response to the approaching rat, whereas clonazepam attenuated all flight reactions. In contrast to their mild and inconsistent actions on flight, the non-selective BZ (omega) receptor agonists displayed clear effects on risk assessment when subjects were chased by the rat. When contact was forced between the subject and the rat, the non-selective BZ (omega) receptor full agonists reduced defensive threat and attack reactions, while the partial agonists imidazenil and bretazenil only weakly attenuated defensive attack behavior. Similarly, after the rat had been removed from the test area, the non-selective BZ (omega) receptor full agonists displayed greater efficacy than the partial agonists in reducing escape attempts. Overall, results obtained with the selective BZ-1 (omega1) receptor ligands demonstrated either no clear effects or no specific action on defensive reactions. Taken together, these data demonstrate that: (1) non-selective BZ (omega) agonists displaying high intrinsic activity affect a wider range of defensive behaviors than non-selective BZ (omega) receptor partial agonists; (2) the defense system does not involve

  9. Prototypical anxiolytics do not reduce anxiety-like behavior in the open field in C57BL/6J mice. (United States)

    Thompson, Trey; Grabowski-Boase, Laura; Tarantino, Lisa M


    Understanding and effectively treating anxiety disorders are a challenge for both scientists and clinicians. Despite a variety of available therapies, the efficacy of current treatments is still not optimal and adverse side effects can result in non-compliance. Animal models have been useful for studying the underlying biology of anxiety and assessing the anxiolytic properties of potential therapeutics. The open field (OF) is a commonly used assay of anxiety-like behavior. The OF was developed and validated in rats and then transferred to use in the mouse with only limited validation. The present study tests the efficacy of prototypical benzodiazepine anxiolytics, chlordiazepoxide (CDP) and diazepam (DZ), for increasing center time in the OF in C57BL/6J (B6) mice. Multiple doses of CDP and DZ did not change time spent in the center of the OF. Increasing illumination in the OF did not alter these results. The non-benzodiazepine anxiolytic, buspirone (BUSP) also failed to increase center time in the OF while the anxiogenic meta-chlorophenylpiperazine (mCPP) increased center time. Additional inbred mouse strains, BALB/cJ (BALB) and DBA/2J (D2) did not show any change in center time in response to CDP. Moreover, evaluation of CDP in B6 mice in the elevated plus maze (EPM), elevated zero maze (EZM) and light dark assay (LD) did not reveal changes in anxiety-like behavior while stress-induced hyperthermia (SIH) was decreased by DZ. Pharmacokinetic (PK) studies suggest that adequate CDP is present to induce anxiolysis. We conclude that the measure of center time in the OF does not show predictive validity for anxiolysis in these inbred mouse strains.

  10. Toxicological screening of human plasma by on-line SPE-HPLC-DAD: identification and quantification of basic drugs and metabolites. (United States)

    Mut, Ludmila; Grobosch, Thomas; Binscheck-Domaß, Torsten; Frenzel, Wolfgang


    An automated multi-analyte screening method for the identification and quantification of 92 drugs and metabolites based on on-line solid-phase extraction-high-performance liquid chromatography-diode array detection technique was developed and successfully validated. In addition, a database with 870 entries including UV-spectra, relative/retention times and response factors of toxicologically relevant compounds was created. Plasma samples (0.2 mL) were treated with methanol, diluted with buffer and on-line extracted (Strata X, 20 ×2 mm, 25 µm) at pH 9. Analytical separation was carried out on a Gemini NX column (150 ×4.6 mm, 3 µm) using gradient elution with acetonitrile-water (90:10,v/v) and 0.05 m potassium dihydrogen phosphate buffer (pH 2.3). Linear calibration curves with correlation coefficients ≥0.9950 were obtained for 78 analytes. As an additional benefit, the newly developed method allows the quantification of 42 analytes (e.g. antidepressants, neuroleptics and anticonvulsants) in a concentration range suitable for therapeutic drug monitoring. Limits of quantitation ranged from 0.02 mg/L (chlordiazepoxide) to 3.4 mg/L (mexiletine). Inter- and intra-day precisions of quality control samples (low/high) were better than 15% (zolpidem) and accuracy (bias) ranged from -11% (opipramol, venlafaxine) to 11% (venlafaxine, trazodone). Tests for carry-over and sample stability under different storage conditions were also performed and stability was adequate. Four cases of poisoning analysis are presented.

  11. Zebrafish assessment of cognitive improvement and anxiolysis: filling the gap between in vitro and rodent models for drug development. (United States)

    Levin, Edward D


    Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxiolytic drugs. They are economical and can provide a relatively quick indication of possible functional efficacy. In as much as they have a complex nervous system and elaborate behavioral repertoire, zebrafish can provide a good intermediate model between in vitro receptor and cell-based assays and classic mammalian models for drug screening. In addition, the variety of molecular tools available in zebrafish makes them outstanding models for helping to determine the neuromolecular mechanisms for psychoactive drugs. However, to use zebrafish as a translational model we must have validated, sensitive and efficient behavioral tests. In a series of studies, our lab has developed tests of cognitive function and stress response, which are sensitive to drug effects in a similar manner as rodent models and humans for cognitive enhancement and alleviating stress response. In particular, the three-chamber task for learning and memory was shown to be sensitive to the cognitive enhancing effects of nicotine and has been useful in helping to determine neural mechanisms crucial for nicotinic-induced cognitive enhancement. The novel tank diving test was shown to be a valid and efficient test of stress response. It is sensitive to the reduction in stress-related behaviors due to the amxiolytic drugs diazepam and buspirone but not chlordiazepoxide. Nicotine also causes stress alleviating effects which can be interpreted as anxiolytic effects. Zebrafish models of behavioral pharmacology can be useful to efficiently screen test compounds for drug development and can be useful in helping to determine the mechanisms crucial for new therapeutic treatments of neurobehavioral impairments.

  12. Identification of a Glycogen Synthase Kinase-3[beta] Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice

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    Kozikowski, Alan P.; Gunosewoyo, Hendra; Guo, Songpo; Gaisina, Irina N.; Walter, Richard L.; Ketcherside, Ariel; McClung, Colleen A.; Mesecar, Andrew D.; Caldarone, Barbara (Psychogenics); (Purdue); (UIC); (UTSMC)


    Bipolar disorder is characterized by a cycle of mania and depression, which affects approximately 5 million people in the United States. Current treatment regimes include the so-called 'mood-stabilizing drugs', such as lithium and valproate that are relatively dated drugs with various known side effects. Glycogen synthase kinase-3{beta} (GSK-3{beta}) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK-3{beta}. We designed a series of second generation benzofuran-3-yl-(indol-3-yl)maleimides containing a piperidine ring that possess IC{sub 50} values in the range of 4 to 680 nM against human GSK-3{beta}. One of these compounds exhibits reasonable kinase selectivity and promising preliminary absorption, distribution, metabolism, and excretion (ADME) data. The administration of this compound at doses of 10 to 25 mg kg{sup -1} resulted in the attenuation of hyperactivity in amphetamine/chlordiazepoxide-induced manic-like mice together with enhancement of prepulse inhibition, similar to the effects found for valproate (400 mg kg{sup -1}) and the antipsychotic haloperidol (1 mg kg{sup -1}). We also tested this compound in mice carrying a mutation in the central transcriptional activator of molecular rhythms, the CLOCK gene, and found that the same compound attenuates locomotor hyperactivity in response to novelty. This study further demonstrates the use of inhibitors of GSK-3{beta} in the treatment of manic episodes of bipolar/mood disorders, thus further validating GSK-3{beta} as a relevant therapeutic target in the identification of new therapies for bipolar patients.

  13. Antidepressants alleviate the impact of reinforcer downshift. (United States)

    Nikiforuk, Agnieszka; Popik, Piotr


    Depressive disorder is associated with problems of coping with life's difficulties, including episodes of frustration and disappointment, operationally defined as an unexpected reinforcer omission or a reduction of reinforcer magnitude. In a novel model aimed at detecting potential antidepressants, rats were trained in the operant task under progressive ratio schedule of reinforcement with the break point (BP, the value of the last completed response ratio) as a behavioral endpoint. In the main experiment, a 32% sucrose solution was initially used as the reinforcer. Once the stable responding was achieved, for the following 5 days animals were treated once daily with the experimental drugs, and were offered a 4% sucrose solution instead. In vehicle-treated controls, the reduction of sucrose concentration resulted in a decrease in responding from a BP of about 40 (totaling 166 responses) to a BP of about 9 (totaling 22 responses). Chlordiazepoxide (4 and 8 mg/kg), fluoxetine (3 mg/kg), citalopram (6 mg/kg) and cocaine (2.5 and 5 mg/kg) markedly inhibited this response decrement, while fluoxetine (6 mg/kg) augmented it. Neither desipramine (1-6 mg/kg) nor morphine (1-5 mg/kg) affected responding under the reduced sucrose concentration condition. In the control experiment, the rats have never been offered 32% sucrose solution but their responding was always maintained by 4% sucrose. Under these unchanged conditions, only cocaine (5 mg/kg) affected (increased) responding. The present results suggest that the antidepressants selectively inhibiting serotonin reuptake and a benzodiazepine anxiolytic but not psychostimulant cocaine may specifically protect animals from the effects of a reinforcer downshift.

  14. Acute inhibition of corticosteroidogenesis by inhibitors of calmodulin action. (United States)

    Carsia, R V; Moyle, W R; Wolff, D J; Malamed, S


    To identify the possible role of calmodulin in ACTH function, we tested the ability of chlorpromazine (CP) and other calmodulin antagonists to inhibit steroidogenesis of isolated adrenocortical cells of the rat. CP reversibly inhibited maximal ACTH-induced corticosterone (B) production. The presence of the drug did not alter the ED50 of ACTH stimulation (3.2 X 10(3) pg/ml), suggesting that it inhibited ACTH-induced steroidogenesis in a noncompetitive manner. The CP concentration required for half-maximal inhibition was 8.2 microM, a value close to the dissociation constant of the CP-calmodulin complex (5.3 microM). Concentrations greater than 40 microM resulted in complete inhibition. Similar concentrations of CP inhibited ACTH-induced cAMP accumulation in a dose-dependent manner, indicating an effect of the drug on early events in ACTH action. In addition, CP also apparently acted at a site distal to the point of cAMP formation, as shown by the finding that it inhibited cAMP-induced B production. CP inhibition of ACTH-induced B production was independent of the Ca2+ concentration, suggesting that the drug did not compete with Ca2+ directly. Concentrations of CP greater than 20 microM inhibited protein synthesis as measured by leucine incorporation into cellular proteins. Thus, although the inhibitory effect of high concentrations of CP on steroidogenesis might be explained by an effect on protein synthesis, the inhibition seen at 10 microM appeared to be independent of protein synthesis. Other antagonists of calmodulin action inhibited maximal ACTH-induced B production with the following relative potencies: trifluoperazine greater than CP greater than haloperidol greater than chlordiazepoxide. This order is similar to that reported for inhibition of calmodulin-activated phosphodiesterase and for binding to calmodulin. These findings suggest that calmodulin may modulate the effect of ACTH on steroidogenesis at multiple sites.

  15. Relation of benzodiazepine use to the risk of selected cancers: breast, large bowel, malignant melanoma, lung, endometrium, ovary, non-Hodgkin's lymphoma, testis, Hodgkin's disease, thyroid, and liver. (United States)

    Rosenberg, L; Palmer, J R; Zauber, A G; Warshauer, M E; Strom, B L; Harlap, S; Shapiro, S


    Some animal data have raised the possibility that benzodiazepines influence the risk of selected cancers. With data collected in 1977-1991 in a US hospital-based study, the authors assessed the relation of benzodiazepine use to the risk of 11 cancers: breast (6,056 patients), large bowel (2,203), malignant melanoma (1,457), lung (1,365), endometrium (812), ovary (767), non-Hodgkin's lymphoma (382), testis (314), Hodgkin's disease (299), thyroid (111), and liver (37). Cases were compared with cancer controls (3,777 patients with other cancers) and noncancer controls (1,919 patients admitted for acute nonmalignant disorders). Relative risks were estimated for benzodiazepine use at least 4 days a week for at least 1 month, initiated at least 2 years before admission (sustained use) by multiple logistic regression with control for confounding factors. Results derived with noncancer controls were similar to those derived with cancer controls. For sustained benzodiazepine use relative to no use, relative risk estimates for all 11 cancers were compatible with 1.0 at the 0.05 level of significance. Relative risk estimates for durations of at least 5 years were also compatible with 1.0, with the exceptions of an increased estimate, of borderline statistical significance, for endometrial cancer, and a decreased estimate for ovarian cancer. Relative risk estimates both for sustained use that continued into the 2-year period before admission and for sustained use that ended up to > or = 10 years previously were compatible with 1.0, suggesting a lack of tumor promotion and no increase in the risk after a latent interval. Results were also null for diazepam, chlordiazepoxide, and other benzodiazepines considered separately. The results suggest absence of association between benzodiazepine use and the cancers considered, with the evidence stronger for the cancers with larger numbers of subjects. The similarity of results derived with cancer and noncancer controls suggests that

  16. Oral gavage in rats: animal welfare evaluation. (United States)

    Turner, Patricia V; Vaughn, Elizabeth; Sunohara-Neilson, Janet; Ovari, Jelena; Leri, Francesco


    The effect of chronic daily orogastric gavage with water (5 mL/kg) on behavior and physiology was evaluated in male Sprague-Dawley rats. Treatment groups included: unmanipulated control, restraint control, dry gavage, and gavage, with all rats singly housed (n = 9 or 10 per group). In addition, a group of pair-housed rats (n = 18) was included to determine whether social housing affected response to gavage. Weekly body weights and food consumption were recorded as well as use of a nylon chew toy for enrichment. Feces were collected biweekly at the end of the light and dark phases for fecal corticoid metabolite determinations. After 28 d of treatment, animals underwent conditioned place preference testing to evaluate sensitivity to motivational properties of the anxiolytic drug chlordiazepoxide (5.6 mg/kg SC). Brain and paired adrenal gland weights were collected at necropsy. Week 2 total fecal corticosterone levels were elevated in all groups and attributed to a fire alarm accidentally tripped during building renovations. No differences occurred in body weight or food consumption between any groups. All groups used a nylon chew toy given for enrichment and demonstrated mild preference for the drug-associated chamber. Fecal weights and corticoid metabolite levels were similar between all groups at week 4 and showed normal diurnal variation. No biologically significant variations were noted in brain or paired adrenal gland to body weight ratios. We conclude that orogastric gavage of aqueous solutions at 5 mL/kg does not negatively affect the welfare of laboratory rats acclimated to handling.

  17. The effects of lactation on impulsive behavior in vasopressin-deficient Brattleboro rats. (United States)

    Aliczki, Mano; Fodor, Anna; Balogh, Zoltan; Haller, Jozsef; Zelena, Dora


    Vasopressin (AVP)-deficient Brattleboro rats develop a specific behavioral profile, which-among other things-include altered cognitive performance. This profile is markedly affected by alterations in neuroendocrine state of the animal such as during lactation. Given the links between AVP and cognition we hypothesized that AVP deficiency may lead to changes in impulsivity that is under cognitive control and the changes might be altered by lactation. Comparing virgin and lactating AVP-deficient female Brattleboro rats to their respective controls, we assessed the putative lactation-dependent effects of AVP deficiency on impulsivity in the delay discounting paradigm. Furthermore, to investigate the basis of such effects, we assessed possible interactions of AVP deficiency with GABAergic and serotonergic signaling and stress axis activity, systems playing important roles in impulse control. Our results showed that impulsivity was unaltered by AVP deficiency in virgin rats. In contrast a lactation-induced increase in impulsivity was abolished by AVP deficiency in lactating females. We also found that chlordiazepoxide-induced facilitation of GABAergic and imipramine-induced enhancement of serotonergic activity in virgins led to increased and decreased impulsivity, respectively. In contrast, during lactation these effects were visible only in AVP-deficient rats. These rats also exhibited increased stress axis activity compared to virgin animals, an effect that was abolished by AVP deficiency. Taken together, AVP appears to play a role in the regulation of impulsivity exclusively during lactation: it has an impulsivity increasing effect which is potentially mediated via stress axis-dependent mechanisms and fine-tuning of GABAergic and serotonergic function.

  18. Simultaneous Determination of Six Benzodiazepines in Spiked Soft Drinks by High Performance Liquid Chromatography with Ultra Violet Detection (HPLC-UV). (United States)

    Soltaninejad, Kambiz; Karimi, Mohammad; Nateghi, Alireza; Daraei, Bahram


    A high performance liquid chromatographic method with ultra violet detection for simultaneous analysis of six benzodiazepines (BZDs) (chlordiazepoxide, diazepam, clonazepam, midazolam , flurazpam, and lorazepam) has been developed for forensic screening of adulterated non-alcoholic drinks. Samples were analyzed after a simple procedure for preparation using pH adjustment and filtering. Isocratic elution on a C18 column (250mm × 4.6 mm, 5μm) in the temperature 45ºC with a mobile phase consisting of 15mM phosphate buffer: methanol (50:50 v/v) at a flow rate 1.4 mL/min has been done. The column eluent was monitored with a UV detector at 245 nm. This allowed a rapid detection and identification as well as quantization of the eluting peaks. Calibration curves for all drugs in the range of 0.5- 10 µg/ mL that all the linear regression and has more than 0.996. Recovery rates for the BZDs were in the range 93.7- 108.7%. The limits of detection were calculated between 0.01- 0.02 µg/ mL. Also, the limits of quantification were 0.03- 0.05 µg/mL. Within-day and between -day coefficient of variation for all BZDs at all concentrations in the range of 0.45 - 7.69 % was calculated. The procedure can provide a simple, sensitive and fast method for the screening of six BZDs in adulterated soft drinks in forensic analysis.

  19. Kinetic analysis of ligand binding to the Ehrlich cell nucleoside transporter: Pharmacological characterization of allosteric interactions with the sup 3 Hnitrobenzylthioinosine binding site

    Energy Technology Data Exchange (ETDEWEB)

    Hammond, J.R. (Department of Pharmacology and Toxicology, University of Western Ontario, London (Canada))


    Kinetic analysis of the binding of {sup 3}Hnitrobenzylthioinosine ({sup 3}H NBMPR) to Ehrlich ascites tumor cell plasma membranes was conducted in the presence and absence of a variety of nucleoside transport inhibitors and substrates. The association of {sup 3}H NBMPR with Ehrlich cell membranes occurred in two distinct phases, possibly reflecting functional conformation changes in the {sup 3}HNBMPR binding site/nucleoside transporter complex. Inhibitors of the equilibrium binding of {sup 3}HNBMPR, tested at submaximal inhibitory concentrations, generally decreased the rate of association of {sup 3}HNBMPR, but the magnitude of this effect varied significantly with the agent tested. Adenosine and diazepam had relatively minor effects on the association rate, whereas dipyridamole and mioflazine slowed the rate dramatically. Inhibitors of nucleoside transport also decreased the rate of dissociation of {sup 3}HNBMPR, with an order of potency significantly different from their relative potencies as inhibitors of the equilibrium binding of {sup 3}HNBMPR. Dilazep, dipyridamole, and mioflazine were effective inhibitors of both {sup 3}HNBMPR dissociation and equilibrium binding. The lidoflazine analogue R75231, on the other hand, had no effect on the rate of dissociation of {sup 3}HNBMPR at concentrations below 300 microM, even though it was one of the most potent inhibitors of {sup 3}HNBMPR binding tested (Ki less than 100 nM). In contrast, a series of natural substrates for the nucleoside transport system enhanced the rate of dissociation of {sup 3}HNBMPR with an order of effectiveness that paralleled their relative affinities for the permeant site of the transporter. The most effective enhancers of {sup 3}HNBMPR dissociation, however, were the benzodiazepines diazepam, chlordiazepoxide, and triazolam.

  20. Evidências advindas do consumo de medicamentos moduladores do apetite no Brasil: um estudo farmacoeconométrico Evidence for the use of appetite suppressant drugs in Brazil: a pharmacoeconometric study

    Directory of Open Access Journals (Sweden)

    Daniel Marques Mota


    cross-sectional data to analyze the relationship between the use of appetite suppressants (mg/per capita and the independent variables selected (gender, race/color, age, schooling, income, health insurance coverage, and use of fluoxetine and chlordiazepoxide using multiple linear regression analysis. This study used these variables in level of aggregation by states for 2009. The analyses were performed using the Gretl software. RESULTS: We highlight that São Paulo showed the highest use of appetite suppressants with 97.3 mg/per capita, followed by Goiás with 94.8 mg/per capita. The lowest use of appetite suppressants was seen in Ceará (3.8 mg/per capita. The biggest fluoxetine users were in Rio Grande do Sul, with 58.0 mg/per capita, and in Goiás, with 51.5 mg/per capita. Ceará showed the lowest fluoxetine use (2.3 mg/per capita. For chlordiazepoxide, the highest values were seen in Minas Gerais (7.5 mg/per capita and in Rio de Janeiro (4.8 mg/per capita, while Amazonas (0.08 mg/per capita showed the lowest use. Based on regression analysis, we can highlight: 1 the use of appetite suppressants is related to income, education, and fluoxetine use; and 2 race/color, gender, age, health insurance coverage, and use of chlordiazepoxide showed no relation to the use of appetite suppressants. CONCLUSION: These evidences may contribute to the improvement of regulatory actions, sanitary surveillance, and ethical conduct, particularly with regard to the concomitant use of appetite suppressants and fluoxetine, which is prohibited by the Federal Council of Medicine (Conselho Federal de Medicina and also by Anvisa (Agência Nacional de Vigilância Sanitária - National Health Surveillance Agency.

  1. Development and validation of a fast ionic liquid-based dispersive liquid-liquid microextraction procedure combined with LC-MS/MS analysis for the quantification of benzodiazepines and benzodiazepine-like hypnotics in whole blood. (United States)

    De Boeck, Marieke; Missotten, Sophie; Dehaen, Wim; Tytgat, Jan; Cuypers, Eva


    To date, thorough clean-up of complex biological samples remains an essential part of the analytical process. The solid phase extraction (SPE) technique is the well-known standard, however, its main weaknesses are the labor-intensive and time-consuming protocols. In this respect, dispersive liquid-liquid microextractions (DLLME) seem to offer less complex and more efficient extraction procedures. Furthermore, ionic liquids (ILs) - liquid salts - are emerging as new promising extraction solvents, thanks to their non-flammable nature, negligible vapor pressure and easily adaptable physiochemical properties. In this study, we investigated whether ILs can be used as an extraction solvent in a DLLME procedure for the extraction of a broad range of benzodiazepines and benzodiazepine-like hypnotics in whole blood samples. 1.0mL whole blood was extracted using an optimized 30-min IL-based DLLME procedure, followed by LC-ESI(+)-MS/MS analysis in scheduled MRM scan mode. The optimized analytical method was successfully validated for 7-aminoflunitrazepam, alprazolam, bromazepam, clobazam, clonazepam, clotiazepam, diazepam, estazolam, ethyl loflazepate, etizolam, flurazepam, lormetazepam, midazolam, oxazepam, prazepam, temazepam, triazolam, zolpidem and zopiclone. The method showed good selectivity for endogenous interferences based on 12 sources of blank whole blood. No benzodiazepine interferences were observed, except for clorazepate and nordiazepam, which were excluded from the quantitative method. Matrix-matched calibration curves were constructed covering the whole therapeutic range, including low toxic plasma concentrations. Accuracy and precision results met the proposed acceptance criteria for the vast majority of compounds, except for brotizolam, chlordiazepoxide, cloxazolam, flunitrazepam, loprazolam, lorazepam and nitrazepam, which can only be determined in a semi-quantitative way. Recoveries were within the range of 24.7%-127.2% and matrix effects were within 20

  2. Neuropharmacological properties of neurons derived from human stem cells. (United States)

    Coyne, Leanne; Shan, Mu; Przyborski, Stefan A; Hirakawa, Ryoko; Halliwell, Robert F


    Human pluripotent stem cells have enormous potential value in neuropharmacology and drug discovery yet there is little data on the major classes and properties of receptors and ion channels expressed by neurons derived from these stem cells. Recent studies in this lab have therefore used conventional patch-clamp electrophysiology to investigate the pharmacological properties of the ligand and voltage-gated ion channels in neurons derived and maintained in vitro from the human stem cell (hSC) line, stem cells were differentiated with retinoic acid and used in electrophysiological experiments 28-50 days after beginning differentiation. HSC-derived neurons generated large whole cell currents with depolarizing voltage steps (-80 to 30 mV) comprised of an inward, rapidly inactivating component and a delayed, slowly deactivating outward component. The fast inward current was blocked by the sodium channel blocker tetrodotoxin (0.1 μM) and the outward currents were significantly reduced by tetraethylammonium ions (TEA, 5 mM) consistent with the presence of functional Na and K ion channels. Application of the inhibitory neurotransmitters, GABA (0.1-1000 μM) or glycine (0.1-1000 μM) evoked concentration dependent currents. The GABA currents were inhibited by the convulsants, picrotoxin (10 μM) and bicuculline (3 μM), potentiated by the NSAID mefenamic acid (10-100 μM), the general anaesthetic pentobarbital (100 μM), the neurosteroid allopregnanolone and the anxiolytics chlordiazepoxide (10 μM) and diazepam (10 μM) all consistent with the expression of GABA(A) receptors. Responses to glycine were reversibly blocked by strychnine (10 μM) consistent with glycine-gated chloride channels. The excitatory agonists, glutamate (1-1000 μM) and NMDA (1-1000 μM) activated concentration-dependent responses from hSC-derived neurons. Glutamate currents were inhibited by kynurenic acid (1 mM) and NMDA responses were blocked by MgCl(2) (2 mM) in a

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


    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.

  4. Further evidence for differences between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands in murine models of "state" and "trait" anxiety. (United States)

    Griebel, G; Sanger, D J; Perrault, G


    The behavioural effects of several BZ (omega) receptor ligands were compared in mice using the light/dark choice task, an animal model of "state" anxiety, and the free-exploration test, which has been proposed as an experimental model of "trait" anxiety. The drugs used included non-selective full (alprazolam, clorazepate, chlordiazepoxide and diazepam), partial agonists (bretazenil, imidazenil and Ro 19-8022) and BZ-1 (omega 1) selective receptor ligands (abecarnil, CL 218,872 and zolpidem). In the light/dark choice task, non-selective full agonists elicited clear anxiolytic-like effects increasing time spent in the lit box and simultaneously reducing attempts at entry into the illuminated cage followed by withdrawal responses, a measure of risk assessment. With the exception of abecarnil, both non-selective partial agonists and BZ-1 (omega 1) selective receptor ligands displayed reduced efficacy compared to the full agonists as they decreased risk assessment responses without altering time in the lit box. In addition, the weak anxiolytic-like actions displayed by selective BZ-1 (omega 1) agents were evident only at doses which reduced locomotor activity, indicating that this effect may be non-specific. In the free-exploration test, non-selective BZ (omega) receptor agonists markedly increased the percentage of time spent in the novel compartment and reduced the number of attempts to enter whereas selective BZ-1 (omega 1) receptor ligands displayed a weaker neophobia-reducing effect as they reduced risk assessment responses only. As was the case in the light/dark choice task, this latter effect was observed at locomotor depressant doses. These findings indicate that while both full and partial BZ (omega) receptor agonists are equally effective against "trait" anxiety, full agonists may be superior in reducing "state" anxiety. In addition, the lack of specific effects of selective BZ-1 (omega 1) receptor ligands in reducing both types of anxiety suggests that the BZ

  5. Alcohol abuse and related disorders treatment of alcohol dependence

    Directory of Open Access Journals (Sweden)

    Yu. P. Sivolap


    Full Text Available Alcohol abuse and alcoholism are the leading causes of worse health and increased mortality rates. Excessive alcohol consumption is the third leading cause of the global burden of diseases and a leading factor for lower lifespan and higher mortality. Alcohol abuse decreases working capacity and efficiency and requires the increased cost of the treatment of alcohol-induced disorders, which entails serious economic losses. The unfavorable medical and social consequences of excessive alcohol use determine the importance of effective treatment for alcoholism. The goals of rational pharmacotherapy of alcohol dependence are to enhance GABA neurotransmission, to suppress glutamate neurotransmission, to act on serotonin neurotransmission, to correct water-electrolyte balance, and to compensate for thiamine deficiency. Alcoholism treatment consists of two steps: 1 the prevention and treatment of alcohol withdrawal syndrome and its complications (withdrawal convulsions and delirium alcoholicum; 2 antirecurrent (maintenance therapy. Benzodiazepines are the drugs of choice in alleviating alcohol withdrawal and preventing its convulsive attacks and delirium alcoholicum. Diazepam and chlordiazepoxide are most commonly used for this purpose; the safer drugs oxazepam and lorazepam are given to the elderly and patients with severe liver lesions. Anticonvulsants having normothymic properties, such as carbamazepine, valproic acid, topiramate, and lamotrigine, are a definite alternative to benzodiazepines. The traditional Russian clinical practice (clearance detoxification has not a scientific base or significant impact on alcohol withdrawal-related states in addicts. Relapse prevention and maintenance therapy for alcohol dependence are performed using disulfiram, acamprosate, and naltrexone; since 2013 the European Union member countries have been using, besides these agents, nalmefene that is being registered in Russia. Memantine and a number of other

  6. Decreases in nestlet shredding of mice by serotonin uptake inhibitors: comparison with marble burying. (United States)

    Li, Xia; Morrow, Denise; Witkin, Jeffrey M


    Methods for detection of anxiolytic-like behavioral effects of serotonin uptake inhibitors are limited. The present study introduces a new quantitative method that permits dose-effect analysis of these compounds. Male NIH Swiss mice were given 60-min access to a piece of cotton gauze and the amount of material not torn into nesting material was weighed. Other groups of mice were individually placed in containers with 20 marbles resting on top of sawdust bedding. The number of marbles buried (2/3) by sawdust after 30 min was counted. Mice were first placed on a 6-rpm rotorod and the number of mice falling off twice in 2 min was measured. Serotonin uptake inhibitors (clomipramine, citalopram, fluoxetine, and venlafaxine) dose-dependently suppressed nestlet shredding and marble burying at doses that were generally without effect on rotorod performance. The amine-based antidepressant agents imipramine and desipramine as well as the selective norepinephrine transport inhibitor nisoxetine produced similar qualitative effects on these behaviors. Anxiolytics (chlordiazepoxide, bretazenil, buspirone, and pentobarbital) produced effects in the nestlet assay that were similar to those reported using another anxiolytic assay in mice (punished responding), whereas these compounds were not active at non-motor-impairing doses in the marble burying assay. The antipsychotic agents chlorpromazine and risperidone generally demonstrated suppression of nestlet shredding and marble burying at doses that impaired rotorod performance. Although d-amphetamine suppressed nestlet shredding and marble burying at doses without effect on the rotorod, d-amphetamine but not fluoxetine stimulated locomotor activity. Both nestlet shredding and marble burying behaviors were generally consistent across five consecutive experimental sessions and fluoxetine did not produce any systematic trends over repeated testing. The methods should have utility in defining pharmacological effects of these compounds

  7. Is Long-term Use of Benzodiazepine a Risk for Cancer? (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)


    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

  8. [Dependence on benzodiazepines. Clinical and biological aspects]. (United States)

    Pelissolo, A; Bisserbe, J C


    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

  9. Detection of 9 Kinds of Illegally Added Chemical Medicines in Traditional Chinese Medicine Phenobarbital Preparations and Health Foods by UPLC-MS/MS%超高效液相色谱-串联四级杆质谱法检测镇静安神类中药制剂及保健品中非法添加的9种化学药品

    Institute of Scientific and Technical Information of China (English)

    田兰; 张继春; 陈睿; 储忠英; 包综方


    目的 建立镇静安神类中药制剂及保健品中非法添加9种化学药品的检测方法.方法 采用超高效液相色谱-串联四级杆质谱,多反应监测(MRM)模式进行定性和定量检测.C18色谱柱(50mm×2.1mm,1.7μm),0.1%甲酸-甲醇梯度洗脱,流速0.3 mL/min;离子源为ESI源,正离子检测,对中成药及保健品中添加氯硝西泮、氯氮(卓)、艾司唑仑、阿普唑仑、地西泮、硝西泮、三唑仑、奥沙西泮和马来酸咪达唑仑进行定性、定量检测.结果 9种化学药品测定的质量浓度线性范围分别为26.55 ~1 062,27.5 ~1 100,24.7 ~988,26.325~1 053,26.075 ~ 1043,27.35 ~1 094,28.075 ~1 123,25.3 ~1 012,23.826 15~ 953.046 ng/mL,9种化学药品平均回收率在97.6% ~ 111.1%之间.结论 该方法选择性强、灵敏度高、处理方法简单,测定快速,可用于镇静安神类中成药及保健品中添加9种化学药品的测定.%Objective To establish a specific method for the determination of 9 kinds of illegally added chemical medicines in the traditional Chinese medicine preparations of tranquilizing the mind and health foods. Methods UPLC - MS/MS and multi - reactions moni-toring(MRM) technique was adopted to perform the qualitative and quantitative determination with the Cis analytical column(2. lmm × 50 mm, 1. 7 μm),0. 1% formic acid - methanol for the gradient elution and the flow rate of 0.3 mL/min. The ion source was electro-spray ionization (ESI + ) with the positive ion detection. Clonazepan, chlordiazepoxide estazolam, alprazolam, diazepam, nitrazepan, triazolam, oxazepam and midazolam maleate added in the traditional Chinese patent medicines and health foods were qualitatively and quantitatively identified. Results The linear ranges of 9 kinds of chemical medicines were 26. 55 - 1 062,27. 5 - 1 100,24. 7 -988,26. 325 - 1 053, 26. 075 - 1 043 , 27. 35 - 1 094 ,28. 075-1 123 ,25. 3 - 1 012 , 23. 826 15 - 953. 046 ng/mL, respectively. The average

  10. Pharmacological studies on synthetic flavonoids: comparison with diazepam. (United States)

    Griebel, G; Perrault, G; Tan, S; Schoemaker, H; Sanger, D J


    were confronted with a natural threat (a rat), 6-bromoflavone and 6-bromo-3'-nitroflavone failed to decrease flight reactions after the rat was introduced into the test area and risk assessment behavior displayed when subjects were constrained in a straight alley, and only weakly affected risk assessment of mice chased by the rat and defensive biting upon forced contact with the threat stimulus. In a drug discrimination experiment 6-bromoflavone and 6-bromo-3'-nitroflavone up to 30 and 3 mg/kg, respectively, did not substitute for the BZ chlordiazepoxide. Taken together, these results failed to demonstrate that the synthetic flavonoids 6-bromoflavone and 6-bromo-3'-nitroflavone possess anxiolytic-like properties similar or superior to that of diazepam, as was suggested previously. Furthermore, they question the contribution of BZ-omega receptors to the behavioral effects of 6-bromoflavone and 6-bromo-3'-nitroflavone.

  11. 磁固相萃取-液相色谱-串联质谱法检测牛肉中4种苯二氮卓类药物的残留%Magnetic solid phase extraction-liquid chromatography-tandem mass spectrometry for the determination of 4 kinds of benzodiazepines residues in beef

    Institute of Scientific and Technical Information of China (English)

    甘蓓; 况慧娟; 涂瑾


    Objective To establish a novel method for the determination of 4 kinds of benzodiazepines (BZDs, chlordiazepoxide, diazepam, oxazepam, and triazolam) by magnetic solid phase extraction (MSPE)-liquid chromatography-tandem mass spectrometry (LC-MS/MS), based on the sulfo-functionalized magnetic beads. Methods After optimization of the extraction/desorption conditions, 4 BZDs were extracted with sulfo-functionalized magnetic beads, and detected by liquid chromatography-tandem mass spectrometry in multiple-reaction monitoring mode. Results The average recoveries of 4 benzodiazepines were 49.6%~83.5%, the relative standard deviation (RSD) of this method was between 2.2%~16.0%. The limits of detection (LOD) and limits of quantification (LOQ) of 4 kinds of benzodiazepines were in the range of 0.13~0.79 and 0.44~2.63 ng/mL, respectively. This method had a good linearity in the range of 1.0~25.0μg/L between the peak areas and concentration in 4 kinds of benzodiazepines with the correlation coefficients were 0. 9992~0.999. Conclusion The method was fast, accurate and sensitive, which could be applied in the routine assay on benzodiazepines in beef.%目的:以磺酸化磁珠作为磁固相萃取吸附剂,建立了磁固相萃取-液相色谱-串联质谱法联用分析苯二氮卓类药物的新方法。方法萃取和吸附条件优化后,地西泮、奥沙西泮、三唑仑和氯氮卓4种苯二氮卓类药物经磺酸化磁珠富集后,采用液相色谱-串联质谱的多反应方法检测牛肉样品中4种苯二氮卓类药物的残留。结果4种苯二氮卓类药物的方法回收率为49.6%~83.5%,相对标准偏差(RSD, n=5)为2.2%~16.0%,检出限范围为0.13~0.79 ng/mL,定量限范围为0.44~2.63 ng/mL,在1.0~25.0µg/L 范围内线性相关系数为0.9992~0.9999。结论该法具有操作简便、灵敏度高、测定准确等特点,适用于牛肉中苯二氮卓类物质的残留检测。