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  1. Zolpidem

    MedlinePlus

    ... the pump, hold the container upright. Point the black spray opening away from your face and other ... zolpidem spray, hold the container upright with the black spray opening pointed directly into your mouth, over ...

  2. Zolpidem-induced compulsive evening eating behavior.

    PubMed

    Kim, Hyung Ki; Kwon, Jun Tack; Baek, Jeehun; Park, Duck Su; Yang, Kwang Ik

    2013-01-01

    Zolpidem is associated with an amnestic sleep-related eating disorder, but not with compulsive eating behaviors. A 57-year-old woman receiving zolpidem for insomnia showed compulsive evening eating behavior under a wakeful state. Her compulsive evening eating behavior disappeared when zolpidem treatment was halted. Here, we report her case. PMID:24045611

  3. Zolpidem in Progressive Supranuclear Palsy

    PubMed Central

    Dash, Sandip K.

    2013-01-01

    Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder, characterized by motor symptoms, postural instability, personality changes, and cognitive impairment. There is no effective treatment for this disorder. Reduced neurotransmission of GABA in the striatum and globus pallidus may contribute to the symptoms of motor and cognitive symptoms seen in PSP. Zolpidem is a GABA agonist of the benzodiazepine subreceptor BZ1. Here a nondiabetic, normotensive case of PSP is (Progressive Supranuclear Palsy) described, which showed improvement in swallowing, speech, and gaze paresis after zolpidem therapy and possible mechanism of actions are discussed. However, more trials are needed with large number of patients to confirm the effectiveness of zolpidem in progressive supranuclear palsy. PMID:23762677

  4. Zolpidem modified-release in insomnia.

    PubMed

    Kirkwood, Cynthia; Neill, Jason; Breden, Ericka

    2007-01-01

    Zolpidem modified-release (MR) is the first hypnotic agent to be marketed in an extended-release formulation. Zolpidem MR is a two-layered, biphasic release tablet indicated for the management of induction of sleep and sleep maintenance. The pharmacokinetics of the drug are similar to those of immediate-release zolpidem. Two double-blind, placebo-controlled, parallel-group trials demonstrated efficacy in adults and elderly patients treated with zolpidem MR for 3 weeks without significant impairment in next-day psychomotor functioning. The most common adverse effects with zolpidem MR were dizziness, somnolence, and headache. A starting dose of zolpidem MR 12.5 mg is recommended for adults and 6.25 mg for elderly patients. PMID:19300582

  5. Two Cases of Zolpidem-Associated Homicide

    PubMed Central

    Siegel, Lawrence A.; Kleinman, Stuart B.

    2012-01-01

    Zolpidem is the most commonly prescribed medication for the short-term treatment of insomnia. Adverse reactions include nightmares, confusion, and memory deficits. Reported rare adverse neuropsychiatric reactions include sensory distortions such as hallucinations. Previous research has identified 4 factors that may place a patient at increased risk of zolpidem-associated psychotic or delirious reactions: (1) concomitant use of a selective serotonin reuptake inhibitor (SSRI), (2) female gender, (3) advanced age, and (4) zolpidem doses of 10 mg or higher. In this article, 2 cases are presented in which individuals killed their spouses and claimed total or partial amnesia. Neither individual had a history of aggressive behavior. Both had concomitantly taken 10 mg or more of zolpidem in addition to an SSRI (paroxetine). PMID:23251862

  6. "I did what?" Zolpidem and the courts.

    PubMed

    Daley, Christopher; McNiel, Dale E; Binder, Renée L

    2011-01-01

    Zolpidem is a widely prescribed nonbenzodiazepine hypnotic medication available in the United States since 1992. Attention has been drawn recently to its potential to cause sleep-related, complex behaviors such as sleepwalking and sleep driving. These automatic behaviors have led to a deluge of legal claims. To the authors' knowledge, this is the first review in the forensic literature of the legal ramifications of zolpidem. In this article, the medical literature will be reviewed to explore the current understanding of zolpidem's specific psychopharmacology. Case law will be explored to determine how the courts have handled the claims surrounding sleep-related, complex behaviors alleged to be caused by zolpidem. Finally, a summary of recommendations will be provided for forensic psychiatrists who are asked to be experts in these cases. PMID:22159981

  7. Zolpidem dependence, abuse and withdrawal: A case report

    PubMed Central

    Heydari, Mostafa; Isfeedvajani, Mohsen Saberi

    2013-01-01

    Zolpidem, a nonbenzodiazepine hypnotic, binds to the benzodiazepine binding site on the gamma-aminobutyric acid type A (GABA-A) receptors. Many studies have reported efficacy and safety of zolpidem in treatment of insomnia, low abuse, and dependence capability. However, many cases of zolpidem abuse and dependence were reported around the world. This case showed that zolpidem can exert abuse capability, euphoric mood, tolerance, and withdrawal syndrome. PMID:24520235

  8. Zolpidem

    MedlinePlus

    ... this medication.If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

  9. Zolpidem-induced suicide attempt: a case report

    PubMed Central

    2013-01-01

    Zolpidem is a popular drug indicated for the short-term treatment of insomnia. Side effects are not uncommon with zolpidem. Herein we describe an Iranian 27-year-old man with no known mood disorder or neuropsychological disease who attempted suicide upon taking zolpidem. There are two interesting facts about this case: Firstly, the patient had not history of suicide attempt or thinking. Secondly, this case had experienced suicide ideation after taking 20 mg of zolpidem, suggesting a possible correlation between zolpidem psychological effects and dangerous psychological behaviors. PMID:24359886

  10. Zolpidem induced hyponatremia: a case report.

    PubMed

    Priya S, Shanmuga; Dl, Britto; T, Saravanan

    2014-09-01

    Zolpidem is a non-benzodiazepine hypnotic that acts by binding to (GABAA) receptor. This is a case report of a patient with chronic insomnia for which he had initially been receiving benzodiazepine hypnotic alprazolam and for the past three years, he had switched himself to non-benzodiazepine hypnotic, zolpidem and had progressively increased the dose to 20 mg. The patient presented with history of drowsiness, nausea and vomiting of short duration. Investigations revealed that the patient had hyponatremia. Decreased serum sodium, elevated urine sodium with normal urine osmolarity was detected. Therefore, we report this as a case of drug induced syndrome of inappropriate antidiuretic hormone (SIADH) as other likely causes were ruled out by appropriate investigations. The causality assessment was done according to the WHO scale and found to be "Probable". PMID:25386461

  11. [An Autopsy Case of Abnormal Behaviour Induced by Zolpidem].

    PubMed

    Usumoto, Yosuke; Kudo, Keiko; Sameshima, Naomi; Sato, Kazuo; Tsuji, Akiko; Ikeda, Noriaki

    2015-06-01

    Zolpidem is a widely used ultrashort-acting non-benzodiazepine in clinical practice; compared with benzodiazepines, it does not have side effects such as daytime hangover, rebound insomnia, and development of tolerance. We report an autopsy case of abnormal behaviour induced by zolpidem. A man in his 60's had suffered from postherpetic neuralgia about 2 months ago and had been prescribed zolpidem for insomnia. According to his family, he had no memory of his actions such as striking a wall, taking his futon outside, and eating 5 times a day after he took zolpidem. Because his postherpetic neuralgia did not improve, he was hospitalized and treated with an epidural block. During hospitalization, he took off his clothes, removed the epidural block catheter by himself, and slept on others' beds. He disappeared from the hospital one day; the next day, he was found dead in a narrow water storage tank 10 km away from the hospital. He was thought to have driven a car by himself to reach the place. Forensic autopsy revealed that the cause of death was drowning. Zolpidem and several other drugs were detected by toxicological analysis of his blood; the concentrations of these drugs were within therapeutic range. There are several reports about somnambulism induced by zolpidem such as sleepwalking, sleep driving, and eating. Considering the strange episodes following zolpidem administration, his behaviour on the day of his death was considered abnormal behaviour induced by zolpidem. PMID:26306385

  12. Zolpidem dependence case series: possible neurobiological mechanisms and clinical management.

    PubMed

    Liappas, I A; Malitas, P N; Dimopoulos, N P; Gitsa, O E; Liappas, A I; Nikolaou, Ch K; Christodoulou, G N

    2003-03-01

    Zolpidem is a short-acting imidazopyridine hypnotic that is an agonist at the gamma-aminobutyric acid A type (GABAA) receptor. It has been suggested that it acts selectively on alpha1 subunit-containing GABAA benzodiazepine (BZ1) receptors presenting (contrary to classic benzodiazepines) low or no affinity for other subtypes. Therefore, it has been proposed that it lacks the benzodiazepines-like side-effects, having minimal abuse and dependence potential. Nevertheless, there is a considerable number of zolpidem dependence case reports in the literature. We present eight cases of zolpidem abuse and dependence without criminal record, without history of substance abuse (except for one alcohol abuser), with minor psychiatric disorders, who took zolpidem after physicians prescription in order to deal with their insomnia. However, they became zolpidem abusers not craving its sedative, but its anxiolytic and stimulating action, which helped them to cope with everyday activities. It is possible that, in the high doses that our patients used, zolpidem abandons its selectivity for BZ1 receptors and demonstrates all the actions of classic benzodiazepines. Molecular biology, via possible mutations on GABA receptors, may provide some answers as to why our eight patients (who did not differ much from the thousands of insomniacs who use zolpidem) and other zolpidem abusers, raised the dose progressively, and sought something from the drug other than hypnotic action. PMID:12680751

  13. Sleep-related eating disorder secondary to zolpidem

    PubMed Central

    Nzwalo, Hipólito; Ferreira, Ligia; Peralta, Rita; Bentes, Carla

    2013-01-01

    Sleep-related eating disorder (SRED) is characterised by eating episodes during the first period of the night sleep with partial loss consciousness, and amnesia. It can rarely be induced by some drugs, including zolpidem. We present a video report of a patient with a 1-year history of SRED caused by zolpidem causing important repercussions in the sleep structure and life quality. The night eating episodes ceased promptly with discontinuation of zolpidem. Upon the follow-up, the sleep structure improved and the daily consequences disappeared. As in few reported cases of zolpidem-induced SRED, our patient was suffering from the parasomnia for a long time before the diagnosis. Active exclusion of symptoms suggestive of SRED in patients under zolpidem treatment can avoid the deleterious effect of the sleep disorder. PMID:23436890

  14. Zolpidem-induced amnesia and somnambulism: rare occurrences?

    PubMed

    Tsai, Jui-Hsiu; Yang, Pinchen; Chen, Cheng-Chung; Chung, Weilum; Tang, Tze-Chun; Wang, Shing-Yaw; Liu, Jong-Kang

    2009-01-01

    Zolpidem, a non-benzodiazepine hypnotic of the imidazopyridine class, is very effective in treating insomnia with previous claims of little adverse effects. However, zolpidem-induced somnambulism and amnesic sleep-related behavioral problems were begun to be reported in literature but no systemic investigation has been undertaken in non-Western cultures. In our current retrospective survey, 5.1% (13 out of 255) of Taiwanese patients reported change in sleep-related behavior as adverse effects. This serves as a reminder for clinicians to inquire regarding any unusual behavior of parasomniac activities when prescribing zolpidem. PMID:18819779

  15. Sleep-Walking a Rarest Side Effect of Zolpidem

    PubMed Central

    Singh, Harmanjit; Thangaraju, Pugazhenthan; Natt, Navreet Kaur

    2015-01-01

    A 46-years-old male, with past history of road traffic accident and with no current/past history of substance abuse and no family history of sleep-walking, took zolpidem 10 mg without any prescription and after few days, the patient's son noticed the patient waking up in the middle of night and walking into their room with a staring expression and some incoherent speech. The patient had no memory of this event in the morning. This sleep-walking episode was attributed to zolpidem, as no medication change was made besides new start of zolpidem and the patient had no history of such episodes in the past. Zolpidem treatment was stopped, and since then, no further complaints of sleep-walking were reported. PMID:25722525

  16. Sleep-walking a rarest side effect of zolpidem.

    PubMed

    Singh, Harmanjit; Thangaraju, Pugazhenthan; Natt, Navreet Kaur

    2015-01-01

    A 46-years-old male, with past history of road traffic accident and with no current/past history of substance abuse and no family history of sleep-walking, took zolpidem 10 mg without any prescription and after few days, the patient's son noticed the patient waking up in the middle of night and walking into their room with a staring expression and some incoherent speech. The patient had no memory of this event in the morning. This sleep-walking episode was attributed to zolpidem, as no medication change was made besides new start of zolpidem and the patient had no history of such episodes in the past. Zolpidem treatment was stopped, and since then, no further complaints of sleep-walking were reported. PMID:25722525

  17. HPLC quantification of zolpidem and prothipendyl in a voluntary intoxication.

    PubMed

    Debailleul, G; Khalil, F A; Lheureux, P

    1991-01-01

    Zolpidem, a recently developed sleep inducer, and prothipendyl, a neuroleptic azaphenothiazine, were involved in a voluntary intoxication along with ethanol. After administration of flumazenil, a specific benzodiazepines antagonist, respiratory depression was corrected. HPLC with UV detection methods after selective extraction were developed to measure simultaneously prothipendyl and zolpidem without flumazenil interaction. These methods could be applied in drug monitoring and in emergency toxicology. PMID:1675298

  18. [Sleep related eating disorders as a side effect of zolpidem].

    PubMed

    Valiensi, Stella Maris; Cristiano, Edgardo; Martínez, Oscar A; Reisin, Ricardo C; Alvarez, Florencia

    2010-01-01

    Zolpidem is a hypnotic drug used in sleep disorders. It binds selectively to alpha 1 subunit of the GABA A benzodiazepine receptor. Zolpidem reduces sleep latency, number of arousals and increases the total time of sleep. However, it is considered that it may increase phase 3 of non rapid eye movement sleep, where somnambulism can take place. Our aim is to report 8 cases of sleep related eating disorders associated with the use of this drug. We have evaluated the medical history of 8 patients who had received zolpidem for sleeping disorders and who have presented sleep related eating disorders. Eight patients (6 women, 2 men) aged between 32 to 72 years old, which received 10 mg of zolpidem/night except 1 that received 12.5 mg, were presented. They have referred strange eating behavior compatible to sleep related eating disorder. Symptoms appeared at a mean of 39.8 days after starting the medication. The numbers of nocturnal episodes recorded by the family or by the patient were 1 to 8 episodes of nocturnal eating per night. The morning after, patients found leftovers from the night before which they did not recall to have eaten. The remission was complete after discontinuing zolpidem. Zolpidem may induce sleep related eating disorder in about 1% of patients, although we consider there may be a subdiagnosis of this phenomenon. It will be important to bear in mind and look for this side effect because all the episodes could easily be controlled by withdrawing the drug. PMID:20529770

  19. Antipsychotic-like effects of zolpidem in Wistar rats.

    PubMed

    Mierzejewski, Pawel; Kolaczkowski, Marcin; Marcinkowska, Monika; Wesolowska, Anna; Samochowiec, Jerzy; Pawlowski, Maciej; Bienkowski, Przemyslaw

    2016-02-15

    Aside from their use in the treatment of anxiety disorders and insomnia, benzodiazepines and other GABAA receptor positive modulators are widely used as add-on treatments in schizophrenic and non-schizophrenic psychoses. However, there is relatively little direct clinical or pre-clinical evidence for antipsychotic effects of GABAergic medications. Previous studies have indicated that zolpidem, a GABAergic drug acting preferentially at α1-containing GABAA receptors, may produce catalepsy through interactions with dopaminergic neurotransmission. The aim of the present study was to investigate effects of zolpidem in experimental models of antipsychotic activity and extrapyramidal side effects in Wistar rats. Effects of zolpidem were compared with that of a classic benzodiazepine drug, diazepam and a second-generation antipsychotic medication, risperidone. High doses of risperidone (10.0mg/kg, i.p.) and zolpidem (10.0mg/kg, i.p.), but not diazepam, induced relatively short-lasting cataleptic responses in the bar test. Zolpidem and risperidone, but not diazepam, produced some antipsychotic-like effects at doses, which produced no catalepsy and did not inhibit spontaneous locomotor activity and apomorphine-induced stereotypies. The present results tend to indicate that zolpidem exerts some neuroleptic-like effects at doses, which do not produce motor side effects. Our findings may provide further rationale for the development of new subtype-selective GABAA receptor modulators for the treatment of psychotic symptoms. PMID:26825544

  20. Risks and benefits of zolpidem use in Taiwan: a narrative review.

    PubMed

    Lai, Shih-Wei

    2016-06-01

    Zolpidem is a non-benzodiazepine hypnotic drug commonly used for the treatment of insomnia. However, to date, extensive evidence has shown that zolpidem use is a factor associated with certain clinical conditions, not that it treats these conditions. The aim of this review is to summarize current published articles on the risks and benefits of zolpidem use. PMID:27154196

  1. The antinociceptive effect of zolpidem and zopiclone in mice.

    PubMed

    Pick, Chaim G; Chernes, Yakov; Rigai, Tova; Rice, Kenner C; Schreiber, Shaul

    2005-07-01

    Zolpidem and zopiclone are two of a newer hypno-sedative class of drugs, the "Z compounds". Their use for the treatment of short-term insomnia has been expanding constantly during the last two decades. The "Z compounds" are considered to cause less significant rebound insomnia or tolerance than the conventional hypnotic benzodiazepines. Their possible antinociceptive effect and interaction with the opioid system has not been studied yet. Our results demonstrate a significant difference between the antinociceptive properties of zopiclone and zolpidem when injected s.c. in the hotplate analgesic assay in mice. Zopiclone induced a weak, dose-dependent antinociceptive effect, antagonized only by the alpha2-adrenergic receptor antagonist yohimbine. Zolpidem induced a weak, biphasic dose-dependent antinociceptive effect, antagonized primarily by the non-selective opioid antagonist naloxone and by yohimbine. The weak antinociceptive effect of both drugs, evident only at very high doses (far beyond those used clinically to induce sleep), implies no clinical use for zopiclone or zolpidem in the management of pain. However, the possible interaction of zolpidem with the opioid system should be further investigated (in behavioral models, which do not overlap with the acute-pain antinociception model we used), both for possible side effects in special populations (i.e. elderly) and for possible drug-drug interactions, in order to minimize possible hazards and maximize clinical beneficial effects of its use for sleep. PMID:15913749

  2. Persistent Psychosis after Abuse of High Dose of Zolpidem

    PubMed Central

    Eslami-Shahrbabaki, Mahin; Barfeh, Babak; Nasirian, Mansoureh

    2014-01-01

    Background Zolpidem is a non-benzodiazepine medication which selectively affects GABA A receptors and treats insomnia. There are numerous reports of psychosis following the consumption of zolpidem all of which recovered after stopping the medication. Case Report A 27 year old male law student, who was treated with 10 mg zolpidem due to insomnia, increased the dosage to 500 mg during 3 months. Not only was his insomnia remained untreated, but also he gradually became isolated, suspicious, and aggressive, and dropped out of university. He was then hospitalized in a psychiatric ward for 2 months, and was treated with antipsychotics and gradual discontinuation of zolpidem. With no improvement in psychosis and sleep improvement he was discharged. After two weeks he was hospitalized again and went under electroconvulsive therapy (ECT) and antipsychotic therapy, and was discharged with relative improvement. Now, after three years, he is diagnosed with schizophrenia and with modest improvements he is under care and treatment. Conclusion Zolpidem is a fairly useful medication for treating sleep problems, especially improving beginning of sleep. However, physicians ýand clinicians should consider the conditions, predispositions, and personal and family history of types of psychosis, alcohol and drug abuse in the comprehensive assessment and treatment plan for patients with insomnia. PMID:25984284

  3. Zolpidem increases GABA in depressed volunteers maintained on SSRIs.

    PubMed

    Licata, Stephanie C; Jensen, J Eric; Conn, Nina A; Winer, Jeffrey P; Lukas, Scott E

    2014-10-30

    Individuals with major depressive disorder (MDD) often use hypnotics like zolpidem (Ambien(®)) to improve sleep in addition to their selective serotonin reuptake inhibitor (SSRI) regimen. SSRIs act in part to restore disrupted GABAergic activity, but benzodiazepines and related drugs have been shown to lower GABA in a way that may be counter to these therapeutic effects. The present within-subject, single-blind, placebo-controlled study measured changes in GABA in the anterior cingulate (ACC) and thalamus of volunteers maintained on SSRIs for the treatment of MDD (n=14) following zolpidem (10mg) administration. In addition to neurochemical measurements obtained using proton magnetic resonance spectroscopy ((1)H MRS) at 4 T, a series of questionnaires were administered to assess subjective effects associated with acute zolpidem exposure. Zolpidem elevated GABA levels in both voxels of interest (P<0.05) in the depressed participants, which could imply normalization, given the lower baseline levels associated with depression. The subjective drug experience in the depressed cohort was similar to that reported previously by healthy volunteers, and no relationships existed between GABA increases and the observed behavioral effects. Aside from treating insomnia, using zolpidem in the presence of SSRIs may have some unidentified therapeutic effects for depressed individuals. PMID:25082715

  4. Higher-dose uses of zolpidem will increase the subsequent risk of developing benign brain tumors.

    PubMed

    Harnod, Tomor; Li, Yu-Fen; Lin, Cheng-Li; Chang, Shih-Ni; Sung, Fung-Chang; Kao, Chia-Hung

    2015-01-01

    This study identified 37,810 patients with anxiety or sleep disorder (mean age=53.2 years, SD=16.0 years) who had zolpidem prescribed for at least 2 months from January 1, 2000 through December 31, 2009. Another non-zolpidem cohort was selected by 1:1 matching with the zolpidem cohort on the estimated probability (propensity score) of being treated. The zolpidem cohort had a higher incidence of benign brain tumors compared with the non-zolpidem cohort, particularly for elderly patients. The matched propensity score analysis showed that the highest risk of benign brain tumors occurred in participants with zolpidem exposure ≥520 mg/year (hazard ratio=1.85, 95% confidence interval=1.21-2.82) compared with those not taking zolpidem. PMID:25923854

  5. Zolpidem Use and Risk of Fracture in Elderly Insomnia Patients

    PubMed Central

    Kang, Dong-Yoon; Park, Soyoung; Rhee, Chul-Woo; Kim, Ye-Jee; Choi, Nam-Kyong; Lee, Joongyub

    2012-01-01

    Objectives To evaluate the risk of fractures related with zolpidem in elderly insomnia patients. Methods Health claims data on the entire South Korean elderly population from January 2005 to June 2006 were extracted from the Health Insurance Review and Assessment Service database. We applied a case-crossover design. Cases were defined as insomnia patients who had a fracture diagnosis. We set the hazard period of 1 day length prior to the fracture date and four control periods of the same length at 5, 10, 15, and 20 weeks prior to the fracture date. Time independent confounding factors such as age, gender, lifestyle, cognitive function level, mobility, socioeconomic status, residential environment, and comorbidity could be controlled using the casecrossover design. Time dependent confounding factors, especially co-medication of patients during the study period, were adjusted by conditional logistic regression analysis. The odds ratios and their 95% confidence intervals (CIs) were estimated for the risk of fracture related to zolpidem. Results One thousand five hundred and eight cases of fracture were detected in insomnia patients during the study period. In our data, the use of zolpidem increased the risk of fracture significantly (adjusted odds ratio [aOR], 1.72; 95% CI, 1.37 to 2.16). However, the association between benzodiazepine hypnotics and the risk of fracture was not statistically significant (aOR, 1.00; 95% CI, 0.83 to 1.21). Likewise, the results were not statistically significant in stratified analysis with each benzodiazepine generic subgroup. Conclusions Zolpidem could increase the risk of fracture in elderly insomnia patients. Therefore zolpidem should be prescribed carefully and the elderly should be provided with sufficient patient education. PMID:22880153

  6. Determining zolpidem compliance: urinary metabolite detection and prevalence in chronic pain patients.

    PubMed

    Schwope, David M; DePriest, Anne; Black, David L; Caplan, Yale H; Cone, Edward J; Heltsley, Rebecca

    2014-10-01

    Zolpidem (Ambien(®)) is the most prescribed insomnia treatment in the USA; however, little is known about zolpidem metabolite excretion in chronic pain patients. As zolpidem is extensively metabolized in vivo to zolpidem 4-phenyl carboxylic acid (ZCA), metabolite detection may provide improved accuracy for compliance determinations, thereby improving clinical decisions. Zolpidem and ZCA were extracted from 1 mL human urine by mixed-mode solid-phase extraction. Samples were analyzed by LC-MS-MS using positive electrospray ionization with multiple reaction monitoring mode employed for detection and quantification. Gradient chromatographic separation was achieved with a reversed-phase column in a rapid 1.8 min analysis. The assay was linear from 4 to 1,000 µg/L for zolpidem and 4 to 10,000 µg/L for ZCA. Interday recovery (bias) and imprecision (n = 20) were 100-107% of target and 2.4-3.7% relative standard deviation, respectively. Extraction efficiencies were 78-90%. Pain compliance samples (n = 3,142) were de-identified and analyzed for zolpidem and ZCA. Zolpidem was detected greater than limit of quantification in 720 specimens (22.9%), while ZCA was detected in 1,579 specimens (50.3%). Only five specimens contained zolpidem alone. ZCA was observed without parent zolpidem in 864 specimens, thereby increasing population detection rates by 27.5%. Addition of a zolpidem metabolite to compliance determinations substantially improved detection for zolpidem intake and also should prove useful in clinical and forensic settings. PMID:25217539

  7. Multimodal Hallucination (Audio-visual, Kinaesthetic and Scenic) Associated with the Use of Zolpidem

    PubMed Central

    Ram, Dushad; Eiman, Najla; Gowdappa, Basavana

    2015-01-01

    We are reporting a case of zolpidem induced multimodal hallucinations in a 22 year old female without any history of psychiatric disorders. Zolpidem, by acting on gamma-amino butyric acid type A receptor has a potential to cause a paradoxical reaction and there also exists a possibility of an induced delirium with its use. This case reports evaluates its potential to cause multimodal hallucinations. Zolpidem needs to be prescribed judiciously with the caution of potential side effects particularly in females. PMID:26243852

  8. Multimodal Hallucination (Audio-visual, Kinaesthetic and Scenic) Associated with the Use of Zolpidem.

    PubMed

    Ram, Dushad; Eiman, Najla; Gowdappa, Basavana

    2015-08-31

    We are reporting a case of zolpidem induced multimodal hallucinations in a 22 year old female without any history of psychiatric disorders. Zolpidem, by acting on gamma-amino butyric acid type A receptor has a potential to cause a paradoxical reaction and there also exists a possibility of an induced delirium with its use. This case reports evaluates its potential to cause multimodal hallucinations. Zolpidem needs to be prescribed judiciously with the caution of potential side effects particularly in females. PMID:26243852

  9. Pediatric zolpidem ingestion demonstrating zero-order kinetics treated with flumazenil.

    PubMed

    Thornton, Stephen L; Negus, Elezer; Carstairs, Shaun D

    2013-11-01

    Zolpidem is a widely prescribed anti-insomnia agent. Although most pediatric zolpidem ingestions are benign, large ingestions can cause significant central nervous system (CNS) depression. Flumazenil has been reported to reverse the CNS effects of zolpidem. We describe a case of a large pediatric zolpidem ingestion resulting in profound CNS depression that responded to flumazenil administration. Serial zolpidem serum levels confirmed the ingestion. A 10-year-old boy with trisomy 21 presented to the emergency department 1 hour after he was found sedate with several zolpidem 5-mg tablets in his mouth. Seventeen tables (85 mg) were unaccounted for from a prescription bottle. He became unarousable approximately 2 hours after his ingestion. Flumazenil 0.2 mg intravenously was given with rapid return to his baseline mental status. He became resedate 1 hour later but was arousable. Sixteen hours after his presentation, he was asymptomatic. Serial zolpidem serum levels were obtained, showed an initial level of 310 ng/mL, and demonstrated zero-order kinetics. Zolpidem is an imidazopyridine, which binds to the benzodiazepine receptor. It is rapidly absorbed and has a short-half life. Unintentional pediatric ingestions of zolpidem are typically well tolerated. However, this case demonstrates that large ingestions may cause significant and prolonged CNS depression. Flumazenil, a benzodiazepine receptor antagonist, has been described to reverse the effects of zolpidem in adult ingestions. There are few published reports describing flumazenil use in pediatric ingestion patients. This case suggests that flumazenil may be an effective treatment for zolpidem-induced CNS depression in the pediatric patient. PMID:24196090

  10. Effects of Eszopiclone and Zolpidem on Sleep and Waking States in the Adult Guinea Pig

    PubMed Central

    Xi, Mingchu; Chase, Michael H.

    2008-01-01

    Study Objective: The present study was designed to compare and contrast the effects of eszopiclone and zolpidem on the states of sleep and wakefulness in chronically instrumented, unanesthetized adult guinea pigs. Design: Adult guinea pigs were implanted with electrodes to record sleep and waking states and to perform a frequency analysis of the EEG. Eszopiclone (1 and 3 mg/kg) and zolpidem (1 and 3 mg/kg) were administered intraperitoneally. Measurements and Results: The administration of eszopiclone (1 and 3 mg/kg) resulted in a significant dose-dependent increase in NREM sleep. Zolpidem produced a significant increase in NREM sleep, but only at a dose of 3 mg/kg. The following changes in NREM and REM sleep, as well as in the power spectra, were all significant when the effects of 1 and 3 mg/kg of eszopiclone were compared with responses induced with 1 and 3 mg/kg of zolpidem, respectively: The increase in NREM sleep produced by eszopiclone was greater than that following the administration of zolpidem. The mean latency to NREM sleep following the administration of eszopiclone was significantly shorter than zolpidem. Eszopiclone significantly increased the latency to REM sleep. The mean duration of episodes of NREM sleep was increased by eszopiclone, but not by zolpidem. The EEG power increased in the delta band and decreased in the theta band during NREM sleep following the administration of eszopiclone. No significant changes occurred in any of the frequency bands analyzed following zolpidem administration. Conclusions: The differences in the effects of eszopiclone and zolpidem on sleep and waking states and the power spectra of the EEG likely reflect the fact that eszopiclone and zolpidem bind to different subunits of the GABAA receptor complex. Citation: Xi M; Chase MH. Effects of eszopiclone and zolpidem on sleep and waking states in the adult guinea pig. SLEEP 2008;31(7):1043-1051. PMID:18652100

  11. Zolpidem-induced Hallucinations: A Brief Case Report from the Indian Subcontinent

    PubMed Central

    Singh, Gurvinder Pal; Loona, Neeraj

    2013-01-01

    We are reporting a case of zolpidem-induced hallucinations in a 20-year-old patient. The duration of this phenomenon was brief, 15-20 minutes. Our case suggests that clinicians must be aware of this phenomenon while prescribing zolpidem. PMID:24049236

  12. Desensitization of GABAergic receptors as a mechanism of zolpidem-induced somnambulism.

    PubMed

    Juszczak, Grzegorz R

    2011-08-01

    Sleepwalking is a frequently reported side effect of zolpidem which is a short-acting hypnotic drug potentiating activity of GABA(A) receptors. Paradoxically, the most commonly used medications for somnambulism are benzodiazepines, especially clonazepam, which also potentiate activity of GABA(A) receptors. It is proposed that zolpidem-induced sleepwalking can be explained by the desensitization of GABAergic receptors located on serotonergic neurons. According to the proposed model, the delay between desensitization of GABA receptors and a compensatory decrease in serotonin release constitutes the time window for parasomnias. The occurrence of sleepwalking depends on individual differences in receptor desensitization, autoregulation of serotonin release and drug pharmacokinetics. The proposed mechanism of interaction between GABAergic and serotonergic systems can be also relevant for zolpidem abuse and zolpidem-induced hallucinations. It is therefore suggested that special care should be taken when zolpidem is used in patients taking at the same time selective serotonin reuptake inhibitors. PMID:21565448

  13. Comorbid Functional Shoulder Pain and Zolpidem Dependence Treated with Pramipexole.

    PubMed

    Kandre, Dhiraj; Banwari, Girish; Sharma, Prateek

    2015-01-01

    Pramipexole is a dopamine agonist with higher affinity for D3 receptors. Treatment with pramipexole in clinical conditions such as restless legs syndrome, fibromyalgia, and parkinsonism has been found to significantly improve measures of pain and sleep along with the other symptoms. There is no research data available that explores the usefulness of pramipexole in somatoform/functional pain syndromes. We report a case of a 65-year-old male with bilateral functional shoulder pain associated with insomnia and zolpidem dependence effectively treated with pramipexole. PMID:26702179

  14. Changes in cerebral metabolism in patients with a minimally conscious state responding to zolpidem

    PubMed Central

    Chatelle, Camille; Thibaut, Aurore; Gosseries, Olivia; Bruno, Marie-Aurélie; Demertzi, Athena; Bernard, Claire; Hustinx, Roland; Tshibanda, Luaba; Bahri, Mohamed A.; Laureys, Steven

    2014-01-01

    Background: Zolpidem, a short-acting non-benzodiazepine GABA agonist hypnotic, has been shown to induce paradoxical responses in some patients with disorders of consciousness (DOC), leading to recovery of arousal and cognitive abilities. We here assessed zolpidem-induced changes in regional brain metabolism in three patients with known zolpidem response in chronic post-anoxic minimally conscious state (MCS). Methods: [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and standardized clinical assessments using the Coma Recovery Scale-Revised were performed after administration of 10 mg zolpidem or placebo in a randomized double blind 2-day protocol. PET data preprocessing and comparison with a healthy age-matched control group were performed using statistical parametric mapping (SPM8). Results: Behaviorally, all patients recovered functional communication after administration of zolpidem (i.e., emergence from the MCS). FDG-PET showed increased metabolism in dorsolateral prefrontal and mesiofrontal cortices after zolpidem but not after placebo administration. Conclusion: Our data show a metabolic activation of prefrontal areas, corroborating the proposed mesocircuit hypothesis to explain the paradoxical effect of zolpidem observed in some patients with DOC. It also suggests the key role of the prefrontal cortices in the recovery of functional communication and object use in hypoxic patients with chronic MCS. PMID:25520636

  15. Relationship between zolpidem concentrations and sleep parameters in pediatric burn patients.

    PubMed

    Stockmann, Chris; Gottschlich, Michele M; Healy, Daniel; Khoury, Jane C; Mayes, Theresa; Sherwin, Catherine M T; Spigarelli, Michael G; Kagan, Richard J

    2015-01-01

    Zolpidem is a short-acting non-benzodiazepine hypnotic that is used to improve sleep architecture in patients with burn injuries. This study evaluated the relationship between zolpidem administration and sleep parameters in a cohort of children with severe burn injuries. Standard age-based zolpidem dosing practices were employed. Polysomnography data were recorded at 30-second intervals throughout the night. Serum concentrations of zolpidem were measured at 0, 1, 2, 4, 5, 6, and 8 hours after administration of the first dose. The relationship between zolpidem concentrations and sleep parameters was evaluated using Markov mixed-effects pharmacodynamic models. Ten children received two doses of zolpidem at 22:00 and 02:00 hours. The median total amount of sleep was 361.0 (interquartile range [IQR]: 299.0-418.5) minutes; approximately 65% of the normal reference value for an 8-hour period. Slow-wave and rapid eye movement (REM) sleep were also dramatically reduced (18-37% of normal). With two doses of zolpidem, stage 2 sleep was 99% of normal levels. Higher peak zolpidem concentrations were associated with increased stage 2 sleep (r = .54; P = .04). Despite this, a median of 120.0 (IQR: 99.5-143.5) transitions between nocturnal sleep stages were recorded, with a median of 55.5 (IQR: 36-75) night-time awakenings per patient. In pediatric burn patients, higher zolpidem serum concentrations were associated with restoration of stage 2 sleep to normal levels. Nonetheless, slow-wave and REM sleep were profoundly depressed with frequent transitions between sleep stages, suggesting that alternative hypnotic agents may be required to restore normal sleep architecture in severely burned children. PMID:25185933

  16. Zolpidem extended-release: a single insomnia treatment option for sleep induction and sleep maintenance symptoms.

    PubMed

    Barkin, Robert L

    2007-01-01

    It is imperative that primary care clinicians have a thorough understanding of insomnia, because they are often the first point of contact for patients who seek assistance when they have difficulty sleeping. Insomnia may appear with different presentations: sleep onset, sleep maintenances, sleep offset, nonrestorative sleep, or a combination of these symptoms. Untreated symptoms result in clinically significant distress or impairment in social, occupational, or other important areas of following-day functionality. Physicians, pharmacists, and other clinicians should be aware of the conditions that contribute to, are antecedent to, and associated with insomnia. These pathophysiological conditions include advanced age; female gender; respiratory, gastrointestinal, vascular, and rheumatologic pain syndromes; and other conditions such as depression and/or anxiety. Additional health factors contributing to insomnia include chronic pain, stressors, grief reaction, pharmacotherapeutic side effects, lifestyle contributors such as social/recreational drugs, phytopharmaceuticals, and ethanol use. The pharmacotherapy focus in this article is a modified-release formulation of the BZ1 (omega1) receptor agonist zolpidem, zolpidem extended-release. Pharmacokinetic, pharmacodynamic, and safety studies that compare 12.5 mg zolpidem extended-release (Ambien CRtrade markCIV) and 10 mg original zolpidem were initially conducted in healthy volunteers to assess the potential for an improved clinical profile. Zolpidem extended-release (12.5 mg and 6.25 mg extended-release dosage forms) is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Zolpidem extended-release is devoid of any short-term use limitation and can be prescribed for the duration of medical necessity. The modified-release zolpidem is a two-layer tablet with a biphasic release profile, releasing the first layer immediately, whereas the second layer is released at

  17. Involvement of ATP-sensitive potassium channels and the opioid system in the anticonvulsive effect of zolpidem in mice.

    PubMed

    Sheikhi, Mehdi; Shirzadian, Armin; Dehdashtian, Amir; Amiri, Shayan; Ostadhadi, Sattar; Ghasemi, Mehdi; Dehpour, Ahmad Reza

    2016-09-01

    Zolpidem is a hypnotic medication that mainly exerts its function through activating γ-aminobutyric acid (GABA)A receptors. There is some evidence that zolpidem may have anticonvulsive effects. However, the mechanisms underlying this effect have not been elucidated yet. In the present study, we used the pentylentetrazole (PTZ)-induced generalized seizure model in mice to investigate whether zolpidem can affect seizure threshold. We also further evaluated the roles of ATP-sensitive potassium (KATP) channels as well as μ-opioid receptors in the effects of zolpidem on seizure threshold. Our data showed that zolpidem in a dose-dependent manner increased the PTZ-induced seizure threshold. The noneffective (i.e., did not significantly alter the PTZ-induced seizure threshold by itself) doses of KATP channel blocker (glibenclamide) and nonselective opioid receptor antagonist (naloxone) were able to inhibit the anticonvulsive effect of zolpidem. Additionally, noneffective doses of either KATP channel opener (cromakalim) or nonselective μ-opioid receptor agonist (morphine) in combination with a noneffective dose of zolpidem exerted a significant anticonvulsive effect on PTZ-induced seizures in mice. A combination of noneffective doses of naloxone and glibenclamide, which separately did not affect zolpidem effect on seizure threshold, inhibited the anticonvulsive effects of zolpidem. These results suggest a role for KATP channels and the opioid system, alone or in combination, in the anticonvulsive effects of zolpidem. PMID:27521722

  18. Zolpidem Use Associated With Increased Risk of Pyogenic Liver Abscess: A Case-Control Study in Taiwan.

    PubMed

    Liao, Kuan-Fu; Lin, Cheng-Li; Lai, Shih-Wei; Chen, Wen-Chi

    2015-08-01

    The purpose of this study was to explore the association between zolpidem use and pyogenic liver abscess in Taiwan.This was a population-based case-control study using the database of the Taiwan National Health Insurance Program since 2000 to 2011. We identified 1325 patients aged 20 to 84 years with the first-attack of pyogenic liver abscess as the cases, and 5082 patients without pyogenic liver abscess matched with sex, age, comorbidities, and index year of hospitalization for pyogenic liver abscess as the controls. Patients whose last remaining 1 tablet for zolpidem was noted ≤7 days before the date of admission for pyogenic liver abscess were defined as current use of zolpidem. Patients whose last remaining 1 tablet for zolpidem was noted >7 days before the date of admission for pyogenic liver abscess were defined as late use of zolpidem. Patients who never received 1 prescription for zolpidem were defined as never use of zolpidem. A multivariable unconditional logistic regression model was used to measure the odds ratio (OR) and 95% confidence interval (CI) to explore the association between zolpidem use and pyogenic liver abscess.After adjustment for possible confounding variables, the adjusted OR of pyogenic liver abscess was 3.89 for patients with current use of zolpidem (95% CI 2.89, 5.23), when compared with those with never use of zolpidem. The adjusted OR decreased to 0.85 for those with late use of zolpidem (95% CI 0.70, 1.03), but without statistical significance.Current use of zolpidem is associated with the increased risk of pyogenic liver abscess. Physicians should take the risk of pyogenic liver abscess into account when prescribing zolpidem. PMID:26266369

  19. Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects.

    PubMed

    de Haas, S L; Schoemaker, R C; van Gerven, J M A; Hoever, P; Cohen, A F; Dingemanse, J

    2010-11-01

    Zolpidem is one of the most frequently prescribed hypnotics, as it is a very short-acting compound with relatively few side effects. Zolpidem's short duration of action is partly related to its short elimination half-life, but the associations between plasma levels and pharmacodynamic (PD) effects are not precisely known. In this study, the concentration-effect relationships for zolpidem were modelled. Zolpidem (10 mg) was administered in a double-blind, randomised, placebo-controlled trial to determine PD and pharmacokinetics (PK) in 14 healthy volunteers. Zolpidem was absorbed and eliminated quickly, with a median T(max) of 0.78 h (range: 0.33-2.50) and t(1/2) of 2.2 h. Zolpidem reduced saccadic peak velocity (SPV), adaptive tracking performance, electroencephalogram (EEG) alpha power and visual analogue scale (VAS) alertness score and increased body sway, EEG beta power and VAS 'feeling high'. Short- and long-term memory was not affected. Central nervous system effects normalised more rapidly than the decrease of plasma concentrations. For most effects, zolpidem's short duration of action could be adequately described by both a sigmoid E(max) model and a transit tolerance model. For SPV and EEG alpha power, the tolerance model seemed less suitable. These PK/PD models have different implications for the mechanism underlying zolpidem's short duration of action. A sigmoid E(max) model (which is based on ligand binding theory) would imply a threshold value for the drug's effective concentrations. A transit tolerance model (in which a hypothetical factor builds up with time that antagonises the effects of the parent compound) is compatible with a rapid reversible desensitisation of GABAergic subunits. PMID:19648220

  20. Temazepam, but not zolpidem, causes orthostatic hypotension in astronauts after spaceflight

    NASA Technical Reports Server (NTRS)

    Shi, Shang-Jin; Garcia, Kathleen M.; Meck, Janice V.

    2003-01-01

    Insomnia is a common symptom, not only in the adult population but also in many astronauts. Hypnotics, such as temazepam (a benzodiazepine) and zolpidem (an imidazopyridine), are often taken to relieve insomnia. Temazepam has been shown clinically to have hemodynamic side effects, particularly in the elderly; however, the mechanism is not clear. Zolpidem does not cause hemodynamic side effects. The purpose of this study was to determine whether the use of different hypnotics during spaceflight might contribute significantly to the high incidence of postflight orthostatic hypotension, and to compare the findings in astronauts with clinical research. Astronauts were separated into three groups: control (n = 40), temazepam (15 or 30 mg; n = 9), and zolpidem (5 or 10 mg; n = 8). In this study, temazepam and zolpidem were only taken the night before landing. The systolic and diastolic blood pressures and heart rates of the astronauts were measured during stand tests before spaceflight and on landing day. On landing day, systolic pressure decreased significantly and heart rate increased significantly in the temazepam group, but not in the control group or in the zolpidem group. Temazepam may aggravate orthostatic hypotension after spaceflight when astronauts are hemodynamically compromised. Temazepam should not be the initial choice as a sleeping aid for astronauts. These results in astronauts may help to explain the hemodynamic side effects in the elderly who are also compromised. Zolpidem may be a better choice as a sleeping aid in these populations.

  1. Effect of zolpidem in chronic disorders of consciousness: a prospective open-label study

    PubMed Central

    Thonnard, Marie; Gosseries, Olivia; Demertzi, Athena; Lugo, Zulay; Vanhaudenhuyse, Audrey; Bruno, Marie-Aurélie; Chatelle, Camille; Thibaut, Aurore; Charland-Verville, Vanessa; Habbal, Dina; Schnakers, Caroline; Laureys, Steven

    2013-01-01

    Summary Zolpidem has been reported as an “awakening drug” in some patients with disorders of consciousness (DOC). We here present the results of a prospective open-label study in chronic DOC patients. Sixty patients (35±15 years; 18 females; mean time since insult ± SD: 4±5.5 years; 31 with traumatic etiology) with a diagnosis of vegetative state/unresponsive wakefulness syndrome (n=28) or minimally conscious state (n=32) were behaviorally assessed using the Coma Recovery Scale-Revised (CRS-R) before and one hour after administration of 10 mg of zolpidem. At the group level, the diagnosis did not change after intake of zolpidem (p=0.10) and CRS-R total scores decreased (p=0.01). Twelve patients (20%) showed improved behaviors and/or CRS-R total scores after zolpidem administration but in only one patient was the diagnosis after zolpidem intake found to show a significant improvement (functional object use), which suggested a change of diagnosis. However, in this patient, a double-blind placebo-controlled trial was performed in order to better specify the effects of zolpidem, but the patient, on this trial, failed to show any clinical improvements. The present open-label study therefore failed to show any clinically significant improvement (i.e., change of diagnosis) in any of the 60 studied chronic DOC patients. PMID:24598393

  2. Analysis of zolpidem in postmortem fluids and tissues using ultra-performance liquid chromatography-mass spectrometry.

    PubMed

    Thompson, Kristi S; Lewis, Russell J; Ritter, Roxane M

    2014-10-01

    Zolpidem is a nonbenzodiazepine sedative hypnotic drug used for the short-term treatment of insomnia. While quite effective in producing sedation, zolpidem has potentially hazardous side effects when put in the context of complex tasks. Therefore, to more fully understand the postmortem concentrations of zolpidem, our laboratory has developed a sensitive method for the quantitation of zolpidem in biological specimens. Additionally, we have evaluated the distribution of zolpidem in various postmortem tissues and fluids from 10 aviation fatalities. This method incorporated a modified acetonitrile 'crash and shoot' extraction and a Waters Xevo TQ-S with an Acquity ultra-performance liquid chromatograph. The linear dynamic range was 0.4-800 ng/mL. The extraction efficiencies ranged from 78 to 87%, depending on the concentration. Postmortem blood zolpidem concentrations in these 10 cases ranged from 7.6 to 76.5 ng/mL. The highest concentrations of zolpidem present in each victim were found in the liver, spleen, lung and kidney tissues. Distribution coefficients for zolpidem were determined for each of the specimen types analyzed. These coefficients are expressed relative to the blood concentration in each case. This method proved to be simple, accurate and robust for the identification and quantitation of zolpidem in postmortem fluids and tissues. PMID:25217538

  3. Virus-mediated swapping of zolpidem-insensitive with zolpidem-sensitive GABAA receptors in cortical pyramidal cells

    PubMed Central

    Sumegi, Mate; Fukazawa, Yugo; Matsui, Ko; Lorincz, Andrea; Eyre, Mark D; Nusser, Zoltan; Shigemoto, Ryuichi

    2012-01-01

    Recently developed pharmacogenetic and optogenetic approaches, with their own advantages and disadvantages, have become indispensable tools in modern neuroscience. Here, we employed a previously described knock-in mouse line (GABAARγ277Ilox) in which the γ2 subunit of the GABAA receptor (GABAAR) was mutated to become zolpidem insensitive (γ277I) and used viral vectors to swap γ277I with wild-type, zolpidem-sensitive γ2 subunits (γ277F). The verification of unaltered density and subcellular distribution of the virally introduced γ2 subunits requires their selective labelling. For this we generated six N- and six C-terminal-tagged γ2 subunits, with which cortical cultures of GABAARγ2−/− mice were transduced using lentiviruses. We found that the N-terminal AU1 tag resulted in excellent immunodetection and unimpaired synaptic localization. Unaltered kinetic properties of the AU1-tagged γ2 (AU1γ277F) channels were demonstrated with whole-cell patch-clamp recordings of spontaneous IPSCs from cultured cells. Next, we carried out stereotaxic injections of lenti- and adeno-associated viruses containing Cre-recombinase and the AU1γ277F subunit (Cre-2A-AU1γ277F) into the neocortex of GABAARγ277Ilox mice. Light microscopic immunofluorescence and electron microscopic freeze-fracture replica immunogold labelling demonstrated the efficient immunodetection of the AU1 tag and the normal enrichment of the AU1γ277F subunits in perisomatic GABAergic synapses. In line with this, miniature and action potential-evoked IPSCs whole-cell recorded from transduced cells had unaltered amplitudes, kinetics and restored zolpidem sensitivity. Our results obtained with a wide range of structural and functional verification methods reveal unaltered subcellular distributions and functional properties of γ277I and AU1γ277F GABAARs in cortical pyramidal cells. This transgenic–viral pharmacogenetic approach has the advantage that it does not require any extrinsic protein that

  4. Zolpidem-induced sleepwalking, sleep related eating disorder, and sleep-driving: fluorine-18-flourodeoxyglucose positron emission tomography analysis, and a literature review of other unexpected clinical effects of zolpidem.

    PubMed

    Hoque, Romy; Chesson, Andrew L

    2009-10-15

    Zolpidem is a hypnotic which acts at the GABAA receptor and is indicated for short-term insomnia. Sleep related disorders including somnambulism, sleep related eating and sleep-driving have been reported with zolpidem. A 51-year-old insomniac who used zolpidem 10 mg nightly starting at 44 years of age is described. A few weeks after starting zolpidem she began walking, eating, and had one episode of driving while asleep. Episodes of sleep related eating, sleepwalking, and sleeptalking occurred 3 nights per week, 1 to 2 h after sleep onset. After her evaluation, the patient's zolpidem was gradually discontinued, and all sleep related activities immediately ceased. An 18F-FDG-PET was obtained 2 months after discontinuation of zolpidem. The following day, FDG was administered 1 h after oral administration of 10 mg zolpidem, and then a second PET was performed. We report the results and a review of the literature regarding other unintended effects seen with zolpidem use. PMID:19961034

  5. Common resting brain dynamics indicate a possible mechanism underlying zolpidem response in severe brain injury

    PubMed Central

    Williams, Shawniqua T; Conte, Mary M; Goldfine, Andrew M; Noirhomme, Quentin; Gosseries, Olivia; Thonnard, Marie; Beattie, Bradley; Hersh, Jennifer; Katz, Douglas I; Victor, Jonathan D; Laureys, Steven; Schiff, Nicholas D

    2013-01-01

    Zolpidem produces paradoxical recovery of speech, cognitive and motor functions in select subjects with severe brain injury but underlying mechanisms remain unknown. In three diverse patients with known zolpidem responses we identify a distinctive pattern of EEG dynamics that suggests a mechanistic model. In the absence of zolpidem, all subjects show a strong low frequency oscillatory peak ∼6–10 Hz in the EEG power spectrum most prominent over frontocentral regions and with high coherence (∼0.7–0.8) within and between hemispheres. Zolpidem administration sharply reduces EEG power and coherence at these low frequencies. The ∼6–10 Hz activity is proposed to arise from intrinsic membrane properties of pyramidal neurons that are passively entrained across the cortex by locally-generated spontaneous activity. Activation by zolpidem is proposed to arise from a combination of initial direct drug effects on cortical, striatal, and thalamic populations and further activation of underactive brain regions induced by restoration of cognitively-mediated behaviors. DOI: http://dx.doi.org/10.7554/eLife.01157.001 PMID:24252875

  6. Zolpidem Ingestion, Automatisms, and Sleep Driving: A Clinical and Legal Case Series

    PubMed Central

    Poceta, J. Steven

    2011-01-01

    Study Objectives: To describe zolpidem-associated complex behaviors, including both daytime automatisms and sleep-related parasomnias. Methods: A case series of eight clinical patients and six legal defendants is presented. Patients presented to the author after an episode of confusion, amnesia, or somnambulism. Legal defendants were being prosecuted for driving under the influence, and the author reviewed the cases as expert witness for the defense. Potential predisposing factors including comorbidities, social situation, physician instruction, concomitant medications, and patterns of medication management were considered. Results: Patients and defendants exhibited abnormal behavior characterized by poor motor control and confusion. Although remaining apparently interactive with the environment, all reported amnesia for 3 to 5 hours. In some cases, the episodes began during daytime wakefulness because of accidental or purposeful ingestion of the zolpidem and are considered automatisms. Other cases began after ingestion of zolpidem at the time of going to bed and are considered parasomnias. Risk factors for both wake and sleep-related automatic complex behaviors include the concomitant ingestion of other sedating drugs, a higher dose of zolpidem, a history of parasomnia, ingestion at times other than bedtime or when sleep is unlikely, poor management of pill bottles, and living alone. In addition, similar size and shape of two medications contributed to accidental ingestion in at least one case. Conclusions: Sleep driving and other complex behaviors can occur after zolpidem ingestion. Physicians should assess patients for potential risk factors and inquire about parasomnias. Serious legal and medical complications can occur as a result of these forms of automatic complex behaviors. Citation: Poceta JS. Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series. J Clin Sleep Med 2011;7(6):632-638. PMID:22171202

  7. [Evaluation of the conservability of zolpidem and zaleplon in the hepatic tissue].

    PubMed

    Chepunaya, G P; Kartashov, V A; Chernova, L V

    2015-01-01

    This paper reports the experimental data on the conservability of zolpidem and zalepion in the samples of the cadaveric liver tissue stored under different conditions. The authors describe the method that includes isolation of the substances of interest from the hepatic tissue by means of acetone extraction, their solvent and chromatographic purification, and subsequent identification with the help of the spectrophotometric technique. It is shown that zolpidem and zaleplon remain in the cadaveric hepatic tissue within 6 months after intoxication regardless of temperature which makes possible their detection, isolation, and identification by the proposed method. PMID:26710513

  8. Zolpidem Induced Sleep-related Eating and Complex Behaviors in a Patient with Obstructive Sleep Apnea and Restless Legs Syndrome

    PubMed Central

    Park, Young-Min; Shin, Hyun-Woo

    2016-01-01

    Zolpidem-induced sleep-related complex behaviors (SRCB) with anterograde amnesia have been reported. We describe herein a case in which the development of zolpidem-induced sleep-related eating disorder (SRED) and SRCB was strongly suspected. A 71-year-old Korean male was admitted to the Department of Psychiatry due to his repetitive SRED and SRCB with anterograde amnesia, which he reported as having occurred since taking zolpidem. The patient also had restless legs syndrome (RLS) and obstructive sleep apnea (OSA). His baseline serum iron level was low at admission. Zolpidem discontinuation resulted in the immediate disappearance of his SRED, but did not affect his RLS symptoms. These symptoms rapidly improved after adding a single i.v. iron injection once daily, and so he was discharged to day-clinic treatment. These findings indicate that zolpidem can induce SRCB. Although the pathophysiology of zolpidem-induced SRED and other SRCB remains unclear, clinicians should carefully monitor for the potential induction of complex behaviors associated with zolpidem in patients with comorbid RLS or OSA. PMID:27489385

  9. Zolpidem Induced Sleep-related Eating and Complex Behaviors in a Patient with Obstructive Sleep Apnea and Restless Legs Syndrome.

    PubMed

    Park, Young-Min; Shin, Hyun-Woo

    2016-08-31

    Zolpidem-induced sleep-related complex behaviors (SRCB) with anterograde amnesia have been reported. We describe herein a case in which the development of zolpidem-induced sleep-related eating disorder (SRED) and SRCB was strongly suspected. A 71-year-old Korean male was admitted to the Department of Psychiatry due to his repetitive SRED and SRCB with anterograde amnesia, which he reported as having occurred since taking zolpidem. The patient also had restless legs syndrome (RLS) and obstructive sleep apnea (OSA). His baseline serum iron level was low at admission. Zolpidem discontinuation resulted in the immediate disappearance of his SRED, but did not affect his RLS symptoms. These symptoms rapidly improved after adding a single i.v. iron injection once daily, and so he was discharged to day-clinic treatment. These findings indicate that zolpidem can induce SRCB. Although the pathophysiology of zolpidem-induced SRED and other SRCB remains unclear, clinicians should carefully monitor for the potential induction of complex behaviors associated with zolpidem in patients with comorbid RLS or OSA. PMID:27489385

  10. Implication of mGlu5 receptor in the enhancement of morphine-induced hyperlocomotion under chronic treatment with zolpidem.

    PubMed

    Shibasaki, Masahiro; Ishii, Kazunori; Masukawa, Daiki; Ando, Koji; Ikekubo, Yuiko; Ishikawa, Yutori; Shibasaki, Yumiko; Mori, Tomohisa; Suzuki, Tsutomu

    2014-09-01

    Long-term exposure to zolpidem induces drug dependence, and it is well known that the balance between the GABAergic and glutamatergic systems plays a critical role in maintaining the neuronal network. In the present study, we investigated the interaction between GABAA receptor α1 subunit and mGlu5 receptor in the limbic forebrain including the N.Acc. after treatment with zolpidem for 7 days. mGlu5 receptor protein levels were significantly increased after treatment with zolpidem for 7 days, and this change was accompanied by the up-regulation of phospholipase Cβ1 and calcium/calmodulin-dependent protein kinase IIα, which are downstream of mGlu5 receptor in the limbic forebrain. To confirm that mGlu5 receptor is directly involved in dopamine-related behavior in mice following chronic treatment with zolpidem, we measured morphine-induced hyperlocomotion after chronic treatment with zolpidem in the presence or absence of an mGlu5 receptor antagonist. Although chronic treatment with zolpidem significantly enhanced morphine-induced hyperlocomotion, this enhancement of morphine-induced hyperlocomotion was suppressed by treating it with the mGlu5 receptor antagonist MPEP. These results suggest that chronic treatment with zolpidem caused neural plasticity in response to activation of the mesolimbic dopaminergic system accompanied by an increase in mGlu5 receptor. PMID:24930812

  11. Effect of fluvoxamine on the pharmokinetics of zolpidem: a two-treatment period study in healthy volunteers.

    PubMed

    Vlase, Laurian; Popa, Adina; Neag, Maria; Muntean, Dana; Achim, Marcela; Leucuţa, Sorin Emilian

    2012-01-01

    1. Our objective was to evaluate a possible pharmacokinetic interaction between zolpidem and fluvoxamine in healthy volunteers. 2. The study consisted of two periods: Period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem; and Period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 100 mg fluvoxamine. Between the two periods, the subjects were treated for 6 days with a single daily dose of 100 mg fluvoxamine. 3. Pharmacokinetic parameters of zolpidem given in each treatment period were calculated using non-compartmental analysis and the data from two periods were compared to determine statistically significant differences. 4. In the two periods of treatments, the mean peak plasma concentrations (C(max)) were 56.4 ± 25.6 ng/mL (zolpidem alone) and 67.3 ± 25.8 ng/mL (zolpidem after pretreatment with fluvoxamine). The t(max), times taken to reach C(max), were 0.83 ± 0.44 and 1.26 ± 0.74 h, respectively, and the total areas under the curve (AUC(0-∞)) were 200.9 ± 116.8 and 512.0 ± 354.6 ng h/mL, respectively. The half-life of zolpidem was 2.24 ± 0.81 h when given alone and 4.99 ± 2.92 h after pretreatment with fluvoxamine. 5. Fluvoxamine interacts with zolpidem in healthy volunteers and increases its exposure by approximately 150%. The experimental data showed the pharmacokinetic interaction between zolpidem and fluvoxamine, and suggest that the observed interaction might be clinically significant, but its relevance has to be confirmed. PMID:21985609

  12. Design and in vitro evaluation of multiparticulate floating drug delivery system of zolpidem tartarate.

    PubMed

    Amrutkar, P P; Chaudhari, P D; Patil, S B

    2012-01-01

    Zolpidem tartarate is a non-benzodiazepine, sedative-hypnotic, which finds its major use in various types of insomnia. The present work relates to development of multiparticulate floating drug delivery system based on gas generation technique to prolong the gastric residence time and to increase the overall bioavailability. Modified release dosage form of zolpidem tartarate adapted to release over a predetermined time period, according to biphasic profile of dissolution, where the first phase is immediate release phase for inducing the sleep and the second phase is modified release phase for maintaining the sleep up to 10 h. The system consists of zolpidem tartarate layered pellets coated with effervescent layer and polymeric membrane. The floating ability and in vitro drug release of the system were dependent on amount of the effervescent agent (sodium bicarbonate) layered onto the drug layered pellets, and coating level of the polymeric membrane (Eudragit(®) NE 30D). The system could float completely within 5 min and maintain the floating over a period of 10 h. The multiparticulate floating delivery system of zolpidem tartarate with rapid floating and modified drug release was obtained. PMID:21974910

  13. Fast-Acting Sublingual Zolpidem for Middle-of-the-Night Wakefulness

    PubMed Central

    Pergolizzi, Joseph V.; Taylor, Robert; Raffa, Robert B.; Chopra, Maninder

    2014-01-01

    Sleep disorders (somnipathies) are conditions characterized by disruptions of sleep quality or of sleep pattern. They can involve difficulty falling asleep (prolonged sleep onset latency), difficulty staying asleep (disturbance of sleep maintenance), sleep of poor quality (unrefreshing), or combinations of these and can lead to poor health and quality of life problems. A subtype of sleep-maintenance insomnia is middle-of-the-night wakefulness, a relatively common occurrence. Zolpidem, a nonbenzodiazepine benzodiazepine receptor agonist, allosterically modulates an ion channel and increases the influx of Cl−, thereby dampening the effect of excitatory (sleep disrupting) input. Recently, product label changes to some zolpidem containing products have been implemented by the FDA in order to reduce the risk associated with their morning after residual side effects. A new formulation of zolpidem tartrate (Intermezzo) sublingual tablet, an approved product indicated exclusively for the treatment of middle-of-the-night wakefulness and difficulty returning to sleep, did not have its label changed. We present a short summary of its basic science and clinical attributes in light of the recent regulatory changes for zolpidem products. PMID:24649369

  14. Development of modified-release tablets of zolpidem tartrate by biphasic quick/slow delivery system.

    PubMed

    Mahapatra, Anjan Kumar; Sameeraja, N H; Murthy, P N

    2015-06-01

    Zolpidem tartrate is a non-benzodiazepine analogue of imidazopyridine of sedative and hypnotic category. It has a short half-life with usual dosage regimen being 5 mg, two times a day, or 10 mg, once daily. The duration of action is considered too short in certain circumstances. Thus, it is desirable to lengthen the duration of action. The formulation design was implemented by preparing extended-release tablets of zolpidem tartrate using the biphasic delivery system technology, where sodium starch glycolate acts as a superdisintegrant in immediate-release part and hydroxypropyl methyl cellulose as a release retarding agent in extended-release core. Tablets were prepared by direct compression. Both the core and the coat contained the drug. The pre-compression blends were evaluated for angle of repose, bulk density, and compressibility index. The tablets were evaluated for thickness, hardness, weight variation test, friability, and in vitro release studies. No interaction was observed between zolpidem tartrate and excipients from the Fourier transform infrared spectroscopy and differential scanning calorimetry analysis. The results of all the formulations prepared were compared with reference product Stilnoct®. Optimized formulations showed release patterns that match the United States Pharmacopeia (USP) guidelines for zolpidem tartrate extended-release tablets. The mechanism of drug release was studied using different mathematical models, and the optimized formulation has shown Fickian diffusion. Accelerated stability studies were performed on the optimized formulation. PMID:25391273

  15. Rapidly-progressive catatonia responsive to zolpidem in a patient with ovarian teratoma-associated paraneoplastic encephalitis.

    PubMed

    Amorim, Edilberto; McDade, Eric M

    2016-08-01

    Psychiatric symptoms and catatonia are key components of the clinical presentation of paraneoplastic encephalitis; additionally symptoms can be long-lasting and often difficult to treat. We report a 73-year-old patient with rapidly progressive catatonia not responsive to immunotherapy, tumor resection, electroconvulsive therapy, or benzodiazepines who had significant improvement after zolpidem administration. This report suggests that zolpidem is an option in the treatment of patients with refractory catatonia and paraneoplastic encephalitis. PMID:26964475

  16. Zolpidem Reduces Hippocampal Neuronal Activity in Freely Behaving Mice: A Large Scale Calcium Imaging Study with Miniaturized Fluorescence Microscope

    PubMed Central

    Berdyyeva, Tamara; Otte, Stephani; Aluisio, Leah; Ziv, Yaniv; Burns, Laurie D.; Dugovic, Christine; Yun, Sujin; Ghosh, Kunal K.; Schnitzer, Mark J.; Lovenberg, Timothy; Bonaventure, Pascal

    2014-01-01

    Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics. We visualized these dynamics with and without a systemic administration of Zolpidem, a GABAA agonist that is the most commonly prescribed drug for the treatment of insomnia in the United States. Despite growing concerns about the potential adverse effects of Zolpidem on memory and cognition, it remained unclear whether Zolpidem alters neuronal activity in the hippocampus, a brain area critical for cognition and memory. Zolpidem, when delivered at a dose known to induce and prolong sleep, strongly suppressed CA1 calcium signaling. The rate of calcium transients after Zolpidem administration was significantly lower compared to vehicle treatment. To factor out the contribution of changes in locomotor or physiological conditions following Zolpidem treatment, we compared the cellular activity across comparable epochs matched by locomotor and physiological assessments. This analysis revealed significantly depressive effects of Zolpidem regardless of the animal’s state. Individual hippocampal CA1 pyramidal cells differed in their responses to Zolpidem with the majority (∼65%) significantly decreasing the rate of calcium transients, and a small subset (3%) showing an unexpected and significant increase. By linking molecular mechanisms with the dynamics of neural circuitry and behavioral states, this approach has the potential to contribute substantially to the development of new therapeutics for the treatment of CNS disorders. PMID:25372144

  17. Association between GABAA Receptor Subunit Gene Cluster and Zolpidem-Induced Complex Sleep Behaviors in Han Chinese

    PubMed Central

    Tsai, Jui-Hsiu; Yang, Pinchen; Lin, Hung-Hsun; Cheng, Kuang-hung; Yang, Yi-Hsin; Wu, Ming-Tsang; Chen, Cheng-Chung

    2013-01-01

    Study Objectives: To investigate and elucidate the role of GABAA receptor subunits, specifically the 2 genetic markers at the GABAA α1 and GABAA α6 receptors, in zolpidem-induced complex sleep behaviors (CSBs). Design: Genetic association study. Setting: Kaohsiung Medical University-affiliated hospitals, Kaohsiung, Taiwan. Patients: 30 zolpidem-induced CSB subjects and 37 controls. Interventions: N/A. Measurements and Results: The χ2 test demonstrated an association between the A15G variant at the GABAA α1 receptor subunit gene and zolpidem-induced CSBs (P = 0.007). The adjusted odds ratio of the GABAA α1 receptor subunit genotype for the risk of zolpidem-induced CSBs was approximately 10 (OR = 9.99, 95% CI = 1.82, 74.87; P = 0.013). Conclusions: The finding reveals that the A15G variant at the GABAA α1 receptor subunit gene confers a high risk of zolpidem-induced CSBs and may be considered in clinical services. Citation: Tsai JH; Yang P; Lin HH; Cheng Kh; Yang YH; Wu MT; Chen CC. Association between GABAA receptor subunit gene cluster and zolpidem-induced complex sleep behaviors in Han Chinese. SLEEP 2013;36(2):197–202. PMID:23372267

  18. Zolpidem Mucoadhesive Formulations for Intranasal Delivery: Characterization, In Vitro Permeability, Pharmacokinetics, and Nasal Ciliotoxicity in Rats.

    PubMed

    Wang, Yanfeng; Li, Mi; Qian, Shuai; Zhang, Qizhi; Zhou, Limin; Zuo, Zhong; Lee, Benjamin; Toh, Melvin; Ho, Tony

    2016-09-01

    Zolpidem is a non-benzodiazepine hypnotic for the treatment of insomnia characterized by difficulties with sleep initiation. Our study aimed at developing a zolpidem mucoadhesive formulation with minimal local toxicity, prolonged nasal residence time, and enhanced absorption after intranasal delivery. In vitro permeability studies using artificial membrane and Calu-3 cell culture model indicated efficient permeability of zolpidem. Aqueous solubility of zolpidem was found to be significantly improved by hydroxypropyl-β-cyclodextrin. Various mucoadhesive formulations were then prepared comprising zolpidem, hydroxypropyl-β-cyclodextrin, and mucoadhesive polymers such as hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and sodium alginate. Pharmacokinetic studies in rats demonstrated that intranasally administered zolpidem could achieve significantly faster absorption rate and higher plasma concentration than that from oral route. In comparison with solution formulation (ZLP-S03), the optimized mucoadhesive formulation (ZLP-B01) containing 0.25% hydroxypropyl methylcellulose was found to improve Cmax from 352.6 ± 86.0 to 555.7 ± 175.8 ng/mL, and AUC0-inf from 32,890 ± 7547 to 65,447 ± 36,996 ng·min/mL with mild nasal ciliotoxicity in rats. PMID:27189774

  19. Zolpidem is a potent stoichiometry-selective modulator of α1β3 GABAA receptors: evidence of a novel benzodiazepine site in the α1-α1 interface

    PubMed Central

    Che Has, Ahmad Tarmizi; Absalom, Nathan; van Nieuwenhuijzen, Petra S.; Clarkson, Andrew N.; Ahring, Philip K.; Chebib, Mary

    2016-01-01

    Zolpidem is not a typical GABAA receptor hypnotic. Unlike benzodiazepines, zolpidem modulates tonic GABA currents in the rat dorsal motor nucleus of the vagus, exhibits residual effects in mice lacking the benzodiazepine binding site, and improves speech, cognitive and motor function in human patients with severe brain injury. The receptor by which zolpidem mediates these effects is not known. In this study we evaluated binary α1β3 GABAA receptors in either the 3α1:2β3 or 2α1:3β3 subunit stoichiometry, which differ by the existence of either an α1-α1 interface, or a β3-β3 interface, respectively. Both receptor stoichiometries are readily expressed in Xenopus oocytes, distinguished from each other by using GABA, zolpidem, diazepam and Zn2+. At the 3α1:2β3 receptor, clinically relevant concentrations of zolpidem enhanced GABA in a flumazenil-sensitive manner. The efficacy of diazepam was significantly lower compared to zolpidem. No modulation by either zolpidem or diazepam was detected at the 2α1:3β3 receptor, indicating that the binding site for zolpidem is at the α1-α1 interface, a site mimicking the classical α1-γ2 benzodiazepine site. Activating α1β3 (3α1:2β3) receptors may, in part, mediate the physiological effects of zolpidem observed under distinct physiological and clinical conditions, constituting a potentially attractive drug target. PMID:27346730

  20. Zolpidem is a potent stoichiometry-selective modulator of α1β3 GABAA receptors: evidence of a novel benzodiazepine site in the α1-α1 interface.

    PubMed

    Che Has, Ahmad Tarmizi; Absalom, Nathan; van Nieuwenhuijzen, Petra S; Clarkson, Andrew N; Ahring, Philip K; Chebib, Mary

    2016-01-01

    Zolpidem is not a typical GABAA receptor hypnotic. Unlike benzodiazepines, zolpidem modulates tonic GABA currents in the rat dorsal motor nucleus of the vagus, exhibits residual effects in mice lacking the benzodiazepine binding site, and improves speech, cognitive and motor function in human patients with severe brain injury. The receptor by which zolpidem mediates these effects is not known. In this study we evaluated binary α1β3 GABAA receptors in either the 3α1:2β3 or 2α1:3β3 subunit stoichiometry, which differ by the existence of either an α1-α1 interface, or a β3-β3 interface, respectively. Both receptor stoichiometries are readily expressed in Xenopus oocytes, distinguished from each other by using GABA, zolpidem, diazepam and Zn(2+). At the 3α1:2β3 receptor, clinically relevant concentrations of zolpidem enhanced GABA in a flumazenil-sensitive manner. The efficacy of diazepam was significantly lower compared to zolpidem. No modulation by either zolpidem or diazepam was detected at the 2α1:3β3 receptor, indicating that the binding site for zolpidem is at the α1-α1 interface, a site mimicking the classical α1-γ2 benzodiazepine site. Activating α1β3 (3α1:2β3) receptors may, in part, mediate the physiological effects of zolpidem observed under distinct physiological and clinical conditions, constituting a potentially attractive drug target. PMID:27346730

  1. The Effectiveness of Zolpidem for the Treatment of Disorders of Consciousness.

    PubMed

    Tucker, Calvin; Sandhu, Kirsten

    2016-06-01

    Approximately, five million people in the United States live with the residual effects of brain injury. The causes of acquired brain injury can be categorized as traumatic brain injury or non-traumatic brain injury. There are currently no treatments shown to consistently enhance recovery from disorders of consciousness (DOC). Sporadic recovery from DOC after the administration of various pharmacological agents has been described in several case reports. Increase in arousal after zolpidem administration is seen in patients with vegetative state or minimally conscious state for treatment of restlessness and disturbances of their sleep-wake cycle. The use of zolpidem could be reasonable in select patients with neurologic injury but promising integrity of brain structures, such as intact deep and superficial gray matter structures and white matter connections. PMID:26718349

  2. The Non-Benzodiazepine Hypnotic Zolpidem Impairs Sleep-Dependent Cortical Plasticity

    PubMed Central

    Seibt, Julie; Aton, Sara J.; Jha, Sushil K.; Coleman, Tammi; Dumoulin, Michelle C.; Frank, Marcos G.

    2008-01-01

    Study Objectives: The effects of hypnotics on sleep-dependent brain plasticity are unknown. We have shown that sleep enhances a canonical model of in vivo cortical plasticity, known as ocular dominance plasticity (ODP). We investigated the effects of 3 different classes of hypnotics on ODP. Design: Polysomnographic recordings were performed during the entire experiment (20 h). After a baseline sleep/wake recording (6 h), cats received 6 h of monocular deprivation (MD) followed by an i.p. injection of triazolam (1–10 mg/kg i.p.), zolpidem (10 mg/kg i.p.), ramelteon (0.1–1 mg/kg i.p.), or vehicle (DMSO i.p.). They were then allowed to sleep ad lib for 8 h, after which they were prepared for optical imaging of intrinsic cortical signals and single-unit electrophysiology. Setting: Basic neurophysiology laboratory Patients or Participants: Cats (male and female) in the critical period of visual development (postnatal days 28–41) Interventions: N/A Measurements and Results: Zolpidem reduced cortical plasticity by ∼50% as assessed with optical imaging of intrinsic cortical signals. This was not due to abnormal sleep architecture because triazolam, which perturbed sleep architecture and sleep EEGs more profoundly than zolpidem, had no effect on plasticity. Ramelteon minimally altered sleep and had no effect on ODP. Conclusions: Our findings demonstrate that alterations in sleep architecture do not necessarily lead to impairments in sleep function. Conversely, hypnotics that produce more “physiological” sleep based on polysomnography may impair critical brain processes, depending on their pharmacology. Citation: Seibt J; Aton SJ; Jha SK; Coleman T; Dumoulin MC; Frank MG. The non-benzodiazepine hypnotic zolpidem impairs sleep-dependent cortical plasticity. SLEEP 2008;31(10):1381–1391. PMID:18853935

  3. Temazepam, But Not Zolpidem, Causes Orthostatic Hypotension in Astronauts After Spaceflight

    NASA Technical Reports Server (NTRS)

    Shi, Shang-Jin; Garcia, Kathleen M.; Meck, Janice V.

    2002-01-01

    Many astronauts do not sleep well due to the difficult environment in space. Hypnotics such as temazepam or zolpidem are often taken while in space and/or the night prior to returning to Earth. Until now, no data have illustrated the effect of these sleeping medications on postflight hemodynamic responses. The purpose of this study was to determine if the use of different hypnotics during flight has any effect on cardiovascular responses to standing in astronauts upon returning to Earth's gravity.

  4. Assessment of the Abuse Potential of the Orexin Receptor Antagonist, Suvorexant, Compared With Zolpidem in a Randomized Crossover Study.

    PubMed

    Schoedel, Kerri A; Sun, Hong; Sellers, Edward M; Faulknor, Janice; Levy-Cooperman, Naama; Li, Xiaodong; Kennedy, William P; Cha, Jang-Ho; Lewis, Nicole M; Liu, Wen; Bondiskey, Phung; McCrea, Jacqueline B; Panebianco, Deborah L; Troyer, Matthew D; Wagner, John A

    2016-08-01

    Suvorexant is a dual orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia at a maximum dose of 20 mg. This randomized double-blind crossover study evaluated the abuse potential of suvorexant in 36 healthy recreational polydrug users with a history of sedative and psychedelic drug use. Single doses of suvorexant (40, 80, and 150 mg: 2-7.5 × maximum dose), zolpidem (15 and 30 mg: 1.5-3 × maximum dose), and placebo were administered, with a 10-day washout between treatments. Subjective and objective measures, including visual analog scales (VASs), Addiction Research Center Inventory, and cognitive/psychomotor tests, were evaluated for 24-hour postdose. Suvorexant had significantly greater peak effects on "drug liking" VAS (primary endpoint) than placebo. Although effects of suvorexant on abuse potential measures were generally similar to zolpidem, they remained constant across doses, whereas zolpidem often had greater effects at higher doses. Suvorexant (all doses) had significantly fewer effects than zolpidem 30 mg on secondary measures, such as "high" VAS, Bowdle VAS, and Addiction Research Center Inventory morphine-benzedrine group. The overall incidence of abuse-related adverse events, such as euphoric mood and hallucination, was numerically lower with suvorexant than zolpidem. In agreement with its classification as a schedule IV drug, suvorexant demonstrated abuse potential, compared with placebo. The abuse potential was similar to zolpidem using certain measures, but with a reduced incidence of abuse-related adverse events. Although this suggests that the overall abuse liability of suvorexant may be lower than zolpidem, the actual abuse rates will be assessed with the postmarketing experience. PMID:27253658

  5. Effects of eszopiclone and zolpidem on sleep-wake behavior, anxiety-like behavior and contextual memory in rats

    PubMed Central

    Huang, Max P.; Radadia, Kushan; Macone, Brian W.; Auerbach, Sanford H.; Datta, Subimal

    2010-01-01

    At present, eszopiclone and zolpidem are the most commonly prescribed drugs for treating insomnia. Despite the established relationship between sleep disturbance and anxiety, it remains unknown whether targeted treatment for insomnia may affect acute anxiety. Therefore, the objective of this study was to examine the effects of three different doses (1, 3, and 10 mg/kg) of eszopiclone and zolpidem on the states of sleep and wakefulness, levels of anxiety-like behavior, and long-term contextual memory in footshock-induced anxious rats. The results of this study demonstrated that the administration of eszopiclone and zolpidem both were equally effective in attenuating footshock stressor-induced suppression of slow-wave sleep (SWS). The administration of eszopiclone at 1 mg/kg or zolpidem at 1 and 3 mg/kg doses showed a tendency for attenuating stressor-induced suppression of REM sleep. However, the REM sleep attenuating effects of these drugs disappeared when they were administered at higher doses. The administration of eszopiclone at 3 and 10 mg/kg doses and zolpidem at all three doses reduced the power of electroencephalographic theta band frequencies during wakefulness. In addition, the administration of eszopiclone at 1 and 3 mg/kg doses suppressed stressor-induced anxiety-like behavior. The administration of zolpidem at 1, 3, or 10 mg/kg doses was not effective in attenuating stressor-induced anxiety-like behavior. Contextual memory after administration of eszopiclone at 1 mg/kg dose had no effects, but was reduced significantly with increased dosage. Contextual memory after administration of zolpidem, at all three doses, was severely disrupted. The results of this study suggest that eszopiclone at a low dose could be used effectively to control anxiety and anxiety-induced insomnia. PMID:20153782

  6. Impact of a US Food and Drug Administration Drug Safety Communication on Zolpidem Dosing: An Observational Retrospective Cohort

    PubMed Central

    Harward, Jonathan L.; Clinard, Valerie B.; Jiroutek, Michael R.; Lingerfeldt, Beverly H.

    2015-01-01

    Introduction/background: Zolpidem is a sedative-hypnotic widely prescribed in the United States. Recently, the US Food and Drug Administration (FDA) issued a drug safety communication regarding its dosing in women. Objective: To compare compliance with FDA-approved dosing for zolpidem in women before and after a drug safety communication, and to evaluate compliance based on pharmacy location and prescriber type. Method: This was a retrospective, observational cohort study. New prescriptions for Ambien, Ambien CR, Edluar, or Zolpimist or their respective generics dispensed from Kerr Drug pharmacies in North Carolina to women 18–64 years of age between April and September of 2012 (“before” cohort) or April and September of 2013 (“after” cohort) were included. χ2 tests were conducted to assess overall compliance, as well as compliance based on location (urban or rural) and prescriber type (physician or midlevel), with FDA-approved dosing for zolpidem. Trends in total prescription volume and total zolpidem prescription volume for all Kerr Drug pharmacies over the study period were also described. Results: A total of 14,156 prescriptions for zolpidem were included in the primary analysis. Sixteen percent of prescriptions dispensed were in compliance with FDA recommendations following the FDA alert. A statistically significant increase was observed in compliance with FDA-approved dosing for zolpidem (odds ratio = 1.49; 95% CI, 1.35–1.65; P < .0001) postdrug safety communication. Significant increases in compliance were also observed in the post-FDA communication subgroups based on location and prescriber type, though no subgroup was found to be significantly more compliant than another. Conclusions: The release of a drug safety communication by the FDA resulted in a statistically significant increase in proper dosing of zolpidem in women. Further research is needed in order to determine the impact of FDA alerts on prescribing patterns and the reasons for

  7. Effect of Zolpidem on Sleep Quality of Professional Firefighters; a Double Blind, Randomized, Placebo-Controlled Crossover Clinical Trial.

    PubMed

    Mehrdad, Ramin; Sadeghniiat Haghighi, Khosro; Naseri Esfahani, Amir Hossein

    2015-01-01

    Professional firefighting is among the most demanding jobs. Prior studies have showed the notable prevalence of poor sleep quality among professional firefighters that may result in catastrophes. The aim of this study was in field confirmation of zolpidem usage (10 mg/PO/bed time) for short term management of poor sleeps quality among professional firefighters. In a double-blind, randomized, placebo-controlled crossover clinical trial among professional firefighters, 27 poor sleepers were assigned randomly to one of the two groups. Two 14 days experimental periods were separated by a 14-day washout phase. Sleep quality was assessed using the Persian version of Pittsburgh Sleep Quality Index (PSQI). Six of the 27 enrolled voluntaries dropped out. Two rare side effects of zolpidem occurred in the study. A significant improvement of the PSQI score was detected in zolpidem period versus placebo in both groups (7.14 ± 3.02 vs 12.38 ± 2.51, P<0.001) although zolpidem had no significant effect on time of waking up (6.76 ± 1.21 vs.6.64 ± 1.27, P=0.89). Zolpidem significantly improved all components of PSQI (Subjective sleep quality, Sleep latency, Sleep duration, Habitual sleep efficiency, Sleep disturbances and Daytime dysfunction) in the current study except the use of sleep medication. Sleep onset latency was the component of PSQI with the greatest degree of abnormality among firefighters in a previous study. Interestingly, sleep latency was the component of PSQI with the most treatment effect of zolpidem in the current study. Zolpidem can be used asa part of treatment regimens in short time management of poor sleep quality among professional firefighters. PMID:26553086

  8. Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats

    PubMed Central

    Peer, Cody J.; Strope, Jonathan D.; Beedie, Shaunna; Ley, Ariel M.; Holly, Alesia; Calis, Karim; Farkas, Ronald; Parepally, Jagan; Men, Angela; Fadiran, Emmanuel O.; Scott, Pamela; Jenkins, Marjorie; Theodore, William H.; Sissung, Tristan M.

    2016-01-01

    Objectives: The recommended zolpidem starting dose was lowered in females (5 mg vs. 10 mg) since side effects were more frequent and severe than those of males; the mechanism underlying sex differences in pharmacokinetics (PK) is unknown. We hypothesized that such differences were caused by known sex-related variability in alcohol dehydrogenase (ADH) expression. Methods: Male, female, and castrated male rats were administered 2.6 mg/kg zolpidem, ± disulfiram (ADH/ALDH pathway inhibitor) to compare PK changes induced by sex and gonadal hormones. PK analyses were conducted in rat plasma and rat brain. Key findings: Sex differences in PK were evident: females had a higher CMAX (112.4 vs. 68.1 ug/L) and AUC (537.8 vs. 231.8 h∗ug/L) than uncastrated males. Castration induced an earlier TMAX (0.25 vs. 1 h), greater CMAX (109.1 vs. 68.1 ug/L), and a corresponding AUC increase (339.7 vs. 231.8 h∗ug/L). Administration of disulfiram caused more drastic CMAX and TMAX changes in male vs. female rats that mirrored the effects of castration on first-pass metabolism, suggesting that the observed PK differences may be caused by ADH/ALDH expression. Brain concentrations paralleled plasma concentrations. Conclusion: These findings indicate that sex differences in zolpidem PK are influenced by variation in the expression of ADH/ALDH due to gonadal androgens. PMID:27574509

  9. Evaluation of a new computerized psychometric test battery: Effects of zolpidem and caffeine

    PubMed Central

    Pilli, Raveendranadh; Naidu, MUR; Pingali, Usharani; Shobha, JC

    2013-01-01

    Objective: To evaluate the effects of centrally active drugs using a new indigenously developed automated psychometric test system and compare the results with that obtained using pencil- and paper-based techniques. Materials and Methods: The tests were standardized in 24 healthy participants. Reproducibility of the test procedure was evaluated by performing the tests by a single experimenter on two occasions (interday reproducibility). To evaluate the sensitivity of the tests, the effects of zolpidem (5 mg) and caffeine (500 mg) versus placebo were studied in 24 healthy participants in a randomized, double-blind three-way crossover design. Results: Psychometric tests were performed at baseline and at 1, 2, and 3 h after administration of study medication. The effects of zolpidem and caffeine on the psychomotor performance were most pronounced 1 h after administration. At this time, a significant impairment of performance in the simple reaction test (SRT), choice discrimination test (CDT), digit symbol substitution test (DSST), digit vigilance test (DVT), and card sorting test (CST) was observed with zolpidem. In contrast, caffeine showed a significant improvement in performance in CDT and DVT only. Conclusion: The results suggest that the tests of the computerized system are more sensitive and reliable then the pencil and paper tests in detecting the effects of central acting agents and are suitable for use in clinical areas to conduct studies with patients. PMID:24250201

  10. Possible interactions between zolpidem, a new sleep inducer and chlorpromazine, a phenothiazine neuroleptic.

    PubMed

    Desager, J P; Hulhoven, R; Harvengt, C; Hermann, P; Guillet, P; Thiercelin, J F

    1988-01-01

    The combined use of a hypnotic and a neuroleptic is a rather frequent situation, encountered especially in the psychiatric sphere. We therefore tested zolpidem and chlorpromazine in six healthy subjects by using a double-blind latin square design. All of them received single doses of 20 mg zolpidem (ZOL), 50 mg chlorpromazine (CPZ) and the combination of ZOL + CPZ. The medication was given as a single dose in the morning and each treatment being separated by a 1-week interval. Zolpidem produced moderate to severe sedation varying according to the subjects. Psychometric performances (manual dexterity, Stroop test), alertness and psychomotricity (visual analogue scales) were reduced up to 3 h after drug intake. Chlorpromazine alone did not have much effect. Combined administration of ZOL and CPZ was rather more effective than ZOL alone. The pharmacokinetics of ZOL or CPZ remained unchanged except for the elimination half-life of CPZ, which increased significantly when administered along with ZOL. No other pharmacodynamic or pharmacokinetic interaction between ZOL and CPZ was evident. The fact that the ZOL and CPZ combination accentuated the pharmacodynamical effects can be explained to result from the summation of each of their own pharmacological effect. PMID:3147477

  11. Zolpidem and Sleep in Pediatric Burn Patients with Attention Deficit/Hyperactivity Disorder.

    PubMed

    Cronin, Stephanie D; Gottschlich, Michele M; Gose, Lacy M; Kagan, Richard J

    2015-01-01

    Existing research shows that hospitalized patients, especially pediatric burn patients, are often sleep deprived. A pre-existing diagnosis of attention deficit/hyperactivity disorder (ADHD) further compounds a burn patient's inability to sleep. This retrospective study compared the effectiveness of zolpidem on patients with acute burns with ADHD (n = 23) and patients with acute burns without ADHD (n = 23). Effectiveness was defined based on the need for a change in the sleep medication or an increase in the zolpidem dose during the first 12 days of treatment. This study found that sleep dysfunction was similar in pediatric burn patients with and without a concurrent diagnosis of ADHD. Sixteen (69.6%) patients with and 13 (56.5%) patients without ADHD required a sleep medication change (p = 0.541). Further, while patients with ADHD required a sleep medication change (median = 5 days) sooner than those without ADHD (median = 9 days), it appears that zolpidem is not an effective drug for managing sleep in pediatric burn patients with or without ADHD. PMID:26201171

  12. Effects of acute and repeated zolpidem treatment on pentylenetetrazole-induced seizure threshold and on locomotor activity: comparison with diazepam.

    PubMed

    Vlainić, Josipa; Pericić, Danka

    2009-06-01

    Zolpidem and diazepam are widely used drugs acting via benzodiazepine binding sites on GABA(A) receptors. While diazepam is non-selective, zolpidem has a high affinity for alpha1-, and no affinity for alpha5-containing receptors. Several studies suggested that behavioral effects of zolpidem might be more similar to classical benzodiazepines than previously thought. To compare the sedative and anticonvulsant properties of these drugs and to evaluate the importance of GABA(A) receptor subunits for development of tolerance during chronic treatment, we tested the effects of acute and repeated administration of zolpidem and diazepam on ambulatory locomotor activity (a measure of sedation) and on the threshold for myoclonic, clonic and tonic seizures in response to i.v. infusion of pentylenetetrazole (PTZ). Both drugs given acutely in doses 0.3, 1 and 3 mg/kg reduced locomotion, and in doses 1 and 3 mg/kg elevated the threshold for PTZ-induced seizures. The effects of zolpidem and diazepam on the tonic seizure threshold were greater than on myoclonus and clonic seizure threshold. Diazepam and zolpidem (3 mg/kg), given 18 or 42 h after repeated drug treatment (10 days, 5 mg/kg, twice daily), decreased the PTZ seizure threshold and increased the locomotor activity as compared to control mice, indicating development of tolerance to their anticonvulsant and sedative effects. After repeated treatment the PTZ seizure threshold was not different between the two drugs, while differences in sedation became larger than after the acute treatment. The results suggest that alpha5-containing GABA(A) receptors are not crucial for the development of sedative and anticonvulsant tolerance. PMID:19345234

  13. Trial of Zolpidem, Eszopiclone, and Other GABA Agonists in a Patient with Progressive Supranuclear Palsy

    PubMed Central

    Chang, Andrew Young; Weirich, Erica

    2014-01-01

    Progressive supranuclear palsy (PSP) is a progressive, debilitating neurodegenerative disease of the Parkinson-plus family of syndromes. Unfortunately, there are no pharmacologic treatments for this condition, as most sufferers of the classic variant respond poorly to Parkinson medications such as levodopa. Zolpidem, a gamma aminobutyric acid (GABA) agonist specific to the α-1 receptor subtype, has been reported to show improvements in symptoms of PSP patients, including motor dysfunction, dysarthria, and ocular disturbances. We observed a 73-year-old woman with a six-year history of PSP, who, upon administration of a single 12.5 mg dose of sustained-release zolpidem, exhibited marked enhancements in speech, facial expressions, and fine motor skills for five hours. These results were reproduced upon subsequent clinic visits. In an effort to find a sustainable medication that maximized these beneficial effects while minimizing side effects and addressing some of her comorbid neuropsychological conditions, a trial of five other GABA receptor agonists was performed with the patient's consent, while she and her caregivers were blinded to the specific medications. She and her caretakers subsequently reported improvements, especially visual, while on eszopiclone, and, to a lesser degree, temazepam and flurazepam. PMID:25371679

  14. The hypnotic zolpidem increases the synchrony of BOLD signal fluctuations in widespread brain networks during a resting paradigm

    PubMed Central

    Licata, Stephanie C.; Nickerson, Lisa D.; Lowen, Steven B.; Trksak, George H.; MacLean, Robert R.; Lukas, Scott E.

    2013-01-01

    Networks of brain regions having synchronized fluctuations of the blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) time-series at rest, or “resting state networks” (RSNs), are emerging as a basis for understanding intrinsic brain activity. RSNs are topographically consistent with activity-related networks subserving sensory, motor, and cognitive processes, and studying their spontaneous fluctuations following acute drug challenge may provide a way to understand better the neuroanatomical substrates of drug action. The present within-subject double-blind study used BOLD fMRI at 3T to investigate the functional networks influenced by the non-benzodiazepine hypnotic zolpidem (Ambien®). Zolpidem is a positive modulator of γ-aminobutyric acidA (GABAA) receptors, and engenders sedative effects that may be explained in part by how it modulates intrinsic brain activity. Healthy participants (n= 12) underwent fMRI scanning 45 min after acute oral administration of zolpidem (0, 5, 10, or 20 mg), and changes in BOLD signal were measured while participants gazed at a static fixation point (i.e., at rest). Data were analyzed using group independent component analysis (ICA) with dual regression and results indicated that compared to placebo, the highest dose of zolpidem increased functional connectivity within a number of sensory, motor, and limbic networks. These results are consistent with previous studies showing an increase in functional connectivity at rest following administration of the positive GABAA receptor modulators midazolam and alcohol, and suggest that investigating how zolpidem modulates intrinsic brain activity may have implications for understanding the etiology of its powerful sedative effects. PMID:23296183

  15. Residual effects of zolpidem, triazolam, rilmazafone and placebo in healthy elderly subjects: a randomized double-blind study.

    PubMed

    Uemura, Sachiko Ito; Kanbayashi, Takashi; Wakasa, Masahiko; Satake, Masahiro; Ito, Wakako; Shimizu, Kazumi; Shioya, Takanobu; Shimizu, Tetsuo; Nishino, Seiji

    2015-11-01

    With current hypnotic agents, next-day residual effects are a common problem. The purpose of the present study was to evaluate the residual effects of the commercially available hypnotics - zolpidem, triazolam, and rilmazafone - on the physical and cognitive functions of healthy elderly people in the early morning and the day following drug administration. In this study, the next-day residual effects of zolpidem, triazolam, and rilmazafone, following bedtime dosing in elderly subjects, were evaluated. Women (n = 11) and men (n = 2) aged 60-70 years received a single dose (at 23:00) of one of these, zolpidem 5 mg, triazolam 0.125 mg, rilmazafone 1 mg and placebo in a randomized, double-blind, crossover design. Measures of objective parameters and psychomotor performances (Timed up and Go test, Functional Reach Test, body sway test, critical flicker fusion test, simple discrimination reaction test, short-term memory test) and subjective ratings were obtained at 04:00, 07:00, and the next time of the day. All hypnotics were generally well tolerated; there were no serious adverse side effects and no subjects discontinued the evaluations. Compared to placebo, zolpidem and rilmazafone had good results on the Functional Reach Test. Although subjective assessments tended to be poor in the early morning, rilmazafone significantly improved the body sway test in the other hypnotics. A single dose of zolpidem 5 mg and triazolam 0.125 mg did not have any next-day residual effects on healthy elderly subjects. Residual effects appeared to be related to the compound's half-life and the dose used. Rilmazafone 1 mg exhibited steadiness in static and dynamic balance and seemed to be more favorable for the elderly with early morning awakening. PMID:26498242

  16. Structural and Thermal Characterization of Zolpidem Hemitartrate Hemihydrate (Form E) and Its Decomposition Products by Laboratory X-Ray Powder Diffraction

    SciTech Connect

    Halasz, I.; Dinnebier, R

    2010-01-01

    The crystal structure of zolpidem hemitartrate hemihydrate (I, Form E) has been solved from high-resolution laboratory powder diffraction data. It crystallizes in the orthorhombic P2{sub 1}2{sub 1}2{sub 1} space group with a = 22.4664(6) {angstrom}, b = 26.0420(7) {angstrom}, and c = 7.4391(1) {angstrom}. Protonation of zolpidem molecules could not be unambiguously determined. Thermal stability of Form E has been investigated by TG-DTA and in situ by temperature resolved X-ray powder diffraction. Water loss occurs between 50 C {le} t {le} 100 C while structure decomposition commences at approximately 120 C yielding zolpidem tartrate (II) and pure zolpidem base (III) in approximately equimolar amounts. Crystal structures of II and III have been solved simultaneously from a single powder pattern of thermally decomposed I. Zolpidem tartrate crystallizes in the orthorhombic P2{sub 1}2{sub 1}2{sub 1} space group with a = 19.9278(8) {angstrom}, b = 15.1345(8) {angstrom}, and c = 7.6246(2) {angstrom} (at 140 C). Zolpidem base crystallizes in the orthorhombic Pcab space group with a = 9.9296(4) {angstrom}, b = 18.4412(9) {angstrom}, and c = 18.6807(9) {angstrom} (at 140 C). In the reported crystal structures zolpidem molecules form stacks through {pi}-{pi} interaction or dipole-dipole interactions while tartrate moieties, if present, form hydrogen bonded chains. Water molecule in I forms a hydrogen bond to the imidazole nitrogen atom of the zolpidem molecule. Free space in the crystal structure of I could allow for the additional water molecules and thus a variable water content.

  17. Determination of zaleplon and zolpidem by liquid chromatography-turbo-ionspray mass spectrometry: application to forensic cases.

    PubMed

    Giroud, Christian; Augsburger, Marc; Menetrey, Annick; Mangin, Patrice

    2003-06-01

    Zolpidem and zaleplon are two short-acting hypnotic agents used in Europe and in the USA. An atmospheric pressure ionisation liquid chromatography-mass spectrometry (Sciex API 150 EX) method was developed for the determination of zolpidem and zaleplon in whole blood. After single-step liquid-liquid extraction, the hypnotics were separated by gradient-elution with an ammonium formate buffer/acetonitrile eluent on an Inertsil ODS-3 column. Methaqualone was used as internal standard. The recovery was higher than 70% for both hypnotics and the internal standard. The best fit for the calibration curve was achieved, between 1 and 250 ng/ml, with 1/x quadratic regression. Coefficients of intra- and inter-assay variation calculated at 5, 25 and 100 ng/ml were less than 10%. The method was successfully applied to forensic cases. PMID:12726851

  18. Zolpidem withdrawal induced uncoupling of GABA(A) receptors in vitro associated with altered GABA(A) receptor subunit mRNA expression.

    PubMed

    Jembrek, Maja Jazvinšćak; Vlainić, Josipa; Šuran, Jelena

    2015-01-01

    Hypnotic zolpidem produces its effects via the benzodiazepine binding site in α1-containing GABAA receptors. The aim of the study was to assess the influence of duration of zolpidem treatment and its withdrawal, as well as the role of alpha1-containing GABAA receptors in the development of physical dependence and tolerance. Namely, recombinant receptors can be used to characterize mechanisms involved in different processes in the brain and to delineate the contribution of specific receptor subtypes. To address the influence of chronic zolpidem treatment we exposed HEK293 cells stably expressing alpha1beta2gamma2S recombinant GABAA receptors for seven consecutive days, while withdrawal periods lasted for 24, 48, 72 and 96 hours. Using radioligand binding studies we determined that chronic zolpidem treatment did not induce changes in either GABAA receptor number or in the expression of subunit mRNAs. We observed the enhancement of binding sites and upregulated expression of subunit mRNAs only following 96-hour withdrawal. Moreover, zolpidem treatment and its withdrawal (All time points) induced functional uncoupling between GABA and benzodiazepine binding sites in the GABAA receptor complex. Accordingly, it might be assumed that zolpidem withdrawal-induced uncoupling of GABAA receptors is associated with altered GABAA receptor subunit mRNA expression. The results presented here provide an insight into molecular and cellular mechanisms probably underlying adaptive changes of GABAA receptor function in response to chronic usage and withdrawal of zolpidem and perhaps the observed molecular changes could be linked to the tolerance and dependence produced upon prolonged treatment with other GABAergic drugs. PMID:26232993

  19. An increased risk of reversible dementia may occur after zolpidem derivative use in the elderly population: a population-based case-control study.

    PubMed

    Shih, Hsin-I; Lin, Che-Chen; Tu, Yi-Fang; Chang, Chia-Ming; Hsu, Hsiang-Chin; Chi, Chih-Hsien; Kao, Chia-Hung

    2015-05-01

    We evaluate the effects of zolpidem use to develop dementia or Alzheimer disease from the Taiwan National Health Insurance Research Database (NHIRD).A retrospective population-based nested case-control study. Newly diagnosed dementia patients 65 years and older and controls were sampled. A total of 8406 dementia and 16,812 control subjects were enrolled from Taiwan NHIRD during 2006 to 2010. The relationships between zolpidem use and dementia were measured using odds and adjusted odds ratios. The relationship between the average cumulative doses for zolpidem and dementia was also analyzed.Zolpidem alone or with other underlying diseases, such as hypertension, diabetes, and stroke, was significantly associated with dementia after controlling for potential confounders, such as age, sex, coronary artery disease, diabetes, anti-hypertension drugs, stroke, anticholesterol statin drugs, depression, anxiety, benzodiazepine, anti-psychotic, and anti-depressant agents' use (Adjusted OR = 1.33, 95% CI 1.24-1.41). Zolpidem use also has significant dose-response effects for most of the types of dementia. In patient with Alzheimer diseases, the effects of zolpidem among patients with Alzheimer's disease remained obscure. The adjusted OR for patients whose cumulative exposure doses were between 170 and 819 mg/year (adjusted OR: 1.65, 95% CI 1.08-2.51, P = 0.0199) was significant; however, the effects for lower and higher cumulative dose were not significant.Zolpidem used might be associated with increased risk for dementia in elderly population. Increased accumulative dose might have higher risk to develop dementia, especially in patients with underlying diseases such as hypertension, diabetes, and stroke. PMID:25929937

  20. Influence of zolpidem, a novel hypnotic, on the intermediate-stage and paradoxical sleep in the rat.

    PubMed

    Gottesmann, C; Trefouret, S; Depoortere, H

    1994-02-01

    Paradoxical sleep (PS) in mice, rats, and cats is preceded and sometimes followed by a short-lasting stage characterized by cortical high-amplitude spindles and hippocampal low-frequency theta rhythm. This intermediate stage (IS) seems to correspond to a transient functional disconnection of the forebrain from the brainstem. Pentobarbital and benzodiazepines greatly extend IS at the expense of PS, which is suppressed. Zolpidem, a new imidazopyridine hypnotic, was studied at 2.5, 5, and 7.5 mg/kg IP. At 2.5 mg/kg, which is already a true hypnotic dose, it only decreased PS during the first 2 h of recording with a rebound during the following 4 h of recording. At 5 mg/kg, zolpidem increased the number and total duration of IS episodes, increased IS episodes not followed by PS, and increased PS latency of occurrence. PS amount was decreased during the first three h with a rebound in the next 3 h. At 7.5 mg/kg, the total amount of PS was also decreased. The eye movement number and theta rhythm frequency of PS were unchanged. These results show that zolpidem produces less disruption of the association between IS and PS than do previous hypnotics. PMID:8146229

  1. Is Zolpidem Associated with Increased Risk of Fractures in the Elderly with Sleep Disorders? A Nationwide Case Cross-Over Study in Taiwan

    PubMed Central

    Chu, Fang-Ying; Chen, Hung-An; Yin, Yun-Ju; Lee, Hua-Chin; Chu, William Cheng-Chung; Yeh, Hui-Wen; Chiang, Wei-Shan; Yeh, Chia-Lun; Huang, Hui-Ling; Tzeng, Nian-Sheng

    2015-01-01

    Background We conducted a study using a case-crossover design to clarify the risk of acute effects of zolpidem and benzodiazepine on all-sites of fractures in the elderly. Design of study Case-crossover design. Methods and Materials Elderly enrollees (n = 6010) in Taiwan’s National Health Insurance Research Database with zolpidem or benzodiazepine use were analyzed for the risk of developing fractures. Results After adjusting for medications such as antipsychotics, antidepressants, and diuretics, or comorbidities such as hypertension, osteoarthritis, osteoporosis, rheumatoid arthritis and depression, neither zolpidem nor benzodiazepine was found to be associated with increased risk in all-sites fractures. Subjects without depression were found to have an increased risk of fractures. Diazepam is the only benzodiazepine with increased risk of fractures after adjusting for medications and comorbidities. Hip and spine were particular sites for increased fracture risk, but following adjustment for comorbidities, the associations were found to be insignificant. Conclusion Neither zolpidem nor benzodiazepine was associated with increased risk of all-site fractures in this case cross-over study after adjusting for medications or comorbidities in elderly individuals with insomnia. Clinicians should balance the benefits and risks for prescribing zolpidem or benzodiazepine in the elderly accordingly. PMID:26716836

  2. Can a Positive Allosteric Modulation of GABAergic Receptors Improve Motor Symptoms in Patients with Parkinson's Disease? The Potential Role of Zolpidem in the Treatment of Parkinson's Disease

    PubMed Central

    Daniele, Antonio; Panza, Francesco; Greco, Antonio; Logroscino, Giancarlo; Seripa, Davide

    2016-01-01

    At present, patients with advanced Parkinson's disease (PD) are unsatisfactorily controlled by currently used anti-Parkinsonian dopaminergic drugs. Various studies suggest that therapeutic strategies based on nondopaminergic drugs might be helpful in PD. Zolpidem, an imidazopyridine widely used as sleep inducer, shows high affinity only for GABAA receptors containing the α-1 subunit and facilitates GABAergic neurotransmission through a positive allosteric modulation of GABAA receptors. Various observations, although preliminary, consistently suggest that in PD patients zolpidem may induce beneficial (and sometimes remarkable) effects on motor symptoms even after single doses and may also improve dyskinesias. Since a high density of zolpidem binding sites is in the two main output structures of the basal ganglia which are abnormally overactive in PD (internal globus pallidus, GPi, and substantia nigra pars reticulata, SNr), it was hypothesized that in PD patients zolpidem may induce through GABAA receptors an inhibition of GPi and SNr (and, possibly, of the subthalamic nucleus also), resulting in an increased activity of motor cortical areas (such as supplementary motor area), which may give rise to improvement of motor symptoms of PD. Randomized clinical trials are needed in order to assess the efficacy, safety, and tolerability of zolpidem in treating motor symptoms of PD. PMID:27293955

  3. Zolpidem-Induced Arousal by Paradoxical GABAergic Stimulation: A Case Report With F-18 Flumazenil Positron Emission Tomography and Single Photon Emission Computed Tomography Study

    PubMed Central

    Kim, Changjae; Nam, Ki Yeun; Park, Jin Woo; Lee, Ho Jun

    2016-01-01

    Zolpidem is a non-benzodiazepine drug that has selectivity for the gamma-aminobutyric acid (GABA) receptors. We experienced paradoxical effect of zolpidem in a 48-year-old male patient with hypoxic-ischemic brain injury after cardiac arrest. The patient was in stupor and could not communicate. His Glasgow Coma Scale (GCS) was E2M4V2 and Rancho Los Amigos (RLA) was grade III to IV. Zolpidem was prescribed to induce sedation but paradoxically, he became alert (GCS 15, RLA VII) and was able to communicate. The arousal lasted for 2 hours repeatedly following each administration of the medication. While he was alert, electroencephalogram showed the reversal of slow wave into beta range fast activity and F-18 flumazenil positron emission tomography (PET) showed increased GABAergic receptor activity in both frontoparietotemporal cortices. Single photon emission computed tomography (SPECT) also showed increased cerebral perfusion and reversal of cerebellar diaschisis. PMID:26949686

  4. Zolpidem-Induced Arousal by Paradoxical GABAergic Stimulation: A Case Report With F-18 Flumazenil Positron Emission Tomography and Single Photon Emission Computed Tomography Study.

    PubMed

    Kim, Changjae; Kwon, Bum Sun; Nam, Ki Yeun; Park, Jin Woo; Lee, Ho Jun

    2016-02-01

    Zolpidem is a non-benzodiazepine drug that has selectivity for the gamma-aminobutyric acid (GABA) receptors. We experienced paradoxical effect of zolpidem in a 48-year-old male patient with hypoxic-ischemic brain injury after cardiac arrest. The patient was in stupor and could not communicate. His Glasgow Coma Scale (GCS) was E2M4V2 and Rancho Los Amigos (RLA) was grade III to IV. Zolpidem was prescribed to induce sedation but paradoxically, he became alert (GCS 15, RLA VII) and was able to communicate. The arousal lasted for 2 hours repeatedly following each administration of the medication. While he was alert, electroencephalogram showed the reversal of slow wave into beta range fast activity and F-18 flumazenil positron emission tomography (PET) showed increased GABAergic receptor activity in both frontoparietotemporal cortices. Single photon emission computed tomography (SPECT) also showed increased cerebral perfusion and reversal of cerebellar diaschisis. PMID:26949686

  5. Zolpidem, triazolam, and diazepam decrease distress vocalizations in mouse pups: differential antagonism by flumazenil and beta-Carboline-3-carboxylate-t-butyl ester (beta-CCt).

    PubMed

    Rowlett, J K; Tornatzky, W; Cook, J M; Ma, C; Miczek, K A

    2001-04-01

    In response to stressful events, neonatal mice emit ultrasonic vocalizations (USVs), which are suppressed by BZ agonists. The present study examined the role of the benzodiazepine/alpha1 (BZ/alpha1) receptor subtype in the suppression engendered by the BZ/alpha1-preferring agonist zolpidem and the nonselective BZ agonists triazolam and diazepam. The role of BZ receptor subtypes was explored further by conducting antagonism studies using the BZ/alpha1-preferring antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt), in comparison with the nonselective BZ antagonist flumazenil. Mouse pups (CFW strain) were separated from their dam and littermates at day 7, and placed for 4 min in a test chamber with reduced ambient temperature (19 +/- 1 degrees C) for recording USVs, motor incoordination (measured as a pup rolling on its back per grid cross), and body temperature. Zolpidem, triazolam, and diazepam suppressed USVs in a dose-dependent manner, concomitant with increases in incoordination and augmentation of hypothermia. These effects of the three BZ agonists were blocked by flumazenil in a manner consistent with surmountable antagonism. The ability of zolpidem, but not triazolam or diazepam, to suppress USVs and augment hypothermia was antagonized by beta-CCt, whereas the increase in motor incoordination engendered by zolpidem, triazolam, and diazepam was not sensitive to beta-CCt administration. Collectively, these results suggest that zolpidem suppresses distress USVs in mouse pups by a mechanism distinct from that of typical BZs. Furthermore, suppression of distress USVs by zolpidem may involve BZ/alpha1 receptors and a nonanxiolytic mechanism, such as hypothermia. PMID:11259551

  6. Zolpidem and eszopiclone prime α1β2γ2 GABAA receptors for longer duration of activity

    PubMed Central

    Dixon, Christine L; Harrison, Neil L; Lynch, Joseph W; Keramidas, Angelo

    2015-01-01

    Background and Purpose GABAA receptors mediate neuronal inhibition in the brain. They are the primary targets for benzodiazepines, which are widely used to treat neurological disorders including anxiety, epilepsy and insomnia. The mechanism by which benzodiazepines enhance GABAA receptor activity has been extensively studied, but there is little mechanistic information on how non-benzodiazepine drugs that bind to the same site exert their effects. Eszopiclone and zolpidem are two non-benzodiazepine drugs for which no mechanism of action has yet been proposed, despite their clinical importance as sleeping aids. Here we investigate how both drugs enhance the activity of α1β2γ2 GABAA receptors. Experimental Approach We used rapid ligand application onto macropatches and single-channel kinetic analysis to assess rates of current deactivation. We also studied synaptic currents in primary neuronal cultures and in heterosynapses, whereby native GABAergic nerve terminals form synapses with HEK293 cells expressing α1β2γ2 GABAA receptors. Drug binding and modulation was quantified with the aid of an activation mechanism. Key Results At the single-channel level, the drugs prolonged the duration of receptor activation, with similar KD values of ∼80 nM. Channel activation was prolonged primarily by increasing the equilibrium constant between two connected shut states that precede channel opening. Conclusions and Implications As the derived mechanism successfully simulated the effects of eszopiclone and zolpidem on ensemble currents, we propose it as the definitive mechanism accounting for the effects of both drugs. Importantly, eszopiclone and zolpidem enhanced GABAA receptor currents via a mechanism that differs from that proposed for benzodiazepines. PMID:25817320

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

    PubMed

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

    2015-12-01

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

  8. Determination of zolpidem in human plasma by liquid chromatography-tandem mass spectrometry for clinical application.

    PubMed

    Byeon, Ji-Yeong; Lee, Hye-In; Lee, Yun-Jeong; Lee, Jung-Eun; Kim, Se-Hyung; Kim, Young-Hoon; Na, Han-Sung; Jang, Choon-Gon; Lee, Seok-Yong

    2015-04-01

    Zolpidem (ZPD) is widely described for the short-term treatment of insomnia. We have developed and validated a simple and rapid liquid chromatography analytical method using tandem mass spectrometry (LC-MS/MS) for the quantification of ZPD in human plasma. Using dibucaine as an internal standard (IS), the analyte was extracted with methyl t-butyl ether (MTBE). Chromatographic separation of ZPD was performed on a reversed-phase Luna C18 column (50 mm × 2.0 mm i.d., 5 μm particles) with a mobile phase of 10mM ammonium formate buffer (pH 3.0)-methanol (15:85, v/v) at a flow rate of 250 μm/min. The total run-time was 2.5 min and the retention times of ZPD and IS were 0.66 and 0.74 min, respectively. The mass-to-charge transition monitored for quantification of ZPD and IS was 308.2→235.2 and 344.0→271.0, respectively. The lower limit of quantification (LLOQ) using 100 μL of human plasma was 0.05 ng/mL and the calibration curves were linear over a range of 0.05-200 ng/mL (r(2)>0.9964). The mean accuracy and precision for intra- and inter-run validation of ZPD were within acceptable limits. In the present LC-MS/MS method, we showed improved sensitivity for quantification of the ZPD in human plasma using lower volume of plasma compared with previously described analytical methods for ZPD. This validated method was successfully applied to a pharmacokinetic study in humans. PMID:25728370

  9. Drug-facilitated sexual assault and analytical toxicology: the role of LC-MS/MS A case involving zolpidem.

    PubMed

    Kintz, Pascal; Villain, Marion; Dumestre-Toulet, Véronique; Ludes, Bertrand

    2005-02-01

    The use of a drug to modify a person's behavior for criminal gain is not a recent phenomenon. However, the recent increase in reports of drug-facilitated crimes (sexual assault, robbery) has caused alarm in the general public. Drugs involved can be pharmaceuticals, such as benzodiazepines (flunitrazepam, lorazepam, etc.), hypnotics (zopiclone, zolpidem), sedatives (neuroleptics, some histamine H1-antagonists) or anaesthetics (gamma-hydroxybutyrate, ketamine), drugs of abuse, such as cannabis, ecstasy or lysergide, or more often ethanol. Drugs said to be used to facilitate sexual assaults can be difficult to detect (active products at low dosages, chemical instability), possess amnesic properties and can be rapidly cleared from the body (short half-life). We present here a case involving a 23-year old girl that declared a sexual assault 6 days after the event was said to have occurred. To the Police, the victim claimed a total amnesia of the offense associated with intense sedation. Toxicological analyses for unknown sedative drugs achieved by LC-MS/MS revealed the presence of zolpidem (Stilnox), a non-benzodiazepine hypnotic. Concentrations after 6 days were 16 and 32 pg/mL in blood and urine, respectively. The drug tested also positive in the corresponding hair segment at 0.75 pg/mg. The requested extraordinary sensitivity of LC-MS/MS appears as a pre-requisite to document any case involving drug-facilitated sexual assault. PMID:15763689

  10. A rapid HPLC method for determination of zolpidem and its degradation product in tablets using a monolithic column.

    PubMed

    Rezaee Zavareh, Elham; Kiani, Azin; Sheikholeslam, Zahra; Shafaati, Alireza; Tabatabai, Sayyed Abbas

    2015-01-01

    A simple, accurate reverse phase high-performance liquid chromatographic method, utilizing a monolithic silica column, for determination of zolpidem hemitartrate and its degradation product in tablet dosage form was developed. Analysis was achieved on the monolithic, C18 (100 mm, 3.9 mm) column, in isocratic mode with acetonitrile-NaH2PO4 (pH 7.0; 0.01 M; 35:65, v/v) as mobile phase and a flow rate of 2.5 mL/min at room temperature with UV detection at 245 nm. Diazepam was applied as an internal standard. The retention time of zolpidem and its degradation product was 2.14 and 1.89, respectively. Calibration curve was linear in the range of 0.12-5 µg/mL and the recovery values were found to be 97-101%. The limit of quantitation was determined 0.12 μg/mL. The relative standard deviation values of intraday and interday studies were calculated as 0.13-1.1% and 0.54-1.3%, respectively. PMID:25754693

  11. Randomised clinical trial of the effects of prolonged-release melatonin, temazepam and zolpidem on slow-wave activity during sleep in healthy people.

    PubMed

    Arbon, Emma L; Knurowska, Malgorzata; Dijk, Derk-Jan

    2015-07-01

    Current pharmacological treatments for insomnia include benzodiazepine and non-benzodiazepine hypnotics targeting γ-aminobutyric acid (GABA)A receptors, as well as agonists of the melatonin receptors MT1 and MT2. Melatonin, temazepam and zolpidem are thought to exert their effect through different mechanisms of action, but whether this leads to differential effects on electroencephalogram (EEG) power spectra during sleep in middle-aged people is currently not known. To establish whether the effects of prolonged-release melatonin (2 mg) on the nocturnal sleep EEG are different to those of temazepam (20 mg) and zolpidem (10 mg). Sixteen healthy men and women aged 55-64 years participated in a double-blind, placebo-controlled, four-way cross-over trial. Nocturnal sleep was assessed with polysomnography and spectral analysis of the EEG. The effects of single oral doses of prolonged-release melatonin, temazepam and zolpidem on EEG slow-wave activity (SWA, 0.75-4.5 Hz) and other frequencies during nocturnal non-rapid eye movement (NREM) sleep were compared. In an entire night analysis prolonged-release melatonin did not affect SWA, whereas temazepam and zolpidem significantly reduced SWA compared with placebo. Temazepam significantly reduced SWA compared with prolonged-release melatonin. Prolonged-release melatonin only reduced SWA during the first third of the night compared with placebo. These data show that the effects of prolonged-release melatonin on the nocturnal sleep EEG are minor and are different from those of temazepam and zolpidem; this is likely due to the different mechanisms of action of the medications. PMID:25922426

  12. Quantitative determination of zopiclone and zolpidem in whole blood by liquid-liquid extraction and UHPLC-MS/MS.

    PubMed

    Eliassen, E; Kristoffersen, L

    2014-11-15

    An ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the determination of zopiclone and zolpidem in whole blood, for use in cases with suspected driving under influence of drugs (DUID) and autopsy cases. Sample preparation was performed with liquid-liquid extraction (LLE) using ethyl acetate/n-heptane (80:20, v/v) and 0.1mL whole blood. Deuterated analogues were used as internal standards (IS) for both compounds. The compounds were separated using a reversed phase C18-column (2.1mm×100mm, 1.7μm), with a flow rate of 0.5mL/min, 1μL injected and gradient elution with 5mM ammonium formate pH 10.2 and acetonitrile. Quantification was done by MS/MS using multiple reaction monitoring (MRM) in positive mode. The run time of the method was 4.5min including equilibration time. The calibration curves of extracted whole blood standards were fitted by linear-order calibration curves weighted 1/x, with R(2) values above 0.999 for both compounds. Intermediate precision and accuracies (bias) were 2.4-12.9% RSD and from -5.9 to 6.8%, respectively. Recoveries of the compounds were ≥70%. The lower limit of quantification (LLOQ) for zopiclone was 0.50nmol/L (0.19ng/mL) or 0.05pg injected on column, and 3.5nmol/mL (1.10ng/mL) for zolpidem, or 0.27pg injected on column. The limit of detection (LOD) was 0.2nmol/L (0.08ng/mL) for zopiclone and 0.3nmol/L (0.09ng/mL) for zolpidem. Matrix effects (ME) were between 108 and 115% when calculated against IS. A comparison with former confirmation LC-MS method at the Norwegian Institute of Public Health, Division of Forensic Medicine (NIPH) was performed during method validation. Good correlation was seen for both compounds. The method has been running on a routine basis for two years, and has proven to be very robust and reliable with satisfactory long term precision and bias and with results for external quality samples corresponding well to consensus mean or median

  13. A rapid and highly sensitive UPLC-MS-MS method for the quantification of zolpidem tartrate in human EDTA plasma and its application to pharmacokinetic study.

    PubMed

    Reddy, Dendhi Chandrapal; Bapuji, Akula Tukaram; Rao, Vepakomma Suryanarayana; Himabindu, Vurimindi; Ravinder, Sreedasyam

    2012-07-01

    A rapid and high sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed and validated for the quantification of zolpidem in human EDTA plasma using ondansetron (IS) as an internal standard. The analyte and IS were extracted from human plasma using ethyl acetate and separated on a C18 column (Inertsil-ODS, 5 µm, 4.6 × 50 mm) interfaced with a triple quadrupole tandem mass spectrometer. The mobile phase, which consisted of a mixture of methanol and 20 mM ammonium formate (pH 5.00 ± 0.05; 75:25 v/v), was injected at a flow rate of 0.40 mL/min. The retention times of zolpidem and IS were approximately 1.76 and 1.22. The LC run time was 3 min. The electrospray ionization source was operated in positive ion mode. Multiple reaction monitoring used the [M + H](+) ions m/z 308.13 → 235.21 for zolpidem and m/z 294.02 → 170.09 for the ondansetron, respectively. Five freeze-thaw cycles was established at -20 and -70°C.The linearity of the response/concentration curve was established in human EDTA plasma over the concentration range 0.10-149.83 ng/mL. The lower detection limit [(signal-to-noise (S/N) > 3] was 0.04 ng/mL and the lower limit of quantification (S/N > 10) was 0.10 ng/mL. This LC-MS-MS method was validated with intra-batch and inter-batch precision of 0.52-8.66.The intra-batch and inter-batch accuracy was 96.66-106.11. Recovery of zolpidem in human plasma was 87.00% and IS recovery was 81.60%. The primary pharmacokinetic parameters were T(max) (h) = (1.25 ± 0.725), C(max) (ng/mL) (127.80 ± 34.081), AUC(0→t), = (665.37 ± 320.982) and AUC(0→∞), 686.03 ± 342.952, respectively. PMID:22689921

  14. Residual Effects of Low-Dose Sublingual Zolpidem on Highway Driving Performance the Morning after Middle-of-the-Night Use

    PubMed Central

    Vermeeren, Annemiek; Vuurman, Eric F.P.M.; Leufkens, Tim R.M.; Van Leeuwen, Cees J.; Van Oers, Anita C.M.; Laska, Eugene; Rico, Salvador; Steinberg, Frank; Roth, Thomas

    2014-01-01

    Study Objective: To evaluate next-morning driving performance after middle-of-the-night use of zolpidem 3.5 mg in a buffered sublingual formulation (ZST). Design: Single-center, four-period, randomized, double-blind, placebo-controlled, crossover study. Setting: Maastricht University, The Netherlands. Participants: Forty healthy volunteers (20 females). Interventions: Single dose of ZST administered in the middle of the night at 3 and 4 h before driving, zopiclone 7.5 mg at bedtime 9 h before driving, and placebo. Measurements: Performance in a 100-km standardized highway driving test in normal traffic measuring standard deviation of lateral position (SDLP) — an index of weaving. Drug-placebo changes in SDLP > 2.5 cm were considered to reflect clinically relevant driving impairment. Result: For ZST, Max McNemar symmetry analyses showed that the proportion of drivers classified as impaired was increased 3 h after dosing (P < 0.012), but not 4 h after dosing. Mean increases in SDLP from placebo, although statistically significant, were small (1.46 cm [P < 0.0001] at 3 h and 0.83 cm [P = 0.0174] at 4 h). The morning after zopiclone, 45% of the drivers were classified as impaired with a mean increase in SDLP of 2.46 cm (P < 0.0001). There were no significant sex differences in effects of ZST and zopiclone. Conclusion: Zolpidem 3.5 mg in a buffered sublingual formulation has a minimal risk of impairing driving performance in the morning ≥ 4 hours after middle-of-the night use. When taken 3 hours before driving, the drug may have impairing effects so caution should be exercised if medication is taken other than as indicated. Clinical Trial Information: ClinicalTrials.gov Identifier: NCT01106859; Trial Name: Driving Performance After Middle of the Night Administration of 3.5 mg Zolpidem Tartrate Sublingual Tablet; http://clinicaltrials.gov/ct2/show/NCT01106859. Citation: Vermeeren A; Vuurman EF; Leufkens TR; Van Leeuwen CJ; Van Oers AC; Laska E; Rico S; Steinberg F

  15. Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration with Zolpidem.

    PubMed

    Xia, Binfeng; Yang, Zhen; Zhou, Haiying; Lukacova, Viera; Zhu, Wei; Milewski, Mikolaj; Kesisoglou, Filippos

    2015-05-01

    Intraoral (IO) delivery is an alternative administration route to deliver a drug substance via the mouth that provides several advantages over conventional oral dosage forms. The purpose of this work was to develop and evaluate a novel, physiologically based oral cavity model for projection and mechanistic analysis of the clinical pharmacokinetics of intraoral formulations. The GastroPlus™ Oral Cavity Compartmental Absorption and Transit (OCCAT™) model was used to simulate the plasma concentration versus time profiles and the fraction and rate of intraoral drug transit/absorption for Intermezzo® sublingual tablets (zolpidem tartrate). The model was evaluated by the goodness-of-fit between simulated and observed concentrations and the deviation of key PK parameters (e.g., C max, T max, and AUC). In addition, a sensitivity analysis was conducted to demonstrate the interplay and impact of key modeling parameters on the fraction absorbed via oral mucosa (F a_IO). The OCCAT™ model captured the observed pharmacokinetics for Intermezzo® sublingual tablets (R (2) > 0.9). The predicted deviations (%) for C max, AUC0-inf, AUC0-20 min, and T max were 5.7, 28.0, 11.8, and 28.6%, respectively, indicating good prediction accuracy. The model also estimated ~18% of total drug was absorbed via the IO route. Furthermore, the sensitivity analysis indicated that the F a_IO was not only associated with drug diffusivity and unbound fraction in epithelium tissue (f ut) but also depended on the physicochemical properties of compounds for IO delivery (e.g., solubility and logD pH = 7.4). The novel physiologically based IO absorption OCCAT™ model showed satisfactory performance and will be helpful to guide development of future intraoral formulations. PMID:25716146

  16. Differential effects of the dual orexin receptor antagonist almorexant and the GABA(A)-α1 receptor modulator zolpidem, alone or combined with ethanol, on motor performance in the rat.

    PubMed

    Steiner, Michel A; Lecourt, Hugues; Strasser, Daniel S; Brisbare-Roch, Catherine; Jenck, François

    2011-03-01

    Current insomnia treatments such as γ-aminobutyric acid (GABA) receptor modulators are associated with sedative and muscle-relaxant effects, which increase when drug intake is combined with alcohol. This study compared the novel sleep-enabling compound almorexant (ACT-078573-hydrochloride), a dual orexin receptor antagonist, with the positive GABA(A)-α1 receptor modulator zolpidem. Both compounds were administered alone or in combination with ethanol, and their effects on forced motor performance were determined in Wistar rats upon waking after treatment. To detect substance-induced sedation and myorelaxation, time spent on an accelerating rotating rod (rotarod) and forepaw grip strength were measured. Zolpidem (10, 30, and 100 mg/kg, p.o.) and ethanol (0.32, 1, and 1.5 g/kg, i.p.) dose-dependently decreased rotarod performance and grip strength, whereas almorexant (30, 100, and 300 mg/kg, p.o.) did not. Doses of ethanol (0.32 and 1 g/kg), which were ineffective when administered alone, showed interactions with zolpidem (10 and 30 mg/kg) leading to reduced rotarod performance and grip strength; in contrast, combination of ethanol (0.32 and 1 g/kg) with almorexant (100 and 300 mg/kg) did not reduce performance or grip strength below ethanol alone. We conclude that unlike zolpidem, almorexant does not interfere with forced motor performance or grip strength in the rat, nor does it further increase the sedative effects of ethanol. Our results suggest that the effect of almorexant can be immediately reversed to full alertness like under physiological sleep, and that almorexant is less likely to show strong sedation, excessive myorelaxation, or interaction with alcohol than commonly prescribed hypnotics such as zolpidem. PMID:21150905

  17. Simultaneous analysis method for GHB, ketamine, norketamine, phenobarbital, thiopental, zolpidem, zopiclone and phenytoin in urine, using C18 poroshell column.

    PubMed

    Anilanmert, Beril; Çavuş, Fatma; Narin, Ibrahim; Cengiz, Salih; Sertler, Şefika; Özdemir, Ali Acar; Açikkol, Münevver

    2016-06-01

    Date-rape drugs have the potential to be used in drug-facilitated sexual assault, organ theft and property theft. Since they are colorless, tasteless and odorless, victims can drink without noticing, when added to the beverages. These drugs must be detected in time, before they are cleared up from the biofluids. A simultaneous extraction and determination method in urine for GHB, ketamine, norketamine, phenobarbital, thiopental, zolpidem, zopiclone and phenytoin (an anticonvulsant and antiepileptic drug) with LC-MS/MS was developed for the first time with analytically acceptable recoveries and validated. A 4 steps liquid-liquid extraction was applied, using only 1.000mL urine. A new age commercial C18 poroshell column with high column efficiency was used for LC-MS/MS analysis with a fast isocratic elution as 5.5min. A new MS transition were introduced for barbital. 222.7>179.8 with the effect of acetonitrile. Recoveries (%) were between 80.98-99.27 for all analytes, except for GHB which was 71.46. LOD and LOQ values were found in the ranges of 0.59-49.50 and 9.20-80.80ngmL(-1) for all the analytes (except for GHB:3.44 and 6.00μgmL(-1)). HorRat values calculated (between 0.25-1.21), revealed that the inter-day and interanalist precisions (RSD%≤14.54%) acceptable. The simultaneous extraction and determination of these 8 analytes in urine is challenging because of the difficulty arising from the different chemical properties of some. Since the procedure can extract drugs from a wide range of polarity and pKa, it increases the window of detection. Group representatives from barbiturates, z-drugs, ketamine, phenytoin and polar acidic drugs (GHB) have been successfully analyzed in this study with low detection limits. The method is important from the point of determining the combined or single use of these drugs in crimes and finding out the reasons of deaths related to these drugs. PMID:27107852

  18. Myocardial Injury without Electrocardiographic Changes after a Suicide Attempt by an Overdose of Glimepiride and Zolpidem: A Case Report and Literature Review.

    PubMed

    Chou, Shengpu; Ayabe, Seiji; Sekine, Nobuo

    2015-01-01

    A 40-year-old diabetic man was admitted to our hospital for poor glycemic control. During hospitalization, he took 42 mg glimepiride and 50 mg zolpidem as a suicide attempt. The following day, the creatine kinase-MB fraction and troponin I levels were elevated to 112 IU/L and 8.77 ng/mL, respectively, without any electrocardiographic abnormalities. The patient recovered completely without any complications. Four weeks later, coronary computed tomography angiography and myocardial perfusion scintigraphy revealed moderate one-vessel coronary disease without the evidence of myocardial ischemia or old infarction. Cardiac-specific markers must be considered in sulfonylurea-induced hypoglycemic patients, particularly when the patient is unconscious and does not exhibit any clinical manifestations. PMID:26521901

  19. Determination of 14 benzodiazepines and hydroxy metabolites, zaleplon and zolpidem as tert-butyldimethylsilyl derivatives compared with other common silylating reagents in whole blood by gas chromatography-mass spectrometry.

    PubMed

    Gunnar, Teemu; Ariniemi, Kari; Lillsunde, Pirjo

    2005-04-25

    The most common commercially available silylating reagents, N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA), N,O-bis-(trimethylsilyl)trifluoroacetamide+1% trimethylchlorosilane (BSTFA+1% TMCS) and N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (MTBSTFA) were evaluated to achieve optimal derivatization conditions for analyzing various benzodiazepines based on gas chromatography-electron impact ionization-mass spectrometry (GC-EI-MS). Sensitivity, repeatability, retention times and stability of the derivatives, as well as specificity of mass fragmentation, were studied in detail. Also other parameters affecting the derivatization chemistry of benzodiazepines are discussed. tert-Butyldimethylsilyl (TBDMS) derivatives proved to be more stable, reproducible and sensitive than corresponding trimethylsilyl (TMS) derivatives for the GC-EI-MS analysis of benzodiazepines. Based on the TBDMS derivatives, a rapid, reliable, sensitive and quantitative GC-MS method was developed for the determination of 14 benzodiazepines and two hydroxy metabolites, as well as two non-benzodiazepine hypnotic agents, zolpidem and zaleplon, using 50 microl of whole blood. The method was completely validated in terms of accuracy, intra- and interday precision, limit of detection (LOD), limit of quantitation (LOQ), linearity, selectivity and extraction efficiency; these were all within the required limits, except for the accuracy of nitrazepam at a medium concentration level. PMID:15734157

  20. The RNA surveillance complex Pelo-Hbs1 is required for transposon silencing in the Drosophila germline

    PubMed Central

    Yang, Fu; Zhao, Rui; Fang, Xiaofeng; Huang, Huanwei; Xuan, Yang; Ma, Yanting; Chen, Hongyan; Cai, Tao; Qi, Yijun; Xi, Rongwen

    2015-01-01

    Silencing of transposable elements (TEs) in the metazoan germline is critical for genome integrity and is primarily dependent on Piwi proteins and associated RNAs, which exert their function through both transcriptional and posttranscriptional mechanisms. Here, we report that the evolutionarily conserved Pelo (Dom34)-Hbs1 mRNA surveillance complex is required for transposon silencing in the Drosophila germline. In pelo mutant gonads, mRNAs and proteins of some selective TEs are up-regulated. Pelo is not required for piRNA biogenesis, and our studies suggest that Pelo may function at the translational level to silence TEs: This function requires interaction with Hbs1, and overexpression of RpS30a partially reverts TE-silencing defects in pelo mutants. Interestingly, TE silencing and spermatogenesis defects in pelo mutants can also effectively be rescued by expressing the mammalian ortholog of Pelo. We propose that the Pelo-Hbs1 surveillance complex provides another level of defense against the expression of TEs in the germline of Drosophila and possibly all metazoa. PMID:26124316

  1. Identificação de radiofontes puntiformes presentes na região observada pelo telescópio BEAST

    NASA Astrophysics Data System (ADS)

    Oliveira, M. S.; Wuensche, C. A.; Leonardi, R.; Tello, C.

    2003-08-01

    Radiofontes extragalácticas são um dos principais contaminantes nas medidas da Radiação Cósmica de Fundo (RCF) em freqüências abaixo de 200 GHz. O estudo de seu comportamento espectral permite determinar a contribuição destas fontes às anisotropias intrísincas da RCF. Um dos experimentos recentes concebidos para estudar a RCF é o BEAST (Background Emission Anisotropy Scanning Telescope), cujos primeiros resultados foram publicados em fevereiro de 2003. Nos últimos meses, geramos mapas do céu nas freqüências de 30 GHz e 41 GHz, para um total de 648 horas de observação entre julho e outubro de 2002. Identificamos 4 fontes puntiformes extragalácticas na região do céu situada entre 0h < RA < 24 h e +32° < DEC < +42°, com relação S/R > 4,3 e situadas a pelo menos 25° acima do Plano Galáctico. Suas contrapartidas em 5 GHz, segundo o catálogo GB6, são: J1613+3412, J1635+3808, J0927+3902 e J1642+3948. Estas fontes também foram identificadas pelo satélite WMAP sendo que três coincidem com as observadas pelo BEAST dentro da incerteza do feixe do telescópio e a quarta encontra-se bastante próxima (J1613+3412), embora não seja coincidente. As estimativas preliminares de fluxos obtidas para esses objetos são, respectivamente, 0,51; 0,97; 1,08 e 1,6 Jy em 41 GHz. Usando estes resultados e medidas de fluxos em outras frequências existentes na literatura, apresentamos uma estimativa dos índices espectrais destes objetos no intervalo de frequências entre 4,85 GHz e 41 GHz.

  2. 10 "Poison Pills" for Pets

    MedlinePlus

    ... left on the bedside table. Zolpidem may make cats wobbly and sleepy, but most pets become very ... very common pain killer found in most households. Cats are extremely sensitive to acetaminophen, but dogs can ...

  3. From synapse to behavior: rapid modulation of defined neuronal types with engineered GABAA receptors

    PubMed Central

    Wulff, Peer; Goetz, Thomas; Leppä, Elli; Linden, Anni-Maija; Renzi, Massimiliano; Swinny, Jerome D; Vekovischeva, Olga Y; Sieghart, Werner; Somogyi, Peter; Korpi, Esa R; Farrant, Mark; Wisden, William

    2007-01-01

    In mammals, identifying the contribution of specific neurons or networks to behavior is a key challenge. Here we describe an approach that facilitates this process by enabling the rapid modulation of synaptic inhibition in defined cell populations. Binding of zolpidem, a systemically active allosteric modulator that enhances the function of the GABAA receptor, requires a phenylalanine residue (Phe77) in the γ2 subunit. Mice in which this residue is changed to isoleucine are insensitive to zolpidem. By Cre recombinase-induced swapping of the γ2 subunit (that is, exchanging Ile77 for Phe77), zolpidem sensitivity can be restored to GABAA receptors in chosen cell types. We demonstrate the power of this method in the cerebellum, where zolpidem rapidly induces significant motor deficits when Purkinje cells are made uniquely sensitive to its action. This combined molecular and pharmacological technique has demonstrable advantages over targeted cell ablation and will be invaluable for investigating many neuronal circuits. PMID:17572671

  4. From synapse to behavior: rapid modulation of defined neuronal types with engineered GABAA receptors.

    PubMed

    Wulff, Peer; Goetz, Thomas; Leppä, Elli; Linden, Anni-Maija; Renzi, Massimiliano; Swinny, Jerome D; Vekovischeva, Olga Y; Sieghart, Werner; Somogyi, Peter; Korpi, Esa R; Farrant, Mark; Wisden, William

    2007-07-01

    In mammals, identifying the contribution of specific neurons or networks to behavior is a key challenge. Here we describe an approach that facilitates this process by enabling the rapid modulation of synaptic inhibition in defined cell populations. Binding of zolpidem, a systemically active allosteric modulator that enhances the function of the GABAA receptor, requires a phenylalanine residue (Phe77) in the gamma2 subunit. Mice in which this residue is changed to isoleucine are insensitive to zolpidem. By Cre recombinase-induced swapping of the gamma2 subunit (that is, exchanging Ile77 for Phe77), zolpidem sensitivity can be restored to GABAA receptors in chosen cell types. We demonstrate the power of this method in the cerebellum, where zolpidem rapidly induces significant motor deficits when Purkinje cells are made uniquely sensitive to its action. This combined molecular and pharmacological technique has demonstrable advantages over targeted cell ablation and will be invaluable for investigating many neuronal circuits. PMID:17572671

  5. Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons.

    PubMed

    Prokic, Emma J; Weston, Cathryn; Yamawaki, Naoki; Hall, Stephen D; Jones, Roland S G; Stanford, Ian M; Ladds, Graham; Woodhall, Gavin L

    2015-08-01

    Tonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically-induced beta-frequency (15-30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage-clamp studies of fast spiking cells showed that 10 nM zolpidem augmented a tonic inhibitory GABAA receptor mediated current in fast spiking cells whilst higher concentrations of zolpidem reduced the tonic current. A kinetic model of zolpidem-sensitive GABAA receptors suggested that incubation with 10 nM zolpidem resulted in a high proportion of GABAA receptors locked in a kinetically slow desensitized state whilst 30 nM zolpidem favoured rapid transition into and out of desensitized states. This was confirmed experimentally using a challenge with saturating concentrations of GABA. Selective modulation of an interneuron-specific tonic current may underlie the reversal of cognitive and motor deficits afforded by low-dose zolpidem in neuropathological states. PMID:25797493

  6. Risk of Type 2 Diabetes in Patients With Nonapnea Sleep Disorders in Using Different Types of Hypnotics: A Population-Based Retrospective Cohort Study.

    PubMed

    Lin, Chia-Ling; Yeh, Mei-Chang; Harnod, Tomor; Lin, Cheng-Li; Kao, Chia-Hung

    2015-09-01

    There has been insufficient evidence on whether exposure to hypnotics affects the risk of type 2 diabetes (T2DM). The aim of this study was to examine patients with nonapnea sleep disorders using zolpidem, benzodiazepines (BZDs), or a combination of both, and their risk of T2DM. This was a population-based retrospective cohort study using data from 1997 to 2011. Data from the Taiwan National Health Insurance Research Database were employed for this study. A total of 45,602 patients with nonapnea sleep disorders and use of hypnotics were identified as the study cohort. The control cohort comprised 40,799 age- and sex-matched patients. We conducted a Cox proportional hazard regression analysis to estimate the effects of hypnotics on risk of T2DM. The overall incidence of T2DM was 20.1 per 1000 person-years for patients using zolpidem, which was significantly higher than that of the control group (11.9 per 1000 person-years). Overall, patients with nonapnea sleep disorders using zolpidem had a higher risk of T2DM compared with patients not using zolpidem and the control cohort (adjusted hazard ratio [HR] = 1.41, 95% confidence interval [CI] = 1.35-1.48). We also observed a significantly higher risk of T2DM in patients with both zolpidem and BZD use (adjusted HR = 1.77, 95% CI = 1.64-1.91) than that of those without zolpidem use and BZD use. Compared with patients not using hypnotics, patients using zolpidem had a higher risk of developing T2DM; the risk was particularly pronounced in those using both zolpidem and BZDs. PMID:26402831

  7. Effect of a Sleep Aid in Analgesia after Arthroscopic Rotator Cuff Repair

    PubMed Central

    Cho, Chul-Hyun; Lee, Young-Kuk; Shin, Hong-Kwan; Hwang, Ilseon

    2015-01-01

    Purpose The aim of this study was to evaluate the effects and safety of a sleep aid for postoperative analgesia in patients undergoing arthroscopic rotator cuff repair. Materials and Methods Seventy-eight patients were prospectively assigned to either the zolpidem group (multimodal analgesia+zolpidem; 39 patients) or the control group (multimodal analgesia; 39 patients). Self-rated pain levels were assessed twice a day using a visual analog scale (VAS). The need for additional rescue analgesic, duration of functional recovery, and adverse effects were assessed for the first 5 days after surgery. Results The mean number of times that additional rescue analgesic was required during 5 days after surgery was 2.1±2.0 in the zolpidem group and 3.3±2.8 in the control group, a significant difference. There were no significant differences between the two groups in mean VAS pain scores during the first 5 days after surgery, although the zolpidem group had lower VAS pain scores than the control group. Additionally, there were no significant differences in duration of functional recovery and adverse effects between the two groups. Conclusion The use of zolpidem for analgesia after arthroscopic rotator cuff repair provided a significant reduction in the need for rescue analgesic without increasing adverse effects. Nevertheless, mean VAS pain scores during the first 5 days after surgery did not differ between the zolpidem group and the control group. PMID:25837184

  8. Alterações Induzidas Pelo Exercício no Número, Função e Morfologia de Monócitos de Ratos

    PubMed Central

    GUERESCHI, MARCIA G.; PRESTES, JONATO; DONATTO, FELIPE F.; DIAS, RODRIGO; FROLLINI, ANELENA B.; FERREIRA, CLÍLTON KO.; CAVAGLIERI, CLAUDIA R.; PALANCH, ADRIANNE C.

    2008-01-01

    O propósito desse estudo foi verificar as alterações histofisiológicas em monócitos e macrófagos induzidas por curtos períodos de exercícios. Ratos Wistar (idade = 2 meses, peso corporal = 200g) foram divididos em sete grupos (n=6 cada): controle sedentário (C), grupos exercitados (natação) na intensidade leve por 5 (5L), 10 (10L) e 15 minutos (15L), e grupos exercitados em intensidade moderada por 5 (5M), 10 (10M) e 15 minutes (15M). Na intensidade moderada os animais carregaram uma carga de 5% do peso corporal dos mesmos em seus respectivos dorsos. Os monócitos sangüíneos foram avaliados quanto à quantidade e morfologia e os macrófagos peritoneais foram analisados quanto à quantidade e atividade fagocitária. Os dados foram analisados usando ANOVA e Tukey’s post hoc test (p ≤ 0,05). Os grupos de intensidade leve e 5M apresentaram aumento nos níveis dos monócitos quando comparados com o controle. Foi observado aumento na área celular dos monócitos para os grupos 5L, 10L, 5M e 10M; a área nuclear aumentou para os grupos 10L, 5M e 10M em comparação com o controle. Houve aumento nos macrófagos peritoneais para os grupos 15L, 10M, 15M e diminuição no grupo 5M. A capacidade fagocitária dos macrófagos aumentou nos grupos de intensidade leve e para o grupo 10M. O exercício realizado por curtos períodos modulou o número e função dos macrófagos, assim como o número e morfologia dos monócitos, sendo tais alterações dependentes da intensidade. A soma das respostas agudas observadas nesse estudo pode exercer um efeito protetor contra doenças, podendo ser utilizada para a melhora da saúde e qualidade de vida.

  9. A comparison of complex sleep behaviors with two short-acting Z-hypnosedative drugs in nonpsychotic patients

    PubMed Central

    Chen, Li-Fen; Lin, Ching-En; Chou, Yu-Ching; Mao, Wei-Chung; Chen, Yi-Chyan; Tzeng, Nian-Sheng

    2013-01-01

    Objective Complex sleep behaviors (CSBs) are classified as “parasomnias” in the International Classifcation of Sleep Disorders, Second Edition (ICSD-2). To realize the potential danger after taking two short-acting Z-hypnosedative drugs, we estimated the incidence of CSBs in nonpsychotic patients in Taiwan. Methods Subjects (N = 1,220) using zolpidem or zopiclone were enrolled from the psychiatric outpatient clinics of a medical center in Taiwan over a 16-month period in 2006–2007. Subjects with zolpidem (N = 1,132) and subjects with zopiclone (N = 88) were analyzed. All subjects completed a questionnaire that included demographic data and complex sleep behaviors after taking hypnotics. Results Among zolpidem and zopiclone users, 3.28% of patients reported incidents of somnambulism or amnesic sleep-related behavior problems. The incidence of CSBs with zolpidem and zopiclone were 3.27%, and 3.41%, respectively, which was signifcantly lower than other studies in Taiwan. Conclusion These results serve as a reminder for clinicians to make inquiries regarding any unusual performance of parasomnic activities when prescribing zolpidem or zopiclone. PMID:23976857

  10. Putting Tuberculosis (TB) To Rest: Transformation of the Sleep Aid, Ambien, and “Anagrams” Generated Potent Antituberculosis Agents

    PubMed Central

    2015-01-01

    Zolpidem (Ambien, 1) is an imidazo[1,2-a]pyridine-3-acetamide and an approved drug for the treatment of insomnia. As medicinal chemists enamored by how structure imparts biological function, we found it to have strikingly similar structure to the antitubercular imidazo[1,2-a]pyridine-3-carboxyamides. Zolpidem was found to have antituberculosis activity (MIC of 10–50 μM) when screened against replicating Mycobacterium tuberculosis (Mtb) H37Rv. Manipulation of the Zolpidem structure, notably, to structural isomers (“anagrams”), attains remarkably improved potency (5, MIC of 0.004 μM) and impressive potency against clinically relevant drug-sensitive, multi- and extensively drug-resistant Mtb strains (MIC < 0.03 μM). Zolpidem anagrams and analogues were synthesized and evaluated for their antitubercular potency, toxicity, and spectrum of activity against nontubercular mycobacteria and Gram-positive and Gram-negative bacteria. These efforts toward the rational design of isomeric anagrams of a well-known sleep aid underscore the possibility that further optimization of the imidazo[1,2-a]pyridine core may well “put TB to rest”. PMID:25984566

  11. Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: a study in healthy volunteers.

    PubMed

    Nutt, David; Wilson, Sue; Lingford-Hughes, Anne; Myers, Jim; Papadopoulos, Andreas; Muthukumaraswamy, Suresh

    2015-01-01

    A range of medications target different aspects of the GABA system; understanding their effects is important to inform further drug development. Effects on the waking EEG comparing these mechanisms have not been reported; in this study we compare the effects on resting MEG spectra of the benzodiazepine receptor agonist zolpidem, the delta sub-unit selective agonist gaboxadol (also known as THIP) and the GABA reuptake inhibitor tiagabine. These were two randomised, single-blind, placebo-controlled, crossover studies in healthy volunteers, one using zolpidem 10 mg, gaboxadol 15 mg and placebo, and the other tiagabine 15 mg and placebo. Whole head MEG recordings and individual MEG spectra were divided into frequency bands. Baseline spectra were subtracted from each post-intervention spectra and then differences between intervention and placebo compared. After zolpidem there were significant increases in beta frequencies and reduction in alpha frequency power; after gaboxadol and tiagabine there were significant increases in power at all frequencies up to beta. Enhancement of tonic inhibition via extrasynaptic receptors by gaboxadol gives rise to a very different MEG signature from the synaptic action of zolpidem. Tiagabine theoretically can affect both types of receptor; from these MEG results it is likely that the latter is the more prominent effect here. PMID:25195191

  12. A single dose of hypnotic corrects sleep and EEG abnormalities in symptomatic Huntington's disease mice.

    PubMed

    Kantor, Sandor; Varga, Janos; Morton, A Jennifer

    2016-06-01

    Sleep and electroencephalogram abnormalities are prominent early features of Huntington's disease (HD) that typically appear before the onset of characteristic motor symptoms. The changes in sleep and electroencephalogram seen in HD patients are largely recapitulated in mouse models of HD such as transgenic R6/2 lines. To test whether or not drugs with hypnotic properties can correct the sleep and electroencephalogram abnormalities seen in HD mice, we treated male wild-type (WT; N = 7) and R6/2 mice (N = 9) acutely with intraperitoneal injections of vehicle, zolpidem (5, 10 or 20 mg/kg) or amitriptyline (5, 10 or 20 mg/kg), and then monitored their sleep-wake behavior. In R6/2 mice, both zolpidem and amitriptyline suppressed the abnormally high REM sleep amount and electroencephalographic gamma (30-46 Hz) oscillations in a dose-dependent manner. Amitriptyline's effect on sleep was similar in both genotypes, whereas zolpidem showed significant genotype differences. Zolpidem exerted a strong hypnotic effect in WT mice by increasing electroencephalographic delta power, doubling the mean bout duration and the total amount of non-rapid eye movement sleep. However, no such effect was seen in R6/2 mice. Our study demonstrates that the pathophysiological changes seen in sleep and electroencephalogram are not 'hard-wired' in HD brain and can be reversed even at late stages of the disease. The diminished hypnotic effect of zolpidem suggests that the GABAergic control of sleep-wake states is impaired in HD mice. A better understanding of the neurochemical basis underlying these abnormalities should lead to more effective and rational therapies for HD. PMID:26805423

  13. In the Zzz zone: the effects of Z-drugs on human performance and driving.

    PubMed

    Gunja, Naren

    2013-06-01

    Despite their improved pharmacokinetic profile, the Z-drugs, zolpidem, zopiclone, and zaleplon, have a spectrum of adverse effects comparable to benzodiazepines. This review focuses on the impairment from Z-drugs on cognition, behavior, psychomotor performance, and driving ability. Z-drugs are short-acting GABA agonists that reduce sleep latency without disturbing sleep architecture. Bizarre behavioral effects have prompted warnings on the prescription, dispensation, and use of Z-drugs. Psychomotor impairment, falls, and hip fractures are more likely to occur with Z-drugs that have longer half-lives, that are taken at higher-than-recommended doses and when mixed with other psychoactive substances including alcohol. Zopiclone and higher doses of zolpidem are more likely to cause anterograde amnesia than zaleplon. Z-drugs, especially zolpidem, are associated with complex behaviors such as sleepwalking, sleep-driving, and hallucinations. Patients taking zopiclone and zolpidem have an increased risk of motor vehicle collisions, over double that of unexposed drivers. Driving impairment occurs with zopiclone and higher doses of zolpidem but is unlikely to occur after 4 h post-zaleplon administration. The residual effect of Z-drugs on next-day cognitive and psychomotor performance has significant impact on lifestyle, safety, and occupational considerations, including motor vehicle and machine operation. The risk-benefit analysis of Z-drugs in the treatment of insomnia, particularly in the elderly, may not favor treatment due to the increased risks of falls and motor vehicle collisions. Prescribers should warn patients taking Z-drugs of minimum time thresholds before they operate machinery or drive motor vehicles. PMID:23456542

  14. Sleep Quality Effects Recovery After Total Knee Arthroplasty (TKA)--A Randomized, Double-Blind, Controlled Study.

    PubMed

    Gong, Long; Wang, ZhenHu; Fan, Dong

    2015-11-01

    This study examined the effects of sleep quality on early recovery after total knee arthroplasty. A total of 148 patients were randomized 1:1 to receive either zolpidem or placebo for 2 weeks. VAS pain scores (rest, ambulation and night), range of motion (ROM), total amount of opioid analgesics and antiemetics taken, postoperative nausea and vomiting (PONV), sleep efficacy and satisfaction were recorded. It was found that patients taking zolpidem achieved greater improvement in quality of life and reported better satisfaction. Patients in the intervention group had lower pain score and took less antiemetics. Moreover, a significant correlation between sleep quality and ROM was detected. These results demonstrated that improved sleep quality is beneficial to patients' post-TKA recovery. PMID:26344094

  15. GABA-mediated changes in inter-hemispheric beta frequency activity in early-stage Parkinson's disease.

    PubMed

    Hall, S D; Prokic, E J; McAllister, C J; Ronnqvist, K C; Williams, A C; Yamawaki, N; Witton, C; Woodhall, G L; Stanford, I M

    2014-09-28

    In Parkinson's disease (PD), elevated beta (15-35Hz) power in subcortical motor networks is widely believed to promote aspects of PD symptomatology, moreover, a reduction in beta power and coherence accompanies symptomatic improvement following effective treatment with l-DOPA. Previous studies have reported symptomatic improvements that correlate with changes in cortical network activity following GABAA receptor modulation. In this study we have used whole-head magnetoencephalography to characterize neuronal network activity, at rest and during visually cued finger abductions, in unilaterally symptomatic PD and age-matched control participants. Recordings were then repeated following administration of sub-sedative doses of the hypnotic drug zolpidem (0.05mg/kg), which binds to the benzodiazepine site of the GABAA receptor. A beamforming based 'virtual electrode' approach was used to reconstruct oscillatory power in the primary motor cortex (M1), contralateral and ipsilateral to symptom presentation in PD patients or dominant hand in control participants. In PD patients, contralateral M1 showed significantly greater beta power than ipsilateral M1. Following zolpidem administration contralateral beta power was significantly reduced while ipsilateral beta power was significantly increased resulting in a hemispheric power ratio that approached parity. Furthermore, there was highly significant correlation between hemispheric beta power ratio and Unified Parkinson's Disease Rating Scale (UPDRS). The changes in contralateral and ipsilateral beta power were reflected in pre-movement beta desynchronization and the late post-movement beta rebound. However, the absolute level of movement-related beta desynchronization was not altered. These results show that low-dose zolpidem not only reduces contralateral beta but also increases ipsilateral beta, while rebalancing the dynamic range of M1 network oscillations between the two hemispheres. These changes appear to underlie the

  16. Primary health care practitioner perspectives on the management of insomnia: a pilot study.

    PubMed

    Cheung, Janet M Y; Atternäs, Kristina; Melchior, Madeleine; Marshall, Nathaniel S; Fois, Romano A; Saini, Bandana

    2014-01-01

    This paper reports a qualitative pilot study exploring primary care health practitioners' perspectives on the management of insomnia following the extensive media coverage on the adverse effects of zolpidem in 2007-08. General practitioners and community pharmacists were recruited throughout metropolitan Sydney, New South Wales using a convenience sampling and snowballing technique. Demographic information was collected from each participant followed by a semistructured interview. In total 22 participants were interviewed, including eight general practitioners and 14 community pharmacists. Interview transcripts were analysed using 'framework analysis'. Participants' responses illuminated some of the key issues facing primary care practitioners in the management of insomnia. Practitioners perceived there to be an overreliance on pharmacotherapy among insomnia patients and inadequate support for directing patients to alternative treatment pathways if they require or prefer non-pharmacological management. Current prescribing trends appear to favour older benzodiazepines in new cases of insomnia whereas some successful sporadic users of zolpidem have continued to use zolpidem after the media coverage in 2007-08. The findings of this pilot study suggest the need to address the limitations in the management of insomnia within the current health care system, to revise and disseminate updated insomnia guidelines and to provide educational opportunities and resources to primary care practitioners concerning management options. PMID:24200195

  17. The role of α1 and α5 subunit-containing GABAA receptors in motor impairment induced by benzodiazepines in rats.

    PubMed

    Milić, Marija; Divljaković, Jovana; Rallapalli, Sundari; van Linn, Michael L; Timić, Tamara; Cook, James M; Savić, Miroslav M

    2012-04-01

    Benzodiazepines negatively affect motor coordination and balance and produce myorelaxation. The aim of the present study was to examine the extent to which populations of γ-aminobutyric acid A (GABAA) receptors containing α1 and α5 subunits contribute to these motor-impairing effects in rats. We used the nonselective agonist diazepam and the α1-selective agonist zolpidem, as well as nonselective, α1-subunit and α5-subunit-selective antagonists flumazenil, βCCt, and XLi093, respectively. Ataxia and muscle relaxation were assessed by rotarod and grip strength tests performed 20 min after intraperitoneal treatment. Diazepam (2 mg/kg) induced significant ataxia and muscle relaxation, which were completely prevented by pretreatment with flumazenil (10 mg/kg) and βCCt (20 mg/kg). XLi093 antagonized the myorelaxant, but not the ataxic actions of diazepam. All three doses of zolpidem (1, 2, and 5 mg/kg) produced ataxia, but only the highest dose (5 mg/kg) significantly decreased the grip strength. These effects of zolpidem were reversed by βCCt at doses of 5 and 10 mg/kg, respectively. The present study demonstrates that α1 GABAA receptors mediate ataxia and indirectly contribute to myorelaxation in rats, whereas α5 GABAA receptors contribute significantly, although not dominantly, to muscle relaxation but not ataxia. PMID:22327019

  18. A suicide involving intraperitoneal injection of pentobarbital.

    PubMed

    Hangartner, Sarah; Steiner, Jasmin; Dussy, Franz; Moeckli, Regula; Gerlach, Kathrin; Briellmann, Thomas

    2016-09-01

    We present an unusual case of suicide by intraperitoneal injection of pentobarbital, an overdose of zolpidem and the intake of diazepam, ethanol and other psychoactive substances. The autopsy and specimen collection were conducted in a 10 to 18 h postmortem interval. The toxicological analysis revealed a significantly higher pentobarbital concentration in femoral blood compared to cardiac blood (36 vs. 15 mg/L). On the contrary, zolpidem and diazepam concentrations in cardiac blood (2700 and 590 µg/L) were found to be significantly higher than in femoral blood (1500 and 230 µg/L). These findings point to a postmortem redistribution with a distinct gradient from areas of high drug concentrations in the gastrointestinal tract (zolpidem and diazepam) and the injection site (pentobarbital) to peripheral tissue. Ethanol concentration was 0.95 ‰ which amplified the CNS depression. The choice of this unusual suicide method was associated with the deceased's former job as a veterinarian's assistant. In veterinary medicine, the intraperitoneal injection of a lethal dose of pentobarbital is quite commonly performed to euthanise small animals. Intraperitoneal injection is rare as route of administration in humans. PMID:26174446

  19. A mouse model mimicking human first night effect for the evaluation of hypnotics.

    PubMed

    Xu, Qi; Xu, Xin-Hong; Qu, Wei-Min; Lazarus, Michael; Urade, Yoshihiro; Huang, Zhi-Li

    2014-01-01

    In humans, a first night effect (FNE) is characterized by increased sleep latency and decreased total sleep time in an unfamiliar environment, but the mechanism and treatment options for this universally experienced acute insomnia are unclear. We continuously recorded electroencephalography (EEG) and electromyogram (EMG) and measured plasma corticosterone levels to develop a mouse FNE model by inducing acute insomnia in mice that have been placed in unfamiliar cage environments. The sleep latency of mice 'moved to clean cages' (MCC) was longer than that for mice 'moved to dirty ones' (MDC). As compared to MDC mice, MCC mice showed stronger decreases in the amount of non-rapid eye movement (non-REM, NREM) and REM sleep, with a lower power density of NREM sleep, increased fragmentation and decreased stage transitions from NREM sleep to wake, and higher variation in plasma corticosterone levels. Treatment of MCC mice with zolpidem, diazepam, raclopride, pyrilamine, except SCH23390 shortened NREM sleep latency. In addition, zolpidem significantly increased NREM and REM sleep with the increase in slow wave activity (1.00-2.75 Hz), while raclopride significantly increased NREM and REM sleep without changing the EEG power density in MCC mice, whereas diazepam increased sleep with a drastic decrease in power density of the frequency band between 1.00 and 4.00 Hz, diazepam also increased the frequency band between 9.75 and 24.75 Hz during NREM sleep. These results indicate that a MCC mouse can mimic a FNE phenotype of humans and that zolpidem and raclopride may be useful drugs to prevent acute insomnia, including FNE. PMID:24316349

  20. Increased Estradiol and Improved Sleep, But Not Hot Flashes, Predict Enhanced Mood during the Menopausal Transition

    PubMed Central

    Petrillo, Laura Fagioli; Koukopoulos, Alexia; Viguera, Adele C.; Hirschberg, April; Nonacs, Ruta; Somley, Brittny; Pasciullo, Erica; White, David P.; Hall, Janet E.; Cohen, Lee S.

    2011-01-01

    Background: The antidepressant effect of estrogen in women undergoing the menopause transition is hypothesized to be mediated by central nervous system effects of increasing estradiol on mood or through a pathway involving suppression of hot flashes and associated sleep disturbance. Estrogen therapy (ET) and the hypnotic agent zolpidem were selected as interventions in a three-arm, double-blind, placebo-controlled trial to distinguish the effects of estradiol, sleep, and hot flashes on depression. Methods: Women with depressive disorders, hot flashes, and sleep disturbance were randomly assigned to transdermal 17β-estradiol 0.05 mg/d, zolpidem 10 mg/d, or placebo for 8 wk. Changes in serum estradiol, perceived sleep quality, objectively measured sleep, and hot flashes were examined as predictors of depression improvement [Montgomery-Åsberg Depression Rating Scale (MADRS)] using multivariate linear regression. Results: Seventy-two peri/postmenopausal women with depression disorders were randomized to 17β-estradiol (n = 27), zolpidem (n = 31), or placebo (n = 14). There was no significant difference between groups in depression improvement (overall MADRS decrease 11.8 ± 8.6). Increasing estradiol (P = 0.009) and improved sleep quality (P < 0.001) predicted improved mood in adjusted models but reduced hot flashes (P = 0.99) did not. Post hoc subgroup analyses revealed that the therapeutic effect of increasing estradiol levels on mood was seen in perimenopausal (P = 0.009), but not postmenopausal, women. Conclusions: For women with menopause-associated depression, improvement in depression is predicted by improved sleep, and among perimenopausal women, by increasing estradiol levels. These results suggest that changes in estradiol and sleep quality, rather than hot flashes, mediate depression during the menopause transition. Therapies targeting insomnia may be valuable in treating menopause-associated depression. PMID:21525161

  1. Characterisation of the contribution of the GABA-benzodiazepine α1 receptor subtype to [11C]Ro15-4513 PET images

    PubMed Central

    Myers, James FM; Rosso, Lula; Watson, Ben J; Wilson, Sue J; Kalk, Nicola J; Clementi, Nicoletta; Brooks, David J; Nutt, David J; Turkheimer, Federico E; Lingford-Hughes, Anne R

    2012-01-01

    This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [11C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [11C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [11C]Ro15-4513 time-activity curves was used to describe distribution volume (VT) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that zolpidem caused a significant VT decrease (∼10%) in [11C]flumazenil, but no decrease in [11C]Ro15-4513 binding. Further analysis of [11C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean±s.d.: 71%±41%), presumed to reflect α1-subtype binding, but not another (13%±22%), presumed to reflect α5. The proposed method for [11C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands. PMID:22214903

  2. Deleterious effects of a low amount of ethanol on LTP-like plasticity in human cortex.

    PubMed

    Lücke, Caroline; Heidegger, Tonio; Röhner, Mirjam; Toennes, Stefan W; Krivanekova, Lucia; Müller-Dahlhaus, Florian; Ziemann, Ulf

    2014-05-01

    Ingesting ethanol (EtOH) at low doses during social drinking is a common human behavior for its facilitating effects on social interactions. However, low-dose EtOH may have also detrimental effects that so far are underexplored. Here we sought to test the effects of low-dose EtOH on long-term potentiation (LTP)-like plasticity in human motor cortex. Previous cellular experiments showed that low-dose EtOH potentiates extrasynaptic GABAAR and reduces NMDAR-mediated currents, processes that would limit the expression of LTP. Paired associative transcranial magnetic stimulation (PASLTP) was employed in nine healthy subjects for induction of LTP-like plasticity, indexed by a long-term increase in motor-evoked potential input-output curves. Synaptic α1-GABAAR function was measured by saccadic peak velocity (SPV). Very low doses of EtOH (resulting in blood concentrations of <5 mM) suppressed LTP-like plasticity but did not affect SPV when compared with a placebo condition. In contrast, 1 mg of alprazolam, a classical benzodiazepine, or 10 mg of zolpidem, a non-benzodiazepine hypnotic, decreased SPV but did not significantly affect LTP-like plasticity when compared with placebo. This double dissociation of low-dose EtOH vs alprazolam/zolpidem effects is best explained by the putatively high affinity of EtOH but not alprazolam/zolpidem to extrasynaptic GABAARs and to NMDARs. Findings suggest that enhancement of extrasynaptic GABAAR-mediated tonic inhibition and/or reduction of NMDAR-mediated neurotransmission by EtOH blocks LTP-like plasticity in human cortex at very low doses that are easily reached during social drinking. Therefore, low-dose EtOH may jeopardize LTP-dependent processes, such as learning and memory formation. PMID:24385131

  3. Dual orexin receptor antagonists show distinct effects on locomotor performance, ethanol interaction and sleep architecture relative to gamma-aminobutyric acid-A receptor modulators

    PubMed Central

    Ramirez, Andres D.; Gotter, Anthony L.; Fox, Steven V.; Tannenbaum, Pamela L.; Yao, Lihang; Tye, Spencer J.; McDonald, Terrence; Brunner, Joseph; Garson, Susan L.; Reiss, Duane R.; Kuduk, Scott D.; Coleman, Paul J.; Uslaner, Jason M.; Hodgson, Robert; Browne, Susan E.; Renger, John J.; Winrow, Christopher J.

    2013-01-01

    Dual orexin receptor antagonists (DORAs) are a potential treatment for insomnia that function by blocking both the orexin 1 and orexin 2 receptors. The objective of the current study was to further confirm the impact of therapeutic mechanisms targeting insomnia on locomotor coordination and ethanol interaction using DORAs and gamma-aminobutyric acid (GABA)-A receptor modulators of distinct chemical structure and pharmacological properties in the context of sleep-promoting potential. The current study compared rat motor co-ordination after administration of DORAs, DORA-12 and almorexant, and GABA-A receptor modulators, zolpidem, eszopiclone, and diazepam, alone or each in combination with ethanol. Motor performance was assessed by measuring time spent walking on a rotarod apparatus. Zolpidem, eszopiclone and diazepam [0.3–30 mg/kg administered orally (PO)] impaired rotarod performance in a dose-dependent manner. Furthermore, all three GABA-A receptor modulators potentiated ethanol- (0.25–1.5 g/kg) induced impairment on the rotarod. By contrast, neither DORA-12 (10–100 mg/kg, PO) nor almorexant (30–300 mg/kg, PO) impaired motor performance alone or in combination with ethanol. In addition, distinct differences in sleep architecture were observed between ethanol, GABA-A receptor modulators (zolpidem, eszopiclone, and diazepam) and DORA-12 in electroencephalogram studies in rats. These findings provide further evidence that orexin receptor antagonists have an improved motor side-effect profile compared with currently available sleep-promoting agents based on preclinical data and strengthen the rationale for further evaluation of these agents in clinical development. PMID:24399926

  4. Investigating the Discriminatory Power of BCS-Biowaiver in Vitro Methodology to Detect Bioavailability Differences between Immediate Release Products Containing a Class I Drug.

    PubMed

    Colón-Useche, Sarin; González-Álvarez, Isabel; Mangas-Sanjuan, Victor; González-Álvarez, Marta; Pastoriza, Pilar; Molina-Martínez, Irene; Bermejo, Marival; García-Arieta, Alfredo

    2015-09-01

    The purpose of this work is to investigate the discriminatory power of the Biopharmaceutics Classification System (BCS)-biowaiver in vitro methodology, i.e., to investigate if a BCS-biowaiver approach would have detected the Cmax differences observed between two zolpidem tablets and to identify the cause of the in vivo difference. Several dissolution conditions were tested with three zolpidem formulations: the reference (Stilnox), a bioequivalent formulation (BE), and a nonbioequivalent formulation (N-BE). Zolpidem is highly soluble at pH 1.2, 4.5, and 6.8. Its permeability in Caco-2 cells is higher than that of metoprolol and its transport mechanism is passive diffusion. None of the excipients (alone or in combination) showed any effect on permeability. All formulations dissolved more than 85% in 15 min in the paddle apparatus at 50 rpm in all dissolution media. However, at 30 rpm the nonbioequivalent formulation exhibited a slower dissolution rate. A slower gastric emptying rate was also observed in rats for the nonbioequivalent formulation. A slower disintegration and dissolution or a delay in gastric emptying might explain the Cmax infra-bioavailability for a highly permeable drug with short half-life. The BCS-biowaiver approach would have declared bioequivalence, although the in vivo study was not conclusive but detected a 14% mean difference in Cmax that precluded the bioequivalence demonstration. Nonetheless, these findings suggest that a slower dissolution rate is more discriminatory and that rotation speeds higher than 50 rpm should not be used in BCS-biowaivers, even if a coning effect occurs. PMID:26287948

  5. Ethanol activation of protein kinase A regulates GABAA α1 receptor function and trafficking in cultured cerebral cortical neurons.

    PubMed

    Carlson, Stephen L; Kumar, Sandeep; Werner, David F; Comerford, Christopher E; Morrow, A Leslie

    2013-05-01

    Ethanol exposure produces alterations in GABAergic signaling that are associated with dependence and withdrawal. Previously, we demonstrated that ethanol-induced protein kinase C (PKC) γ signaling selectively contributes to changes in GABAA α1 synaptic receptor activity and surface expression. Here, we demonstrate that protein kinase A (PKA) exerts opposing effects on GABAA receptor adaptations during brief ethanol exposure. Cerebral cortical neurons from day 0-1 rat pups were tested after 18 days in culture. Receptor trafficking was assessed by Western blot analysis, and functional changes were measured using whole-cell patch-clamp recordings of evoked and miniature inhibitory postsynaptic current (mIPSC) responses. One-hour ethanol exposure increased membrane-associated PKC and PKA, but steady-state GABAA α1 subunit levels were maintained. Activation of PKA by Sp-adenosine 3',5'-cyclic monophosphothioate triethylamine alone increased GABAA α1 subunit surface expression and zolpidem potentiation of GABA responses, whereas coexposure of ethanol with the PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine decreased α1 subunit expression and zolpidem responses. Exposure to the PKC inhibitor calphostin-C with ethanol mimicked the effect of direct PKA activation. The effects of PKA modulation on mIPSC decay τ were consistent with its effects on GABA currents evoked in the presence of zolpidem. Overall, the results suggest that PKA acts in opposition to PKC on α1-containing GABAA receptors, mediating the GABAergic effects of ethanol exposure, and may provide an important target for the treatment of alcohol dependence/withdrawal. PMID:23408117

  6. The Use of Hypnotics and Mortality - A Population-Based Retrospective Cohort Study

    PubMed Central

    Lan, Tzuo-Yun; Zeng, Ya-Fang; Tang, Gau-Jun; Kao, Hui-Chuan; Chiu, Hsien-Jane; Lan, Tsuo-Hung; Ho, Hsiao-Feng

    2015-01-01

    Background Sleep disorders, especially chronic insomnia, have become major health problem worldwide and, as a result, the use of hypnotics is steadily increasing. However, few studies with a large sample size and long-term observation have been conducted to investigate the relationship between specific hypnotics and mortality. Methods We conducted this retrospective cohort study using data from the National Health Insurance Research Database in Taiwan. Information from claims data including basic characteristics, the use of hypnotics, and survival from 2000 to 2009 for 1,320,322 individuals were included. The use of hypnotics was divided into groups using the defined daily dose and the cumulative length of use. Hazard ratios (HRs) were calculated from a Cox proportional hazards model, with two different matching techniques to examine the associations. Results Compared to the non-users, both users of benzodiazepines (HR = 1.81; 95% confidence interval [CI] = 1.78–1.85) and mixed users (HR = 1.44; 95% CI = 1.42–1.47) had a higher risk of death, whereas the users of other non-benzodiazepines users showed no differences. Zolpidem users (HR = 0.73; 95% CI = 0.71–0.75) exhibited a lower risk of mortality in the adjusted models. This pattern remained similar in both matching techniques. Secondary analysis indicated that zolpidem users had a reduced risk of major cause-specific mortality except cancer, and that this protective effect was dose-responsive, with those using for more than 1 year having the lowest risk. Conclusions The effects of different types of hypnotics on mortality were diverse in this large cohort with long-term follow-up based on representative claims data in Taiwan. The use of zolpidem was associated with a reduced risk of mortality. PMID:26709926

  7. Benzodiazepines consumption: does dependence vary with age?

    PubMed

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

    2014-09-01

    We have compared two groups of chronic benzodiazepines (or zolpidem/zopiclone) users: "Seniors," aged 65 years or more, and "Adults," aged less than 65 years. The study took place in the Pays de Loire region. The questionnaire assesses dependence based on items from the DSM-IV. The analysis was based on 176 Senior questionnaires and 212 Adult questionnaires. Whereas Senior patients take benzodiazepines routinely with little negative consequences, Adults suffer from underlying psychological trouble, mention a higher consumption than planned, which causes negative consequences. 35.2% of Seniors are dependent on benzodiazepines versus 49.8% of Adults. PMID:24810390

  8. Regioselective Copper-Catalyzed Dicarbonylation of Imidazo[1,2-a]pyridines with N,N-Disubstituted Acetamide or Acetone: An Approach to 1,2-Diketones Using Molecular Oxygen.

    PubMed

    Wang, Changcheng; Lei, Sai; Cao, Hua; Qiu, Shuxian; Liu, Jingyun; Deng, Hao; Yan, Caijuan

    2015-12-18

    A novel copper-catalyzed regioselective double carbonylation of imidazo[1,2-a]pyridines with N,N-disubstituted acetamide or acetone using molecular oxygen has been described. It has provided a new approach to synthesize 1,2-carbonyl imidazo[1,2-a]pyridines, which are important substrates and intermediates in preparation of fine chemicals. The product shares a skeleton similar to that of Zolpidem, one of the most prescribed drugs in the world. (18)O-labeling experiments unambiguously established that the oxygen source of products originated from O2 rather than H2O. PMID:26595127

  9. Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target.

    PubMed

    Hiu, Takeshi; Farzampour, Zoya; Paz, Jeanne T; Wang, Eric Hou Jen; Badgely, Corrine; Olson, Andrew; Micheva, Kristina D; Wang, Gordon; Lemmens, Robin; Tran, Kevin V; Nishiyama, Yasuhiro; Liang, Xibin; Hamilton, Scott A; O'Rourke, Nancy; Smith, Stephen J; Huguenard, John R; Bliss, Tonya M; Steinberg, Gary K

    2016-02-01

    Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem's potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery. PMID:26685158

  10. A Computerized Stroop Test for the Evaluation of Psychotropic Drugs in Healthy Participants

    PubMed Central

    Pilli, Raveendranadh; Naidu, MUR; Pingali, Usha Rani; Shobha, J. C.; Reddy, A. Praveen

    2013-01-01

    Background: The Stroop paradigm evaluates susceptibility to interference and is sensitive to dysfunction in frontal lobes and drug effects. The aim of the present study was to establish a simple and reliable computerized version of Stroop color-word test, which can be used for screening of various psychotropic drugs. Materials and Methods: The standardized method was followed in all cases, by recording the reaction time (RT) in msec in 24 healthy participants using computerized version of Stroop color-word test. Reproducibility of the test procedure was evaluated by recording the RTs by a single experimenter on two sessions (interday reproducibility). Validity of the model was further tested by evaluating the psychotropic effect of Zolpidem 5 mg, Caffeine 500 mg, or Placebo on 24 healthy subjects in a randomized, double blind three-way crossover design. Results: The method was found to produce low variability with coefficient of variation less than 10%. Interday reproducibility was very good as shown by Bland-Altman plot with most of the values within ±2SD. There was a significant increase in RTs in Stroop performance with Zolpidem at 1 hr and 2 hrs; in contrast, caffeine significantly decreased RTs in Stroop performance at 1 hr only compared to placebo. Conclusion: The Stroop color-word recording and analysis system is simple, sensitive to centrally acting drug effects, and has potential for future experimental psychomotor assessment studies. PMID:24049230

  11. Single hair analysis of small molecules using MALDI-triple quadrupole MS imaging and LC-MS/MS: investigations on opportunities and pitfalls.

    PubMed

    Poetzsch, Michael; Steuer, Andrea E; Roemmelt, Andreas T; Baumgartner, Markus R; Kraemer, Thomas

    2014-12-01

    Single hair analysis normally requires extensive sample preparation microscale protocols including time-consuming steps like segmentation and extraction. Matrix assisted laser desorption and ionization mass spectrometric imaging (MALDI-MSI) was shown to be an alternative tool in single hair analysis, but still, questions remain. Therefore, an investigation of MALDI-MSI in single hair analysis concerning the extraction process, usage of internal standard (IS), and influences on the ionization processes were systematically investigated to enable the reliable application to hair analysis. Furthermore, single dose detection, quantitative correlation to a single hair, and hair strand LC-MS/MS results were performed, and the performance was compared to LC-MS/MS single hair monitoring. The MALDI process was shown to be independent from natural hair color and not influenced by the presence of melanin. Ionization was shown to be reproducible along and in between different hair samples. MALDI image intensities in single hair and hair snippets showed good semiquantitative correlation to zolpidem hair concentrations obtained from validated routine LC-MS/MS methods. MALDI-MSI is superior to LC-MS/MS analysis when a fast, easy, and cheap sample preparation is necessary, whereas LC-MS/MS showed higher sensitivity with the ability of single dose detection for zolpidem. MALDI-MSI and LC-MS/MS segmental single hair analysis showed good correlation, and both are suitable for consumption monitoring of drugs of abuse with a high time resolution. PMID:25289728

  12. Possibilities and problems with identification and determination of "new" hypnotics.

    PubMed

    Ondra, Peter; Zedníková, Katerina; Matlach, Radek

    2005-12-01

    Authors discuss problems with identification and determination of flunitrazepam and zolpidem in biological material (BM). Over the recent years, these two structurally different substances have become the most frequently used as well as abused hypnotic drugs. This study presents applicability of immunochemical methods in the screening of flunitrazepam, one of the most commonly prescribed drugs among the benzodiazepines. Herein described techniques, a liquid-liquid (L-L) extraction, solid phase extraction (SPE) and the so-called "freeze out" method are used for isolation of the above mentioned compounds from BM. Besides the thin layer chromatography (TLC) and gas chromatography - mass spectrometry (GC-MS) applied in qualitative analysis, the study also describes a gas chromatography with electron capture detector (GC-ECD) and gas chromatography with nitrogen phosphorus detector (GC-NPD) optimized for the determination of flunitrazepam and zolpidem in blood (serum). Successful analyses of these two substances are of major importance, especially in interpreting the results of forensic toxicological examinations. PMID:16601812

  13. To Sleep or Not To Sleep: A Systematic Review of the Literature of Pharmacological Treatments of Insomnia in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Barrett, Jessica R.; Tracy, Derek K.

    2013-01-01

    Abstract Objective: This systematic review assessed current evidence on sleep medication for attention-deficit/hyperactivity disorder (ADHD) patients, to establish appropriate guidance for clinicians faced with prescribing such medications. Methods: Five articles (based on four pharmacological compounds) out of a total 337 were identified as evidence to guide pharmacological treatment of ADHD-related sleep disorders. Data regarding participant characteristics, measures of ADHD diagnosis, measures of sleep, and outcome data were extracted. Results: Zolpidem and L-theanine both displayed a poor response in reducing sleep latency and increasing total sleep time, however L-theanine did produce an increase in sleep efficiency. Zolpidem produced high levels of side effects, leading to the largest dropout rate of all five studies. Clonidine reduced insomnia; and melatonin also exhibited a positive response, with reduced sleep latency, higher total sleep time, and higher sleep efficiency. Conclusions: There is a relative paucity of evidence for the pharmacological treatment of ADHD-related sleep disorders; therefore, further research should be conducted to replicate these findings and obtain reliable results. PMID:24261659

  14. GABAA receptor complex function in frontal cortex membranes from control and neurological patients.

    PubMed

    Lloyd, G K; Lowenthal, A; Javoy-Agid, F; Constantidinis, J

    1991-05-01

    The functional integrity of the GABAA receptor-benzodiazepine (BZ) recognition site-Cl- ionophore complex was assessed by means of [35S]TBPS (t-butylbicyclophosphorothionate) binding to frontal cortex membranes prepared from frozen postmortem brain tissue taken from control (n = 4), Alzheimer (n = 7), Parkinson (n = 3) and Huntington's chorea (n = 2) patients. Specific [35S]TBPS binding was similar in control, Parkinson's disease and Huntington's chorea brains, but was significantly reduced (78% control, P less than 0.01) in frontal cortex membranes from Alzheimer's patients. The linkage between the BZ recognition sites and the GABAA receptor-linked Cl- ionophore was functionally intact in these membranes as BZ site agonists (zolpidem, alpidem, flunitrazepam and clonazepam) enhanced [35S]TBPS binding under the conditions used (well-washed membranes in the presence of 1.0 M NaCl). Zolpidem (BZ1 selective) exhibited a biphasic enhancement in control membranes whereas the other compounds induced a bell-shaped concentration-response curve. The enhancement of [35S]TBPS binding by alpidem, flunitrazepam and clonazepam was greater in frontal cortex membranes from Alzheimer's patients than in controls whereas it tended to be reduced in membranes from the brains of Huntington's chorea patients. These studies demonstrate the functional integrity of the GABAA receptor macromolecular complex and also the usefulness of [35S]TBPS binding in the study of human postmortem tissue. PMID:1654259

  15. Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians.

    PubMed

    Asnis, Gregory M; Thomas, Manju; Henderson, Margaret A

    2016-01-01

    Insomnia is a prevalent disorder with deleterious effects such as decreased quality of life, and a predisposition to a number of psychiatric disorders. Fortunately, numerous approved hypnotic treatments are available. This report reviews the state of the art of pharmacotherapy with a reference to cognitive behavioral therapy for insomnia (CBT-I) as well. It provides the clinician with a guide to all the Food and Drug Administration (FDA) approved hypnotics (benzodiazepines, nonbenzodiazepines, ramelteon, low dose sinequan, and suvorexant) including potential side effects. Frequently, chronic insomnia lasts longer than 2 years. Cognizant of this and as a result of longer-term studies, the FDA has approved all hypnotics since 2005 without restricting the duration of use. Our manuscript also reviews off-label hypnotics (sedating antidepressants, atypical antipsychotics, anticonvulsants and antihistamines) which in reality, are more often prescribed than approved hypnotics. The choice of which hypnotic to choose is discussed partially being based on which segment of sleep is disturbed and whether co-morbid illnesses exist. Lastly, we discuss recent label changes required by the FDA inserting a warning about "sleep-related complex behaviors", e.g., sleep-driving for all hypnotics. In addition, we discuss FDA mandated dose reductions for most zolpidem preparations in women due to high zolpidem levels in the morning hours potentially causing daytime carry-over effects. PMID:26729104

  16. Altered pharmacology and GABA-A receptor subunit expression in dorsal midline thalamic neurons in limbic epilepsy.

    PubMed

    Rajasekaran, Karthik; Sun, Chengsan; Bertram, Edward H

    2009-01-01

    The mediodorsal (MD) and paraventricular (PV) thalamic nuclei play a significant role in limbic epilepsy, and previous reports have shown changes in GABA-A receptor (GABAAR) mediated synaptic function. In this study, we examined changes in the pharmacology of GABAergic drugs and the expression of the GABAAR subunits in the MD and PV neurons in epilepsy. We observed nucleus specific changes in the sensitivity of sIPSCs to zolpidem and phenobarbital in MD and PV neurons from epileptic animals. In contrast, the magnitude of change in electrically evoked response (eIPSC) to zolpidem and phenobarbital were uniformly diminished in both MD and PV neurons in epilepsy. Immunohistochemical studies revealed that in epilepsy, there was a reduction in GAD65 expression and NeuN positive neurons in the MD neurons. Also, there was a decrease in immunoreactivity of the alpha1 and beta2/3 subunit of GABAARs, but not the gamma2 of the GABAAR in both MD and PV in epilepsy. These findings demonstrate significant alterations in the pharmacology of GABA and GABAARs in a key region for seizure generation, which may have implications for the physiology and pharmacology of limbic epilepsy. PMID:18992345

  17. [Research Progress on Forensic Toxicology of Z-drugs].

    PubMed

    Zhang, Yong-zhi; He, Hong-yuan; She, Cai-meng; Lian, Jie

    2015-08-01

    The Z-drugs (zolpidem, zopiclone, and zaleplon), as the innovative hypnotics, have an improvement over the traditional benzodiazepines in the management of insomnia. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. As benzodiazepines, Z-drugs exert their effects through increasing the transmission of γ-aminobutyric acid. Z-drugs overdose are less likely to be fatal, more likely would result in poisoning. Z-drugs can be detected in blood, urine, saliva, and other postmortem specimens through liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Z-drugs have improved pharmacokinetic profiles, but incidence of neuropsychiatric sequelae, poisoning, and death may prove to be similar to the other hypnotics. This review focuses on the pharmacology and toxicology of Z-drugs with respect to their adverse effect profile and toxicity and toxicology data in the field of forensic medicine. PMID:26665884

  18. Reactivation of chronic hepatitis B during treatment with tenofovir disoproxil fumarate: drug interactions or low adherence?

    PubMed

    Caroleo, Benedetto; Staltari, Orietta; Gallelli, Luca; Perticone, Francesco

    2015-01-01

    We describe a case of a 61-year-old man with chronic hepatitis B, hepatitis B e antibody (HBeAb) positive, treated with tenofovir disoproxil fumarate (TDF), who developed virological and biochemical viremic reactivation with an increase in transaminase plasma levels. The patient's history revealed that he had discontinued TDF about 5 days before admission and, from December 2013, had been taking venlafaxine, paroxetine and zolpidem for some episodes of depression. Clinical evaluation and laboratory findings excluded the presence of systemic diseases that might have been able to explain the drug inefficacy, while pharmacological evaluation suggested a possible drug-drug interaction. In order to assess the possible occurrence of resistance, mutational analysis of hepatitis B virus (HBV) was performed and excluded the presence of resistance for TDF. TDF was prescribed, and venlafaxine, paroxetine and zolpidem were discontinued. The follow-up at 3, 6 and 12 months documented a good response to TDF with a time-related decrease of HBV-DNA and alanine aminotransferase. PMID:26123461

  19. GABAA Receptor-Mediated Bidirectional Control of Synaptic Activity, Intracellular Ca2+, Cerebral Blood Flow, and Oxygen Consumption in Mouse Somatosensory Cortex In Vivo.

    PubMed

    Jessen, Sanne Barsballe; Brazhe, Alexey; Lind, Barbara Lykke; Mathiesen, Claus; Thomsen, Kirsten; Jensen, Kimmo; Lauritzen, Martin

    2015-09-01

    Neural activity regulates local increases in cerebral blood flow (ΔCBF) and the cortical metabolic rate of oxygen (ΔCMRO2) that constitutes the basis of BOLD functional neuroimaging signals. Glutamate signaling plays a key role in brain vascular and metabolic control; however, the modulatory effect of GABA is incompletely understood. Here we performed in vivo studies in mice to investigate how THIP (which tonically activates extrasynaptic GABAARs) and Zolpidem (a positive allosteric modulator of synaptic GABAARs) impact stimulation-induced ΔCBF, ΔCMRO2, local field potentials (LFPs), and fluorescent cytosolic Ca(2+) transients in neurons and astrocytes. Low concentrations of THIP increased ΔCBF and ΔCMRO2 at low stimulation frequencies. These responses were coupled to increased synaptic activity as indicated by LFP responses, and to Ca(2+) activities in neurons and astrocytes. Intermediate and high concentrations of THIP suppressed ΔCBF and ΔCMRO2 at high stimulation frequencies. Zolpidem had similar but less-pronounced effects, with similar dependence on drug concentration and stimulation frequency. Our present findings suggest that slight increases in both synaptic and extrasynaptic GABAAR activity might selectively gate and amplify transient low-frequency somatosensory inputs, filter out high-frequency inputs, and enhance vascular and metabolic responses that are likely to be reflected in BOLD functional neuroimaging signals. PMID:24692513

  20. Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians

    PubMed Central

    Asnis, Gregory M.; Thomas, Manju; Henderson, Margaret A.

    2015-01-01

    Insomnia is a prevalent disorder with deleterious effects such as decreased quality of life, and a predisposition to a number of psychiatric disorders. Fortunately, numerous approved hypnotic treatments are available. This report reviews the state of the art of pharmacotherapy with a reference to cognitive behavioral therapy for insomnia (CBT-I) as well. It provides the clinician with a guide to all the Food and Drug Administration (FDA) approved hypnotics (benzodiazepines, nonbenzodiazepines, ramelteon, low dose sinequan, and suvorexant) including potential side effects. Frequently, chronic insomnia lasts longer than 2 years. Cognizant of this and as a result of longer-term studies, the FDA has approved all hypnotics since 2005 without restricting the duration of use. Our manuscript also reviews off-label hypnotics (sedating antidepressants, atypical antipsychotics, anticonvulsants and antihistamines) which in reality, are more often prescribed than approved hypnotics. The choice of which hypnotic to choose is discussed partially being based on which segment of sleep is disturbed and whether co-morbid illnesses exist. Lastly, we discuss recent label changes required by the FDA inserting a warning about “sleep-related complex behaviors”, e.g., sleep-driving for all hypnotics. In addition, we discuss FDA mandated dose reductions for most zolpidem preparations in women due to high zolpidem levels in the morning hours potentially causing daytime carry-over effects. PMID:26729104

  1. Hormonal responses to exercise after partial sleep deprivation and after a hypnotic drug-induced sleep.

    PubMed

    Mougin, F; Bourdin, H; Simon-Rigaud, M L; Nguyen, N U; Kantelip, J P; Davenne, D

    2001-02-01

    The aim of this study was to determine the hormonal responses, which are dependent on the sleep wake cycle, to strenuous physical exercise. Exercise was performed after different nocturnal regimens: (i) a baseline night preceded by a habituation night; (ii) two nights of partial sleep deprivation caused by a delayed bedtime or by an early awakening; and (iii) two nights of sleep after administration of either a hypnotic compound (10 mg zolpidem) or a placebo. Eight well-trained male endurance athletes with a maximal oxygen uptake of 63.5 +/- 3.8 ml x kg(-1) x min(-1) (mean value +/- s(x)) were selected on the basis of their sleeping habits and their physical training. Polygraphic recordings of EEG showed that both nights with partial sleep loss led to a decrease (P< 0.01) in stage 2 and rapid eye movement sleep. A delayed bedtime also led to a decrease (P < 0.05) in stage 1 sleep. Zolpidem had no effect on the different stages of sleep. During the afternoon after an experimental night, exercise was performed on a cycle ergometer. After a 10-min warm-up, the participants performed 30 min steady-state cycling at 75% VO(2-max) followed by a progressively increased workload until exhaustion. The recovery period lasted 30 min. Plasma growth hormone, prolactin, cortisol, catecholamine and lactate concentrations were measured at rest, during exercise and after recovery. The concentration of plasma growth hormone and catecholamine were not affected by partial sleep deprivation, whereas that of plasma prolactin was higher (P < 0.05) during the trial after an early awakening. Plasma cortisol was lower (P < 0.05) during recovery after both sleep deprivation conditions. Blood lactate was higher (P < 0.05) during submaximal exercise performed after both a delayed bedtime and an early awakening. Zolpidem-induced sleep did not affect the hormonal and metabolic responses to subsequent exercise. Our results demonstrate only minor alterations in the hormonal responses to exercise

  2. An interesting case of barbiturate automatism and review of literature.

    PubMed

    Gokhale, Sankalp; Ramos-Estebanez, Ciro

    2013-01-01

    A 48 year old man with a diagnosis of HIV infection since 1993, on highly active anti-retro viral therapy (HAART) with stable CD4 count and undetectable viral load for years and seizure disorder presented with recurrent drowsiness. His seizures were well controlled on phenobarbitone for years. Repeated laboratory evaluation demonstrated toxic levels of phenobarbitone in his blood. A thorough clinical, psychiatric, laboratory and imaging evaluation did not reveal any obvious etiology for the recurrent barbiturate intoxication in this man. Our findings suggest the possible diagnosis of barbiturate drug automatism in this patient. Though drug automatism is a controversial entity, it merits continued attention. There are recent reports of similar phenomenon with newer sedative agents such as Zolpidem. It is important to be aware of this phenomenon as a possible explanation for recurrent intoxication with barbiturates without a clear etiology for drug overdose. PMID:24222872

  3. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-10-01

    [Methoxy-11c]PD-153035; Afamelanotide, Agalsidase beta, Alemtuzumab, Alkaline phosphatase, Amlodipine, Anecortave acetate, Apixaban, Aripiprazole, Atomoxetine hydrochloride; Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brimonidine tartrate/timolol maleate, Brivudine; Canakinumab, Cetuximab, Chlorotoxin, Cinaciguat; Dapagliflozin, Decitabine, Duloxetine hydrochloride; Elagolix sodium, Eplerenone, Eritoran tetrasodium, Escitalopram oxalate, Etoricoxib, Ezetimibe; Fospropofol disodium; G-207, Gabapentin enacarbil, Gefitinib, Golimumab; Human plasmin; Inotuzumab ozogamicin, Insulin glargine, Insulin glulisine, Istaroxime, Ixabepilone; KLH; Levodopa/carbidopa/entacapone; Miglustat, Mitumprotimut-T, MP-470; Oblimersen sodium, Olmesartan medoxomil; P53-SLP, PAN-811, Patupilone, Pazopanib hydrochloride, PC-515, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Pemetrexed disodium, Plitidepsin, Pregabalin; Rasagiline mesilate, Rotigotine; SCH-697243, Sirolimus-eluting stent, Sumatriptan succinate/naproxen sodium, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, TMC-207; V-211, Valganciclovir hydrochloride; Zolpidem tartrate. PMID:19967103

  4. Suvorexant: efficacy and safety profile of a dual orexin receptor antagonist in treating insomnia.

    PubMed

    Owen, R T

    2016-01-01

    Suvorexant is a hypnotic representing the first-in-class of a new group of agents known as dual orexin receptor antagonists. They target cerebral orexin receptors which, when activated, contribute to arousal and wakefulness. Suvorexant was shown to decrease sleep onset times and increase sleep duration, whether assessed objectively by polysomnography or subjectively by sleep diaries in primary insomnia patients. Overall tolerability was good, with somnolence being the commonest adverse event (≤ 7% in 3-month studies). No strong signals for rebound or withdrawal were seen after 1-12 months of treatment and few adverse events suggestive of residual psychomotor or cognitive events have been recorded. Further studies are required in patients with insomnia comorbid with depression and head-to-head studies with established hypnotics such as zolpidem and eszopiclone. Studies augmenting the small number of patients evaluating the initial recommended dose (10 mg) would also be prudent. PMID:26937493

  5. [Pharmacovigilance update].

    PubMed

    Diezi, Léonore; Renard, Delphine; Rothuizen, Laura E; Livio, Françoise

    2014-01-15

    The main pharmacovigilance updates in 2013 are reviewed. Nitrofurantoin: lower efficacy and an increased risk of adverse events when creatinine clearance is below 60 ml/min. Dabigatran: contraindicated in patients with mechanical heart valves. Azithromycin: QT prolongation and increased risk of death. Zolpidem: towards a lower dosage. Roflumilast: avoid in patients known or at risk for mood disorders. Retigabine: indication restricted to last-line use and new monitoring requirements after reports of pigment changes in retina and other tissues. Telaprevir and rituximab: severe mucocutaneous reactions. Fingolimod: rare cases of progressive multifocal leucoencephalopathy. Tolvaptan: potential for hepatotoxicity. Nicotinic acid/laropiprant: suspension of marketing authorization as benefits no longer outweigh risks. PMID:24558915

  6. Gender differences in sleep in older men and women.

    PubMed

    Guidozzi, F

    2015-10-01

    Sleep disturbances increase with increasing age in both males and females and become fairly common in the older community when compared to their younger counterparts. Even though these sleep disturbances increase with advancing age, there are nevertheless inherent differences in sleep disturbances between males and females. When compared to older men, older women will have a longer sleep latency (number of minutes it takes to fall asleep), more daytime sleepiness, will sleep about 20 min less per day, have less NREM stages 1 and 2 sleep, have more slow-wave sleep, and are more predisposed to REM sleep. Women have at least a 40% increased risk for developing insomnia, are at twice the risk for restless legs syndrome, will have different obstructive sleep apnea symptoms and more partial obstructions during sleep compared to men. They are also less likely to use antidepressants but will metabolize zolpidem 50% slower than men. PMID:26249643

  7. Identification and management of tardive dyskinesia: A case series and literature review.

    PubMed

    Khouzam, Hani Raoul

    2015-01-01

    Tardive dyskinesia (TD) is a serious, disabling and potentially permanent, neurological hyperkinetic movement disorder that occurs after months or years of taking dopamine receptor-blocking agents. The pathophysiology of TD is complex, multifactorial and still not fully understood. Although there is no identified effective and standard treatment for TD, several agents have been tried for the management of this motor disturbance. The aim of this case series is to review the literature in regard to the identification, diagnosis and the treatment of TD with anticholinergics, anticholinergic medication withdrawal, cholinergic agents, botulinum toxin intramuscular injections, tetrabenazine, levetiracetam, propranolol and zolpidem, and to describe one case of TD that responded favorably to clonazepam and two cases of TD that responded favorably to Ginkgo biloba. PMID:26216578

  8. Insomnia and sleep disruption: relevance for athletic performance.

    PubMed

    Leger, Damien; Metlaine, Arnaud; Choudat, Dominique

    2005-04-01

    Insomnia is a common sleep complaint even in young adults and has important daytime consequences. Several subjective and objective tools are recommended to assess the magnitude of the problem and to try to find a cause. Chronic insomnia is often caused by precipitating factors, such as acute stress, work conditions, illness, and travel, and perpetuating factors, such as poor sleep hygiene, anxiety, and medications. Insomnia may have implications in athletic performance resulting from physical and cognitive effects. Several pharmacologic and nonpharmacologic approaches are employed in the management of insomnia that have proven effective for short-term treatment. The pharmacologic approaches include the use of zolpidem and specific GABA agonists, benzodiazepines for specific indications, antidepressants, and melatonin. The nonpharmacologic approaches include stimulus control, sleep restriction, relaxation strategies, and cognitive behavioral therapy. PMID:15892923

  9. Nontarget analysis of polar contaminants in freshwater sediments influenced by pharmaceutical industry using ultra-high-pressure liquid chromatography-quadrupole time-of-flight mass spectrometry.

    PubMed

    Terzic, Senka; Ahel, Marijan

    2011-02-01

    A comprehensive analytical procedure for a reliable identification of nontarget polar contaminants in aquatic sediments was developed, based on the application of ultra-high-pressure liquid chromatography (UHPLC) coupled to hybrid quadrupole time-of-flight mass spectrometry (QTOFMS). The procedure was applied for the analysis of freshwater sediment that was highly impacted by wastewater discharges from the pharmaceutical industry. A number of different contaminants were successfully identified owing to the high mass accuracy of the QTOFMS system, used in combination with high chromatographic resolution of UHPLC. The major compounds, identified in investigated sediment, included a series of polypropylene glycols (n=3-16), alkylbenzene sulfonate and benzalkonium surfactants as well as a number of various pharmaceuticals (chlorthalidone, warfarin, terbinafine, torsemide, zolpidem and macrolide antibiotics). The particular advantage of the applied technique is its capability to detect less known pharmaceutical intermediates and/or transformation products, which have not been previously reported in freshwater sediments. PMID:21056522

  10. Management of benzodiazepine misuse and dependence

    PubMed Central

    Brett, Jonathan; Murnion, Bridin

    2015-01-01

    Summary There are well-recognised harms from long-term use of benzodiazepines. These include dependency, cognitive decline and falls. It is important to prevent and recognise benzodiazepine dependence. A thorough risk assessment guides optimal management and the necessity for referral. The management of dependence involves either gradual benzodiazepine withdrawal or maintenance treatment. Prescribing interventions, substitution, psychotherapies and pharmacotherapies can all contribute. Unless the patient is elderly, it is helpful to switch to a long-acting benzodiazepine in both withdrawal and maintenance therapy. The dose should be gradually reduced over weeks to lower the risk of seizures. Harms from drugs such as zopiclone and zolpidem are less well characterised. Dependence is managed in the same manner as benzodiazepine dependence. PMID:26648651

  11. Mechanically strong geopolymers offer new possibilities in treatment of chronic pain.

    PubMed

    Jämstorp, Erik; Forsgren, Johan; Bredenberg, Susanne; Engqvist, Håkan; Strømme, Maria

    2010-09-15

    We propose that a clay derived class of materials, known as geopolymers, may solve the problem of finding materials for controlled release with the right combination of properties necessary for a safe and sustained oral delivery of highly potent opioids. We show that the opioid Fentanyl, and its structurally similar sedative Zolpidem, can be embedded into metakaolin based geopolymer pellets to provide prolonged release dosage forms with mechanical strengths of the same order of magnitude as that of human teeth. The results presented in the current work may open up new opportunities for future development of drug delivery for high potency drugs employing high-strength and variable-pore-structure geopolymers and materials alike. PMID:20685295

  12. The sleep-wake cycle and sleeping pills.

    PubMed

    Lemmer, Björn

    2007-02-28

    Sleeping pills are drugs which are used world-wide to combat sleep disturbances, and to prevent symptoms due to maladjustment to shiftwork or jet-lag. Today, benzodiazepines and the so-called "non-benzodiazepines", such as zolpidem, which both act on benzodiazepine receptors, are drugs of first choice and they are substitutes for barbiturates. Their use as sleeping pills in insomniacs is established after appropriate medical diagnosis. Symptoms from shiftwork or jet-lag are due to an internal desynchronisation of biological rhythms, and there is ample evidence that benzodiazepines are not effective in preventing these symptoms. Cabin crews in particular should never take sleeping pills, in order not to impair cognitive functions or to reduce the reactivity needed to fly an aircraft safely. The biological clock(s) cannot be reset instantaneously by any drug. PMID:17049955

  13. Coupling of Thalamocortical Sleep Oscillations Are Important for Memory Consolidation in Humans

    PubMed Central

    Niknazar, Mohammad; Krishnan, Giri P.; Bazhenov, Maxim; Mednick, Sara C.

    2015-01-01

    Sleep, specifically non-rapid eye movement (NREM) sleep, is thought to play a critical role in the consolidation of recent memories. Two main oscillatory activities observed during NREM, cortical slow oscillations (SO, 0.5–1.0Hz) and thalamic spindles (12–15Hz), have been shown to independently correlate with memory improvement. Yet, it is not known how these thalamocortical events interact, or the significance of this interaction, during the consolidation process. Here, we found that systemic administration of the GABAergic drug (zolpidem) increased both the phase-amplitude coupling between SO and spindles, and verbal memory improvement in humans. These results suggest that thalamic spindles that occur during transitions to the cortical SO Up state are optimal for memory consolidation. Our study predicts that the timely interactions between cortical and thalamic events during consolidation, contribute to memory improvement and is mediated by the level of inhibitory neurotransmission. PMID:26671283

  14. Management of benzodiazepine misuse and dependence.

    PubMed

    Brett, Jonathan; Murnion, Bridin

    2015-10-01

    There are well-recognised harms from long-term use of benzodiazepines. These include dependency, cognitive decline and falls. It is important to prevent and recognise benzodiazepine dependence. A thorough risk assessment guides optimal management and the necessity for referral. The management of dependence involves either gradual benzodiazepine withdrawal or maintenance treatment. Prescribing interventions, substitution, psychotherapies and pharmacotherapies can all contribute. Unless the patient is elderly, it is helpful to switch to a long-acting benzodiazepine in both withdrawal and maintenance therapy. The dose should be gradually reduced over weeks to lower the risk of seizures. Harms from drugs such as zopiclone and zolpidem are less well characterised. Dependence is managed in the same manner as benzodiazepine dependence. PMID:26648651

  15. Coupling of Thalamocortical Sleep Oscillations Are Important for Memory Consolidation in Humans.

    PubMed

    Niknazar, Mohammad; Krishnan, Giri P; Bazhenov, Maxim; Mednick, Sara C

    2015-01-01

    Sleep, specifically non-rapid eye movement (NREM) sleep, is thought to play a critical role in the consolidation of recent memories. Two main oscillatory activities observed during NREM, cortical slow oscillations (SO, 0.5-1.0 Hz) and thalamic spindles (12-15 Hz), have been shown to independently correlate with memory improvement. Yet, it is not known how these thalamocortical events interact, or the significance of this interaction, during the consolidation process. Here, we found that systemic administration of the GABAergic drug (zolpidem) increased both the phase-amplitude coupling between SO and spindles, and verbal memory improvement in humans. These results suggest that thalamic spindles that occur during transitions to the cortical SO Up state are optimal for memory consolidation. Our study predicts that the timely interactions between cortical and thalamic events during consolidation, contribute to memory improvement and is mediated by the level of inhibitory neurotransmission. PMID:26671283

  16. Differential Roles of GABAA Receptor Subtypes in Benzodiazepine-Induced Enhancement of Brain-Stimulation Reward

    PubMed Central

    Reynolds, Lauren M; Engin, Elif; Tantillo, Gabriella; Lau, Hew Mun; Muschamp, John W; Carlezon, William A; Rudolph, Uwe

    2012-01-01

    Benzodiazepines such as diazepam are widely prescribed as anxiolytics and sleep aids. Continued use of benzodiazepines, however, can lead to addiction in vulnerable individuals. Here, we investigate the neural mechanisms of the behavioral effects of benzodiazepines using the intracranial self-stimulation (ICSS) test, a procedure with which the reward-enhancing effects of these drugs can be measured. Benzodiazepines bind nonselectively to several different GABAA receptor subtypes. To elucidate the α subunit(s) responsible for the reward-enhancing effects of benzodiazepines, we examined mice carrying a histidine-to-arginine point mutation in the α1, α2, or α3 subunit, which renders the targeted subunit nonresponsive to diazepam, other benzodiazepines and zolpidem. In wild-type and α1-point-mutated mice, diazepam caused a dose-dependent reduction in ICSS thresholds (reflecting a reward-enhancing effect) that is comparable to the reduction observed following cocaine administration. This effect was abolished in α2- and α3-point-mutant mice, suggesting that these subunits are necessary for the reward-enhancing action of diazepam. α2 Subunits appear to be particularly important, since diazepam increased ICSS thresholds (reflecting an aversive-like effect) in α2-point-mutant animals. Zolpidem, an α1-preferring benzodiazepine-site agonist, had no reward-enhancing effects in any genotype. Our findings implicate α2 and α3 subunit containing GABAA receptors as key mediators of the reward-related effects of benzodiazepines. This finding has important implications for the development of new medications that retain the therapeutic effects of benzodiazepines but lack abuse liability. PMID:22763624

  17. Long-lasting distortion of GABA signaling in MS/DB neurons after binge-like ethanol exposure during initial synaptogenesis.

    PubMed

    Wang, Haiying; DuBois, Dustin W; Tobery, Angelika N; Griffith, William H; Brandt, Paul; Frye, Gerald D

    2013-07-01

    Using a well-established model of binge-like ethanol treatment of rat pups on postnatal days (PD) 4-9, we found that maturation of GABAA receptor (GABAAR) miniature postsynaptic currents (mPSCs) was substantially blunted for medial septum/diagonal band (MS/DB) neurons in brain slices on PD 11-16. Ethanol reduced mPSC amplitude, frequency, and decay kinetics, while attenuating or exaggerating allosteric actions of zolpidem and allopregnanolone, respectively. The impact of ethanol in vivo was long lasting as most changes in MS/DB GABAAR mPSCs were still observed as late as PD 60-85. Maturing MS/DB neurons in naïve brain slices PD 4-16 showed increasing mPSC frequency, decay kinetics, and zolpidem sensitivity that were nearly identical to our earlier findings in cultured septal neurons (DuBois et al., 2004, 2006). These rapidly developing mPSC parameters continued to mature through the first month of life then stabilized throughout the remainder of the lifespan. Finally, equivalent ethanol-induced alterations in GABAAR mPSC signaling were present in MS/DB neurons from both male and female animals. Previously, we showed ethanol treatment of cultured embryonic day 20 septal neurons distorts the maturation of GABAAR mPSCs predicting that early stages of GABAergic transmission in MS/DB neurons are vulnerable to intoxication injury (DuBois et al., 2004, 2006). Since the overall character, timing, and magnitude of GABAergic mPSC developmental- and ethanol-induced changes in the in vivo model so closely mirror chronologically equivalent adaptations in cultured septal neurons, this suggests that such parallel models of ethanol impairment of GABAergic synaptic development in vivo and in vitro should be useful for translational studies exploring the efficacy and mechanism of action of potential therapeutic interventions from the cellular to whole animal level. PMID:23685190

  18. TMS-EEG signatures of GABAergic neurotransmission in the human cortex.

    PubMed

    Premoli, Isabella; Castellanos, Nazareth; Rivolta, Davide; Belardinelli, Paolo; Bajo, Ricardo; Zipser, Carl; Espenhahn, Svenja; Heidegger, Tonio; Müller-Dahlhaus, Florian; Ziemann, Ulf

    2014-04-16

    Combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) constitutes a powerful tool to directly assess human cortical excitability and connectivity. TMS of the primary motor cortex elicits a sequence of TMS-evoked EEG potentials (TEPs). It is thought that inhibitory neurotransmission through GABA-A receptors (GABAAR) modulates early TEPs (<50 ms after TMS), whereas GABA-B receptors (GABABR) play a role for later TEPs (at ∼100 ms after TMS). However, the physiological underpinnings of TEPs have not been clearly elucidated yet. Here, we studied the role of GABAA/B-ergic neurotransmission for TEPs in healthy subjects using a pharmaco-TMS-EEG approach. In Experiment 1, we tested the effects of a single oral dose of alprazolam (a classical benzodiazepine acting as allosteric-positive modulator at α1, α2, α3, and α5 subunit-containing GABAARs) and zolpidem (a positive modulator mainly at the α1 GABAAR) in a double-blind, placebo-controlled, crossover study. In Experiment 2, we tested the influence of baclofen (a GABABR agonist) and diazepam (a classical benzodiazepine) versus placebo on TEPs. Alprazolam and diazepam increased the amplitude of the negative potential at 45 ms after stimulation (N45) and decreased the negative component at 100 ms (N100), whereas zolpidem increased the N45 only. In contrast, baclofen specifically increased the N100 amplitude. These results provide strong evidence that the N45 represents activity of α1-subunit-containing GABAARs, whereas the N100 represents activity of GABABRs. Findings open a novel window of opportunity to study alteration of GABAA-/GABAB-related inhibition in disorders, such as epilepsy or schizophrenia. PMID:24741050

  19. Studying Cerebellar Circuits by Remote Control of Selected Neuronal Types with GABAA Receptors

    PubMed Central

    Wisden, William; Murray, Andrew J.; McClure, Christina; Wulff, Peer

    2009-01-01

    Although GABAA receptor-mediated inhibition of cerebellar Purkinje cells by molecular layer interneurons (MLIs) has been studied intensely at the cellular level, it has remained unclear how this inhibition regulates cerebellum-dependent behaviour. We have implemented two complementary approaches to investigate the function of the MLI-Purkinje cell synapse on the behavioural level. In the first approach we permanently disrupted inhibitory fast synaptic transmission at the synapse by genetically removing the postsynaptic GABAA receptors from Purkinje cells (PC-Δγ2 mice). We found that chronic disruption of the MLI-Purkinje cell synapse strongly impaired cerebellar learning of the vestibular occular reflex (VOR), presumably by disrupting the temporal patterns of Purkinje cell activity. However, in PC-Δγ2 mice the baseline VOR reflex was only mildly affected; indeed PC-Δγ2 mice show no ataxia or gait abnormalities, suggesting that MLI control of Purkinje cell activity is either not involved in ongoing motor tasks or that the system compensates for its loss. To investigate the latter possibility we developed an alternative genetic technique; we made the MLI-Purkinje cell synapse selectively sensitive to rapid manipulation with the GABAA receptor modulator zolpidem (PC-γ2-swap mice). Minutes after intraperitoneal zolpidem injection, these PC-γ2-swap mice developed severe motor abnormalities, revealing a substantial contribution of the MLI-Purkinje cell synapses to real time motor control. The cell-type selective permanent knockout of synaptic GABAergic input and the fast reversible modulation of GABAergic input at the same synapse illustrate how pursuing both strategies gives a fuller view. PMID:20076763

  20. Studies on drug metabolism by fungi colonizing decomposing human cadavers. Part II: biotransformation of five model drugs by fungi isolated from post-mortem material.

    PubMed

    Martínez-Ramírez, Jorge A; Walther, Grit; Peters, Frank T

    2015-04-01

    The present study investigated the in vitro metabolic capacity of 28 fungal strains isolated from post-mortem material towards five model drugs: amitriptyline, metoprolol, mirtazapine, promethazine, and zolpidem. Each fungal strain was incubated at 25 °C for up to 120 h with each of the five models drugs. Cunninghamella elegans was used as positive control. Aliquots of the incubation mixture were centrifuged and 50 μL of the supernatants were diluted and directly analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with product ion scanning. The remaining mixture was analyzed by full scan gas chromatography-mass spectrometry (GC-MS) after liquid-liquid extraction and acetylation. The metabolic activity was evaluated through the total number of detected metabolites (NDM) produced in each model and fungal strains and the percentage of parent drug remaining (%RPD) after up to five days of incubation. All the tested fungal strains were capable of forming mammalian phase I metabolites. Fungi from the normal fungal flora of the human body such as Candida sp., Geotrichum candidum, and Trichosporon asahii) formed up to seven metabolites at %RPD values greater than 52% but no new fungal metabolites (NFM). In contrast, some airborne fungal strains like Bjerkandera adusta, Chaetomium sp, Coriolopsis sp., Fusarium solani and Mucor plumbeus showed NDM values exceeding those of the positive control, complete metabolism of the parent drug in some models and formation of NFM. NFM (numbers in brackets) were detected in four of the five model drugs: amitriptyline (18), metoprolol (4), mirtazapine (8), and zolpidem (2). The latter NFM are potential candidates for marker substances indicating post-mortem fungal metabolism. PMID:24898183

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

    PubMed

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

    2015-10-01

    Dried Blood Spot (DBS) has been used a blood extraction method for inherited metabolic disorder screening since 1960s. With introduction of LC-MS/MS, not only DBS could be used to analysis drugs in small blood volume, but in various fields, such as toxicology, drug therapeutic monitoring, drug diagnostic screening, and illicit drugs. In toxicology field, many drugs (e.g. benzodiazepines, acetaminophen, small molecule drugs) have been tested with DBS. Compared with earlier blood extraction methods (SPE and LLE), DBS has lots of advantages; lower blood volume (less than 50μL), shorter analysis time caused by a more concise analysis procedure and lower cost. We optimized the DBS procedure and LC-MS/MS conditions for 18 benzodiazepines, seven benzodiazepine metabolites, and one z-drug (zolpidem) analysis in blood. 30μL of whole blood was spotted on FTA DMPK card C and dried for 2h in a desiccator. A 6-mm disk was punched and vortexed for 1min in a centrifuge tube with 300μL methanol/acetonitrile mixture (1:1, v/v). After evaporation, redissolved in 100μL mobile phase of LC-MS/MS and 5μL was injected. In the analysis for 26 target compounds in blood, all of the method validation parameters - LLOD, LLOQ, accuracy (intra- and inter-assay), and precision (intra- and inter-assay) - were satisfied with method validation criteria, within 15%. The results of matrix effect, recovery, and process efficiency were good. We developed a fast and reliable sample preparation method using DBS for 26 benzodiazepines, benzodiazepine metabolites, and z-drug (zolpidem). PMID:26255955

  2. Self-administration of bretazenil under progressive-ratio schedules: Behavioral economic analysis of the role intrinsic efficacy plays in the reinforcing effects of benzodiazepines

    PubMed Central

    Licata, Stephanie C.; Rowlett, James K.

    2010-01-01

    Previous research suggests that intrinsic efficacy of benzodiazepines is an important determinant of their behavioral effects. We evaluated the reinforcing effects of the benzodiazepine partial agonist bretazenil using behavioral economic models referred to as “consumer demand” and “labor supply”. Four rhesus monkeys were trained under a progressive ratio (PR) schedule of i.v. midazolam injection. A range of doses of bretazenil (0.001–0.03 mg/kg/injection and vehicle) was evaluated for self-administration with an initial response requirement of 40 that doubled to 640; significant self-administration was maintained at doses of 0.003 to 0.03 mg/kg/injection. Next, a dose of bretazenil that maintained peak injections/session was made available with initial response requirements doubling from 10 to 320 (maximum possible response requirements of 160 and 5120, respectively), and increasing response requirements decreased self-administration (mean number of injections/session) of a peak dose (0.01 mg/kg/injection). Analyses based on consumer demand revealed that a measure of reinforcing strength termed “essential value”, for bretazenil was similar to that previously obtained with midazolam (non-selective full agonist), but less than that observed for zolpidem (full agonist, selective for α1 subunit-containing GABAA receptors). According to labor supply analysis, the reinforcing effects of bretazenil were influenced by the economic concept referred to as a “price effect”, similar to our previous findings with midazolam but not zolpidem. In general, behavioral economic indicators of reinforcing effectiveness did not differentiate bretazenil from a non-selective full agonist. These findings raise the possibility that degree of intrinsic efficacy of a benzodiazepine agonist may not be predictive of relative reinforcing effectiveness. PMID:20800977

  3. Functional expression of the GABAA receptor α2 and α3 subunits at synapses between intercalated medial paracapsular neurons of mouse amygdala

    PubMed Central

    Geracitano, Raffaella; Fischer, David; Kasugai, Yu; Ferraguti, Francesco; Capogna, Marco

    2012-01-01

    In the amygdala, GABAergic neurons in the intercalated medial paracapsular cluster (Imp) have been suggested to play a key role in fear learning and extinction. These neurons project to the central (CE) amygdaloid nucleus and to other areas within and outside the amygdala. In addition, they give rise to local collaterals that innervate other neurons in the Imp. Several drugs, including benzodiazepines (BZ), are allosteric modulators of GABAA receptors. BZ has both anxiolytic and sedative actions, which are mediated through GABAA receptors containing α2/α3 and α1 subunits, respectively. To establish whether α1 or α2/α3 subunits are expressed at Imp cell synapses, we used paired recordings of anatomically identified Imp neurons and high resolution immunocytochemistry in the mouse. We observed that a selective α3 subunit agonist, TP003 (100 nM), significantly increased the decay time constant of the unitary IPSCs. A similar effect was also induced by zolpidem (10 μM) or by diazepam (1 μM). In contrast, lower doses of zolpidem (0.1–1 μM) did not significantly alter the kinetics of the unitary IPSCs. Accordingly, immunocytochemical experiments established that the α2 and α3, but not the α1 subunits of the GABAA receptors, were present at Imp cell synapses of the mouse amygdala. These results define, for the first time, some of the functional GABAA receptor subunits expressed at synapses of Imp cells. The data also provide an additional rationale to prompt the search of GABAA receptor α3 selective ligands as improved anxiolytic drugs. PMID:22666188

  4. Differentiation of activities within the GABAA-chloride ionophore complex by means of 35-S-TBPS binding.

    PubMed

    Lloyd, K G; Danielou, G; Thuret, F

    1988-01-01

    From the above results, it is evident that both alpidem and zolpidem modulate the GABAA receptor linked chloride ionophore in an allosteric manner via omega 1 anxiolytic/hypnotic recognition sites. As both are highly specific for the omega 1 site, with little affinity for the omega 2 site, it appears that omega 1 site activation is sufficient to fully engage the various linkages within the GABAA receptor supramolecular complex, resulting in modulation of the chloride ionophore. This action is related to an enhanced affinity of the recognition site for TBPS. Under the present conditions (high sodium chloride, frozen well-washed membranes), several (but not all, e.g. zolpidem) anxiolytics and hypnotics decreased TBPS binding at very high (100-500 microM) concentrations. This effect is unlikely related to the pharmacological activity of these compounds, as it is insensitive to flumazenil and occurs only at concentrations which would be supra-toxic. In contrast, the enhancement of TBPS binding by these anxiolytics and hypnotics occurs within the range of, and correlates with, their therapeutic plasma levels and their affinity for omega 1/omega 2 receptors. The present findings suggest that a different degree of linkage for different compounds occurs between the GABAA receptor and the omega 1/omega 2 receptor mediated enhancement of TBPS binding, as the action of alpidem is completely reversed by bicuculline, whereas for zopidem and flunitrazepam a component of the TBPS enhancement is bicuculline insensitive. A Ro 5-4864 sensitive site (probably not the omega 3 site) occurs with the GABAA receptor supramolecular complex, which apparently participates in the enhancement of TBPS binding.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2459920

  5. Testing for the undetectable in drug-facilitated sexual assault using hair analyzed by tandem mass spectrometry as evidence.

    PubMed

    Kintz, Pascal; Villain, Marion; Ludes, Bertrand

    2004-04-01

    The use of a drug to modify a person's behavior for criminal gain is not a recent phenomenon. However, the recent increase in reports of drug-facilitated crimes (sexual assault, robbery) has caused alarm in the general public. Drugs involved can be pharmaceuticals such as benzodiazepines (flunitrazepam, lorazepam, etc), hypnotics (zopiclone, zolpidem), sedatives (neuroleptics, some histamine H, antagonists), or anesthetics (gamma-hydroxybutyrate, ketamine), drugs of abuse such as cannabis, ecstasy, or lysergide, or more often ethanol. Drugs used to facilitate sexual assaults can be difficult to detect (active products at low dosages, chemical instability), possess amnesic properties, and can be rapidly cleared from the body (short half-life). In these situations, blood or even urine can be of little interest. This is the reason why this laboratory developed an original approach based on hair testing. Hair was suggested as a valuable specimen in situations where, as a result of a delay in reporting the crime, natural processes have eliminated the drug from typical biologic specimens. Although there are many papers focused on the identification of drugs in hair following chronic drug use, those dealing with a single dose are very scarce. The experience of the authors is documented in cases involving zolpidem, GHB, lorazepam, methylenedioxymethamphetamine, and flunitrazepam. The expected concentrations in hair are in the low picogram per milligram range for the hypnotics. Drug exposure is demonstrated by hair segmentation. Hair analysis may be a useful adjunct to conventional drug testing in sexual assault. It should not be considered as an alternative to blood and urine analyses but as a complement. MS/MS technologies appear to be a prerequisite. PMID:15228167

  6. Ethanol reduces GABAA alpha1 subunit receptor surface expression by a protein kinase Cgamma-dependent mechanism in cultured cerebral cortical neurons.

    PubMed

    Kumar, Sandeep; Suryanarayanan, Asha; Boyd, Kevin N; Comerford, Chris E; Lai, Marvin A; Ren, Qinglu; Morrow, A Leslie

    2010-05-01

    Prolonged ethanol exposure causes central nervous system hyperexcitability that involves a loss of GABAergic inhibition. We previously demonstrated that long-term ethanol exposure enhances the internalization of synaptic GABA(A) receptors composed of alpha1beta2/3gamma2 subunits. However, the mechanisms of ethanol-mediated internalization are unknown. This study explored the effect of ethanol on surface expression of GABA(A) alpha1 subunit-containing receptors in cultured cerebral cortical neurons and the role of protein kinase C (PKC) beta, gamma, and epsilon isoforms in their trafficking. Cultured neurons were prepared from rat pups on postnatal day 1 and maintained for 18 days. Cells were exposed to ethanol, and surface receptors were isolated by biotinylation and P2 fractionation, whereas functional analysis was conducted by whole-cell patch-clamp recording of GABA- and zolpidem-evoked responses. Ethanol exposure for 4 h decreased biotinylated surface expression of GABA(A) receptor alpha1 subunits and reduced zolpidem (100 nM) enhancement of GABA-evoked currents. The PKC activator phorbol-12,13-dibutyrate mimicked the effect of ethanol, and the selective PKC inhibitor calphostin C prevented ethanol-induced internalization of these receptors. Ethanol exposure for 4 h also increased the colocalization and coimmunoprecipitation of PKCgamma with alpha1 subunits, whereas PKCbeta/alpha1 association and PKCepsilon/alpha1 colocalization were not altered by ethanol exposure. Selective PKCgamma inhibition by transfection of selective PKCgamma small interfering RNAs blocked ethanol-induced internalization of GABA(A) receptor alpha1 subunits, whereas PKCbeta inhibition using pseudo-PKCbeta had no effect. These findings suggest that ethanol exposure selectively alters PKCgamma translocation to GABA(A) receptors and PKCgamma regulates GABA(A) alpha1 receptor trafficking after ethanol exposure. PMID:20159950

  7. Age- and gender-related differences in GABAA receptor-mediated postsynaptic currents in GABAergic neurons of the substantia nigra reticulata in the rat.

    PubMed

    Chudomel, O; Herman, H; Nair, K; Moshé, S L; Galanopoulou, A S

    2009-09-29

    The responsiveness of the rat anterior substantia nigra pars reticulata (SNR) GABAergic neurons to GABA(A)ergic drugs changes with age and gender, altering its role in seizure control. To determine whether maturational and gender-specific differences in the properties of spontaneous GABA(A)Rs-mediated inhibitory postsynaptic currents (sIPSCs) underlie these events, we studied sIPSCs at baseline and after application of the alpha1 GABA(A)Rs subunit selective agonist zolpidem, at postnatal days (PN) 5-9, PN12-15, and PN28-32. Results were correlated with the alpha1 and alpha 3 GABA(A)Rs subunit immunoreactivity (-ir) at PN5, PN15, and PN30, using immunochemistry. The mean frequency, amplitude and charge transfer increased whereas the 10-90% rise time and decay time accelerated with age in both genders. The faster sIPSC kinetics in older rats were paralleled by increased alpha1-ir and decreased alpha 3-ir. At PN5-9, males had more robust sIPSCs (frequency, amplitude, charge carried per event and charge transfer) than females. At PN28-32, males exhibited higher amplitudes and faster kinetics than females. The zolpidem-induced increase of decay times, amplitude and charge transfer and alpha1-ir expression were the lowest in PN5-9 males but increased with age, in both genders. Our findings demonstrate that alterations in GABA(A)Rs subunit expression partially underlie age- and gender-specific sIPSC changes in SNR neurons. However, the observation of gender differences in sIPSC kinetics that cannot be attributed to changes in perisomatic alpha1 expression suggests the existence of additional gender-specific factors that control the sIPSC kinetics in rat SNR. PMID:19531372

  8. Relationship of Prescribed Drugs with the Risk of Fall in Inpatients.

    PubMed

    Kozono, Aki; Isami, Keisuke; Shiota, Kimiko; Tsumagari, Kyouichi; Nagano, Masahisa; Inoue, Daisuke; Adachi, Rui; Hiraki, Yoichi; Nakagawa, Yoshihiro; Kamimura, Hidetoshi; Yamamichi, Ken

    2016-01-01

    Falls are common in elderly patients and are often serious. Several drugs have been associated with an increased risk of fall. Older adults often take multiple drugs for chronic diseases, and thus may be at increased risk from drugs associated with fall. We investigated the association between drug use and falling in hospitalized older people, with the goal of identifying medications that may increase the risk of a fall. A retrospective case control study was performed at the National Hospital Organization Kumamoto Saishunso Hospital in Japan. Medications taken by patients who fell (n=57) were compared with those taken by patients who did not fall (n=63). The median age (interquartile range; IQR) of the fall and non-fall groups were 75.0 (67.0-83.0) and 80.0 (70.3-84.5) years, respectively. The characteristics of the two groups were similar, with no significant differences in age, sex, or body weight. The probability of falling increased when the patients used zolpidem [odds ratio (OR)=2.47; 95%CI: 1.09-5.63; p<0.05] and calcium channel antagonists (OR=0.299; 95%CI: 0.13-0.68; p<0.01), and was also related to physical factors (OR=2.27; 95%CI: 1.01-5.09; p<0.05). Elderly patients taking zolpidem may fall due to sleepiness, and blood pressure control may be important to prevent orthostatic high blood pressure. In the treatment of elderly people, medical staff should try to choose drugs that prevent fall or are not associated with falling. PMID:27150933

  9. Search for fungi-specific metabolites of four model drugs in postmortem blood as potential indicators of postmortem fungal metabolism.

    PubMed

    Martínez-Ramírez, Jorge A; Strien, Juliane; Walther, Grit; Peters, Frank T

    2016-05-01

    Fungi colonizing cadavers are capable of drug metabolism and may thus change the metabolite pattern or concentration of drugs in forensic postmortem samples. The purpose of this study was to check for the presence of such changes by searching fungi-specific metabolites of four model drugs (amitriptyline, metoprolol, mirtazapine, and zolpidem) in decomposed postmortem blood samples from 33 cases involving these drugs. After isolation and identification of fungal strains present in the samples, each isolate was incubated in Sabouraud medium at 25°C for up to 120h with each model drug. One part of the supernatants was directly analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), another after liquid-liquid extraction with chlorobutane and concentration. From 21 out of 33 decomposed postmortem blood samples (64%) a total of 30 different strains could be isolated, one from the class of Ascomycete and the rest belonging to 15 species from 8 different genera (number of species): Aspergillus (2), Botrytis (1), Candida (8), Fusarium (1), Mucor (1), Penicillium (1), and Rodothorula (1). In the in vitro studies, these microorganisms were found capable of N-demethylation and N-oxidation of amitriptyline and mirtazapine, O-demethylation followed by side chain oxidation of metoprolol as well as hydroxylation of all four-model drugs. In two of the postmortem blood samples, from which the fungi Aspergillus jensenii, Candida parapsilosis. and Mucor circinelloides had been isolated, a fungi-specific hydroxy zolpidem metabolite was detected. The presence of this metabolite in postmortem samples likely indicates postmortem fungal biodegradation. PMID:27022860

  10. Benzodiazepine-site pharmacology on GABAA receptors in histaminergic neurons

    PubMed Central

    May, A C; Fleischer, W; Kletke, O; Haas, H L; Sergeeva, O A

    2013-01-01

    Background and Purpose The histaminergic tuberomamillary nucleus (TMN) of the posterior hypothalamus controls the cognitive aspects of vigilance which is reduced by common sedatives and anxiolytics. The receptors targeted by these drugs in histaminergic neurons are unknown. TMN neurons express nine different subunits of the GABAA receptor (GABAAR) with three α- (α1, α2 and α5) and two γ- (γ1, γ 2) subunits, which confer different pharmacologies of the benzodiazepine-binding site. Experimental Approach We investigated the actions of zolpidem, midazolam, diazepam, chlordiazepoxide, flumazenil (Ro15-1788) and methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) in TMN neurons using mouse genetics, electrophysiological and molecular biological methods. Key Results We find the sensitivity of GABAAR to zolpidem, midazolam and DMCM significantly reduced in TMN neurons from γ2F77I mice, but modulatory activities of diazepam, chlordiazepoxide and flumazenil not affected. Potencies and efficacies of these compounds are in line with the dominance of α2- and α1-subunit containing receptors associated with γ2- or γ1-subunits. Functional expression of the γ1-subunit is supported by siRNA-based knock-down experiments in γ2F77I mice. Conclusions and Implications GABAAR of TMN neurons respond to a variety of common sedatives with a high affinity binding site (γ2F77I) involved. The γ1-subunit likely contributes to the action of common sedatives in TMN neurons. This study is relevant for understanding the role of neuronal histamine and benzodiazepines in disorders of sleep and metabolism. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 PMID:23799902

  11. Neuroligin-2 accelerates GABAergic synapse maturation in cerebellar granule cells.

    PubMed

    Fu, Zhanyan; Vicini, Stefano

    2009-09-01

    Neuroligins (NLGs) are postsynaptic cell adhesion molecules that are thought to function in synaptogenesis. To investigate the role of NLGs on synaptic transmission once the synapse is formed, we transfected neuroligin-2 (NLG-2) in cultured mouse cerebellar granule cells (CGCs), and recorded GABA(A) (gamma-aminobutyric acid) receptor mediated miniature postsynaptic currents (mIPSCs). NLG-2 transfected cells had mIPSCs with faster decay than matching GFP expressing controls at young culture ages (days in vitro, DIV7-8). Down-regulation of NLG-2 by the isoform specific shRNA-NLG-2 resulted in an opposite effect. We and others have shown that the switch of alpha subunits of GABA(A)Rs from alpha2/3 to alpha1 underlies developmental speeding of the IPSC decay in various CNS regions, including the cerebellum. To assess whether the reduced decay time of mIPSCs by NLG-2 is due to the recruitment of more alpha1 containing GABA(A)Rs at the synapses, we examined the prolongation of current decay by the Zolpidem, which has been shown to preferentially enhance the activity of alpha1 subunit-containing GABA channel. The application of Zolpidem resulted in a significantly greater prolongation kinetics of synaptic currents in NLG-2 over-expressing cells than control cells, suggesting that NLG-2 over-expression accelerates synapse maturation by promoting incorporation of the alpha1 subunit-containing GABA(A)Rs at postsynaptic sites in immature cells. In addition, the effect of NLG-2 on the speeding of decay time course of synaptic currents was abolished when we used CGC cultures from alpha1-/- mice. Lastly, to exclude the possibility that the fast decay of mIPSCs induced by NLG-2 could be also due to the impacts of NLG-2 on the GABA transient in synaptic cleft, we measured the sensitivity of mIPSCs to the fast-off competitive antagonists TPMPA. We found that TPMPA similarly inhibits mIPSCs in control and NLG-2 over-expressing CGCs both at young age (DIV8) and old age (DIV14) of

  12. National Use of Prescription Medications for Insomnia: NHANES 1999-2010

    PubMed Central

    Bertisch, Suzanne M.; Herzig, Shoshana J.; Winkelman, John W.; Buettner, Catherine

    2014-01-01

    Study Objectives: To determine current patterns and predictors of use of prescription medications commonly used for insomnia (MCUFI) in the U.S. Design: Cross-sectional study. Setting: National Health and Nutrition Examination Survey, 1999-2010. Participants: 32,328 noninstitutionalized community-dwelling U.S. adults. Interventions: N/A. Measurements and Results: We defined MCUFI use as use of any of the following medications in the preceding month: benzodiazepine receptor agonists (eszopiclone, zaleplon, zolpidem, estazolam, flurazepam, quazepam, temazepam, triazolam), barbiturates (amobarbital, amobarbitalsecobarbital, chloral hydrate), doxepin, quetiapine, ramelteon, and trazodone. We estimated prevalence of MCUFI use and concurrent use of another sedating medication. We determined predictors of MCUFI use using multivariate logistic regression. Overall, 3% percent of adults used a MCUFI within the preceding month. Zolpidem and trazodone were used most commonly. Overall MCUFI use increased between 1999-2000 and 2009-2010 (P value for trend < 0.001). Concurrent use of other sedating medications was high, with 55% of MCUFI users taking at least one other sedating medication and 10% taking ≥ 3 other sedating medications. Concurrent use of MCUFIs with opioids (24.6%) and non-MCUFI benzodiazepines (19.5%) were most common. After adjustment, adults seeing a mental health provider (aOR 4.68, 95% C.I. 3.79, 5.77), using other sedating medications (aOR 4.18, 95% C.I. 3.36, 5.19), and age ≥ 80 years (aOR 2.55, 95% C.I. 1.63, 4.01) had highest likelihood of MCUFI use. Conclusion: In this nationally representative sample, reported use of prescription medications commonly used for insomnia (MCUFIs) within the preceding month was common, particularly among older adults and those seeing a mental health provider, with high use of sedative polypharmacy among MCUFI users. Citation: Bertisch SM; Herzig SJ; Winkelman JW; Buettner C. National use of prescription medications for

  13. A study on the quality of outpatient prescription of psychopharmaceuticals in the City of Zagreb 2006-2009.

    PubMed

    Zivković, Kresimir; Zelić-Kerep, Ana; Stimac, Danijela; Ozić, Sanja; Zivković, Nikica

    2014-06-01

    The lack of Croatian studies which could determine the justifiability of excessive psychopharmaceutical utilization was an encouragement to conduct this research. Furthermore, regarding the conduction of this study, it would be possible to determine whether the trend of drug utilization has increased, decreased or perhaps stabilized. The data on the outpatient utilization of psycholeptics and psychoanaleptics were collected from all Zagreb pharmacies, 2006-2009. Based on the collected data for all N05 and N06 groups of drugs, the defined daily doses (DDD) and DDD per thousand inhabitants per day (DDD/TID) have been calculated using the Anatomical-Therapeutic-Chemical classification (ATC) for 2006, 2007, 2008 and 2009. To indicate the quality of drug prescription the Drug Utilization 90% (DU 90%) method was used. Moreover, in order to determine a more precise quality of individual drug group prescriptions, the indicators have been calculated by determining the proportion of the total utilization of individual therapeutic and pharmacological therapeutic subgroups in DDD/TID a day. The utilization of anxiolytics (N05B) accounts for most of the psycholeptic utilization in the City of Zagreb throughout the entire study period. In the study period, the utilization of antidepressants has slightly increased, by 10.5%, taking the first and the last years of the period into account. In 2006, 5 benzodiazepines and the hypnotic zolpidem, as well as 5 selective serotonin reuptake inhibitors (SSRIs) and 1 third generation antipsychotic (olanzapin) were found in the DU 90% segment. In 2009, the DU 90% segment also comprised 5 benzodiazepines and the hypnotic zolpidem, as well as 6 SSRIs and 1 third generation antipsychotic (olanzapin). In the City of Zagreb, a general insight into the quality of psychopharmaceutical prescriptions indicates stability in comparison to earlier studies. The ratio index of the first generation antipsychotic utilization, compared to the third

  14. Central amygdalar nucleus treated with orexin neuropeptides evoke differing feeding and grooming responses in the hamster.

    PubMed

    Alò, Raffaella; Avolio, Ennio; Mele, Maria; Di Vito, Anna; Canonaco, Marcello

    2015-04-15

    Interaction of the orexinergic (ORXergic) neuronal system with the excitatory (glutamate, l-Glu) or the inhibitory (GABA) neurosignaling complexes evokes major homeostatic physiological events. In this study, effects of the two ORXergic neuropeptides (ORX-A/B) on their receptor (ORX-2R) expression changes were correlated to feeding and grooming actions of the hibernating hamster (Mesocricetus auratus). Infusion of the central amygdala nucleus (CeA) with ORX-A caused hamsters to consume notable quantities of food, while ORX-B accounted for a moderate increase. Interestingly the latter neuropeptide was responsible for greater frequencies of grooming with respect to both controls and the hamsters treated with ORX-A. These distinct behavioral changes turned out to be even greater in the presence of l-Glu agonist (NMDA) while the α1 GABAA receptor agonist (zolpidem, Zol) greatly reduced ORX-A-dependent feeding bouts. Moreover, ORX-A+NMDA mainly promoted greater ORX-2R expression levels with respect to ORX-A-treated hamsters while ORX-B+Zol was instead largely responsible for a down-regulatory trend. Overall, these features point to CeA ORX-2R sites as key sensory limbic elements capable of regulating eating and grooming responses, which may provide useful insights regarding the type of molecular mechanism(s) operating during feeding bouts. PMID:25732800

  15. Drug screening of whole blood by ultra-performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Oiestad, Elisabeth Leere; Johansen, Unni; Oiestad, Ase Marit Leere; Christophersen, Asbjørg Solberg

    2011-06-01

    An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method for screening of drugs in whole blood has been developed and validated. Samples were prepared by supported liquid-liquid extraction on ChemElute(®) columns with ethyl acetate/heptane (4:1). LC separation was achieved with an Acquity HSS T3-column (2.1 100 mm, 1.8-μm particle). Mass detection was performed by positive ion mode electrospray MS-MS and included the following drugs/metabolites: morphine, codeine, ethyl morphine, oxycodone, buprenorphine, methadone, cocaine, methylphenidate, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), Δ(9)-tetrahydrocannabinol (THC), fentanyl, alprazolam, bromazepam, clonazepam, diazepam, nordiazepam, 3-OH-diazepam, fenazepam, flunitrazepam, lorazepam, nitrazepam, oxazepam, zopiclone, zolpidem, carisoprodol, and meprobamate. The cycle time was 9 min, and within- and between-day relative coefficients of variation varied from 1% to 33% and 2% to 58%, respectively. Extraction recoveries from whole blood were > 50% except for morphine and THC. The limit of quantitation was 0.1 to 521 ng/mL, depending on the drug. PMID:21619723

  16. [Determination of ten sedative residues in pork and kidney by ultra performance liquid chromatography-tandem mass spectrometry].

    PubMed

    Sun, Lei; Zhang, Li; Xu, Qian; Wang, Shuhuai; Wang, Xia

    2010-01-01

    An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/ MS) method was established for the determination of methaqualone, chloropromazine, promethazine, diazepam, nitrazepam, oxazepam, temazepam, midazolam, triazolam and zolpidem residues in pork and kidney. After enzymolysis, the samples were extracted by ethyl acetate and tert-butyl methyl ether, separately. The separation of the ten sedatives was performed on a Waters Acquity UPLC system with a BEH C18 column. The mobile phases were acetonitrile (containing 0.1% formic acid) and water (containing 0.1% formic acid) at a flow rate of 0.3 mL/min. The electrospray was operated in the positive ionization mode and the ten sedatives were identified by multiple reaction monitoring (MRM) mode. The method of matrix-matched standard solution was adopted as the quantitative method. The calibration curves showed good linearity within the concentrations of 2 - 100 microg/L with the correlation coefficients r > 0. 998. The limits of detection of the ten sedatives were 0.5 microg/kg, and the limit of quantification was 1 microg/kg. The recoveries of the ten sedatives were 64.5% - 111.4% at the spiked levels of 2, 5 and 10 microg/kg. The relative standard deviations of intra- and inter-day coefficients of variation were both less than 15%. This method is simple, sensitive and accurate in the determination of sedative residues. PMID:20458918

  17. Which medications are safe and effective for improving sleep at high altitude?

    PubMed

    Luks, Andrew M

    2008-01-01

    Given the well-established problems with sleep at high altitude, it is not uncommon for people planning trips to the mountains to seek advice from clinicians regarding pharmacologic options for improving sleep during their trip. This review article considers the various medications that have been studied for this purpose at high altitude with an emphasis on both their efficacy and safety. The available data support the use of either acetazolamide, temazepam, zolpidem or zaleplon in this environment. Other agents commonly used at sea-level such as eszopiclone and diphenhydramine have not been studied at high altitude but are likely safe to use given their mechanism of action and known side effects. Limited evidence suggests diazepam may cause hypoventilation at high altitude and its use in this environment should be discouraged. Insufficient data exist to determine which agent is most effective at altitude nor do we know whether combination therapy with acetazolamide and a hypnotic agent offers any benefits over monotherapy. PMID:18800955

  18. [Insomnia and cerebral hypoperfusion].

    PubMed

    Káposzta, Zoltán; Rácz, Klára

    2007-11-18

    Insomnia is defined as difficulty with the initiation, maintenance, duration, or quality of sleep that results in the impairment of daytime functioning, despite adequate opportunity and circumstances for sleep. In most countries approximately every third inhabitant has insomnia. Insomnia can be classified as primary and secondary. The pathogenesis of primary insomnia is unknown, but available evidence suggests a state of hyperarousal. Insomnia secondary to other causes is more common than primary insomnia. Cerebral hypoperfusion can be the cause of insomnia in some cases. In such patients the cerebral blood flow should be improved using parenteral vascular therapy. If insomnia persists despite treatment, then therapy for primary insomnia should be instituted using benzodiazepine-receptor agonists such as Zolpidem, Zopiclone, or Zaleplon. In those cases Midazolam cannot be used for the treatment of insomnia due to its marked negative effect on cerebral blood flow. In Hungary there is a need to organize multidisciplinary Insomnia Clinics because insomnia is more than a disease, it is a public health problem in this century. PMID:17988972

  19. Medications for the Treatment of Sleep Disorders: An Overview

    PubMed Central

    Pagel, J. F.; Parnes, Bennett L.

    2001-01-01

    Sleep disorders can be divided into those producing insomnia, those causing daytime sleepiness, and those disrupting sleep. Transient insomnia is extremely common, afflicting up to 80% of the population. Chronic insomnia affects 15% of the population. Benzodiazepines are frequently used to treat insomnia; however, there may be a withdrawal syndrome with rapid eye movement (REM) rebound. Two newer benzodiazepine-like agents, zolpidem and zaleplon, have fewer side effects, yet good efficacy. Other agents for insomnia include sedating antidepressants and over-the-counter sleep products (sedating antihistamines). Nonpharmacologic behavioral methods may also have therapeutic benefit. An understanding of the electrophysiologic and neurochemical correlates of the stages of sleep is useful in defining and understanding sleep disorders. Excessive daytime sleepiness is often associated with obstructive sleep apnea or depression. Medications, including amphetamines, may be used to induce daytime alertness. Parasomnias include disorders of arousal and of REM sleep. Chronic medical illnesses can become symptomatic during specific sleep stages. Many medications affect sleep stages and can thus cause sleep disorders or exacerbate the effect of chronic illnesses on sleep. Conversely, medications may be used therapeutically for specific sleep disorders. For example, restless legs syndrome and periodic limb movement disorder may be treated with dopamine agonists. An understanding of the disorders of sleep and the effects of medications is required for the appropriate use of medications affecting sleep. PMID:15014609

  20. Sleep driving: sleepwalking variant or misuse of z-drugs?

    PubMed

    Pressman, Mark R

    2011-10-01

    Sleep driving is most often classified as a variant of sleepwalking, but should be distinguished from impaired driving due to misuse or abuse of sedative/hypnotic drugs. Z-drugs; zolpidem and zopiclone in particular, have been associated with the majority of reported cases of impaired driving. Numerous studies have found z-drugs in driving under influence (DUI) related police stops, arrests and accidents. Impaired drivers are reported to have 1) blood levels of z-drugs that exceed therapeutic ranges 2) failed to take the medication at the correct time or remain in bed for sufficient time and/or 3) combined z-drugs with other central nervous system (CNS) depressants and/or alcohol. Consistent with CNS depression, z-drug-impaired drivers may demonstrate cognitive function at low levels with drivers still able to understand and respond to questions while sleepwalkers are completely unable to understand or interact with police. Z-drug-impaired drivers are often severely physically impaired, unable to stand up or maintain balance while sleepwalkers are able to stand and walk unaided. Sleep driving and impaired driving due to z-drugs may overlap. Sleep driving and drug-impaired driving are statistically rare events, but due to the billions of doses prescribed each year may still result in numerous DUI related arrests and accidents. PMID:21367628

  1. [Nighttime eating disorders--clinical symptoms and treatment].

    PubMed

    Zawilska, Jolanta B; Santorek-Strumiłło, Edyta J; Kuna, Paulina

    2010-01-01

    Nighttime eating is categorized as either night eating syndrome (NES) or the sleep-related eating disorder (SRED). Both diseases are often connected with an increase of the body mass, obesity, and with psychiatric disturbances. NES is characterized by evening hyperphagia, abnormally increased food intake after the evening meal, nocturnal awakings with ingestions, morning anorexia, and insomnia. Patients suffering from NES are aware of their nocturnal ingestions. It is suggested that NES is an abnormality in the circadian rhythm of meal timing that occurs in people with normal circadian rhythm of sleep. Other factors underlying NES include genetic predispositions, hormonal and neurochemical disturbances, and mood disorders. SRED is characterized by recurrent episodes of eating or drinking after arousal from nighttime sleep, unaware in tight the most cases, with adverse consequences. The distinctive features of SRED are amnesia of night eating episodes and consumption of non-typical food or dangerous articles. SRED is frequently associated with other sleep disorders, e.g., restless leg syndrome, periodic limb movement disorder, obstructive sleep apnea, and somnambulism. It can be also induced by medicines applied by a patient (e.g. zolpidem). It is hypothesized that the syndrome represents a variation of somnambulism. In the treatment of NES both non-pharmacological methods (psychotherapy, phototherapy) as well as the pharmacotherapy (aimed to increase serotoninergic neurotransmission in the brain, predominantly by sertraline, a selective serotonin re-uptake inhibitor) are used. SRED can be treated by controlling comorbid sleep disorders and eliminating provocative sedative hypnotics. PMID:21387771

  2. Silencing the brain may be better than stimulating it. The GABA effect.

    PubMed

    Pistoia, Francesca; Sarà, Marco; Sacco, Simona; Franceschini, Marco; Carolei, Antonio

    2014-01-01

    Cases of recovery from vegetative and minimally conscious state after the administration of various pharmacological agents have been recently reported. These agents include CNS depressants (zolpidem, baclofen, lamotrigine) and CNS stimulants (tricyclic antidepressants, selective serotonin reuptake inhibitors, dopaminergic agents, methylphenidate). The action of CNS depressants as awakening agents sounds paradoxical, as they are commonly prescribed to slow down brain activity in the management of anxiety, muscle tension, pain, insomnia and seizures. How these drugs may improve the level of consciousness in some brain-injured patients is the subject of intense debate. Here we hypothesize that CNS depressants may promote consciousness recovery by reversing a condition of GABA impairment in the injured brain, restoring the normal ratio between synaptic excitation and inhibition, which is the prerequisite for any transition from a resting state to goal-oriented activities (GABA impairment hypothesis). Alternative or complementary mechanisms underlying the improvement of consciousness may include the reversal of a neurodormant state within areas affected by diaschisis (diaschisis hypothesis) and the modulation of an informative overload to the cortex as a consequence of filter failure in the injured brain (informative overload hypothesis). A better understanding of how single agents act on neural networks, whose functioning is critical for recovery, may help to advance a tailored pharmacological approach in the treatment of severely brain injured patients. PMID:24025066

  3. Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target

    PubMed Central

    Paz, Jeanne T.; Wang, Eric Hou Jen; Badgely, Corrine; Olson, Andrew; Micheva, Kristina D.; Wang, Gordon; Lemmens, Robin; Tran, Kevin V.; Nishiyama, Yasuhiro; Liang, Xibin; Hamilton, Scott A.; O’Rourke, Nancy; Smith, Stephen J.; Huguenard, John R.; Bliss, Tonya M.

    2016-01-01

    Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem’s potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery. PMID:26685158

  4. GABAA-receptor modification in taurine transporter knockout mice causes striatal disinhibition

    PubMed Central

    Sergeeva, O A; Fleischer, W; Chepkova, A N; Warskulat, U; Häussinger, D; Siebler, M; Haas, H L

    2007-01-01

    The Striatum is involved in the regulation of movements and motor skills. We have shown previously, that the osmolyte and neuromodulator taurine plays a role in striatal plasticity. We demonstrate now that hereditary taurine deficiency in taurine-transporter knock-out (TAUT KO) mice results in disinhibition of striatal network activity, which can be corrected by taurine supplementation. Modification of GABAA but not glycine receptors (taurine is a ligand for both receptor types) underlies this disinhibition. Whole-cell recordings from acutely isolated as well as cultured striatal neurons revealed a decreased agonist sensitivity of the GABAA receptor in TAUT KO neurons in the absence of changes in the maximal GABA-evoked current amplitude. The striatal GABA level in TAUT KO mice was unchanged. The amplitude enhancement of spontaneous IPSCs by zolpidem was stronger in TAUT KO than in wild-type (WT) animals. Tonic inhibition was absent in striatal neurons under control conditions but was detected after incubation with the GABA-transaminase inhibitor vigabatrin: bicuculline induced a larger shift of baseline current in WT as compared to TAUT KO neurons. Lack of taurine leads to reduced sensitivity of synaptic and extrasynaptic GABAA receptors and consequently to disinhibition. These findings help in understanding neuropathologies accompanied by the loss of endogenous taurine, for instance in hepatic encephalopathy. PMID:17962336

  5. Age- and Sex-Related Characteristics of Tonic Gaba Currents in the Rat Substantia Nigra Pars Reticulata

    PubMed Central

    Hasson, H.; Bojar, M.; Moshé, S. L.; Galanopoulou, A. S.

    2015-01-01

    Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4β3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age-and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved. PMID:25645446

  6. Multidrug-related leukocytoclastic vasculitis raising suspicion of sexual homicide-things are not always what they seem.

    PubMed

    Tattoli, Lucia; Krocker, Klaus; Sautter, Julia; Tsokos, Michael

    2016-01-01

    Ambiguous findings during external examination of a deceased in combination with dubious autopsy findings can raise doubts concerning the manner and cause of death. We report the case of a 35-year-old female deceased who had suffered from a borderline personality and depressive disorder with suicidal ideation. At the death scene, the body showed massive facial swelling accompanied by complete reddening of the skin of the face, with patchy skin abrasions on the forehead and neck, and purple bruise-like discolorations distributed symmetrically over both shoulders, elbows, hands, hips, knees, lower legs, and feet, raising the suspicion of underlying massive external blunt force injury. Police investigators strongly suspected sexual homicide. At autopsy, dissection in layers revealed massive subcutaneous hemorrhages as the cause of the reddish skin discolorations. Toxicological analyses showed fatal levels of lamotrigine with additional proof of zopiclone, zolpidem, diphenhydramine, O-desmethylvenlafaxine, pregabalin, tramadol, and modafinil in venous blood. Histologically, both the macroscopically impressive purple skin changes with underlying bleeding into the subcutaneous tissue and the skin abrasions were due to leukocytoclastic vasculitis, a form of acute hypersensitivity vasculitis that was a reaction to the multiple therapeutic drugs that the woman had taken shortly before death. The manner of death was classified as suicide, and sexual homicide was ruled out. PMID:25957602

  7. Mitochondrial benzodiazepine receptors regulate steroid biosynthesis

    SciTech Connect

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

    1989-12-01

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

  8. Pharmacology for sleep disturbance in PTSD.

    PubMed

    Lipinska, Gosia; Baldwin, David S; Thomas, Kevin G F

    2016-03-01

    Symptoms of sleep disturbance, particularly nightmares and insomnia, are a central feature of post-traumatic stress disorder (PTSD). Emerging evidence suggests that specific treatment of PTSD-related sleep disturbance improves other symptoms of the disorder, which in turn suggests that such disturbance may be fundamental to development and maintenance of the disorder. This mini-review focuses on pharmacological treatment of sleep disturbance in adult PTSD (specifically, studies testing the efficacy of antidepressants, adrenergic inhibiting agents, antipsychotics and benzodiazepine and non-benzodiazepine hypnotics). We conclude that only prazosin, an adrenergic inhibiting agent, has had its efficacy established by multiple randomised controlled trials. There is also high-level evidence supporting use of eszopiclone, as well as risperidone and olanzapine as adjunct therapy. Antidepressants such as sertraline, venlafaxine and mirtazapine, benzodiazepines such as alprazolam and clonazepam and non-benzodiazepine hypnotics such as zolpidem appear ineffective in treating PTSD-related sleep disturbance. Most studies that report reduced frequency of nightmares and insomnia also report decreases in overall symptom severity. Such findings suggest that (i) sleep disruption is central to PTSD; (ii) treating sleep disruption may be an effective way to address other symptoms of the disorder and (iii) PTSD symptoms tend to cluster together in predictable ways. PMID:26856810

  9. Hearing Loss and Tinnitus in Military Personnel with Deployment-Related Mild Traumatic Brain Injury.

    PubMed

    Karch, Stephanie J; Capó-Aponte, José E; McIlwain, D Scott; Lo, Michael; Krishnamurti, Sridhar; Staton, Roger N; Jorgensen-Wagers, Kendra

    2016-01-01

    The objective of this study was to analyze differences in incidence and epidemiologic risk factors for significant threshold shift (STS) and tinnitus in deployed military personnel diagnosed with mild traumatic brain injury (mTBI) due to either a blast exposure or nonblast head injury. A retrospective longitudinal cohort study of electronic health records of 500 military personnel (456 met inclusion criteria) diagnosed with deployment-related mTBI was completed. Chi-square tests and STS incidence rates were calculated to assess differences between blast-exposed and nonblast groups; relative risks and adjusted odds ratios of developing STS or tinnitus were calculated for risk factors. Risk factors included such characteristics as mechanism of injury, age, race, military occupational specialty, concurrent diagnosis of posttraumatic stress disorder (PTSD), and nicotine use. Among blast-exposed and nonblast patients, 67% and 58%, respectively, developed STS, (P=.06); 59% and 40%, respectively, developed tinnitus (P<.001). Incidence of STS was 24% higher in the blast-exposed than nonblast group. Infantry service was associated with STS; Marine Corps service, PTSD, and zolpidem use were associated with tinnitus. Unprotected noise exposure was associated with both STS and tinnitus. This study highlights potential risk factors for STS and tinnitus among blast-exposed and nonblast mTBI patient groups. PMID:27613210

  10. Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments

    PubMed Central

    2013-01-01

    Background Tau is a microtubule stabilizing protein and is mainly expressed in neurons. Tau aggregation into oligomers and tangles is considered an important pathological event in tauopathies, such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Tauopathies are also associated with deficits in synaptic plasticity such as long-term potentiation (LTP), but the specific role of tau in the manifestation of these deficiencies is not well-understood. We examined long lasting forms of synaptic plasticity in JNPL3 (BL6) mice expressing mutant tau that is identified in some inherited FTDs. Results We found that aged (>12 months) JNPL3 (BL6) mice exhibit enhanced hippocampal late-phase (L-LTP), while young JNPL3 (BL6) mice (age 6 months) displayed normal L-LTP. This enhanced L-LTP in aged JNPL3 (BL6) mice was rescued with the GABAAR agonist, zolpidem, suggesting a loss of GABAergic function. Indeed, we found that mutant mice displayed a reduction in hippocampal GABAergic interneurons. Finally, we also found that expression of mutant tau led to severe sensorimotor-gating and hippocampus-dependent memory deficits in the aged JNPL3 (BL6) mice. Conclusions We show for the first time that hippocampal GABAergic function is impaired by pathological tau protein, leading to altered synaptic plasticity and severe memory deficits. Increased understanding of the molecular mechanisms underlying the synaptic failure in AD and FTD is critical to identifying targets for therapies to restore cognitive deficiencies associated with tauopathies. PMID:24252661

  11. Involvement of dorsal striatal α1-containing GABAA receptors in methamphetamine-associated rewarding memories.

    PubMed

    Jiao, D-L; Liu, Y; Long, J-D; Du, J; Ju, Y-Y; Zan, G-Y; Liu, J-G; Zhao, M

    2016-04-21

    Rewarding memories induced by addictive drugs may contribute to persistent drug-seeking behaviors, which is an important contributing factor to drug addiction. However, the biological mechanisms underlying drug-associated rewarding memories have not yet been fully understood, especially the new synthetic drugs, such as amphetamine-type stimulants (ATS). In this study, using the rat-conditioned place preference (CPP) model, a classic animal model for the reward-associated effects of addictive drugs, we found that the expression level of GABAA α1 subunits was significantly decreased in the dorsal striatum (Dstr) after conditioned methamphetamine (METH) pairing, and no significant differences were observed in the other four rewarding memory-associated areas (medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala (Amy), and dorsal hippocampus (DH)). Intra-Dstr injection of either the GABAA receptor agonist muscimol or the specific α1GABAA receptor-preferring benzodiazepine (BDZ) agonist zolpidem significantly abolished METH CPP formation. Thus, this study extends previous findings by showing that GABAA receptors, particularly the α1-containing GABAA receptors, may be strongly implicated in METH-associated rewarding memories. This work provides us with a new perspective on the goal of treating ATS addiction. PMID:26868969

  12. Pharmacotherapy for disorders of consciousness: are 'awakening' drugs really a possibility?

    PubMed

    Ciurleo, Rosella; Bramanti, Placido; Calabrò, Rocco Salvatore

    2013-11-01

    Disorders of consciousness, including the coma state, vegetative state and minimally conscious state, are among the least understood and least curable conditions in modern neurology. Structural or functional injuries may produce impairments in the neuronal circuits (the ascending reticular activating system and thalamocortical loops) responsible for maintaining the wakefulness state and awareness, associated with a change in neurotransmitter concentrations. Pharmacological agents that are able to restore the levels of neurotransmitters and, consequently, neural synaptic plasticity and functional connectivity of consciousness networks, may play an important role as drugs useful in improving the consciousness state. Currently, there is growing interest in the scientific community with regard to pharmacological agents that act on the gamma amino-butyric acid (GABA) system, such as zolpidem and baclofen, and monoamine systems, such as dopaminergic agents and some antidepressants. The purpose of this article is to provide a comprehensive overview of these potential 'awakening' drugs in patients with disorders of consciousness. The possible mechanisms by which these drugs may exert their effects in promoting recovery of consciousness are discussed, highlighting how many findings are often the result of sporadic events rather than prospective controlled trials or implementation of standard treatment guidelines. PMID:24170667

  13. A One Pot Synthesis of Novel Bioactive Tri-Substitute-Condensed-Imidazopyridines that Targets Snake Venom Phospholipase A2.

    PubMed

    Anilkumar, Nirvanappa C; Sundaram, Mahalingam S; Mohan, Chakrabhavi Dhananjaya; Rangappa, Shobith; Bulusu, Krishna C; Fuchs, Julian E; Girish, Kesturu S; Bender, Andreas; Basappa; Rangappa, Kanchugarakoppal S

    2015-01-01

    Drugs such as necopidem, saripidem, alpidem, zolpidem, and olprinone contain nitrogen-containing bicyclic, condensed-imidazo[1,2-α]pyridines as bioactive scaffolds. In this work, we report a high-yield one pot synthesis of 1-(2-methyl-8-aryl-substitued-imidazo[1,2-α]pyridin-3-yl)ethan-1-onefor the first-time. Subsequently, we performed in silico mode-of-action analysis and predicted that the synthesized imidazopyridines targets Phospholipase A2 (PLA2). In vitro analysis confirmed the predicted target PLA2 for the novel imidazopyridine derivative1-(2-Methyl-8-naphthalen-1-yl-imidazo [1,2-α]pyridine-3-yl)-ethanone (compound 3f) showing significant inhibitory activity towards snake venom PLA2 with an IC50 value of 14.3 μM. Evidently, the molecular docking analysis suggested that imidazopyridine compound was able to bind to the active site of the PLA2 with strong affinity, whose affinity values are comparable to nimesulide. Furthermore, we estimated the potential for oral bioavailability by Lipinski's Rule of Five. Hence, it is concluded that the compound 3f could be a lead molecule against snake venom PLA2. PMID:26196520

  14. Modeling structure-function relationships for diffusive drug transport in inert porous geopolymer matrices.

    PubMed

    Jämstorp, Erik; Strømme, Maria; Frenning, Göran

    2011-10-01

    A unique structure-function relationship investigation of mechanically strong geopolymer drug delivery vehicles for sustained release of potent substances is presented. The effect of in-synthesis water content on geopolymer pore structure and diffusive drug transport is investigated. Scanning electron microscopy, N2 gas adsorption, mercury intrusion porosimetry, compression strength test, drug permeation, and release experiments are performed. Effective diffusion coefficients are measured and compared with corresponding theoretical values as derived from pore size distribution and connectivity via pore-network modeling. By solely varying the in-synthesis water content, mesoporous and mechanically strong geopolymers with porosities of 8%-45% are obtained. Effective diffusion coefficients of the model drugs Saccharin and Zolpidem are observed to span two orders of magnitude (∼1.6-120 × 10(-8) cm(2) /s), comparing very well to theoretical estimations. The ability to predict drug permeation and release from geopolymers, and materials alike, allows future formulations to be tailored on a structural and chemical level for specific applications such as controlled drug delivery of highly potent substances. PMID:21656516

  15. Polymer excipients enable sustained drug release in low pH from mechanically strong inorganic geopolymers.

    PubMed

    Jämstorp, Erik; Yarra, Tejaswi; Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne; Strømme, Maria

    2012-01-01

    Improving acid resistance, while maintaining the excellent mechanical stability is crucial in the development of a sustained and safe oral geopolymer dosage form for highly potent opioids. In the present work, commercially available Methacrylic acid-ethyl acrylate copolymer, Polyethylene-glycol (PEG) and Alginate polymer excipients were included in dissolved or powder form in geopolymer pellets to improve the release properties of Zolpidem, herein acting as a model drug for the highly potent opioid Fentanyl. Scanning electron microscopy, compression strength tests and drug release experiments, in gastric pH 1 and intestinal pH 6.8 conditions, were performed. The polymer excipients, with an exception for PEG, reduced the drug release rate in pH 1 due to their ability to keep the pellets in shape, in combination with the introduction of an insoluble excipient, and thereby maintain a barrier towards drug diffusion and release. Neither geopolymer compression strength nor the release in pH 6.8 was considerably impaired by the incorporation of the polymer excipients. The geopolymer/polymer composites combine high mechanical strength and good release properties under both gastric and intestinal pH conditions, and are therefore promising oral dosage forms for sustained release of highly potent opioids. PMID:25755991

  16. Polymer excipients enable sustained drug release in low pH from mechanically strong inorganic geopolymers

    PubMed Central

    Jämstorp, Erik; Yarra, Tejaswi; Cai, Bing; Engqvist, Håkan; Bredenberg, Susanne; Strømme, Maria

    2012-01-01

    Improving acid resistance, while maintaining the excellent mechanical stability is crucial in the development of a sustained and safe oral geopolymer dosage form for highly potent opioids. In the present work, commercially available Methacrylic acid–ethyl acrylate copolymer, Polyethylene-glycol (PEG) and Alginate polymer excipients were included in dissolved or powder form in geopolymer pellets to improve the release properties of Zolpidem, herein acting as a model drug for the highly potent opioid Fentanyl. Scanning electron microscopy, compression strength tests and drug release experiments, in gastric pH 1 and intestinal pH 6.8 conditions, were performed. The polymer excipients, with an exception for PEG, reduced the drug release rate in pH 1 due to their ability to keep the pellets in shape, in combination with the introduction of an insoluble excipient, and thereby maintain a barrier towards drug diffusion and release. Neither geopolymer compression strength nor the release in pH 6.8 was considerably impaired by the incorporation of the polymer excipients. The geopolymer/polymer composites combine high mechanical strength and good release properties under both gastric and intestinal pH conditions, and are therefore promising oral dosage forms for sustained release of highly potent opioids. PMID:25755991

  17. A One Pot Synthesis of Novel Bioactive Tri-Substitute-Condensed-Imidazopyridines that Targets Snake Venom Phospholipase A2

    PubMed Central

    Anilkumar, Nirvanappa C.; Sundaram, Mahalingam S.; Mohan, Chakrabhavi Dhananjaya; Rangappa, Shobith; Bulusu, Krishna C.; Fuchs, Julian E.; Girish, Kesturu S.; Bender, Andreas; Basappa; Rangappa, Kanchugarakoppal S.

    2015-01-01

    Drugs such as necopidem, saripidem, alpidem, zolpidem, and olprinone contain nitrogen-containing bicyclic, condensed-imidazo[1,2-α]pyridines as bioactive scaffolds. In this work, we report a high-yield one pot synthesis of 1-(2-methyl-8-aryl-substitued-imidazo[1,2-α]pyridin-3-yl)ethan-1-onefor the first-time. Subsequently, we performed in silico mode-of-action analysis and predicted that the synthesized imidazopyridines targets Phospholipase A2 (PLA2). In vitro analysis confirmed the predicted target PLA2 for the novel imidazopyridine derivative1-(2-Methyl-8-naphthalen-1-yl-imidazo [1,2-α]pyridine-3-yl)-ethanone (compound 3f) showing significant inhibitory activity towards snake venom PLA2 with an IC50 value of 14.3 μM. Evidently, the molecular docking analysis suggested that imidazopyridine compound was able to bind to the active site of the PLA2 with strong affinity, whose affinity values are comparable to nimesulide. Furthermore, we estimated the potential for oral bioavailability by Lipinski's Rule of Five. Hence, it is concluded that the compound 3f could be a lead molecule against snake venom PLA2. PMID:26196520

  18. Point mutations of the alpha 1 beta 2 gamma 2 gamma-aminobutyric acid(A) receptor affecting modulation of the channel by ligands of the benzodiazepine binding site.

    PubMed

    Buhr, A; Baur, R; Malherbe, P; Sigel, E

    1996-06-01

    Clinically relevant benzodiazepines allosterically stimulate neurotransmitter-evoked chloride currents at the gamma-aminobutyric acid type A(GABAA) receptor. Rat wild-type or mutated alpha 1, beta 2, and gamma 2S subunits were coexpressed in Xenopus oocytes and investigated with electrophysiological techniques. Point mutations in two subunits were identified that affect the response of gamma-aminobutyric acid (GABA)-induced currents by benzodiazepines. Mutation of one of three amino acid residues to alanine (alpha Tyr161 and alpha Thr206) or leucine (gamma Phe77) resulted in a approximately 3-fold increase in potentiation by diazepam. The response to zolpidem was increased in two mutant channels containing the mutated alpha subunit but was nearly absent in channels containing the mutated gamma subunit. In the former cases, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) acted as a negative allosteric modulator of the channel, much stronger than in the wild-type channel, whereas there was no significant difference to the wild-type channel in the latter case. Thus, the mutant gamma subunit has different functional consequences for the various types of ligand of the benzodiazepine binding site. All three amino acid residues, alpha Tyr161, alpha Thr206, and gamma Phe77, are close or identical to homologous residues that are implicated in GABA binding. If the residues binding the channel agonist GABA are located at subunit interfaces, the residues influencing the benzodiazepine effects must also be located at subunit interfaces. PMID:8649346

  19. Manners of Death in Drug-Related Fatalities in Florida.

    PubMed

    Lee, Dayong; Delcher, Chris; Maldonado-Molina, Mildred M; Thogmartin, Jon R; Goldberger, Bruce A

    2016-05-01

    To understand the mortality patterns among drug users and potential risk factors, we evaluated drug-related deaths reported to the Florida Medical Examiners Commission from 2001 to 2013, by substances, demographics, and manner of death. The annual drug-related fatalities increased by 57% from 2001 to 2013 (total n = 100,882); 51.8% were accidental, 7.9% homicide, 18.6% natural, and 19.6% suicide. The different manners of death exhibited distinct demographic profiles and drug composition. The gender gap was more prominent in homicide. Age ≥55 years was more closely associated with natural death and suicide. Age <35 years and central nervous system (CNS) stimulants including amphetamines and cocaine showed higher relative risks for accidental death and homicide, whereas CNS depressants including benzodiazepines, carisoprodol, opioids, and zolpidem were more strongly associated with accidental death and/or suicide. The findings aid in identifying populations more vulnerable to drug-related deaths, developing targeted interventions and thereby improving efficiency of preventive efforts. PMID:27122413

  20. Emerging role of orexin antagonists in insomnia therapeutics: An update on SORAs and DORAs.

    PubMed

    Kumar, Anil; Chanana, Priyanka; Choudhary, Supriti

    2016-04-01

    The pharmacological management of insomnia has lately become a challenge for researchers worldwide. As per the third International Classification of Sleep disorders (ICSD-3) insomnia can be defined as a state with repeated difficulty in sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment. The conventional treatments approved for management of insomnia were benzodiazepines (BZDs) (estazolam, quazepam, triazolam, flurazepam and temazepam) and non-BZDs, also known as z-drugs (zaleplon, zolpidem, and eszopiclone), tricyclic antidepressant (TCA) doxepin as well as melatonin agonists, e.g. ramelteon. But the potential of these agents to address sleep problems has been limited due to substantial side effects associated with them like hangover, dependence and tolerance, rebound insomnia, muscular atonia, inhibition of respiratory system, cognitive dysfunctions, and increased anxiety. Recently, orexin neuropeptides have been identified as regulators of transition between wakefulness and sleep and documented to aid an initial transitory effect towards wakefulness by activating cholinergic/monoaminergic neural pathways of the ascending arousal system. This has led to the development of orexin peptides and receptors, as possible therapeutic targets for the treatment of sleep disorders with the advantage of having lesser side effects as compared to conventional treatments. The present review focuses on the orexin peptides and receptors signifying their physiological profile as well as the development of orexin receptor antagonists as novel strategies in sleep medicine. PMID:26922522

  1. Thoracic spine injury after a high-speed motor vehicle crash.

    PubMed

    Tilney, Peter

    2010-01-01

    In late October, a hospital-based flight team was activated at 9:30 pm for an approximately 30-year-old man involved in a high-speed motor vehicle crash into a tree. Per emergency medical services (EMS) documentation, flight service was requested for advanced airway management and rapid transport of the patient to a Level 1 trauma center. Ground transport was estimated at 60+ minutes, whereas actual flight time was less than 15 minutes. On the crew's arrival at the designated landing zone, they were escorted to an ambulance where a 100-kg man was immobilized on a stretcher. Because the landing area was at a remote location, the flight team did not witness the scene; however, the ground paramedic reported that the patient was the single-occupant driver of a small sedan. Given the extent of damage to the front and passenger side of the vehicle, it was determined that the patient was driving at a high rate of speed when he struck the tree. He required approximately 20 to 25 minutes of extrication. An empty bottle of zolpidem (Ambien) was found on the floor of the vehicle; the 30-day prescription had been filled approximately a week before the accident occurred. PMID:20207304

  2. Common High Altitudes Illnesses a Primer for Healthcare Provider

    PubMed Central

    Mohsenin, Vahid

    2015-01-01

    Exposure to high altitude imposes significant strain on cardiopulmonary system and the brain. As a consequence, sojourners to high altitude frequently experience sleep disturbances, often reporting restless and sleepless nights. At altitudes above 3,000 meters (9,800 ft) almost all healthy subjects develop periodic breathing especially during NREM sleep. Sleep architecture gradually improves with increased NREM and REM sleep despite persistence of periodic breathing. The primary reason for periodic breathing at high altitude is a hypoxic-induced increase in chemoreceptor sensitivity to changes in PaCO2 – both above and below eupnea, leading to periods of apnea and hyperpnea. Acetazolamide improves sleep by reducing the periodic breathing through development of metabolic acidosis and induced hyperventilation decreasing the plant gain and widening the PCO2 reserve. This widening of the PCO2 reserve impedes development of central apneas during sleep. Benzodiazepines and GABA receptor antagonist such as zolpidem improve sleep without affecting breathing pattern or cognitive functions. PMID:27057512

  3. A Case of Undiagnosed Sleep Disorder with Hearing Difficulty and Dizziness

    PubMed Central

    Goto, Fumiyuki; Arai, Miki; Kitamura, Mitusru; Otomo, Tomoko; Nagai, Ryoto; Minami, Shuujiro; Shimada, Takanobu; Matsunaga, Tatsuo; Tsunoda, Kouichi; Fujii, Masato

    2016-01-01

    Introduction: The aim of this case report was to investigate the relationship between sleep disorders and audio vestibular symptoms. Case Report: A case of undiagnosed sleep disorder, presenting as a temporary auditory processing difficulty, is presented. The disorder was initially treated as sudden deafness with dizziness. A 23-year-old male patient complained of acute hearing disturbance despite normal results on pure tone audiometry. The patient was initially administered a steroid injection in the hospital. After treatment, his hearing symptoms improved only slightly and he reported balance difficulty with rightward spontaneous nystagmus. Vestibular rehabilitation was performed. We also suspected that his hearing symptom was due to an auditory processing difficulty. Despite steroid treatment and vestibular rehabilitation, neither of his symptoms improved. We subsequently identified the presence of insomnia. He was prescribed zolpidem 5 mg, which slightly improved his symptoms, and referred to a sleep specialist for further examination. Polysomnography was performed, which identified restless leg syndrome and sleep disturbance with delayed sleep phase syndrome. After pharmacological treatment, his sleep disturbance, hearing difficulty, and balance disorder completely resolved. Conclusion: Sleep disorders may provoke reversible auditory processing difficulties. We should carefully evaluate patients for a potentially undiagnosed sleep disorder, even in patients chiefly complaining of intractable sensory dysfunction such as hearing or balance disturbance. PMID:27280102

  4. Poisoning of dogs and cats by drugs intended for human use.

    PubMed

    Cortinovis, Cristina; Pizzo, Fabiola; Caloni, Francesca

    2015-01-01

    One of the main causes of poisoning of small animals is exposure to drugs intended for human use. Poisoning may result from misuse by pet owners, off-label use of medicines or, more frequently, accidental ingestion of drugs that are improperly stored. This review focuses on classes of drugs intended for human use that are most commonly involved in the poisoning of small animals and provides an overview of poisoning episodes reported in the literature. To perform this review a comprehensive search of public databases (PubMed, Web of Science, Scopus, Google Scholar) using key search terms was conducted. Additionally, relevant textbooks and reference lists of articles pertaining to the topic were reviewed to locate additional related articles. Most published information on small animal poisoning by drugs intended for human use was from animal and human poison control centres or from single case reports. The dog was the species most frequently poisoned. The major drugs involved included analgesics (nonsteroidal anti-inflammatory drugs), antihistamines (H1-antihistamines), cardiovascular drugs (calcium channel blockers), central nervous system drugs (selective serotonin reuptake inhibitors, baclofen, benzodiazepines and zolpidem), gastrointestinal drugs (loperamide), nutritional supplements (vitamin D and iron salts) and respiratory drugs (β2-adrenergic receptor agonists). PMID:25475169

  5. Postnatal down-regulation of the GABAA receptor γ2 subunit in neocortical NG2 cells accompanies synaptic-to-extrasynaptic switch in the GABAergic transmission mode.

    PubMed

    Balia, Maddalena; Vélez-Fort, Mateo; Passlick, Stefan; Schäfer, Christoph; Audinat, Etienne; Steinhäuser, Christian; Seifert, Gerald; Angulo, María Cecilia

    2015-04-01

    NG2 cells, a main pool of glial progenitors, express γ-aminobutyric acid A (GABA(A)) receptors (GABA(A)Rs), the functional and molecular properties of which are largely unknown. We recently reported that transmission between GABAergic interneurons and NG2 cells drastically changes during development of the somatosensory cortex, switching from synaptic to extrasynaptic communication. Since synaptic and extrasynaptic GABA(A)Rs of neurons differ in their subunit composition, we hypothesize that GABA(A)Rs of NG2 cells undergo molecular changes during cortical development accompanying the switch of transmission modes. Single-cell RT-PCR and the effects of zolpidem and α5IA on evoked GABAergic currents reveal the predominance of functional α1- and α5-containing GABA(A)Rs at interneuron-NG2 cell synapses in the second postnatal week, while the α5 expression declines later in development when responses are exclusively extrasynaptic. Importantly, pharmacological and molecular analyses demonstrate that γ2, a subunit contributing to the clustering of GABA(A)Rs at postsynaptic sites in neurons, is down-regulated in NG2 cells in a cell type-specific manner in concomitance with the decline of synaptic activity and the switch of transmission mode. In keeping with the synaptic nature of γ2 in neurons, the down-regulation of this subunit is an important molecular hallmark of the change of transmission modes between interneurons and NG2 cells during development. PMID:24217990

  6. Benzodiazepines and Z-drug use among HIV-infected patients in Taiwan: a 13-year nationwide cohort study.

    PubMed

    Wei, Han-Ting; Chen, Mu-Hong; Wong, Wing-Wai; Chou, Yuan-Hwa; Liou, Ying-Jay; Su, Tung-Ping; Chen, Tzeng-Ji; Bai, Ya-Mei

    2015-01-01

    Introduction. Benzodiazepines (BZDs) and zolpidem, zopiclone, and zaleplon (Z-drugs) are commonly prescribed to HIV-infected patients. We hypothesized that frequent BZD and Z-drug use among these patients may be associated with psychiatric illnesses, particularly in long-term users. Methods. We included 1,081 patients with HIV between 1998 and 2011 from the Taiwan National Health Insurance Research Database and matched them according to age, sex, and comorbidity with uninfected controls to investigate the psychiatric diagnoses and prescriptions of BZDs and Z-drugs. Cumulative defined daily dose (cDDD) was assessed as the indicator of the duration of medication exposure. Patients exhibiting a cDDD exceeding 180 were defined as long-term users. Results. The patients with HIV had an increased risk of any use (odds ratio (OR): 8.70, 95% confidence interval (CI): 6.82-10.97) and long-term use (OR: 5.06, 95% CI: 3.63-7.04) of BZD and Z-drugs compared with those without HIV during the follow-up after demographic data and psychiatric comorbidities were adjusted. Conclusion. A large proportion of the HIV-infected patients received prescriptions of BZDs and Z-drugs. Mood disorders, insomnia, anxiety disorders, HIV infection, and substance use disorder were substantial predictors among the BZD and Z-drug users. These findings suggest that providing psychiatric services for HIV-infected patients is vital. PMID:25654104

  7. Age- and sex-related characteristics of tonic GABA currents in the rat substantia nigra pars reticulata.

    PubMed

    Chudomel, O; Hasson, H; Bojar, M; Moshé, S L; Galanopoulou, A S

    2015-04-01

    Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4β3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age- and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved. PMID:25645446

  8. MALDI-TOF mass spectrometric determination of eight benzodiazepines with two of their metabolites in blood.

    PubMed

    Nozawa, Hideki; Minakata, Kayoko; Yamagishi, Itaru; Hasegawa, Koutaro; Wurita, Amin; Gonmori, Kunio; Suzuki, Osamu; Watanabe, Kanako

    2015-05-01

    A rapid and sensitive method was developed for the determination of benzodiazepines and benzodiazepine-like substances (BZDs) by matrix-assisted laser desorption ionization (MALDI)-time-of-flight (TOF)-mass spectrometry (MS). In this method, α-cyano-4-hydroxy cinnamic acid was used as the matrix to assist the ionization of BZDs. Determination of 8 BZDs (with two of their metabolites) belonging to top 12 medical drugs detected in poisonous cases in Japan, was performed using diazepam-d5 as the internal standard. The limit of detection of zolpidem was 0.07ng/ml with its quantification range of 0.2-20ng/ml in blood, in the best case, and the limit of detection of flunitrazepam was 2ng/ml with its quantification range of 6-200ng/ml in blood, in the worst case. The spectra of zopiclone in MALDI-MS and MS/MS were different from those in electrospray ionization MS and MS/MS. Present method provides a simple and high throughput method for the screening of these BZDs using only 20μl of blood. The developed method was successfully used for the determination of BZDs in biological fluids obtained from two victims. PMID:25542365

  9. Speed and trajectory of changes of insomnia symptoms during acute treatment with cognitive–behavioral therapy, singly and combined with medication

    PubMed Central

    Morin, Charles M.; Beaulieu-Bonneau, Simon; Ivers, Hans; Vallières, Annie; Guay, Bernard; Savard, Josée; Mérette, Chantal

    2014-01-01

    Objectives To examine the speed and trajectory of changes in sleep/wake parameters during short-term treatment of insomnia with cognitive–behavioral therapy (CBT) alone versus CBT combined with medication; and to explore the relationship between early treatment response and post-treatment recovery status. Methods Participants were 160 adults with insomnia (mean age, 50.3 years; 97 women, 63 men) who underwent a six-week course of CBT, singly or combined with 10 mg zolpidem nightly. The main dependent variables were sleep onset latency, wake after sleep onset, total sleep time, sleep efficiency, and sleep quality, derived from sleep diaries completed daily by patients throughout the course of treatment. Results Participants treated with CBT plus medication exhibited faster sleep improvements as evidenced during the first week of treatment compared to those receiving CBT alone. Optimal sleep improvement was reached on average after only one week for the combined treatment compared to two to three weeks for CBT alone. Early treatment response did not reliably predict post-treatment recovery status. Conclusions Adding medication to CBT produces faster sleep improvement than CBT alone. However, the magnitude of early treatment response is not predictive of final response after the six-week therapy. Additional research is needed to examine mechanisms involved in this early treatment augmentation effect and its impact on long-term outcome. PMID:24831251

  10. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study

    PubMed Central

    Pearce, Hannah Louise; Croft, Peter; Singh, Swaran; Crome, Ilana; Bashford, James; Frisher, Martin

    2014-01-01

    Objective To test the hypothesis that people taking anxiolytic and hypnotic drugs are at increased risk of premature mortality, using primary care prescription records and after adjusting for a wide range of potential confounders. Design Retrospective cohort study. Setting 273 UK primary care practices contributing data to the General Practice Research Database. Participants 34 727 patients aged 16 years and older first prescribed anxiolytic or hypnotic drugs, or both, between 1998 and 2001, and 69 418 patients with no prescriptions for such drugs (controls) matched by age, sex, and practice. Patients were followed-up for a mean of 7.6 years (range 0.1-13.4 years). Main outcome All cause mortality ascertained from practice records. Results Physical and psychiatric comorbidities and prescribing of non-study drugs were significantly more prevalent among those prescribed study drugs than among controls. The age adjusted hazard ratio for mortality during the whole follow-up period for use of any study drug in the first year after recruitment was 3.46 (95% confidence interval 3.34 to 3.59) and 3.32 (3.19 to 3.45) after adjusting for other potential confounders. Dose-response associations were found for all three classes of study drugs (benzodiazepines, Z drugs (zaleplon, zolpidem, and zopiclone), and other drugs). After excluding deaths in the first year, there were approximately four excess deaths linked to drug use per 100 people followed for an average of 7.6 years after their first prescription. Conclusions In this large cohort of patients attending UK primary care, anxiolytic and hypnotic drugs were associated with significantly increased risk of mortality over a seven year period, after adjusting for a range of potential confounders. As with all observational findings, however, these results are prone to bias arising from unmeasured and residual confounding. PMID:24647164

  11. Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds.

    PubMed

    Griffiths, Roland R; Johnson, Matthew W

    2005-01-01

    Hypnotic drugs, including benzodiazepine receptor ligands, barbiturates, antihistamines, and melatonin receptor ligands, are useful in treating insomnia, but clinicians should consider the relative abuse liability of these drugs when prescribing them. Two types of problematic hypnotic self-administration are distinguished. First, recreational abuse occurs when medications are used purposefully for the subjective "high." This type of abuse usually occurs in polydrug abusers, who are most often young and male. Second, chronic quasi-therapeutic abuse is a problematic use of hypnotic drugs in which patients continue long-term use despite medical recommendations to the contrary. Relative abuse liability is defined as an interaction between the relative reinforcing effects (i.e., the capacity to maintain drug self-administration behavior, thereby increasing the likelihood of nonmedical problematic use) and the relative toxicity (i.e., adverse effects having the capacity to harm the individual and/or society). An algorithm is provided that differentiates relative likelihood of abuse and relative toxicity of 19 hypnotic compounds: pentobarbital, methaqualone, diazepam, flunitrazepam, lorazepam, GHB (gamma-hydroxybutyrate, also known as sodium oxybate), temazepam, zaleplon, eszopiclone, triazolam, zopiclone, flurazepam, zolpidem, oxazepam, estazolam, diphenhydramine, quazepam, tra-zodone, and ramelteon. Factors in the analysis include preclinical and clinical assessment of reinforcing effects, preclinical and clinical assessment of withdrawal, actual abuse, acute sedation/memory impairment, and overdose lethality. The analysis shows that both the likelihood of abuse and the toxicity vary from high to none across these compounds. The primary clinical implication of the range of differences in abuse liability is that concern about recreational abuse, inappropriate long-term use, or adverse effects should not deter physicians from prescribing hypnotics when clinically

  12. A 3-year survey quantifying the risk of dose escalation of benzodiazepines and congeners to identify risk factors to aid doctors to more rationale prescribing

    PubMed Central

    Tvete, Ingunn Fride; Bjørner, Trine; Aursnes, Ivar Andreas; Skomedal, Tor

    2013-01-01

    Objectives This study investigated and quantified risk factors of dose escalation, as an indication of drug misuse and dependency of benzodiazepines and congeners, among presumably drug naïve patients in the Norwegian drug prescription database, observed over 3 years. Design Observational study. Setting Prescription database study. Participants We defined an excessive user as one redeeming more than two defined daily doses per day in 3 months. Primary and secondary outcome measures We examined the risk of excessive use over time and the effect of risk factors through multistate logistic regression and scenarios. Results Most of the 81 945 patients had zopiclone or zolpidem as the initial drug (63.8%), followed by diazepam (25.3%), oxazepam (6.1%), nitrazepam/flunitrazepam (2.9%), hydroxyzine/buspirone (1.6%) and alprazolam (0.3%). At any time 23% redeemed prescriptions, about 34% did not redeem any prescriptions beyond any 3-month period and 0.9% ended up as excessive users. Patients previously using drugs, such as opioids, antialcohol or smoke cessation treatment, had a higher risk to become excessive users compared to patients who had not. Patients whose first prescription was for oxazepam or nitrazepam/flunitrazepam had a higher risk of becoming an excessive user compared to those who started with diazepam. A specialist in general practice as the first-time prescriber was associated with a lower risk compared to doctors without specialty. Conclusions Most benzodiazepine use occurred according to guidelines. Still, some experienced dose escalation over time, and risk factors were previous use of other psychotropic drugs, long time use, choice of first-time drug and prescriber's specialty. This could incite doctors to have a cessation plan when issuing first-time prescriptions. PMID:24097305

  13. Is suvorexant a better choice than alternative hypnotics?

    PubMed Central

    Kripke, Daniel F.

    2015-01-01

    Suvorexant is a novel dual orexin receptor antagonist (DORA) newly introduced in the U.S. as a hypnotic, but no claim of superiority over other hypnotics has been offered.  The manufacturer argued that the 5 and 10 mg starting doses recommended by the FDA might be ineffective.  The manufacturer's main Phase III trials had not even included the 10 mg dosage, and the 5 mg dosage had not been tested at all in registered clinical trials at the time of approval.  Popular alternative hypnotics may be similarly ineffective, since the FDA has also reduced the recommended doses for zolpidem and eszopiclone.  The "not to exceed" suvorexant dosage of 20 mg does slightly increase sleep.  Because of slow absorption, suvorexant has little effect on latency to sleep onset but some small effect in suppressing wakening after sleep onset and in improving sleep efficiency. The FDA would not approve the manufacturer's preferred 40 mg suvorexant dosage, because of concern with daytime somnolence, driving impairment, and possible narcolepsy-like symptoms.  In its immediate benefits-to-risks ratio, suvorexant is unlikely to prove superior to currently available hypnotics—possibly worse—so there is little reason to prefer over the alternatives this likely more expensive hypnotic less-tested in practice.  Associations are being increasingly documented relating hypnotic usage with incident cancer, with dementia risks, and with premature death.  There is some basis to speculate that suvorexant might be safer than alternative hypnotics in terms of cancer, dementia, infections, and mortality.  These safety considerations will remain unproven speculations unless adequate long-term trials can be done that demonstrate suvorexant advantages. PMID:26594338

  14. Clobazam and Its Active Metabolite N-desmethylclobazam Display Significantly Greater Affinities for α2- versus α1-GABAA–Receptor Complexes

    PubMed Central

    Jensen, Henrik Sindal; Nichol, Kathryn; Lee, Deborah; Ebert, Bjarke

    2014-01-01

    Clobazam (CLB), a 1,5-benzodiazepine (BZD), was FDA-approved in October 2011 for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years and older. BZDs exert various CNS effects through allosteric modulation of GABAA receptors. The structurally distinct, 1,4-BZD clonazepam (CLN) is also approved to treat LGS. The precise mechanisms of action and clinical efficacy of both are unknown. Data show that the GABAA α1-subunit–selective compound zolpidem [ZOL] exhibits hypnotic/sedative effects. Conversely, data from knock-in mice carrying BZD binding site mutations suggest that the α2 subunit mediates anticonvulsant effects, without sedative actions. Hence, the specific pattern of interactions across the GABAA receptor complexes of BZDs might be reflected in their clinical efficacies and adverse effect profiles. In this study, GABAA-receptor binding affinities of CLB, N-desmethylclobazam (N-CLB, the major metabolite of CLB), CLN, and ZOL were characterized with native receptors from rat-brain homogenates and on cloned receptors from HEK293 cells transfected with combinations of α (α1, α2, α3, or α5), β2, and γ2 subtypes. Our results demonstrate that CLB and N-CLB have significantly greater binding affinities for α2- vs. α1-receptor complexes, a difference not observed for CLN, for which no distinction between α2 and α1 receptors was observed. Our experiments with ZOL confirmed the high preference for α1 receptors. These results provide potential clues to a new understanding of the pharmacologic modes of action of CLB and N-CLB. PMID:24533090

  15. Melatonin for sedative withdrawal in older patients with primary insomnia: a randomized double-blind placebo-controlled trial

    PubMed Central

    Lähteenmäki, Ritva; Puustinen, Juha; Vahlberg, Tero; Lyles, Alan; Neuvonen, Pertti J; Partinen, Markku; Räihä, Ismo; Kivelä, Sirkka-Liisa

    2014-01-01

    Aim We compared the efficacy of melatonin and placebo as adjuvants in the withdrawal of patients from long term temazepam, zopiclone or zolpidem (here ‘BZD’) use. Methods A double-blind, placebo-controlled, randomized trial was conducted in a primary health care outpatient clinic. Ninety-two men or women (≥55 years) with primary insomnia and chronic BZD use received controlled release melatonin 2 mg (CRM) (n = 46) or placebo (n = 46) during the 1 month withdrawal from BZDs. Psychosocial support was provided. Follow-up continued for up to 6 months. Successful BZD withdrawal by the end of 1 month was confirmed by BZD plasma determinations, while reduction in BZD use and abstinence continuing for 6 months were noted. Results There were two drop-outs on CRM and one on placebo. After a 1 month withdrawal, 31 participants (67%; 95% CI 54, 81) on CRM and 39 (85%; 74, 95) on placebo had withdrawn completely (intention-to-treat analysis between groups, P = 0.051; per protocol P = 0.043). Reduction in BZD use was similar or even more rare in the CRM than in the placebo group (P = 0.052 per protocol). After 6 months, 14 participants in the CRM group and 20 in the placebo group remained non-users of BZD (NS between groups). BZD doses were higher in the CRM than in the placebo group at the end of the 6 month follow-up (P = 0.025). Withdrawal symptoms did not differ between the groups. Conclusions Gradual dose reduction of BZDs combined with CRM or placebo, and psychosocial support produced high short term and moderate long term BZD abstinence. CRM showed no withdrawal benefit compared with placebo. PMID:24286360

  16. Locus Coeruleus and Tuberomammillary Nuclei Ablations Attenuate Hypocretin/Orexin Antagonist-Mediated REM Sleep.

    PubMed

    Schwartz, Michael D; Nguyen, Alexander T; Warrier, Deepti R; Palmerston, Jeremiah B; Thomas, Alexia M; Morairty, Stephen R; Neylan, Thomas C; Kilduff, Thomas S

    2016-01-01

    Hypocretin 1 and 2 (Hcrts; also known as orexin A and B), excitatory neuropeptides synthesized in cells located in the tuberal hypothalamus, play a central role in the control of arousal. Hcrt inputs to the locus coeruleus norepinephrine (LC NE) system and the posterior hypothalamic histaminergic tuberomammillary nuclei (TMN HA) are important efferent pathways for Hcrt-induced wakefulness. The LC expresses Hcrt receptor 1 (HcrtR1), whereas HcrtR2 is found in the TMN. Although the dual Hcrt/orexin receptor antagonist almorexant (ALM) decreases wakefulness and increases NREM and REM sleep time, the neural circuitry that mediates these effects is currently unknown. To test the hypothesis that ALM induces sleep by selectively disfacilitating subcortical wake-promoting populations, we ablated LC NE neurons (LCx) or TMN HA neurons (TMNx) in rats using cell-type-specific saporin conjugates and evaluated sleep/wake following treatment with ALM and the GABAA receptor modulator zolpidem (ZOL). Both LCx and TMNx attenuated the promotion of REM sleep by ALM without affecting ALM-mediated increases in NREM sleep. Thus, eliminating either HcrtR1 signaling in the LC or HcrtR2 signaling in the TMN yields similar effects on ALM-induced REM sleep without affecting NREM sleep time. In contrast, neither lesion altered ZOL efficacy on any measure of sleep-wake regulation. These results contrast with those of a previous study in which ablation of basal forebrain cholinergic neurons attenuated ALM-induced increases in NREM sleep time without affecting REM sleep, indicating that Hcrt neurotransmission influences distinct aspects of NREM and REM sleep at different locations in the sleep-wake regulatory network. PMID:27022631

  17. Locus Coeruleus and Tuberomammillary Nuclei Ablations Attenuate Hypocretin/Orexin Antagonist-Mediated REM Sleep123

    PubMed Central

    Nguyen, Alexander T.; Warrier, Deepti R.; Palmerston, Jeremiah B.; Thomas, Alexia M.; Morairty, Stephen R.; Neylan, Thomas C.

    2016-01-01

    Abstract Hypocretin 1 and 2 (Hcrts; also known as orexin A and B), excitatory neuropeptides synthesized in cells located in the tuberal hypothalamus, play a central role in the control of arousal. Hcrt inputs to the locus coeruleus norepinephrine (LC NE) system and the posterior hypothalamic histaminergic tuberomammillary nuclei (TMN HA) are important efferent pathways for Hcrt-induced wakefulness. The LC expresses Hcrt receptor 1 (HcrtR1), whereas HcrtR2 is found in the TMN. Although the dual Hcrt/orexin receptor antagonist almorexant (ALM) decreases wakefulness and increases NREM and REM sleep time, the neural circuitry that mediates these effects is currently unknown. To test the hypothesis that ALM induces sleep by selectively disfacilitating subcortical wake-promoting populations, we ablated LC NE neurons (LCx) or TMN HA neurons (TMNx) in rats using cell-type-specific saporin conjugates and evaluated sleep/wake following treatment with ALM and the GABAA receptor modulator zolpidem (ZOL). Both LCx and TMNx attenuated the promotion of REM sleep by ALM without affecting ALM-mediated increases in NREM sleep. Thus, eliminating either HcrtR1 signaling in the LC or HcrtR2 signaling in the TMN yields similar effects on ALM-induced REM sleep without affecting NREM sleep time. In contrast, neither lesion altered ZOL efficacy on any measure of sleep–wake regulation. These results contrast with those of a previous study in which ablation of basal forebrain cholinergic neurons attenuated ALM-induced increases in NREM sleep time without affecting REM sleep, indicating that Hcrt neurotransmission influences distinct aspects of NREM and REM sleep at different locations in the sleep–wake regulatory network. PMID:27022631

  18. Early postnatal switch in GABAA receptor α-subunits in the reticular thalamic nucleus.

    PubMed

    Pangratz-Fuehrer, Susanne; Sieghart, Werner; Rudolph, Uwe; Parada, Isabel; Huguenard, John R

    2016-03-01

    The GABAergic neurons of the thalamic reticular nucleus (nRt) provide the primary source of inhibition within the thalamus. Using physiology, pharmacology, and immunohistochemistry in mice, we characterized postsynaptic developmental changes in these inhibitory projection neurons. First, at postnatal days 3-5 (P3-5), inhibitory postsynaptic currents (IPSCs) decayed very slowly, followed by a biphasic developmental progression, becoming faster at P6-8 and then slower again at P9-11 before stabilizing in a mature form around P12. Second, the pharmacological profile of GABA(A) receptor (GABA(A)R)-mediated IPSCs differed between neonatal and mature nRt neurons, and this was accompanied by reciprocal changes in α3 (late) and α5 (early) subunit expression in nRt. Zolpidem, selective for α1- and α3-containing GABA(A)Rs, augmented only mature IPSCs, whereas clonazepam enhanced IPSCs at all stages. This effect was blocked by the α5-specific inverse agonist L-655,708, but only in immature neurons. In α3(H126R) mice, in which α3-subunits were mutated to become benzodiazepine insensitive, IPSCs were enhanced compared with those in wild-type animals in early development. Third, tonic GABA(A)R activation in nRt is age dependent and more prominent in immature neurons, which correlates with early expression of α5-containing GABA(A)Rs. Thus neonatal nRt neurons show relatively high expression of α5-subunits, which contributes to both slow synaptic and tonic extrasynaptic inhibition. The postnatal switch in GABA(A)R subunits from α5 to α3 could facilitate spontaneous network activity in nRt that occurs at this developmental time point and which is proposed to play a role in early circuit development. PMID:26631150

  19. Orexin receptor antagonist-induced sleep does not impair the ability to wake in response to emotionally salient acoustic stimuli in dogs

    PubMed Central

    Tannenbaum, Pamela L.; Stevens, Joanne; Binns, Jacquelyn; Savitz, Alan T.; Garson, Susan L.; Fox, Steven V.; Coleman, Paul; Kuduk, Scott D.; Gotter, Anthony L.; Marino, Michael; Tye, Spencer J.; Uslaner, Jason M.; Winrow, Christopher J.; Renger, John J.

    2014-01-01

    The ability to awaken from sleep in response to important stimuli is a critical feature of normal sleep, as is maintaining sleep continuity in the presence of irrelevant background noise. Dual orexin receptor antagonists (DORAs) effectively promote sleep across species by targeting the evolutionarily conserved wake-promoting orexin signaling pathway. This study in dogs investigated whether DORA-induced sleep preserved the ability to awaken appropriately to salient acoustic stimuli but remain asleep when exposed to irrelevant stimuli. Sleep and wake in response to DORAs, vehicle, GABA-A receptor modulators (diazepam, eszopiclone and zolpidem) and antihistamine (diphenhydramine) administration were evaluated in telemetry-implanted adult dogs with continuous electrocorticogram, electromyogram (EMG), electrooculogram (EOG), and activity recordings. DORAs induced sleep, but GABA-A modulators and antihistamine induced paradoxical hyperarousal. Thus, salience gating studies were conducted during DORA-22 (0.3, 1, and 5 mg/kg; day and night) and vehicle nighttime sleep. The acoustic stimuli were either classically conditioned using food reward and positive attention (salient stimulus) or presented randomly (neutral stimulus). Once conditioned, the tones were presented at sleep times corresponding to maximal DORA-22 exposure. In response to the salient stimuli, dogs woke completely from vehicle and orexin-antagonized sleep across all sleep stages but rarely awoke to neutral stimuli. Notably, acute pharmacological antagonism of orexin receptors paired with emotionally salient anticipation produced wake, not cataplexy, in a species where genetic (chronic) loss of orexin receptor signaling leads to narcolepsy/cataplexy. DORA-induced sleep in the dog thereby retains the desired capacity to awaken to emotionally salient acoustic stimuli while preserving uninterrupted sleep in response to irrelevant stimuli. PMID:24904334

  20. Pharmacologic Therapy for Posttraumatic Stress Disorder: Review of Prescriptions and Potential Drug-Drug Interactions in a Military Cohort

    PubMed Central

    Jablonski, Kara L.; Devore, Maria D.; Ryan, Margaret A.; Streeter, Emily L.; Tolentino, Jerlyn C.; Klinski, Angelica A.; Bahlawan, Nahed

    2015-01-01

    Objective: To describe outpatient prescription treatment for active-duty military members with posttraumatic stress disorder (PTSD). Medical records were screened for drug-drug interactions with PTSD-related medications and for adverse drug events. Method: A retrospective chart review was conducted of the medical records of active-duty service members aged 18 to 65 years who had a diagnosis of PTSD (ICD-9 criteria) and received psychiatric treatment at Naval Hospital Camp Pendleton, Camp Pendleton, California, between October 1, 2010, and October 31, 2010. Prescription medication treatment over a 6-month period (October 1, 2010, through March 31, 2011) was reviewed. Results: Among 275 patients, 243 (88.4%) had at least 1 prescription dispensed and 219 (79.6%) had at least 1 PTSD-related medication dispensed. More than 1 PTSD-related medication was dispensed to 153 (55.6%) patients. The most common medication classes dispensed were selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (35.1%), novel antidepressants (15.6%), and anticonvulsants (15.0%). The most frequently dispensed PTSD-related medications were zolpidem: 149 (9.8%), sertraline: 147 (9.7%), gabapentin: 134 (8.8%), prazosin: 111 (7.3%), and trazodone: 110 (7.2%). In the subgroup of 219 patients who received PTSD-related medications, overlapping periods of treatment between an SSRI and another PTSD-related medication occurred in 58 (26.5%) patients. Potential drug-drug interactions with this combination involved 44 (20.1%) patients; no adverse drug events were reported. Among these 44 patients, 55 different potential drug-drug interactions were identified. Conclusions: Patients receiving medications for PTSD are frequently treated with SSRIs or SNRIs and are likely to be prescribed more than 1 PTSD-related medication. PMID:27057415

  1. Sedation and antinociception induced by a new pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivative (LASSBio-873) is modulated by activation of muscarinic receptors.

    PubMed

    Mendes, Thaiana C F; Raimundo, Juliana M; Nascimento-Junior, Nailton M; Fraga, Carlos A M; Barreiro, Eliezer J; Sudo, Roberto T; Zapata-Sudo, Gisele

    2009-11-01

    New substances designed for the treatment of anxiety have previously been synthesized, which resulted in the identification of four new pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives structurally designed by using zolpidem as lead compound. Among them, LASSBio-873 was the most potent to produce analgesic, sedative and hypnotic effects. Thus, we investigated the possible mechanisms involved in LASSBio-873-induced sedation, as well as its effects on different models of inflammatory pain. LASSBio-873 (4 mg/kg) reduced locomotor activity of mice in the open field test from 205.2+/-25.6 to 87.6+/-16.2 movements/min. Atropine, a non-selective muscarinic antagonist, prevented the LASSBio-873-induced sedation and increased locomotor activity to 192.9+/-30.2 movements/min. In the formalin test, LASSBio-873 (4 mg/kg) significantly reduced the duration of nociceptive behavior during the inflammatory phase, reducing the control reactivity from 197.6+/-14.5s to 84.4+/-10.3s. Carrageenan reduced the latency for the animal reaction from 5.1+/-0.2s (control) to 2.1+/-0.3s which was completely reverted by LASSBio-873 (6 mg/kg) to 5.6+/-0.6s. Atropine prevented the LASSBio-873-induced antinociceptive and antihyperalgesic activities, indicating the interference of the cholinergic system. LASSBio-873 is a novel prototype of drug that modulates muscarinic activity and could be used for neuropsychiatric and cognitive disorders and other conditions associated to acute and chronic pain. PMID:19635495

  2. Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability

    PubMed Central

    Chetty, Manoranjenni; Rose, Rachel H.; Abduljalil, Khaled; Patel, Nikunjkumar; Lu, Gaohua; Cain, Theresa; Jamei, Masoud; Rostami-Hodjegan, Amin

    2014-01-01

    This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-rich physiologically based pharmacokinetic (PBPK) models with pharmacodynamics (PDs) models. Four distinct applications that were developed and tested are presented here. PBPK models were developed for metoprolol using different CYP2D6 genotypes based on in vitro data. Application of the models for prediction of phenotypic differences in the pharmacokinetics (PKs) and PD compared favorably with clinical data, demonstrating that these differences can be predicted prior to the availability of such data from clinical trials. In the second case, PK and PD data for an immediate release formulation of nifedipine together with in vitro dissolution data for a controlled release (CR) formulation were used to predict the PK and PD of the CR. This approach can be useful to pharmaceutical scientists during formulation development. The operational model of agonism was used in the third application to describe the hypnotic effects of triazolam, and this was successfully extrapolated to zolpidem by changing only the drug related parameters from in vitro experiments. This PBPK modeling approach can be useful to developmental scientists who which to compare several drug candidates in the same therapeutic class. Finally, differences in QTc prolongation due to quinidine in Caucasian and Korean females were successfully predicted by the model using free heart concentrations as an input to the PD models. This PBPK linked PD model was used to demonstrate a higher sensitivity to free heart concentrations of quinidine in Caucasian females, thereby providing a mechanistic understanding of a clinical observation. In general, permutations of certain conditions which potentially change PK and hence PD may not be amenable to the conduct of clinical studies but linking PBPK with PD provides an alternative method of investigating the potential impact of PK changes on PD. PMID:25505415

  3. Drug Use on Mont Blanc: A Study Using Automated Urine Collection

    PubMed Central

    Robach, Paul; Trebes, Gilles; Lasne, Françoise; Buisson, Corinne; Méchin, Nathalie; Mazzarino, Monica; de la Torre, Xavier; Roustit, Matthieu; Kérivel, Patricia; Botré, Francesco; Bouzat, Pierre

    2016-01-01

    Mont Blanc, the summit of Western Europe, is a popular but demanding high-altitude ascent. Drug use is thought to be widespread among climbers attempting this summit, not only to prevent altitude illnesses, but also to boost physical and/or psychological capacities. This practice may be unsafe in this remote alpine environment. However, robust data on medication during the ascent of Mont Blanc are lacking. Individual urine samples from male climbers using urinals in mountain refuges on access routes to Mont Blanc (Goûter and Cosmiques mountain huts) were blindly and anonymously collected using a hidden automatic sampler. Urine samples were screened for a wide range of drugs, including diuretics, glucocorticoids, stimulants, hypnotics and phosphodiesterase 5 (PDE-5) inhibitors. Out of 430 samples analyzed from both huts, 35.8% contained at least one drug. Diuretics (22.7%) and hypnotics (12.9%) were the most frequently detected drugs, while glucocorticoids (3.5%) and stimulants (3.1%) were less commonly detected. None of the samples contained PDE-5 inhibitors. Two substances were predominant: the diuretic acetazolamide (20.6%) and the hypnotic zolpidem (8.4%). Thirty three samples were found positive for at least two substances, the most frequent combination being acetazolamide and a hypnotic (2.1%). Based on a novel sampling technique, we demonstrate that about one third of the urine samples collected from a random sample of male climbers contained one or several drugs, suggesting frequent drug use amongst climbers ascending Mont Blanc. Our data suggest that medication primarily aims at mitigating the symptoms of altitude illnesses, rather than enhancing performance. In this hazardous environment, the relatively high prevalence of hypnotics must be highlighted, since these molecules may alter vigilance. PMID:27253728

  4. A multi-targeted liquid chromatography-mass spectrometry screening procedure for the detection in human urine of drugs non-prohibited in sport commonly used by the athletes.

    PubMed

    Mazzarino, Monica; Cesarei, Lorenzo; de la Torre, Xavier; Fiacco, Ilaria; Robach, Paul; Botrè, Francesco

    2016-01-01

    This work presents an analytical method for the simultaneous analysis in human urine of 38 pharmacologically active compounds (19 benzodiazepine-like substances, 7 selective serotonin reuptake inhibitors, 4 azole antifungal drugs, 5 inhibitors of the phosphodiesterases type 4 and 3 inhibitors of the phosphodiesterase type 5) by liquid-chromatography coupled with tandem mass spectrometry. The above substances classes include both the most common "non banned" drugs used by the athletes (based on the information reported on the "doping control form") and those drugs who are suspected to be performance enhancing and/or act as masking agents in particular conditions. The chromatographic separation was performed by a reverse-phase octadecyl column using as mobile phases acetonitrile and ultra-purified water, both with 0.1% formic acid. The detection was carried out using a triple quadrupole mass spectrometric analyser, positive electro-spray as ionization source and selected reaction monitoring as acquisition mode. Sample pre-treatment consisted in an enzymatic hydrolysis followed by a liquid-liquid extraction in neutral field using tert-butyl methyl-ether. The analytical procedure, once developed, was validated in terms of sensitivity (lower limits of detection in the range of 1-50 ng mL(-1)), specificity (no interferences were detected at the retention time of all the analytes under investigation), recovery (≥60% with a satisfactory repeatability, CV % lower than 10), matrix effect (lower than 30%) and reproducibility of retention times (CV% lower than 0.1) and of relative abundances (CV% lower than 15). The performance and the applicability of the method was evaluated by analyzing real samples containing benzodiazepines (alprazolam, diazepam, zolpidem or zoplicone) or inhibitors of the phosphodiesterases type 5 (sildenafil or vardenafil) and samples obtained incubating two of the phosphodiesterases type 4 studied (cilomilast or roflumilast) with pooled human liver

  5. GABAB Receptors, Schizophrenia and Sleep Dysfunction

    PubMed Central

    Kantrowitz, Joshua; Citrome, Leslie; Javitt, Daniel

    2016-01-01

    Evidence for an intrinsic relationship between sleep, cognition and the symptomatic manifestations of schizophrenia is accumulating. This review presents evidence for the possible utility of GABAB receptor agonists for the treatment of subjective and objective sleep abnormalities related to schizophrenia. At the phenotypic level, sleep disturbance occurs in 16–30% of patients with schizophrenia and is related to reduced quality of life and poor coping skills. On the neurophysiological level, studies suggest that sleep deficits reflect a core component of schizophrenia. Specifically, slow-wave sleep deficits, which are inversely correlated with cognition scores, are seen. Moreover, sleep plays an increasingly well documented role in memory consolidation in schizophrenia. Correlations of slow-wave sleep deficits with impaired reaction time and declarative memory have also been reported. Thus, both behavioural insomnia and sleep architecture are critical therapeutic targets in patients with schizophrenia. However, long-term treatment with antipsychotics often results in residual sleep dysfunction and does not improve slow-wave sleep, and adjunctive GABAA receptor modulators, such as benzodiazepines and zolpidem, can impair sleep architecture and cognition in schizophrenia. GABAB receptor agonists have therapeutic potential in schizophrenia. These agents have minimal effect on rapid eye movement sleep while increasing slow-wave sleep. Preclinical associations with increased expression of genes related to slow-wave sleep production and circadian rhythm function have also been reported. GABAB receptor deficits result in a sustained hyperdopaminergic state and can be reversed by a GABAB receptor agonist. Genetic, postmortem and electrophysiological studies also associate GABAB receptors with schizophrenia. While studies thus far have not shown significant effects, prior focus on the use of GABAB receptor agonists has been on the positive symptoms of schizophrenia, with

  6. Learning and Memory Deficits in Male Adult Mice Treated with a Benzodiazepine Sleep-Inducing Drug during the Juvenile Period

    PubMed Central

    Furukawa, Yusuke; Tanemura, Kentaro; Igarashi, Katsuhide; Ideta-Otsuka, Maky; Aisaki, Ken-Ichi; Kitajima, Satoshi; Kitagawa, Masanobu; Kanno, Jun

    2016-01-01

    Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, is also known to be important for brain development. Therefore, disturbances of GABA receptor (GABA-R) mediated signaling (GABA-R signal) during brain development may influence normal brain maturation and cause late-onset brain malfunctions. In this study, we examined whether the stimulation of the GABA-R signal during brain development induces late-onset adverse effects on the brain in adult male mice. To stimulate the GABA-R signal, we used either the benzodiazepine sleep-inducing drug triazolam (TZ) or the non-benzodiazepine drug zolpidem (ZP). We detected learning and memory deficits in mice treated with TZ during the juvenile period, as seen in the fear conditioning test. On the other hand, ZP administration during the juvenile period had little effect. In addition, decreased protein expression of GluR1 and GluR4, which are excitatory neurotransmitter receptors, was detected in the hippocampi of mice treated with TZ during the juvenile period. We measured mRNA expression of the immediate early genes (IEGs), which are neuronal activity markers, in the hippocampus shortly after the administration of TZ or ZP to juvenile mice. Decreased IEG expression was detected in mice with juvenile TZ administration, but not in mice with juvenile ZP administration. Our findings demonstrate that TZ administration during the juvenile period can induce irreversible learning and memory deficits in adult mice. It may need to take an extra care for the prescription of benzodiazepine sleep-inducing drugs to juveniles because it might cause learning and memory deficits. PMID:27489535

  7. Pharmacological modulation of the state of awareness in patients with disorders of consciousness: an overview.

    PubMed

    Mura, Elisa; Pistoia, Francesca; Sara, Marco; Sacco, Simona; Carolei, Antonio; Govoni, Stefano

    2014-01-01

    The neurobiological approach to consciousness moves from the assumption that all phenomenal experiences are based on neuronal activity in the brain. Consciousness has two main components: wakefulness and awareness. While it may be relatively easy to determine the neuronal correlates of wakefulness, it is not the same for awareness, of which the neural correlates are poorly understood. Knowledge of the circuitry and the neurochemistry of the sleep/wake condition is necessary but not sufficient to understand the circuitry and neurochemistry of consciousness. Disorders of consciousness (DOCs) include coma, vegetative state and minimally conscious state. The study of DOCs and of the electrophysiological changes underlying general anaesthesia-induced loss of consciousness may help in understanding the neuronal correlates of consciousness. In turn, the understanding of the neural bases of consciousness may help in designing interventions aimed at restoring consciousness in DOC patients. Sporadic cases of recovery from a DOC have been reported after the administration of various pharmacological agents (baclofen, zolpidem, amantadine etc.). This review provides an overview of such drugs, which are from various and diverging classes but can be grouped into two main categories: CNS stimulants and CNS depressants. The available data seem to suggest an awakening effect obtained with CNS depressants rather than stimulants, the latter being more effective at improving functional cognitive and behavioral recovery in patients who have spontaneously regained an appreciable level of consciousness. There is a need for more rigorous systematic trials and further investigation of the above treatments, with particular attention paid to their mechanisms of action and the neurotransmitters involved. PMID:24025054

  8. The hypocretin/orexin antagonist almorexant promotes sleep without impairment of performance in rats

    PubMed Central

    Morairty, Stephen R.; Wilk, Alan J.; Lincoln, Webster U.; Neylan, Thomas C.; Kilduff, Thomas S.

    2014-01-01

    The hypocretin receptor (HcrtR) antagonist almorexant (ALM) has potent hypnotic actions but little is known about neurocognitive performance in the presence of ALM. HcrtR antagonists are hypothesized to induce sleep by disfacilitation of wake-promoting systems whereas GABAA receptor modulators such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. To test the hypothesis that less functional impairment results from HcrtR antagonist-induced sleep, we evaluated the performance of rats in the Morris Water Maze in the presence of ALM vs. ZOL. Performance in spatial reference memory (SRM) and spatial working memory (SWM) tasks were assessed during the dark period after equipotent sleep-promoting doses (100 mg/kg, po) following undisturbed and sleep deprivation (SD) conditions. ALM-treated rats were indistinguishable from vehicle (VEH)-treated rats for all SRM performance measures (distance traveled, latency to enter, time within, and number of entries into, the target quadrant) after both the undisturbed and 6 h SD conditions. In contrast, rats administered ZOL showed impairments in all parameters measured compared to VEH or ALM in the undisturbed conditions. Following SD, ZOL-treated rats also showed impairments in all measures. ALM-treated rats were similar to VEH-treated rats for all SWM measures (velocity, time to locate the platform and success rate at finding the platform within 60 s) after both the undisturbed and SD conditions. In contrast, ZOL-treated rats showed impairments in velocity and in the time to locate the platform. Importantly, ZOL rats only completed the task 23–50% of the time while ALM and VEH rats completed the task 79–100% of the time. Thus, following equipotent sleep-promoting doses, ZOL impaired rats in both memory tasks while ALM rats performed at levels comparable to VEH rats. These results are consistent with the hypothesis that less impairment results from HcrtR antagonism than from GABAA-induced inhibition

  9. Hair analysis by liquid chromatography-tandem mass spectrometry in toxicological investigation of drug-facilitated crimes: report of 128 cases over the period June 2003-May 2004 in metropolitan Paris.

    PubMed

    Chèze, Marjorie; Duffort, Gaëlle; Deveaux, Marc; Pépin, Gilbert

    2005-10-01

    In recent years, reports of drug-facilitated crimes (DFC) have been increasing. The drugs involved are sometimes difficult to detect, because of their low dosages and the long time ellapsed between alleged DFC and blood and urine sampling. In order to detect benzodiazepines and benzodiazepine-like hypnotics, we developed an approach for hair analysis by liquid chromatography-tandem mass spectrometry using a triple stage quadrupole with an electrospray ionization (LC-ESI-MS/MS). Separation was performed on an Uptisphere ODB C18 column using a gradient of 2mM formate buffer and acetonitrile. For the 23 compounds studied, detection limits are lower than 2 pg/mg, but a specific extraction procedure is needed for 7-amino metabolites. Over a 1-year period within the city limits of Paris and three suburbs, we tested blood and urine from victims of sexual assaults, robbery and battery in which psychoactive substances were suspected of being involved. Hair was collected 4-8 weeks after the alleged DFC. Over the 128 cases studied, results of simultaneous analysis of blood, urine, and hair allowed us to conclude that 23 cases were real DFC. In 18 cases, no conclusion was possible since no hair was sampled and/or results were negative. In 56 cases, victims were previously using narcotics, cannabis, and/or a prescribed drug, according to the compounds detected in hair strands. Thirty-one cases were not DFC cases. This study indicates that the prevalence of zolpidem and clonazepam is high, followed by bromazepam, nordazepam, and midazolam. Others benzodiazepines and analogs are rare. LC-ESI-MS/MS is a good tool for toxicological investigations of DFC. Testing blood, urine, and hair by this technique may reveal drug presence, even if it was administered at a single therapeutic dose. That may be helpful to prosecute perpretators or to exclude a drug-facilitated crime. PMID:15922526

  10. Chemical abuse in the elderly: evidence from hair analysis.

    PubMed

    Kintz, Pascal; Villain, Marion; Cirimele, Vincent

    2008-04-01

    The use of a drug to modify a person's behavior for criminal gain is not a recent phenomenon. However, the recent increase in reports of drug-facilitated crimes (sexual assault, robbery) has caused some alarm in the general public. Drugs involved can be pharmaceuticals such as benzodiazepines (flunitrazepam, lorazepam, clonazepam), hypnotics (zopiclone, zolpidem), sedatives (neuroleptics, some antihistamines), or anesthetics (GHB, ketamine); drugs of abuse such as cannabis, ecstasy, or LSD; or, more often, ethanol. Mistreatment of older people, whether it is abuse or neglect, can be classified as physical, psychologic, or financial/material. Several types of mistreatment may occur simultaneously. Very few data are available in the international literature. It seems that mental abuse and neglect are more frequent, but physical abuse such as beating, pushing, kicking, and possibly sexual abuse have also been reported. Drugs used to facilitate sexual assaults can be difficult to detect (active products at low dosages, chemical instability), can possess amnesic properties, and can be rapidly cleared from the body (short half-life). In these situations, blood, or even urine, can be inadequate. This is the reason why some laboratories have developed an original approach based on hair testing. Hair was suggested as a valuable specimen in situations in which, as a result of a delay in reporting the crime, natural processes have eliminated the drug from typical biologic specimens. Hair analysis may be a useful adjunct to conventional drug testing in sexual assault. It should not be considered as an alternative to blood and urine analyses, but as a complement. Mass spectrometry/mass spectrometry technologies appear to be required for analyses in drug-facilitated cases. The experience of the authors is presented in cases involving the elderly and chemical poisoning. PMID:18367982

  11. Low Doses of Ethanol Enhance LTD-like Plasticity in Human Motor Cortex.

    PubMed

    Fuhl, Anna; Müller-Dahlhaus, Florian; Lücke, Caroline; Toennes, Stefan W; Ziemann, Ulf

    2015-12-01

    Humans liberally use ethanol for its facilitating effects on social interactions but its effects on central nervous system function remain underexplored. We have recently described that very low doses of ethanol abolish long-term potentiation (LTP)-like plasticity in human cortex, most likely through enhancement of tonic inhibition [Lücke et al, 2014, Neuropsychopharmacology 39:1508-18]. Here, we studied the effects of low-dose ethanol on long-term depression (LTD)-like plasticity. LTD-like plasticity was induced in human motor cortex by paired associative transcranial magnetic stimulation (PASLTD), and measured as decreases of motor evoked potential input-output curve (IO-curve). In addition, sedation was measured by decreases in saccade peak velocity (SPV). Ethanol in two low doses (EtOH<10mM, EtOH<20mM) was compared to single oral doses of alprazolam (APZ, 1mg) a classical benzodiazepine, and zolpidem (ZLP, 10 mg), a non-benzodiazepine hypnotic, in a double-blinded randomized placebo-controlled crossover design in ten healthy human subjects. EtOH<10mM and EtOH<20mM but not APZ or ZLP enhanced the PASLTD-induced LTD-like plasticity, while APZ and ZLP but not EtOH<10mM or EtOH<20mM decreased SPV. Non-sedating low doses of ethanol, easily reached during social drinking, enhance LTD-like plasticity in human cortex. This effect is most likely explained by the activation of extrasynaptic α4-subunit containing gamma-aminobutyric type A receptors by low-dose EtOH, resulting in increased tonic inhibition. Findings may stimulate cellular research on the role of tonic inhibition in regulating excitability and plasticity of cortical neuronal networks. PMID:26038159

  12. Isoflurane modulates excitability in the mouse thalamus via GABA-dependent and GABA-independent mechanisms.

    PubMed

    Ying, Shui-Wang; Werner, David F; Homanics, Gregg E; Harrison, Neil L; Goldstein, Peter A

    2009-02-01

    GABAergic neurons in the reticular thalamic nucleus (RTN) synapse onto thalamocortical neurons in the ventrobasal (VB) thalamus, and this reticulo-thalamocortical pathway is considered an anatomic target for general anesthetic-induced unconsciousness. A mutant mouse was engineered to harbor two amino acid substitutions (S270H, L277A) in the GABA(A) receptor (GABA(A)-R) alpha1 subunit; this mutation abolished sensitivity to the volatile anesthetic isoflurane in recombinant GABA(A)-Rs, and reduced in vivo sensitivity to isoflurane in the loss-of-righting-reflex assay. We examined the effects of the double mutation on GABA(A)-R-mediated synaptic currents and isoflurane sensitivity by recording from thalamic neurons in brain slices. The double mutation accelerated the decay, and decreased the (1/2) width of, evoked inhibitory postsynaptic currents (eIPSCs) in VB neurons and attenuated isoflurane-induced prolongation of the eIPSC. The hypnotic zolpidem, a selective modulator of GABA(A)-Rs containing the alpha1 subunit, prolonged eIPSC duration regardless of genotype, indicating that mutant mice incorporate alpha1 subunit-containing GABA(A)-Rs into synapses. In RTN neurons, which lack the alpha1 subunit, eIPSC duration was longer than in VB, regardless of genotype. Isoflurane reduced the efficacy of GABAergic transmission from RTN to VB, independent of genotype, suggesting a presynaptic action in RTN neurons. Consistent with this observation, isoflurane inhibited both tonic action potential and rebound burst firing in the presence of GABA(A)-R blockade. The suppressed excitability in RTN neurons is likely mediated by isoflurane-enhanced Ba(2+)-sensitive, but 4-aminopyridine-insenstive, potassium conductances. We conclude that isoflurane enhances inhibition of thalamic neurons in VB via GABA(A)-R-dependent, but in RTN via GABA(A)-R-independent, mechanisms. PMID:18948126

  13. Human locus coeruleus neurons express the GABA(A) receptor gamma2 subunit gene and produce benzodiazepine binding.

    PubMed

    Hellsten, Kati S; Sinkkonen, Saku T; Hyde, Thomas M; Kleinman, Joel E; Särkioja, Terttu; Maksimow, Anu; Uusi-Oukari, Mikko; Korpi, Esa R

    2010-06-21

    Noradrenergic neurons of the locus coeruleus project throughout the cerebral cortex and multiple subcortical structures. Alterations in the locus coeruleus firing are associated with vigilance states and with fear and anxiety disorders. Brain ionotropic type A receptors for gamma-aminobutyric acid (GABA) serve as targets for anxiolytic and sedative drugs, and play an essential regulatory role in the locus coeruleus. GABA(A) receptors are composed of a variable array of subunits forming heteropentameric chloride channels with different pharmacological properties. The gamma2 subunit is essential for the formation of the binding site for benzodiazepines, allosteric modulators of GABA(A) receptors that are clinically often used as sedatives/hypnotics and anxiolytics. There are contradictory reports in regard to the gamma2 subunit's expression and participation in the functional GABA(A) receptors in the mammalian locus coeruleus. We report here that the gamma2 subunit is transcribed and participates in the assembly of functional GABA(A) receptors in the tyrosine hydroxylase-positive neuromelanin-containing neurons within postmortem human locus coeruleus as demonstrated by in situ hybridization with specific gamma2 subunit oligonucleotides and autoradiographic assay for flumazenil-sensitive [(3)H]Ro 15-4513 binding to benzodiazepine sites. These sites were also sensitive to the alpha1 subunit-preferring agonist zolpidem. Our data suggest a species difference in the expression profiles of the alpha1 and gamma2 subunits in the locus coeruleus, with the sedation-related benzodiazepine sites being more important in man than rodents. This may explain the repeated failures in the transition of novel drugs with a promising neuropharmacological profile in rodents to human clinical usage, due to intolerable sedative effects. PMID:20417252

  14. Amygdala-specific reduction of alpha1-GABAA receptors disrupts the anticonvulsant, locomotor, and sedative, but not anxiolytic, effects of benzodiazepines in mice.

    PubMed

    Heldt, Scott A; Ressler, Kerry J

    2010-05-26

    The heterogeneity and distribution of GABA(A) receptor subunits mediates differential roles in behavior. It is thought that particular behavioral responses to benzodiazepine (BZ) ligands might be associated with an action at a regionally defined receptor subtype. However, the role of specific GABA(A) receptor subtypes in particular brain regions is less clear. Such detailed knowledge of regional alpha1-GABA(A) receptor function will advance our understanding of the neural circuitry underlying the role of GABA(A) receptors and the effects of GABA(A)-modulating drugs on behavior. By combining inducible, site-specific alpha1 subunit deletion, using a lentivirus expressing Cre-recombinase in mice with the alpha1 subunit gene flanked by loxP sites, we examine baseline and pharmacological effects of deletion of amygdala alpha1-GABA(A) receptors. We find that amygdala-specific reduction of alpha1 receptor subunits does not affect mRNA or protein levels of amygdala alpha2 or alpha3 subunit receptors. Nor does this inducible reduction affect baseline locomotion or measures of anxiety. However, we also find that this inducible, site-specific deletion does disrupt the normal sedative-locomotor inhibition as well as the anticonvulsive effects, of two distinct BZ-site ligands, diazepam and zolpidem, which is relatively alpha1-subunit selective. These data, using inducible, region and subunit-specific deletion, combined with pharmacogenetic approaches, demonstrate that amygdala expression of the alpha1-GABA(A) receptor subunit is required for normal BZ effects on sedation, locomotion, and seizure inhibition, but not for anxiolysis. PMID:20505082

  15. Risk of severe driver injury by driving with psychoactive substances.

    PubMed

    Hels, Tove; Lyckegaard, Allan; Simonsen, Kirsten Wiese; Steentoft, Anni; Bernhoft, Inger Marie

    2013-10-01

    Driving with alcohol and other psychoactive substances imposes an increased risk of severe injury accidents. In a population-based case-control design, the relative risks of severe driver injury (MAIS≥2) by driving with ten substance groups were approximated by odds ratios (alcohol, amphetamines, benzoylecgonine, cocaine, cannabis, illicit opiates, benzodiazepines and Z-drugs, i.e. zolpidem and zopiclone, medicinal opioids, alcohol-drug combinations and drug-drug combinations). Data from six countries were included in the study: Belgium, Denmark, Finland, Italy, Lithuania and the Netherlands. Case samples (N=2490) were collected from severely injured drivers of passenger cars or vans in selected hospitals in various regions of the countries. Control samples (N=15,832) were sampled in a uniform sampling scheme stratified according to country, time, road type and season. Relative risks were approximated by odds ratios and calculated by logistic regression. The estimates were adjusted for age, gender and country. The highest risk of the driver being severely injured was associated with driving positive for high concentrations of alcohol (≥0.8 g/L), alone or in combination with other psychoactive substances. For alcohol, risk increased exponentially with blood alcohol concentration (BAC). The second most risky category contained various drug-drug combinations, amphetamines and medicinal opioids. Medium increased risk was associated with medium sized BACs (at or above 0.5 g/L, below 0.8 g/L) and benzoylecgonine. The least risky drug seemed to be cannabis and benzodiazepines and Z-drugs. For male drivers, the risk of being severely injured by driving with any of the psychoactive substances was about 65% of that of female drivers. For each of the substance groups there was a decrease in the risk of severe driver injury with increasing age. It is concluded that among psychoactive substances alcohol still poses the largest problem in terms of driver risk of getting

  16. Reducing Prescriptions of Long-Acting Benzodiazepine Drugs in Denmark: A Descriptive Analysis of Nationwide Prescriptions during a 10-Year Period.

    PubMed

    Eriksen, Sophie Isabel; Bjerrum, Lars

    2015-06-01

    Prolonged consumption of benzodiazepine drugs (BZD) and benzodiazepine receptor agonists (zolpidem, zaleplon, zopiclone; altogether Z drugs) is related to potential physiological and psychological dependence along with other adverse effects. This study aimed to analyse the prescribing of long-acting BZD (half-life >10 hr), compared to short-acting BZD in Denmark during a 10-year period. Descriptive analysis of total sales data from the Danish Register of Medicinal Product Statistics, to individuals in the primary healthcare sector, of all BZD and Z drugs in the period of 2003-2013. Prescription data derive from all community and hospital pharmacies in Denmark. The prescribing of long-acting BZD was reduced from 25.8 defined daily doses (DDD)/1000 inhabitants/day in 2003 to 8.8 DDD/1000 inhabitants/day in 2013, a relative reduction of 66%. The prescribing of short-acting BZD was reduced from 26.1 DDD/1000 inhabitants/day in 2003 to 16.4 DDD/1000 inhabitants/day in 2013, a relative reduction of 37%. Prescription data in this study did not include information about indications for initiating treatments. In addition, due to compliance problems, some of the prescribed drugs may not have been consumed according to the prescription. The observed reduction in BZD use was correlated to the introduction of new national guidelines on prescription of addictive drugs, but this study was not designed to detect a causal relationship. The prescribing of long-acting BZD decreased considerably more than the prescribing of short-acting BZD in the 10-year period. PMID:25382355

  17. [Catatonia].

    PubMed

    Pot, A-L; Lejoyeux, M

    2015-06-01

    In the new classification of the DSM-V, catatonia is individualized as a disease of its own. It is defined by presence of at least two out of five criteria: motor immobility, negativism, echolalia or echopraxia, sterile motor activity, atypical movements. The priority is to look first for organic causes: the main ones are neurologic disorders. Intoxication may also be found (illegal drugs or medication), and the role of neuroleptic malignant syndrome in catatonia remains unclear. Among the psychiatric causes, first come bipolar disorders, especially mania; then schizophrenia. Idiopathic forms can also be observed. Epidemiological work on catatonia show highly variable results, highlighting a possible underestimation of the diagnosis. Among the differential diagnoses, which are rare motor syndromes, neuroleptic malignant syndrome and serotonin syndrome are also discussed. The diagnosis of catatonia is clinical and can be obtained using standardized diagnostic scales. The use of zolpidem provides both a diagnostic and therapeutic guidance for the degree of response to drug treatment. The physiopathological hypotheses describe an intracerebral GABAergic, dopaminergic and glutamatergic dysfunction in catatonic patients. The complete mechanisms are still partly unknown. Benzodiazepines are the first treatment of choice. Electroconvulsive therapy is used secondarily or in severe cases. First-generation antipsychotics are prohibited, at the risk of worsening the catatonia in becoming malignant and lethal. The renewed interest in the catatonic syndrome during the past recent years has expanded research on the mechanisms of this syndrome and opened the way to new therapeutic options. The latest works tend to modulate the strict prohibition of antipsychotic in a catatonic patient. PMID:25858694

  18. Is suvorexant a better choice than alternative hypnotics?

    PubMed

    Kripke, Daniel F

    2015-01-01

    Suvorexant is a novel dual orexin receptor antagonist (DORA) newly introduced in the U.S. as a hypnotic, but no claim of superiority over other hypnotics has been offered.  The manufacturer argued that the 5 and 10 mg starting doses recommended by the FDA might be ineffective.  The manufacturer's main Phase III trials had not even included the 10 mg dosage, and the 5 mg dosage had not been tested at all in registered clinical trials at the time of approval.  Popular alternative hypnotics may be similarly ineffective, since the FDA has also reduced the recommended doses for zolpidem and eszopiclone.  The "not to exceed" suvorexant dosage of 20 mg does slightly increase sleep.  Because of slow absorption, suvorexant has little effect on latency to sleep onset but some small effect in suppressing wakening after sleep onset and in improving sleep efficiency. The FDA would not approve the manufacturer's preferred 40 mg suvorexant dosage, because of concern with daytime somnolence, driving impairment, and possible narcolepsy-like symptoms.  In its immediate benefits-to-risks ratio, suvorexant is unlikely to prove superior to currently available hypnotics-possibly worse-so there is little reason to prefer over the alternatives this likely more expensive hypnotic less-tested in practice.  Associations are being increasingly documented relating hypnotic usage with incident cancer, with dementia risks, and with premature death.  There is some basis to speculate that suvorexant might be safer than alternative hypnotics in terms of cancer, dementia, infections, and mortality.  These safety considerations will remain unproven speculations unless adequate long-term trials can be done that demonstrate suvorexant advantages. PMID:26594338

  19. Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain.

    PubMed

    Vazquez-DeRose, Jacqueline; Schwartz, Michael D; Nguyen, Alexander T; Warrier, Deepti R; Gulati, Srishti; Mathew, Thomas K; Neylan, Thomas C; Kilduff, Thomas S

    2016-03-01

    Hypocretin/orexin (HCRT) neurons provide excitatory input to wake-promoting brain regions including the basal forebrain (BF). The dual HCRT receptor antagonist almorexant (ALM) decreases waking and increases sleep. We hypothesized that HCRT antagonists induce sleep, in part, through disfacilitation of BF neurons; consequently, ALM should have reduced efficacy in BF-lesioned (BFx) animals. To test this hypothesis, rats were given bilateral IgG-192-saporin injections, which predominantly targets cholinergic BF neurons. BFx and intact rats were then given oral ALM, the benzodiazepine agonist zolpidem (ZOL) or vehicle (VEH) at lights-out. ALM was less effective than ZOL at inducing sleep in BFx rats compared to controls. BF adenosine (ADO), γ-amino-butyric acid (GABA), and glutamate levels were then determined via microdialysis from intact, freely behaving rats following oral ALM, ZOL or VEH. ALM increased BF ADO and GABA levels during waking and mixed vigilance states, and preserved sleep-associated increases in GABA under low and high sleep pressure conditions. ALM infusion into the BF also enhanced cortical ADO release, demonstrating that HCRT input is critical for ADO signaling in the BF. In contrast, oral ZOL and BF-infused ZOL had no effect on ADO levels in either BF or cortex. ALM increased BF ADO (an endogenous sleep-promoting substance) and GABA (which is increased during normal sleep), and required an intact BF for maximal efficacy, whereas ZOL blocked sleep-associated BF GABA release, and required no functional contribution from the BF to induce sleep. ALM thus induces sleep by facilitating the neural mechanisms underlying the normal transition to sleep. PMID:25431268

  20. Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia.

    PubMed

    Bonaventure, Pascal; Shelton, Jonathan; Yun, Sujin; Nepomuceno, Diane; Sutton, Steven; Aluisio, Leah; Fraser, Ian; Lord, Brian; Shoblock, James; Welty, Natalie; Chaplan, Sandra R; Aguilar, Zuleima; Halter, Robin; Ndifor, Anthony; Koudriakova, Tatiana; Rizzolio, Michele; Letavic, Michael; Carruthers, Nicholas I; Lovenberg, Timothy; Dugovic, Christine

    2015-09-01

    Dual orexin receptor antagonists have been shown to promote sleep in various species, including humans. Emerging research indicates that selective orexin-2 receptor (OX2R) antagonists may offer specificity and a more adequate sleep profile by preserving normal sleep architecture. Here, we characterized JNJ-42847922 ([5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone), a high-affinity/potent OX2R antagonist. JNJ-42847922 had an approximate 2-log selectivity ratio versus the human orexin-1 receptor. Ex vivo receptor binding studies demonstrated that JNJ-42847922 quickly occupied OX2R binding sites in the rat brain after oral administration and rapidly cleared from the brain. In rats, single oral administration of JNJ-42847922 (3-30 mg/kg) during the light phase dose dependently reduced the latency to non-rapid eye movement (NREM) sleep and prolonged NREM sleep time in the first 2 hours, whereas REM sleep was minimally affected. The reduced sleep onset and increased sleep duration were maintained upon 7-day repeated dosing (30 mg/kg) with JNJ-42847922, then all sleep parameters returned to baseline levels following discontinuation. Although the compound promoted sleep in wild-type mice, it had no effect in OX2R knockout mice, consistent with a specific OX2R-mediated sleep response. JNJ-42847922 did not increase dopamine release in rat nucleus accumbens or produce place preference in mice after subchronic conditioning, indicating that the compound lacks intrinsic motivational properties in contrast to zolpidem. In a single ascending dose study conducted in healthy subjects, JNJ-42847922 increased somnolence and displayed a favorable pharmacokinetic and safety profile for a sedative/hypnotic, thus emerging as a promising candidate for further clinical development for the treatment of insomnia. PMID:26177655

  1. Functional properties of GABA synaptic inputs onto GABA neurons in monkey prefrontal cortex.

    PubMed

    Rotaru, Diana C; Olezene, Cameron; Miyamae, Takeaki; Povysheva, Nadezhda V; Zaitsev, Aleksey V; Lewis, David A; Gonzalez-Burgos, Guillermo

    2015-03-15

    In rodent cortex GABAA receptor (GABAAR)-mediated synapses are a significant source of input onto GABA neurons, and the properties of these inputs vary among GABA neuron subtypes that differ in molecular markers and firing patterns. Some features of cortical interneurons are different between rodents and primates, but it is not known whether inhibition of GABA neurons is prominent in the primate cortex and, if so, whether these inputs show heterogeneity across GABA neuron subtypes. We thus studied GABAAR-mediated miniature synaptic events in GABAergic interneurons in layer 3 of monkey dorsolateral prefrontal cortex (DLPFC). Interneurons were identified on the basis of their firing pattern as fast spiking (FS), regular spiking (RS), burst spiking (BS), or irregular spiking (IS). Miniature synaptic events were common in all of the recorded interneurons, and the frequency of these events was highest in FS neurons. The amplitude and kinetics of miniature inhibitory postsynaptic potentials (mIPSPs) also differed between DLPFC interneuron subtypes in a manner correlated with their input resistance and membrane time constant. FS neurons had the fastest mIPSP decay times and the strongest effects of the GABAAR modulator zolpidem, suggesting that the distinctive properties of inhibitory synaptic inputs onto FS cells are in part conferred by GABAARs containing α1 subunits. Moreover, mIPSCs differed between FS and RS interneurons in a manner consistent with the mIPSP findings. These results show that in the monkey DLPFC GABAAR-mediated synaptic inputs are prominent in layer 3 interneurons and may differentially regulate the activity of different interneuron subtypes. PMID:25540225

  2. Determinants of cortisol awakening responses to naps and nighttime sleep.

    PubMed

    Devine, Jaime K; Wolf, Jutta M

    2016-01-01

    The cortisol awakening response (CAR) is a phenomenon describing the sharp increase in basal cortisol levels shortly after waking from sleep. While extensively studied, little is known about the role of sleep architecture contributing to CAR. Furthermore, the potential for CAR after a shorter bout of sleep--a nap--has not been directly investigated. The current studies thus aimed at assessed sleep duration, time of day, and sleep architecture as potential determinants of the cortisol awakening response. Saliva samples were collected during the first hour (0, 30, 45, 60 min) following several EEG-monitored laboratory sleep conditions. Those included afternoon naps wherein 17 participants (4 men; ages 18-26) napped for 50 min and 24 participants (11 men; ages 18-24) napped for 90 min. Furthermore, 20 participants (10 men; ages 18-35) visited the lab twice and in addition to staying overnight, napped 90 min in the morning either under placebo conditions or pharmacologically-manipulated sleep conditions (5mg Zolpidem). Cortisol increases were observed in response to each sleep condition except to 50-min afternoon naps. Furthermore, CARs were predicted by Stage 2 sleep when following nighttime sleep (r=.46, p=.04) and by Stage 1 sleep when following placebo morning naps (r=.54, p=.01). The current study established cortisol awakening responses to naps and implicates sleep duration and architecture in the generation of CAR to both napping and nighttime sleep. Assessing CAR in conjunction with the specific type of sleep may thus contribute to our understanding of mechanisms underlying positive and negative health effects of napping. PMID:26441231

  3. The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems.

    PubMed

    Parks, Gregory S; Warrier, Deepti R; Dittrich, Lars; Schwartz, Michael D; Palmerston, Jeremiah B; Neylan, Thomas C; Morairty, Stephen R; Kilduff, Thomas S

    2016-03-01

    The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wake-promoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH- or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos(+) cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH- and ALM-treated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL- but not in VEH- or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL. PMID:26289145

  4. Seeking potential anticonvulsant agents that target GABAA receptors using experimental and theoretical procedures.

    PubMed

    Saavedra-Vélez, Margarita Virginia; Correa-Basurto, José; Matus, Myrna H; Gasca-Pérez, Eloy; Bello, Martiniano; Cuevas-Hernández, Roberto; García-Rodríguez, Rosa Virginia; Trujillo-Ferrara, José; Ramos-Morales, Fernando Rafael

    2014-12-01

    The aim of this study was to identify compounds that possess anticonvulsant activity by using a pentylenetetrazol (PTZ)-induced seizure model. Theoretical studies of a set of ligands, explored the binding affinities of the ligands for the GABA(A) receptor (GABA(A)R), including some benzodiazepines. The ligands satisfy the Lipinski rules and contain a pharmacophore core that has been previously reported to be a GABA(A)R activator. To select the ligands with the best physicochemical properties, all of the compounds were analyzed by quantum mechanics and the energies of the highest occupied molecular orbital and lowest unoccupied molecular orbital were determined. Docking calculations between the ligands and the GABA(A)R were used to identify the complexes with the highest Gibbs binding energies. The identified compound D1 (dibenzo(b,f)(1,4)diazocine-6,11(5H,12H)-dione) was synthesized, experimentally tested, and the GABA(A)R-D1 complex was submitted to 12-ns-long molecular dynamics (MD) simulations to corroborate the binding conformation obtained by docking techniques. MD simulations were also used to analyze the decomposition of the Gibbs binding energy of the residues involved in the stabilization of the complex. To validate our theoretical results, molecular docking and MD simulations were also performed for three reference compounds that are currently in commercial use: clonazepam (CLZ), zolpidem and eszopiclone. The theoretical results show that the GABA(A)R-D1, and GABA(A)R-CLZ complexes bind to the benzodiazepine binding site, share a similar map of binding residues, and have similar Gibbs binding energies and entropic components. Experimental studies using a PTZ-induced seizure model showed that D1 possesses similar activity to CLZ, which corroborates the predicted binding free energy identified by theoretical calculations. PMID:25298123

  5. Toxicological screening of human plasma by on-line SPE-HPLC-DAD: identification and quantification of basic drugs and metabolites.

    PubMed

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

    2015-06-01

    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. PMID:25400270

  6. Low-Dose Atypical Antipsychotic Risperidone Improves the 5-Year Outcome in Alzheimer's Disease Patients with Sleep Disturbances.

    PubMed

    Yin, You; Liu, Yan; Zhuang, Jianhua; Pan, Xiao; Li, Peng; Yang, Yuechang; Li, Yan-Peng; Zhao, Zheng-Qing; Huang, Liu-Qing; Zhao, Zhong-Xin

    2015-01-01

    Sleep disturbances (SD) accelerate the progression of Alzheimer's disease (AD) and increase the stress of caregivers. However, the long-term outcome of disturbed nocturnal sleep/wake patterns in AD and on increased stress of spousal caregivers is unclear. This study assessed the 5-year effect of nocturnal SD on the long-term outcome in AD patients. A total of 156 donepezil-treated mild-moderate AD patients (93 AD + SD and 63 AD - SD as a control group) were recruited. The AD + SD patients were formed into 4 subgroups according to the preferences of spousal caregivers for treatment with atypical antipsychotics (0.5-1 mg risperidone, n = 22), non-benzodiazepine hypnotic (5-10 mg zolpidem tartrate, n = 33), melatonin (2.55 mg, n = 9), or no-drug treatment (n = 29). SD were evaluated by polysomnography, sleep scale, and cognitive scale examinations. Moreover, all spousal caregivers of AD patients were assessed using a series of scales, including sleep, anxiety, mood, and treatment attitude scales. Our data showed that nocturnal sleep/wake disturbances were significantly associated with lower 5-year outcomes for AD patients, earlier nursing home placement, and more negative emotions of spousal caregivers. Treatment with low-dose atypical antipsychotic risperidone improved the 5-year outcome in AD + SD patients. In conclusion, low-dose atypical antipsychotic risperidone improves the 5-year outcome in AD patients with SD. Moreover, improvement of nocturnal sleep problems in AD patients will also bring better emotional stability for AD caregivers. PMID:26279176

  7. Learning and Memory Deficits in Male Adult Mice Treated with a Benzodiazepine Sleep-Inducing Drug during the Juvenile Period.

    PubMed

    Furukawa, Yusuke; Tanemura, Kentaro; Igarashi, Katsuhide; Ideta-Otsuka, Maky; Aisaki, Ken-Ichi; Kitajima, Satoshi; Kitagawa, Masanobu; Kanno, Jun

    2016-01-01

    Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, is also known to be important for brain development. Therefore, disturbances of GABA receptor (GABA-R) mediated signaling (GABA-R signal) during brain development may influence normal brain maturation and cause late-onset brain malfunctions. In this study, we examined whether the stimulation of the GABA-R signal during brain development induces late-onset adverse effects on the brain in adult male mice. To stimulate the GABA-R signal, we used either the benzodiazepine sleep-inducing drug triazolam (TZ) or the non-benzodiazepine drug zolpidem (ZP). We detected learning and memory deficits in mice treated with TZ during the juvenile period, as seen in the fear conditioning test. On the other hand, ZP administration during the juvenile period had little effect. In addition, decreased protein expression of GluR1 and GluR4, which are excitatory neurotransmitter receptors, was detected in the hippocampi of mice treated with TZ during the juvenile period. We measured mRNA expression of the immediate early genes (IEGs), which are neuronal activity markers, in the hippocampus shortly after the administration of TZ or ZP to juvenile mice. Decreased IEG expression was detected in mice with juvenile TZ administration, but not in mice with juvenile ZP administration. Our findings demonstrate that TZ administration during the juvenile period can induce irreversible learning and memory deficits in adult mice. It may need to take an extra care for the prescription of benzodiazepine sleep-inducing drugs to juveniles because it might cause learning and memory deficits. PMID:27489535

  8. Drug Use on Mont Blanc: A Study Using Automated Urine Collection.

    PubMed

    Robach, Paul; Trebes, Gilles; Lasne, Françoise; Buisson, Corinne; Méchin, Nathalie; Mazzarino, Monica; de la Torre, Xavier; Roustit, Matthieu; Kérivel, Patricia; Botré, Francesco; Bouzat, Pierre

    2016-01-01

    Mont Blanc, the summit of Western Europe, is a popular but demanding high-altitude ascent. Drug use is thought to be widespread among climbers attempting this summit, not only to prevent altitude illnesses, but also to boost physical and/or psychological capacities. This practice may be unsafe in this remote alpine environment. However, robust data on medication during the ascent of Mont Blanc are lacking. Individual urine samples from male climbers using urinals in mountain refuges on access routes to Mont Blanc (Goûter and Cosmiques mountain huts) were blindly and anonymously collected using a hidden automatic sampler. Urine samples were screened for a wide range of drugs, including diuretics, glucocorticoids, stimulants, hypnotics and phosphodiesterase 5 (PDE-5) inhibitors. Out of 430 samples analyzed from both huts, 35.8% contained at least one drug. Diuretics (22.7%) and hypnotics (12.9%) were the most frequently detected drugs, while glucocorticoids (3.5%) and stimulants (3.1%) were less commonly detected. None of the samples contained PDE-5 inhibitors. Two substances were predominant: the diuretic acetazolamide (20.6%) and the hypnotic zolpidem (8.4%). Thirty three samples were found positive for at least two substances, the most frequent combination being acetazolamide and a hypnotic (2.1%). Based on a novel sampling technique, we demonstrate that about one third of the urine samples collected from a random sample of male climbers contained one or several drugs, suggesting frequent drug use amongst climbers ascending Mont Blanc. Our data suggest that medication primarily aims at mitigating the symptoms of altitude illnesses, rather than enhancing performance. In this hazardous environment, the relatively high prevalence of hypnotics must be highlighted, since these molecules may alter vigilance. PMID:27253728

  9. Fatal intravenous fentanyl abuse: four cases involving extraction of fentanyl from transdermal patches.

    PubMed

    Tharp, Amy M; Winecker, Ruth E; Winston, David C

    2004-06-01

    The transdermal fentanyl system delivers a specific dose at a constant rate. Even after the prescribed application time has elapsed, enough fentanyl remains within a patch to provide a potentially lethal dose. Death due to the intravenous injection of fentanyl extracted from transdermal patches has not been previously reported. We present 4 cases in which the source of fentanyl was transdermal patches and was injected. In all of these cases, the victim was a white male who died at home. Case 1 was a 35-year-old with no known history of drug use, who was found by his wife on the floor of his workshop. Police recovered a fentanyl patch, needle, and syringe at the scene. Case 2 was a 38-year-old with a known history of drug use whose family claimed that he was in a treatment program that used fentanyl patches for unknown reasons. His brother found him dead in bed, and law enforcement officers found a hypodermic needle beside the body; a ligature around his left hand, and apparent needle marks between his first and second digits were also noted. Case 3 was a 42-year-old with a recent attempted suicide via overdose who was found dead at his home. An empty box of fentanyl patches, Valium, Ritalin, and 2 syringes were found at the scene. Case 4 was a 39-year-old found by his mother, who admitted to removing a needle with attached syringe from the decedent's arm. Medications at the scene included hydrocodone, alprazolam, zolpidem, and fentanyl patches. All reported deaths were attributed to fentanyl intoxication, with blood concentrations ranging from 5 to 27 microg/L. PMID:15166776

  10. SB242084, flumazenil, and CRA1000 block ethanol withdrawal-induced anxiety in rats.

    PubMed

    Knapp, Darin J; Overstreet, David H; Moy, Sheryl S; Breese, George R

    2004-02-01

    Anxiety-like behaviors are integral features of withdrawal from chronic ethanol exposure. In the experiments in the current study, we tested the hypothesis that anxiety can be regulated independently of other withdrawal signs and thus may be responsive to selective pharmacological agents. For 17 days, rats were fed ethanol (8-12 g/kg/day) in a liquid diet. Between 5 and 6 h after cessation of ethanol treatment, rats were tested in either the social interaction or plus-maze test of anxiety-like behavior after treatment with drugs hypothesized to have anxiolytic action. SB242084, flumazenil, and CRA1000-antagonists for 5-hydroxytryptamine (serotonin) (5-HT) 2C (5-HT(2C)), benzodiazepine, and corticotropin-releasing factor type 1 (CRF(1)) receptors, respectively-attenuated decreased social interaction without concomitant effects on activity measures. In contrast, ifenprodil, MDL 72222, and zolpidem-antagonists for N-methyl-d-aspartate (NMDA) and 5-HT(3) receptors, and agonist for benzodiazepine type 1 receptors, respectively-did not share this effect. Results for SB242084, flumazenil, and ifenprodil in the elevated plus-maze test were comparable to those in the social interaction test. These results support the suggestion that multiple neuronal systems (CRF(1), 5-HT(2C), and benzodiazepine receptors) contribute to the ethanol withdrawal sign of decreased social interaction. Furthermore, the selective effects of pharmacological agents on social interaction seem to indicate that this behavior can be dissociated from other signs. Because anxiety may be a complicating factor in alcohol withdrawal and relapse, future studies of this type are needed to provide focus for the effort to define selective and novel antianxiety agents for these disorders. PMID:15163561