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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. 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

  19. [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

  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. 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

  2. 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

  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. 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

  7. 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

  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. 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

  10. 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

  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

    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

  9. 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

  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. 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

  13. 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

  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. 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

  16. 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

  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

    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

  20. 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

  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. 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

  5. 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

  6. 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

  7. 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

  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. 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

  11. 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

  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. 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

  2. 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

  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. 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

  14. 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

  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. 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

  3. 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

  4. 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 ...

  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. 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

  13. 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

  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. 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

  18. 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

  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. 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

  6. 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

  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. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. [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

  17. 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

  18. 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

  19. 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

  20. 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

  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. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. [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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  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. 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

  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. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. [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

  7. 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

  8. 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

  9. [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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. [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

  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. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  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. 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

  13. 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

  14. 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

  15. [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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  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

  11. On sopro do magnetar

    NASA Astrophysics Data System (ADS)

    Allen, M. P.; Horvath, J. E.

    2003-08-01

    Magnetares sao estrelas de nêutrons com campos magnéticos acima do limiar quântico de 4,4´1013 G. Por causa desse intenso campo magnético, que exige período de rotação inicial da ordem de 1 ms, o torque eletromagnético é capaz de injetar 2´1052 erg, em menos de um dia, no Remanescente de Supernova (RSN) formado por ocasião da formação do magnetar. A energia injetada acelera a expansão do RSN, de modo que estimativas de idade do RSN feitas sem considerar a injeção de energia superestimarão a idade verdadeira. Além do cenário usual de formação de magnetares em colapsos gravitacionais de estrelas massivas, estudamos a possibilidade de formação dos mesmos através do Colapso Induzido por Acresção em anãs brancas. Estudamos, através de simulação numérica unidimensional, com diversas massas ejetadas e diversas densidades de meio interestelar local, as associações propostas entre candidatos a magnetar e RSNs, incluindo a injeção de energia. Concluímos que aproximadamente metade delas podem ser verdadeiras, e determinamos a faixa de velocidades e idades possíveis de cada associação. As incertezas observacionais a respeito do tamanho e densidade do meio interestelar local limitam a acurácia da análise.

  12. Environments with Families in Mind: Beginnings Workshop.

    ERIC Educational Resources Information Center

    Pelo, Ann; Garrett, Julie; Hilliard, Deadru; Cecil, Jane; Cothran, Kimberly; White, Lynn; Bergman, Roberta; Gainer, Sue; Albrecht, Kay

    2002-01-01

    Five articles suggest ways to design welcoming, comforting, supporting, stimulating caregiving environments that are respectful to children and families: (1) "From Borders to Bridges: Transforming Our Relationships with Parents" (Ann Pelo); (2) "Supporting Multicultural, Multilingual Families" (Julie Garrett); (3) "Making Families Welcome" (Deadru…

  13. Fifty-year flood-inundation maps for El Progreso, Honduras

    USGS Publications Warehouse

    Kresch, David L.; Mastin, Mark C.; Olsen, T.D.

    2002-01-01

    After the devastating floods caused by Hurricane Mitch in 1998, maps of the areas and depths of the 50-year-flood inundation at 15 municipalities in Honduras were prepared as a tool for agencies involved in reconstruction and planning. This report, which is one in a series of 15, presents maps of areas in the municipality of El Progreso that would be inundated by a 50-year flood of Rio Pelo. Geographic Information System (GIS) coverages of the flood inundation are available on a computer in the municipality of El Progreso as part of the Municipal GIS project and on the Internet at the Flood Hazard Mapping Web page (http://mitchnts1.cr.usgs.gov/projects/floodhazard.html). These coverages allow users to view the flood inundation in much more detail than is possible using the maps in this report. Water-surface elevations for a 50-year-flood on Rio Pelo at El Progreso were estimated using HEC-RAS, a one-dimensional, steady-flow, step-backwater computer program. The channel and floodplain cross sections used in HEC-RAS were developed from an airborne light-detection-and-ranging (LIDAR) topographic survey of the area. There are no nearby long-term stream-gaging stations on Rio Pelo; therefore, the 50-year-flood discharge for Rio Pelo, 235 cubic meters per second, was estimated using a regression equation that relates the 50-year-flood discharge to drainage area and mean annual precipitation. The drainage area and mean annual precipitation estimated for Rio Pelo at El Progreso are 47.4 square kilometers and 1,920 millimeters, respectively.

  14. Determination of safety margins for whole blood concentrations of alcohol and nineteen drugs in driving under the influence cases.

    PubMed

    Kristoffersen, Lena; Strand, Dag Helge; Liane, Veronica Horpestad; Vindenes, Vigdis; Tvete, Ingunn Fride; Aldrin, Magne

    2016-02-01

    Legislative limits for driving under the influence of 20 non-alcohol drugs were introduced in Norway in February 2012. Per se limits corresponding to blood alcohol concentrations (BAC) of 0.2g/kg were established for 20 psychoactive drugs, and limits for graded sanctions corresponding to BACs of 0.5 and 1.2g/kg were determined for 13 of these drugs. This new legislation made it possible for the courts to make sentences based on the analytical results, similar to the situation for alcohol. To ensure that the reported concentration is as least as high as the true concentration, with a 99% safety level, safety margins had to be calculated for each of the substances. Diazepam, tetrahydrocannabinol (THC) and alcohol were used as model substances to establish a new model for estimating the safety margins. The model was compared with a previous used model established several years ago, by a similar yet much simpler model, and they were found to be in agreement. The measurement uncertainties depend on the standard batch used, the work list and the measurements' replicate. A Bayesian modelling approach was used to determine the parameters in the model, using a dataset of 4700 diazepam positive specimens and 5400 THC positive specimens. Different safety margins were considered for low and high concentration levels of diazepam (≤2μM (0.6mg/L) and >2μM) and THC (≤0.01μM (0.003mg/L) and >0.01μM). The safety margins were for diazepam 19.5% (≤2μM) and 34% (>2μM), for THC 19.5% (≤0.01μM) and 24.9% (>0.01μM). Concentration dependent safety margins for BAC were based on a dataset of 29500 alcohol positive specimens, and were in the range 10.4% (0.1g/kg) to 4.0% (4.0g/kg) at a 99% safety level. A simplified approach was used to establish safety margins for the compounds amphetamine, MDMA, methamphetamine, alprazolam, phenazepam, flunitrazepam, clonazepam, nitrazepam, oxazepam, buprenorphine, GHB, methadone, ketamine, cocaine, morphine, zolpidem and zopiclone. The

  15. Hypnosedative-induced complex behaviours : incidence, mechanisms and management.

    PubMed

    Dolder, Christian R; Nelson, Michael H

    2008-01-01

    A number of news items and case reports describing complex behaviours (e.g. sleep driving, sleep cooking, sleep eating, sleep conversations, sleep sex) associated with the use of hypnosedative medications have recently received considerable attention. Regulatory agencies examining these reports have subsequently issued warnings regarding the potential of hypnosedative agents to produce complex behaviours. Despite these warnings, little is known about the likelihood, presentation, treatment or prevention of hypnosedative-induced complex behaviours. The purpose of this review is to evaluate the published evidence regarding the clinical presentation, incidence, mechanism and management of sleep-related behaviours induced by nonbenzodiazepine receptor agonists (NBRAs).Review of the literature identified ten published case reports of NBRA-induced complex behaviours involving 17 unique patients. Fifteen of the 17 patients described in the case reports had taken zolpidem, one had taken zaleplon and one had taken zopiclone. The complex behaviours most commonly reported were sleep eating, sleepwalking with object manipulation, sleep conversations, sleep driving, sleep sex and sleep shopping. Elevated serum concentrations resulting from increased medication dose or drug-drug interactions appeared to play a role in some but not all cases. Sex, age, previous medication exposure and concomitant disease states were not consistently found to be related to the risk of experiencing a medication-induced complex behaviour.From a pharmacological standpoint, enhancement of GABA activity at GABAA receptors (particularly alpha1-GABAA receptors) is a possible mechanism for hypnosedative complex behaviours and amnesia. Evidence suggests that complex behaviour risk may increase with both dose and binding affinity at alpha1-GABAA receptors. The amnesia that accompanies complex behaviours is possibly due to inhibition of consolidation of short- to long-term memory, suggesting that the risk

  16. Use of benzodiazepines and related drugs in Manitoba: a population-based study

    PubMed Central

    Bolton, James M.; Enns, Murray W.; Dahl, Matthew; Collins, David M.; Chateau, Dan; Sareen, Jitender

    2014-01-01

    Background Despite their favourable toxicology profile, benzodiazepines and the related Z-drugs (zopiclone, zolpidem and zaleplon) have been associated with physiological tolerance, dependence and addiction. Evidence of harm (e.g., falls, motor vehicle collisions and cognitive disturbances) has been reported in older populations. The aim of this study was to determine the relation between users’ characteristics and the use of benzodiazepines and Z-drugs in Manitoba over a 16-year period. Methods This time-series analysis was based on prescription data from Apr. 1, 1996, to Mar. 31, 2012, obtained from the Drug Product Information Network database of Manitoba. We obtained sociodemographic information on benzodiazepine and Z-drug users from the Population Registry and determined changes in utilization rates over time using generalized estimating equations. Results Overall, the prevalence of benzodiazepine use remained stable at about 61.0 per 1000 population between 1996/97 and 2011/12; however, the prevalence of Z-drug use increased steadily from 10.9 to 37.0 per 1000 over the same period. In older people (≥ 65 years), the incidence of benzodiazepine use decreased from 55.5 to 30.3 users per 1000, whereas the incidence of Z-drug use increased from 7.3 to 20.3 users per 1000 over the study period. Among those 18–64 years of age, the incidence of benzodiazepine use decreased from 30.1 to 27.6 users per 1000, but the increase in incidence of Z-drug use was more than 2-fold. The youngest population (≤ 17 years) showed the lowest rates of use of these drugs. The highest rates of use were observed among older women and the low-income population. Interpretation Over the study period, benzodiazepines have been prescribed less frequently to older patients in Manitoba; however, zopiclone prescribing has continued to increase for all age groups. The reasons for this increase remain to be determined. PMID:25485245

  17. Hypnotics' association with mortality or cancer: a matched cohort study

    PubMed Central

    Langer, Robert D; Kline, Lawrence E

    2012-01-01

    Objectives An estimated 6%–10% of US adults took a hypnotic drug for poor sleep in 2010. This study extends previous reports associating hypnotics with excess mortality. Setting A large integrated health system in the USA. Design Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis. Subjects Subjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between January 2002 and January 2007. Main outcome measures Data were adjusted for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use and prior cancer. Hazard ratios (HRs) for death were computed from Cox proportional hazards models controlled for risk factors and using up to 116 strata, which exactly matched cases and controls by 12 classes of comorbidity. Results As predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4–18, 18–132 and >132 doses/year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a dose–response association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR=1.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease. Conclusions Receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year. This association held in separate analyses for several commonly used

  18. Inappropriate drug prescribing in older adults: the updated 2002 Beers criteria – a population-based cohort study

    PubMed Central

    van der Hooft, Cornelis S; Jong, Geert W 't; Dieleman, Jeanne P; Verhamme, Katia M C; van der Cammen, Tischa J M; Stricker, Bruno H CH; Sturkenboom, Miriam C J M

    2005-01-01

    Background In 1997, Beers and colleagues developed explicit criteria for potentially inappropriate drug prescribing in ambulatory older adults aged 65 years and over. Several studies have been performed to estimate the prevalence of inappropriate drug prescribing based on these criteria. In 2002, the criteria were updated. Aims To examine the extent and trend of inappropriate drug prescribing to ambulatory older adults in the Netherlands between 1997 and 2001, according to the 1997 and the updated Beers criteria. Methods Data were retrieved from the Integrated Primary Care Information (IPCI) project, a general practice research database with data from computer-based patient records of a group of 150 general practitioners in the Netherlands. All subjects aged 65 and over were included. Prescriptions were classified as inappropriate if they fulfilled the Beers criteria of prescriptions that generally should be avoided in older adults because of a high risk of adverse effects, while also considering dose and comorbidity. Results Between 1997 and 2001, the 1-year risk of receiving at least one inappropriate drug prescription for older adults ranged between 16.8% (95% CI: 16.3–17.3%) and 18.5% (18.3–18.7%) according to the 1997 criteria and between 19.1% (18.6–19.6%) and 20.0% (19.5–20.5%) according to the updated Beers criteria. According to the updated criteria, the most frequently prescribed inappropriate drugs were nitrofurantoin, long-acting benzodiazepines, amitriptyline, promethazine and cimetidine. Temazepam and zolpidem were mostly prescribed in supratherapeutic dose. Conventional NSAIDs in persons with a history of gastric/duodenal ulcer were the most frequently prescribed contra-indicated drugs. Conclusions Prescribing potentially inappropriate prescriptions to ambulatory older people in the Netherlands is substantial. Compared with other studies using the 1997 Beers criteria, inappropriate prescribing to the elderly is lower than in the USA but

  19. The Treatment of Central Sleep Apnea Syndromes in Adults: Practice Parameters with an Evidence-Based Literature Review and Meta-Analyses

    PubMed Central

    Aurora, R. Nisha; Chowdhuri, Susmita; Ramar, Kannan; Bista, Sabin R.; Casey, Kenneth R.; Lamm, Carin I.; Kristo, David A.; Mallea, Jorge M.; Rowley, James A.; Zak, Rochelle S.; Tracy, Sharon L.

    2012-01-01

    CSAS. (OPTION)The use of zolpidem and triazolam may be considered for the treatment of primary CSAS only if the patient does not have underlying risk factors for respiratory depression. (OPTION)The following possible treatment options for CSAS related to end-stage renal disease may be considered: CPAP, supplemental oxygen, bicarbonate buffer use during dialysis, and nocturnal dialysis. (OPTION) Citation: Aurora RN; Chowdhuri S; Ramar K; Bista SR; Casey KR; Lamm CI; Kristo DA; Mallea JM; Rowley JA; Zak RS; Tracy SL. The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. SLEEP 2012;35(1):17-40. PMID:22215916

  20. Determination of 19 drugs of abuse and metabolites in whole blood by high-performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Bjørk, Marie Kjaergaard; Nielsen, Marie K K; Markussen, Lotte Ø; Klinke, Helene B; Linnet, Kristian

    2010-04-01

    A high-performance liquid chromatography (LC)-tandem mass spectrometry (MS/MS) method has been developed and validated for the determination of 19 drugs of abuse and metabolites and used in whole blood. The following compounds were included: amphetamine, methylenedioxyamphetamine, methylenedioxyethylamphetamine, methylenedioxymethamphetamine, methamphetamine, cocaine, benzoylecgonine, morphine, 6-acetylmorphine, codeine, methadone, buprenorphine, norbuprenorphine, ketobemidone, tramadol, O-desmethyltramadol, zaleplone, zolpidem, and zopiclone. The sample pretreatment consisted of solid-phase extraction using mixed-mode columns (Isolute Confirm HCX). Deuterated analogues were used as internal standards for all analytes, except for ketobemidone and O-desmethyltramadol. The analytes were separated by a methanol/ammonium formate gradient using high-performance LC (Agilent HPLC 1100) with a 3 mm x 100 mm Varian Pursuit 3 C(18) column, 3-microm particle size, and were quantified by MS/MS (Waters Quattro micro tandem quadrupole mass spectrometer) using multiple reaction monitoring in positive mode. Two transitions were used for all analytes, except for tramadol and O-desmethyltramadol. The run time of the method was 35 min including the equilibration time. For all analytes, responses were linear over the range investigated, with R(2) > 0.99. One-point calibration was found to be adequate by validation, thereby saving analysis of multiple calibrators. The limits of quantification (LOQs) for the analytes ranged from 0.0005 to 0.01 mg/kg. Absolute recoveries of the analytes were from 34 to 97%, except for zaleplone (6%). Both the interday precision and the intraday precision were less than 15% (20% at the LOQ) for all analytes, except buprenorphine, norburprenorphine, and zaleplone (less than 18%). Accuracy (bias) was within +/-15% (+/-20% at the LOQ) for all analytes, except MDMA and O-desmethyltramadol (within +/-19%). No ion suppression or enhancement was seen nor was

  1. Early cerebral activities of the environmental estrogen bisphenol A appear to act via the somatostatin receptor subtype sst(2).

    PubMed Central

    Facciolo, Rosa Maria; Alò, Raffaella; Madeo, Maria; Canonaco, Marcello; Dessì-Fulgheri, Francesco

    2002-01-01

    Recently, considerable interest has been aroused by the specific actions of bisphenol A (BPA). The present investigation represents a first study dealing with the interaction of BPA with the biologically more active somatostatin receptor subtype (sst(2)) in the rat limbic circuit. After treating pregnant female Sprague-Dawley rats with two doses (400 microg/kg/day; 40 microg/kg/day) of BPA, the binding activity of the above receptor subtype was evaluated in some limbic regions of the offspring. The higher dose proved to be the more effective one, as demonstrated by the elevated affinity of sst(2) with its specific radioligand, [(125)I]-Tyr(0)somatostatin-14. The most dramatic effects of BPA on sst(2) levels occurred at the low-affinity states of such a subtype in some telencephalic limbic areas of postnatal rats (10 days of age; postnatal day [PND] 10). These included lower (p < 0.05) sst(2) levels in the gyrus dentate of the hippocampus and basomedial nucleus of the amygdala; significantly higher (p < 0.01) levels were observed only for the high-affinity states of the periventricular nucleus of the hypothalamus. A similar trend was maintained in PND 23 rats with the exception of much lower levels of the high-affinity sst(2) receptor subtype in the amygdala nucleus and ventromedial hypothalamic nucleus. However, greater changes produced by this environmental estrogen were reported when the binding activity of sst(2) was checked in the presence of the two more important selective agonists (zolpidem and Ro 15-4513) specific for the alpha-containing Gamma-aminobutyric acid (GABA) type A receptor complex. In this case, an even greater potentiating effect (p < 0.001) was mainly obtained for the low-affinity sst(2) receptor subtype in PND 10 animals, with the exception of the high-affinity type in the ventromedial hypothalamic nucleus and gyrus dentate. These results support the contention that an sst(2) subtype alpha-containing GABA type A receptor system might

  2. Electroencephalographic Power Spectral Density Profile of the Orexin Receptor Antagonist Suvorexant in Patients with Primary Insomnia and Healthy Subjects

    PubMed Central

    Ma, Junshui; Svetnik, Vladimir; Snyder, Ellen; Lines, Christopher; Roth, Thomas; Herring, W. Joseph

    2014-01-01

    Study Objectives: Suvorexant, an orexin receptor antagonist, improves sleep in healthy subjects (HS) and patients with insomnia. We compared the electroencephalographic (EEG) power spectral density (PSD) profile of suvorexant with placebo using data from a phase 2 trial in patients with insomnia. We also compared suvorexant's PSD profile with the profiles of other insomnia treatments using data from 3 HS studies Design: Phase 2 trial—randomized, double-blind, two-period (4 w per period) crossover. HS studies—randomized, double-blind, crossover. Setting: Sleep laboratories. Participants: Insomnia patients (n = 229) or HS (n = 124). Interventions: Phase 2 trial—suvorexant 10 mg, 20 mg, 40 mg, 80 mg, placebo; HS study 1—suvorexant 10 mg, 50 mg, placebo; HS study 2— gaboxadol 15 mg, zolpidem 10 mg, placebo; HS study 3—trazodone 150 mg, placebo. Measurements and Results: The PSD of the EEG signal at 1–32 Hz of each PSG recording during nonrapid eye movement (NREM) and rapid eye movement (REM) sleep were calculated. The day 1 and day 28 PSD profiles of suvorexant at all four doses during NREM and REM sleep in patients with insomnia were generally flat and close to 1.0 (placebo) at all frequencies. The day 1 PSD profile of suvorexant in HS was similar to that in insomnia patients. In contrast, the other three drugs had distinct PSD profiles in HS that differed from each other. Conclusions: Suvorexant at clinically effective doses had limited effects on power spectral density compared with placebo in healthy subjects and in patients with insomnia, in contrast to the three comparison insomnia treatments. These findings suggest the possibility that antagonism of the orexin pathway might lead to improvements in sleep without major changes in the patient's neurophysiology as assessed by electroencephalographic. Citation: Ma J, Svetnik V, Snyder E, Lines C, Roth T, Herring WJ. Electroencephalographic power spectral density profile of the orexin receptor antagonist

  3. Bioanalytical procedures for detection of chemical agents in hair in the case of drug-facilitated crimes.

    PubMed

    Kintz, Pascal

    2007-08-01

    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. The drugs involved can be pharmaceuticals, such as benzodiazepines (flunitrazepam, lorazepam, etc.), hypnotics (zopiclone, zolpidem), sedatives (neuroleptics, some anti-H1) or anaesthetics (gamma-hydroxybutyrate, ketamine), drugs of abuse, such as cannabis, ecstasy or LSD, or more often ethanol. To perform successful toxicological examinations, the analyst must follow some important rules: (1) obtain as soon as possible the corresponding biological specimens (blood and urine); (2) collect hair about 1 month after the alleged event; (3) use sophisticated analytical techniques (gas or liquid chromatography coupled to tandem mass spectrometry, MS/MS, headspace gas chromatography); and (4) take care in the interpretation of the findings. Drugs used to facilitate sexual assaults can be difficult to detect (active products at low doses, 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 low interest. 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 where, as a result of a delay in reporting the crime, natural processes have eliminated the drug from typical biological specimens. While there are a lot of papers that have 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 author and a review of the existing literature will be presented for cases involving benzodiazepines, hypnotics, gamma-hydroxybutyrate and various sedatives or chemical weapons. The expected concentrations in hair are in the low picogram/milligram range for most compounds

  4. Detection of Drugs in Nails: Three Year Experience.

    PubMed

    Shu, Irene; Jones, Joseph; Jones, Mary; Lewis, Douglas; Negrusz, Adam

    2015-10-01

    Nails (fingernails and toenails) are made of keratin. As the nail grows, substances incorporate into the keratin fibers where they can be detected 3-6 months after use. Samples are collected by clipping of 2-3 mm of nail from all fingers (100 mg). We present drug testing results from 10,349 nail samples collected from high-risk cases during a 3-year period of time. Samples were analyzed by validated analytical methods. The initial testing was performed mostly using enzyme-linked immunosorbent assay, but by liquid chromatography-tandem mass spectrometry (LC-MS-MS) as well. Presumptive positive samples were subjected to confirmatory testing with sample preparation procedures including washing, pulverizing, digestion and extraction optimized for each drug class. The total of 7,799 samples was analyzed for amphetamines. The concentrations ranged from 40 to 572,865 pg/mg (median, 100-3,687) for all amphetamine analytes. Amphetamine and methamphetamine were present in 14% of the samples, 22 samples were positive for 3,4-methylenedioxymethamphetamine (0.3%), 7 for methylenedioxyamphetamine (0.09%) and 4 for 3,4-methylenedioxy-N-ethylamphetamine (0.05%). Cocaine and related analytes were found in 5% samples (7,787 total), and the concentration range was 20-265,063 pg/mg (median 84-1,768). Opioids overall ranged from 40 to 118,229 pg/mg (median 123-830). The most prevalent opioid was oxycodone (15.1%) and hydrocodone (11.4%) compared with 1.0-3.6% for the others, including morphine, codeine, hydromorphone, methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine and oxymorphone. Carboxy-Δ-9-tetrahydrocannabinol positivity rate was 18.1% (0.04-262 pg/mg, median 6.41). Out of 3,039 samples, 756 were positive (24.9%) for ethyl glucuronide (20-3,754 pg/mg, median 88). Other drugs found in nails included barbiturates, benzodiazepines, ketamine, meperidine, tramadol, zolpidem, propoxyphene, naltrexone and buprenorphine. Nail analyses have become a reliable way of determining

  5. Sleep complaints: Whenever possible, avoid the use of sleeping pills.

    PubMed

    2008-10-01

    (1) Most sleep complaints involve difficulties in getting to sleep or staying asleep, or not feeling refreshed on awakening. Misconceptions and worrying over the lack of sleep and its consequences can contribute to reinforcing these disorders; (2) How can patients who complain of poor-quality sleep be helped, without resorting to treatments that can have adverse effects? To answer this question, we conducted a systematic review of the literature based on the standard Prescrire procedure; (3) One effective approach is to explain the basic physiology of sleep, to discuss misconceptions, and to adopt a strategy of "stimulus control". This method has a similar efficacy to prescribing a benzodiazepine. and the effect is longer lasting; (4) Moderate, regular physical exercise, especially in the morning, seems to help some patients, but the evidence is weak; (5) Some clinical trials of phytotherapy have shown a positive risk-benefit balance of weak aqueous or hydroalcoholic valerian extracts. Efficacy is limited, however; (6) A meta-analysis of placebo-controlled trials showed that benzodiazepines and related drugs increase the duration of sleep and help patients to fall asleep sooner. However, none of these trials provides comparative data spanning periods of more than two weeks. Efficacy is uncertain in the longer term, as patients quickly develop a tolerance to the hypnotic effects of benzodiazepines; (7) The adverse effects of benzodiazepines include frequent memory disorders, daytime drowsiness, falls, fractures and road accidents, and a withdrawal syndrome after treatment cessation. Related drugs such as zolpidem and zopiclone provoke similar adverse effects; (8) Sedative antihistamines have not been as well-evaluated as benzodiazepines in this setting. Small comparative trials of doxylamine and diphenhydramine showed no major difference in efficacy versus benzodiazepines and related drugs. The main adverse effects of sedative antihistamines are daytime drowsiness

  6. Concentration of drugs in blood of suspected impaired drivers.

    PubMed

    Augsburger, Marc; Donzé, Nicolas; Ménétrey, Annick; Brossard, Clarisse; Sporkert, Frank; Giroud, Christian; Mangin, Patrice

    2005-10-01

    Analytical records concerning 440 living drivers suspected of driving under the influence of drug (DUID) were collected and examined during a 2 years period ranging from 2002 to 2003 in canton de Vaud, Valais, Jura and Fribourg (Switzerland). This study included 400 men (91%) and 40 women (9%). The average age of the drivers was 28+/-10 years (minimum 16 and maximum 81). One or more psychoactive drugs were found in 89% of blood samples. Half of cases (223 of 440, 50.7%) involved consumption of mixtures (from 2 to 6) of psychoactive drugs. The most commonly detected drugs in whole blood were cannabinoids (59%), ethanol (46%), benzodiazepines (13%), cocaine (13%), amphetamines (9%), opiates (9%) and methadone (7%). Among these 440 cases, 11-carboxy-THC (THCCOOH) was found in 59% (median 25 ng/ml (1-215 ng/ml)), Delta(9)-tetrahydrocannabinol (THC) in 53% (median 3 ng/ml (1-35 ng/ml)), ethanol in 46% (median 1.19 g/kg (0.14-2.95 g/kg)), benzoylecgonine in 13% (median 250 ng/ml (29-2430 ng/ml)), free morphine in 7% (median 10 ng/ml (1-111 ng/ml)), methadone in 7% (median 110 ng/ml (27-850 ng/ml)), 3,4-methylenedioxymethamphetamine (MDMA) in 6% (median 218 ng/ml (10-2480 ng/ml)), nordiazepam in 5% (median 305 ng/ml (30-1560 ng/ml)), free codeine in 5% (median 5 ng/ml (1-13 ng/ml)), midazolam in 5% (median 44 ng/ml (20-250 ng/ml)), cocaine in 5% (median 50 ng/ml (15-560 ng/ml)), amphetamine in 4% (median 54 ng/ml (10-183 ng/ml)), diazepam in 2% (median 200 ng/ml (80-630 ng/ml)) and oxazepam in 2% (median 230 ng/ml (165-3830 ng/ml)). Other drugs, such as lorazepam, zolpidem, mirtazapine, methaqualone, were found in less than 1% of the cases. PMID:15923096

  7. Pharmacological and toxicological profile of opioid-treated, chronic low back pain patients entering a mindfulness intervention randomized controlled trial

    PubMed Central

    Wallace, Margaret L.; Burzinski, Cindy A.; Cox, Jennifer; Backonja, Miroslav

    2015-01-01

    OBJECTIVE Refractory chronic low back pain (CLBP) often leads to treatment with long-term opioids. Our goal was to describe the pharmaco-toxicological profile of opioid-treated CLBP patients and identify potential areas for care optimization. DESIGN Cross-sectional analysis. SETTING Outpatient primary care. PARTICIPANTS CLBP patients prescribed >30 mg/day of morphine-equivalent dose (MED) for ≥3 months. INTERVENTION N/A OUTCOME MEASURES Self-reported clinical, medication (verified) and substance use, and urine drug testing (UDT) data were collected. RESULTS Participants (N=35) were 51.8±9.7 years old, 80% female with CLBP for 14.2±10.1 years, treated with opioids for 7.9±5.7 years, with severe disability (Oswestry Disability Index score: 66.7±11.4), and average pain score of 5.6±1.5 (0–10 rating scale). Participants reported using tobacco (N=14), alcohol (N=9) and illicit drugs or unprescribed medications (N=10). On average, participants took 13.4±6.8 daily medications, including 4.7±1.8 pain-modulating and 4.7±2.0 sedating medications. Among prescribed opioids, 57.1% were long-acting and 91.4% were short-acting, with a total of 144.5±127.8 mg/day of MED. Sixteen participants were prescribed benzodiazepines and/or zolpidem/zaleplon. Fifteen participants had UDT positive for illicit drugs or unprescribed medications; in addition, 8 tested positive for alcohol and 19 for cotinine. Compared to those with negative UDTs, those with positive UDTs (N=15) received lower daily “total” and “extended release” opioid doses, and were more likely to test positive for cotinine (p<0.05). CONCLUSIONS Study findings corroborate existing evidence for high medication burden and high likelihood of substance misuse among opioid-treated CLBP patients. Further research is needed to help understand causality and ways to optimize care and clinical outcomes. PMID:25350474

  8. A Novel Route Controlling Begomovirus Resistance by the Messenger RNA Surveillance Factor Pelota

    PubMed Central

    Lapidot, Moshe; Karniel, Uri; Gelbart, Dana; Fogel, Doron; Evenor, Dalia; Kutsher, Yaarit; Makhbash, Zion; Nahon, Sahadia; Shlomo, Haviva; Chen, Lea; Reuveni, Moshe; Levin, Ilan

    2015-01-01

    Tomato yellow leaf curl virus (TYLCV) is a devastating disease of tomato (Solanum lycopersicum) that can be effectively controlled by the deployment of resistant cultivars. The TYLCV-resistant line TY172 carries a major recessive locus for TYLCV resistance, designated ty-5, on chromosome 4. In this study, the association between 27 polymorphic DNA markers, spanning the ty-5 locus, and the resistance characteristics of individual plants inoculated with TYLCV in 51 segregating recombinant populations were analyzed. These analyses localized ty-5 into a 425 bp region containing two transversions: one in the first exon of a gene encoding the tomato homolog of the messenger RNA surveillance factor Pelota (Pelo), and a second in its proximal promoter. Analyses of susceptible and resistant lines revealed that the relative transcript level of the gene remained unchanged, regardless of whether the plants were infected with TYLCV or not. This suggests that the polymorphism discovered in the coding region of the gene controls the resistance. Silencing of Pelo in a susceptible line rendered the transgenic plants highly resistant, while in the resistant line TY172 had no effect on symptom development. In addition, over-expression of the susceptible allele of the gene in the resistant TY172 line rendered it susceptible, while over-expression of the resistant allele in susceptible plants had no effect. These results confirm that Pelo is the gene controlling resistance at the ty-5 locus. Pelo, implicated in the ribosome recycling-phase of protein synthesis, offers an alternative route to promote resistance to TYLCV and other viruses. PMID:26448569

  9. Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development.

    PubMed

    Wang, Bo; Zhou, Shu-Feng

    2009-01-01

    Human cytochrome P450 1A2 (CYP1A2) is one of the major CYPs in the liver ( approximately 13%) and metabolizes about 20% of clinically used drugs. CYP1A2 is a 515-residue protein with a molecular mass of 58,294 Dal. The recently published crystal structure of CYP1A2 in complex with alpha-naphthoflavone has showed a rather compact active site with a relatively small volume of the cavity of 375 A(3), which is 44.2% and 49.3% larger than that of CYP2A6 (260 A(3)) and CYP2E1 (190 A(3)), respectively. A series of residues in the substrate recognition regions of CYP1A2 (e.g. Arg108, Thr124, Thr223, Glu225, Phe226, Lys250, Arg251, Lys253, Asn312, Asp313, Glu318, Thr319, Asp320, Thr321, Val322, Leu382, Thr385, and Ile386) have been shown to play important roles in ligand-enzyme binding based on site-directed mutagenesis and homology modeling studies. Typical CYP1A2 substrates generally contain planar ring that can fit the narrow and planar active site of the enzyme, such as propranolol, clozapine, guanabenz, flutamide, imatinib, thalidomide, carbamazepine, lidocaine, theophylline, tacrine, tizanidine, zolpidem, riluzole, zileuton, and leflunomide. CYP1A2 is one of the major enzymes that bioactivate a number of procarcinogens including polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene), heterocyclic aromatic amines/amides (e.g. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine), mycotoxins (e.g. aflatoxin B(1)) and some natural compounds such as aristolochic acids present in several Chinese herbal medicines. This enzyme also metabolizes several important endogenous compounds including retinols, melatonin, steroids, uroporphyrinogen and arachidonic acids. Like many of other CYPs, CYP1A2 is subject to induction and inhibition by a number of compounds. In particular, several therapeutic drugs including antofloxacin, carbamazepine, dihydralazine, furafylline, isoniazid, rofecoxib, clorgyline, thiabendazole, and zileuton are mechanism-based inhibitors of CYP1A2. Reversible and

  10. Emergency Department Visits by Adults for Psychiatric Medication Adverse Events

    PubMed Central

    Hampton, Lee M.; Daubresse, Matthew; Chang, Hsien-Yen; Alexander, G. Caleb; Budnitz, Daniel S.

    2015-01-01

    and anxiolytics, 2.9 (95% CI, 2.3–3.5) for stimulants, and 2.4 (95% CI, 2.1–2.7) for antidepressants. The commonly used sedative zolpidem tartrate was implicated in 11.5% (95% CI, 9.5%–13.4%) of all adult psychiatric medication ADE ED visits and in 21.0% (95% CI, 16.3%–25.7%) of visits involving adults 65 years or older, in both cases significantly more than any other psychiatric medication. CONCLUSIONS AND RELEVANCE Psychiatric medications are implicated in many ADEs treated in US EDs. Efforts to reduce ADEs should include adults of all ages but might prioritize medications causing high numbers and rates of ED visits. PMID:25006837

  11. Comparação de modelos para o cálculo de perturbações orbitais devidas à maré terrestre

    NASA Astrophysics Data System (ADS)

    Vieira Pinto, J.; Vilhena de Moraes, R.

    2003-08-01

    Aplicações recentes de satélites artificiais com finalidades geodinâmicas requerem órbitas determinadas com bastante precisão. Em particular marés terrestres influenciam o potencial terrestre causando perturbações adicionais no movimento de satélites artificiais, as quais tem sido medidas por diversos processos. A atração exercida pela lua e pelo sol sobre a terra produz deslocamentos elásticos em seu interior e uma protuberância em sua superfície. O resultado é uma pequena variação na distribuição da massa na terra, consequentemente no geopotencial. As perturbações nos elementos orbitais de satélites artificiais terrestres devidas a maré terrestre podem ser estudadas a partir das equações de Lagrange, considerando-se um conveniente potencial. Por outro lado, como tem sido feito pelo IERS, as mudanças induzidas pela maré terrestre no geopotencial podem ser convenientemente modeladas como variações nos coeficientes Cnm e Snm do geopotencial. As duas teorias ainda não foram comparados para um mesmo satélite. Neste trabalho são apresentadas e comparadas as variações de longo período e seculares nas perturbações orbitais devidas à maré terrestre, calculadas por um modelo simples, o de Kozai, e pelo modelo do IERS. Resultados preliminares mostram, para os satélites SCD2 e CBERS1, e para a Lua em movimento elíptico e precessionando, as perturbações seculares no argumento do perigeu e na longitude do nodo ascendente.

  12. Vínculos observacionais para o processo-S em estrelas gigantes de Bário

    NASA Astrophysics Data System (ADS)

    Smiljanic, R. H. S.; Porto de Mello, G. F.; da Silva, L.

    2003-08-01

    Estrelas de bário são gigantes vermelhas de tipo GK que apresentam excessos atmosféricos dos elementos do processo-s. Tais excessos são esperados em estrelas na fase de pulsos térmicos do AGB (TP-AGB). As estrelas de bário são, no entanto, menos massivas e menos luminosas que as estrelas do AGB, assim, não poderiam ter se auto-enriquecido. Seu enriquecimento teria origem em uma estrela companheira, inicialmente mais massiva, que evolui pelo TP-AGB, se auto-enriquece com os elementos do processo-s e transfere material contaminado para a atmosfera da atual estrela de bário. A companheira evolui então para anã branca deixando de ser observada diretamente. As estrelas de bário são, portanto, úteis como testes observacionais para teorias de nucleossíntese pelo processo-s, convecção e perda de massa. Análises detalhadas de abundância com dados de alta qualidade para estes objetos são ainda escassas na literatura. Neste trabalho construímos modelos de atmosferas e, procedendo a uma análise diferencial, determinamos parâmetros atmosféricos e evolutivos de uma amostra de dez gigantes de bário e quatro normais. Determinamos seus padrões de abundância para Na, Mg, Al, Si, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Sr, Y, Zr, Ba, La, Ce, Nd, Sm, Eu e Gd, concluindo que algumas estrelas classificadas na literatura como gigantes de bário são na verdade gigantes normais. Comparamos dois padrões médios de abundância, para estrelas com grandes excessos e estrelas com excessos moderados, com modelos teóricos de enriquecimento pelo processo-s. Os dois grupos de estrelas são ajustados pelos mesmos parâmetros de exposição de nêutrons. Tal resultado sugere que a ocorrência do fenômeno de bário com diferentes intensidades não se deve a diferentes exposições de nêutrons. Discutimos ainda efeitos nucleossintéticos, ligados ao processo-s, sugeridos na literatura para os elementos Cu, Mn, V e Sc.

  13. Pelota Regulates Epidermal Differentiation by Modulating BMP and PI3K/AKT Signaling Pathways.

    PubMed

    Elkenani, Manar; Nyamsuren, Gunsmaa; Raju, Priyadharsini; Liakath-Ali, Kifayathullah; Hamdaoui, Aicha; Kata, Aleksandra; Dressel, Ralf; Klonisch, Thomas; Watt, Fiona M; Engel, Wolfgang; Thliveris, James A; Krishna Pantakani, D V; Adham, Ibrahim M

    2016-08-01

    The depletion of evolutionarily conserved pelota protein causes impaired differentiation of embryonic and spermatogonial stem cells. In this study, we show that temporal deletion of pelota protein before epidermal barrier acquisition leads to neonatal lethality due to perturbations in permeability barrier formation. Further analysis indicated that this phenotype is a result of failed processing of profilaggrin into filaggrin monomers, which promotes the formation of a protective epidermal layer. Molecular analyses showed that pelota protein negatively regulates the activities of bone morphogenetic protein and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways in the epidermis. To address whether elevated activities of bone morphogenetic protein and PI3K/AKT signaling pathways were the cause for the perturbed epidermal barrier in Pelo-deficient mice, we made use of organotypic cultures of skin explants from control and mutant embryos at embryonic day 15.5. Inhibition of PI3K/AKT signaling did not significantly affect the bone morphogenetic protein activity. However, inhibition of bone morphogenetic protein signaling caused a significant attenuation of PI3K/AKT activity in mutant skin and, more interestingly, the restoration of profilaggrin processing and normal epidermal barrier function. Therefore, increased activity of the PI3K/AKT signaling pathway in Pelo-deficient skin might conflict with the dephosphorylation of profilaggrin and thereby affect its proper processing into filaggrin monomers and ultimately the epidermal differentiation. PMID:27164299

  14. Basic Concepts of Astronomy: a Methodological Proposal. (Spanish Title: Conceptos Básicos de Astronomía: Una Propuesta Metodológica.) Conceitos Básicos de Astronomia: Uma Proposta Metodológica

    NASA Astrophysics Data System (ADS)

    Darroz, Luiz Marcelo; Heineck, Renato; Samudio Pérez, Carlos Ariel

    2011-12-01

    obtenidos en diferentes momentos, por los comentarios efectuados por los participantes durante las actividades y por los altos índices de aprobación al final de la etapa, consideramos que la propuesta atingió los objetivos establecidos y puede ser repetida con certeza de éxito. Neste relato, descreve-se o desenvolvimento de uma proposta metodológica que aborda conceitos básicos de astronomia fundamentada pedagogicamente na Aprendizagem Significativa. A proposta, que compreende quatro encontros, foi desenvolvida por professores e acadêmicos do curso de Licenciatura em Física da Universidade de Passo Fundo (UPF), através de um curso de extensão, a um grupo de dez estudantes do ensino médio de uma escola pública da cidade de Passo Fundo, RS. O trabalho centrou-se em conceitos básicos de astronomia. Os indícios da aprendizagem significativa foram obtidos por instrumentos de pesquisa e avaliação aplicados ao término de cada encontro. A avaliação da proposta foi efetuada através de um questionário final respondido pelos participantes ao término do desenvolvimento das atividades. Pelos resultados obtidos nos diferentes instrumentos, pelos comentários efetuados pelos participantes durante as atividades e pelos altos índices de aprovação alcançados no questionário final, consideramos que a proposta atingiu os objetivos estabelecidos e pode ser repetida com convicção de sucesso.

  15. Uso de modelos mecânicos em curso informal de astronomia para deficientes visuais. Resgate de uma experiência

    NASA Astrophysics Data System (ADS)

    Tavares, E. T., Jr.; Klafke, J. C.

    2003-08-01

    O presente trabalho propõe-se a resgatar uma experiência que teve lugar no Planetário de São Paulo nos anos 60. Em 1962, o Sr. Acácio, então com 37 anos, deficiente visual desde os 27, passou a assistir às aulas ministradas pelo Prof. Aristóteles Orsini aos integrantes do corpo de servidores do Planetário. O Sr. Acácio era o único deficiente da turma e, embora possuísse conhecimentos básicos e relativamente avançados de matemática, enfrentava dificuldades na compreensão e acompanhamento da exposição, como também em estudos posteriores. Com o intuito de auxiliá-lo na superação desses problemas, o Prof. Orsini solicitou a construção de modelos mecânicos que, através do sentido do tato, permitissem o acompanhamento das aulas e a transposição do modelo para o "constructo" mental. Essa prática mostrou-se tão eficaz que facilitou sobejamente o aprendizado da matéria pelo sujeito. O Sr. Acácio passou a integrar o corpo de professores do Planetário/Escola Municipal de Astrofísica, tendo ficado responsável pelo curso de "Introdução à Astronomia" por vários anos. Além disso, a experiência foi tão bem sucedida que alguns dos modelos tiveram seus elementos constitutivos pintados diferencialmente para serem utilizados em cursos regulares do Planetário, tornando-se parte integrante do conjunto de recursos didáticos da instituição. É pensando nessa eficácia, tanto em seu objetivo original permitir o aprendizado de um deficiente visual quanto no subsidiário recurso didático sistemático da instituição que decidimos resgatar essa experiência. Estribados nela, acreditamos ser extremamente produtivo, em termos educacionais, o aperfeiçoamento dos modelos originais, agora resgatados e restaurados, e a criação de outros que pudessem ser utilizados no ensino dessa ciência a deficientes visuais.

  16. A misexpression study examining dorsal thorax formation in Drosophila melanogaster.

    PubMed Central

    Peña-Rangel, María Teresa; Rodriguez, Isabel; Riesgo-Escovar, Juan Rafael

    2002-01-01

    We studied thorax formation in Drosophila melanogaster using a misexpression screen with EP lines and thoracic Gal4 drivers that provide a genetically sensitized background. We identified 191 interacting lines showing alterations of thoracic bristles (number and/or location), thorax and scutellum malformations, lethality, or suppression of the thoracic phenotype used in the screen. We analyzed these lines and showed that known genes with different functional roles (selector, prepattern, proneural, cell cycle regulation, lineage restriction, signaling pathways, transcriptional control, and chromatin organization) are among the modifier lines. A few lines have previously been identified in thorax formation, but others, such as chromatin-remodeling complex genes, are novel. However, most of the interacting loci are uncharacterized, providing a wealth of new genetic data. We also describe one such novel line, poco pelo (ppo), where both misexpression and loss-of-function phenotypes are similar: loss of bristles and scutellum malformation. PMID:11901120

  17. Incorporando a variabilidade no processo de identificação do modelo de máximo global no Grade of Membership (GoM): considerações metodológicas

    PubMed Central

    Guedes, Gilvan Ramalho; Siviero, Pamila Cristina Lima; Caetano, André Junqueira; Machado, Carla Jorge; Brondízio, Eduardo

    2012-01-01

    A disponibilidade de bases de dados cada vez mais complexas e multidimensionais é um dos principais motivadores para o aumento do número de estudos que utilizam análises multivariadas baseadas em lógica de conjuntos nebulosos. Apesar da disseminação do método Grade of Membership nos trabalhos empíricos brasileiros da área de ciências sociais e saúde, questões relativas à identificabilidade e estabilidade dos parâmetros finais estimados pelo programa GoM 3.4 não foram suficientemente aprofundadas. Dada a relevância de se obterem parâmetros únicos e estáveis, Guedes et al. (2010) propuseram um procedimento empírico para localizar um modelo de máximo global (MG) com parâmetros estáveis. Entretanto, seu localizador de MG não incorpora qualquer medida de variabilidade. Neste artigo, tal limitação é contornada por meio da utilização de uma estatística de ponderação – Máximo Global Ponderado (MGP) – semelhante ao coeficiente de variação. Esse indicador busca não penalizar de forma desproporcional situações nas quais os desvios médios, apesar de diferentes de zero, são muito pequenos. Apresentam-se evidências de que o localizador MGP reduz a distância do modelo identificado à real estrutura latente dos dados em análise, quando comparados ao modelo identificado pelo localizador não ponderado, MG. PMID:23293402

  18. Minilaparoscopy-assisted transumbilical laparoscopic cholecystectomy.

    PubMed

    Lima, Geraldo José DE Souza; Leite, Rodrigo Fabiano Guedes; Abras, Gustavo Munayer; Pires, Livio José Suretti; Castro, Eduardo Godoy

    2016-01-01

    The role of laparoscopy in the modern surgery era is well established. With the prospect of being able to improve the already privileged current situation, new alternatives have been proposed, such as natural orifice endoscopic surgery (NOTES), the method for single transumbilical access (LESS - Laparo-endoscopic single-site surgery) and minilaparoscopy (MINI). The technique proposed by the authors uses a laparoscope with an operative channel like the flexible endoscope used in NOTES. All operative times are carried out through the umbilical trocar as in LESS, and assisted by a minilaparoscopy grasper. This new technic combines, and results from, the rationalization of technical particularities and synergy of these three approaches, seeking to join their advantages and minimize their disadvantages. RESUMO O papel da videolaparoscopia na era moderna da cirurgia encontra-se bem estabelecido. Com a perspectiva de ser possível melhorar a já privilegiada situação atual, novas alternativas têm sido propostas, como a cirurgia por orifícios naturais (NOTES), o método por acesso único transumbilical (LESS - Laparo-endoscopic single-site surgery) e a minilaparoscopia (MINI). A técnica proposta pelos autores utiliza-se de óptica com canal de trabalho como o endoscópio flexível do NOTES, executa-se todos os tempos operatórios pelo trocarte umbilical, como no LESS, e é assistido por pinça de minilaparoscopia. Esta nova técnica combina e resulta da racionalização de particularidades técnicas e do sinergismo destas três abordagens, buscando agregar suas vantagens e minimizar as suas desvantagens. PMID:27556545

  19. On Ensino de Astronomia: Desafios para Implantação

    NASA Astrophysics Data System (ADS)

    Faria, R. Z.; Voelzke, M. R.

    2008-09-01

    Em 2002 o ensino de Astronomia foi proposto como um dos temas estruturadores pelos Parâmetros Curriculares Nacionais e sugerido como facilitador para que o aluno compreendesse a Física como construção humana e parte do seu mundo vivencial, mas raramente seus conceitos foram ensinados. A presente pesquisa discute dois aspectos relacionados à abordagem de Astronomia. O primeiro aspecto é se ela está sendo abordada pelos professores do Ensino Médio e o segundo, aborda a maneira como ela está sendo ensinada. Optou-se pela aplicação de um questionário a partir do 2° semestre de 2006 e durante o ano de 2007 com professores que ministram a disciplina de Física, os quais trabalham em escolas estaduais em Rio Grande da Serra, Ribeirão Pires e Mauá no estado São Paulo. Dos 66,2% dos professores que responderam ao questionário nos municípios de Rio Grande da Serra, Ribeirão Pires e Mauá, 57,4% não aplicaram nenhum tópico de astronomia, 70,2% não utilizaram laboratório, 89,4% não utilizaram qualquer tipo de programa computacional, 83,0% nunca fizeram visitas com alunos a museus e planetários e 38,3% não indicaram qualquer tipo de livro ou revista referente à astronomia aos seus alunos. Mesmo considerando a Astronomia um conteúdo potencialmente significativo, esta não fez parte dos planejamentos escolares. Portanto são necessárias propostas que visem estratégias para a educação continuada dos professores como, por exemplo, cursos específicos sobre o ensino em Astronomia.

  20. Telescópio de pequeno porte como suporte ao ensino em cidades com intensa poluição luminosa II

    NASA Astrophysics Data System (ADS)

    Pereira, P. C. R.; Santos-Júnior, J. M.; Cruz, W. S.

    2003-08-01

    Para a maioria dos estudantes, sua passagem pelo ensino formal fundamental envolve a transmissão de fatos que devem ser guardados para um exame, a habilidade para lembrar fórmulas e, eventualmente, a repetição de experimentos que devem produzir resultados exigidos pelo professor. O resultado deste modelo de ensino, ao longo dos anos, é conhecido por todos: desconhecimento e descontentamento, por parte dos estudantes, de temas relativos ao papel e aos processos da ciência. Acreditamos que a Astronomia, pelo seu caráter observacional, é uma das áreas do conhecimento que pode contribuir neste cenário. A Fundação Planetário da Cidade do Rio de Janeiro possui um telescópio Meade LX-200 (25cm) que, juntamente com as câmeras CCD ST-7E e ST8E, tem sido utilizado em projetos voltados aos estudantes do ensino médio desde o ano 2000. Tais projetos envolvem a condução de um projeto de pesquisa observacional num nível apropriado, e possibilitam o contato com técnicas e novas tecnologias: computador, software para manipulação de dados e gráficos, programas de tratamento e redução de dados, uso de equipamentos óptico-eletrônicos (telescópio e CCD), bem como o processo de aquisição de conhecimento. Dentro da proposta dos anos anteriores, priorizamos projetos de uma noite, ou seja, procuramos trabalhar com fenômenos que apresentem variabilidade com intervalo de recorrência relativamente curto. Em todos os casos, optamos pela fotometria diferencial, que tem se mostrado bastante eficiente para o céu luminoso como o da cidade do Rio de Janeiro. Neste painel, apresentamos alguns dos projetos desenvolvidos no último ano, com 25 estudantes. Apresentamos os resultados da observação da variável pulsante AI Vel (V = 6,6) e da variável cataclísmica FO Aqr (V = 13,5), e do monitoramento do trânsito da lua de Júpiter, Europa, ocorrido em 30 de abril de 2003. As curvas de luz produzidas para as primeiras estão concordantes com as da literatura, assim

  1. Observações das explosões cósmicas de raios gama GRB021004 e GRB021211 com o satélite HETE

    NASA Astrophysics Data System (ADS)

    Braga, J.; Ricker, G.; Hurley, K.; Lamb, D.; Grew, G.; et al.

    2003-08-01

    O High Energy Transient Explorer (HETE) é o primeiro satélite inteiramente dedicado ao estudo das explosões cósmicas de raios gama (ECRGs). Lançado em 9 de outubro de 2000, o HETE possui instrumentação capaz de observar as ECRGs desde o UV até raios gama e localizá-las com precisão de ~ 1-10 minutos de arco. As localizações das ECRGs detectadas são disseminadas rapidamente (em alguns segundos) pela Internet através de uma rede de estações de recepção ao longo do equador. A participação brasileira nesse projeto se dá através da montagem e operação de uma estação de recepção em Natal, RN, e da participação na equipe científica da missão. Neste trabalho são apresentados resultados da observação pelo HETE de duas ECRGs: GRB 021004 e GRB 021211. A GRB021004 foi detectada em raios gama pelo HETE em 4 de outubro de 2002 e localizada em raios-X em apenas 48 s, quando a emissão de raios gama ainda estava se processando. A explosão, relativamente brilhante e longa, durou aproximadamente 100 s. Um transiente óptico de magnitude 15 foi detectado no local da explosão nove minutos após o evento, e observações realizadas após 7 horas determinaram um desvio para o vermelho de absorção de 1,6. O GRB021004 foi o burst mais bem observado até o momento e suas observações em vários comprimentos de onda têm sido fundamentais para o aprimoramento dos modelos de ECRGs. O GRB21211, um burst brilhante e rico em raios-X, foi detectado em 11 de dezembro de 2002 e localizado em raios-X em 22 s após o início do evento. A duração do burst foi de 2,3 s em altas energias (85 a 400 keV) e de 8,5 s em baixas energias (2 a 10 keV). Caso essa explosão não tivesse sido rapidamente localizada pelo HETE, ela teria sido classificada como "opticamente escura", já que o transiente óptico decaiu rapidamente de R < 14 a R»19 dentro dos primeiros 20 minutos e já estava mais fraco do que R»23 depois de 24 horas da ocorrência do burst. Ser

  2. Melhoramentos no código Wilson-Devinney para binárias eclipsantes

    NASA Astrophysics Data System (ADS)

    Vieira, L. A.; Vaz, L. P. R.

    2003-08-01

    A análise de curvas de luz e velocidades radiais de sistemas binários eclipsantes pode ser feita por meio de vários modelos. Um desses é o Modelo Wilson-Devinney (WD). Ao longo dos anos, esse modelo sofreu várias alterações em seus códigos principais, com a finalidade de torná-lo mais consistente tanto fíisica como numericamente. O Modelo WD tem sido melhorado de várias maneiras em seus dois códigos: um para a predição das curvas de luz teórica e de velocidade radiais e outra para as soluções destas curvas. Teoricamente, na física do modelo, nós introduzimos a possibilidade de levar em conta os efeitos do movimento apsidal. Numericamente, nós introduzimos a possibilidade de usar o Método SIMPLEX no procedimento da solução, como uma alternativa para o já implementado Método de Mínimos Quadrados (Least Squares Method). Estas modificações, juntamente com outras já introduzidas pelo nosso grupo anteriormente, tornam o código mais eficiente na solução das curvas de luz e de velocidade radiais de binárias eclipsantes. Como o modelo tem sido usado para analisar sistemas com componentes pré-sequência principal (TY CrA, Casey et al. 1998, Vaz et al. 1998), SM 790, Stassun et al. 2003), este melhoramento beneficiará estes casos também. Apresentamos os resultados obtidos com a modificação do código WD por meio do uso de dados da estrela GL Carinae, comprovando, (1) que os parâmetros orbitais calculados por nós são coerentes com os obtidos anteriormente na literatura (Giménez & Clausen, 1986) e com os obtidos por Faria (1987), e (2) que a implementação do Método SIMPLEX torna o código mais lento mas completamente consistente internamente e evita os problemas gerados pelo uso do Método de Mínimos Quadrados, tais como imprecisão no cálculo das derivadas parciais e convergência para mínimos locais.

  3. Camões e a cosmogonia

    NASA Astrophysics Data System (ADS)

    Costa, J. M.

    2003-08-01

    Os Lusíadas, escrito por Luis de Camões em 1572, é um poema épico renascentista e a visão Cosmogônica do autor é apresentada, principalmente, no último canto do poema, quando Tétis mostra ao Gama a Máquina do Mundo. A Cosmogonia de Camões neste poema reflete uma visão de uma época de transição, que ainda não incorporou os elementos da revolução Copernicana. É uma visão Grego- Ptolomaica e também medieval. O poeta guia-se pela tradução e notas feita por Pedro Nunes, inventor do Nonio, do Tratado da Esfera "De Sphaera" do Astrônomo Inglês John Holywood, mais conhecido pelo nome latinizado de Johannes Sacrobosco. Outra provável fonte de Camões, de acordo com Luciano Antonio Pereira da Silva em Astronomia de os Lusíadas, é o "Theoricae novae Planetarum" (1460) do astrólogo Alemão Jorge Purbáquio (1423 - 1461). A Astronomia de Os Lusíadas representa a ciência do tempo de Camões. Camões nunca emprega a palavra constelação e seu catálogo é bastante completo. A Máquina do Mundo tem a Terra no centro. Em redor, em círculos concêntricos, a lua (Diana), Mercúrio, Vênus, o Sol (Febo), Marte, Júpiter e Saturno. Envolvendo estes astros tem o firmamento seguido pelo "Céu Áqueo" ou cristalino, depois o 1o Móbil, esfera que arrasta todas as outras consigo. Este trabalho, multidisciplinar, serve tanto para ensinar aos alunos da Física como das Ciências Humanas, a concepção de mundo do renascimento de uma forma belamente poética em versos decassílabos Este trabalho também ajuda na apreciação do maior clássico da língua portuguesa e mostra como as Ciências e as artes, em geral, estão correlacionadas e refletem a visão de mundo da época em que foi produzida.

  4. Projeto do sistema anti-ressonante da fiação dos transdutores para o detector Mario Schenberg

    NASA Astrophysics Data System (ADS)

    Vieira, S. J.., Jr.; Melo, J. L.

    2003-08-01

    O detector de ondas gravitacionais Mario Schenberg está sendo projetado e construído pelo grupo Gráviton. Sua construção está ocorrendo no Laboratório de Estado Sólido e Baixas Temperaturas (LESBT) da Universidade de São Paulo, na cidade de São Paulo. Esse detector possui uma massa ressonante esférica de cobre-alumínio, com 65 cm de diâmetro, pesando aproximadamente 1150 Kg, suspensa por um sistema de isolamento vibracional, que se encontra em fase de testes preliminares. A real eficácia desse sistema, entretanto, só poderá ser comprovada quando o detector estiver aparelhado com, pelo menos, um transdutor eletromecânico de altíssima sensibilidade acoplado à massa ressonante. Neste momento, não só este sistema de isolamento vibracional será posto em teste, como o do projeto da fiação que transporta os sinais de microondas até os transdutores e destes para a pré-amplificação. Apesar dessa fiação ter sido projetada para não apresentar nenhum contato com a superfície esférica da antena, de maneira a não haver nenhuma transmissão de ruído vibracional do laboratório para esta, deve-se minimizar o ruído microfônico produzido nessa fiação por oscilações mecânicas, uma vez que ela não utiliza nenhum sistema de isolamento vibracional. Com o intuito de resolver este problema, projetamos uma estrutura, formada por pequenos cilindros conectados por barras, a qual não terá nenhuma ressonância mecânica na faixa de freqüências de interesse para detecção (3000 - 3400 Hz). Desta forma, as vibrações nessa faixa não serão amplificadas. O projeto foi feito usando iterativamente, de maneira a otimizar os resultados obtidos, o programa de elementos finitos Msc/Nastran. Através de simulações feitas neste programa, determinamos os parâmetros geométricos ideais a serem utilizados, os quais proporcionam a maior região espectral de interesse livre de ressonâncias.

  5. Implementação de um algoritmo para a limpeza de mapas da RCFM

    NASA Astrophysics Data System (ADS)

    Souza, C. L.; Wuensche, C. A.

    2003-08-01

    A Radiação Cósmica de Fundo em Microondas (RCFM), descoberta por Penzias e Wilson em 1965, é uma das ferramentas mais poderosas para o estudo da cosmologia. Com a descoberta de flutuações de temperatura na RCFM, da ordem de uma parte em 105, pelo COBE (1992), uma nova era teve início. Nos últimos onze anos, diversos instrumentos fizeram novas medidas de alta precisão, refinando os resultados apresentados pelo COBE, culminando com os resultados recentes do satélite WMAP. A análise de dados da RCFM, especialmente no caso de experimentos com pequena cobertura do céu, apresenta uma série de dificuldades devido a emissões de contaminantes externos, tais como a emissão da Galáxia e de fontes pontuais, e de ruídos intrínsecos tanto ao sistema de detecção quanto à estratégia de observação do céu. Uma das soluções típicas para a filtragem de dados brutos de um experimento para medir flutuações de temperatura é aplicar um gabarito (template) e um filtro passa alta ao produzir mapas simplificados (sem considerar matrizes de correlação ou covariância). No caso de experimentos que utilizam detectores HEMT, essa combinação de filtros remove, satisfatoriamente, ruídos do tipo 1/f gerados pela instabilidade no ganho do detector acoplado ao movimento do instrumento, definido pela estratégia de observação. Entretanto, o sinal resultante medido, tanto em simulações quanto em séries temporais reais, sugere que parte do sinal cosmológico pode estar sendo removido junto com o ruído dos detectores. Este trabalho descreve as etapas para a produção de um mapa típico (simulado) e os testes preliminares de um algoritmo para remover ruídos do tipo 1/f introduzidos pela estratégia de observação sem prejudicar a qualidade do sinal cosmológico presente no mapa.

  6. Ensino de Astronomia no Ensino Médio

    NASA Astrophysics Data System (ADS)

    Albrecht, E.; Voelzke, M. R.

    2008-09-01

    O presente trabalho de intervenção foi realizado junto a Escola Estadual Colônia dos Pescadores na cidade de Caraguatatuba, com três turmas do terceiro ano do Ensino Médio, envolvendo 119 alunos, 40 na turma A, 40 na turma B e 39 na turma C. A fase inicial foi composta de um questionário de vinte questões dissertativas e objetivas para diagnosticar nos educandos os conceitos prévios sobre Astronomia e, partindo destes realizar uma interferência nas classes envolvidas utilizando metodologias diferentes sendo elas: a tradicional, onde o professor é um repassador de informações, fazendo uso exclusivo de lousa e giz; a segunda também de forma tradicional, porém com auxílio de multimídia para desenvolvimento das aulas e a terceira sob forma de seminários, elaborados e apresentados pelos educandos, no qual o educador faz apenas as intervenções necessárias. Ao final do trabalho as mesmas turmas da fase inicial orientadas pelo mesmo professor responderam novamente ao questionário proposto para diagnosticar dentre as três metodologias utilizadas qual apresentou melhores resultados, sendo os iniciais comparados com os finais. Quando questionados a respeito do significado de Astronomia observou-se inicialmente que os acertos na turma A foram de 100%,turma B: 64%, turma C: 84%, após a intervenção os acertos foram: 100%, 97% e 85% respectivamente, demonstrando claramente uma absorção de conhecimentos. Quando interrogados sobre quantos planetas você acha que existem em nosso Sistema Solar? os acertos foram: turma A: 39%, turma B: 48% e turma C: 46%, após o desenvolvimento do trabalho os acertos foram 94%, 97% e 90% respectivamente.Dentro das respostas obtidas observa-se que a metodologia tradicional com o auxílio de multimeios, aplicada na turma B, demonstrou melhores resultados, foi a mais significativa.

  7. Diferentes metodologias aplicadas ao ensino de astronomia no Ensino Médio

    NASA Astrophysics Data System (ADS)

    Albrecht, E.; Voelzke, M. R.

    2009-03-01

    O presente trabalho de intervenção foi realizado junto à Escola Estadual Colònia dos Pescadores na cidade de Caraguatatuba, com très turmas do terceiro ano do Ensino Médio, envolvendo 119 alunos com idades entre 16 e 19 anos. A fase inicial foi composta de um questionário de vinte questíes dissertativas e objetivas, aplicado pelo professor titular da sala, que era o mesmo nas très turmas, para diagnosticar nos educandos os conceitos prévios sobre Astronomia e, partindo destes realizar um trabalho de intervenção nas classes envolvidas utilizando, em cada uma, metodologias diferentes: (A) sob forma de seminários, elaborados e apresentados pelos educandos, no qual o educador faz apenas as intervençíes necessárias; (B) de forma tradicional, com auxílio de multimídias para desenvolvimento das aulas e a terceira (C) tradicional, fazendo uso exclusivo de lousa e giz. Ao final do trabalho os alunos responderam novamente o questionário inicial para diagnosticar dentre as très metodologias utilizadas qual apresentou melhores aplicaçíes, os resultados iniciais foram comparados com os finais. Quando questionados a respeito do significado de Astronomia observou-se inicialmente que os acertos na turma A foram de 100%, turma B: 64%, turma C: 84%, após a intervenção os acertos foram: 100%, 97% e 85% respectivamente, demonstrando que houve um avanço significativo na turma B, a turma A manteve seu índice e a turma C evoluiu, porém não tanto quanto a B. Quando interrogados sobre quantos planetas vocè acha que existem em nosso Sistema Solar? os acertos foram: turma A: 39%, turma B: 48% e turma C: 46%, após o desenvolvimento do trabalho os acertos foram 94%, 97% e 90% respectivamente. Dentro das respostas obtidas observa-se que a metodologia tradicional com o auxílio de multimeios, aplicada na turma B, demonstrou melhores resultados, sendo a mais significativa. Outra conclusão muito importante é que apesar de o tema Astronomia ser amplamente

  8. Imagens do céu ontem e hoje - um multimídia interativo de astronomia e uma nova exposição no MAST

    NASA Astrophysics Data System (ADS)

    Caretta, C. A.; Lima, F. P.; Requeijo, F.; Vieira, G. G.; Alves, F.; Valente, M. E. A.; de Almeida, R.; de Garcia, G. C.; Quixadá, A. C.

    2003-08-01

    "Imagens do Céu Ontem e Hoje" é o título de uma nova exposição que está sendo inaugurada no Museu de Astronomia e Ciências Afins (MCT), que inclui experimentos interativos, maquetes, réplicas e 8 terminais de computador com um multimídia interativo sobre Astronomia para consulta dos visitantes. O multimídia apresenta um conteúdo bastante extenso, que engloba quase todos os temas em Astronomia, consistindo numa fonte de divulgação e pesquisa para um público que vai das crianças até estudantes universitários. O conteúdo está distribuído em mais de 500 páginas de texto divididas em 4 módulos: "O Universo", "Espectroscopia", "Telescópios" e "Observando o Céu". Cada módulo é subdividido em 5 seções, em média, cada uma iniciada por uma animação que ilustra os temas a serem abordados na seção. Ao final da animação, uma lista de temas é apresentada sob o título "Saiba Mais". Para exemplificar, o módulo "O Universo" contém as seguintes seções: "O Universo visto pelo homem", "Conhecendo o Sistema Solar", "Indo além do Sistema Solar", "Nossa Galáxia, a Via-Láctea" e "Indo mais além, a imensidão do Universo". A seção "Conhecendo o Sistema Solar", por sua vez, tem os seguintes temas: "A origem do Sistema Solar", "O Sol", "Os planetas", "Satélites, asteróides, cometas e outros bichos..." e "O Sistema Solar em números". Cada texto é repleto de imagens, quadros, desenhos, esquemas, etc, além de passatempos ao final de cada seção, incluindo jogos interativos, quadrinhos e curiosidades, que auxiliam o aprendizado de forma divertida. Apresentamos neste trabalho as idéias gerais que permearam a produção da exposição, e uma viagem pelo multimídia para exemplificar sua estrutura e conteúdo. O multimídia será posteriormente disponibilizado para o público externo pela página eletrônica do MAst e/ou por intermédio de uma publicação comercial.

  9. On Ensino da Astronomia no Ensino Médio sob Diferentes Abordagens Metodológicas

    NASA Astrophysics Data System (ADS)

    Voelzke, Marcos Rincon; Albrecht, Evonir

    2011-12-01

    O presente trabalho, sobre a intervenção de metodologias de ensino, foi desenvolvido na Escola Estadual Colônia dos Pescadores, na cidade de Caraguatatuba - SP, em três turmas do terceiro ano do Ensino Médio, perfazendo um total de 119 educandos, entre 16 e 19 anos. Antes de iniciar-se a intervenção, um questionário de vinte perguntas objetivas e dissertativas foi desenvolvido, aplicado pelo professor da classe, que ministrou as aulas correspondentes. Este questionário foi o mesmo em todas as três classes com o objetivo de diagnosticar o conhecimento prévio dos alunos sobre Astronomia. Começando a intervenção nas turmas, o professor envolvido usou três diferentes metodologias de ensino: (A) em forma de seminários, elaborados e apresentados pelos alunos, nos quais o professor fazia apenas as intervenções necessárias, (B) na forma tradicional, com a ajuda de multimídia para o desenvolvimento das aulas e a terceira (C) a tradicional, fazendo uso exclusivo de lousa e giz. No final do trabalho os alunos responderam o mesmo questionário novamente, de modo que os três métodos utilizados puderam ser comparados. Os resultados apresentados após a intervenção foram melhores que os resultados iniciais indicando a ocorrência de uma aprendizagem significativa. Quando os estudantes foram inicialmente questionados sobre quantos planetas existem no nosso sistema solar, a classe A obteve 39% de respostas certas, a classe B 48% e a classe C 46%, mas após o desenvolvimento das atividades, as classes obtiveram respectivamente 94%, 97 % e 90% de aproveitamento. No término do bimestre, foi sugerido aos educandos que elaborassem uma história em quadrinhos, a qual serviu para averiguar se os conceitos inicialmente observados foram alterados e se novos foram agregados. A análise das histórias foi dividida em três partes: Criatividade; Temas abordados; Emprego correto dos conceitos estudados. Ao final quatorze histórias foram confeccionadas. O aprendizado

  10. Abundâncias em estrelas de Bário

    NASA Astrophysics Data System (ADS)

    Allen, D. M.

    2003-08-01

    Estrelas de Bário apresentam linhas intensas de elementos produzidos pelo processos (ex: Ba, Y, Sr, Zr) e bandas intensas de CN, C2 e CH. A hipótese mais aceita sobre a origem deste grupo peculiar é a de que essas estrelas façam parte de sistemas binários, tendo recebido material enriquecido em elementos pesados da companheira mais evoluída. Apresentamos neste trabalho uma análise detalhada de uma amostra de estrelas desta classe, incluindo determinação de parâmetros atmosféricos e cálculo de abundâncias. As temperaturas efetivas foram determinadas a partir de dados fotométricos obtidos com o Fotrap instalado no telescópio Zeiss do LNA (Laboratório Nacional de Astrofísica) (B-V, V-I, R-I, V-R), e coletados na literatura nos catálogos Hipparcos (B-V), 2MASS (Two Micron All Sky Survey) (V-K) e The General Catalogue Photometric Data (sistema Geneva). Obtivemos uma faixa de temperaturas de 4400 £ Tef £ 6500. As metalicidades foram determinadas a partir de linhas de Fe I e Fe II, estando os resultados no intervalo -1 £ [Fe/H] £ +0.1. O log g foi determinado pelo equilíbrio de ionização e pela relação com a magnitude bolométrica, a temperatura e a massa, sendo os resultados na faixa 1.5 £ log g £ 4.5. As distâncias utilizadas foram determinadas com o auxílio das paralaxes Hipparcos, e as massas determinadas por modelos de isócronas. Os espectros utilizados foram obtidos com o espectrógrafo FEROS no Telescópio de 1,5m do ESO (European Southern Observatory). As abundâncias foram calculadas por meio de síntese espectral de linhas individuais incluindo elementos alfa, pico do Fe, s e r. Encontramos um excesso de elementos pesados em relação ao Fe, como esperado para estrelas de Bário.

  11. On Ensino de Astronomia nas Cidades de Ribeirão Pires e Rio Grande da Serra

    NASA Astrophysics Data System (ADS)

    Faria, R. Z.; Voelzke, M. R.

    2007-08-01

    Apesar da astronomia ser um dos temas indicados pelos Parâmetros Curriculares Nacionais, observa-se que poucas mudanças ocorreram desde a implementação do mesmo em sala de aula. A presente pesquisa diz respeito sobre como os tópicos de astronomia estão sendo abordados pelos professores no ensino médio. Optou-se por aplicar um questionário com os professores que ministram a disciplina de física. Os mesmos trabalham em escolas estaduais situadas nas cidades de Ribeirão Pires e Rio Grande da Serra, ambas subordinadas a Diretoria de Ensino de Mauá, no Estado de São Paulo. O questionário foi aplicado durante o 2° semestre de 2006. Até o momento os resultados são preliminares. Dos 82,0% dos professores que responderam ao questionário no município de Rio Grande da Serra, 66,7% não aplicaram nenhum tópico de astronomia, 77,8% não utilizaram qualquer tipo de programa computacional, 66,7% não utilizaram laboratório, que 77,8% nunca levaram os alunos a museus e ou planetários e que 66,7% não indicaram qualquer tipo de revista ou livro sobre astronomia aos seus alunos. No município de Ribeirão Pires, 53,3% dos professores responderam ao questionário, destes 75,0% não aplicaram nenhum tópico de astronomia, 93,8% não utilizaram qualquer tipo de programa computacional, 75,0% não utilizaram laboratório, 81,3% nunca levaram os alunos a museus e ou planetário e 56,3% não indicaram qualquer tipo de revista ou livro sobre astronomia ao seus alunos. Apesar da maioria dos professores reconhecerem que o conteúdo de astronomia influi na formação do jovem, os mesmos não incluem o tema em seus planejamentos escolares.

  12. Memória fonológica em crianças bilíngues bimodais e crianças com implante coclear

    PubMed Central

    de Quadros, Ronice Müller; Cruz, Carina Rebello; Pizzio, Aline Lemos

    2014-01-01

    RESUMO Este estudo comparou o desempenho de crianças bilíngues bimodais ouvintes (filhas de pais surdos) e crianças surdas usuárias de implante coclear (filhas de pais surdos e de pais ouvintes), com diferentes contextos de acesso à Língua Brasileira de Sinais (Libras), em tarefas que envolvem memória fonologica. Os testes utilizados foram: Teste de Pseudopalavras (Santos e Bueno, 2003) e Teste de Pseudosinais (desenvolvido pelos pesquisadores responsáveis pelo Projeto ‘Desenvolvimento Bilíngue Bimoda’). Além disso, foram incluídos dois grupos de controle, formados por crianças surdas (usuarias de Libras), e adultos bilíngues bimodais ouvintes. Na análise dos resultados, em relação ao desempenho entre os dois grupos testados foi constatado que o grupo de crianças bilíngues bimodais ouvintes apresentou desempenho superior, nos dois testes. No entanto, ao ser analisado o desempenho da criança surda usuaria de implante coclear, filha de pais surdos, que possui acesso irrestrito à Libras e comparado com o das crianças surdas usuárias de implante coclear, que possuem acesso restrito à Libras, foi constatado que o seu desempenho foi semelhante ao do grupo de crianças bilíngues bimodais ouvintes. As crianças surdas usuárias de implante coclear com acesso restrito à Libras e, portanto, com acesso maior ao Português apresentaram escores mais baixos nas tarefas, principalmente do teste em Português. Os resultados sugerem que as crianças surdas usuárias de implante coclear em processo de aquisição da línguagem podem se beneficiar com o acesso irrestrito à Libras, atingindo inclusive desempenho semelhante a de crianças bilíngues bimodais ouvintes. PMID:25110473

  13. Pre-Columbian origins of Native American dog breeds, with only limited replacement by European dogs, confirmed by mtDNA analysis.

    PubMed

    van Asch, Barbara; Zhang, Ai-bing; Oskarsson, Mattias C R; Klütsch, Cornelya F C; Amorim, António; Savolainen, Peter

    2013-09-01

    Dogs were present in pre-Columbian America, presumably brought by early human migrants from Asia. Studies of free-ranging village/street dogs have indicated almost total replacement of these original dogs by European dogs, but the extent to which Arctic, North and South American breeds are descendants of the original population remains to be assessed. Using a comprehensive phylogeographic analysis, we traced the origin of the mitochondrial DNA lineages for Inuit, Eskimo and Greenland dogs, Alaskan Malamute, Chihuahua, xoloitzcuintli and perro sín pelo del Peru, by comparing to extensive samples of East Asian (n = 984) and European dogs (n = 639), and previously published pre-Columbian sequences. Evidence for a pre-Columbian origin was found for all these breeds, except Alaskan Malamute for which results were ambigous. No European influence was indicated for the Arctic breeds Inuit, Eskimo and Greenland dog, and North/South American breeds had at most 30% European female lineages, suggesting marginal replacement by European dogs. Genetic continuity through time was shown by the sharing of a unique haplotype between the Mexican breed Chihuahua and ancient Mexican samples. We also analysed free-ranging dogs, confirming limited pre-Columbian ancestry overall, but also identifying pockets of remaining populations with high proportion of indigenous ancestry, and we provide the first DNA-based evidence that the Carolina dog, a free-ranging population in the USA, may have an ancient Asian origin. PMID:23843389

  14. Discos de acresção em sistemas Be-X

    NASA Astrophysics Data System (ADS)

    Lopes de Oliveira, R.; Janot-Pacheco, E.

    2003-08-01

    Alguns fenômenos de outbursts em Be-X sugerem a existência, mesmo que temporária, de um disco de acresção quando da passagem do objeto compacto pelo periastro orbital. Neste trabalho avaliamos a possibilidade de formação do disco de acresção em sistemas Be+estrela de neutrons e Be+anã branca, e a influência da excentricidade orbital na ocorrência deste fenômeno. Utilizamos a expressão analítica para o momento angular específico da matéria constituinte de um meio em expansão lenta, como é o caso do disco circunstelar das estrelas Be, proposta por Wang(1981), sob a condição básica de que o raio de circularização deva ser maior do que o raio de Alfvén. Concluímos que existe um limite para o período orbital do sistema acima do qual não é possível a formação do disco de acresção, e que este valor aumenta para sistemas com excentricidade orbital maior.

  15. PubMed

    Silva, Cristiane Gonçalves da; Santos, Alessandro Oliveira; Licciardi, Daniele Carli; Paiva, Vera; Parker, Richard

    2008-01-01

    Esse artigo descreve como jovens religiosos e autoridades religiosas de sua comunidade compreendem a sexualidade, considerando suas experiências pessoais e como membros de comunidades religiosas. A análise pretende contribuir para que políticas públicas dedicadas à promoção da saúde sexual da juventude considerem a religiosidade, no contexto de um estado laico e da promoção do direito à prevenção. Foram realizadas 26 entrevistas abertas e semidirigidas em diferentes comunidades da região metropolitana da cidade de São Paulo (comunidades católicas, da umbanda, do candomblé e de diferentes denominações evangélicas) sobre iniciação sexual, casamento, gravidez, contracepção e prevenção das DST/Aids, homossexualidade, aborto e direitos humanos. Observou-se como jovens e autoridades religiosas convivem com a tensão entre tradição e modernidade e os distintos discursos sobre a sexualidade. Como sujeitos religiosos (do discurso religioso) e sujeitos sexuais (de discursos sobre sexualidade), devem ser incorporados pelos programas como sujeitos de direito nos termos de sua religiosidade. PMID:21886456

  16. Religiosidade, juventude e sexualidade: entre a autonomia e a rigidez1

    PubMed Central

    Silva, Cristiane Gonçalves da; Santos, Alessandro Oliveira; Licciardi, Daniele Carli; Paiva, Vera; Parker, Richard

    2009-01-01

    Esse artigo descreve como jovens religiosos e autoridades religiosas de sua comunidade compreendem a sexualidade, considerando suas experiências pessoais e como membros de comunidades religiosas. A análise pretende contribuir para que políticas públicas dedicadas à promoção da saúde sexual da juventude considerem a religiosidade, no contexto de um estado laico e da promoção do direito à prevenção. Foram realizadas 26 entrevistas abertas e semidirigidas em diferentes comunidades da região metropolitana da cidade de São Paulo (comunidades católicas, da umbanda, do candomblé e de diferentes denominações evangélicas) sobre iniciação sexual, casamento, gravidez, contracepção e prevenção das DST/Aids, homossexualidade, aborto e direitos humanos. Observou-se como jovens e autoridades religiosas convivem com a tensão entre tradição e modernidade e os distintos discursos sobre a sexualidade. Como sujeitos religiosos (do discurso religioso) e sujeitos sexuais (de discursos sobre sexualidade), devem ser incorporados pelos programas como sujeitos de direito nos termos de sua religiosidade. PMID:21886456

  17. [Deep-sea research ground for the study of living matter properties in extreme conditions].

    PubMed

    Polikarpov, G G

    2011-01-01

    The Black Sea hollow bottom is a promising research ground in the field of deep-sea radiochemoecology and exobiology. It has turned out to be at the intersection of the earth and cosmic scientific interests such as deep-sea marine radiochemoecology from the perspective of the study of extreme biogeocenological properties of the Earth biosphere and exobiology from the standpoint of the study of life phenomena (living matter) outside the Earth biosphere, i.e. on other planets and during hypothetical transfer of spores in the outer space. The potential of this ground is substantiated with the data published by the author and co-workers on accumulation of 90Sr, 137Cs and Pu isotopes with silts of bathyal pelo-contour, on the quality of deep-sea hydrogen sulphide waters (after their contact with air) for vital functions of planktonic and benthic aerobes, as well as the species composition of marine, freshwater and terrestrial plants grown from the spores collected from the bottom sediments of the Black Sea bathyal. Discussion was based on V.I. Vernadsky's ideas about the living matter and biosphere, which allowed conclusions about the biospheric and outer space role of the described phenomena. PMID:22279770

  18. Um satélite brasileiro para observação do diâmetro solar

    NASA Astrophysics Data System (ADS)

    Emilio, M.; Leister, N. V.; Benevides Soares, P.; Teixeira, R.; Kuhn, J.

    2003-08-01

    Propomos uma missão espacial para medir a forma e o diâmetro solar com o objetivo de ajudar a determinar o potencial gravitacional do Sol e a sua rotação com precisão, testar modelos teóricos de variação de energia e pela primeira vez medir os modos g de oscilação. As observações serão obtidas através do instrumento denominado APT (Astrometric and Photometric Telescope) descrito por Kuhn(1983). A sensibilidade do instrumento é de 0,2 mas em 27 dias para as observações do diâmetro solar feitas a cada minuto. Esta é uma missão de três anos de duração e pode complementar as medidas que serão feitas pelo satélite PICARD (a ser lançado em 2007). Outros parâmetros físicos podem ser obtidos com as mesmas imagens o que certamente interessará à comunidade de física solar. Um primeiro contato foi realizado com a agência espacial brasileira que pretende lançar um satélite científico a cada dois anos.

  19. Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.

    PubMed

    Liu, Ching-Ti; Raghavan, Sridharan; Maruthur, Nisa; Kabagambe, Edmond Kato; Hong, Jaeyoung; Ng, Maggie C Y; Hivert, Marie-France; Lu, Yingchang; An, Ping; Bentley, Amy R; Drolet, Anne M; Gaulton, Kyle J; Guo, Xiuqing; Armstrong, Loren L; Irvin, Marguerite R; Li, Man; Lipovich, Leonard; Rybin, Denis V; Taylor, Kent D; Agyemang, Charles; Palmer, Nicholette D; Cade, Brian E; Chen, Wei-Min; Dauriz, Marco; Delaney, Joseph A C; Edwards, Todd L; Evans, Daniel S; Evans, Michele K; Lange, Leslie A; Leong, Aaron; Liu, Jingmin; Liu, Yongmei; Nayak, Uma; Patel, Sanjay R; Porneala, Bianca C; Rasmussen-Torvik, Laura J; Snijder, Marieke B; Stallings, Sarah C; Tanaka, Toshiko; Yanek, Lisa R; Zhao, Wei; Becker, Diane M; Bielak, Lawrence F; Biggs, Mary L; Bottinger, Erwin P; Bowden, Donald W; Chen, Guanjie; Correa, Adolfo; Couper, David J; Crawford, Dana C; Cushman, Mary; Eicher, John D; Fornage, Myriam; Franceschini, Nora; Fu, Yi-Ping; Goodarzi, Mark O; Gottesman, Omri; Hara, Kazuo; Harris, Tamara B; Jensen, Richard A; Johnson, Andrew D; Jhun, Min A; Karter, Andrew J; Keller, Margaux F; Kho, Abel N; Kizer, Jorge R; Krauss, Ronald M; Langefeld, Carl D; Li, Xiaohui; Liang, Jingling; Liu, Simin; Lowe, William L; Mosley, Thomas H; North, Kari E; Pacheco, Jennifer A; Peyser, Patricia A; Patrick, Alan L; Rice, Kenneth M; Selvin, Elizabeth; Sims, Mario; Smith, Jennifer A; Tajuddin, Salman M; Vaidya, Dhananjay; Wren, Mary P; Yao, Jie; Zhu, Xiaofeng; Ziegler, Julie T; Zmuda, Joseph M; Zonderman, Alan B; Zwinderman, Aeilko H; Adeyemo, Adebowale; Boerwinkle, Eric; Ferrucci, Luigi; Hayes, M Geoffrey; Kardia, Sharon L R; Miljkovic, Iva; Pankow, James S; Rotimi, Charles N; Sale, Michele M; Wagenknecht, Lynne E; Arnett, Donna K; Chen, Yii-Der Ida; Nalls, Michael A; Province, Michael A; Kao, W H Linda; Siscovick, David S; Psaty, Bruce M; Wilson, James G; Loos, Ruth J F; Dupuis, Josée; Rich, Stephen S; Florez, Jose C; Rotter, Jerome I; Morris, Andrew P; Meigs, James B

    2016-07-01

    Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci. PMID:27321945

  20. Tão perto de casa, tão longe de nós: etnografia das novas margens no centro da urbe

    PubMed Central

    Fernandes, Por Luís

    2011-01-01

    Philippe Bourgois é, desde 2007, “Richard Perry University professor” no Departamento de Antropologia e de Medicina Familiar e de Práticas Comunitárias na Universidade da Pensilvânia. Esteve durante largos anos ligado ao Departamento de Antropologia, História e Medicina Social da Universidade da Califórnia, São Francisco. A publicação, em 1995, de In Search of Respect: Selling Crack in El Barrio1 projectaria o seu nome muito para além dos Estados Unidos: uma etnografia no coração porto-riquenho do Harlem, em torno dos actores e dos ambientes da venda de crack. Seguir-se-ia um longo trabalho de terreno em acampamentos de dependentes de heroína em São Francisco, orientando o seu trabalho para as formas mais radicais da pobreza e da marginalidade nos EUA. É deste trabalho de terreno que sai o seu último livro, Righteous Dopefiend2. Em Junho de 2007 esteve em Lisboa para participar na 3.a edição do “Ethnografeast”. Foi então que aproveitámos a oportunidade para ouvir um percurso invulgar contado pelo próprio: uma longa conversa no Hotel Zurique, cujo nome só vem ao caso por evocar o país onde passou uma parte da infância. PMID:22013286

  1. A correlação índice espectral vs. luminosidade em QSOs e suas implicações

    NASA Astrophysics Data System (ADS)

    Garcia-Rissmann, A.

    2003-08-01

    Estudos de variabilidade de núcleos ativos já demonstraram ser comum o fato de seu contínuo óptico/UV tornar-se mais "duro" à medida que a luminosidade aumenta. Essa tendência ocorre tanto de forma individual quanto global, e pode ter implicações importantes (1) para estudos fotométricos de variabilidade conduzidos numa banda fixa no referencial do observador, comparando objetos a diferentes redshifts, e (2) no cálculo da correção K, com consequente impacto na determinação de massas de buracos negros e bojos de galáxias hospedeiras (através da relação de Magorrian). Confirmo aqui as correlações positivas entre o índice espectral e a luminosidade óptica, utilizando dados espectroscópicos de 11 QSOs monitorados no Brasil e no Chile, durante ~2 anos. O estudo é complementado com parâmetros extraídos de espectros e de dados fotométricos públicos de quasares. Destaco ainda as diferenças observadas em tais correlações para objetos do tipo radio-loud e radio-quiet. Este projeto é financiado pelo I. Milênio/CNPq.

  2. Perfil de temperatura dos funis magnetosféricos de estrelas T Tauri com aquecimento alfvênico

    NASA Astrophysics Data System (ADS)

    Vasconcelos, M. J.

    2003-08-01

    Estrelas T Tauri Clássicas são objetos jovens circundados por discos de gás e poeira e que apresentam uma intensa atividade magnética. Seu espectro mostra linhas de emissão alargadas que são razoavelmente reproduzidas nos modelos de acresção magnetosférica. No entanto, o perfil de temperatura dos funis magnéticos é desconhecido. Aquecimento magnético compressional e difusão ambipolar foram considerados para estas estruturas, porém as temperaturas obtidas não são suficientes para explicar as observações. Neste trabalho, examinamos o aquecimento gerado pelo amortecimento de ondas Alfvén através de quatro mecanismos, os amortecimentos não-linear, turbulento, viscoso-resistivo e colisional como função da freqüência da onda. Inicialmente, a temperatura é ajustada para reproduzir as observações e o grau de turbulência requerido para que o mecanismo seja viável é calculado. Os resultados mostram que este é compatível com os dados observacionais. Apresentam-se, também, resultados preliminares do cálculo auto-consistente do perfil de temperatura dos funis, levando-se em conta fontes de aquecimento Alfvênica e fontes de resfriamento.

  3. The advances and new technologies for the study of mitochondrial diseases.

    PubMed

    Bianco, Bianca; Montagna, Erik

    2016-01-01

    ABSTRACTGenetic mitochondrial disorders are responsible for the most common inborn errors of metabolism, caused by mutations in either nuclear genes or in mitochondrial DNA. This article presents the prokaryotic origin of the organelle and the relation between nuclear and mitochondrial genomes, as well as current evolutionary models for such mechanisms. It also addresses the structure of mitochondrial genes, their expression pattern, clinical features of gene defects, risk of transmission and current techniques to avoid these events in assisted human reproduction. Finally, it discusses the ethical implications of these possibilities.RESUMOAs doenças genéticas mitocondriais são responsáveis pelos erros inatos do metabolismo mais comuns, causados por mutações tanto em genes nucleares como no DNA mitocondrial. Este artigo apresenta a origem procariótica dessa organela, e a relação entre os genomas nuclear e mitocondrial, bem como modelos evolutivos correntes para esses mecanismos. Também trata da estrutura dos genes mitocondriais, seu padrão de expressão, características clínicas de defeitos genéticos, riscos de transmissão e técnicas atualmente utilizadas para evitar esses eventos em reprodução humana assistida. Finalmente, discute as implicações éticas dessas possibilidades. PMID:27462900

  4. Population structure of eleven Spanish ovine breeds and detection of selective sweeps with BayeScan and hapFLK.

    PubMed

    Manunza, A; Cardoso, T F; Noce, A; Martínez, A; Pons, A; Bermejo, L A; Landi, V; Sànchez, A; Jordana, J; Delgado, J V; Adán, S; Capote, J; Vidal, O; Ugarte, E; Arranz, J J; Calvo, J H; Casellas, J; Amills, M

    2016-01-01

    The goals of the current work were to analyse the population structure of 11 Spanish ovine breeds and to detect genomic regions that may have been targeted by selection. A total of 141 individuals were genotyped with the Infinium 50 K Ovine SNP BeadChip (Illumina). We combined this dataset with Spanish ovine data previously reported by the International Sheep Genomics Consortium (N = 229). Multidimensional scaling and Admixture analyses revealed that Canaria de Pelo and, to a lesser extent, Roja Mallorquina, Latxa and Churra are clearly differentiated populations, while the remaining seven breeds (Ojalada, Castellana, Gallega, Xisqueta, Ripollesa, Rasa Aragonesa and Segureña) share a similar genetic background. Performance of a genome scan with BayeScan and hapFLK allowed us identifying three genomic regions that are consistently detected with both methods i.e. Oar3 (150-154 Mb), Oar6 (4-49 Mb) and Oar13 (68-74 Mb). Neighbor-joining trees based on polymorphisms mapping to these three selective sweeps did not show a clustering of breeds according to their predominant productive specialization (except the local tree based on Oar13 SNPs). Such cryptic signatures of selection have been also found in the bovine genome, posing a considerable challenge to understand the biological consequences of artificial selection. PMID:27272025

  5. Population structure of eleven Spanish ovine breeds and detection of selective sweeps with BayeScan and hapFLK

    PubMed Central

    Manunza, A.; Cardoso, T. F.; Noce, A.; Martínez, A.; Pons, A.; Bermejo, L. A.; Landi, V.; Sànchez, A.; Jordana, J.; Delgado, J. V.; Adán, S.; Capote, J.; Vidal, O.; Ugarte, E.; Arranz, J. J.; Calvo, J. H.; Casellas, J.; Amills, M.

    2016-01-01

    The goals of the current work were to analyse the population structure of 11 Spanish ovine breeds and to detect genomic regions that may have been targeted by selection. A total of 141 individuals were genotyped with the Infinium 50 K Ovine SNP BeadChip (Illumina). We combined this dataset with Spanish ovine data previously reported by the International Sheep Genomics Consortium (N = 229). Multidimensional scaling and Admixture analyses revealed that Canaria de Pelo and, to a lesser extent, Roja Mallorquina, Latxa and Churra are clearly differentiated populations, while the remaining seven breeds (Ojalada, Castellana, Gallega, Xisqueta, Ripollesa, Rasa Aragonesa and Segureña) share a similar genetic background. Performance of a genome scan with BayeScan and hapFLK allowed us identifying three genomic regions that are consistently detected with both methods i.e. Oar3 (150–154 Mb), Oar6 (4–49 Mb) and Oar13 (68–74 Mb). Neighbor-joining trees based on polymorphisms mapping to these three selective sweeps did not show a clustering of breeds according to their predominant productive specialization (except the local tree based on Oar13 SNPs). Such cryptic signatures of selection have been also found in the bovine genome, posing a considerable challenge to understand the biological consequences of artificial selection. PMID:27272025

  6. Pre-Columbian origins of Native American dog breeds, with only limited replacement by European dogs, confirmed by mtDNA analysis

    PubMed Central

    van Asch, Barbara; Zhang, Ai-bing; Oskarsson, Mattias C. R.; Klütsch, Cornelya F. C.; Amorim, António; Savolainen, Peter

    2013-01-01

    Dogs were present in pre-Columbian America, presumably brought by early human migrants from Asia. Studies of free-ranging village/street dogs have indicated almost total replacement of these original dogs by European dogs, but the extent to which Arctic, North and South American breeds are descendants of the original population remains to be assessed. Using a comprehensive phylogeographic analysis, we traced the origin of the mitochondrial DNA lineages for Inuit, Eskimo and Greenland dogs, Alaskan Malamute, Chihuahua, xoloitzcuintli and perro sín pelo del Peru, by comparing to extensive samples of East Asian (n = 984) and European dogs (n = 639), and previously published pre-Columbian sequences. Evidence for a pre-Columbian origin was found for all these breeds, except Alaskan Malamute for which results were ambigous. No European influence was indicated for the Arctic breeds Inuit, Eskimo and Greenland dog, and North/South American breeds had at most 30% European female lineages, suggesting marginal replacement by European dogs. Genetic continuity through time was shown by the sharing of a unique haplotype between the Mexican breed Chihuahua and ancient Mexican samples. We also analysed free-ranging dogs, confirming limited pre-Columbian ancestry overall, but also identifying pockets of remaining populations with high proportion of indigenous ancestry, and we provide the first DNA-based evidence that the Carolina dog, a free-ranging population in the USA, may have an ancient Asian origin. PMID:23843389

  7. Datação do disco galáctico pela nucleocosmocronologia do [Th/Eu

    NASA Astrophysics Data System (ADS)

    del Peloso, E. F.; da Silva, L.; Arany-Prado, L. I.

    2003-08-01

    A nucleocosmocronologia emprega abundâncias de nuclídeos radioativos na datação de escalas de tempo astrofísicas. O 232Th é um nuclídeo radioativo com meia-vida de 14 Gano, enquanto que os dois isótopos mais abundantes do Eu são estáveis. O decaimento radioativo do Th modifica as razões de abundâncias [Th/Eu], fornecendo assim um meio de sondar a escala de formação das populações estelares. O objetivo deste trabalho é averiguar a possibilidade de estimar uma idade para o disco Galáctico através da nucleocosmocronologia do [Th/Eu] e investigar o nível de incerteza associado a esta estimativa. Para tanto, foi selecionada uma amostra de 20 estrelas anãs ou subgigantes de tipos espectrais F5 a G9, com -1,00 £ [Fe/H] £ +0,30 e idade(Gano) £ 13. As abundâncias de Th e Eu foram obtidas por síntese espectral das linhas localizadas em 4019,1 Å e 4129,7 Å, respectivamente. Uma comparação destas abundâncias com outros resultados da literatura demonstra que nossos valores apresentam dispersão 2 a 3 vezes menor que qualquer trabalho anterior. Os parâmetros atmosféricos e abundâncias dos elementos que contaminam as regiões espectrais destas linhas foram determinados por nós, de maneira totalmente autoconsistente, através de análise espectral detalhada diferencial em relação ao Sol. As idades estelares individuais foram determinadas através de curvas isócronas teóricas no diagrama HR. Foi realizada, então, uma análise cronológica dos gráficos [Th/Eu] vs. [Fe/H] e [Th/Eu] vs. idade. Os dados estelares foram comparados a curvas calculadas para 3 idades do disco Galáctico - 9, 12, 15 Gano - e foi estudada a sensibilidade à idade assumida no cálculo do ajuste destas curvas aos dados. Estas curvas foram calculadas com base num modelo analítico de evolução química da Galáxia que leva em consideração a formação de refugos, que são compostos pelos remanescentes da evolução estelar, pelos resíduos da formação de estrelas de

  8. Evolução rotacional de corpos reacumulados

    NASA Astrophysics Data System (ADS)

    Penteado, P.; Lazzaro, D.; Roig, F.; Duffard, R.; Kodama, T.

    2003-08-01

    Asteróides reacumulados (rubble-piles) são corpos formados por um conjunto de fragmentos agregados primariamente pela sua gravidade. A importância do estudo de corpos reacumulados para a compreensão da evolução do Cinturão de Asteróides tem sido bastante evidenciada, não apenas pela constatação de que estes devem corresponder a uma grande parcela da população de asteróides, mas também por recentes estudos da estrutura e evolução colisional deste tipo de asteróide. A evolução rotacional de corpos reacumulados e a formação de famílias têm sido estudadas pelo nosso grupo, com base no modelo de elipsóides interagentes. Este modelo foi desenvolvido recentemente pelo grupo, e baseia-se na integração numérica das equações de movimento para translação e rotação de corpos formados por um conjunto de elipsóides que interagem entre si pela sua gravidade, força de contato e dissipação de energia por atrito. Considerar a rotação de cada fragmento é a principal diferenciação do nosso modelo em relação aos que têm sido desenvolvidos recentemente. Apresentamos aqui os resultados obtidos para a evolução da rotação de populações de corpos reacumulados. Estes foram submetidos a séries de colisões com projéteis de altas velocidades (5Km/s, típicas do Cinturão atual), distribuídos em uma lei de potências de tamanhos. Estes resultados são comparados com os de Harris (1979), um dos poucos trabalhos analíticos existentes para evolução rotacional de asteróides. O principal resultado obtido por Harris foi a distribuição final de velocidades de rotação como uma lei de potências para corpos pequenos, passando de forma bem definida para rotação constante para os grandes. Nas nossas simulações observamos que as distribuições de velocidades de rotação resultantes tendem a leis de potência, com a inclinação evoluindo no decorrer de colisões subsequentes.

  9. 30 years later: Social Representations about AIDS and sexual practices of rural towns residents.

    PubMed

    Furtado, Francisca Marina de Souza Freire; Santos, José Anderson Galdino; Loredanna, Stedile; Araújo, Eunice; Saldanha, Ana Alayde Werba; Silva, Josevânia da

    2016-06-01

    no estado da Paraíba/Brasil. Os dados foram coletados por um meio de um questionário e o teste de associação livre de palavras. Os resultados mostraram baixa preocupação com doença, percepção de invulnerabilidade à contaminação pelo HIV e o não uso do preservativo nas relações sexuais, sendo a confiança no parceiro o principal motivo relacionado. Também mostraram perdurar representações de natureza pejorativa e estereotipada, revelando que ainda perduram, no meio rural, crenças e representações referentes ao início da epidemia. A partir de tais achados, é possível apontar deficiências em termos de cuidados oferecidos pelos serviços de saúde nestas localidades, o que pode resultar em maiores vulnerabilidades dessa população ao adoecimento, havendo assim a necessidade da intensificação de campanhas de informação e intervenção. PMID:27384279

  10. The Moon Phases in a Paper Box. (Spanish Title: Las Fases de la Luna en Una Caja de Cartón.) As Fases da Lua Numa Caixa de Papelão

    NASA Astrophysics Data System (ADS)

    de Fátima O. Saraiva, Maria; Amador, Cláudio B.; Kemper, Érico; Goulart, Paulo; Muller, Angela

    2007-12-01

    material didático de baixo custo para demonstração do conceito de fases de um corpo iluminado. O principal objetivo de nosso material é facilitar a compreensão das fases da Lua da perspectiva de um observador na Terra. O material ajuda na visualização de dois efeitos importantes: (1º) mesmo tendo sempre a metade da "Lua" (representada por uma bolinha de isopor ou de ping-pong) iluminada pelo "Sol" (representado por uma fonte de luz natural ou artificial), nós vemos diferentes frações de sua superfície iluminada, dependendo do ângulo pelo qual a olhamos; (2º) a orientação da borda convexa da Lua nas fases Crescente e Minguante também depende da perspectiva pela qual a olhamos da Terra. O uso de uma caixa fechada permite observar o contraste entre as diferentes fases sem necessidade de estar em uma sala escurecida. Apresentamos também um texto explicativo sobre fases da Lua, enfatizando a dependência da aparência da parte iluminada com o ângulo de visada.

  11. Is the Dark Side of the Moon Ever Illuminated by the Sun? (Breton Title: O Lado Escuro da Lua Nunca Apanha Sol?) El Lado Oscuro de la Luna Nunca Toma Sol?

    NASA Astrophysics Data System (ADS)

    Giovannini, Odilon; Pellenz, Daiana; Catelli, Francisco

    2014-07-01

    This work presents the elaboration of an answer to the question "Is the dark side of the moon ever illuminated by the sun?", in which issues related to the students' conceptions, how they arise, and the core elements that constitute a "good answer" are considered. These issues are initially elaborated from a literature review of the research in the field; then, and also based on this review, a didactic model that involves the relative motions of the Earth - Moon - Sun system is proposed. A description of the application of this model in a learning environment within middle school students is described. This work confirms the students' initial concepts described in the literature; on the other hand, the questions asked by students during the activity provide evidence that meaningful learning, at least to some degree, has occurred. Este trabalho apresenta a elaboração de uma resposta à pergunta "O lado escuro da Lua nunca apanha sol?" na qual são consideradas questões relacionadas às concepções iniciais dos alunos, de onde elas surgem e os elementos centrais que constituem uma "boa resposta". Essas questões são tratadas, inicialmente, a partir de uma revisão da literatura sobre pesquisas na área e, em seguida, também com base nessa revisão, um objeto modelo didático que envolve os movimentos relativos do sistema Terra - Lua - Sol é proposto. Uma descrição detalhada da aplicação deste modelo em um ambiente de aprendizagem com alunos do ensino fundamental é relatada. As concepções iniciais apresentadas na literatura se confirmam e os questionamentos feitos pelos estudantes por ocasião da aplicação do modelo fornecem indícios de que uma aprendizagem significativa, pelo menos em algum grau, ocorreu. El artículo se presenta el desarrollo de una respuesta a la pregunta "¿El lado oscuro de la luna nunca toma sol?", en la que se consideran algunas cuestiones vinculadas que se refieren a las concepciones iniciales de los estudiantes, dónde surgen

  12. Astronomy at School: Measurements of the Earth-Moon Distance. (Spanish Title: Astronomía en la Escuela: Medición de la Distancia Tierra-Luna.) Astronomia na Escola: Medida da Distância Terra-Lua

    NASA Astrophysics Data System (ADS)

    Paolantonio, Santiago; Pintado, Olga I.

    2006-12-01

    The aim of this project is to approach High School students to Science. We propose to measure the Earth-Moon distance using the parallax. The observation and measurements techniques and all the calculations needed are described in this paper. The results obtained in a test experience realized during 2003 are presented. This test shows that this is a feasible project and also shows which things needed to be improved. Se plantea la propuesta de un proyecto educativo dirigido al Nivel Medio de enseñanza, consistente en la determinación de la distancia Tierra - Luna por paralaje. Se describen las técnicas de observación, mediciones y cálculos. Se proporcionan a continuación los resultados obtenidos en la experiencia piloto realizada en el 2003, la que permitió comprobar la factibilidad de llevar a cabo la propuesta, así como perfeccionar los diferentes aspectos involucrados en la misma. Propomos neste trabalho um projeto educativo dirigido ao Ensino Médio que consiste na determinação da distância Terra-Lua pelo efeito da paralaxe. As técnicas de observação, medidas e cálculos auxiliares são descritos, e os resultados obtidos numa experiência-teste realizada no ano de 2003 apresentados. Este último teste permitiu comprovar a viabilidade de execução da proposta e aperfeiçoar diversos aspectos da mesma.

  13. A eficiência de formação estelar em Musca

    NASA Astrophysics Data System (ADS)

    Hickel, G. R.; Vilas-Boas, J. W. S.; Roberto, A. J.., Jr.; Khan, R. P.

    2003-08-01

    Apresentamos os resultados de um survey no infravermelho próximo (bandas J e H), executado no Laboratório Nacional de Astrofísica, na direção da nuvem escura em forma de filamento de Musca (observamos ao longo de todo o filamento, além de todas as fontes pontuais IRAS e/ou fontes ROSAT brilhantes a uma distância de 2o da nuvem). Nosso objetivo é determinar a eficiência de formação estelar para esta nuvem escura (massa de estrelas formadas/massa da nuvem), procurando por objetos estelares jovens de pequena massa no seu interior e/ou evoluídos o suficiente para estarem afastados do local de nascimento, mas ainda mostrando características de objetos pré-seqüência principal como emissão de raios-X e excesso de emissão no infravermelho próximo. Este survey não estabeleceu nenhum viés na seleção de fontes pontuais IRAS ou fontes ROSAT, uma vez que a imensa maioria das fontes pontuais IRAS nesta região têm qualidade de fluxo ruim. Os candidatos a objetos estelares jovens foram selecionados pelo excesso no índice de cor (J-H), descontados os efeitos da extinção interestelar na linha de visada, determinada através da emissão estendida no infravermelho distante (IRAS). Estimativas de massa foram feitas para estes candidatos, através da relação massa-luminosidade, para calcular a eficiência de formação estelar de Musca.

  14. Inauguração do Telescópio SOAR

    NASA Astrophysics Data System (ADS)

    Steiner, João

    2004-04-01

    A comunidade astronômica brasileira de há muito almeja ter a sua disposição um instrumento científico com o qual possa fazer pesquisa de vanguarda e manter a competitividade científica a nível internacional. Hoje este sonho se torna uma realidade. O Brasil tem tido uma política de pesquisa e de pós-graduação bem sucedida. Estamos formando 7000 doutores por ano e produzimos 1,5% da ciência mundial. Nosso desafio, hoje, é associar a esta capacidade de gerar conhecimento também a capacidade de usar o conhecimento em beneficio da sociedade. A Astronomia não é exceção. Temos 7 programas de pós-graduação em nível de doutorado e 11 em nível de mestrado. O telescópio SOAR será o principal instrumento que sustentará estes programas nas próximas décadas. A inauguração do telescópio SOAR simboliza de forma concreta e decidida o apoio do MCT, do CNPq e da FAPESP para o financiamento à pesquisa básica em nosso país. O Laboratório Nacional de Astrofísica, criado a cerca de 20 anos pelo CNPq, a par do Laboratório Nacional de Luz Sincrotron, são até hoje, os únicos laboratórios nacionais do Brasil e ambos voltados basicamente ao avanço do conhecimento. Os vinte anos de existência do LNA foram decisivos para a estruturação da comunidade astronômica no Brasil e para a construção das parcerias como o SOAR.

  15. The Illness Experience: Palliative Care Given the impossibility of Healing.

    PubMed

    Dantas, Margarida Maria Florêncio; Amazonas, Maria Cristina Lopes de Almeida

    2016-06-01

    This paper presents a reflection about being terminally ill and the various ways that the subject has at its disposal to deal with this event. The objective is to understand the experience of palliation for patients undergoing no therapeutic possibilities of cure. The methodology of this study has the instruments to semi-structured interview, the participant observation and the field diary, and the Descriptive Analysis of Foucault's inspiration how the narratives of the subjects were perceived. The Results of paper there was the possibility of looking at the experience of illness through the eyes of a subject position assumed by the very sick. As conclusion we have than when choosing palliative care, the terminally ill opts for a way to feel more comfortable and resists the impositions of the medical model of prolonging life. O presente trabalho traz uma reflexão a respeito do ser um doente terminal e das várias maneiras que o sujeito tem a seu dispor para lidar com esse acontecimento. Nosso objetivo foi compreender a experiência da paliação por sujeitos doentes sem possibilidades terapêuticas de cura. A metodologia deste estudo teve como instrumentos a Entrevista Narrativa, a Observação Participante e o Diário de Campo, sendo a Análise Descritiva de inspiração foucaultiana o modo como as narrativas dos sujeitos foram percebidas. O resultado do estudo mostrou a possibilidade de olhar a experiência do adoecer através da ótica de uma posição de sujeito assumida pelo próprio enfermo. E concluímos que ao escolher os cuidados paliativos, o doente terminal opta por um modo de se sentir mais confortável e resiste às imposições do modelo médico de prolongamento da vida. PMID:27384275

  16. A Concepção de Universo entre Alunos do Ensino Médio de São Paulo e suas Fontes de Aquisição

    NASA Astrophysics Data System (ADS)

    Araújo, M. A. A.; Elias, D. C. N.; Amaral, L. H.; Araújo, M. S. T.; Voelzke, M. R.

    2006-08-01

    Nesse trabalho procurou-se identificar por meio de um questionário as concepções de Universo, de espaço e tempo que sustentam a visão de mundo de um grupo de 270 estudantes de Ensino Médio, pertencentes a três escolas de São Paulo. As questões relacionadas aos conhecimentos prévios dos estudantes permitiram constatar que há pouco conhecimento acerca dos temas investigados, destacando-se que apenas 20% dos alunos foram capazes de relacionar as semanas com as fases da lua, enquanto 28% associaram as estações do ano à inclinação do eixo de rotação da Terra e 23% tinham noções das distâncias entre objetos celestes próximos da Terra. Enquanto 56% conseguiram relacionar o Big Bang com a origem do Universo, verificou-se que 37% reconheciam ano-luz como unidade de distância e 60% concebiam o Sol como uma estrela. No que se refere às fontes de aquisição que proporcionaram esses conhecimentos, apesar de 60% dos alunos indicarem a escola como principal fonte dos conhecimentos de Ast! ronomia, verificou-se claramente que para a maioria dos alunos seus conceitos ainda são inadequados, havendo necessidade de aprimoramento da abordagem desses conteúdos, pois apesar de popular, a Astronomia ainda é veiculada de maneira pouco esclarecedora e com imprecisões. Nesse contexto, são discutidas algumas possíveis contribuições que podem ser dadas para o ensino de Astronomia pelo uso das ferramentas computacionais nas escolas.

  17. On telescópio remoto do Observatório Abrahão de Moraes - Obelix

    NASA Astrophysics Data System (ADS)

    Neres, N. L.; Raffaelli, J. C.; Medina Tanco, G. A.; Horvath, J. E.; Maluhy, R.; Martins, A.; Orselli, M. I. V.

    2003-08-01

    Foi desenvolvido um telescópio totalmente automático situado no Observatório Abrahão de Moraes, em Valinhos-SP, que possibilita observações remotas via Internet tanto para fins profissionais como didáticos. Usando um programa navegador da WWW, o observador tem acesso a páginas interativas que permitem não só apontar o telescópio e receber as imagens, como também controlar a abertura e o fechamento da cúpula, monitorar temperatura, umidade e orvalho e receber imagens das câmaras de segurança. O fechamento da cúpula é feito automaticamente em caso de perigo de condensação. O sistema consiste de uma câmara Apogee, uma roda de filtros SBIG modelo CFW-8 com filtros RGB e um telescópio Meade. A observação remota é feita usando programas comerciais da área. Uma caixa de controle com lógica programável controla o movimento da cúpula e a energização do telescópio. Um software em LabView adquire os dados da estação meteorológica, que inclui um sensor de chuva desenvolvido no IAG, e apresenta seus valores atuais e históricos. Usando uma facilidade do próprio LabView, a saída desse software é exportada para a Internet. Um programa em C disponibiliza as imagens das câmaras de segurança usando uma placa de captura de vídeo e um seqüencial de vídeo que foi adaptado para ser controlado pelo PC. O sistema completo já se encontra operacional.

  18. Aquecimento alfvênico viscoso-resistivo em discos de acresção ao redor de estrelas T Tauri clássicas

    NASA Astrophysics Data System (ADS)

    Santana, W. M.; Vasconcelos, M. J.

    2003-08-01

    Com a crescente disponibilidade de dados observacionais sobre estrelas T Tauri, a busca por modelos mais precisos vem se tornando cada vez maior. Estes modelos devem explicar, entre outras coisas, o mecanismo dissipativo responsável pelo transporte de momento angular no disco de acresção que acredita-se, circunda estas estrelas. O mecanismo mais viável, do ponto de vista teórico, é uma instabilidade MHD conhecida como "instabilidade magnetorotacional ou Balbus-Hawley" (IBH). Esta instabilidade veio mostrar que o campo magnético desempenha um papel importante na evolução destes objetos mas requer, no entanto, um acoplamento mínimo entre o gás e o campo magnético no disco que não é atingido para os valores de temperatura obtidos do modelo padrão. Contudo, alguns mecanismos de aquecimento para o disco precisam ser examinados. Neste trabalho, propomos a dissipação de ondas Alfvén como uma fonte de aquecimento para o disco. Se o gás apresentar uma condutividade elétrica finita e viscosidade, teremos um tipo de amortecimento para as ondas denominado amortecimento viscoso-resistivo que será aqui considerado. Este mecanismo é aplicado ao modelo de disco em camadas. Calculam-se as taxas de aquecimento Alfvênico, a temperatura efetiva do disco bem como as taxas de ionização decorrentes deste aquecimento e do aquecimento gerado pela absorção de raios cósmicos. Comparações com os dados observacionais de Kitamura et. al. (2001) são efetuadas, ressaltando-se os pontos comuns entre suas observações e nossos dados teóricos.

  19. Determinação do extremo de baixa luminosidade da função de luminosidade através de simulações de Monte Carlo

    NASA Astrophysics Data System (ADS)

    Campos, P. E.; Mendes de Oliveira, C.

    2003-08-01

    Neste trabalho apresentamos os principais resultados do estudo da população de galáxias anãs de baixo brilho superficial dos grupos compactos HCG44 e HCG68. A inclinação do extremo de baixa luminosidade a da função de luminosidade desses grupos foi estimado através de simulações de Monte Carlo. O método consistiu em simular galáxias anãs de baixo brilho superficial em imagens reais seguindo uma distribuição de magnitudes dada uma função de Schechter. Foram testados vários modelos com diferentes valores para os parâmetros M* e a da função de Schechter, e para cada um dos modelos foi repetido o mesmo processo de recuperação, seleção e análise usados com as galáxias anãs dos grupos. Os resultados de cada modelo foram então comparados com o observado nos grupos. Nossos resultados indicam que a distribuição de magnitudes (para magnitudes absolutas até MR»-12) observadas nos grupos são compatíveis com uma função de luminosidade de Schechter dada por um M* = -16 e um a entre -1.0 e -1.4, e portanto de acordo com a tendência observada de uma inclinação do extremo de baixa luminosidade da função de luminosidade de grupos mais plana (~1.2, Trentham & Tully 2002, MNRAS, 335, 712) que esperado pelo modelo hierárquico de formação de estruturas CDM (Cold Dark Matter - Matéria Escura Fria).

  20. Análise da medição do raio solar em ultravioleta

    NASA Astrophysics Data System (ADS)

    Saraiva, A. C. V.; Giménez de Castro, C. G.; Costa, J. E. R.; Selhorst, C. L.; Simões, P. J. A.

    2003-08-01

    A medição acurada do raio solar em qualquer banda do espectro eletromagnético é de relevância na formulação e calibração de modelos da estrutura e atmosfera solar. Esses modelos atribuem emissão do contínuo do Sol calmo em microondas à mesma região da linha Ha do Hell. Apresentamos a medição do raio solar em UV com imagens do EIT (Extreme Ultraviolet Image Telescope) entre 1996 e 2002, no comprimento de onda 30,9 nm (Ha do Hell), que se forma na região de transição/cromosfera solar. A técnica utilizada para o cálculo do raio UV foi baseada na transformada Wavelet B3spline. Fizemos um banco de dados com 1 imagem por dia durante o período citado. Obtivemos como resultado o raio médio da ordem de 975.61" e uma diminuição do mesmo para o período citado variando em média -0,45" /ano. Comparamos estes dados com os valores obtidos pelo ROI (Radio Observatório de Itapetinga) em 22/48 GHz e Nobeyama Radio Heliograph em 17 GHz mostrando que os raios médios são muito próximos o que indica que a região de formação nessas freqüências é a mesma conforme os modelos. Comparamos os resultados também com outros índices de atividade solar.

  1. A review of the taxonomy, ethnobotany, chemistry and pharmacology of Sutherlandia frutescens (Fabaceae).

    PubMed

    van Wyk, B-E; Albrecht, C

    2008-10-28

    Sutherlandia frutescens (tribe Galegeae, Fabaceae), a popular plant in traditional medicine, is indigenous to South Africa, Lesotho, southern Namibia and southeastern Botswana. It is chemically, genetically and geographically extremely variable and has been divided into three subspecies and several regional forms. A second species, Sutherlandia tomentosa, is localized along the Cape coast. Sutherlandia is sometimes treated as part of the genus Lessertia. There are numerous vernacular names and a wide diversity of uses, including poor appetite, indigestion, stomach complaints, dysentery, colds, influenza, kidney conditions, fever, diabetes, internal cancers, uterine troubles, liver conditions, backache, rheumatoid arthritis, urinary tract infections, stress and anxiety, dropsy and heart failure. Notable is the use as a bitter tonic ("blood purifier"), anti-stress medication ('musa-pelo) and, at least since 1895, specifically as a cancer tonic (both as treatment and as prophylaxis). Externally it is applied to haemorrhoids, inflamed wounds and eye infections. Recent in vitro and in vivo studies have shown antiproliferative, anti-HIV, anti-diabetic, anti-inflammatory, analgesic, antibacterial, anti-stress, anticonvulsant and antithrombotic activities. Aqueous extracts often differ in activity from organic solvent extracts. The presence of high levels of free amino acids, non-protein amino acids such as canavanine and GABA, the cyclitol pinitol, flavonols and triterpenes (including SU1, a cycloartane-type triterpene saponin) provide plausible hypotheses on how these compounds, individually or collectively, may be responsible for the reputed efficacy in a wide range of ailments. Results of animal studies, as well as a phase I clinical study, have shown no indications of toxicity. Sufficient preclinical data are now available to justify controlled clinical studies. PMID:18761068

  2. Teaching of Astronomy: Scenarios of Teaching Practice in Elementary Schools. (Spanish Title: Enseñanza de la Astronomía: Semblanzas de la Práctica Docente en Educación Primaria.) Ensino de Astronomia: Cenários da Prática Docente no Ensino Fundamental

    NASA Astrophysics Data System (ADS)

    Marchi Gonzatti, Sônia Elisa; Spessatto De Maman, Andréia; Fernandes Borragini, Eliana; Kerber, Júlia Cristina; Haetinger, Werner

    2013-12-01

    atomización de los asuntos, aunque temas como movimientos de la Tierra y fenómenos astronómicos hayan sido citados por la mayoría de los participantes. En cuanto a las estrategias, se verifico que se emplean principalmente clases con el apoyo de recursos bidimensionales, como películas, textos, mapas y búsqueda en internet. Las principales dificultades fueron la falta de formación específica con respecto a los contenidos de Astronomía, y el nivel de abstracción exigido por los contenidos. De modo general, esos indicadores convergen para los resultados ya encontrados en otros estudios, en el que las deficiencias de la formación inicial de los profesores, o incluso su ausencia, dificulta el adecuado abordaje de la Astronomía en las clases. Neste trabalho são apresentados os principais resultados de uma investigação realizada no campo da Educação em Astronomia, com professores do ensino fundamental de duas regiões do Rio Grande do Sul. O objetivo do estudo foi caracterizar o cenário regional do ensino de Astronomia, estabelecendo um comparativo com o cenário nacional. Esse estudo abordou três questões: identificar os principais temas de astronomia trabalhados em sala de aula, as estratégias metodológicas e quais as dificuldades apresentadas pelos professores ao desenvolver sua prática. Quanto aos conteúdos, encontrouse uma pulverização dos assuntos abordados, embora temas como movimentos da Terra e fenômenos astronômicos tenham sido citados pela maioria dos participantes. Sobre estratégias, são utilizadas principalmente aulas com apoio de recursos bidimensionais, como filmes, textos, mapas e pesquisa na internet. As principais dificuldades foram: falta de formação específica em relação a conteúdos de Astronomia; nível de abstração dos conteúdos, que dificultam sua compreensão, tanto pelos alunos quanto pelos próprios professores. De maneira geral, esses indicadores convergem para resultados já encontrados em outros estudos que

  3. Precessão do jato de 3C120: simulações hidrodinâmicas 3D

    NASA Astrophysics Data System (ADS)

    Caproni, A.; de Gouveia dal Pino, E. M.; Abraham, Z.; Raga, A. C.

    2003-08-01

    Observações com técnicas de interferometria com longa linha de base têm mostrado a existência de um jato relativístico com componentes superluminais na região central de 3C 120. Estas componentes são ejetadas em distintas direções no plano do céu e com diferentes velocidades aparentes. Estas características foram interpretadas em trabalhos anteriores como efeitos da precessão do jato relativístico. Neste trabalho, realizamos simulações tri-dimensionais do jato de 3C 120 utilizando os parâmetros de precessão determinados em trabalhos anteriores e variando as características iniciais do jato e meio ambiente, tais como densidade numérica e temperatura. Todas as simulações foram feitas com o código hidrodinâmico YGUAZÚ-A, assumindo-se um jato adiabático descrito por uma equação de estado relativística. Pelo fato de estarmos utilizando um código hidrodinâmico, nós assumimos que a intensidade do campo magnético e a distribuição de partículas, necessários para se calcular a emissão sincrotron, são proporcionais à pressão hidrodinâmica. Comparação entre dois cenários distintos, nos quais o material do jato é ejetado com velocidade constante (jato contínuo) e com velocidade modulada por um padrão sinusoidal no tempo (jato intermitente), é apresentada e discutida. Para jatos que apresentam fenômenos de precessão e intermitência, com amplitude de variação na velocidade de injeção maior que dez por cento da velocidade média de injeção, a hipótese balística, controlada pela intermitencia, é mais provável. Por outro lado, para jatos com precessão mas sem intermitência (ou com amplitude de variabilidade em velocidade mais baixa que no caso anterior), o efeito da precessão na morfologia do jato não é desprezível. Portanto, de um modo geral, ambos efeitos (precessão e movimentos balísticos) devem estar concorrendo para afetar a morfologia dos jatos superluminais.

  4. Analysis of the Presence of Content about Astronomy in a Decade of the National High School Examination (1998-2008). (Spanish Title: Análisis de la Presencia de Contenidos de Astronomía em Uma Década del Examen Nacional de Enseñaza Secundária (1998-2008).) Análise da Presença de Conteúdos de Astronomia em Uma DÉcada do Exame Nacional do Ensino Médio (1998-2008)

    NASA Astrophysics Data System (ADS)

    Gomide, Hanny Angeles; Longhini, Marcos Daniel

    2011-07-01

    In this paper we analyzed the presence of contents of Astronomy in the National High School Examination (ENEM) in its first decade (1998-2008). We verified the number of questions addressing this topic that were present over the years, as well as the most recurrent subjects. We discussed the results from what is proposed by the official documents regarding the teaching of Astronomy in the Elementary and Secondary Education and we entertain future expectations about the presence of contents of this science in future official examinations. En este trabajo realizamos un análisis de la presencia de contenidos de Astronomía em las pruebas del Examen Nacional de Enseñanza Secundaria (ENEM) em su primera década de existência (1998-2008). Contabilizamos la cantidad de preguntas incluyendo este tema que estuvieron presentes en el transcurso de los años, así como los temas más recurrentes. Discutimos los resultados a partir de lo propuesto por los documentos oficiales en relación a la enseñanza de Astronomía en la Educación Básica y elaboramos algunos apuntes sobre futuras expectativas em relación a la presencia de contenidos de esta ciencia en examenes oficiales. No presente trabalho fizemos uma análise da presença de conteúdos de Astronomia nas provas do Exame Nacional do Ensino Médio (ENEM), em sua primeira década de existência (1998-2008). Verificamos a quantidade de questões envolvendo essa temática que estiveram presentes no decorrer dos anos, assim como os temas mais recorrentes. Discutimos os resultados a partir do que é proposto pelos documentos oficiais em relação ao ensino de Astronomia na Educação Básica e tecemos alguns apontamentos sobre a expectativa futura quanto à presença de conteúdos dessa ciência nesse exame oficial.

  5. Identificabilidade e estabilidade dos parâmetros no método Grade of Membership (GoM): considerações metodológicas e práticas

    PubMed Central

    Guedes, Gilvan Ramalho; Caetano, André Junqueira; Machado, Carla Jorge; Brondízio, Eduardo Sonewend

    2011-01-01

    O método Grade of Membership (GoM) tem sido cada vez mais utilizado por demógrafos brasileiros e tem a vantagem de possuir um parâmetro que mensura a heterogeneidade individual, com base nas correlações não-observáveis entre as categorias de resposta das variáveis de interesse, gerando um medida do grau de pertencimento de cada indivíduo a perfis extremos. Alguns autores, contudo, chamam atenção para questões importantes na calibragem dos modelos finais que utilizam o programa GoM versão 3.4, como o problema de identificabilidade – soluções múltiplas para parâmetros estimados. Neste artigo, é sugerido um procedimento capaz de identificar um modelo final com solução única que descreva os tipos puros mais fidedignos à base de dados, em uma tentativa de otimização. Para ilustrar esse processo, utilizou-se uma base de dados correspondente a um levantamento econômico e sociodemográfico de uma população de pequenos agricultores residentes ao longo da Rodovia Transamazônica, no Estado do Pará. Também identificou-se a existência de instabilidade nos parâmetros estimados pelo programa GoM 3.4, sendo proposto um método de estabilização de seus valores. Com esses procedimentos combinados, os usuários do programa GoM 3.4 poderão descrever sua base de dados de forma mais adequada e responder às críticas sobre questões de identificabilidade e estabilidade dos modelos resultantes. Essas soluções empíricas são relevantes por afetarem cálculos de prevalência e de incidência de eventos de interesse, além de trazerem consequências importantes sobre o ponto e o momento corretos para intervenções de políticas públicas ou de planejamento prospectivo em análises de projeção. PMID:21709732

  6. Detecção da fase impulsiva de uma explosão solar gigante até 405 GHz

    NASA Astrophysics Data System (ADS)

    Raulin, J.-P.; Makhmutov, V.; Kaufmann, P.; Pacini, A. A.; Luethi, T.; Hudson, H. S.; Gary, D. E.; Yoshimori, M.

    2003-08-01

    A explosão ocorrida no dia 25/08/2001 foi uma das mais intensas do presente ciclo solar em ondas de rádio de altas frequências. Foram medidas em ondas milimétricas e submilimétricas, aproximadamente, 105 e vários milhares de unidades de fluxo solar, respectivamente. Apresentamos um estudo deste evento em múltiplas frequências, desde microondas (1GHz), até ondas submilimétricas (405 GHz) detectadas pelo Telescópio Solar para ondas Submilimétricas (SST). Esta base de dados foi complementada utilizando-se o experimento Yohkoh, incluindo a emissão em raios-X duros e raios-g (até 100 MeV), e imagens em raios-X moles da região ativa envolvida. Enfocamos e discutimos principalmente os seguintes aspectos da fase impulsiva do evento: (i) as implicações deduzidas do espectro eletromagnético, obtido pela primeira vez até 405 GHz; (ii) a dinâmica da região ativa. Os resultados mostram que para explicar o espectro rádio observado, são necessários entre 3.5×1037 e 1.5×1039 elétrons acelerados acima de 20 keV em uma região de campo magnético entre 300 e 800 Gauss. A estimativa do fluxo de fótons que seria produzido por estes elétrons, mostra que grande parte deles não precipitou na baixa atmosfera. A evolução temporal da emissão em raios-X moles revela que a configuração magnética da região ativa foi muito dinâmica durante a fase impulsiva da explosão. Em particular, mostramos que a produção dos elétrons altamente energéticos foi iniciada junto com a aparição, na baixa coroa solar, de um novo sistema compacto de estruturas magnéticas. Este fato sugere que os locais de aceleração estão localizados na baixa atmosfera do Sol, como resultado da interação entre o novo sistema compacto e o campo magnético ambiente da região ativa.

  7. Projeto educação em ciências com observatórios virtuais: a participação da Escola Moppe no período 2000-2003

    NASA Astrophysics Data System (ADS)

    Wuensche, C. A.; Gavioli, E.; Oliveira, A. L. P. R. S.; da Silva, C.; Cardoso, H. P.; Estácio, S.

    2003-08-01

    O projeto Educação em Ciências com Observatórios Virtuais foi concebido pelo Instituto Astronômico e Geofísico da USP, agregando diversas instituições de ensino e pesquisa no país para desenvolver competências diversas na educação fundamental, média e superior utilizando a astronomia como ferramenta multidisciplinar. Este trabalho descreve a participação da MOPPE, escola-piloto do INPE no projeto, no período de 2000-2003. Serão apresentadas 1) a criação de um clube de ciências (1999 a 2001) cujo tema foi a colonização de Marte e 2) a ementa de astronomia trabalhada com as 7a. e 8a. séries do ensino fundamental. A proposta do projeto Colonizando Marte foi estudar diversos aspectos de uma missão interplanetária e construir experiementos que permitissem quantificar esses aspectos. Os resultados obtidos incluiram apresentações nas SBPC Jovem em 2000 e 2001. Discutiremos também as ementas de astronomia trabalhadas desde 2001 e o envolvimento dos alunos com atividades ligadas a astronomia, fora da aula de ciências. A inclusão de astronomia no currículo das últimas séries motivou a participação de mais alunos culminando com a conquista de duas medalhas para alunos da 7a. série na Olimpiada Brasileira de Astronomia em 2002. Houve também um aumento no número de participantes na OBA 2003 e nos projetos de astronomia mais elaborados nas Feira de Ciências de 2001 e 2002. Destacamos em 2003 a inclusão da MOPPE no projeto TIE - Telescopes in Education - da NASA, que utiliza o telescópio do Observatório de Mount Wilson (EUA) para observações remotas em projetos pedagógicos para o ensino de astronomia.

  8. Estudo exaustivo e sistemático de erros nas provas da olimpíada brasileira de astronomia - resultados preliminares

    NASA Astrophysics Data System (ADS)

    Oliveira, F. S.; Canalle, J. B. G.; Villas da Rocha, J. F.

    2003-08-01

    A Olimpíada Brasileira de Astronomia (OBA) contou, em sua quinta edição, com a participação de mais de 60 mil alunos dos ensinos fundamental e médio de praticamente todo o território nacional. Uma das formas de controle que a sua coordenação nacional possui sobre a correção, levada a cabo pelos professores que as aplicaram, é a do envio, por parte destes professores, das 10 melhores provas de cada um dos três níveis nos quais a Olimpíada é realizada. Assim, e dado ao caráter discursivo das provas da Olimpíada, a sua coordenação nacional dispõe de um vasto acervo sobre as concepções, certas ou erradas, dos alunos que dela participaram. Este conjunto de dados jamais fora explorado até o presente trabalho que pretende ser, neste sentido, inaugural. Nas provas dos níveis I e II da V OBA, que abrangem todo o conjunto do ensino fundamental, uma das questões versava sobre a noção que os alunos tinham sobre como os habitantes da Terra situam-se sobre sua superfície. Fizemos um estudo sistemático das respostas a esta questão. Primeiramente, todas as modalidades de erros foram levantadas; em seguida, realizamos uma distribuição por idade tanto do índice de acerto como da ocorrência e da distribuição de cada erro. Como resultado, obtivemos que, em ambos os níveis: 1) as concepções errôneas não se apresentam distribuídas aleatoriamente; 2) há uma concentração no tipo de erro apresentado; 3) há uma tendência de progressivo acerto com relação à idade quando os dados são considerados em termos nacionais; 4) esta tendência nacional é fraca ou mesmo não é verificada em alguns dos estados com maior patamar de acerto.

  9. Estimativa de imagens solares soho através de redes neurais artificiais

    NASA Astrophysics Data System (ADS)

    Andrade, M. C.; Fernandes, F. C. R.; Cecatto, J. R.; Rios Neto, A.; Rosa, R. R.; Sawant, H. S.

    2003-08-01

    A Rede Neural Artificial (RNA), no âmbito da teoria computacional, constitui uma teoria emergente que, por possuir habilidade em aprender a partir de dados de entrada, encontra diferentes aplicações em diferentes áreas. Um exemplo é a utilização de RNA na caracterização de padrões associados à dinâmica de processos espaço-temporais relacionados a fenômenos físicos não-lineares. Para obter informações sobre o comportamento destes fenômenos físicos utiliza-se, em diversos casos, seqüências de imagens digitalizadas, onde a caracterização de alguns fenômenos espaço-temporais é o procedimento mais viável para descrever a dinâmica das regiões ativas do Sol. Com base em imagens observadas por telescópios a bordo de satélites, estudos de previsão de eventos solares podem ser programados, permitindo prever possíveis efeitos posteriores nas regiões mais próximas da Terra (tempestades geomagnéticas e irregularidades ionosféricas). Neste trabalho avaliamos o desempenho da RNA para estimar padrões espaço-temporais, ou seja, imagens solares em ultravioleta, obtidas através do telescópio a bordo do satélite SOHO. Os resultados mostraram que as RNA conseguem generalizar os padrões de maneira satisfatória sem perder de forma significativa os principais aspectos da configuração global da atmosfera solar, comprovando a eficácia da RNA como ferramenta para esse tipo de aplicação. Portanto, este trabalho comprova a viabilidade de uso desta ferramenta em projetos voltados ao estudo do comportamento solar, em trabalhos do grupo de Física do Meio Interplanetário (FMI) na DAS e em programas desenvolvidos pelo Núcleo de Simulação e Análise de Sistemas Complexos (NUSASC) do Laboratório Associado de Computação e Matemática Aplicada (LAC) do INPE.

  10. Ensino de gravitação clássica no nível médio: uma proposta de abordagem e resultados preliminares

    NASA Astrophysics Data System (ADS)

    Medeiros, G. C. M.; Jafelice, L. C.

    2003-08-01

    O ensino de gravitação clássica é comumente realizado de maneira formal e descontextualizado da experiência com a força-peso e da história do tema. Fustigados por anos de experiência de ensino no assunto, nem sempre com bons resultados, propomos uma abordagem ancorada nos eixos: a) contextualização histórica; e b) reconhecimento do peso como a força de atração gravitacional. O primeiro eixo integra o tema no desenvolvimento cultural do ser humano, praticando a interdisciplinaridade. O segundo eixo embasa construtivamente a abordagem, levando o aluno a realizar experiências e a vivenciar o reconhecimento de uma força universal. A abordagem foi construída através das etapas: 1) análise crítica do tema em livros didáticos; 2) elaboração de um curso para professores das várias disciplinas do ensino médio, identificando conexões para a prática da interdisciplinaridade; 3) elaboração de material didático; e 4) avaliação da eficácia da abordagem. No trabalho discutimos em detalhe as quatro etapas. Como resultados, adiantamos que: tabulamos a abordagem de gravitação nos livros didáticos, ainda muito tradicional e carecedora de atividades criativas que poderiam melhor explorar esse assunto; mapeamos, junto aos professores, padrões de conceitos espontâneos e erros associados ao tema; e, no curso, adaptamos e testamos a eficiência de materiais instrucionais existentes e criamos outros novos (e.g., para trabalhar excentricidades das órbitas planetárias), além disto elaboramos roteiros e figuras para tratamentos qualitativo e quantitativo da lei da gravitação universal. As avaliações feitas pelos professores foram muito animadoras. O espaço da presente reunião será aproveitado para socializar a proposta e os resultados obtidos e para submeter o projeto à análise crítica. (PPGECNM/UFRN; PRONEX/FINEP; NUPA/USP; Temáticos/FAPESP)

  11. Cosmoeducação: uma proposta para o ensino de astronomia

    NASA Astrophysics Data System (ADS)

    Medeiros, L. A. L.; Jafelice, L. C.

    2003-08-01

    Entende-se por cosmoeducação o desenvolvimento vivencial da unidade homem-cosmo. Este conceito é norteado pela psicologia transpessoal, que estuda o ser humano em sua totalidade, onde suas relações ecológicas e cósmicas são de grande importância. Constata-se uma necessidade latente no ser humano moderno em resgatar uma relação holística com o Universo. Neste trabalho exploramos meios de cultivar a consciência de que o ser humano constitui parte integrante do cosmo e se relaciona com este com o objetivo de promover em si uma percepção ambiental mais ampla. Nossa hipótese de trabalho inicial foi que o ensino de conteúdos básicos em astronomia realizado através de uma abordagem holística, que incorpore práticas vivenciais correlacionadas àqueles conteúdos, pode despertar no indivíduo sua identidade cósmica. O método que utilizamos é o fenomenológico e o universo desta pesquisa é um grupo de estudantes da disciplina de Astronomia (Curso de Licenciatura em Geografia/UFRN), onde realizamos observação participante, entrevistas, depoimentos e as práticas vivenciais mencionadas. Neste caso estamos desenvolvendo e adaptando exercícios de algumas técnicas terapêuticas de psicologia transpessoal, que um de nós (LALM) tem aplicado no contexto clínico, para trabalhar aspectos cognitivos envolvidos naquele processo de conscientização cósmica. Resultados parciais claramente referendam a hipótese inicial. Um resultado a destacar é fruto de uma dinâmica de representação corporal interiorizada do eclipse lunar, envolvendo um pequeno grupo daqueles estudantes, na qual conteúdos míticos afloraram de maneira espontânea e contundente para todos, sugerindo ressonância, ou pelo menos isomorfismo, entre o macro e o microcosmo. Este e outros resultados são discutidos em detalhe neste trabalho. (PPGECNM/UFRN; PRONEX/FINEP; NUPA/USP; Temáticos/FAPESP).

  12. A teoria da percolação aplicada às galáxias aneladas peculiares

    NASA Astrophysics Data System (ADS)

    Poppe, P. C. R.; Martin, V. A. F.; de Medeiros, N. G. F.; Faúndez-Abans, M.; Oliveira-Abans, M.

    2003-08-01

    Formulado no final da década de 50, o modelo de percolação concentra-se em descrever o meio poroso, que será visto neste trabalho como uma rede de canais aleatórios, por onde escoa um fluido determinístico. Se o número de canais for suficientemente grande, então eles estarão ligados e o meio se tornará permeável à passagem do fluido. Neste caso, dizemos que houve a percolação do fluido. Reformulando o modelo acima, podemos escrever um código particularmente adaptado para simulações em Galáxias, onde iremos supor que os canais formam um reticulado, e que cada sítio da rede representa um poro que será interpretado como uma região ativa de formação estelar. Para cada elo teremos um pequeno canal ligando dois sítios vizinhos, que poderá, após um tempo "t", induzir ou não a formação de uma região ativa no poro vizinho. Para simular a passagem desta região ativa através dos poros, diremos que um elo está aberto com probabilidade p e fechado com probabilidade 1-p. Dessa forma, passamos a imaginar configurações de elos abertos e fechados, onde cada configuração ocorre com uma certa probabilidade, dada por p|A|(1-p)|F|, onde |A| é o número de elos abertos e |F| o número de elos fechados da configuração. A expressão anterior só tem importância física se |A| e |F| forem ambos finitos, pois, caso contrário, a probabilidade de ocorrência de uma dada configuração será sempre nula. Neste trabalho, foram considerados dados cinemáticos publicados na literatura bem como aqueles obtidos pelos autores a partir de observações fotométricas realizadas no Observatório de Las Campanãs, em 1994, para a Galáxia Anelada Peculiar HRG 03401. Mostraremos que para certos valores de p, situados entre 0,5 e 0,6, os clusters assim formados irão simular, de maneira coerente, o referido objeto.

  13. Cometa Hyakutake (C/1996 B2): análise do gás e características físicas das partículas de poeira

    NASA Astrophysics Data System (ADS)

    Sanzovo, G. C.; de Almeida, A. A.; Boczko, R.

    2003-08-01

    A completa caracterização e compreensão do núcleo de um cometa novo é de fundamental importância para a elucidação dos processos físicos e químicos atuantes na época da formação do Sistema Solar. O Cometa Hyakutake, conjuntamente com o Cometa Hale-Bopp representam os objetos mais brilhantes que visitaram o Sistema Solar Interno nos últimos 20 anos. Neste Trabalho, nós aplicamos o Método Semi-Empírico das Magnitudes Visuais (MSEMV) à aproximadamente 4000 dados observacionais que correlacionam a magnitude visual absoluta com a distância heliocêntrica para o Cometa Hyakutake nas fases pré- e pós-periélicas. Como produto da aplicação desse método, conseguimos caracterizar dimensionalmente seu núcleo e área ativa efetiva. As taxas de produção dos radicais CN, C2 e C3, obtidos a partir de dados disponíveis na literatura, revelam que, além de muito brilhante, o Hyakutake é um cometa "normal" no sentido de Cochran (1986). Desse modo, deduzimos as taxas de perdas de água (em moléculas/s) a partir da análise de sua magnitude visual aparente, e as convertemos em taxas de perdas de gás (em g/s), despreendido pelo nucleo cometário. Com o auxílio do modelo fotométrico clássico da poeira, realizamos uma análise sistemática e uniforme dessa componente cometária, a partir dos fluxos observacionais no contínuo, para os comprimentos de onda 365,0 e 484,5 nm, assumindo que esses fluxos são o resultado da radiação solar espalhada por grãos de partículas micrométricos presentes na coma. Com isso, pudemos obter as taxas de produção (em g/s), cores (relativas à cor neutra solar), e as dimensões efetivas médias das partículas de poeira, bem como as razões poeira-gás.

  14. Simulação de ejeções de massa coronal

    NASA Astrophysics Data System (ADS)

    Corsini, M. A.; Silva, A. V. R.

    2003-08-01

    Ejeções de massa coronal (EMC) são bolhas gigantes de gás permeadas por campos magnéticos que são ejetadas do Sol durante um período de várias horas. Caso estas ejeções atinjam a Terra, geralmente, causam uma série de distúrbios às comunicações de longa distância e navegação, além de danos a satélites e transformadores. Portanto, é desejável que sejamos capazes de prever quando estas ejeções atingirão a Terra. Para tanto, é necessário um bom entendimento dos mecanismos causadores das ejeções e, principalmente, de como se dá a propagação das EMC e sua interação com o vento solar que permeia o meio interplanetário. Nesse sentido foi desenvolvido um programa computacional para resolver as equações MHD (Magneto-Hidro-Dinâmica) que regem a evolução das EMC. Primeiramente foram estabelecidas as condições necessárias para descrever o vento solar, no estado estacionário, que permeia todo o meio interplanetário. Num primeiro momento, resolveu-se o sistema de equações para o caso do vento isotérmico, conhecida como a solução de Parker, a fim de testarmos o modelo. Então, foi considerado o caso do vento solar com temperatura variável no meio interplanetário. Este resultado foi utilizado como a base de nosso sistema em seu instante inicial. Posteriormente foram feitas as considerações necessárias para descrever a propagação da Ejeção de Massa Coronal. As EMC foram simuladas como um aumento de densidade e temperatura local na coroa solar. A órbita e a posição da Terra foram incluídas no sistema. Os dados gerados possibilitaram uma análise da evolução da EMC pelo meio interplanetário até encontrar-se com a Terra. Os perfis de densidade e temperatura a 1 Unidade Astronômica são comparados com os dados de satélites reportados na literatura.

  15. Observação do abrilhantamento de limbo solar e de estruturas filamentares em 48 ghz utilizando a técnica de regularização adaptativa

    NASA Astrophysics Data System (ADS)

    Machado, W. R. S.; Mascarenhas, N.; Costa, J. E. R.; Silva, A. V. R.

    2003-08-01

    O radiotelescópio do Itapetinga tem sido utilizado em campanhas de observações de explosões solares gerando um grande número de mapas diários em 48 GHz como sub-produto destas observações. A resolução espacial do telescópio de 14m do Itapetinga nesta freqüência é de aproximadamente dois minutos de arco. Estruturas de interesse para análise da atmosfera solar quiescente tais como os filamentos e o anel de abrilhantamento do limbo são de dimensão angular moderada da ordem ou ligeiramente menores que a resolução do telescópio. É conhecido que a convolução da função de espalhamento do telescópio, PSF (padrão de ganho do feixe) borra as estruturas de dimensão angular abaixo do HPBW (largura a meia potência do feixe) e portanto é comum a busca por técnicas de restauração que eliminem pelo menos em parte este borramento. Estudamos a restauração destas radioimagens usando a técnica de regularização adaptativa e os resultados ressaltam estas estruturas espaciais de pequeno contraste. O algoritmo da regularização adaptativa faz uso de k imagens, chamadas protótipos, obtidas através da variação de parâmetros de um filtro de regularização. Para controle da qualidade da restauração utilizamos uma imagem de alta resolução espacial obtida na linha H-a e a PSF do Itapetinga para borrá-la. Pequenos desvios, entre a PSF utilizada para o borramento e a PSF utilizada na restauração, produziram alguns desvios notáveis na imagem restaurada porém a adição de ruído nas simulações de restauração foram mais influentes no cálculo da rugosidade da imagem e portanto mais limitante para a restauração. Apresentamos como nosso primeiro resultado uma imagem em 48 GHz com a presença clara do abrilhantamento de limbo que não estava evidente na imagem original e traços de estruturas filamentares, porém ainda sem grande evidência.

  16. Astronomy in Science Textbooks: An Analysis of Pnld 2008. (Spanish Title: Astronomía en los Libros de Ciencia: un Análisis del Pnld 2008.) Astronomia Nos Livros Didáticos de Ciências: Uma Análise do Pnld 2008

    NASA Astrophysics Data System (ADS)

    Amaral, Patrícia; Quintanilha Vaz de Oliveira, Carlos Eduardo

    2011-12-01

    The importance of the textbooks in classrooms is revealed when studies are pointing that these pedagogical sources are, most of the times, the only source used by the elementary school teachers when preparing their Science lessons. When we analyzed the Astronomy contents in the textbooks approved by the Brazilian Textbook Program 2008 and which, in theory, are the best available in the Brazilian editorial market, we examined some categories in the 2008 Textbook Guide. This research characterizes the frequency of Astronomical contents appearing in the texts, in the pictures, and in the hands-on activities. Additionally, it describes some misconceptions and presents additional information on the collections. La importancia de los libros de texto en las aulas se pone de manifiesto cuando los estudios indican que este recurso educativo es a menudo la única fuente de consulta utilizada por el profesor de ciencias de la escuela primaria para preparar sus lecciones. Cuando analizamos el contenido presente en los libros de texto de astronomía aprobados por el Programa Nacional de Libros de Texto de 2008 y que, en teoría, son los mejores libros disponibles en el mercado editorial brasileño, buscamos examinar algunas categorías que figuran en los libros de texto de la Guía de Libros Didácticos de 2008. El estudio caracteriza la frecuencia del contenido de Astronomía en el texto, en las figuras, y en las actividades de experimentación. También describe algunos errores conceptuales y presenta un conjunto de información adicional sobre las colecciones. A importância dos livros didáticos nas salas de aula revela-se quando estudos apontam que este recurso pedagógico é, muitas vezes, a única fonte de consulta utilizada pelo professor de Ciências do ensino fundamental para a preparação de suas aulas. Quando analisamos os conteúdos de Astronomia presentes nos livros didáticos aprovados no Programa Nacional do Livro Didático de 2008 e que, teoricamente, são os

  17. A cosmologia no ensino da geografia

    NASA Astrophysics Data System (ADS)

    Santos, S. C.; Chiaradia, A. P. M.

    2003-08-01

    O principal objetivo deste trabalho é auxiliar o professor de Geografia em sala de aula no ensino de tópicos relacionados com a Cosmologia. A idéia deste trabalho surgiu quando foi constatado que o professor de Geografia tem dificuldades de ensinar este tópico. Esta constatação foi feita por uma das autoras ao lecionar este tópico no ensino fundamental e em discussões com outros professores de Geografia. Da mesma maneira que ocorria desde os tempos mais antigos, os alunos têm muito interesse em conhecer os fenômenos que ocorrem no Cosmo, porém os livros didáticos de Geografia utilizados em sala de aula não são ricos em informações sobre este assunto. Assim, o professor de Geografia tem poucas informações para discutir este assunto em sala de aula e não dá a devida importância para este tópico. Então, foi desenvolvido um material de apoio para professores de Geografia sobre a origem do Universo, sua evolução e seu possível futuro evolutivo segundo as mais recentes teorias, com base em perguntas feitas pelos alunos de ensino fundamental e as informações trazidas nos livros didáticos Não cabe a este material inovar e tão pouco trazer uma metodologia de ensino de Cosmologia. Neste material o professor de Geografia pode encontrará um banco de informações, que constitui no estabelecimento de conceitos, teorias e hipóteses, sobre a Cosmologia, em linguagem simples e de fácil entendimento. Para desenvolvê-lo, foram feitas pesquisas não exaustivas em livros e revistas científicas, compilação e discussão em forma cronológica das teorias aceitas sobre modelos cosmológicos. Portanto, este material será apresentado neste trabalho.

  18. Ensino de astronomia no 1o. e 2o. ciclos do nível fundamental e na educação de jovens e adultos: exemplos e discussões

    NASA Astrophysics Data System (ADS)

    Queiroz, A. S. B.; Jafelice, L. C.

    2003-08-01

    Tem-se constatado uma preocupante carência no ensino de astronomia nos diversos níveis de escolaridade. Neste trabalho discutimos várias práticas didático-pedagógicas que vimos desenvolvendo para crianças, jovens e adultos em processo de alfabetização, visando contribuir para reparar aquela carência. Propomos uma metodologia que incorpora as recentes exigências das políticas públicas educacionais, estimula o desenvolvimento de textos e materiais instrucionais, é compatível com a realidade desse público e é adaptável às respectivas faixas etárias. A observação do céu sempre esteve presente na vida de nossos antepassados, dando suporte à compreensão do ser humano como integrante da natureza. Visamos com este trabalho suprir a deficiência encontrada para se tratar a relação do ser humano com o céu, no ambiente escolar. Os resultados são animadores e envolvem práticas e textos que desenvolvemos e atividades realizadas pelos alunos. No primeiro grupo destacamos o desenvolvimento de várias práticas: "viagem aos planetas" (construímos o "foguete", os planetas em escala, contamos história e redigimos texto de orientação para os professores); "gnômon humano" (os próprios corpos dos alunos são usados para registrar o movimento aparente do Sol); "crateras da Lua" (concretização de "meteoritos" e "solo lunar" de gesso e exploração da relação entre energia cinética do bólido e tamanho da cratera formada); etc. No segundo grupo, produções de desenhos e redações e discussões dos alunos após a realização de cada prática, revelam que estas têm se mostrado muito eficientes, tanto para estimular a imaginação e a fantasia dos envolvidos, como para trabalhar-se habilidades, competências e conteúdos relacionados à astronomia, segundo uma perspectiva interdisciplinar contextualizada. (PPGECNM/UFRN; NUPA/USP; Temáticos/FAPESP)

  19. Intermitência alfvênica gerada por caos na atmosfera solar e no vento solar

    NASA Astrophysics Data System (ADS)

    Rempel, E. L.; Chian, A. C.-L.; Macau, E. E. N.; Rosa, R. R.

    2003-08-01

    Dados medidos no vento solar rápido proveniente dos buracos coronais revelam que os plasmas no meio interplanetário são dominados por flutuações Alfvênicas, caracterizadas por uma alta correlação entre as variações do campo magnético e da velocidade do plasma. As flutuações exibem muitas características esperadas em turbulência magneto-hidrodinâmica totalmente desenvolvida, tais como intermitência e espectros contínuos. Contudo, os mecanismos responsáveis pela evolução de turbulência Alfvênica intermitente não são completamente compreendidos. Neste trabalho a teoria de caos é usada para explicar como sistemas Alfvênicos, modelados pela equação Schrödinger não-linear derivativa e pela equação Kuramoto-Sivashinsky, podem se tornar fortemente caóticos à medida em que parâmetros do plasma são variados. Pequenas perturbações no parâmetro de dissipação podem fazer com que o sistema mude bruscamente de um regime periódico, ou fracamente caótico, para um regime fortemente caótico. As séries temporais das flutuações do campo magnético nos regimes fortemente caóticos exibem comportamento intermitente, em que fases laminares ou fracamente caóticas são interrompidas por fortes estouros caóticos. É mostrado que o regime fortemente caótico é atingido quando as soluções periódicas ou fracamente caóticas globalmente estáveis interagem com soluções do sistema que são fortemente caóticas, mas globalmente instáveis. Estas soluções globalmente instáveis são conjuntos caóticos não-atrativos conhecidos como selas caóticas, e são responsáveis pelos fortes estouros nos regimes intermitentes. Selas caóticas têm sido detectadas experimentalmente em uma grande variedade de sistemas, sendo provável que elas desempenhem um papel importante na turbulência intermitente observada em plasmas espaciais.

  20. BSSDATA - um programa otimizado para filtragem de dados em radioastronomia solar

    NASA Astrophysics Data System (ADS)

    Martinon, A. R. F.; Sawant, H. S.; Fernandes, F. C. R.; Stephany, S.; Preto, A. J.; Dobrowolski, K. M.

    2003-08-01

    A partir de 1998, entrou em operação regular no INPE, em São José dos Campos, o Brazilian Solar Spectroscope (BSS). O BSS é dedicado às observações de explosões solares decimétricas com alta resolução temporal e espectral, com a principal finalidade de investigar fenômenos associados com a liberação de energia dos "flares" solares. Entre os anos de 1999 e 2002, foram catalogadas, aproximadamente 340 explosões solares classificadas em 8 tipos distintos, de acordo com suas características morfológicas. Na análise detalhada de cada tipo, ou grupo, de explosões solares deve-se considerar a variação do fluxo do sol calmo ("background"), em função da freqüência e a variação temporal, além da complexidade das explosões e estruturas finas registradas superpostas ao fundo variável. Com o intuito de realizar tal análise foi desenvolvido o programa BSSData. Este programa, desenvolvido em linguagem C++, é constituído de várias ferramentas que auxiliam no tratamento e análise dos dados registrados pelo BSS. Neste trabalho iremos abordar as ferramentas referentes à filtragem do ruído de fundo. As rotinas do BSSData para filtragem de ruído foram testadas nos diversos grupos de explosões solares ("dots", "fibra", "lace", "patch", "spikes", "tipo III" e "zebra") alcançando um bom resultado na diminuição do ruído de fundo e obtendo, em conseqüência, dados onde o sinal torna-se mais homogêneo ressaltando as áreas onde existem explosões solares e tornando mais precisas as determinações dos parâmetros observacionais de cada explosão. Estes resultados serão apresentados e discutidos.

  1. Análise sobre o Conhecimento de um Grupo de Alunos do Ensino Médio da Rede Estadual de São Paulo sobre Termos e Fenômenos Astronômicos do Cotidiano

    NASA Astrophysics Data System (ADS)

    de Oliveira, E. F.; Voelzke, M. R.; Amaral, L. H.

    2007-08-01

    Embora os Parâmetros Curriculares Nacionais do Ensino Médio (PCN-EM) e as orientações complementares a esses Parâmetros (PCN+) apontem a importância de uma abordagem significativa de conceitos relacionados à astronomia nas aulas de Física, muitos estudantes terminam o Ensino Médio (EM) sem compreender a razão de certos acontecimentos de origem celeste, ainda que estes façam parte de seu cotidiano. Este trabalho tem por objetivo analisar os conhecimentos básicos em astronomia dos alunos de EM da escola estadual Batista Renzi, bem como investigar os meios através dos quais estes conhecimentos foram adquiridos. Para tanto foi elaborado um questionário de múltipla escolha aplicado a 310 alunos distribuídos entre as três séries do EM dos períodos matutino e noturno. Dessa forma, observou-se que apenas 34,5% relacionaram as estações do ano à inclinação do eixo de rotação da Terra, 21,3% indicaram a influência gravitacional da Lua e do Sol como responsáveis pelo fenômeno das marés, 24,5% indicaram corretamente quais são os objetos celestes mais próximos da Terra, 36,1% identificaram ano-luz como uma medida de distância e 34,2% reconheceram uma estrela cadente como meteoro. Em contrapartida, 67,1% compreendiam a sucessão entre dia e noite, 73,9% identificaram o Sol como estrela e 52,3% relacionaram o Big Bang à origem do Universo. Além disso, foram comparadas as respostas de alunos de diferentes séries e períodos, observando-se, dentre outras coisas, que os estudantes do terceiro ano apresentam um percentual de acertos semelhante ao dos alunos do primeiro, caracterizando que a abordagem de tópicos relacionados à astronomia no EM não tem contribuído para uma maior compreensão dos fenômenos e conceitos.

  2. Astronomia cultural e meio ambiente segundo uma abordagem holística

    NASA Astrophysics Data System (ADS)

    Jafelice, L. C.

    2003-08-01

    Neste trabalho ampliamos a discussão da abordagem holística para o ensino de astronomia que temos desenvolvido nos últimos anos, analisamos novos resultados e apresentamos exemplos práticos para interessados em experimentá-la. A constatação básica a orientar este enfoque é que cursos introdutórios em astronomia costumam ser excessiva e prematuramente técnicos, além de assumirem uma visão tradicional, muito estreita, do que seja educação científica, herdada da era cartesiana e positivista da ciência. Fundamentamos porque é importante que elementos de astronomia cultural ofereçam o mote e constituam o eixo norteador daqueles cursos e porque é urgente revermos a visão que temos da relação entre astronomia e meio ambiente. Um ponto central nesta abordagem é explorar formas de reativar e atualizar uma relação orgânica com o meio e excitar a consciência de nossa inevitável e profunda interdependência com ele em nível cósmico. Neste trabalho exemplificamos a possibilidade de concretização desta proposta em três diferentes situações: disciplinas de cursos de licenciatura em geografia e em física; escolas de nível fundamental; e, neste caso ainda a ser implementada, comunidades carentes. Estes casos envolvem públicos e espaços diferenciados para educação formal e não-formal. Dos casos já implementados, destacamos os resultados alcançados pelos alunos: enriquecimento cultural, aprendizagem significativa de conteúdos astronômicos tradicionais; mudanças de comportamento, incorporando contato diário com o céu; e freqüentes vivências de sentimentos empáticos que redirecionam a relação com a natureza e a consciência ecológica global. Além disto, para interessados em aplicar esta proposta, também socializamos procedimentos e cuidados para a implementação de ações alternativas consonantes com a mesma. (PPGECNM/UFRN; PRONEX/FINEP; NUPA/USP; Temáticos/FAPESP)

  3. Otimização de procedimento de manobra para indução de reentrada de um satélite retornável

    NASA Astrophysics Data System (ADS)

    Schulz, W.; Suarez, M.

    2003-08-01

    Veículos espaciais que retornam à Terra passam por regimes de velocidade e condições de vôo distintos. Estas diferenças dificultam sua concepção aerodinâmica e o planejamento de seu retorno. A partir de uma proposta de um veículo orbital retornável (satélite SARA, em desenvolvimento no IAE/CTA) para realização de experimentos científicos e tecnológicos em ambiente de baixa gravidade, surge a necessidade de realizarem-se estudos considerando-se os aspectos relativos à sua aerodinâmica. Após o lançamento, o veículo deve permanecer em órbita pelo tempo necessário para a condução de experimentos, sendo depois direcionado à Terra e recuperado em solo. A concepção aerodinâmica é de importância para o vôo em suas diversas fases e deve considerar aspectos relativos à estabilização Aerodinâmica e ao arrasto atmosférico, sendo este último de importância crucial na análise do aquecimento a ser enfrentado. A manobra de retorno inclui considerações sobre as condições atmosféricas e dinâmica de reentrada, devendo ser calculada de forma mais precisa possível. O trabalho proposto avalia estudos da dinâmica de vôo de um satélite recuperável considerando aspectos relativos à determinação orbital com GPS, técnica utilizada com sucesso na CONAE, e seu comportamento aerodinâmico em vôo balístico de retorno, com ênfase em sua fase de reentrada atmosférica. Busca-se otimizar a manobra de reentrada de tal forma que a utilização do sistema GPS garanta minimizar a área de impacto com o solo.

  4. Estudo de não gaussianidade nas anisotropias da RCF medidas Wmap

    NASA Astrophysics Data System (ADS)

    Andrade, A. P. A.; Wuensche, C. A.; Ribeiro, A. L. B.

    2003-08-01

    A investigação do campo de flutuações da Radiação Cósmica de Fundo (RCF) pode oferecer um importante teste para os modelos cosmológicos que descrevem a origem e a evolução das flutuações primordiais. De um lado, apresenta-se o modelo inflacionário que prevê um espectro de flutuações adiabáticas distribuídas segundo uma gaussiana e, de outro, os modelos de defeitos topológicos (dentre outros) que descrevem um mecanismo para a geração de flutuações de isocurvatura que obedecem a uma distribuição não gaussiana. Este trabalho tem como objetivo caracterizar traços do modelo não gaussiano de campo misto (entre flutuações adiabáticas e de isocurvatura) nos mapas do Wilkinson Microwave Anisotropy Probe (WMAP). Simulações das anisotropias da RCF no contexto de mistura indicam traços marcantes na distribuição das flutuações de temperatura, mesmo quando consideradas pequenas contribuições do campo de isocurvatura (da ordem de 0.001). O efeito da mistura entre os campos resulta na transferência de potência de flutuações em escalas angulares intermediárias para flutuações em pequenas escalas angulares. Este efeito pode ser caracterizado pela relação entre as amplitudes dos primeiros picos acústicos no espectro de potência da RCF. Neste trabalho, investigamos a contribuição do campo de isocurvatura, no contexto de mistura, sobre as observações recentes da RCF realizadas pelo WMAP. As previsões do modelo de campo misto, uma vez confrontadas com as observações em pequenas escalas angulares, podem ajudar a revelar a natureza das flutuações primordiais.

  5. Espectroscopia infravermelha de núcleos ativos de galáxias: resultados adicionais

    NASA Astrophysics Data System (ADS)

    Rodríguez Ardila, A.; Viegas, S.; Pastoria, M. G.

    2003-08-01

    Apresentamos resultados parciais de um levantamento espectroscópico na região do infravermelho próximo (NIR) realizado em 30 núcleos ativos de galáxias (AGN), incluindo vários objetos selecionados do catálogo PG com z de até 0.55. O objetivo é estudar a natureza do contínuo observado e as condições físicas do gas emissor. Todas as fontes de tipo 1 apresentam uma mudança na inclinação do contínuo na região de 1.2mm, associada ao término da contribuição do contínuo emitido pelo AGN e ao início da contribuição do contínuo emitido pela poeira quente atribuída ao tórus que rodeia a fonte central. O índice espectral associado à segunda contribuição varia apreciavelmente de objeto para objeto. Este resultado é comparado com distribuições espectrais de energia preditas por modelos de toroides para testar a validez do modelo unificado. A partir das linhas de FeII observado nos espectros deriva-se, pela primeira vez nessa região espectral, um template empírico de FeII para estudar a intensidade e a origem dessa emissão. A intensidade do FeII é estudada em conjunto com aquela da região visível e comparada às predições de modelos teóricos que incluem fluorescência de Lya, excitação colisional e auto-fluorescência como mecanismos dominantes de exitação. Encontra-se que os dois primeiros processos dominam na formação do espectro de FeII observado. Indicadores de avermelhamento, entre eles Brg/Pab, Pab/Pag, Pab/Pad e [FeII] 1.257/1.644 mm são utilizados para mapear a distribuição de poeira nas regiões emissoras de linhas. Encontra-se valores de extinção Av~3 associados ao último indicador e valores significativamente menores (Av~1.5) para os restantes, o que sugere que o [FeII] se forma em uma região separada da maior parte do gás emissor de linhas estreitas.

  6. Abundâncias químicas de estrelas T Tauri fracas

    NASA Astrophysics Data System (ADS)

    Rojas, G. A.; Gregorio-Hetem, J.

    2003-08-01

    Apresentamos resultados do estudo de 44 estrelas pré-seqüência principal, para as quais buscamos realizar uma classificação espectroscópica e determinar parâmetros estelares e abundâncias químicas. A amostra foi escolhida da seguinte maneira : 21 objetos selecionados a partir de catálogos de objetos jovens, como o Pico dos Dias Survey e o Herbig Bell Catalogue, e 23 objetos selecionados a partir de contrapartidas ópticas de fontes de raios X detectadas pelo satélite ROSAT. Dentre 24 objetos previamente classificados como estrelas T Tauri Fracas, apenas 7 revelaram ser realmente pertencentes à essa classe, sendo os demais objetos T Tauri Clássicas ou estrelas evoluídas da pré-seqüência principal. Esse resultado demonstra que o critério mais utilizado para distinguir as T Tauri Clássicas das T Tauri Fracas, baseado na largura equivelente da emissão Ha, não é suficiente para determinar o estágio evolutivo desses objetos. Para o cálculo de parâmetros estelares e abundâncias, foram escolhidas as estrelas que apresentam características ideais para esse tipo de estudo, como ausência de velamento, baixa velocidade de rotação e espectros com razão sinal-ruído adequada. Os parâmetros estelares como temperatura efetiva e gravidade foram determinados através do equilíbrio de excitação e ionização das linhas de Ferro, e as abundâncias químicas foram calculadas utilizando o método de síntese espectral. Serão apresentados os parâmetros estelares e as abundâncias de Lítio para toda a amostra, e abundâncias de vários elementos quimicos para 7 estrelas estudadas em maior detalhe

  7. A Introdução de Astronomia Básica para Estudantes de 5 e 6 Séries do Ensino Fundamental

    NASA Astrophysics Data System (ADS)

    Gonzaga, E. P.; Voelzke, M. R.

    2008-09-01

    Com intuito de despertar o interesse pelo estudo da astronomia, desenvolveu-se entre 2003 e 2006 no Centro Educacional do Serviço Social da Indústria situado no município de Mauá, São Paulo, um trabalho com duração de 12 meses para turmas de 11 e 12 anos, sendo três turmas por período (2003 / 2004, 2004 / 2005 e 2005 / 2006). O trabalho realizado, objetivando a introdução da astronomia básica com observações de constelações e das fases da Lua, permitindo estender-se a outros corpos celestes, iniciou-se com visita ao planetário Mundo Estelar, localizado no Ipiranga, São Paulo levantou-se a questão da importância do estudo da astronomia e foi lançado aos estudantes um trabalho de observação, com a proposta de localizar as constelações e compreender as fases da Lua, para o registro de tais observações, foram distribuídos mapas celestes, pastas, planilhas de anotações com lacunas para, constelações, fases da Lua e relatos, onde os estudantes acrescentaram pesquisas e relatórios. Os resultados dos 346 estudantes foram que 86,7% (300) concluíram a etapa de observação, destes 300 estudantes 43,3% (130) pesquisaram sobre as constelações e 19,0% (57) localizaram até quatro constelações. Dos 346 estudantes, 44,2% (153) registraram as fases da Lua equivocadamente e 10,4% (36) anexaram reportagens sobre astronomia. Conclui-se que os estudantes se dividiram em pesquisadores, sendo os estudantes que registraram e anexaram informações e, os observadores que preencheram as planilhas de observações, além de desenvolverem habilidades e competências relacionadas ao estudo da astronomia.

  8. PubMed

    Guedes, Gilvan Ramalho; Caetano, André Junqueira; Machado, Carla Jorge; Brondízio, Eduardo Sonewend

    2010-01-01

    O método Grade of Membership (GoM) tem sido cada vez mais utilizado por demógrafos brasileiros e tem a vantagem de possuir um parâmetro que mensura a heterogeneidade individual, com base nas correlações não-observáveis entre as categorias de resposta das variáveis de interesse, gerando um medida do grau de pertencimento de cada indivíduo a perfis extremos. Alguns autores, contudo, chamam atenção para questões importantes na calibragem dos modelos finais que utilizam o programa GoM versão 3.4, como o problema de identificabilidade - soluções múltiplas para parâmetros estimados. Neste artigo, é sugerido um procedimento capaz de identificar um modelo final com solução única que descreva os tipos puros mais fidedignos à base de dados, em uma tentativa de otimização. Para ilustrar esse processo, utilizou-se uma base de dados correspondente a um levantamento econômico e sociodemográfico de uma população de pequenos agricultores residentes ao longo da Rodovia Transamazônica, no Estado do Pará. Também identificou-se a existência de instabilidade nos parâmetros estimados pelo programa GoM 3.4, sendo proposto um método de estabilização de seus valores. Com esses procedimentos combinados, os usuários do programa GoM 3.4 poderão descrever sua base de dados de forma mais adequada e responder às críticas sobre questões de identificabilidade e estabilidade dos modelos resultantes. Essas soluções empíricas são relevantes por afetarem cálculos de prevalência e de incidência de eventos de interesse, além de trazerem consequências importantes sobre o ponto e o momento corretos para intervenções de políticas públicas ou de planejamento prospectivo em análises de projeção. PMID:21709732

  9. Correlação de longo alcance em sistemas binários de raios-x usando remoção de flutuações

    NASA Astrophysics Data System (ADS)

    Pereira, M. G.; Moret, M. A.; Zebende, G. F.; Nogueira, E., Jr.

    2003-08-01

    Neste trabalho é proposta uma metodologia de analise de series temporais de fontes astrofísicas, baseada no método proposto por Peng et al. (1994) e Liu et al. (1999), o qual consiste na idéia de que uma série temporal correlacionada pode ser mapeada por um processo de busca de auto-similaridades em diversas escalas de tempo n. Removendo as eventuais tendências e integrando o sinal observado, é obtida uma medida do desvio médio quadrático das flutuações do sinal integrado F(n)~na, onde a representa o fator de escala associado com a auto-similaridade da correlação de longo alcance do sinal. Baseado nos valores obtidos de a, é possível distinguir entre os casos de sinais não-correlacionados, tipo ruído branco (a = 0,5), sinal anti-persistentes (a < 0,5) e sinal persistente (a > 0,5). Usando esta metodologia, foram analisadas 129 curvas de luz de sistemas binários de raios-X, provenientes do banco de dados públicos de observações feitas pelo instrumento All Sky Monitor, a bordo do satélite Rossi X-Ray Timing Explorer (ASM-RXTE). Foram identificadas a presença de a'0,5 em mais de 90% dos sistemas estudados, implicando em dizer que as flutuações de intensidade observadas apresentam correlação de auto-similaridade, sem entretanto, indícios de apresentarem uma escala de tempo característica das flutuações de intensidade. Sistemas onde são observadas erupções (flares), apresentam sistematicamente a > 0,5, característica esta, possivelmente associada com persistência das flutuações de densidade de disco ou taxa de acréscimo de massa. Os sistemas com curvas de luz onde nao são observadas as erupções apresentam uma distribuição normal centrada em a~0,62+/-0,10. Referências ¾ Peng, C.-K., Buldyrev, S.V., Havlin, S., Simons, M., Stanley, H.E., e Goldberg, A.L., Phys. Rev. E, (49), 1685 (1994). ¾ Liu, Y., Gopikrishnan, P., Cizeau, P., Meyer, M., Peng,C.-K., e Stanley, H.E., Phys. Rev. E, (60), 1390 (1999).

  10. Uma análise do fenômeno “alternância de línguas” na fala de bilíngues intermodais (Libras e Português)

    PubMed Central

    de Sousa, Aline Nunes; de Quadros, Ronice Müller

    2013-01-01

    Um interessante fenômeno lingüístico presente nas interações das pessoas bilíngues é a alternância de línguas. Neste trabalho, estamos investigando a alternância entre a língua portuguesa oral e a língua de sinais brasileira – Libras, numa mesma cadeia enunciativa, com o objetivo de identificar e analisar o uso dessa alternância na fala de uma criança e de um adulto (ambos ouvintes, filhos de pais surdos), interagindo em uma situação de bilinguismo intermodal, com interlocutores surdos e ouvintes. A alternância de línguas, nesse caso, ocorre quando se para de falar em português e se alterna para sinalizar. O presente trabalho se caracteriza como um estudo inicial, com análise qualitativa de dados. Fazem parte do nosso corpus nove sessões de interações em Libras e em português oral, gravadas em vídeo, que fazem parte do Projeto Desenvolvimento Bilíngue Bimodal da UFSC. Os dados revelam que as características da alternância de línguas pelo adulto e pela criança parecem ter semelhanças e diferenças. O sujeito adulto parece ter feito um uso da alternância mais preocupado com o curso da interação. A criança, por sua vez, não parece tê-la usado com propósitos pragmáticos específicos. Quanto à extensão das alternâncias, pode-se perceber que tanto a criança quanto o adulto utilizaram enunciados maiores do que uma única palavra isolada. O papel dos interlocutores parece ter sido decisivo nas interações aqui investigadas – especialmente nas do adulto, já que a criança ainda está em processo de tomada de consciência do papel do interlocutor na interação. PMID:24379831

  11. Excitação e fotoabsorção de moléculas interestelares no ultra violeta

    NASA Astrophysics Data System (ADS)

    Rodrigues, A. M. F.; Boechat-Roberty, H. M.; Souza, G. B.; Turci, C. C.

    2003-08-01

    O estudo dos processos de excitação, fotoabsorção e ionização molecular nas nuvens interestelar, permite a análise dos processos químicos, como a formação e destruição de moléculas, até mesmo daquelas que dão origem à vida. Acredita-se que as moléculas como CS2, NH3, CO2 e N2O estão presentes nas nuvens onde são formadas as estrelas e seus sistemas planetários. Estas moléculas são congeladas na superfície de objetos densos, como aqueles encontrados na Nuvem de Oort do nosso Sistema Solar. Quando esses objetos (cometas) desprendem-se dessa região, aproximam-se do Sol, sofrem a interação da radição Ultra Violeta (UV), passam à fase gasosa e são bombardeados por íons e elétrons presentes nos ventos solares. Obtivemos os espectros de fotoabsorção do CS2, NH3 e N2O na faixa do UV, convertendo espectros de Perda de Energia de Elétrons, medidos no menor ângulo de espalhamento e na energia de impacto de 1000 eV. Destes espectros determinamos os valores de força de oscilador (f) e de seção de choque absolutas na faixa de 500 a 2000 Å. Para tal, estudamos e comparamos dois diferentes métodos de conversão. Neste trabalho também geramos muitos dados moleculares como, valores absolutos de seção de choque elástica em função do ângulo de espalhamento e a distribuição de força do oscilador generalizada (df/dE) em função da energia de excitação para diversos ângulos de espalhamento. Comparando nossos espectros de fotoabsorção com o espectro da atmosfera de Júpiter, obtido pelo Telescópio Espacial Hubble, logo após o impacto do cometa Shoemaker-Levy 9, confirmamos a presença do CS2 e da amônia.

  12. Propriedades de estruturas temporais rápidas submilimétricas durante uma grande explosão solar

    NASA Astrophysics Data System (ADS)

    Raulin, J.-P.; Kaufmann, P.; Gimenez de Castro, C. G.; Pacini, A. A.; Makhmutov, V.; Levato, H.; Rovira, M.

    2003-08-01

    Apresentamos novas propriedades de variações rápidas da emissão submilimétrica durante uma das maiores explosões solares do ciclo solar 23. Os dados analisados neste estudo foram obtidos com o Telescópio Solar Submilimétrico (SST), que observa o Sol em 212 GHz e 405 GHz, e comparados com emissões em Raios-X duros e Raios-gama (fótons de energia > 10 MeV), que foram obtidas pelo experimento GRS do Yohkoh. Aplicamos diferentes metodologias para detectar e caracterizar, ao longo do evento, os pulsos submilimétricos (duração de 50-300 ms) detectados acima de uma componente mais lenta (alguns minutos). Os resultados mostram que durante a fase impulsiva, num instante próximo ao tempo do máximo do evento, houve um aumento da ocorrência de maiores e de mais rápidas estruturas temporais. Também identificamos uma boa correlação com as emissões em raios-X e raios-gama (até a faixa de energia 10-100 MeV), indicando que os pulsos rápidos submilimétricos refletiram injeções primárias de energia durante o evento.O espectro do fluxo desses pulsos é crescente com a freqüência entre 212 and 405 GHz, na maioria dos casos, ao contrário do observado para a componente gradual. As posições calculadas para as estruturas rápidas são discretas, compactas e localizadas em toda a área da região ativa, o que é previsto nos modelos de explosões solares decorrentes de instabilidades múltiplas em diferentes pequenas regiões. Por outro lado, a posição calculada para a componente lenta é estável durante a fase impulsiva. Assim, a comparação entre as características do espectro de fluxo e da localização da emissão, para os pulsos rápidos e para a componente gradual, sugere que as respectivas emissões são de natureza diferente.

  13. Determinação da massa de júpiter a partir das órbitas de seus satélites: um experimento didático

    NASA Astrophysics Data System (ADS)

    Schlickmann, M. S.; Saito, R. K.; Becker, D. A.; Rezende, M. F., Jr.; Cid Fernandes, R.

    2003-08-01

    Este trabalho apresenta o roteiro piloto de uma prática observacional em astronomia, junto com os primeiros resultados obtidos nesta fase de implementacão. O projeto, que será executado em duas etapas, visa introduzir noções de Astronomia a alunos do Ensino Médio e iniciantes nos cursos de Física. O experimento consiste em medir as órbitas dos satélites Galileanos e, a partir da análise dos dados coletados, verificar a validade da Lei das órbitas de Kepler, determinando a massa do planeta Júpiter. Em uma primeira etapa, as observações serão feitas utilizando um telescópio Meade LX200 10" e câmera CCD para obter uma seqüência de imagens do planeta, que possibilitará medir o movimento de seus satélites. A segunda etapa terá início a partir do funcionamento do telescópio em modo robótico, com a possibilidade de observações via internet por instituições de ensino. Para o desenvolvimento deste experimento foram inicialmente coletadas várias imagens de Júpiter obtidas com os instrumentos citados acima. Estas imagens serviram como base para confecção dos roteiros para a experiência no nível médio e superior. Os roteiros serão inicialmente apresentados em uma home-page. Nela também se buscará uma contextualização histórica da experiência bem como o estabelecimento de relações com professores e alunos, propostas metodológicas e a disponibilização dos programas computacionais necessários para a utilização "on-line" pelos usuários. O projeto conta com apoio da Fundação VITAE.

  14. Astronomia para/com crianças carentes em Limeira

    NASA Astrophysics Data System (ADS)

    Bretones, P. S.; Oliveira, V. C.

    2003-08-01

    Em 2001, o Instituto Superior de Ciências Aplicadas (ISCA Faculdades de Limeira) iniciou um projeto pelo qual o Observatório do Morro Azul empreendeu uma parceria com o Centro de Promoção Social Municipal (CEPROSOM), instituição mantida pela Prefeitura Municipal de Limeira para atender crianças e adolescentes carentes. O CEPROSOM contava com dois projetos: Projeto Centro de Convivência Infantil (CCI) e Programa Criança e Adolescente (PCA), que atendiam crianças e adolescentes em Centros Comunitários de diversas áreas da cidade. Esses projetos têm como prioridades estabelecer atividades prazerosas para as crianças no sentido de retirá-las das ruas. Assim sendo, as crianças passaram a ter mais um tipo de atividade - as visitas ao observatório. Este painel descreve as várias fases do projeto, que envolveu: reuniões de planejamento, curso de Astronomia para as orientadoras dos CCIs e PCAs, atividades relacionadas a visitas das crianças ao Observatório, proposta de construção de gnômons e relógios de Sol nos diversos Centros Comunitários de Limeira e divulgação do projeto na imprensa. O painel inclui discussões sobre a aprendizagem de crianças carentes, relatos que mostram a postura das orientadoras sobre a pertinência do ensino de Astronomia, relatos do monitor que fez o atendimento no Observatório e o que o número de crianças atendidas representou para as atividades da instituição desde o início de suas atividades e, em particular, em 2001. Os resultados são baseados na análise de relatos das orientadoras e do monitor do Observatório, registros de visitas e matérias da imprensa local. Conclui com uma avaliação do que tal projeto representou para as Instituições participantes. Para o Observatório, em particular, foi feita uma análise com relação às outras modalidades de atendimentos que envolvem alunos de escolas e público em geral. Também é abordada a questão do compromisso social do Observatório na educação do

  15. On the Formation of a Study Group to the Realization of Workshops for Teachers: Astronomy in Basic Education in Umuarama-Pr (Spanish Title: De la Formación de un Grupo de Estudios a la Realización de los Talleres Para los Profesores: la Astronomía en la Educación Básica en Umuarama-Pr ) Da Formação de um Grupo de Estudos À Realização de Oficinas Para Professores: a Astronomia na Educação Básica em Umuarama-Pr

    NASA Astrophysics Data System (ADS)

    Belusso, Diane; Akira Sakai, Otávio

    2013-12-01

    In this article, we aimed to present the activities developed by the Astronomy Study Group (ASG) to contribute to the dissemination and improvement of the astronomy teaching-learning. The results of a research carried out in schools of Umuarama-PR are shown, with the intention of checking the students' knowledge and interest in relation to Astronomy. It is reported the realization of workshops for Science teachers linked to the Education Regional Nucleus. The research and the workshop execution promoted the direct contact of the study group with the community; the results were used to diagnose the state of astronomy teaching-learning, in the basic education in Umuarama-PR. En este artículo se intenta presentar las actividades desarrolladas por el Grupo de Estudios de Astronomía (GEA) y contribuir para la divulgación y mejoría de la enseñanza-aprendizaje de la Astronomía. Se presentan los resultados de una investigación realizada en las escuelas de Umuarama-PR, con la intención de determinar el grado de conocimiento y el interés de los estudiantes en relación a la astronomía. Se relata la realización de talleres de capacitación para los profesores de ciencias vinculados al Núcleo Regional del Educación. La ejecución de la investigación y de los talleres promovió el contacto directo del grupo de estudios con la comunidad; los resultados sirvieron de diagnóstico de la enseñanza aprendizaje de la astronomía en la educación básica en Umuarama-PR. Neste artigo, objetiva-se apresentar as atividades desenvolvidas pelo Grupo de Estudos de Astronomia (GEA) e contribuir para a divulgação e melhoria do ensino-aprendizagem de astronomia. São apresentados os resultados de uma pesquisa realizada nas escolas de Umuarama-PR, com o intuito de averiguar o conhecimento e o interesse dos estudantes em relação à astronomia. Relata-se a realização de oficinas de capacitação para professores de ciências vinculados ao Núcleo Regional de Educação. A

  16. Free the Globe. (Spanish Title: Liberar al Globo Terráqueo.) Soltar o Globo Terrestre

    NASA Astrophysics Data System (ADS)

    Gangui, Alejandro

    2014-07-01

    íses de las sombras largas". En este trabajo, primeramente reseñamos el dispositivo, sus fundamentos básicos de armado y funcionamiento. En la segunda parte, describimos en detalle algunas actividades que facilitan su empleo en el aula y que hemos venido desarrollando en talleres de formación docente en nuestro grupo de investigación. O globo terrestre paralelo é um antigo dispositivo, muito simples e criativo que, empregado de forma sistemática nas aulas de astronomia, converte-se em uma ferramenta didática de grande potencialidade. Orientado adequadamente de acordo com o meridiano local, esse instrumento permite acompanhar as sombras em qualquer região da Terra que esteja iluminada pelo Sol, além de oferecer uma visualização clara do terminadouro, a linha que divide o dia da noite em nosso planeta. Com o conhecimento das sombras, é possível estimar a latitude de uma localidade e inferir a hora solar local em qualquer lugar do hemisfério iluminado do planeta. Além disso, mediante o emprego do globo terrestre paralelo, pode-se compreender, de maneira simples, que existem regiões onde os objetos às vezes não projetam sombras e outras, pelo contrário, que às vezes se convertem em "países das sombras longas". Neste trabalho, primeiramente, descrevemos o dispositivo, seus fundamentos básicos de construção e funcionamento. Na segunda parte, descrevemos em detalhes algumas atividades que facilitam seu emprego na aula e que temos desenvolvido em oficinas de formação docente em nosso grupo de pesquisa.

  17. The Understanding of Astronomy Concepts by Students from Basic Education of a Public School. (Spanish Title: El Entendimiento de Conceptos de Aastronmía Por Los Alumnos de Educación Básica en Una Escuela Pública.) O Entendimento de Conceitos de Astronomia Por Alunos da Educação Básica: O Caso de Uma Escola Pública Brasileira

    NASA Astrophysics Data System (ADS)

    Iria Machado, Daniel; dos Santos, Carlos

    2011-07-01

    movimiento de la Luna, el movimiento aparente del Sol sobre la esfera celeste, los eclipses, las dimensiones y las distancias en el Universo, el brillo de las estrellas y su observación de la Tierra. Si bien ha habido un pequeño progreso en la proporción de respuestas aceptables científicamente cuando se cotejó el octavo grado de la enseñanza primaria con el quinto, y el último año de la enseñanza secundaria con el primero, se observó un predominio de las concepciones alternativas en relación a la mayoría de los temas explorados, que continuó hasta los últimos años de la educación básica. Una comparación con los datos encontrados en investigaciones realizadas en otros contextos socioculturales revelaron, en muchos aspectos, conceptos y dificultades similares expresadas por los estudiantes. Apresentam-se os resultados de uma investigação sobre a compreensão de conceitos astronômicos básicos, da qual participaram 561 estudantes da quinta série do Ensino Fundamental ao terceiro ano do Ensino Médio de uma escola pública da cidade de Foz do Iguaçu. Um teste com 20 questões de múltipla escolha foi aplicado para identificar as concepções mais comuns expressadas pelos alunos. Esse instrumento de coleta de dados foi elaborado com base na literatura sobre concepções alternativas e abordou os seguintes temas: o ciclo dia-noite; os fusos horários; as estações do ano; as fases da Lua; o movimento da Lua; o movimento aparente do Sol na esfera celeste; os eclipses; as dimensões e distâncias no Universo; o brilho das estrelas e sua observação da Terra. Embora se tenha verificado um pequeno progresso na proporção de respostas cientificamente aceitáveis ao se cotejar a oitava série do Ensino Fundamental com a quinta, e a terceira série do Ensino Médio com a primeira, houve o predomínio de concepções alternativas em relação à maior parte dos temas explorados, as quais persistiram até o último ano da Educação Básica. A comparação com

  18. Solar Physics Topics in High School: Analysis of a Course with Practical Activities at Dietrich Schiel Observatory. (Spanish Title: Temas de Física Solar Para Estudiantes de Escuelas Secundarias: un Análisis de un Curso con Enfoque Práctico en el Observatorio Dietrich Schiel.) Tópicos de Física Solar no Ensino Médio: Análise de um Curso com Atividades Práticas no Observatório Dietrich Schiel

    NASA Astrophysics Data System (ADS)

    Calbo Aroca, Silvia; Donizete Colombo, Pedro, Jr.; Celestino Silva, Cibelle

    2012-12-01

    algunos estudiantes sabían que un espectro puede estar formado por un prisma o red de difracción, la mayor parte de ellos desconocía la naturaleza de las líneas espectrales. A lo largo del curso, esta cuestión fue trabajada con un enfoque práctico mediante la observación del espectro solar y de las lámparas durante clases expositivas/dialogadas. Los resultados obtenidos en el curso mustran la importancia de los centros de ciencia como un apoyo en la educación formal. En este caso en particular, la Sala Solar del Observatorio Dietrich Schiel se destaca como un entorno favorable para la enseñanza de la física moderna en la escuela secundaria. Este trabalho analisa resultados obtidos em um curso sobre física solar para alunos do ensino médio promovido pelo Observatório Dietrich Schiel da USP. O curso foi elaborado pelos autores com a intenção de investigar concepções sobre o Sol, ensinar tópicos de física moderna relacionados ao Sol e conhecimentos gerais sobre o astro rei. A metodologia de coleta de dados consistiu em gravação em áudio e vídeo das aulas e das entrevistas semi-estruturadas, e respostas a questionários escritos. Os resultados mostraram que a maioria dos participantes concebeu o Sol como constituído por fogo e as manchas solares como buracos na superfície solar. Embora alguns alunos soubessem que um espectro pode ser formado por um prisma ou rede de difração, a maior parte deles desconhecia a natureza das linhas espectrais. Ao longo do curso, este tema foi trabalhado com uma abordagem prática com observação do espectro solar e de lâmpadas e em aulas expositivo-dialogadas. Os resultados obtidos no curso apontam para a importância dos centros de ciências como parceiros da educação formal. Neste caso específico, a Sala Solar do Observatório Dietrich Schiel é um ambiente propício para o ensino de física moderna no ensino médio.

  19. Astronomy, Art and Mythology in a Public Elementary School in Itaocara/rj. (Spanish Title: Astronomía, Arte y Mitologia en el Ensino Fundamental en Una Escuela de la Red Estatal en ITAOCARA/RJ.) Astronomia, Arte e Mitologia no Ensino Fundamental em Escola da Rede Estadual em ITAOCARA/RJ

    NASA Astrophysics Data System (ADS)

    Oliveira Bernardes, Adriana; Ramos dos Santos, Arleidimar

    2008-12-01

    conocimientos recibidos. El trabajo en sí ha mostrado además de la posibilidad de la inclusión de la Astronomía en la Educación Primaria, la posibilidad de un trabajo interdisciplinario en los niveles iniciales incluyendo Astronomía, Arte y Mitología. Los resultados presentados por los estudiantes en las Olimpiadas promovidas en la escuela y por la OBA (Olimpiada Brasilera de Astronomía) permitieron verificar un creciente aprendizaje y estimulo hacia las materias científicas, comprobados por la apropiada expresión de los conceptos adquiridos de astronomía y presentados en evaluaciones o en informes obtenidos de ellos mismos, sus familias y profesores. Desenvolvendo um trabalho voluntário junto aos alunos do ensino fundamental no 1º ciclo (1ª a 4ª série), os monitores de Astronomia membros do CAIMP (Clube de Astronomia de Itaocara Marcos Pontes), que eram em sua maioria alunos do ensino médio, desenvolveram um trabalho de aproximação entre os alunos do Colégio Estadual Teotônio Brandão Vilela e os temas envolvendo Ciências e Astronomia. Através de oficinas de informática, artes, vídeos educativos e teatros de fantoches, os alunos puderam expressar seus conhecimentos e emoções diante das lendas mitológicas com as quais começaram a ter contato. O trabalho desenvolvido pelos monitores junto aos alunos proporcionou a integração entre as turmas do colégio e os levou a participação em atividades de maneira a estimular sua oralidade e aumentar sua auto-estima. Trabalhando várias formas de expressões, os alunos puderam realizar seus experimentos e conhecer alguns conceitos de Física e Astronomia, enquanto adquiriam autonomia para se expressarem de acordo com seus sentimentos e conhecimentos adquiridos. O trabalho em si mostrou além da possibilidade de inserção de Astronomia no Ensino Fundamental, a possibilidade de realização de um trabalho interdisciplinar nas séries iniciais envolvendo Astronomia, Arte e Mitologia. Os resultados apresentados

  20. The Practice of Research of a Basic Education Teacher Involving Mental Models of the Phases of the Moon and Eclipses. (Spanish Title: La Práctica de Investigación de un Maestro de Educación BÁsica con El Uso de los Modelos Mentales de Las Fases de la Luna Y Eclipses.) A Prática de Pesquisa de um Professor do Ensino Fundamental Envolvendo Modelos Mentais de Fases da Lua e Eclipses

    NASA Astrophysics Data System (ADS)

    Pessôa Queiroz, Glória; Jubitipan Borges de Sousa, Carlos; Auxiliadora Delgado Machado, Maria

    2009-12-01

    docente. La formación de grupos interinstitucionales para la planificación de la acción y la investigación ha resultado productiva para el trabajo de construcción de conocimiento de apoyo a los procesos educativos en la escuela, mientras que la universidad enriquece su colección de experiencias validadas, considerando los resultados de la educación inicial y continua de maestros. La participación activa del maestro en un grupo de investigación en la universidad lo llevó a reflexiones sobre los posibles caminos didácticos que pueden ser descriptos, analizados y comunicados a los demás docentes. La construcción de una pedagogía propia, que tuvo en cuenta los modelos mentales de los estudiantes sobre los temas básicos de astronomía, y los cambios desarrollados a partir de las lecciones que enseñó, trajeron consecuencias de largo alcance sobre la pedagogía adoptada por el maestro, que ahora incorpora una nueva visión de la ciencia y formas alternativas al diálogo con los estudiantes, los componentes esenciales para un investigador en Educaciónen Ciencias. A inclusão do professor da escola básica no universo da pesquisa é questão controvertida e em pleno debate no meio acadêmico. A oportunidade de trabalho coletivo que incorporou professores de uma escola municipal no Rio de Janeiro a um grupo de ensino de Física da universidade nos possibilitou vislumbrar a ressignificação da função de um professor de Ciências (co-autor deste trabalho) por ele próprio, agora passando a incluir a pesquisa sobre a construção de conhecimento pelos alunos em sua prática como docente. A formação de grupos interinstitucionais para o planejamento de ações e de pesquisas tem-se mostrado produtiva para um trabalho de construção de conhecimentos a fim de subsidiar processos educativos na escola, ao mesmo tempo em que a universidade enriquece seu acervo de experiências validadas criticamente, podendo considerar seus resultados na formação inicial e

  1. Astronomy, Art and Mythology in a Public Elementary School in Itaocara/rj. (Spanish Title: Astronomía, Arte y Mitologia en el Ensino Fundamental en Una Escuela de la Red Estatal en ITAOCARA/RJ.) Astronomia, Arte e Mitologia no Ensino Fundamental em Escola da Rede Estadual em ITAOCARA/RJ

    NASA Astrophysics Data System (ADS)

    Oliveira Bernardes, Adriana; Ramos dos Santos, Arleidimar

    2008-12-01

    conocimientos recibidos. El trabajo en sí ha mostrado además de la posibilidad de la inclusión de la Astronomía en la Educación Primaria, la posibilidad de un trabajo interdisciplinario en los niveles iniciales incluyendo Astronomía, Arte y Mitología. Los resultados presentados por los estudiantes en las Olimpiadas promovidas en la escuela y por la OBA (Olimpiada Brasilera de Astronomía) permitieron verificar un creciente aprendizaje y estimulo hacia las materias científicas, comprobados por la apropiada expresión de los conceptos adquiridos de astronomía y presentados en evaluaciones o en informes obtenidos de ellos mismos, sus familias y profesores. Desenvolvendo um trabalho voluntário junto aos alunos do ensino fundamental no 1º ciclo (1ª a 4ª série), os monitores de Astronomia membros do CAIMP (Clube de Astronomia de Itaocara Marcos Pontes), que eram em sua maioria alunos do ensino médio, desenvolveram um trabalho de aproximação entre os alunos do Colégio Estadual Teotônio Brandão Vilela e os temas envolvendo Ciências e Astronomia. Através de oficinas de informática, artes, vídeos educativos e teatros de fantoches, os alunos puderam expressar seus conhecimentos e emoções diante das lendas mitológicas com as quais começaram a ter contato. O trabalho desenvolvido pelos monitores junto aos alunos proporcionou a integração entre as turmas do colégio e os levou a participação em atividades de maneira a estimular sua oralidade e aumentar sua auto-estima. Trabalhando várias formas de expressões, os alunos puderam realizar seus experimentos e conhecer alguns conceitos de Física e Astronomia, enquanto adquiriam autonomia para se expressarem de acordo com seus sentimentos e conhecimentos adquiridos. O trabalho em si mostrou além da possibilidade de inserção de Astronomia no Ensino Fundamental, a possibilidade de realização de um trabalho interdisciplinar nas séries iniciais envolvendo Astronomia, Arte e Mitologia. Os resultados apresentados

  2. Psychological distress and community approach to the voice of the community health agent.

    PubMed

    Paiva, Pâmela Câmpelo; Torrenté, Mônica de Olivera Nunes de; Landim, Fátima Luna Pinheiro; Branco, July Grassiely de Oliveira; Tamboril, Bruna Caroline Rodrigues; Cabral, Ana Larisse Teles

    2016-06-01

    como a comunidade percebe a pessoa em sofrimento psíquico e como está se posiciona frente às problemáticas do seu cotidiano, no que se refere a rejeição, preconceito, discriminação e perda de identidade. Contudo destaca-se que, pelo fato de estar inserido na comunidade, o agente comunitário de saúde percebe de forma mais apurada como tal grupo social trata a pessoa em sofrimento mental. A rejeição da pessoa que adoeceu é observada como uma reação bastante comum, acompanhada do preconceito e discriminação, marginalizando-a da sociedade. PMID:27384288

  3. Percepção astronómica de um grupo de alunos do ensino médio de uma escola da rede estadual de São Paulo

    NASA Astrophysics Data System (ADS)

    de Oliveria, E. F.; Voelzke, M. R.

    2009-03-01

    Sendo a Astronomia uma das cièncias mais antigas da humanidade, e considerando sua importáncia histórica e cultural, é de extrema releváncia que tópicos relacionados a ela sejam tratados nas escolas. Embora os Parámetros Curriculares Nacionais do Ensino Médio (PCN-EM) e as Orientaçiacute;es Complementares aos Parámetros (PCN+) apontem a importáncia de uma abordagem significativa de conceitos relacionados à Astronomia nas aulas de Física, muitos estudantes terminam o Ensino Médio (EM) sem compreender a razão de certos acontecimentos de origem celeste, ainda que estes façam parte de seu cotidiano e sejam alvos da curiosidade natural dos jovens. Da observação dessa curiosidade em alunos de uma escola pública paulista, na cidade de Suzano, surgiu o interesse em investigar os conhecimentos básicos em Astronomia dos alunos do Ensino Médio desta escola, constituindo-se este como principal objetivo desta pesquisa. Para tanto foi elaborado um questionário de múltipla escolha aplicado inicialmente a 34 alunos do primeiro ano e, posteriormente, a mais 310, distribuídos entre as très séries do Ensino Médio dos períodos matutino e noturno. Dessa forma, observou-se que 73,9% dos estudantes identificaram o Sol como sendo uma estrela, 67,1% mostraram compreender a sucessão entre dia e noite e 52,3% relacionaram o Big Bang à origem do Universo. Em contrapartida, apenas 34,5% relacionaram as estaçíes do ano à inclinação do eixo de rotação da Terra, 21,3% indicaram a influència gravitacional simultánea da Lua e do Sol como responsável pelo fenòmeno das marés, 24,5% indicaram corretamente quais são os objetos celestes mais próximos da Terra, 36,1% identificaram ano-luz como uma medida de distáncia e 34,2% reconheceram as estrelas cadentes como meteoros, evidenciando-se assim o pequeno discernimento dos estudantes quanto aos fenòmenos e termos astronòmicos do cotidiano. Além disso, foram comparadas as respostas de alun! os de diferentes s

  4. Queda dos homicídios em São Paulo, Brasil: uma análise descritiva

    PubMed Central

    Peres, Maria Fernanda Tourinho; Vicentin, Diego; Nery, Marcelo Batista; de Lima, Renato Sérgio; de Souza, Edinilsa Ramos; Cerda, Magdalena; Cardia, Nancy; Adorno, e Sérgio

    2012-01-01

    Objetivo Descrever a evolução da mortalidade por homicídios no Município de São Paulo segundo tipo de arma, sexo, raça ou cor, idade e áreas de exclusão/inclusão social entre 1996 e 2008. Métodos Estudo ecológico de série temporal. Os dados sobre óbitos ocorridos no Município foram coletados da base de dados do Programa de Aprimoramento das Informações sobre Mortalidade, seguindo a Classificação Internacional de Doenças, Décima Revisão (CID-10). Foram calculadas as taxas de mortalidade por homicídio (TMH) para a população total, por sexo, raça ou cor, faixa etária, tipo de arma e área de exclusão/inclusão social. As TMH foram padronizadas por idade pelo método direto. Foram calculados os percentuais de variação no período estudado. Para as áreas de exclusão/inclusão social foram calculados os riscos relativos de morte por homicídio. Resultados As TMH apresentaram queda de 73,7% entre 2001 e 2008. Foi observada redução da TMH em todos os grupos analisados, mais pronunciada em homens (−74,5%), jovens de 15 a 24 anos (−78,0%) e moradores de áreas de exclusão social extrema (−79,3%). A redução ocorreu, sobretudo, nos homicídios cometidos com armas de fogo (−74,1%). O risco relativo de morte por homicídio nas áreas de exclusão extrema (tendo como referência áreas com algum grau de exclusão social) foi de 2,77 em 1996, 3,9 em 2001 e 2,13 em 2008. Nas áreas de alta exclusão social, o risco relativo foi de 2,07 em 1996 e 1,96 em 2008. Conclusões Para compreender a redução dos homicídios no Município, é importante considerar macrodeterminantes que atingem todo o Município e todos os subgrupos populacionais e microdeterminantes que atuam localmente, influenciando de forma diferenciada os homicídios com armas de fogo e os homicídios na população jovem, no sexo masculino e em residentes em áreas de alta exclusão social. PMID:21390415

  5. A Influência da Escola e da Mídia na Obtenção dos Conhecimentos Astronômicos

    NASA Astrophysics Data System (ADS)

    da Cunha, W. S.; Voelzke, M. R.; Amaral, L. H.

    2006-08-01

    O universo em que vivemos possui segredos jamais imaginados pelo homem, fruto da pequena proporção que ocupamos diante de um cosmos infinito. A astronomia funciona como um instrumento que sacia a sede humana em desvendar esses segredos, estudando as galáxias, quasares, pulsares além da existência de todos os elementos que preenchem o espaço cósmico, o vácuo, não mais vazio como se pensou em outros tempos. A mídia explora esse campo de forma mística e também científica. A difusão adequada e dentro dos padrões educacionais vigentes, de conceitos astronômicos, se faz necessária, devido sua presença nos conteúdos escolares, centros de ciência e na mídia, de modo geral. A reforma do Currículo Básico da Escola Pública da maioria dos Estados brasileiros introduziu conceitos astronômicos desde a pré-escola até o Ensino Médio. Num estudo realizado com 1.032 alunos do Ensino Médio de seis escolas estaduais, revelou-se através da aplicação de um questionário que abordava conheciment os básicos em astronomia, como estes foram adquiridos e qual era a infra-estrutura oferecida pela escola: para 66,2% dos entrevistados o professor já fez alguma apresentação a respeito de astronomia. O presente estudo revelou também que 44,5% dos alunos entrevistados adquiriram seus conhecimentos astronômicos na escola, 28,1% através da televisão e 27,4% afirmaram que seus conhecimentos foram obtidos através de outros tipos de mídia (internet, filmes e revistas). Embora o estudo revele claramente que há certo equilíbrio na forma em que os alunos obtiveram seus conhecimentos astronômicos, a mídia ainda explora e muitas vezes desperta o interesse pela astronomia com assuntos que não fazem parte de nosso cotidiano como, por exemplo, o homem na Lua, os projetos espaciais e a primeira viagem de um astronauta brasileiro no espaço. Porém, em certos casos, a mídia pode promover conhecimentos incompletos ou mesmo equivocados sobre os conceitos que envolvam

  6. Estudo em microondas do aprisionamento e precipitação de elétrons em explosões solares

    NASA Astrophysics Data System (ADS)

    Rosal, A. C.; Costa, J. E. R.

    2003-08-01

    Uma explosão solar é uma variação rápida e intensa do brilho que ocorre nas chamadas regiões ativas da atmosfera, constituídas por um plasma magnetizado com intensa indução magnética. Os modelos de explosões solares atuais, discutidos na literatura, apresentam características de aprisionamento e precipitação de elétrons em ambientes magnéticos simplificados. Neste trabalho, nos propusemos a separar a emissão dos elétrons aprisionados da emissão dos elétrons em precipitação apenas a partir da emissão em microondas, melhorando portanto o controle sobre o conjunto de parâmetros inferidos. A emissão em microondas da população em precipitação é bastante fraca e portanto da nossa base de dados de 130 explosões observadas pelo Rádio Polarímetro de Nobeyama, em sete freqüências, apenas para 32 foi possível separar as duas componentes de emissão com uma boa razão sinal/ruído. A partir de estudos das escalas de tempo das emissões devidas à variação gradual da emissão no aprisionamento e da variação rápida da emissão dos elétrons em precipitação foi possível obter a separação utilizando um filtro temporal nas emissões resultantes. Em nossa análise destas explosões estudamos os espectros girossincrotrônicos da emissão gradual, a qual associamos provir do topo dos arcos magnéticos e da emissão de variação rápida associada aos elétrons em precipitação. Estes espectros foram calculados e dos quais inferimos que a indução magnética efetiva do topo e dos pés foi em média, Btopo = 236 G e Bpés = 577 G, inferidas das freqüências de pico dos espectros em ntopo = 11,8 GHz e npés = 14,6 GHz com leve anisotropia (pequeno alargamento espectral). O índice espectral da distribuição não-térmica de elétrons d, inferido do índice espectral de fótons da emissão em regime opticamente fino, foi de dtopo = 3,3 e dpés = 3,9. Estes parâmetros são típicos da maioria das análises realizadas em ambiente único de

  7. The family experience of care in chronic situation.

    PubMed

    Bellato, Roseney; Araújo, Laura Filomena Santos de; Dolina, Janderléia Valéria; Musquim, Cleciene Dos Anjos; Corrêa, Geovana Hagata de Lima Souza Thaines

    2016-06-01

    An essay that aims to reflect on the family experience of care in chronic situation, increasing the understanding of the family as the primary caregiver. It is based on comprehensive approach in studies conducted in three matrix searches from family care experiences. We have taken three axes to organize our reflections: a) conformation of family care in chronic situation, highlighting the multiple costs incurred to the family, which can exhaust the potential of care and establish or increase its vulnerability if it is not backed by networks support and sustenance; b) family rearrangements for the care, giving visibility to care cores in which many loved family members share the care, dynamic, plural and changeable way; c) self care modeling family care, pointing to the range of possibilities of the person taking care of diseased conditions supported by people close to them. We learn that the family takes care of itself in everyday life and in the illness experience, creating networks that can provide you support and sustenance. Thus, professionals in health practices should shape up in a longitudinal and very personal way, by reference to the family care, supporting him in what is his own. Ensaio que tem por objetivo refletir sobre a experiência familiar de cuidado na situação crônica, ampliando a compreensão da família como cuidadora primária. Embasa-se em estudos de abordagem compreensiva realizados em três pesquisas matriciais que abordaram experiências familiares de cuidado. Tomamos três eixos para organizar nossas reflexões: a) conformação do cuidado familiar na situação crônica, destacando os múltiplos custos gerados à família, que podem exaurir seus potenciais de cuidado, instaurando ou ampliando sua vulnerabilidade se não for amparada por redes de apoio e sustentação; b) rearranjos familiares para o cuidado, dando visibilidade aos núcleos de cuidado compartilhados pelos diversos entes familiares, de modo dinâmico, plural e mut

  8. Analysis of astronomy knowledge of the students in the Federal Institute Sao Paulo

    NASA Astrophysics Data System (ADS)

    Moraes, A. C.; Voelzke, M. R.

    2014-08-01

    Este trabalho é parte integrante da pesquisa de mestrado acadêmico em ensino de ciências. Nele, busca-se apresentar os resultados da pesquisa realizada entre os 106 alunos do curso superior de tecnologia em automação industrial do Instituto Federal de Educação, Ciência e Tecnologia de São Paulo campus Cubatão, divididos em cinco turmas, duas no período matutino e três no período noturno. A análise dos resultados deste pré questionárioconstatou a falta de conhecimento básico dos discentes, sobre assuntos relacionados à astronomia, o que pode ser atribuído ao ineficiente processo de aprendizado pelo qual eles passaram tanto no ensino médio como no ensino fundamental, em escolas municipais, estaduais e particulares onde estudaram. No ensino de astronomia, têm-se diagnosticado constantemente diversas dificuldades conceituais tanto por parte de alunos como de professores de todas as áreas e níveis de ensino e poucos de fato a compreendem (ALBRECHT; VOELZKE, 2010). Demonstra-se as duas etapas concluídas do trabalho. A primeira etapa indica a análise dos conhecimentos prévios sobre conceitos astronômicos, através do questionário com 25 perguntas. A fim de corrigir as falhas constatadas, experimentalmente ministrou-se, externo ao conteúdo programático, um curso básico em astronomia, com diferentes estratégias de ensino, tais como, utilização de aulas expositivas dialogadas, recursos audiovisuais e palestras, para corrigir as dificuldades diagnosticadas. Essas estratégias de ensino se comprovaram adequadas às necessidades dos alunos e os conceitos foram finalmente compreendidos. Ao término do curso, completado o interstício de 120 dias, para caracterizar que houve a aprendizagem significativa, realizou-se uma nova pesquisa, quando, exatamente os mesmos 106 alunos responderam as mesmas 25 questões aplicadas na primeira etapa. Constata-se na segunda etapa, após análise, que em todas as questões, houve maior compreensão dos assuntos

  9. Forms of Appropriation of Tools for the Astronomy Education in Continuous Training of Teachers. (Spanish Title: Formas de Apropriación de Herramientas Para la Enseñanza de la Astronomía en la Formación Docente Continua.) Formas de Apropriação de Instrumentos Para o Ensino de Astronomia na Formação Continuada de Professores

    NASA Astrophysics Data System (ADS)

    Marques Soares, Leonardo; Sousa Nascimento, Silvania

    2012-07-01

    siete relatos. O objetivo principal desse artigo é apresentar algumas reflexões sobre a maneira como um grupo de professores se apropriaram dos instrumentos do KIT PARA O ENSINO DE ASTRONOMIA (KITPEA). Os sujeitos dessa pesquisa participaram do curso de especialização em ensino de astronomia oferecido pelo Projeto de Formação Continuada (Foco) no Centro de Ensino de Ciências e Matemática (CECIMIG) da Faculdade de Educação da Universidade Federal de Minas Gerais (FaE/UFMG). Coletamos as informações por meio de um questionário e de uma entrevista, aplicados a esses professores. Estruturamos a análise dessas informações com a ajuda da Teoria da Atividade e da Teoria da Ação Mediada. Interpretamos as falas dos professores usando como dispositivo analítico os elementos constituintes do sistema de atividade e os conceitos de apropriação e domínio. Dentre os 11 sujeitos que participaram da pesquisa, foi possível identificar a apropriação dos instrumentos em 7 narrativas.

  10. A causa das estações do ano: modelos mentais

    NASA Astrophysics Data System (ADS)

    de Campos, J. A. S.; de Araujo, J. F. S.

    2003-08-01

    A década de 70 do século passado foi marcada pelo estudo das concepções alternativas que os alunos trazem para a sala de aula. A identificação destas concepções foi o ponto de partida para promover a mudança conceitual, onde as pré-concepções seriam trocadas pelas concepções científicas. Na década seguinte, surgiram muitas propostas de estratégias educacionais para facilitar esta troca, na sua maioria baseadas na idéia do conflito cognitivo, proposta por Piaget. Entretanto, os resultados pouco animadores conduziram à percepção de que a mudança conceitual é um processo mais complexo. Pelas idéias da Ciência Cognitiva, a mudança conceitual é uma mudança progressiva dos modelos mentais que o aluno tem sobre o mundo físico, através de enriquecimento e revisão. A causa das Estações do Ano é um tópico sobre o qual a maioria dos estudantes apresenta concepções alternativas. Os autores fizeram um levantamento sobre as pré-concepções encontradas em trabalhos sobre o tema (16 referências), procurando encontrar elementos comuns que indicassem a presença de modelos mentais específicos. As pré-concepções encontradas na literatura foram obtidas usando-se diversas metodologias (desde entrevistas clínicas até questionários de múltipla escolha) e envolvendo alunos e professores de diferentes regiões geográficas. A partir de uma análise aprofundada de cada trabalho, e utilizando-se a técnica das Redes Sistêmicas, chegou-se a conclusão que as diversas pré-concepções identificadas (em torno de 50), poderiam ser representadas por 6 modelos mentais, onde a explicação da causa das estações do ano tem um mecanismo causal responsável. Os mecanismos causais identificados foram: a dependência da distância, a dependência da orientação, a dependência conjunta da distância e orientação, a dependência da obstrução, a dependência da velocidade e a dependência da inclinação dos raios solares. Foram ainda identificadas

  11. Modelo de atmosfera solar ajustado às observações do raio solar em 17GHz

    NASA Astrophysics Data System (ADS)

    Selhorst, C. L.; Silva, A. V. R.; Costa, J. E. R.

    2003-08-01

    O estudo das variações do raio solar durante o ciclo de atividades do Sol e das diferenças em relação à sua distribuição angular nos fornece informações importantes sobre as mudanças na estrutura da atmosfera solar. Neste trabalho foram analisados mais de 3600 mapas do Sol em 17 GHz obtidos pelo Rádio Heliógrafo de Nobeyama (NoRH), durante 1 ciclo de atividade solar (1992-2003). O raio solar foi definido no ponto onde a temperatura de brilho do mapa era equivalente à metade da temperatura do Sol calmo (temperatura mais comum no mapa).Em relação à sua variação ao longo do ciclo solar, o estudo foi dividido em duas partes: a) ajuste de uma circunferência a pontos distribuídos ao redor do Sol todo. Este estudo mostrou uma variação correlacionada com o ciclo de atividade do Sol. b) ajuste da circunferência a pontos situados somente nas regiões polares. Neste caso os resultados mostraram que o raio polar sofre pouca variação durante o ciclo, com tendência à anticorrelação com este. Além disto, a média do raio polar, durante o período analisado, foi 1" menor que o raio medido no Sol todo. Para estudar a distribuição angular do raio solar, comparamos a média da distribuição de 10 mapas no período de mínima atividade solar com a média de 10 mapas no período de máximo, este estudo mostrou um grande aumento do raio na região equatorial no período de máxima atividade solar. As medidas do raio foram usadas como um dos parâmetros para a criação de um modelo atmosférico (além da temperatura de brilho do Sol e do abrilhantamento do limbo observado), onde mostramos que um modelo atmosférico com a região de transição situada a 3500 km fornece um raio 5" menor que as medidas observacionais. Esta incompatibilidade do modelo com os dados observacionais foi contornada com a inclusão de espículas, estas fazem com que o raio solar aumente proporcionalmente à altura que estas atingem na atmosfera solar. A anticorrelação do raio

  12. Soil carbon stocks in response to management changes due to vinasse application in sugarcane production in southeast of Brazil

    NASA Astrophysics Data System (ADS)

    Fernandes Zani, Caio; Simoes Barneze, Arlete; Clemente Cerri, Carlos

    2014-05-01

    application at 1 m depth were 117.23 Mg ha-1 and 126.92 Mg ha-1, and at 0.3 m depth we found 50.34 Mg ha-1 and 55.54 Mg ha-1, respectively. It represented an increase 8.3% and 10.3% in soil C stocks in areas with vinasse application at 1 m and 0.3 m soil depth. This information may be used as a basis for public policies decision which dealing of the land use and global warming. The scientific information obtained in this research will be included in carbon footprint calculation of ethanol production and its use as biofuel. References Ellert B.H., Bettany J.R. 1995. Calculation of organic matter and nutrients stored in soils under contrasting management regimes. Can. J. Soil Sci. 75:529-538. Six J., Ogle S.M., Breidt F.J., Conant R.T., Mosier A.R., Paustian K. 2004. The potential to mitigate global warming with no-tillage management is only realized when practiced in the long term. Glob. Chang. Biol. 10:155-160. Soares L.H.B., Alves B.J.R., Urquiaga S., Boddey R.M. 2009. Mitigação das emissões de gases efeito estufa pelo uso de etanol da cana-de-açúcar produzido no Brasil. Embrapa Agrobiologia, Seropédica, RJ. 14p. (Circular Técnica, 27).

  13. Analysis of Service-learning activities adopted in health courses of Federal University of Bahia.

    PubMed

    Baldoino, Aline Silva; Veras, Renata Meira

    2016-06-01

    ática e as principais di culdades. Concluiu-se que esses cursos estão aderindo às mudanças na formação acadêmica em saúde, tendo em vista o grande número de unidades básicas de saúde que integram o processo de ensino serviço. Dessa forma, ressalta-se que a UFBA contempla atividades na área de saúde que viabilizam a integração-ensino no processo de formação superior, embora existam algumas di culdades nesta relação apontadas pelos coordenadores. PMID:27384271

  14. Calibração do sistema imageador do telescópio MASCO

    NASA Astrophysics Data System (ADS)

    Mejía, J.; D'Amico, F.; Villela, T.; Braga, J.

    2003-08-01

    O MASCO (MÁScara COdificada) é um telescópio imageador de raios-X e gama atualmente configurado para operar na faixa de 50 a 600 keV com uma resolução angular de 14 minutos de arco num campo de visada total circular de 23,5° de diâmetro. O MASCO está totalmente operacional e deverá ser lançado em um balão estratosférico no segundo semestre de 2003 para realizar observações durante ~20 horas a ~40 km de altitude. O telescópio utiliza uma máscara codificada de padrão uniformemente redundante modificado (MURA) de dimensões 19 ´ 19. Esse padrão pertence a uma subclasse de MURAs que apresenta anti-simetria de 90° e conseqüentemente permite a utilização da técnica de subtração de variações sistemáticas de ruído de fundo através de utilização da configuração anti-máscara, obtida com uma simples rotação da máscara. Neste trabalho apresentamos resultados de calibrações em laboratório que tiveram como objetivo testar o sistema imageador. Imagens de fontes radioativas foram obtidas com o telescópio em configuração de vôo, com a máscara girando. Serão discutidos os resultados desses testes e as técnicas desenvolvidas para eliminar ambigüidades de posição de fontes, otimização da relação sinal-ruído e observação de fontes fora do campo totalmente codificado. O sistema de máscara/antimáscara mostrou-se capaz de aumentar a relação sinal-ruído de ~60% para fontes intensas (100 s). Com a máscara girando, a técnica de reconstrução de imagens desenvolvida identificou a posição exata da fonte e não introduziu perda de sensibilidade. Imagens de uma fonte colocada a 8,3° - fora do campo totalmente codificado do telescópio -, mostraram uma diminuição de ~40% na relação sinal/ruído em relação ao centro do campo de visada, o que se deve à codificação incompleta pela máscara e à absorção parcial do fluxo pelos detectores de blindagem.

  15. Reviving Erathostenes. (Breton Title: Revivendo Eratóstenes.) Reviviendo a Eratóstenes.

    NASA Astrophysics Data System (ADS)

    Pereira, Paulo Cesar R.

    2006-12-01

    As part of the commemorations of the International Year of the Physics and having as its main objective to introduce students to the scientific method, the Rio de Janeiro Planetarium Foundation, in partnership with many institutions of Brazil and Europe, coordinated the activity "Reviving Eratosthenes" whose objective was the determination of the Earth's circumference. We used the famous procedure adopted by Eratosthenes more than 2000 years ago, with some adaptations. This work considers and analyzes the method used by us, aiming the application in schools. The use of places in different meridians allows a better understanding of the abstract concepts such as geographic coordinate and time zones. We obtained reasonably precise results, which improve for pairs of distant cities. Finally, one of the most important conclusions achieved by the students involved is the importance of the cooperation (international in this case) to solve problems. Fazendo parte das comemorações do Ano Internacional da Física e tendo como principal objetivo introduzir estudantes do ensino médio ao método científico, a Fundação Planetário da Cidade do Rio de Janeiro, em parceria com diversas instituições do Brasil e da Europa, coordenou a atividade "Revivendo Eratóstenes" cujo objetivo foi a determinação da circunferência da Terra. Para isso, utilizou-se um procedimento semelhante ao empregado pelo sábio Eratóstenes há mais de 2.000 anos, com algumas adaptações. Este trabalho propõe e analisa o método que empregamos, visando a aplicação em escolas. A possibilidade de se trabalhar com locais em diferentes meridianos permite uma melhor compreensão dos conceitos mas abstratos, como coordenadas e fusos horários. A precisão dos resultados é bastante razoável, melhorando para cidades bem afastadas. Finalmente, uma das conclusões mais importantes é a percepção, por parte dos estudantes, da importância da colaboração (neste caso, internacional) para resolver

  16. Providing Meaningful Learning for Students of the Sixth Grade of Middle School: a Study on the Moon Phases. (Breton Title: Propiciando Aprendizagem Significativa Para Alunos do Sexto Ano do Ensino Fundamental: um Estudo sobre as Fases da Lua.) Propiciando el Aprendizaje Significativo Para Alumnos del Sexto Nivel de la Educación General Básica: un Estudio sobre Las Fases de la Luna

    NASA Astrophysics Data System (ADS)

    Darroz, Luiz Marcelo; Samudio Pérez, Carlos Ariel; da Rosa, Cleci Werner; Heineck, Renato

    2012-07-01

    We relate in this article a didactic experience studying the moon phases with a group of middle school students of a private school of the municipality of Passo Fundo, RS. Based on David Ausubel's Meaningful Learning Theory, we have sought to develop a proposal following a didactic model which simulates the phases of the Moon, as based on the previous conceptions of the students. The signs of learning were evidenced by means of memory registries of the activity. From the obtained results we believe that the proposal achieved its goals, since the students were able to identify, differentiate and transfer the phenomenon of the moon phases to new contexts. Thus, it is concluded that a methodology focused on a meaningful content for the students is fundamental to the construction and genuine grasping of what is being learned. Neste artigo, relata-se uma experiência didática de estudo das fases da Lua com uma turma do 6° ano do Ensino Fundamental, de uma escola privada do município de Passo Fundo, RS. Tendo como fundamentação teórica a Teoria da Aprendizagem Significativa de David Ausubel, buscou-se desenvolver a proposta a partir de um modelo didático que simula as fases da Lua e com base nas concepções prévias dos estudantes. Os indícios da aprendizagem foram constatados através de registros de memórias da atividade. Pelos resultados apresentados, acredita-se que a proposta alcançou seus objetivos, uma vez que os estudantes conseguiram identificar, diferenciar e transferir o fenômeno das fases da Lua para novos contextos. Assim, conclui-se que uma metodologia com enfoque em um conteúdo significativo ao estudante é fundamental para a construção e compreensão genuína do que está sendo aprendido. En este artículo se relata una experiencia didáctica de estudio de las fases de la Luna con una clase de 6º año de la educación general básica de una escuela privada del municipio de Passo Fundo, RS. Teniendo como fundamentación teórica la Teor

  17. Farmyard Manure and Fertilizer Effects on Seed Potato (Solanum tuberosum L.) Yield in Green House Production

    NASA Astrophysics Data System (ADS)

    László, M.

    2009-04-01

    fertilizer (18.0 g pot-1) with a hard effect (57%). Our results are shown that it was possible developing of the seed potato production under tropical greenhouse conditions by optimalised soil-organic matter-fertilizer system. This datas should be as indicators to sustainable field potato advisory systems. Keywords: potato (Solanum tuberosum L.), greenhouse, latossolo vermelho soil, farmyard manure, burnt rice straw, 4N:14P:8K fertilizer, sustainability, yield Introducáo: Importância e situação actual em produção da batata no Brazíl A batata é atualmente uma das hortaliças de maior importância no Brasíl (Márton 2000a., 2000b.) com um cultivo annual médio de 173.000 ha e uma produção de 2600000 t. A produtividade médio nacional é de 15 t ha-1, muito baixa se considerar que é possivel a obtenção de rendimentos acima de 40 t ha-1. Observa- se também, que existe variação no produtividade entre regiões e estados. E importante como fonte de alimento pelo seu alto valor nutricional a quantidade produzida muito superior por unidade de área a tempo, se comparada com diversas outras culturas (László 2000b., 2000c.). Os estados que tradicionalmente produzem batata em maior ou menor escala são indicados em seguente: Pernambuco, Ceará, Sergipe, Goiás, Mato Grosso, Mato Grosso do Sul, Rondonia e Acre. Os plantios predominantes são o das águas e das secas, sendo o de inverno bem menos expressivo, pois poucas áreas permitem o seu cultivo, na maioria dos casos necessitando- se de irrigação. Considerando as três épocas de plantio e diferentes condições climaticas brasileiras, podemos definir de um modo geral o plantio de batata no Brasíl da seguinte maneira: Nordeste e Centro- Oeste- plantio de inverno, Sudeste- plantio das águas, secas e inverno, Sul- plantio das aguas, secas e inverno. Sendo este último em áreas muito limitadas. Dentre as hortaliças a batata é uma das culturas mais estudadas actualmente. Os principais problemas que afetam a

  18. A proposed contents astronomy for basic education

    NASA Astrophysics Data System (ADS)

    Albrecht, E.; Voelzke, M. R.

    2014-08-01

    A Astronomia é um tema que sempre exerceu fascínio sobre as pessoas de um modo geral. Conhecer e estudar o que há nos “céus”, além de nossos olhos, continua sendo instigador e de grande interesse. Baseado nestas justificativas desenvolveu-se uma pesquisa de Doutorado, na qual, o objetivo principal foi investigar sobre a presença dos conteúdos de Astronomia nas Propostas Curriculares da região Sul do Brasil, a saber, os estados de Paraná, Rio Grande do Sul e Santa Catarina e, posterior comparação com os Parâmetros Curriculares Nacionais (PCN) que trazem propostas de conteúdos para toda a Educação Básica brasileira. Tal investigação pautou-se na abordagem de caráter qualitativo e utilizouse para tal da Análise de Conteúdos (Bardin, 2011), que possibilitou a construção de quatro categorias, nas quais os conteúdos astronômicos foram agrupados: Terra, Sistema Solar, Via Láctea e Universo. Após a leitura, coleta de dados, construção de categorias, observou-se a dicotomia na apresentação destes conteúdos. As propostas curriculares analisadas foram as de Geografia, Ciências e Física dos estados do Paraná (2008), Rio Grande do Sul (2009) e de Santa Catarina (1998), responsáveis pelo trabalho com Astronomia nestes estados. No Ensino Fundamental, a proposta curricular do estado do Paraná apresenta conteúdos ligados à Astronomia desde o sexto ano até o nono ano, como conteúdo do primeiro bimestre, o que também é apresentado na proposta curricular do estado do Rio Grande do Sul, porém, este, não divide os conteúdos por bimestre e nem por ano, mas por ciclos, sexto e sétimo anos como primeiro ciclo e oitavo e nono anos como segundo ciclo, deixando livre para o professor estruturar sua sequência de conteúdos. A proposta curricular de Santa Catarina não apresenta estes conteúdos de maneira explícita, não divide dos conteúdos nem por ano, nem por série, traz uma sequência de conteúdos para serem trabalhados ao longo dos

  19. Ediacaran to Cambrian magmatic suites in the Rio Grande do Norte domain, extreme Northeastern Borborema Province (NE of Brazil): Current knowledge

    NASA Astrophysics Data System (ADS)

    do Nascimento, Marcos Antonio Leite; Galindo, Antonio Carlos; de Medeiros, Vladimir Cruz

    2015-03-01

    úton Japi, U-Pb em zircão), enquanto que a AlcCh foi datada, U-Pb em zircão, em 601 ± 10 Ma e 593 ± 5 Ma (Plúton Umarizal). O magmatismo de idade cambriana no Domínio Rio Grande do Norte está representado pelos diques de pegmatito com idades U-Pb variando entre 515 e 510 Ma.

  20. A Diagnostic Assessment for the Teaching of Astronomy. (Spanish Title: Una Evaluación Diagnóstica Para la Enseñanza de la Astronomia.) Uma Avaliação Diagnóstica Para o Ensino da Astronomia

    NASA Astrophysics Data System (ADS)

    Pacifico Ribeiro de Assis Silveira, Felipa; Soares Gomes de Sousa, Célia Maria; Moreira, Antonio

    2011-07-01

    interpretación, lo que nos permite comprender los significados asignados por el estudiante a estos conceptos. Se desprende de la evaluación diagnóstica que la mayoría de los encuestados ha tenido dificultades para exponer los conceptos científicos sobre el Universo y la Tierra, para iniciar el 6 º grado. Sin embargo, se identificaron ideas relevantes y las representaciones que contribuyeron a la re-significación de los conceptos científicos propuestos para la enseñanza del tema en esta serie. Los resultados de la evaluación diagnóstica han servido como referencia para la organización del Programa, facilitando el proceso de aprendizaje, haciendo coincidir la secuencia didáctica a las características de los estudiantes y el contexto del aula. Se espera que el instrumento presentado en este documento también pueda ser utilizado por otros investigadores en investigaciones relacionadas con el tema. Este artigo tem como objetivo apresentar os resultados de uma avaliação diagnóstica, utilizada como instrumento para a coleta de dados sobre o conhecimento prévio de conceitos científicos, necessários à compreensão do tema Terra e Universo, de um grupo composto por 47 estudantes, da 6ª série do Ensino Fundamental. A ação pedagógica de diagnosticar os conhecimentos prévios, do estudante, antes de ensiná-los, tem fundamento na teoria da Aprendizagem Significativa, proposta por David Ausubel. Essa avaliação diagnóstica foi composta por 25 questões, cujas respostas foram analisadas e categorizadas visando sua interpretação, o que permitiu compreender os significados atribuídos pelo estudante a esses conceitos. Conclui-se, a partir da avaliação diagnóstica, que a maioria dos estudantes pesquisados apresentou dificuldades em expor conceitos científicos sobre o tema Terra e Universo ao iniciar a 6ª série. Entretanto, foram identificadas ideias e representações relevantes que contribuíram para a (re)significação dos conceitos científicos propostos

  1. Value of the Qrs-T Angle in Predicting the Induction of Ventricular Tachyarrhythmias in Patients with Chagas Disease.

    PubMed

    Zampa, Hugo Bizetto; Moreira, Dalmo Ar; Ferreira Filho, Carlos Alberto Brandão; Souza, Charles Rios; Menezes, Camila Caldas; Hirata, Henrique Seichii; Armaganijan, Luciana Vidal

    2014-10-28

    .95; CI 0.99-15.82; p = 0.052). The EF also emerged as a predictor of induction of VT / VF: for each point increase in EF, there was a 4% reduction in the rate of sustained ventricular arrhythmia on EPS. Conclusions: Changes in the QRS-T angle and decreases in EF were associated with an increased risk of induction of VT / VF on EPS.Fundamento: O ângulo QRS-T mostra correlação com prognóstico em pacientes com insuficiência cardíaca e doença coronariana, traduzido por um aumento na mortalidade proporcional ao aumento na diferença entre os eixos do complexo QRS e da onda T no plano frontal. Até hoje, nenhuma informação a este respeito foi obtida em pacientes com cardiopatia chagásica. Objetivo: Correlacionar o ângulo QRS-T com a indução de taquicardia ventricular / fibrilação ventricular (TV / FV) em chagásicos durante estudo eletrofisiológico (EEF). Métodos: Estudo caso-controle em centro terciário. Pacientes sem indução de TV / FV ao EEF foram utilizados como controles. O ângulo QRS-T foi categorizado como normal (0-105º), limítrofe (105-135º) e anormal (135-180º). As diferenças entre os grupos foram analisadas pelo teste t ou teste de Mann-Whitney para variáveis contínuas, e teste exato de Fisher ou qui-quadrado para variáveis categóricas. Valores de p < 0,05 foram considerados significativos. Resultados: De 116 pacientes submetidos ao EEF, 37,9% foram excluídos por estarem com dados incompletos / prontuários inativos ou pela impossibilidade de se calcular corretamente o ângulo QRS-T (presença de bloqueio de ramo esquerdo e fibrilação atrial). De 72 pacientes incluídos, 31 induziram TV / FV ao EEF. Destes, o ângulo QRS-T se encontrava normal em 41,9%, limítrofe em 12,9% e anormal em 45,2%. No grupo de pacientes sem indução de TV / FV, o ângulo QRS-T se encontrava normal em 63,4%, limítrofe em 14,6% e anormal em 17,1% (p = 0,04). Quando comparados aos pacientes com ângulo QRS-T normal, o risco de indução de TV / FV nos

  2. Practical Astronomical Activities during Daytime. (Spanish Title: Actividades Astronómicas Prácticas Diurnas.) Atividades Astronômicas Práticas Diurnas

    NASA Astrophysics Data System (ADS)

    Jackson, Eric

    2009-12-01

    aulas. Se a Astronomia ia ser introduzida, então era preciso encontrar uma forma de resolver essas dificuldades. Nosso grupo, trabalhando com professores e alunos numa abordagem construtivista, encontrou que os princípios da Astronomia podem ser descobertos durante o dia, enquanto os alunos estão na escola. Trabalhando de forma cooperativa os alunos mediram e registraram observações de suas próprias sombras causadas pelos movimentos da estrela mais próxima, o Sol, e nosso planeta Terra. Devido ao fato de os alunos se envolverem muito pessoalmente nas atividades, eles ficaram muito mais interessados nos resultados do estudo. A Astronomia passou a ser um desafio para o professor e seus alunos quando aplicaram suas experiências diurnas à observação noturna desde suas casas, relatada depois em sala de aula.

  3. Conversations with Marcgrave: the Origin of Modern Astronomy in the Southern Hemisphere (Spanish Title: Conversando con Marcgrave: El Origen de la Astronomía Moderna en el Hemisferio Sur) Conversando Com Marcgrave: a Origem da Moderna Astronomia no Hemisfério Sul

    NASA Astrophysics Data System (ADS)

    Medeiros, Alexandre; Araújo, Fábio

    2005-12-01

    ício de Nassau e reúne alguns colegas professores apaixonados pelo ensino da Astronomia. A história é contada, deste modo, em um clima ameno e pretensamente divertido, mas as informações históricas e conceituais nele contidas estão apoiadas em fontes bibliográficas confiáveis devidamente apontadas ao final do texto. Elas vão desde a obra original desse cientista, na qual aparece o seu relato sobre a observação de um eclipse solar no Recife, passando por obras clássicas a seu respeito, como a do professor Juliano Moreira, até fontes bem mais recentes, como o trabalho muito influente do Professor John North. Outros textos de porte sobre o período da colonização holandesa no Brasil, como as obras já clássicas de Charles Boxer, Bouman e Boogaart, dentre outras, são também utilizados na construção desta dramatização pedagógica envolvendo um interessante capítulo da História da Astronomia.

  4. A Diagnostic Assessment for the Teaching of Astronomy. (Spanish Title: Una Evaluación Diagnóstica Para la Enseñanza de la Astronomia.) Uma Avaliação Diagnóstica Para o Ensino da Astronomia

    NASA Astrophysics Data System (ADS)

    Pacifico Ribeiro de Assis Silveira, Felipa; Soares Gomes de Sousa, Célia Maria; Moreira, Antonio

    2011-07-01

    interpretación, lo que nos permite comprender los significados asignados por el estudiante a estos conceptos. Se desprende de la evaluación diagnóstica que la mayoría de los encuestados ha tenido dificultades para exponer los conceptos científicos sobre el Universo y la Tierra, para iniciar el 6 º grado. Sin embargo, se identificaron ideas relevantes y las representaciones que contribuyeron a la re-significación de los conceptos científicos propuestos para la enseñanza del tema en esta serie. Los resultados de la evaluación diagnóstica han servido como referencia para la organización del Programa, facilitando el proceso de aprendizaje, haciendo coincidir la secuencia didáctica a las características de los estudiantes y el contexto del aula. Se espera que el instrumento presentado en este documento también pueda ser utilizado por otros investigadores en investigaciones relacionadas con el tema. Este artigo tem como objetivo apresentar os resultados de uma avaliação diagnóstica, utilizada como instrumento para a coleta de dados sobre o conhecimento prévio de conceitos científicos, necessários à compreensão do tema Terra e Universo, de um grupo composto por 47 estudantes, da 6ª série do Ensino Fundamental. A ação pedagógica de diagnosticar os conhecimentos prévios, do estudante, antes de ensiná-los, tem fundamento na teoria da Aprendizagem Significativa, proposta por David Ausubel. Essa avaliação diagnóstica foi composta por 25 questões, cujas respostas foram analisadas e categorizadas visando sua interpretação, o que permitiu compreender os significados atribuídos pelo estudante a esses conceitos. Conclui-se, a partir da avaliação diagnóstica, que a maioria dos estudantes pesquisados apresentou dificuldades em expor conceitos científicos sobre o tema Terra e Universo ao iniciar a 6ª série. Entretanto, foram identificadas ideias e representações relevantes que contribuíram para a (re)significação dos conceitos científicos propostos

  5. Farmyard Manure and Fertilizer Effects on Seed Potato (Solanum tuberosum L.) Yield in Green House Production

    NASA Astrophysics Data System (ADS)

    László, M.

    2009-04-01

    fertilizer (18.0 g pot-1) with a hard effect (57%). Our results are shown that it was possible developing of the seed potato production under tropical greenhouse conditions by optimalised soil-organic matter-fertilizer system. This datas should be as indicators to sustainable field potato advisory systems. Keywords: potato (Solanum tuberosum L.), greenhouse, latossolo vermelho soil, farmyard manure, burnt rice straw, 4N:14P:8K fertilizer, sustainability, yield Introducáo: Importância e situação actual em produção da batata no Brazíl A batata é atualmente uma das hortaliças de maior importância no Brasíl (Márton 2000a., 2000b.) com um cultivo annual médio de 173.000 ha e uma produção de 2600000 t. A produtividade médio nacional é de 15 t ha-1, muito baixa se considerar que é possivel a obtenção de rendimentos acima de 40 t ha-1. Observa- se também, que existe variação no produtividade entre regiões e estados. E importante como fonte de alimento pelo seu alto valor nutricional a quantidade produzida muito superior por unidade de área a tempo, se comparada com diversas outras culturas (László 2000b., 2000c.). Os estados que tradicionalmente produzem batata em maior ou menor escala são indicados em seguente: Pernambuco, Ceará, Sergipe, Goiás, Mato Grosso, Mato Grosso do Sul, Rondonia e Acre. Os plantios predominantes são o das águas e das secas, sendo o de inverno bem menos expressivo, pois poucas áreas permitem o seu cultivo, na maioria dos casos necessitando- se de irrigação. Considerando as três épocas de plantio e diferentes condições climaticas brasileiras, podemos definir de um modo geral o plantio de batata no Brasíl da seguinte maneira: Nordeste e Centro- Oeste- plantio de inverno, Sudeste- plantio das águas, secas e inverno, Sul- plantio das aguas, secas e inverno. Sendo este último em áreas muito limitadas. Dentre as hortaliças a batata é uma das culturas mais estudadas actualmente. Os principais problemas que afetam a

  6. The Practice of Research of a Basic Education Teacher Involving Mental Models of the Phases of the Moon and Eclipses. (Spanish Title: La Práctica de Investigación de un Maestro de Educación BÁsica con El Uso de los Modelos Mentales de Las Fases de la Luna Y Eclipses.) A Prática de Pesquisa de um Professor do Ensino Fundamental Envolvendo Modelos Mentais de Fases da Lua e Eclipses

    NASA Astrophysics Data System (ADS)

    Pessôa Queiroz, Glória; Jubitipan Borges de Sousa, Carlos; Auxiliadora Delgado Machado, Maria

    2009-12-01

    docente. La formación de grupos interinstitucionales para la planificación de la acción y la investigación ha resultado productiva para el trabajo de construcción de conocimiento de apoyo a los procesos educativos en la escuela, mientras que la universidad enriquece su colección de experiencias validadas, considerando los resultados de la educación inicial y continua de maestros. La participación activa del maestro en un grupo de investigación en la universidad lo llevó a reflexiones sobre los posibles caminos didácticos que pueden ser descriptos, analizados y comunicados a los demás docentes. La construcción de una pedagogía propia, que tuvo en cuenta los modelos mentales de los estudiantes sobre los temas básicos de astronomía, y los cambios desarrollados a partir de las lecciones que enseñó, trajeron consecuencias de largo alcance sobre la pedagogía adoptada por el maestro, que ahora incorpora una nueva visión de la ciencia y formas alternativas al diálogo con los estudiantes, los componentes esenciales para un investigador en Educaciónen Ciencias. A inclusão do professor da escola básica no universo da pesquisa é questão controvertida e em pleno debate no meio acadêmico. A oportunidade de trabalho coletivo que incorporou professores de uma escola municipal no Rio de Janeiro a um grupo de ensino de Física da universidade nos possibilitou vislumbrar a ressignificação da função de um professor de Ciências (co-autor deste trabalho) por ele próprio, agora passando a incluir a pesquisa sobre a construção de conhecimento pelos alunos em sua prática como docente. A formação de grupos interinstitucionais para o planejamento de ações e de pesquisas tem-se mostrado produtiva para um trabalho de construção de conhecimentos a fim de subsidiar processos educativos na escola, ao mesmo tempo em que a universidade enriquece seu acervo de experiências validadas criticamente, podendo considerar seus resultados na formação inicial e

  7. A Proposed Activity for a Meaningful Learning about the Moon Phases. (Breton Title: Uma Proposta de Atividade Para a Aprendizagem Significativa sobre as Fases da Lua.) Una Actividad Propuesta Para EL Aprendizaje Significativo Acerca de Las Fases de la Luna

    NASA Astrophysics Data System (ADS)

    Martins, Bruno Andrade; Langhi, Rodolfo

    2012-12-01

    ínua avaliação durante o processo, culmina com a elaboração de uma história em quadrinhos envolvendo as fases da Lua. Portanto, o objetivo deste trabalho é apresentar uma proposta de atividade didática diferenciada sustentada pelos princípios teóricos da aprendizagem significativa aplicada ao ensino das fases da Lua durante as aulas de Física no ensino médio. En este trabajo se presenta uno de los contenidos de la Astronomía y el evidente fracaso en la enseñanza del tema en la escuela secundaria, a pesar del hecho que los documentos oficiales apuntan para la necesidad de trabajar contenidos de Astronomía en este nivel. Entre los conceptos alternativos en Astronomía que los alumnos secundarios llevan consigo, aún después de terminados los estudios, destacamos aquí el fenómeno de las fases de la Luna. El desarrollo de diferentes estrategias en relación con los métodos tradicionales, dirigidas al proceso de enseñanza-aprendizaje en este tema fue considerado en este trabajo como uno de los resultados obtenidos a la luz de los referenciales del aprendizaje significativo, tal como fueron fundamentados por Ausubel. Según la propuesta que aquí se presenta, la participación activa de los estudiantes en la ejecución de una actividad experimental y otras actividades educativas destinadas a la evaluación continua durante el proceso culminó en la elaboración de una historieta respecto de las fases de la Luna. Por lo tanto, el objetivo de este trabajo es presentar una propuesta de actividad de enseñanza diferenciada con el apoyo de los principios teóricos del aprendizaje significativo aplicado a la enseñanza de las fases de la luna durante las clases de física del ciclo secundario.

  8. Focused Cardiac Ultrasound Using a Pocket-Size Device in the Emergency Room.

    PubMed

    Mancuso, Frederico José Neves; Siqueira, Vicente Nicoliello; Moisés, Valdir Ambrósio; Gois, Aécio Flavio Teixeira; Paola, Angelo Amato Vincenzo de; Carvalho, Antonio Carlos Camargo; Campos, Orlando

    2014-10-28

    direcionada como complemento diagnóstico ao exame físico em um serviço terciário de emergências clínicas. Métodos: Foram incluídos cem pacientes adultos sem doenças cardíacas ou pulmonares conhecidas que procuraram atendimento de urgência com queixas cardiológicas. Foram excluídos pacientes com alterações isquêmicas no eletrocardiograma ou febre. A ecocardiografia direcionada foi realizada logo após a avaliação inicial do paciente na sala de emergência, com aparelho ultraportátil GE Vscan, avaliando subjetivamente: dimensões das cavidades, função sistólica ventricular, fluxos intracardíacos pelo mapeamento de fluxo em cores, pericárdio e aorta. Resultados: A idade média dos pacientes foi 61 ± 17 anos. O quadro clínico inicial foi dor torácica (52 pacientes), dispneia (32 pacientes), arritmia/avaliação da função ventricular (dez pacientes), hipotensão/tontura (cinco pacientes) e edema periférico (um paciente). Em 28 pacientes a ecocardiografia direcionada confirmou a hipótese diagnóstica inicial: 19 pacientes com insuficiência cardíaca, cinco com síndrome coronariana aguda, dois com tromboembolismo pulmonar e dois com tamponamento cardíaco. Em 17 pacientes, a ecocardiografia direcionada alterou o diagnóstico, afastando a hipótese clínica inicial em dez casos com suspeita de insuficiência cardíaca, dois com suspeita de tromboembolismo pulmonar, dois com hipotensão a esclarecer, e em cada um dos três restantes com suspeitas de síndrome coronariana aguda, tamponamento cardíaco e dissecção de aorta. Conclusão: A ecocardiografia direcionada ultraportátil em serviço de emergências clínicas pode definir rapidamente o diagnóstico e, com isso, é possível iniciar mais precocemente o tratamento adequado. PMID:25352461

  9. Mixed-Methods Study that Examines Nine Science Teachers' Perceptions of Slooh Robotic Telescope for Teaching Astronomy. (Breton Title: Métodos Mistos de Estudo que Examinam a Percepção de Nove Professores de Ciências sobre o Telescópio Robótico Slooh Para Ensino de Astronomia.) Métodos Mixtos de Estudio que Examinan la Percepcion de Nueve Profesores de Ciencias sobre EL Telescopio Robótico Slooh Para la Enseñanza de la Astronomía

    NASA Astrophysics Data System (ADS)

    Gershun, Daniel C.; Slater, Timothy F.; Berryhill, Katie J.

    2014-07-01

    Although previous studies show that robotic telescopes have the potential to enhance student learning, there is comparatively little research that focuses on teacher perceptions of this technology. This study investigates: "what is the academic merit of using SLOOH robotic telescopes to teach astronomy as perceived by science teachers?" Our sample consists of nine science teachers of students aged 13-18 years. Pre- and post-tests, interviews, and surveys were collected during two weeks of a summer online course about robotic telescopes. While pre and post-tests do not reveal a statistically significant gain in astronomy content knowledge, analysis of qualitative data reveals five themes which describe the most important aspects of using SLOOH according to participants: "Images," "Interface," "Classroom Application," "Instructor Impact," and "Logistical Issues." Analysis of these themes suggests that SLOOH can provide an interactive and social learning environment with capabilities to incorporate crossdisciplinary themes. Embora estudos anteriores mostram que os telescópios robóticos têm o potencial de melhorar a aprendizagem dos alunos, há relativamente pouca investigação focada nas percepções de professores a respeito desta tecnologia. Este estudo investiga: "qual é o mérito acadêmico da utilização de telescópios robóticos Slooh para ensinar astronomia, tal como percebido pelos professores de ciências?" Nossa amostra é composta por nove professores de ciências de estudantes com idades entre 13-18 anos pré e pós-testes, entrevistas, e levantamentos foram coletados durante duas semanas de um curso on-line de verão sobre telescópios robóticos. Enquanto os testes pré e pós não revelaram um ganho estatisticamente significativo no conhecimento do conteúdo astronomia, a análise de dados qualitativos revela cinco temas que descrevem os aspectos mais importantes da utilização Slooh de acordo aos participantes: "Imagens", "Interface", "Aplica

  10. The Understanding of Astronomy Concepts by Students from Basic Education of a Public School. (Spanish Title: El Entendimiento de Conceptos de Aastronmía Por Los Alumnos de Educación Básica en Una Escuela Pública.) O Entendimento de Conceitos de Astronomia Por Alunos da Educação Básica: O Caso de Uma Escola Pública Brasileira

    NASA Astrophysics Data System (ADS)

    Iria Machado, Daniel; dos Santos, Carlos

    2011-07-01

    movimiento de la Luna, el movimiento aparente del Sol sobre la esfera celeste, los eclipses, las dimensiones y las distancias en el Universo, el brillo de las estrellas y su observación de la Tierra. Si bien ha habido un pequeño progreso en la proporción de respuestas aceptables científicamente cuando se cotejó el octavo grado de la enseñanza primaria con el quinto, y el último año de la enseñanza secundaria con el primero, se observó un predominio de las concepciones alternativas en relación a la mayoría de los temas explorados, que continuó hasta los últimos años de la educación básica. Una comparación con los datos encontrados en investigaciones realizadas en otros contextos socioculturales revelaron, en muchos aspectos, conceptos y dificultades similares expresadas por los estudiantes. Apresentam-se os resultados de uma investigação sobre a compreensão de conceitos astronômicos básicos, da qual participaram 561 estudantes da quinta série do Ensino Fundamental ao terceiro ano do Ensino Médio de uma escola pública da cidade de Foz do Iguaçu. Um teste com 20 questões de múltipla escolha foi aplicado para identificar as concepções mais comuns expressadas pelos alunos. Esse instrumento de coleta de dados foi elaborado com base na literatura sobre concepções alternativas e abordou os seguintes temas: o ciclo dia-noite; os fusos horários; as estações do ano; as fases da Lua; o movimento da Lua; o movimento aparente do Sol na esfera celeste; os eclipses; as dimensões e distâncias no Universo; o brilho das estrelas e sua observação da Terra. Embora se tenha verificado um pequeno progresso na proporção de respostas cientificamente aceitáveis ao se cotejar a oitava série do Ensino Fundamental com a quinta, e a terceira série do Ensino Médio com a primeira, houve o predomínio de concepções alternativas em relação à maior parte dos temas explorados, as quais persistiram até o último ano da Educação Básica. A comparação com