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Sample records for donepezil reverses buprenorphine-induced

  1. Naloxone reversal of buprenorphine-induced respiratory depression.

    PubMed

    van Dorp, Eveline; Yassen, Ashraf; Sarton, Elise; Romberg, Raymonda; Olofsen, Erik; Teppema, Luc; Danhof, Meindert; Dahan, Albert

    2006-07-01

    The objective of this investigation was to examine the ability of the opioid antagonist naloxone to reverse respiratory depression produced by the mu-opioid analgesic, buprenorphine, in healthy volunteers. The studies were designed in light of the claims that buprenorphine is relatively resistant to the effects of naloxone. In a first attempt, the effect of an intravenous bolus dose of 0.8 mg naloxone was assessed on 0.2 mg buprenorphine-induced respiratory depression. Next, the effect of increasing naloxone doses (0.5-7 mg, given over 30 min) on 0.2 mg buprenorphine-induced respiratory depression was tested. Subsequently, continuous naloxone infusions were applied to reverse respiratory depression from 0.2 and 0.4 mg buprenorphine. All doses are per 70 kg. Respiration was measured against a background of constant increased end-tidal carbon dioxide concentration. An intravenous naloxone dose of 0.8 mg had no effect on respiratory depression from buprenorphine. Increasing doses of naloxone given over 30 min produced full reversal of buprenorphine effect in the dose range of 2-4 mg naloxone. Further increasing the naloxone dose (doses of 5 mg or greater) caused a decline in reversal activity. Naloxone bolus doses of 2-3 mg, followed by a continuous infusion of 4 mg/h, caused full reversal within 40-60 min of both 0.2 and 0.4 mg buprenorphine-induced respiratory depression. Reversal of buprenorphine effect is possible but depends on the buprenorphine dose and the correct naloxone dose window. Because respiratory depression from buprenorphine may outlast the effects of naloxone boluses or short infusions, a continuous infusion of naloxone may be required to maintain reversal of respiratory depression.

  2. Donepezil

    MedlinePlus

    Namzaric®(as a combination product containing Donepezil, Memantine) ... Donepezil is used to treat dementia (a brain disorder that affects the ability to remember, think clearly, communicate, and perform daily activities and may cause changes in mood and ...

  3. Effect of donepezil on reversal learning in a touch screen-based operant task.

    PubMed

    Chen, Woei-Shin; Wong, Fong-Kuan; Chapman, Paul F; Pemberton, Darrel J

    2009-10-01

    Impairments in reversal learning, which are commonly observed in patients with psychiatric disorders, remain difficult to treat. There is still a debate over the beneficial effects of cholinergic enhancers on improving behavioural flexibility. The objective of this study was to investigate the effect of an acetylcholinesterase inhibitor, donepezil, on the performance of a rodent Probabilistic Reversal Learning task. Lister-Hooded rats were trained to retrieve food rewards by discriminating two computer-generated stimuli in an automated touch screen-based operant task. When a steady performance was achieved, the stimulus-reward rule was reversed. Each rat was given a 30-min training session daily for 24 days and donepezil was administered 30 min before each training session. Systemic treatment with donepezil had no effect on trial accuracy of the two-stimulus discrimination training. However, the donepezil group showed enhanced performance in the reversal learning. Our result showed that treatment with donepezil significantly enhanced Probabilistic Reversal Learning performance in healthy animals. On the basis of this finding, the inhibition of the central acetylcholinesterase would seem to be a potential therapeutic approach to treat behavioural inflexibility.

  4. Donepezil reverses nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6J mice.

    PubMed

    Poole, Rachel L; Connor, David A; Gould, Thomas J

    2014-10-01

    Withdrawal from chronic nicotine is associated with cognitive deficits. Therapies that ameliorate cognitive deficits during withdrawal aid in preventing relapse during quit attempts. Withdrawal-induced deficits in contextual learning are associated with nicotinic acetylcholine receptor upregulation. The aim of the present study was to determine if the acetylcholinesterase inhibitor donepezil has the ability to reverse nicotine withdrawal-induced deficits in contextual learning. Results demonstrated that low doses of donepezil, which do not enhance contextual learning or alter locomotor activity/anxiety-related behavior, can reverse nicotine withdrawal-induced deficits in contextual learning. Thus, donepezil may have therapeutic value for ameliorating cognitive deficits associated with nicotine withdrawal and for preventing relapse.

  5. Scopolamine-induced deficits in social memory in mice: reversal by donepezil.

    PubMed

    Riedel, G; Kang, S H; Choi, D Y; Platt, B

    2009-12-01

    Deficits in social behaviour is a characteristic of numerous mental disorders including autism, schizophrenia, depression and Alzheimer's disease. For the assessment of pharmacological and genetic experimental disease models, conventional social interaction tasks bear the uncertainty that any drug-induced abnormality of the investigator may feed back to the drug-free companion modifying its reactions. A considerable technical improvement was recently reported by Moy et al. [Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson T, et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behaviours in mice. Genes Brain Behav 2004;3:287-302] in which the drug free partner is confined to a small cage and social contacts of the investigator are recorded uncontaminated of any social reactions of the stranger. Using this novel behavioural paradigm, we here show in C57Bl/6 female mice that sociability (social interaction with a stranger mouse) is not impaired after administration of the anxiolytic diazepam (0.1-1 mg/kg) or the muscarinic antagonist scopolamine hydrobromide (0.1-1 mg/kg). However, social memory tested after a short time interval was impaired by both drugs in a dose-dependent manner (diazepam: > or = 0.5mg/kg; scopolamine: > or = 0.3mg/kg). The scopolamine-induced short-term memory deficit was reversed to normal by the choline esterase inhibitor donepezil (1 mg/kg). Given this dependence of social recognition on the cholinergic system, combined with the clinical observation of reduced social contacts in dementia patients, sociability may offer a novel endpoint biomarker with translational value in experimental models of cognitive dysfunction.

  6. Early postnatal maternal deprivation in rats induces memory deficits in adult life that can be reversed by donepezil and galantamine.

    PubMed

    Benetti, Fernando; Mello, Pâmela Billig; Bonini, Juliana Sartori; Monteiro, Siomara; Cammarota, Martín; Izquierdo, Iván

    2009-02-01

    Early postnatal maternal deprivation is known to cause long-lasting neurobiological effects. Here, we investigated whether some of the cognitive aspects of these deficits might be related to a disruption of the cholinergic system. Pregnant Wistar rats were individually housed and maintained on a 12:12h light/dark cycle with food and water freely available. The mothers were separated from their pups for 3h per day from postnatal day 1 (PND-1) to PND-10. To do that, the dams were moved to a different cage and the pups maintained in the original home cage, which was transferred to a different room kept at 32 degrees C. After they reached 120-150 days of age, maternal-deprived and non-deprived animals were either sacrificed for brain acetylcholinesterase measurement, or trained and tested in an object recognition task and in a social recognition task as described by Rossato et al. (2007) [Rossato, J.I., Bevilaqua, L. R.M., Myskiw, J.C., Medina, J.H., Izquierdo, I., Cammarota, M. 2007. On the role hippocampal synthesis in the consolidation and reconsolidation of object recognition memory. Learn. Mem. 14, 36-46] and Lévy et al. (2003) [Lévy, F., Melo. A.I., Galef. B.G. Jr., Madden, M., Fleming. A.S. 2003. Complete maternal deprivation affects social, but not spatial, learning in adult rats. Dev. Psychobiol. 43, 177-191], respectively. There was increased acetylcholinesterase activity in hippocampus and perirhinal cortex of the deprived animals. In addition, they showed a clear impairment in memory of the two recognition tasks measured 24h after training. Oral administration of the acetylcholinesterase inhibitors, donepezil or galantamine (1mg/kg) 30min before training reversed the memory impairments caused by maternal deprivation. The findings suggest that maternal deprivation affects memory processing at adulthood through a change in brain cholinergic systems.

  7. Reversible and persistent decreases in cocaine self-administration after cholinesterase inhibition: different effects of donepezil and rivastigmine.

    PubMed

    Grasing, Kenneth; Yang, Yungao; He, Shuangteng

    2011-02-01

    We recently observed that pretreatment with the cholinesterase inhibitor, tacrine can produce long-lasting reductions in cocaine-reinforced behavior, described as persistent attenuation. In addition to inhibiting both acetylcholinesterase (AChE) and butyrylcholinesterase, tacrine can potentiate actions of dopamine. This study was carried out to evaluate the effects of donepezil (which selectively inhibits AChE) and rivastigmine (which inhibits both AChE and butyrylcholinesterase) on cocaine self-administration. High self-administration rats self-administered different doses of cocaine under a fixed ratio-5 schedule. Over a 4-day period, vehicle, donepezil, or rivastigmine was infused as animals were maintained in home cages (21 h per day), with signs of cholinergic stimulation (fasciculation, vacuous jaw movements, yawning, and diarrhea) scored by a blinded observer. Both compounds dose-dependently decreased cocaine self-administration, but differed in the potency and temporal pattern of their effects. Self-administration of low-dose cocaine was decreased to a greater degree by rivastigmine than donepezil (50% effective doses of 2.33 and 6.21 mg/kg/day, respectively), but this early effect did not continue beyond sessions immediately after treatment with rivastigmine. Group means for cocaine self-administration were decreased at some time points occurring between 1 and 3 days after the treatment with 10 mg/kg/day of donepezil (late effects), with decreases of more than 80% observed in some individual rats that persisted for 1 week or longer. Early, but not late, effects were correlated with signs of cholinergic stimulation. In summary, pretreatment with donepezil, but not rivastigmine produced persistent reductions in cocaine-reinforced behavior, which were not associated with signs of cholinergic stimulation.

  8. A new HPLC method to determine Donepezil hydrochloride in tablets.

    PubMed

    Pappa, Horacio; Farrú, Romina; Vilanova, Paula Otaño; Palacios, Marcelo; Pizzorno, María Teresa

    2002-01-01

    A HPLC stability-indicating assay for Donepezil hydrochloride in tablets was developed and validated. Donepezil hydrochloride is a reversible inhibitor of acetylcholinesterase, indicated for the treatment of mild to moderate dementia of the Alzheimer's type. The HPLC method was performed with a reversed phase C18 column, detection at 268 nm and a mixture of methanol, phosphate buffer 0.02 M and triethylamine (50:50:0.5) as mobile phase. Typical retention time for Donepezil was 9 min. The method was statistically validated for linearity, accuracy, precision and selectivity following ICH recommendations. Due to its simplicity and accuracy, the method can be used for routine quality control analysis.

  9. Hippocampal P3-like auditory event-related potentials are disrupted in a rat model of cholinergic degeneration in Alzheimer's disease: reversal by donepezil treatment.

    PubMed

    Laursen, Bettina; Mørk, Arne; Kristiansen, Uffe; Bastlund, Jesper Frank

    2014-01-01

    P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 μg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP-treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup.

  10. Donepezil treatment and the subjective effects of intravenous cocaine in dependent individuals.

    PubMed

    Grasing, Kenneth; Mathur, Deepan; Newton, Thomas F; DeSouza, Cherilyn

    2010-02-01

    Acetylcholinesterase (AChE) inhibitors increase synaptic levels of acetylcholine (ACh) by inhibiting its breakdown. Donepezil is a reversible AChE inhibitor that is clinically available and relatively selective for inhibiting AChE but not other cholinesterases. Because AChE inhibitors have been shown to decrease the reinforcing effects of cocaine in animals, our hypothesis was that pretreatment with donepezil would attenuate the perceived value and other positive subjective effects of cocaine. We conducted a within-subject, double-blind, placebo-controlled, laboratory-based evaluation of the subjective effects produced by intravenous cocaine in human subjects receiving oral donepezil. Following three days of daily treatment with 5mg of donepezil or oral placebo, participants received intravenous placebo or cocaine (0.18 and 0.36 mg/kg). After a three-day washout period, participants were crossed over to the opposite oral treatment, which was followed by identical intravenous infusions. Donepezil was well-tolerated with only two drug-related adverse events reported that were mild and self-limiting. Treatment with donepezil increased ratings of 'any' and 'good' drug effect produced by low-dose cocaine, without modifying the response to high-dose cocaine. When collapsed across intravenous dose, treatment with donepezil decreased dysphoric effects and somatic symptoms, but did not modify the value of cocaine injections as determined by the Multiple Choice Questionnaire (MCQ). In summary, pretreatment with donepezil potentiated some measures for nonspecific and positive effects of low-dose cocaine. Across all intravenous treatments, participants receiving donepezil reported fewer somatic-dysphoric effects. Neither of these actions support the value of donepezil as a treatment for cocaine dependence.

  11. Inhibitory effects of cholinesterase inhibitor donepezil on the Kv1.5 potassium channel

    PubMed Central

    Li, Kai; Cheng, Neng; Li, Xian-Tao

    2017-01-01

    Kv1.5 channels carry ultra-rapid delayed rectifier K+ currents in excitable cells, including neurons and cardiac myocytes. In the current study, the effects of cholinesterase inhibitor donepezil on cloned Kv1.5 channels expressed in HEK29 cells were explored using whole-cell recording technique. Exposure to donepezil resulted in a rapid and reversible block of Kv1.5 currents, with an IC50 value of 72.5 μM. The mutant R476V significantly reduced the binding affinity of donepezil to Kv1.5 channels, showing the target site in the outer mouth region. Donepezil produced a significant delay in the duration of activation and deactivation, and mutant R476V potentiated these effects without altering activation curves. In response to slowed deactivation time course, a typical crossover of Kv1.5 tail currents was clearly evident after bath application of donepezil. In addition, both this chemical and mutant R476V accelerated current decay during channel inactivation in a voltage-dependent way, but barely changed the inactivation and recovery curves. The presence of donepezil exhibited the use-dependent block of Kv1.5 currents in response to a series of depolarizing pulses. Our data indicate that donepezil can directly block Kv1.5 channels in its open and closed states. PMID:28198801

  12. Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors.

    PubMed

    Lutfy, Kabirullah; Eitan, Shoshana; Bryant, Camron D; Yang, Yu C; Saliminejad, Nazli; Walwyn, Wendy; Kieffer, Brigitte L; Takeshima, Hiroshi; Carroll, F Ivy; Maidment, Nigel T; Evans, Christopher J

    2003-11-12

    Buprenorphine is a mixed opioid receptor agonist-antagonist used clinically for maintenance therapy in opiate addicts and pain management. Dose-response curves for buprenorphine-induced antinociception display ceiling effects or are bell shaped, which have been attributed to the partial agonist activity of buprenorphine at opioid receptors. Recently, buprenorphine has been shown to activate opioid receptor-like (ORL-1) receptors, also known as OP4 receptors. Here we demonstrate that buprenorphine, but not morphine, activates mitogen-activated protein kinase and Akt via ORL-1 receptors. Because the ORL-1 receptor agonist orphanin FQ/nociceptin blocks opioid-induced antinociception, we tested the hypothesis that buprenorphine-induced antinociception might be compromised by concomitant activation of ORL-1 receptors. In support of this hypothesis, the antinociceptive effect of buprenorphine, but not morphine, was markedly enhanced in mice lacking ORL-1 receptors using the tail-flick assay. Additional support for a modulatory role for ORL-1 receptors in buprenorphine-induced antinociception was that coadministration of J-113397, an ORL-1 receptor antagonist, enhanced the antinociceptive efficacy of buprenorphine in wild-type mice but not in mice lacking ORL-1 receptors. The ORL-1 antagonist also eliminated the bell-shaped dose-response curve for buprenorphine-induced antinociception in wild-type mice. Although buprenorphine has been shown to interact with multiple opioid receptors, mice lacking micro-opioid receptors failed to exhibit antinociception after buprenorphine administration. Our results indicate that the antinociceptive effect of buprenorphine in mice is micro-opioid receptor-mediated yet severely compromised by concomitant activation of ORL-1 receptors.

  13. Treatment with Sildenafil and Donepezil Improves Angiogenesis in Experimentally Induced Critical Limb Ischemia

    PubMed Central

    Constantinescu, Ioana M.; Bolfa, Pompei; Mironiuc, Aurel I.

    2017-01-01

    Objectives. In this study, we aimed to demonstrate the role of sildenafil (an antagonist of phosphodiesterase type 5 (PDE-5)) and donepezil (a specific and reversible inhibitor of acetylcholinesterase (Ach)) in increasing ischemia-induced angiogenesis. Method. Critical limb ischemia was induced by ligation of the common femoral artery followed by ligation of the common iliac artery. The operated animals were divided into 3 groups: receiving sildenafil, receiving donepezil, and surgery alone; the contralateral lower limb was used as a negative control. The results were controlled based on clinical score and Doppler ultrasound. Gastrocnemius muscle samples were taken from all animals, both from the ischemic and nonischemic limb and were used for histopathological and immunohistochemical examination for the evaluation of the number of nuclei/field, endothelial cells (CD31), dividing cells (Ki-67), and vascular endothelial growth factor (VEGFR-3). Results. An increasing tendency of the number of nuclei/field with time was observed both in the case of sildenafil and donepezil treatment. The formation of new capillaries (the angiogenesis process) was more strongly influenced by donepezil treatment compared to sildenafil or no treatment. This treatment significantly influenced the capillary/fiber ratio, which was increased compared to untreated ligated animals. Sildenafil treatment led to a gradual increase in the number of dividing cells, which was significantly compared to the negative control group and compared to the ligation control group. The same effect (increase in the number of Ki-67 positive cells) was more obvious in the case of donepezil treatment. Conclusion. Donepezil treatment has a better effect in ligation-induced ischemia compared to sildenafil, promoting angiogenesis in the first place, and also arteriogenesis. PMID:28243607

  14. Donepezil in Alzheimer’s disease: From conventional trials to pharmacogenetics

    PubMed Central

    Cacabelos, Ramón

    2007-01-01

    Donepezil is the leading compound for the treatment of Alzheimer’s disease (AD) in more than 50 countries. As compared with other conventional acetylcholinesterase inhibitors (AChEIs), donepezil is a highly selective and reversible piperidine derivative with AChEI activity that exhibits the best pharmacological profile in terms of cognitive improvement, responders rate (40%–58%), dropout cases (5%–13%), and side-effects (6%–13%) in AD. Although donepezil represents a non cost-effective treatment, most studies convey that this drug can provide a modest benefit on cognition, behavior, and activities of the daily living in both moderate and severe AD, contributing to slow down disease progression and, to a lesser exetnt, to delay institutionalization. Patients with vascular dementia might also benefit from donepezil in a similar fashion to AD patients. Some potential effects of donepezil on the AD brain, leading to reduced cortico-hippocampal atrophy, include the following: AChE inhibition, enhancement of cholinergic neurotransmission and putative modulation of other neurotransmitter systems, protection against glutamate-induced excitotoxicity, activation of neurotrophic mechanisms, promotion of non-amyloidodgenic pathways for APP processing, and indirect effects on cerebrovascular function improving brain perfusion. Recent studies demonstrate that the therapeutic response in AD is genotype-specific. Donepezil is metabolized via CYP-related enzymes, especially CYP2D6, CYP3A4, and CYP1A2. Approximately, 15%–20% of the AD population may exhibit an abnormal metabolism of AChEIs; about 50% of this population cluster would show an ultrarapid metabolism, requiring higher doses of AChEIs to reach a therapeutic threshold, whereas the other 50% of the cluster would exhibit a poor metabolism, displaying potential adverse events at low doses. In AD patients treated with a multifactorial therapy, including donepezil, the best responders are the CYP2D6-related extensive

  15. The combination of donepezil and procyclidine protects against soman-induced seizures in rats

    SciTech Connect

    Haug, Kristin Huse . E-mail: k.h.haug@medisin.uio.no; Myhrer, Trond; Fonnum, Frode

    2007-04-15

    Current treatment of nerve agent poisoning consists of prophylactic administration of pyridostigmine and therapy using atropine, an oxime and a benzodiazepine. Pyridostigmine does however not readily penetrate the blood-brain barrier giving ineffective protection of Brain against centrally mediated seizure activity. In this study, we have evaluated donepezil hydrochloride, a partial reversible inhibitor of acetylcholinesterase (AChE) clinically used for treating Alzheimer's disease, in combination with procyclidine, used in treatment of Parkinson's disease and schizophrenia, as prophylaxis against intoxication by the nerve agent soman. The results demonstrated significant protective efficacy of donepezil (2.5 mg/kg) combined with procyclidine (3 or 6 mg/kg) when given prophylactically against a lethal dose of soman (1.6x LD{sub 50}) in Wistar rats. No neuropathological changes were found in rats treated with this combination 48 h after soman intoxication. Six hours after soman exposure cerebral AChE activity and acetylcholine (ACh) concentration was 5% and 188% of control, respectively. The ACh concentration had returned to basal levels 24 h after soman intoxication, while AChE activity had recovered to 20% of control. Loss of functioning muscarinic ACh receptors (17%) but not nicotinic receptors was evident at this time point. The recovery in brain AChE activity seen in our study may be due to the reversible binding of donepezil to the enzyme. Donepezil is well tolerated in humans, and a combination of donepezil and procyclidine may prove useful as an alternative to the currently used prophylaxis against nerve agent intoxication.

  16. How many patients complete an adequate trial of donepezil?

    PubMed

    Roe, Catherine M; Anderson, Michael J; Spivack, Barney

    2002-01-01

    Pharmacy claims data were used to evaluate medication adherence among 59 new users of donepezil aged 65 to 94 years. The probability (+/- 95% confidence interval) of a new user continuing donepezil at 90 days was.797 +/-.103 and at 180 days was.627 +/-.124. Additionally, 13.9% of those who continued therapy for at least 180 days showed gaps in treatment of six weeks or more. These results suggest that adherence with donepezil could be improved in clinical practice.

  17. Differential effects of donepezil on methamphetamine and cocaine dependencies.

    PubMed

    Takamatsu, Yukio; Yamanishi, Yoshiharu; Hagino, Yoko; Yamamoto, Hideko; Ikeda, Kazutaka

    2006-08-01

    Donepezil, a choline esterase inhibitor, has been widely used as a medicine for Alzheimer's disease. Recently, a study showed that donepezil inhibited addictive behaviors induced by cocaine, including cocaine-conditioned place preference (CPP) and locomotor sensitization to cocaine. In the present study, we investigated the effects of donepezil on methamphetamine (METH)-induced behavioral changes in mice. In counterbalanced CPP tests, the intraperitoneal (i.p.) administration of 3 mg/kg donepezil prior to 2 mg/kg METH i.p. failed to inhibit METH CPP, whereas pretreatment with 3 mg/kg donepezil abolished the CPP for cocaine (10 mg/kg, i.p.). Similarly, in locomotor sensitization experiments, i.p. administration of 1 mg/kg donepezil prior to 2 mg/kg METH i.p. failed to inhibit locomotor sensitivity to METH, whereas pretreatment with 1 mg/kg donepezil significantly inhibited locomotor sensitivity to cocaine (10 mg/kg, i.p.). These results suggest that donepezil may be a useful tool for treating cocaine dependence but not for treating METH dependence. The differences in the donepezil effects on addictive behaviors induced by METH and cocaine might be due to differences in the involvement of acetylcholine in the mechanisms of METH and cocaine dependencies.

  18. Effects of Donepezil on Cognitive Functioning in Down Syndrome.

    ERIC Educational Resources Information Center

    Johnson, N.; Fahey, C.; Chicoine, B.; Chong, G.; Gitelman, D.

    2003-01-01

    Donepezil, an acetycholinesterase inhibitor, or a placebo were given to 29 subjects with Down syndrome and no dementia. Measures of cognitive functioning and caregiver ratings indicated no improvement in any cognitive subtests (with the exception of language), behavioral scores, or caregiver ratings. Results suggest donepezil may improve language…

  19. Dietary and donepezil modulation of mTOR signaling and neuroinflammation in the brain

    PubMed Central

    Dasuri, Kalavathi; Zhang, Le; Kim, Sun OK Fernandez; Bruce-Keller, Annadora J.; Keller, Jeffrey N.

    2016-01-01

    Recent clinical and laboratory evidences suggest that high fat diet (HFD) induced obesity and its associated metabolic syndrome conditions promotes neuropathology in aging and age-related neurological disorders. However, the effects of high fat diet on brain pathology are poorly understood, and the effective strategies to overcome these effects remain elusive. In the current study, we examined the effects of HFD on brain pathology and further evaluated whether donepezil, an AChE inhibitor with neuroprotective functions, could suppress the ongoing HFD induced pathological changes in the brain. Our data demonstrates that HFD induced obesity results in increased neuroinflammation and increased AChE activity in the brain when compared with the mice fed on low fat diet (LFD). HFD administration to mice activated mTOR pathway resulting in increased phosphorylation of mTORser2448, AKTthr308 and S6K proteins involved in the signaling. Interestingly, donepezil administration with HFD suppressed HFD induced increases in AChE activity, and partially reversed HFD effects on microglial reactivity and the levels of mTOR signaling proteins in the brain when compared to the mice on LFD alone. However, gross levels of synaptic proteins were not altered in the brain tissues of mice fed either diet with or without donepezil. In conclusion, these results present a new insight in to the detrimental effects of HFD on brain via microglial activation and involvement of mTOR pathway, and further demonstrates the possible therapeutic role for donepezil in ameliorating the early effects of HFD that could help preserve the brain function in metabolic syndrome conditions. PMID:26554604

  20. The Anti-dementia Effects of Donepezil Involve miR-206-3p in the Hippocampus and Cortex.

    PubMed

    Wang, Cheng-Niu; Wang, Ying-Jie; Wang, Hao; Song, Lu; Chen, Yu; Wang, Jin-Liang; Ye, Ying; Jiang, Bo

    2017-04-01

    Alzheimer's disease (AD) is a most serious age-related neurodegenerative disorder accompanied with significant memory impairments in this world. Recently, microRNAs (miRNAs) have been reported to be invlolved in the pathophysiology of AD. Previous studies have shown that miRNA-206 (miR-206) is implicated in the pathogenesis of AD via suppressing the expression of brain-derived neurotrophic factor (BDNF) in the brain. Here, we examined the miR-206-3p and miR-206-5p expression in the hippocampus and cortex of Abeta precursor protein (APP)/presenilin-1 (PS1) transgenic mice treated with donepezil, a drug approved for treating AD in clinic. We found that the expression of miR-206-3p was significantly up-regulated in the hippocampus and cortex of APP/PS1 mice, while donepezil administration significantly reversed this dysfunction. In addition, enhancing the miR-206-3p level by the usage of AgomiR-206-3p significantly attenuated the anti-dementia effects of donepezil in APP/PS1 mice. Together, these results suggested that miR-206-3p is involved in the anti-dementia effects of donepezil, and could be a novel pharmacological target for treating AD.

  1. Donepezil regulates energy metabolism and favors bone mass accrual.

    PubMed

    Eimar, Hazem; Alebrahim, Sharifa; Manickam, Garthiga; Al-Subaie, Ahmed; Abu-Nada, Lina; Murshed, Monzur; Tamimi, Faleh

    2016-03-01

    The autonomous nervous system regulates bone mass through the sympathetic and parasympathetic arms. The sympathetic nervous system (SNS) favors bone loss whereas the parasympathetic nervous system (PNS) promotes bone mass accrual. Donepezil, a central-acting cholinergic agonist, has been shown to down-regulate SNS and up-regulate PNS signaling tones. Accordingly, we hypothesize that the use of donepezil could have beneficial effects in regulating bone mass. To test our hypothesis, two groups of healthy female mice were treated either with donepezil or saline. Differences in body metabolism and bone mass of the treated groups were compared. Body and visceral fat weights as well as serum leptin level were increased in donepezil-treated mice compared to control, suggesting that donepezil effects on SNS influenced metabolic activity. Donepezil-treated mice had better bone quality than controls due to a decrease in osteoclasts number. These results indicate that donepezil is able to affect whole body energy metabolism and favors bone mass in young female WT mice.

  2. Donepezil treatment in ethnically diverse patients with Alzheimer disease.

    PubMed

    Tinklenberg, Jared R; Kraemer, Helena C; Yaffe, Kristine; O'Hara, Ruth; Ringman, John M; Ashford, John W; Yesavage, Jerome A; Taylor, Joy L

    2015-04-01

    To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil. Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self-identified their ethnicity. The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data. Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients. Published by Elsevier Inc.

  3. Diverse age-related effects of Bacopa monnieri and donepezil in vitro on cytokine production, antioxidant enzyme activities, and intracellular targets in splenocytes of F344 male rats.

    PubMed

    Priyanka, Hannah P; Singh, Ran Vijay; Mishra, Miti; ThyagaRajan, Srinivasan

    2013-02-01

    Aged people are more prone to developing neurodegenerative and infectious diseases, autoimmune disorders, and cancer due to impairment of neuroendocrine-immune functions. Neuronal degeneration and immunosuppression aided by increased generation of reactive oxygen species combined with loss of antioxidant enzyme activities promote the aging process. Bacopa monnieri (brahmi), an Ayurvedic herb, and donepezil, a reversible acetylcholinesterase inhibitor, have been used to reverse cognitive dysfunctions in several neurodegenerative diseases. The aim of this study was to investigate the effects of in vitro incubation of lymphocytes from spleens of young (3-month-old), early middle-aged (8- to 9-month-old), and old (18-month-old) F344 rats with brahmi (0.001%, 0.01%, 0.05%, 0.1%, and 1%) and donepezil (5, 10, 25, 50, and 100 μg/ml) on Concanavalin (Con A)-induced proliferation of T lymphocytes and cytokine production, and the activities of antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST)]. In addition, the effects of these compounds on the expression of intracellular signaling pathway markers (ERK, p-ERK, CREB, p-CREB, Akt and p-Akt), nitric oxide (NO) production, and the extent of lipid peroxidation were measured in the splenocytes. Age-related decline in Con A-induced proliferation of T lymphocytes was not reversed by treatment with brahmi and donepezil but donepezil alone further reduced the lymphocyte proliferation in young rats. Lower doses of brahmi treatment reversed the age-related decrease in Con A-induced IL-2 and IFN-γ production by the splenocytes while their production by splenocytes was suppressed by treatment with donepezil in the young and early middle-aged rats. An age-associated decline in the activities of SOD, CAT, GPx, and GST was evident in the lymphocytes of spleen. Brahmi enhanced CAT activity of lymphocytes in all the age groups while donepezil increased SOD

  4. Controlled release of donepezil intercalated in smectite clays.

    PubMed

    Park, Jin Kuen; Choy, Young Bin; Oh, Jae-Min; Kim, Ju Young; Hwang, Seong-Ju; Choy, Jin-Ho

    2008-07-09

    The inorganic-organic hybrid for a drug delivery system was successfully realized by intercalating donepezil molecules into smectite clays (laponite XLG, saponite, and montmorillonite). According to the powder XRD patterns, TG profiles, and FT-IR spectra, it was confirmed that donepezil molecules were well stabilized in the interlayer space of clay via mono or double layer stacking. The adsorption amount and molecular structure of donepezil appeared to depend on the cation exchange capacity of the clay, which in turn, tailored the drug release patterns. Especially in the presence of a bulky cationic polymer (Eudragit E-100) in the release media, the release rate was found to be improved due to its effective replacement with intercalated donepezil molecules. Therefore, to formulate a complete drug delivery system, the hybrids were coated with Eudragit E-100 using a spray dryer, which also showed great enhancement in the release rate during a short period of time (180min).

  5. Increased libido associated with donepezil treatment: a case report.

    PubMed

    Segrec, Nusa; Zaman, Rashid; Pregelj, Peter

    2016-01-01

    Inappropriate verbal and physical sexual behaviour is not common among individuals with dementia, but when it does occur, it can have profound consequences. We report a case of 79-year-old woman with dementia of the Alzheimer's type who complained of increased libido after an increased dose of donepezil, which was being used along with tianeptine. Donepezil withdrawal led to the resolution of increased libido, but when it was reintroduced, increased libido reappeared once again (Naranjo score: 7). Increased libido was not reported by the patient during the 6-year follow-up period after donepezil withdrawal. A potential mechanism of acetylcholinesterase inhibitor-induced increased libido and the current literature on hypersexuality as a side-effect of donepezil treatment are discussed.

  6. Cholinesterase inhibitors, donepezil and rivastigmine, attenuate spatial memory and cognitive flexibility impairment induced by acute ethanol in the Barnes maze task in rats.

    PubMed

    Gawel, Kinga; Labuz, Krzysztof; Gibula-Bruzda, Ewa; Jenda, Malgorzata; Marszalek-Grabska, Marta; Filarowska, Joanna; Silberring, Jerzy; Kotlinska, Jolanta H

    2016-10-01

    Central cholinergic dysfunction contributes to acute spatial memory deficits produced by ethanol administration. Donepezil and rivastigmine elevate acetylcholine levels in the synaptic cleft through the inhibition of cholinesterases-enzymes involved in acetylcholine degradation. The aim of our study was to reveal whether donepezil (acetylcholinesterase inhibitor) and rivastigmine (also butyrylcholinesterase inhibitor) attenuate spatial memory impairment as induced by acute ethanol administration in the Barnes maze task (primary latency and number of errors in finding the escape box) in rats. Additionally, we compared the influence of these drugs on ethanol-disturbed memory. In the first experiment, the dose of ethanol (1.75 g/kg, i.p.) was selected that impaired spatial memory, but did not induce motor impairment. Next, we studied the influence of donepezil (1 and 3 mg/kg, i.p.), as well as rivastigmine (0.5 and 1 mg/kg, i.p.), given either before the probe trial or the reversal learning on ethanol-induced memory impairment. Our study demonstrated that these drugs, when given before the probe trial, were equally effective in attenuating ethanol-induced impairment in both test situations, whereas rivastigmine, at both doses (0.5 and 1 mg/kg, i.p.), and donepezil only at a higher dose (3 mg/kg, i.p.) given prior the reversal learning, attenuated the ethanol-induced impairment in cognitive flexibility. Thus, rivastigmine appears to exert more beneficial effect than donepezil in reversing ethanol-induced cognitive impairments-probably due to its wider spectrum of activity. In conclusion, the ethanol-induced spatial memory impairment may be attenuated by pharmacological manipulation of central cholinergic neurotransmission.

  7. Memantine ER/Donepezil: A Review in Alzheimer's Disease.

    PubMed

    Greig, Sarah L

    2015-11-01

    A once-daily, fixed-dose combination of memantine extended-release (ER)/donepezil 28/10 mg (Namzaric™) is available in the USA for patients with moderate to severe Alzheimer's disease (AD) on stable memantine and donepezil therapy. The fixed-dose formulation is bioequivalent to coadministration of the individual drugs. In a 24-week, phase III trial in patients with moderate to severe AD, addition of memantine ER 28 mg once daily to stable cholinesterase inhibitor (ChEI) therapy was more effective than add-on placebo on measures of cognition, global clinical status, dementia behaviour and semantic processing ability, although between-group differences on a measure of daily function did not significantly differ. In subgroup analyses in donepezil-treated patients, add-on memantine ER was more effective than add-on placebo on measures of cognition, dementia behaviour and semantic processing, although there were no significant between-group differences on measures of global clinical status and daily function. Memantine ER plus ChEI combination therapy was generally well tolerated in the phase III trial, with diarrhoea, dizziness and influenza occurring at least twice as often with add-on memantine ER as add-on placebo in donepezil-treated patients. Thus, memantine ER plus donepezil combination therapy is an effective and well tolerated treatment option for patients with moderate to severe AD. The fixed-dose combination is potentially more convenient than coadministration of the individual agents.

  8. Influences of donepezil on cardiovascular system--possible therapeutic benefits for heart failure--donepezil cardiac test registry (DOCTER) study.

    PubMed

    Kubo, Toru; Sato, Takayuki; Noguchi, Tatsuya; Kitaoka, Hiroaki; Yamasaki, Fumiyasu; Kamimura, Naoto; Shimodera, Shinji; Iiyama, Tatsuo; Kumagai, Naoko; Kakinuma, Yoshihiko; Diedrich, André; Jordan, Jens; Robertson, David; Doi, Yoshinori L

    2012-09-01

    To study prospectively influences of donepezil, an acetylcholinesterase inhibitor against Alzheimer disease, on cardiovascular system, we evaluated cardiovascular changes occurring during new initialized treatment with donepezil in 49 dementia patients over 6 months. No patient suffered from cardiovascular events. In clinical changes between baseline and the first evaluation after donepezil treatment, heart rate and plasma brain natriuretic peptide (BNP) levels as a marker for heart failure did not change (BNP: 59.62 ± 62.71 pg/mL at baseline to 53.18 ± 42.34 pg/mL at first evaluation; P = 0.262). We further examined plasma BNP levels in 2 groups into which the patients were divided at baseline according to the cut-off plasma BNP level of 60 pg/mL. In patients with high level of BNP, the BNP levels decreased after administration of donepezil (116.39 ± 76.58 pg/mL at baseline to 82.24 ± 46.64 pg/mL at first evaluation; P = 0.011) with the tendency to be reduced in the follow-up period. BNP did not change in patients with low level of BNP. Donepezil seemed to be safe in patients with dementia without symptomatic heart disease and significantly decreased plasma BNP levels in patients with subclinical chronic heart failure.

  9. Effect of Donepezil on Wernicke Aphasia After Bilateral Middle Cerebral Artery Infarction: Subtraction Analysis of Brain F-18 Fluorodeoxyglucose Positron Emission Tomographic Images.

    PubMed

    Yoon, Seo Yeon; Kim, Je-Kyung; An, Young-Sil; Kim, Yong Wook

    2015-01-01

    Aphasia is one of the most common neurologic deficits occurring after stroke. Although the speech-language therapy is a mainstream option for poststroke aphasia, pharmacotherapy is recently being tried to modulate different neurotransmitter systems. However, the efficacy of those treatments is still controversial. We present a case of a 53-year-old female patient with Wernicke aphasia, after the old infarction in the territory of left middle cerebral artery for 8 years and the recent infarction in the right middle cerebral artery for 4 months. On the initial evaluation, the Aphasia Quotient in Korean version of the Western Aphasia Battery was 25.6 of 100. Baseline brain F-18 fluorodeoxyglucose positron emission tomographic images demonstrated a decreased cerebral metabolism in the left temporoparietal area and right temporal lobe. Donepezil hydrochloride, a reversible acetylcholinesterase inhibitor, was orally administered 5 mg/d for 6 weeks after the initial evaluation and was increased to 10 mg/d for the following 6 weeks. After the donepezil treatment, the patient showed improvement in language function, scoring 51.0 of 100 on Aphasia Quotient. A subtraction analysis of the brain F-18 fluorodeoxyglucose positron emission tomographic images after donepezil medication demonstrated increased uptake in both middle temporal gyri, extended to the occipital area and the left cerebellum. Thus, we suggest that donepezil can be an effective therapeutic choice for the treatment of Wernicke aphasia.

  10. Reversals.

    ERIC Educational Resources Information Center

    National Center on Educational Media and Materials for the Handicapped, Columbus, OH.

    Selected from the National Instructional Materials Information System (NIMIS)--a computer based on-line interactive retrieval system on special education materials--the bibliography covers nine materials for remediating reversals in handicapped students at the early childhood and elementary levels. Entries are presented in order of NIMIS accession…

  11. Donepezil-induced response of Spirulina supplemented rat urinary bladder.

    PubMed

    Nurullahoglu-Atalik, K E; Okudan, N; Gokbel, H; Nurullahoglu, Z U

    2013-01-01

    At present, very little is known about the effects of donepezil on vascular reactivity. The aim of the present study was to evaluate the responses of rat urinary bladder to donepezil (10-10-3x10-4 M) and the role of Spirulina supplementation in these effects. Animals were divided into the two groups of six animals in each group. The first group received only distilled water daily as vehicle for six weeks and served as the control. The second group received Spirulina 750 mg kg -1 orally, daily for six weeks and served as the spirulina group. Preparations of rat urinary bladder were used from both groups. Donepezil produced concentration dependent relaxation of rat urinary bladder preparations pre-contracted with KCl.The pIC50 value, but not the maximal response of donepezil, was significantly lower (p<0.05) in the Spirulina supplemented group. These results demonstrated for the first time that spirulina treatment can affect urinary bladder activity (Fig. 1, Ref. 20).

  12. Spectral studies of Donepezil release from streched PVA polymer films

    NASA Astrophysics Data System (ADS)

    Nechifor, Cristina-Delia; Zelinschi, Carmen-Beatrice; Stoica, Iuliana; Closca, Valentina; Dorohoi, Dana-Ortansa

    2013-07-01

    The focus of this research is to obtain poly vinyl alcohol (PVA) polymer foils containing Donepezil in different concentration, in order to be used in controlled drug release as a palliative treatment of mild to moderate Alzheimer's disease. The influence of polymeric foil stretching degree on drug release was analyzed using spectral measurements.

  13. Combination therapy of donepezil and vitamin E in Alzheimer disease.

    PubMed

    Klatte, Emily T; Scharre, Douglas W; Nagaraja, Haikady N; Davis, Rebecca A; Beversdorf, David Q

    2003-01-01

    A retrospective chart review was performed on 130 patients from the Ohio State University Memory Disorders Clinic to examine the long-term effects of combination therapy with donepezil and vitamin E on patients with Alzheimer disease. Subjects were included if they met National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer disease, had taken at least 5 mg donepezil and at least 1000 U vitamin E daily, had at least a 1-year follow-up while continuing these medications, and had a Mini-Mental State Examination score of 10-24. The Mini-Mental State Examination was then recorded annually thereafter. These data were compared with the Consortium to Establish a Registry for Alzheimer's Disease database for patients collected prior to the availability of these treatment options. Patients declined at a significantly lower rate as compared with the Consortium to Establish a Registry for Alzheimer's Disease data. The long-term combination therapy of donepezil and vitamin E appears beneficial for patients with Alzheimer disease. Future prospective studies would be needed to compare combination treatment to vitamin E and donepezil alone.

  14. Olfactory Deficits in MCI as Predictor of Improved Cognition on Donepezil

    DTIC Science & Technology

    2013-04-01

    cognitively with ACheI treatment is important. Hypotheses. 1. The acute decrease in UPSIT (Odor identification test) scores from pre- to post- atropine...baseline to 24 weeks and 52 weeks of donepezil treatment . 2. Increase in UPSIT scores from baseline to 8 weeks of donepezil treatment will be associated...due to mild cognitive impairment, may improve with donepezil treatment . Olfactory identification deficits may be an early test that can identify who

  15. Donepezil 23 mg in Asian patients with moderate-to-severe Alzheimer's disease.

    PubMed

    Han, S-H; Lee, J-H; Kim, S Y; Park, K W; Chen, C; Tripathi, M; Dash, A; Kubota, N

    2017-02-01

    Ethnic diversity between different populations may affect treatment safety and efficacy. A subanalysis to a global trial (study 326) was carried out to ascertain the safety and efficacy of donepezil 23 mg/day compared with donepezil 10 mg/day in Asian patients with moderate-to-severe Alzheimer's disease. Changes in cognition and global functioning were measured by the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), respectively, at week 24. Cognitive improvement measured by SIB score was greater with donepezil 23 mg than with donepezil 10 mg (+1.36 vs -1.56]; difference, 2.92). There was no difference between the groups in global function measured by the CIBIC-Plus (3.94 and 3.95, respectively). Overall, 119 patients (82.1%) receiving donepezil 23 mg and 56 (71.8%) receiving donepezil 10 mg experienced ≥1 treatment emergent adverse events (TEAEs). In the donepezil 23 mg group, the incidence of TEAEs was higher among patients of lower weight (<55 kg) at baseline than in those of higher weight (64 of 75 patients [85.3%] vs 55 of 70 patients [78.5%]). The benefits and risks associated with donepezil 23 mg in Asian patients are comparable to those of the global study population. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Donepezil in the treatment of opioid-induced sedation: report of six cases.

    PubMed

    Slatkin, N E; Rhiner, M; Bolton, T M

    2001-05-01

    Donepezil, an oral acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease, was given to 6 cancer pain patients having sedation related to the analgesic use of opioids. Each patient was taking more than 200 mg of oral morphine equivalents per day, and several were receiving complex analgesic regimens consisting of multiple adjuvant medications. Sedation improved at least moderately in 5 of the patients and mildly in 1 after they began taking donepezil. Patients reported a decrease in episodes of spontaneous sleeping during the day, fewer myoclonic twitches, improved daily function and greater social interaction. Several also reported improved sleep at night. Analgesia was not compromised by the use of donepezil, and in some cases it appeared improved. Donepezil may be a valuable alternative to psychostimulants in the treatment of opioid-induced sedation. A prospective controlled trial comparing the treatment effects of psychostimulants and donepezil on patients having opioid-induced sedation is underway.

  17. Neuroprotection against vascular dementia after acupuncture combined with donepezil hydrochloride: P300 event related potential

    PubMed Central

    Liu, Qiang; Wang, Xiu-juan; Zhang, Zhe-cheng; Xue, Rong; Li, Ping; Li, Bo

    2016-01-01

    Acupuncture can be used to treat various nervous system diseases. Here, 168 vascular dementia patients were orally administered donepezil hydrochloride alone (5 mg/day, once a day for 56 days), or combined with acupuncture at Shenting (DU24), Tianzhu (BL10), Sishencong (Extra), Yintang (Extra), Renzhong (DU26), Neiguan (PC6), Shenmen (HT7), Fengchi (GB20), Wangu (GB12) and Baihui (DU20) (once a day for 56 days). Compared with donepezil hydrochloride alone, P300 event related potential latency was shorter with an increased amplitude in patients treated with donepezil hydrochloride and acupuncture. Mini-Mental State Examination score was also higher. Moreover, these differences in P300 latency were identified within different infarcted regions in patients treated with donepezil hydrochloride and acupuncture. These findings indicate that acupuncture combined with donepezil hydrochloride noticeably improves cognitive function in patients with vascular dementia, and exerts neuroprotective effects against vascular dementia. PMID:27127486

  18. Donepezil and life expectancy in Alzheimer’s disease: A retrospective analysis in the Tajiri Project

    PubMed Central

    2014-01-01

    Background Cholinesterase inhibitors (ChEIs) such as donepezil have the effect of delaying progression of Alzheimer’s disease (AD), but their effect on life expectancy is unclear. We analyzed the influence of donepezil on life expectancy after onset of AD, together with the effects of antipsychotic drugs and residency in a nursing home. Methods All outpatients at the Tajiri Clinic from 1999–2012 with available medical records and death certificates were included in a retrospective analysis. The entry criteria were a dementia diagnosis based on DSM-IV criteria and diagnosis of AD using NINCDS-ADRDA criteria; medical treatment for more than 3 months; and follow up until less than 1 year before death. Results We identified 390 subjects with medical records and death certificates, of whom 275 had a diagnosis of dementia that met the entry criteria. Of 100 patients diagnosed with AD, 52 had taken donepezil and 48 patients had not received the drug due to treatment prior to the introduction of donepezil in 1999 in Japan. The lifetime expectancies after onset were 7.9 years in the donepezil group and 5.3 years in the non-donepezil group. There was a significant drug effect with a significant covariate effect of nursing home residency. Other covariates did not reach a significant level. Conclusions Although this report has the limitation of all retrospective analyses: the lack of randomization, we found a positive effect of donepezil on lifetime expectancy after onset of AD. This may be due to a decreased mortality rate caused by reduction of concomitant diseases such as pneumonia. The similar life expectancies in patients taking donepezil at home and those not taking donepezil in a nursing home indicated a positive health economic effect of the drug. PMID:24720852

  19. Single dose pharmacokinetics of the novel transdermal donepezil patch in healthy volunteers

    PubMed Central

    Kim, Yo Han; Choi, Hee Youn; Lim, Hyeong-Seok; Lee, Shi Hyang; Jeon, Hae Sun; Hong, Donghyun; Kim, Seong Su; Choi, Young Kweon; Bae, Kyun-Seop

    2015-01-01

    Background Donepezil is an acetylcholinesterase inhibitor indicated for Alzheimer’s disease. The aim of this randomized, single-blind, placebo-controlled, single-dose, dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics of the donepezil patch in healthy male subjects. Methods Each healthy male subject received a single transdermal donepezil patch (72 hours patch-on periods) of 43.75 mg/12.5 cm2, 87.5 mg/25 cm2, or 175 mg/50 cm2. Serial blood samples were collected up to 312 hours after patch application. The plasma concentrations of donepezil were determined by using a validated liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability of the patches and performance of the patches (adhesion, skin irritation, residual donepezil content in the patch) were assessed throughout the study. Results The study was completed by 36 healthy subjects. After patch application, the maximal plasma donepezil concentration (Cmax) and the area under the curve (AUC) increased in a dose-proportional manner. Median time to Cmax was ~74–76 hours (~2–4 hours after patch removal), and mean t1/2β was ~63.77–93.07 hours. The average donepezil residue in the patch after 72 hours was ~73.9%–86.7% of the loading dose. There were neither serious adverse events nor adverse events that lead to discontinuation. Skin adhesion of the patch was good in 97.2% of the subjects. All skin irritations after patch removal were mild and were resolved during the study period. Conclusion The donepezil patch appeared to be generally well tolerated and adhesive. Pharmacokinetic analysis of the donepezil patch demonstrated linear kinetics. PMID:25792802

  20. Donepezil, an acetylcholinesterase inhibitor, attenuates nicotine self-administration and reinstatement of nicotine seeking in rats

    PubMed Central

    Kimmey, Blake A.; Rupprecht, Laura E.; Hayes, Matthew R.; Schmidt, Heath D.

    2013-01-01

    Nicotine craving and cognitive impairments represent core symptoms of nicotine withdrawal and predict relapse in abstinent smokers. Current smoking cessation pharmacotherapies have limited efficacy in preventing relapse and maintaining abstinence during withdrawal. Donepezil is an acetylcholinesterase inhibitor that has been shown previously to improve cognition in healthy non–treatment-seeking smokers. However, there are no studies examining the effects of donepezil on nicotine self-administration and/or the reinstatement of nicotine-seeking behavior in rodents. The present experiments were designed to determine the effects of acute donepezil administration on nicotine taking and the reinstatement of nicotine-seeking behavior, an animal model of relapse in abstinent human smokers. Moreover, the effects of acute donepezil administration on sucrose self-administration and sucrose seeking were also investigated in order to determine whether donepezil's effects generalized to other reinforced behaviors. Acute donepezil administration (1.0 or 3.0 mg/kg, i.p.) attenuated nicotine, but not sucrose self-administration maintained on a fixed-ratio 5 schedule of reinforcement. Donepezil administration also dose-dependently attenuated the reinstatement of both nicotine- and sucrose-seeking behaviors. Commonly reported adverse effects of donepezil treatment in humans are nausea and vomiting. However, at doses required to attenuate nicotine self-administration in rodents, no effects of donepezil on nausea/malaise as measured by pica were observed. Collectively, these results indicate that increased extracellular acetylcholine levels are sufficient to attenuate nicotine taking and seeking in rats and that these effects are not due to adverse malaise symptoms such as nausea. PMID:23231479

  1. Donepezil, an acetylcholinesterase inhibitor, attenuates nicotine self-administration and reinstatement of nicotine seeking in rats.

    PubMed

    Kimmey, Blake A; Rupprecht, Laura E; Hayes, Matthew R; Schmidt, Heath D

    2014-07-01

    Nicotine craving and cognitive impairments represent core symptoms of nicotine withdrawal and predict relapse in abstinent smokers. Current smoking cessation pharmacotherapies have limited efficacy in preventing relapse and maintaining abstinence during withdrawal. Donepezil is an acetylcholinesterase inhibitor that has been shown previously to improve cognition in healthy non-treatment-seeking smokers. However, there are no studies examining the effects of donepezil on nicotine self-administration and/or the reinstatement of nicotine-seeking behavior in rodents. The present experiments were designed to determine the effects of acute donepezil administration on nicotine taking and the reinstatement of nicotine-seeking behavior, an animal model of relapse in abstinent human smokers. Moreover, the effects of acute donepezil administration on sucrose self-administration and sucrose seeking were also investigated in order to determine whether donepezil's effects generalized to other reinforced behaviors. Acute donepezil administration (1.0 or 3.0 mg/kg, i.p.) attenuated nicotine, but not sucrose self-administration maintained on a fixed-ratio 5 schedule of reinforcement. Donepezil administration also dose-dependently attenuated the reinstatement of both nicotine- and sucrose-seeking behaviors. Commonly reported adverse effects of donepezil treatment in humans are nausea and vomiting. However, at doses required to attenuate nicotine self-administration in rodents, no effects of donepezil on nausea/malaise as measured by pica were observed. Collectively, these results indicate that increased extracellular acetylcholine levels are sufficient to attenuate nicotine taking and seeking in rats and that these effects are not due to adverse malaise symptoms such as nausea. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

  2. Donepezil and flight simulator performance: effects on retention of complex skills.

    PubMed

    Yesavage, J A; Mumenthaler, M S; Taylor, J L; Friedman, L; O'Hara, R; Sheikh, J; Tinklenberg, J; Whitehouse, P J

    2002-07-09

    We report a randomized, double-blind, parallel group, placebo-controlled study to test the effects of the acetylcholinesterase inhibitor, donepezil (5 mg/d for 30 days), on aircraft pilot performance in 18 licensed pilots with mean age of 52 years. After 30 days of treatment, the donepezil group showed greater ability to retain the capacity to perform a set of complex simulator tasks than the placebo group, p < 0.05. Donepezil appears to have beneficial effects on retention of training on complex aviation tasks in nondemented older adults.

  3. Bioequivalence Study of Donepezil Hydrochloride Tablets in Healthy Male Volunteers

    PubMed Central

    Rojanasthien, Noppamas; Aunmuang, Siriluk; Hanprasertpong, Nutthiya; Roongapinun, Sukit; Teekachunhatean, Supanimit

    2012-01-01

    The objective of this study was to investigate the bioequivalence of two formulations of 5 mg donepezil HCL tablets: Tonizep as the test and Aricept as the reference. The two products were administered as a single oral dose according to a randomized two-phase crossover with a 3-week washout period in 20 healthy Thai Male volunteers. After drug administration, serial blood samples were collected over a period of 216 hours. Plasma donepezil concentrations were measured by high performance liquid chromatography with UV detection. Pharmacokinetic parameters were analyzed based on noncompartmental analysis. The logarithmically transformed data of AUC0–∞ and Cmax were analyzed for 90% confidence intervals (CI) using ANOVA. The mean (90% CI) values for the ratio of AUC0–∞ and Cmax values of the test product over those of the reference product were 1.08 (1.02–1.14) and 1.08 (0.99–1.17), respectively (within the bioequivalence range of 0.8–1.25). The median Tmax for the test product was similar to that of the reference product (2.0 hr), and the 90% CI for the Tmax difference between the two preparations was –0.19 to 0.29 hr and within the bioequivalence range of ± 20% of the Tmax of the reference formulation. Our study demonstrated the bioequivalence of the two preparations. PMID:23209934

  4. Pharmacodynamics of cholinesterase inhibitors suggests add-on therapy with a low-dose carbamylating inhibitor in patients on long-term treatment with rapidly reversible inhibitors.

    PubMed

    Darreh-Shori, Taher; Hosseini, Sharokh Makvand; Nordberg, Agneta

    2014-01-01

    Despite three decades of intensive research in the field of Alzheimer's disease (AD) and numerous clinical trials of new therapeutic agents, cholinesterase inhibitors (ChEIs) are still the mainstay of therapeutics for AD and dementia with Lewy bodies. Pharmacodynamic analyses of ChEIs provide paradoxical observations. Treatment with the rapidly reversible, noncarbamylating ChEIs (donepezil, galantamine, and tacrine) increases acetylcholinesterase (AChE) protein expression, whereas the carbamylating agent, rivastigmine, produces sustained inhibition with no significant change in AChE protein expression. Still, the symptomatic clinical efficacies of all these agents are similar. We report here for the first time that treatment with phenserine, another carbamylating ChEI, produces a sustained but mild inhibition of AChE in cerebrospinal fluid (CSF) of AD patients. We also show that phenserine treatment reverses donepezil-induced elevation of AChE expression. Further analyses on CSF of another larger patient cohort treated with donepezil revealed that, in addition to its main mode of action, donepezil produced two other pharmacodynamics with potentially contradictory outcomes. Donepezil-induced AChE expression favored an AChE-driven amyloid-β peptide (Aβ) aggregation, whereas donepezil itself concentration-dependently counteracted the AChE-induced Aβ aggregation, most likely by competing with the Aβ peptides for peripheral anionic site on the AChE protein. The reduction of AChE protein expression in the donepezil-treated patients by concomitant administration of the carbamylating agent, phenserine, could allow the donepezil molecule to only prevent interaction between Aβ and AChE. The current study suggests that an add-on therapy with a low-dose formulation of a carbamylating agent in patients on long-term donepezil treatment should be explored as a strategy for enhancing the clinical efficacy of these agents in dementia disorders.

  5. Effects of Donepezil on Behavioral Manifestations of Thalamic Infarction: A Single-Case Observation

    PubMed Central

    Riveros, Rodrigo; Chabriat, Hughes; Flores, Rodrigo; Alvarez, Gonzalo; Slachevsky, Andrea

    2011-01-01

    Objective: To examine the effect of donepezil for the treatment of cognitive and behavioral disorders associated with thalamic lesions in a 45-year-old male who suffered an infarct in the left thalamus. Background: Recent studies suggest that donepezil may improve executive functions impairments due to subcortical ischemic lesions. Method: The effects of donepezil were analyzed in a single-case of thalamic infarction with cognitive and behavioral alterations in an open label study. Results: Significant behavioral modifications related to improved performances in executive functions were observed with the treatment. Conclusion: The results suggest that donepezil may have significant effect on executive functions that can alter behavioral outcomes after thalamic infarctions. PMID:21472029

  6. A rare case of acute renal failure secondary to rhabdomyolysis probably induced by donepezil.

    PubMed

    Sahin, Osman Zikrullah; Ayaz, Teslime; Yuce, Suleyman; Sumer, Fatih; Sahin, Serap Baydur

    2014-01-01

    Introduction. Acute renal failure (ARF) develops in 33% of the patients with rhabdomyolysis. The main etiologic factors are alcoholism, trauma, exercise overexertion, and drugs. In this report we present a rare case of ARF secondary to probably donepezil-induced rhabdomyolysis. Case Presentation. An 84-year-old male patient was admitted to the emergency department with a complaint of generalized weakness and reduced consciousness for two days. He had a history of Alzheimer's disease for one year and he had taken donepezil 5 mg daily for two months. The patient's physical examination revealed apathy, loss of cooperation, and decreased muscle strength. Laboratory studies revealed the following: urea: 128 mg/dL; Creatinine 6.06 mg/dL; creatine kinase: 3613 mg/dL. Donepezil was discontinued and the patient's renal function tests improved gradually. Conclusion. Rhabdomyolysis-induced acute renal failure may develop secondary to donepezil therapy.

  7. A Rare Case of Acute Renal Failure Secondary to Rhabdomyolysis Probably Induced by Donepezil

    PubMed Central

    Sahin, Osman Zikrullah; Ayaz, Teslime; Yuce, Suleyman; Sumer, Fatih

    2014-01-01

    Introduction. Acute renal failure (ARF) develops in 33% of the patients with rhabdomyolysis. The main etiologic factors are alcoholism, trauma, exercise overexertion, and drugs. In this report we present a rare case of ARF secondary to probably donepezil-induced rhabdomyolysis. Case Presentation. An 84-year-old male patient was admitted to the emergency department with a complaint of generalized weakness and reduced consciousness for two days. He had a history of Alzheimer's disease for one year and he had taken donepezil 5 mg daily for two months. The patient's physical examination revealed apathy, loss of cooperation, and decreased muscle strength. Laboratory studies revealed the following: urea: 128 mg/dL; Creatinine 6.06 mg/dL; creatine kinase: 3613 mg/dL. Donepezil was discontinued and the patient's renal function tests improved gradually. Conclusion. Rhabdomyolysis-induced acute renal failure may develop secondary to donepezil therapy. PMID:24864216

  8. Donepezil improves episodic memory in young individuals vulnerable to the effects of sleep deprivation.

    PubMed

    Chuah, Lisa Y M; Chong, Delise L; Chen, Annette K; Rekshan, William R; Tan, Jiat-Chow; Zheng, Hui; Chee, Michael W L

    2009-08-01

    We investigated if donepezil, a long-acting orally administered cholinesterase inhibitor, would reduce episodic memory deficits associated with 24 h of sleep deprivation. Double-blind, placebo-controlled, crossover study involving 7 laboratory visits over 2 months. Participants underwent 4 functional MRI scans; 2 sessions (donepezil or placebo) followed a normal night's sleep, and 2 sessions followed a night of sleep deprivation. The study took place in a research laboratory. 26 young, healthy volunteers with no history of any sleep, psychiatric, or neurologic disorders. 5 mg of donepezil was taken once daily for approximately 17 days. Subjects were scanned while performing a semantic judgment task and tested for word recognition outside the scanner 45 minutes later. Sleep deprivation increased the frequency of non-responses at encoding and impaired delayed recognition. No benefit of donepezil was evident when participants were well rested. When sleep deprived, individuals who showed greater performance decline improved with donepezil, whereas more resistant individuals did not benefit. Accompanying these behavioral effects, there was corresponding modulation of task-related activation in functionally relevant brain regions. Brain regions identified in relation to donepezil-induced alteration in non-response rates could be distinguished from regions relating to improved recognition memory. This suggests that donepezil can improve delayed recognition in sleep-deprived persons by improving attention as well as enhancing memory encoding. Donepezil reduced decline in recognition performance in individuals vulnerable to the effects of sleep deprivation. Additionally, our findings demonstrate the utility of combined fMRI-behavior evaluation in psychopharmacological studies.

  9. Olfactory Deficits in MCI as Predictor of Improved Cognition on Donepezil

    DTIC Science & Technology

    2016-06-01

    predicting which MCI patients are likely to improve cognitively with ACheI treatment is important. Hypotheses. 1. The acute decrease in UPSIT (Odor...improvement (SRT total recall and modified ADAS-cog) from baseline to 26 weeks and 52 weeks of donepezil treatment . 2. Increase in UPSIT scores from...baseline to 8 weeks of donepezil treatment will be associated with cognitive improvement from baseline to 26 and 52 weeks. Exploratory Hypothesis. The

  10. The efficacy, safety, and tolerability of donepezil for the treatment of young adults with Down syndrome.

    PubMed

    Kishnani, Priya S; Sommer, Barbara R; Handen, Benjamin L; Seltzer, Benjamin; Capone, George T; Spiridigliozzi, Gail A; Heller, James H; Richardson, Sharon; McRae, Thomas

    2009-08-01

    The objective of our study was to assess the efficacy and safety of donepezil in young adults with Down syndrome (DS) but no evidence of Alzheimer disease (AD). A 12-week, randomized, double-blind, placebo-controlled study with a 12-week, open-label extension was conducted. The intervention consisted of donepezil (5-10 mg/day) in young adults (aged 18-35 years) with DS, but no AD. The primary measure was the Severe Impairment Battery (SIB) test and secondary measures were the Vineland Adaptive Behavior Scales (VABS), the Rivermead Behavioral Memory Test for Children, and the Clinical Evaluation of Language Fundamentals, Third Edition. At baseline, 123 subjects were randomly assigned treatment with donepezil or placebo. During the double-blind phase, SIB scores improved significantly from baseline in both groups, with no significant between-group differences. During the open-label phase, SIB scores in the original donepezil group remained stable; the original placebo group showed an improvement similar to that seen in the double-blind phase. VABS scores improved for donepezil, but not placebo, during the double-blind phase (observed cases, P = 0.03; last observation carried forward, P = 0.07). Post hoc responder analyses were significant for donepezil using three of five response definitions (P < or = 0.045). Adverse event rates were comparable to AD studies. In this first large-scale, multicenter trial of a pharmacological agent for DS, donepezil appears safe. Efficacy interpretation was limited for the primary measure due to apparent learning/practice and ceiling effects. Outcomes in post hoc analyses suggested efficacy in some, but not all subjects, consistent with phenotypic variability of DS. Additional studies are required to confirm potential benefits of donepezil in this population.

  11. Olfactory Deficits in MCI as Predictor of Improved Cognition on Donepezil

    DTIC Science & Technology

    2014-04-01

    approved for this condition. Therefore, predicting which MCI patients are likely to improve cognitively with ACheI treatment is important. Hypotheses. 1...will be associated with cognitive improvement (SRT total recall and modified ADAS-cog) from baseline to 24 weeks and 52 weeks of donepezil treatment . 2...Increase in UPSIT scores from baseline to 8 weeks of donepezil treatment will be associated with cognitive improvement from baseline to 24 and 52

  12. Cholinergic Neurotransmission in the Posterior Insular Cortex Is Altered in Preclinical Models of Neuropathic Pain: Key Role of Muscarinic M2 Receptors in Donepezil-Induced Antinociception

    PubMed Central

    Ferrier, Jérémy; Bayet-Robert, Mathilde; Dalmann, Romain; El Guerrab, Abderrahim; Aissouni, Youssef; Graveron-Demilly, Danielle; Chalus, Maryse; Pinguet, Jérémy; Eschalier, Alain; Richard, Damien; Daulhac, Laurence; Balayssac, David

    2015-01-01

    Neuropathic pain is one of the most debilitating pain conditions, yet no therapeutic strategy has been really effective for its treatment. Hence, a better understanding of its pathophysiological mechanisms is necessary to identify new pharmacological targets. Here, we report important metabolic variations in brain areas involved in pain processing in a rat model of oxaliplatin-induced neuropathy using HRMAS 1H-NMR spectroscopy. An increased concentration of choline has been evidenced in the posterior insular cortex (pIC) of neuropathic animal, which was significantly correlated with animals' pain thresholds. The screening of 34 genes mRNA involved in the pIC cholinergic system showed an increased expression of the high-affinity choline transporter and especially the muscarinic M2 receptors, which was confirmed by Western blot analysis in oxaliplatin-treated rats and the spared nerve injury model (SNI). Furthermore, pharmacological activation of M2 receptors in the pIC using oxotremorine completely reversed oxaliplatin-induced mechanical allodynia. Consistently, systemic treatment with donepezil, a centrally active acetylcholinesterase inhibitor, prevented and reversed oxaliplatin-induced cold and mechanical allodynia as well as social interaction impairment. Intracerebral microdialysis revealed a lower level of acetylcholine in the pIC of oxaliplatin-treated rats, which was significantly increased by donepezil. Finally, the analgesic effect of donepezil was markedly reduced by a microinjection of the M2 antagonist, methoctramine, within the pIC, in both oxaliplatin-treated rats and spared nerve injury rats. These findings highlight the crucial role of cortical cholinergic neurotransmission as a critical mechanism of neuropathic pain, and suggest that targeting insular M2 receptors using central cholinomimetics could be used for neuropathic pain treatment. SIGNIFICANCE STATEMENT Our study describes a decrease in cholinergic neurotransmission in the posterior insular

  13. The Effects of Donepezil on 15-Item Geriatric Depression Scale Structure in Patients with Alzheimer Disease

    PubMed Central

    Yang, Youngsoon; Kwak, Yong Tae

    2016-01-01

    Background/Aims In Alzheimer disease (AD), depression is among the most common accompanying neuropsychiatric symptoms and has different clinical manifestations when compared with early-life depression. In patients with drug-naïve AD, we tried to explore the structure of the 15-item Geriatric Depression Scale (GDS15) and the effect of donepezil on these substructures. Methods GDS15, cognitive function, and activities of daily living function tests were administered to 412 patients with probable AD who had not been medicated before visiting the hospital. Using principal component analysis, three factors were identified. The patients with AD who received only donepezil were retrospectively analyzed and we compared the change of cognition and GDS15 subgroup after donepezil medication. Results Our study identified three factors and revealed that the GDS15 may be comprised of a heterogeneous scale. The Barthel index was significantly correlated with factor 1 (positively) and factor 2 (negatively). The Korean version of the MMSE (K-MMSE) was significantly correlated with factor 2 and factor 3. Compared to the baseline state, K-MMSE and GDS15 showed significant improvement after taking donepezil. Among GDS15 subgroups, factor 2 and factor 3 showed significant improvement after donepezil treatment. Conclusions These results suggest that the GDS15 may be comprised of a heterogeneous scale and donepezil differentially affects the GDS15 subgroup in AD. PMID:27790242

  14. Effects of cognitive-communication stimulation for Alzheimer's disease patients treated with donepezil.

    PubMed

    Chapman, Sandra Bond; Weiner, Myron F; Rackley, Audette; Hynan, Linda S; Zientz, Jennifer

    2004-10-01

    This randomized study evaluated the combined effect of a cognitive-communication program plus an acetylcholinesterase inhibitor (donepezil; donepezil-plus-stimulation group; n = 26), as compared with donepezil alone (donepezil-only group; n = 28) in 54 patients with mild to moderate Alzheimer's disease (AD; Mini-Mental Status Examination score of 12- 28) ranging in age from 54 to 91 years. It was hypothesized that cognitive-communication stimulation in combination with donepezil would positively affect the following: (a) relevance of discourse, (b) performance of functional abilities, (c) emotional symptoms, (d) quality of life, and (e) overall global function, as measured by caregiver and participant report and standardized measures. Cognitive-communication, neuropsychiatric, functional performance, and quality of life evaluations were conducted at baseline and Month 4, the month after the 2-month active stimulation period. Follow-up evaluations were performed at Months 8 and 12. The stimulation program consisted of 12 hr of intervention over an 8-week period and involved participant-led discussions requiring homework, interactive sessions about AD, and discussions using salient life stories. Additive effects of active stimulation with donepezil were examined in 2 ways: (1) comparing mean group performance over time and (2) evaluating change scores from baseline. A Group x Time interaction was found for the donepezil-plus-stimulation group in the emotional symptoms of apathy and irritability as compared with the donepezil-only group. Evaluation of change scores from baseline to 12 months revealed a positive effect for the donepezil-plus-stimulation group on discourse and functional abilities with a trend on apathy, irritability, and patient-reported quality of life. In sum, the research revealed benefits to the donepezil-plus-stimulation group in the areas of discourse abilities, functional abilities, emotional symptoms, and overall global performance. This study

  15. 3-year study of donepezil therapy in Alzheimer's disease: effects of early and continuous therapy.

    PubMed

    Winblad, B; Wimo, A; Engedal, K; Soininen, H; Verhey, F; Waldemar, G; Wetterholm, A-L; Haglund, A; Zhang, R; Schindler, R

    2006-01-01

    Delays in the diagnosis of Alzheimer's disease, and, therefore, delays in treatment, may have a detrimental effect on a patient's long-term well-being. This study assessed the effects of postponing donepezil treatment for 1 year by comparing patients treated continuously for 3 years with those who received placebo for 1 year followed by open-label donepezil for 2 years. Patients (n = 286) with possible or probable Alzheimer's disease (according to DSM-IV, NINCDS-ADRDA, and Mini-Mental State Examination criteria; see text) were randomized to receive donepezil (5 mg/day for 4 weeks, 10 mg/day thereafter) or placebo (delayed-start group) for 1 year. Of the 192 completers, 157 began a 2-year, open-label phase of donepezil treatment. Outcome measures were the Gottfries-Bråne-Steen scale, the Mini-Mental State Examination, the Global Deterioration Scale, the Progressive Deterioration Scale, the Neuropsychiatric Inventory, and safety (adverse events). Mixed regression analysis was used to compare changes between the groups over 3 years on the efficacy measures. There was a trend for patients receiving continuous therapy to have less global deterioration (Gottfries-Bråne-Steen scale) than those who had delayed treatment (p = 0.056). Small but statistically significant differences between the groups were observed for the secondary measures of cognitive function (Mini-Mental State Examination; p = 0.004) and cognitive and functional abilities (Global Deterioration Scale; p = 0.0231) in favor of continuous donepezil therapy. Over 90% of the patients in both cohorts experienced one treatment-emergent adverse event; most were considered mild or moderate. In conclusion, patients in whom the start of treatment is delayed may demonstrate slightly reduced benefits as compared with those seen in patients starting donepezil therapy early in the course of Alzheimer's disease. These data support the long-term efficacy and safety of donepezil.

  16. Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons.

    PubMed

    Gibbs, R B; Chipman, A M; Nelson, D

    2011-04-01

    Effects of estrogen therapy on cognitive performance appear to diminish with age and time following the loss of ovarian function. We hypothesize that this is due to a reduction in basal forebrain cholinergic function and that treatment with a cholinergic enhancer can reverse the effect. This study tested whether combining the cholinesterase inhibitor donepezil with estradiol treatment can enhance/restore estradiol effects on cognitive performance in young ovariectomized rats with selective lesions of septal cholinergic neurons. 192IgG-saporin was injected directly into the medial septum to produce selective cholinergic lesions. Rats were then treated with donepezil (Don, daily injections of 3mg/kg/day, i.p.) or vehicle, and then with 17β-estradiol (E2, administered by silastic capsule implanted s.c.) or an empty capsule. Rats were trained on a delayed matching-to-position (DMP) T-maze task which previous studies have shown is sensitive to ovariectomy and estrogen replacement. Results show that neither estradiol nor donepezil alone significantly enhanced acquisition of the DMP task in rats with cholinergic lesions. Combination therapy was effective, however, depending on the severity of the lesion. Don+E2 significantly enhanced acquisition of the task in rats with partial lesions (<50% loss of cholinergic neurons), but not in rats with severe lesions. This effect was due largely to a reduction in perseverative behavior. Don+E2 also improved working memory in rats with partial lesions, as evidenced by significantly better performance than controls during increased intertrial delays. These findings suggest that even partial loss of septal cholinergic neurons can reduce effects of estrogen therapy on cognitive performance, and demonstrate that combining a cholinesterase inhibitor with estrogen therapy can help to restore beneficial effects on performance. We propose that combination therapy may have similar beneficial effects in women, particularly in older women who

  17. Phencyclidine-induced cognitive deficits in mice are ameliorated by subsequent subchronic administration of donepezil: role of sigma-1 receptors.

    PubMed

    Kunitachi, Shinsui; Fujita, Yuko; Ishima, Tamaki; Kohno, Mami; Horio, Mao; Tanibuchi, Yuko; Shirayama, Yukihiko; Iyo, Masaomi; Hashimoto, Kenji

    2009-07-07

    This study was undertaken to examine the effects of two acetylcholinesterase inhibitors (donepezil and physostigmine) on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). In the novel object recognition test, PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (14 days) administration of donepezil (1.0 mg/kg/day), but not donepezil (0.1 mg/kg/day). Furthermore, the effect of donepezil (1.0 mg/kg/day) on PCP-induced cognitive deficits was significantly antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1.0 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of donepezil. In contrast, PCP-induced cognitive deficits were not improved by subsequent subchronic (14 days) administration of physostigmine (0.25 mg/kg/day). Moreover, repeated administration of PCP significantly caused the reduction of sigma-1 receptors in the hippocampus. The present study suggests that agonistic activity of donepezil at sigma-1 receptors plays a role in the active mechanisms of donepezil on PCP-induced cognitive deficits in mice. Therefore, it is likely that donepezil would be potential therapeutic drugs for the treatment of the cognitive deficits in schizophrenia.

  18. Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10-17.

    PubMed

    Kishnani, Priya S; Heller, James H; Spiridigliozzi, Gail A; Lott, Ira; Escobar, Luis; Richardson, Sharon; Zhang, Richard; McRae, Thomas

    2010-12-01

    The objective of this 10-week, randomized, double-blind, placebo-controlled multicenter study was to assess the efficacy and safety of donepezil for the treatment of cognitive dysfunction exhibited by children with Down syndrome (DS). Intervention comprised donepezil (2.5-10 mg/day) in children (aged 10-17 years) with DS of mild-to-moderate severity. The primary measures were the Vineland-II Adaptive Behavior Scales (VABS-II) Parent/Caregiver Rating Form (PCRF) the sum of nine subdomain standardized scores and standard safety measures. Secondary measures included the VABS-II/PCRF scores on the following domains and their respective individual subdomains: Communication (receptive, expressive, and written); Daily Living Skills (personal, domestic, and community); Socialization (interpersonal relationships, play and leisure time, and coping skills), and scores on the Test of Verbal Expression and Reasoning, a subject-performance-based measure of expressive language. At baseline, 129 participants were assigned treatment with donepezil or placebo. During the double-blind phase, VABS II/PCRF sum of the nine subdomain standardized scores, called v-scores, improved significantly from baseline in both groups (P < 0.0001), with no significant between-group differences. This trial failed to demonstrate any benefit for donepezil versus placebo in children and adolescents with DS, although donepezil appeared to be well tolerated. © 2010 Wiley-Liss, Inc.

  19. Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer's disease

    PubMed Central

    Bohnen, N; Kaufer, D; Hendrickson, R; Ivanco, L; Lopresti, B; Koeppe, R; Meltzer, C; Constantine, G; Davis, J; Mathis, C; DeKosky, S; Moore, R

    2005-01-01

    Objectives: To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer's disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy. Methods: Cognitive and N-[11C]methyl-piperidin-4-yl propionate ([11C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy. Results: Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = –7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = –14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R2 = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = –2.7; p<0.05). Conclusions: Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions. PMID:15716518

  20. Molecularly imprinted microparticles in lipid-based formulations for sustained release of donepezil.

    PubMed

    Ruela, André Luís Morais; de Figueiredo, Eduardo Costa; de Araújo, Magali Benjamim; Carvalho, Flávia Chiva; Pereira, Gislaine Ribeiro

    2016-10-10

    Donepezil is a drug administered for Alzheimer's disease treatment, and it is a potential template molecule for imprinted microparticles. The precipitation polymerization technique allows the synthesis of spherical imprinted microparticles, and the intermolecular interactions among drug and molecularly imprinted polymers (MIPs) play a promising role for delineating drug delivery systems. Once that donepezil is a poorly-water soluble compound, lipid based-formulations (LBFs) may enhance its oral administration. Based on this, LBFs are useful vehicles to incorporate imprinted microparticles synthesized by precipitation polymerization. In these formulations, the drug dissolved in lipids is accessible to adsorbate in the polymers, and the hydrophobic environment of lipids increases the molecular recognition of MIPs. The formulations based on MIPs using pure oleic acid as vehicle prolong the in vitro release of donepezil up to several hours by a Fickian diffusion mechanism, and it provides a multiphasic release pattern related to the heterogeneity of the binding sites. The modulation of donepezil release from MIPs-based formulations using oil vehicles may contribute to decrease its side effects, possibly regulating its absorption rate in the gastrointestinal tract. These systems represent a novel technological platform to prolong the delivery not only for donepezil, but also for a variety of therapeutics. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Safety and Efficacy of Donepezil in Children and Adolescents with Autism: Neuropsychological Measures

    PubMed Central

    Johnson, Cynthia R.; McAuliffe-Bellin, Sarah; Murray, Patricia Jo; Hardan, Antonio Y.

    2011-01-01

    Abstract Objective There has been recent interest in the use of cognitive enhancing drugs, such as cholinesterase inhibitors, as a possible treatment for executive functioning (EF) deficits in autism spectrum disorder (ASD). The goal of this study was to assess the tolerability, safety, and efficacy of donepezil on EF in a sample of children and adolescents with ASD. Method Thirty-four children and adolescents with ASD (age range 8–17 years; IQ >75) were enrolled in a 10-week, double-blind, placebo-controlled trial of donepezil (doses of 5 and 10 mg), followed by a 10-week open label trial for placebo nonresponders. Results The effect of donepezil treatment on EF was examined. Despite improvement on a number of EF measures, no statistically significant between-group differences were found (with gains observed for both the placebo and donepezil groups). Conclusions The results suggest that short-term treatment with donepezil may have limited impact on cognitive functioning in ASD. Future controlled trials may need to consider a longer treatment period to detect significant gains on EF measures. PMID:21309696

  2. Donepezil nanosuspension intended for nose to brain targeting: In vitro and in vivo safety evaluation.

    PubMed

    Bhavna; Md, Shadab; Ali, Mushir; Ali, Rashid; Bhatnagar, Aseem; Baboota, Sanjula; Ali, Javed

    2014-06-01

    The present study was to develop donepezil loaded nanosuspension for direct olfactory administration which reaches the brain and determining safety profile in Sprague-Dawley rats. Nanosuspension was prepared by ionic-crosslinking method. The developed nanosuspension was intranasally instilled into the nostrils of rats with the help of cannula (size 18/20) so that drug reached into the brain directly via nose to brain pathway. The nanosuspension had an average size of 150-200nm with a polydispersity index of 0.341. The donepezil concentration was estimated in the brain homogenate using HPLC method. The Cmax showed concentration of donepezil in brain and plasma as 7.2±0.86 and 82.8±5.42ng/ml, respectively, for drug suspension and concentration of donepezil in brain and plasma as 147.54±25.08 and 183.451±13.45ng/ml, respectively, for nanosuspension at same dose of 0.5mg/ml when administered intranasally (p<0.05). The in vivo safety evaluation studies showed that no mortality, hematological changes, body weight variations and toxicity in animals was observed, when nanosuspension was administered in different doses as compared to control group (normal saline). Donepezil loaded chitosan nanosuspension is a potential new delivery system for treatment of Alzheimer's disease, when transported via olfactory nasal pathway to the brain.

  3. Donepezil decreases annual rate of hippocampal atrophy in suspected prodromal Alzheimer's disease.

    PubMed

    Dubois, Bruno; Chupin, Marie; Hampel, Harald; Lista, Simone; Cavedo, Enrica; Croisile, Bernard; Louis Tisserand, Guy; Touchon, Jacques; Bonafe, Alain; Ousset, Pierre Jean; Ait Ameur, Amir; Rouaud, Olivier; Ricolfi, Fréderic; Vighetto, Alain; Pasquier, Florence; Delmaire, Christine; Ceccaldi, Mathieu; Girard, Nadine; Dufouil, Carole; Lehericy, Stéphane; Tonelli, Isabelle; Duveau, Françoise; Colliot, Olivier; Garnero, Line; Sarazin, Marie; Dormont, Didier

    2015-09-01

    The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD). A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method. Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups. A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  4. Donepezil Rescues Spatial Learning and Memory Deficits following Traumatic Brain Injury Independent of Its Effects on Neurogenesis

    PubMed Central

    Yu, Tzong-Shiue; Kim, Ahleum; Kernie, Steven G.

    2015-01-01

    Traumatic brain injury (TBI) is ubiquitous and effective treatments for it remain supportive largely due to uncertainty over how endogenous repair occurs. Recently, we demonstrated that hippocampal injury-induced neurogenesis is one mechanism underlying endogenous repair following TBI. Donepezil is associated with increased hippocampal neurogenesis and has long been known to improve certain aspects of cognition following many types of brain injury through unknown mechanisms. By coupling donepezil therapy with temporally regulated ablation of injury-induced neurogenesis using nestin-HSV transgenic mice, we investigated whether the pro-cognitive effects of donepezil following injury might occur through increasing neurogenesis. We demonstrate that donepezil itself enhances neurogenesis and improves cognitive function following TBI, even when injury-induced neurogenesis was inhibited. This suggests that the therapeutic effects of donepezil in TBI occur separately from its effects on neurogenesis. PMID:25714524

  5. Donepezil rescues spatial learning and memory deficits following traumatic brain injury independent of its effects on neurogenesis.

    PubMed

    Yu, Tzong-Shiue; Kim, Ahleum; Kernie, Steven G

    2015-01-01

    Traumatic brain injury (TBI) is ubiquitous and effective treatments for it remain supportive largely due to uncertainty over how endogenous repair occurs. Recently, we demonstrated that hippocampal injury-induced neurogenesis is one mechanism underlying endogenous repair following TBI. Donepezil is associated with increased hippocampal neurogenesis and has long been known to improve certain aspects of cognition following many types of brain injury through unknown mechanisms. By coupling donepezil therapy with temporally regulated ablation of injury-induced neurogenesis using nestin-HSV transgenic mice, we investigated whether the pro-cognitive effects of donepezil following injury might occur through increasing neurogenesis. We demonstrate that donepezil itself enhances neurogenesis and improves cognitive function following TBI, even when injury-induced neurogenesis was inhibited. This suggests that the therapeutic effects of donepezil in TBI occur separately from its effects on neurogenesis.

  6. Effectiveness and safety of donepezil in boys with fragile x syndrome: a double-blind, randomized, controlled pilot study.

    PubMed

    Sahu, Jitendra Kumar; Gulati, Sheffali; Sapra, Savita; Arya, Ravindra; Chauhan, Sandeepa; Chowdhury, Madhumita Roy; Gupta, Neerja; Kabra, Madhulika; Gupta, Y K; Dwivedi, S N; Kalra, Veena

    2013-05-01

    The present study was designed as a 12-week, randomized, double-blind, placebo-controlled pilot study to evaluate the effectiveness and safety of donepezil in boys with fragile X syndrome. Twenty boys with fragile X syndrome were randomized to receive 12 weeks of treatment with either placebo or donepezil (2.5 mg daily for initial 4 weeks followed by 5 mg daily for next 8 weeks). The outcome measures included change in intelligence quotient scores on Stanford-Binet Intelligence Scale (Hindi adaptation by Kulshrestha), change in behavioral scores by Conners 3 Parent Rating Scale (Short) and Childhood Autism Rating Scale, safety, and tolerability of donepezil. The study failed to show significant difference in intelligence quotient and behavioral scales with donepezil therapy over 12 weeks. However, donepezil appeared to be safe and well tolerated.

  7. APOE-ɛ4 Carrier Status and Donepezil Response in Patients with Alzheimer's Disease.

    PubMed

    Waring, Jeffrey F; Tang, Qi; Robieson, Weining Z; King, David P; Das, Ujjwal; Dubow, Jordan; Dutta, Sandeep; Marek, Gerard J; Gault, Laura M

    2015-01-01

    Previous studies have investigated associations between apolipoprotein E (APOE)-ɛ4 allele status and acetylcholinesterase inhibitor treatment response in patients with Alzheimer's disease. The ability to draw definitive conclusions regarding the effect of APOE-ɛ4 genotype on treatment response has been hindered by inconsistent results among studies and methodological limitations that restrict interpretation of study findings. To determine whether APOE-ɛ4 carrier status influences the magnitude of change in 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) score associated with acetylcholinesterase inhibitor treatment (i.e., donepezil). Analyses were performed using pooled data from the donepezil and placebo treatment arms of three consecutive, similarly designed, 12-week, multi-national, randomized clinical studies that enrolled patients with mild-to-moderate Alzheimer's disease. Correlations between APOE-ɛ4 carrier status and ADAS-cog scores were evaluated using analysis of covariance. No appreciable interaction between donepezil response and APOE-ɛ4 carrier status or copy number was detected. Both carriers and non-carriers of APOE-ɛ4 who received donepezil experienced significant improvements from baseline in ADAS-cog score versus placebo (p <  0.05). Change from baseline to final observation in the donepezil treatment group was - 2.95 for APOE-ɛ4 carriers and - 4.09 for non-carriers (p = 0.23). In contrast, non-carriers of APOE-ɛ4 in the placebo treatment group exhibited a greater improvement from baseline versus carriers (-2.38 versus - 0.60, p = 0.05). Within this population, APOE genotype had no statistically significant effect on cognitive response to donepezil treatment; however, APOE-ɛ4 allele status was associated with a difference in the magnitude of the change in ADAS-cog of placebo-treated patients.

  8. Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility

    PubMed Central

    Broad, J; Kung, V W S; Boundouki, G; Aziz, Q; De Maeyer, J H; Knowles, C H; Sanger, G J

    2013-01-01

    BACKGROUND AND PURPOSE Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimize side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the AChE inhibitor donepezil (used for Alzheimer's disease, with reduced cardio-bronchial liability) and prucalopride, the first selective, clinically available 5-HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon. EXPERIMENTAL APPROACH Neuronally mediated muscle contractions and relaxations of human colon were evoked by electrical field stimulation (EFS) and defined phenotypically as cholinergic, nitrergic or tachykinergic using pharmacological tools; the effects of drugs were determined as changes in ‘area under the curve’. KEY RESULTS Prucalopride increased cholinergically mediated contractions (EC50 855 nM; 33% maximum increase), consistent with its ability to stimulate intestinal motility; donepezil (477%) and neostigmine (2326%) had greater efficacy. Concentrations of donepezil (30–100 nM) found in venous plasma after therapeutic doses had minimal ability to enhance cholinergic activity. However, donepezil (30 nM) together with prucalopride (3, 10 μM) markedly increased EFS-evoked contractions compared with prucalopride alone (P = 0.04). For example, the increases observed with donepezil and prucalopride 10 μM together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n = 3–7, each concentration). CONCLUSIONS AND IMPLICATIONS Potential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction. PMID:24032987

  9. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis

    PubMed Central

    Christodoulou, C.; Melville, P.; Scherl, W.F.; Pai, L.-Y.; Muenz, L.R.; He, D.; Benedict, R.H.B.; Goodman, A.; Rizvi, S.; Schwid, S.R.; Weinstock-Guttman, B.; Westervelt, H.J.; Wishart, H.

    2011-01-01

    Objectives: The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT). Methods: Donepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18–59 years, clinically definite multiple sclerosis (MS), and performance ≤½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change. Results: A total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed. Conclusions: Donepezil did not improve memory as compared to placebo on either of the primary outcomes in this study. Classification of evidence: This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average. PMID:21519001

  10. Effects of donepezil treatment on rat nicotinic acetylcholine receptor levels in vivo and in vitro.

    PubMed

    Reid, Richard T; Sabbagh, Marwan N

    2003-12-01

    Research on acetylcholinesterase inhibitors (ChEIs) indicates that long term exposure increases the level of nicotinic acetylcholine receptors (nAChRs) but the effects of donepezil on nAChRs are not well studied. Therefore, we investigated the effects of sub-chronic donepezil administration on nAChRs in rats and rat pheochromocytoma PC-12 cells. Male Sprague Dawley rats were administered donepezil (0.7 and 2.4 micromoles/kg), nicotine (2.5 micromoles/kg) or saline subcutaneously twice daily for 14 days, PC-12 cells were incubated with 10(-6) to 10(-4) M donepezil for 72 hours and nAChR levels were determined by receptor binding assay using the nAChR ligands [3H]-epibatidine (EPI) for non-alpha 7 nAChRs and [3H]-methyllyconitine (MLA) for alpha 7 nAChRs. Chronic donepezil administration at 1.4 micromoles/kg/day and 4.8 micromoles/ kg/day significantly increased [3H]-epibatidine binding in the cortex to 126 +/- 1.3% and 127 +/- 3.2% of the saline control animals, respectively. [3H]-MLA binding in the cortex increased to 114 +/- 4.4% and 124 +/- 2.8% of the control group for the high and low dose groups, respectively. Hippocampal [3H]-EPI binding in the low dose and high dose groups significantly increased to 135 +/- 3.6% and 125 +/- 4.6% of the controls, respectively while there were no changes in the level of [3H]-MLA binding. In striatal homogenates, neither [3H]-EPI nor [3H]-MLA binding were significantly effected at either dose of donepezil. In PC-12 cells, [3H]-EPI binding was increased at the non-physiological 10(-4)M concentration only. There was no effect of donepezil on [3H]-MLA binding at any concentration examined. These results indicate that donepezil increases cortical alpha 7 and non-alpha 7 nAChRs, hippocampal non-alpha 7 nAChRs but does not influence striatal nAChR levels. Furthermore, the lack of an effect on the alpha 7-nAChRs in PC-12 cells suggests that the increase in cortical alpha 7 nAChRs may be an indirect effect of increased acetylcholine

  11. Donepezil Does Not Enhance Perceptual Learning in Adults with Amblyopia: A Pilot Study.

    PubMed

    Chung, Susana T L; Li, Roger W; Silver, Michael A; Levi, Dennis M

    2017-01-01

    Amblyopia is a developmental disorder that results in a wide range of visual deficits. One proven approach to recovering vision in adults with amblyopia is perceptual learning (PL). Recent evidence suggests that neuromodulators can enhance adult plasticity. In this pilot study, we asked whether donepezil, a cholinesterase inhibitor, enhances visual PL in adults with amblyopia. Nine adults with amblyopia were first trained on a low-contrast single-letter identification task while taking a daily dose (5 mg) of donepezil throughout training. Following 10,000 trials of training, participants showed improved contrast sensitivity for identifying single letters. However, the magnitude of improvement was no greater than, and the rate of improvement was slower than, that obtained in a previous study in which six adults with amblyopia were trained using an identical task and protocol but without donepezil (Chung et al., 2012). In addition, we measured transfer of learning effects to other tasks and found that for donepezil, the post-pre performance ratios in both a size-limited (acuity) and a spacing-limited (crowding) task were not significantly different from those found in the previous study without donepezil administration. After an interval of several weeks, six participants returned for a second course of training on identifying flanked (crowded) letters, again with concurrent donepezil administration. Although this task has previously been shown to be highly amenable to PL in adults with amblyopia (Chung et al., 2012; Hussain et al., 2012), only one observer in our study showed significant learning over 10,000 trials of training. Auxiliary experiments showed that the lack of a learning effect on this task during donepezil administration was not due to either the order of training of the two tasks or the use of a sequential training paradigm. Our results reveal that cholinergic enhancement with donepezil during training does not improve or speed up PL of single

  12. Economic evaluation of donepezil for the treatment of Alzheimer's disease in Canada.

    PubMed

    O'Brien, B J; Goeree, R; Hux, M; Iskedjian, M; Blackhouse, G; Gagnon, M; Gauthier, S

    1999-05-01

    Donepezil is a new drug recently approved in the United States and Canada for the treatment of Alzheimer's disease (AD). We estimated the cost-effectiveness of donepezil 5 mg daily as an adjunct to usual care in the management of persons with mild-to-moderate AD defined as a Mini-Mental Health State Examination (MMSE) score in the range 10 to 26. Treatment effect data as MMSE change-over-baseline scores were obtained from a 30-week placebo-controlled trial of donepezil. MMSE scores beyond observed trial data were estimated using a Markov model with 10 cycles of 24 weeks based on the placebo MMSE progression observed in the trial. Data from AD subjects in the Canadian Study of Health and Aging were used to estimate costs of nursing home care, community services, medications, and caregiver time as a function of MMSE score. A clinic-based cohort study from Alberta was used to estimate the distribution of AD patients by MMSE score presenting for treatment. The effectiveness measure for the economic model was expected time (over 5 years) spent with nonsevere AD (MMSE > or = 10). Over 5 years of treatment, donepezil is predicted to reduce health care costs by CA$929 per patient but increase caregiver time costs by CA$48 per patient for an overall cost saving to society of CA$882 per patient. Patients not receiving donepezil are predicted to spend 2.21 years of the 5 years in nonsevere AD compared with 2.41 years for treated patients (a gain of just over 2 months). Sensitivity analysis reveals that cost savings per patient increase if more AD patients are assumed to survive to 5 years; however, if donepezil treatment continues when patients' MMSE score falls below 10, the incremental cost is higher for treatment at CA$1554 per patient. Based on the limited available data, our model predicts that the use of donepezil for mild-to-moderate AD in Canada is associated with lower 5-year costs and less time spent with severe AD when compared with the alternative of usual care

  13. Postmortem redistribution mechanism of donepezil in the rat.

    PubMed

    Nagasawa, Sayaka; Katagiri, Nobuyuki; Nara, Akina; Chiba, Fumiko; Kubo, Yuko; Torimitsu, Suguru; Yajima, Daisuke; Akutsu, Mamoru; Iwase, Hirotaro

    2016-09-01

    Population aging is rapidly advancing in numerous parts of the world and, accordingly, the prevalence of Alzheimer's disease (AD) is rising. The safety of donepezil (DPZ), which is used for AD treatment, has been established in clinical trials. However, some studies have indicated that DPZ may be associated with severe cardiac side effects, and excessive doses may induce toxicity-related symptoms or death. Therefore, the measurement of blood DPZ levels is important for the postmortem investigation of related causes of death. However, postmortem drug concentrations in the blood may not always reflect those obtained antemortem because of the postmortem redistribution (PMR) of drugs. Therefore, the aim of this study was to investigate the potential PMR of DPZ using a rat model. The DPZ concentration was measured using a validated HPLC/Q-TOF-MS system in cardiac and peripheral blood, and in the brain, lungs, myocardium, liver, and thigh muscle at different postmortem intervals (0, 1, 3, 6, 12, and 24h). Overall, the DPZ tissue to peripheral blood ratio decreased throughout the postmortem period. Furthermore, the DPZ concentration increased in the peripheral and cardiac blood but decreased in both of the lungs, postmortem. Furthermore, the blood pH was significantly lowered. We used a perfusion approach to examine the rat lung and heart to further investigate the relationship between the pH and DPZ release from the lungs. The outflow concentrations when the inflow pH changed from 7.4 to 5.5 were approximately 2-fold higher than the inflow pH fixed 7.4. These findings suggest that the antemortem accumulated DPZ in the lungs is released into the pulmonary blood owing to postmortem acidification of blood, and subsequently flows into the cardiac blood, leading to the observed increase in concentration. Although we could not determine the underlying mechanism, we confirmed that PMR occurs similarly in the cardiac and peripheral blood. Copyright © 2016. Published by Elsevier

  14. A novel electronic skin patch for delivery and pharmacokinetic evaluation of donepezil following transdermal iontophoresis.

    PubMed

    Saluja, Sonal; Kasha, Purna C; Paturi, Jyotsna; Anderson, Carter; Morris, Russell; Banga, Ajay K

    2013-09-10

    The nature of Alzheimer's disease limits the effectiveness of available oral treatments. The aim of this study was to assess the feasibility of transdermal iontophoretic delivery of donepezil in a hairless rat model as a potential treatment modality in Alzheimer's and to evaluate the effect of current densities on its pharmacokinetics. Donepezil loaded integrated Wearable Electronic Drug Delivery (WEDD(®)) patches supplied current levels of 0, 0.13, 0.26 and 0.39 mA. Plasma extracted donepezil was analyzed by HPLC. Noncompartmental analysis was used to characterize disposition of the drug. The amount delivered across hairless rat skin and areas under the curve (AUC) were found to rise in proportion to the current levels. Peak plasma levels of 0.094, 0.237 and 0.336 μg/ml were achieved at 0.13, 0.26 and 0.39 mA respectively. Time to peak plasma concentrations was after termination of current and same for all current levels. Transdermal elimination half-life was significantly increased from the true value of 3.2h due to depot formation, prolonging complete absorption of the drug. Donepezil was successfully delivered iontophoretically at levels sufficient to produce pharmacodymanic effect. Pharmacokinetic analysis demonstrated linear kinetics at the current levels used and flip flop kinetics following iontophoretic administration. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Relevance of Donepezil in Enhancing Learning and Memory in Special Populations: A Review of the Literature

    ERIC Educational Resources Information Center

    Yoo, J. Helen; Valdovinos, Maria G.; Williams, Dean C.

    2007-01-01

    This review discusses the laboratory and clinical research supporting the rationale for the efficacy of donepezil (Aricept[R] USA) in enhancing cognition in autism, Alzheimer disease, Down syndrome, traumatic brain injury, Attention Deficit Hyperactivity Disorder (ADHD), and schizophrenia. While preliminary animal models have shown effective,…

  16. Efficacy and safety of donepezil in patients with Alzheimer's disease in assisted living facilities.

    PubMed

    Rosenblatt, Adam; Gao, Jeff; Mackell, Joan; Richardson, Sharon

    2010-09-01

    The aim of this 12-week, open-label study was to determine the safety and efficacy of donepezil in participants with Alzheimer's disease (AD) residing in assisted living facilities (ALFs). Participants received 5 mg donepezil daily for 6 weeks followed by 10 mg daily for 6 weeks. Primary and secondary outcomes were change from baseline in Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory 8 (NPI-8) scores, respectively. Safety was assessed by adverse events (AEs) and laboratory tests. Of the 97 participants, 76 completed the study. Mean MMSE score (18.7 at baseline) improved 1.8 points (P < .0001) at study end. Total NPI-8 score improved 1.8 points (P = .043). The most frequent AEs were nausea and diarrhea. Donepezil improved cognition and behavior and was safe and well tolerated. The results suggest a need for proactive screening and diagnosis of AD and support the value of treatment and use of donepezil in participants residing in ALFs.

  17. Donepezil effects on hippocampal and prefrontal functional connectivity in Alzheimer’s disease: Preliminary report

    PubMed Central

    Zaidel, Liam; Allen, Greg; Cullum, C. Munro; Briggs, Richard W.; Hynan, Linda S.; Weiner, Myron F.; McColl, Roderick; Gopinath, Kaundinya S.; McDonald, Elizabeth; Rubin, Craig D.

    2013-01-01

    We used functional connectivity magnetic resonance imaging (fcMRI) to investigate changes in interhemispheric brain connectivity in 11 patients with mild Alzheimer’s disease (AD) following eight weeks of treatment with the cholinesterase inhibitor donepezil. We examined functional connectivity between four homologous temporal, frontal, and occipital regions. These regions were selected to represent sites of AD neuropathology, sites of donepezil-related brain activation change in prior studies, and sites that are minimally affected by the pathologic changes of AD. Based on previous findings of selective, localized frontal responses to donepezil, we predicted that frontal connectivity would be most strongly impacted by treatment. Of the areas we examined, we found that treatment had a significant effect only on functional connectivity between right and left dorsolateral prefrontal cortices. Implications for understanding the impact of donepezil treatment on brain functioning and behavior in patients with AD are discussed. This preliminary report suggests that fcMRI may provide a useful index of treatment outcome in diseases affecting brain connectivity. Future research should investigate these treatment-related changes in larger samples of patients and age-matched controls. PMID:22886013

  18. Combination treatment in Alzheimer's disease: results of a randomized, controlled trial with cerebrolysin and donepezil.

    PubMed

    Alvarez, X Antón; Cacabelos, R; Sampedro, C; Couceiro, V; Aleixandre, M; Vargas, M; Linares, C; Granizo, E; García-Fantini, M; Baurecht, W; Doppler, E; Moessler, H

    2011-08-01

    Treatment with neurotrophic agents might enhance and/or prolong the effects of cholinesterase inhibitors (ChEIs) in Alzheimer's disease (AD). We compared the safety and efficacy of the neurotrophic compound Cerebrolysin (10 ml; n=64), donepezil (10 mg; n=66) and a combination of both treatments (n=67) in mild-to-moderate (mini-mental state examination-MMSE score 12-25) probable AD patients enrolled in a randomized, double-blind trial. Primary endpoints were global outcome (Clinician's Interview-Based Impression of Change plus caregiver input; CIBIC+) and cognition (change from baseline in AD Assessment Scale-cognitive subscale+; ADAS-cog+) at week 28. Changes in functioning (AD Cooperative Study-Activities of Daily Living scale, ADCS-ADL) and behaviour (Neuropsychiatric Inventory, NPI) were secondary endpoints. Treatment effects in cognitive, functional and behavioral domains showed no significant group differences; whereas improvements in global outcome favored Cerebrolysin and the combination therapy. Cognitive performance improved in all treatment groups (mean±SD for Cerebrolysin: -1.7±7.5; donepezil: -1.2±6.1; combination: -2.3±6.0) with best scores in the combined therapy group at all study visits. Cerebrolysin was as effective as donepezil, and the combination of neurotrophic (Cerebrolysin) and cholinergic (donepezil) treatment was safe in mild-to-moderate AD. The convenience of exploring long-term synergistic effects of this combined therapy is suggested.

  19. Relevance of Donepezil in Enhancing Learning and Memory in Special Populations: A Review of the Literature

    ERIC Educational Resources Information Center

    Yoo, J. Helen; Valdovinos, Maria G.; Williams, Dean C.

    2007-01-01

    This review discusses the laboratory and clinical research supporting the rationale for the efficacy of donepezil (Aricept[R] USA) in enhancing cognition in autism, Alzheimer disease, Down syndrome, traumatic brain injury, Attention Deficit Hyperactivity Disorder (ADHD), and schizophrenia. While preliminary animal models have shown effective,…

  20. Is donepezil therapy associated with reduced mortality in nursing home residents with dementia?

    PubMed

    Gasper, Mason C; Ott, Brian R; Lapane, Kate L

    2005-03-01

    Since cholinesterase inhibitors (CEIs) were approved for use in mild to moderate Alzheimer's disease, the therapeutic efficacy of this class of medications has largely centered on demonstration of short-term improvement in cognition and global function. Later evidence suggested that the beneficial effects of CEIs might be sustainable for at least 3 years and that CEIs may have a disease-modifying effect on Alzheimer's disease. These broad-ranging, long-term effects may explain the recent finding that the use of a CEI among nursing home residents with dementia was associated with lower mortality. The goal of this study was to investigate whether donepezil treatment is associated with reduced mortality in nursing home residents who have dementia. We performed a retrospective matched cohort study using the Systematic Assessment of Geriatric Drug Use via Epidemiology database, which contains data collected with the Minimum Data Set on a cross section of 915,469 nursing home residents aged > 65 years between 1998 and 2000 in 6 US states. We identified users of donepezil (5 and 10 mg) and an equal number of matched nonusers in the same facility, date of donepezil use, level of cognitive function, and dementia diagnosis. Comparisons of the 2 groups were made for sociodemographic variables, dementia severity, number of medications, and major comorbid illnesses (heart disease, cancer, diabetes mellitus, chronic obstructive pulmonary disease, and malnutrition), as well as survival over the 2-year study period. A total of 5423 users and 5423 nonusers of donepezil were identified. Based on Cox proportional hazards models, donepezil users showed a lower mortality rate than nonusers. The hazard rate ratio was 0.89 (95% CI, 0.83-0.95). After adjusting for the confounding variables, sociodemographic factors, other psychotropic drugs, and comorbid conditions, this survival advantage remained (hazard rate ratio, 0.90; 95% CI, 0.84-0.96). A relationship was observed between treatment

  1. Neuroprotection of donepezil against morphine-induced apoptosis is mediated through Toll-like receptors.

    PubMed

    Shafie, Alireza; Moradi, Farshid; Izadpanah, Esmael; Mokarizadeh, Aram; Moloudi, Mohammad Raman; Nikzaban, Mehrnoush; Hassanzadeh, Kambiz

    2015-10-05

    Previously, we had shown that donepezil provides anti-apoptotic effects associated with the prevention of morphine tolerance to the analgesic effect. In this regard, the present study aimed to evaluate the molecular mechanisms involved in this effect considering the possible role of Toll-like receptor (TLR) 2,4, and the balance between pre-apoptotic and anti-apoptotic Bcl family proteins. To this end, male Wistar rats received daily morphine in combination with either normal saline or donepezil (0.5, 1, or 1.5 mg/kg, ip). The analgesic effect was assessed by the plantar test apparatus. The latency was recorded when the animal responded to the light stimulus. On the 15th day, when no significant difference was observed between morphine and saline groups in terms of analgesia, the frontal cortex and lumbar spinal cord of the animals were dissected. Then, TLR2 and 4, Bcl2, and Bax mRNA fold changes were calculated using Real-time PCR method. The results indicated no significant analgesic effect in the morphine group compared with the saline treated animals after 15 days of injection, while daily co-administration of donepezil with morphine preserved significant analgesia. Moreover, Quantitative PCR showed that morphine significantly increased TLRs and Bax gene expressions and decreased the anti-apoptotic Bcl2. In contrast, donepezil prevented these morphine induced changes in the mentioned gene expressions. Taken together, the results suggest that the neuroprotective effects of donepezil in attenuating morphine-induced tolerance and apoptosis are mediated by preventing morphine-induced changes in TLR2 and 4 gene expressions.

  2. Apolipoprotein E epsilon4 allele differentiates the clinical response to donepezil in Alzheimer's disease.

    PubMed

    Bizzarro, A; Marra, C; Acciarri, A; Valenza, A; Tiziano, F D; Brahe, C; Masullo, C

    2005-01-01

    The existence of an association between apolipoprotein E (APOE) and Alzheimer's disease (AD) has been reported in several studies. The possession of an ApoE epsilon4 allele is now considered a genetic risk factor for sporadic AD. There has been a growing agreement about the role exerted by the ApoE epsilon4 allele on the neuropsychological profile and the rate of cognitive decline in AD patients. However, a more controversial issue remains about a possible influence of the APOE genotype on acetylcholinesterase inhibitor therapy response in AD patients. In order to address this issue, 81 patients diagnosed as having probable AD were evaluated by a complete neuropsychological test battery at the time of diagnosis (baseline) and after 12-16 months (retest). Patients were divided into two subgroups: (1) treated with donepezil at a dose of 5 mg once a day (n = 41) and (2) untreated (n = 40). Donepezil therapy was started after baseline evaluation. The APOE genotype was determined according to standardized procedures. We evaluated the possible effect of the APOE genotype on the neuropsychological tasks in relation to donepezil therapy. The statistical analysis of the results showed a global worsening of cognitive performances for all AD patients at the retest. Differences in the clinical outcome were analysed in the four subgroups of AD patients for each neuropsychological task. ApoE epsilon4 carriers/treated patients had improved or unchanged scores at retest evaluation for the following tasks: visual and verbal memory, visual attention and inductive reasoning and Mini Mental State Examination. These results indicate an effect of donepezil on specific cognitive domains (attention and memory) in the ApoE epsilon4 carriers with AD. This might suggest an early identification of AD patients carrying at least one epsilon4 allele as responders to donepezil therapy.

  3. Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial

    PubMed Central

    Rapp, Stephen R.; Case, L. Doug; Peiffer, Ann; Naughton, Michelle M.; Chan, Michael D.; Stieber, Volker W.; Moore, Dennis F.; Falchuk, Steven C.; Piephoff, James V.; Edenfield, William J.; Giguere, Jeffrey K.; Loghin, Monica E.; Shaw, Edward G.

    2015-01-01

    Purpose Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive function. Patients and Methods A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated. Results Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment. Conclusion Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments. PMID:25897156

  4. Neuropsychological test performance in healthy volunteers before and after donepezil administration.

    PubMed

    Beglinger, Leigh J; Gaydos, Brenda L; Kareken, David A; Tangphao-Daniels, Oranee; Siemers, Eric R; Mohs, Richard C

    2004-03-01

    Participants in early Phase I clinical trials for drugs designed to enhance cognition are typically healthy volunteers. If improvement can be detected with a battery of cognitive tests in healthy volunteers, such a battery could be a pharmacodynamic marker in the future development of the compound for treatment of cognitive disorders. In the present exploratory study, a battery of neuropsychological (NP) tests was used to determine if changes in cognition from a pharmacological intervention could be detected in healthy volunteers. A drug with known cognitive-enhancing effects in Alzheimer's disease, donepezil, was compared with placebo and no treatment arms. Carry-over effects of repeated test administration were also assessed. In this double-blind study, 27 healthy adults were randomized into one of three arms (eight donepezil, nine placebo and 10 no treatment) and completed 14 days of donepezil (5 mg q.h.s.) or placebo (q.h.s.). A battery of NP tests was administered on days 0, 7, 14 (randomization), 21, 28 (end of treatment) and 42 (washout). There were no differences in performance between the placebo and the no treatment arms. However, on day 21, subjects in the donepezil group performed slightly but significantly worse on some tests of speed, attention and memory (p < 0.05) compared to the pooled control group (placebo and no treatment arms). No improvement in performance was present while on donepezil at days 21 or 28. While the results are counter to expectations, some tests in the battery did detect a cognitive change (transient mild worsening during drug administration) in healthy volunteers.

  5. Psychoactive drugs and pilot performance: a comparison of nicotine, donepezil, and alcohol effects.

    PubMed

    Mumenthaler, Martin S; Yesavage, Jerome A; Taylor, Joy L; O'Hara, Ruth; Friedman, Leah; Lee, Hana; Kraemer, Helena C

    2003-07-01

    The cholinergic system plays a major role in cognitive abilities that are essential to piloting an aircraft: attention, learning, and memory. In previous studies, drugs that enhance the cholinergic system through different pharmacologic mechanisms have shown beneficial effects on cognition; but dissimilar cognitive measures were used and samples were not comparable. A comparison within the same cognitive tasks, within comparable samples appears desirable. Toward this aim, we compared effect sizes (ES) of performance-enhancing doses of nicotine (a nicotinic receptor agonist) and donepezil (an acetylcholinesterase inhibitor) as found in our prior work on pilot performance. We also compared cholinergic ES to those of performance-impairing doses of alcohol. In three randomized, placebo-controlled trials, we assessed the flight performance of aircraft pilots in a Frasca 141 simulator, testing I: the acute effects of nicotine gum 2 mg; II: the effects of administration of 5 mg donepezil/day for 30 days; and III: the acute and 8 h-carryover effects of alcohol after a target peak BAC of 0.10%. We calculated the ES of nicotine, donepezil, and alcohol on a flight summary score and on four flight component scores. Compared to placebo, nicotine and donepezil significantly improved, while alcohol significantly impaired overall flight performance: ES (nicotine)=0.80; ES (donepezil)=1.02; ES (alcohol acute)=-3.66; ES (alcohol 8 h)=-0.82. Both cholinergic drugs showed the largest effects on flight tasks requiring sustained visual attention. Although the two tested cholinergic drugs have different pharmacologic mechanisms, their effects on flight performance were similar in kind and size. The beneficial effects of the cholinergic drugs on overall flight performance were large and the absolute (ie nondirectional) sizes were about one-fourth of the absolute ES of acute alcohol intoxication and roughly the same as the absolute 8 h-carryover ES of alcohol.

  6. Donepezil delays progression to AD in MCI subjects with depressive symptoms.

    PubMed

    Lu, P H; Edland, S D; Teng, E; Tingus, K; Petersen, R C; Cummings, J L

    2009-06-16

    To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship. The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD. Cox proportional hazards regression, adjusted for age at baseline, gender, apolipoprotein genotype, and NYU paragraph delayed recall score, showed that higher BDI scores were associated with progression to AD (p = 0.03). The sample was stratified into depressed (BDI score > or =10; n = 208) and nondepressed (BDI <10; n = 548) groups. Kaplan-Meier analysis showed that among the depressed subjects, the proportion progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 years (p = 0.023), at 2.2 years (p = 0.025), and remained marginally lower at 2.7 years (p = 0.070). The survival curves among the three treatment groups did not differ within the nondepressed participants. Results suggest that depression is predictive of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and treatment with donepezil delayed progression to AD among depressed subjects with aMCI. Donepezil appears to modulate the increased risk of AD conferred by the presence of depressive symptoms.

  7. Improvement of Visuo-spatial Function Assessed by Raven’s Colored Progressive Matrices in Dementia with Lewy Bodies by Donepezil Treatment

    PubMed Central

    Yoshino, Yuta; Mori, Takaaki; Yoshida, Taku; Toyota, Yasutaka; Shimizu, Hideaki; Iga, Jun-ichi; Nishitani, Shusaku; Ueno, Shu-ichi

    2017-01-01

    Objective Donepezil is used to improve cognitive impairment of dementia with Lewy bodies (DLB). Visuo-spatial dysfunction is a well-known symptom of DLB. Non-verbal Raven’s Colored Progressive Matrices (RCPM) were used to assess both visual perception and reasoning ability in DLB subjects treated with donepezil. Methods Twenty-one DLB patients (mean age, 78.7±4.5 years) were enrolled. RCPM assessment was performed at the time of starting donepezil and within one year after starting donepezil. Results There were significant improvements of RCPM in the total scores between one year donepezil treatment (p=0.013), in both Set A score (p=0.002) and Set AB score (p=0.015), but trend in the Set B score (p=0.083). Conclusion Donepezil is useful for improving visuo-spatial impairment in DLB, but not for problem-solving impairment. PMID:28783933

  8. Conformational analysis and parallel QM/MM X-ray refinement of protein bound anti-Alzheimer drug donepezil.

    PubMed

    Fu, Zheng; Li, Xue; Miao, Yipu; Merz, Kenneth M

    2013-12-03

    The recognition and association of donepezil with acetylcholinesterase (AChE) has been extensively studied in the past several decades because of the former's use as a palliative treatment for mild Alzheimer disease. Herein we examine the conformational properties of donepezil and we re-examine the donepezil-AChE crystal structure using combined quantum mechanical/molecular mechanical (QM/MM) X-ray refinement tools. Donepezil's conformational energy surface was explored using the M06 suite of density functionals and with the MP2/complete basis set (CBS) method using the aug-cc-pVXZ (X = D and T) basis sets. The donepezil-AChE complex (PDB 1EVE) was also re-refined through a parallel QM/MM X-ray refinement approach based on an in-house ab initio code QUICK, which uses the message passing interface (MPI) in a distributed SCF algorithm to accelerate the calculation via parallelization. In the QM/MM re-refined donepezil structure, coordinate errors that previously existed in the PDB deposited geometry were improved leading to an improvement of the modeling of the interaction between donepezil and the aromatic side chains located in the AChE active site gorge. As a result of the re-refinement there was a 93% reduction in the donepezil conformational strain energy versus the original PDB structure. The results of the present effort offer further detailed structural and biochemical inhibitor-AChE information for the continued development of more effective and palliative treatments of Alzheimer disease.

  9. Spectroscopic studies of solid-state forms of donepezil free base and salt forms with various salicylic acids

    NASA Astrophysics Data System (ADS)

    Brittain, Harry G.

    2014-12-01

    The polymorphic forms of donepezil free base have been studied using X-ray powder diffraction, Fourier transform infrared absorption spectroscopy, and differential scanning calorimetry. None of the free base crystal forms was observed to exhibit detectable fluorescence in the solid state under ambient conditions. Crystalline salt products were obtained by the reaction of donepezil with salicylic and methyl-substituted salicylic acids, with the salicylate and 4-methylsalicylate salts being obtained as non-solvated products, and the 3-methylsalicylate and 5-methylsalicylate salts being obtained as methanol solvated products. The intensity of solid-state fluorescence from donepezil salicylate and donepezil 4-methylsalicylate was found to be reduced relative to the fluorescence intensity of the corresponding free acids, while the solid-state fluorescence intensity of donepezil 3-methylsalicylate methanolate and donepezil 5-methylsalicylate methanolate was greatly increased relative to the fluorescence intensity of the corresponding free acids. Desolvation of the solvated salt products led to formation of glassy solids that exhibited strong green fluorescence.

  10. Donepezil combined with natural hirudin improves the clinical symptoms of patients with mild-to-moderate Alzheimer's disease: a 20-week open-label pilot study.

    PubMed

    Li, De-qiang; Zhou, Yu-ping; Yang, Han

    2012-01-01

    To evaluate the efficacy and safety of donepezil plus natural hirudin in patients with mild-to-moderate Alzheimer's Disease. In the 20-week, randomized, open-label and controlled study, 84 patients received either donepezil (5 mg/day for the first 4 weeks and 10 mg/day thereafter) or donepezil plus natural hirudin (3 g/day) treatment. Efficacy was reflected by the change of the total scores of Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog), Activities of Daily Life (ADL) and Neuropsychiatric Inventory (NPI). The patients with the donepezil plus natural hirudin treatment showed more significant improvement in the daily activities and the decline of the cognition than those with donepezil treatment. Significant difference was present in the groups since the 8th week. No group difference was found in the NPI change. However, within the hirudin treatment group, more powerful efficacy including NPI assessment was found in the patients with vascular risk factors (VRF) as comparing to with those without VRF. The combination of donepezil and natural hirudin was well tolerated. The dropout rate was greater in the donepezil and natural hirudin (50%) treatment group than in the donepezil (39%) treatment group. Similar result was found in the incidence of adverse events (23.8% vs 19.0%), but there was no statistical difference between the two groups. Adverse events were the most common reason for the dropout. Although hemorrhage and hypersensitiveness were more common in donepezil plus Maixuekang treatment (11.9% and 7.1%) group than in donepezil treatment (2.4% and 2.4%) group, no significant difference was present between the two groups. Economic problem was another important reason for the patients' withdrawal. Compared with the donepezil treatment in the patients with mild-to-moderate AD, our results suggest that donepezil combined with natural hirudin may improve the treatment effects in the ADL, BPSD and cognition of the patients. Furthermore, this

  11. Clinical Recommendations for the Use of Donepezil 23 mg in Moderate-to-Severe Alzheimer's Disease in the Asia-Pacific Region

    PubMed Central

    Sabbagh, Marwan; Han, SeolHeui; Kim, SangYun; Na, Hae-Ri; Lee, Jae-Hong; Kandiah, Nagaendran; Phanthumchinda, Kammant; Suthisisang, Chuthamanee; Senanarong, Vorapun; Pai, Ming-Chyi; Narilastri, Diatri; Sowani, Ajit M.; Ampil, Encarnita; Dash, Amitabh

    2016-01-01

    Background The ‘Asia-Pacific Expert Panel (APEX) for donepezil 23 mg’ met in November 2015 to review evidence for the recently approved high dose of donepezil and to provide recommendations to help physicians in Asia make informed clinical decisions about using donepezil 23 mg in patients with moderate-to-severe Alzheimer's disease (AD). Summary In a global phase III study (study 326) in patients with moderate-to-severe AD, donepezil 23 mg/day demonstrated significantly greater cognitive benefits versus donepezil 10 mg/day, with a between-treatment difference in mean change in the Severe Impairment Battery score of 2.2 points (p < 0.001) in the overall population and 3.1 points (p < 0.001) in patients with advanced AD. A subanalysis of study 326 demonstrated that the benefits and risks associated with donepezil 23 mg/day versus donepezil 10 mg/day in Asian patients with moderate-to-severe AD were comparable to those in the global study population. Key Message Donepezil 23 mg is a valuable treatment for patients with AD, particularly those with advanced disease. The APEX emphasized the importance of patient selection (AD severity, tolerability of lower doses of donepezil, and absence of contraindications), a stepwise titration strategy for dose escalation, and appropriate monitoring and counseling of patients and caregivers in the management of patients with AD. PMID:27703471

  12. Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A, ABCB1, POR and NR1I2 genotypes on donepezil clearance.

    PubMed

    Noetzli, Muriel; Guidi, Monia; Ebbing, Karsten; Eyer, Stephan; Wilhelm, Laurence; Michon, Agnès; Thomazic, Valérie; Stancu, Ioana; Alnawaqil, Abdel-Messieh; Bula, Christophe; Zumbach, Serge; Gaillard, Michel; Giannakopoulos, Panteleimon; von Gunten, Armin; Csajka, Chantal; Eap, Chin B

    2014-07-01

    A large interindividual variability in plasma concentrations has been reported in patients treated with donepezil, the most frequently prescribed antidementia drug. We aimed to evaluate clinical and genetic factors influencing donepezil disposition in a patient population recruited from a naturalistic setting. A population pharmacokinetic study was performed including data from 129 older patients treated with donepezil. The patients were genotyped for common polymorphisms in the metabolic enzymes CYP2D6 and CYP3A, in the electron transferring protein POR and the nuclear factor NR1I2 involved in CYP activity and expression, and in the drug transporter ABCB1. The average donepezil clearance was 7.3 l h(-1) with a 30% interindividual variability. Gender markedly influenced donepezil clearance (P < 0.01). Functional alleles of CYP2D6 were identified as unique significant genetic covariate for donepezil clearance (P < 0.01), with poor metabolizers and ultrarapid metabolizers demonstrating, respectively, a 32% slower and a 67% faster donepezil elimination compared with extensive metabolizers. The pharmacokinetic parameters of donepezil were well described by the developed population model. Functional alleles of CYP2D6 significantly contributed to the variability in donepezil disposition in the patient population and should be further investigated in the context of individual dose optimization to improve clinical outcome and tolerability of the treatment. © 2014 The British Pharmacological Society.

  13. Memantine and donepezil: a fixed drug combination for the treatment of moderate to severe Alzheimer's dementia.

    PubMed

    Owen, R T

    2016-04-01

    Donepezil (and other cholinesterase inhibitors [ChEIs]) and memantine are the mainstays of treatment in Alzheimer's dementia, addressing respectively, the cholinergic and glutamatergic dysregulation which underlies or results from its pathophysiology. To alleviate the pill burden and swallowing difficulties associated with the condition, a fixed drug combination of extended-release memantine and donepezil was developed. This combination was shown to be both bioequivalent to the components administered separately and could be administered sprinkled over soft food. The mode of action, pharmacokinetics, clinical efficacy and safety and tolerability of the combination are discussed together with the wider, often conflicting trial literature of combination versus monotherapy with memantine and ChEIs, their meta-analyses and treatment guidelines.

  14. GOOD or BAD Responder? Behavioural and Neuroanatomical Markers of Clinical Response to Donepezil in Dementia

    PubMed Central

    Bottini, Gabriella; Berlingeri, Manuela; Basilico, Stefania; Passoni, Serena; Danelli, Laura; Colombo, Nadia; Sberna, Maurizio; Franceschi, Massimo; Sterzi, Roberto; Paulesu, Eraldo

    2012-01-01

    We explored the neuropsychological and neuromorphometrical differences between probable Alzheimer's disease patients showing a good or a bad response to nine months treatment with donepezil. Before treatment, the neuropsychological profile of the two patient groups was perfectly matched. By the ninth month after treatment, the BAD-responders showed a decline of the MMSE score together with a progressive impairment of executive functions. A voxel-based morphometry investigation (VBM), at the time of the second neuropsychological assessment, showed that the BAD-responders had larger grey and white matter atrophies involving the substantia innominata of Meynert bilaterally, the ventral part of caudate nuclei and the left uncinate fasciculus, brain areas belonging to the cholinergic pathways. A more widespread degeneration of the central cholinergic pathways may explain the lack of donepezil efficacy in those patients not responding to a treatment that operates on the grounds that some degree of endogeneous release of acetylcholine is still available. PMID:22530263

  15. Donepezil Treatment of Older Adults with Cognitive Impairment and Depression (DOTCODE study): clinical rationale and design

    PubMed Central

    Pelton, Gregory H.; Andrews, Howard; Roose, Steven P.; Marcus, Sue M.; D’Antonio, Kristina; Husn, Hala; Petrella, Jeffrey R.; Zannas, Anthony S.; Doraiswamy, P. Murali; Devanand, D. P.

    2014-01-01

    Treatment strategies for patients with depression and cognitive impairment (DEP-CI), who are at high risk to develop a clinical diagnosis of dementia, are not established. This issue is addressed in the donepezil treatment of cognitive impairment and depression (DOTCODE) pilot clinical trial. The DOTCODE study is the first long-term treatment trial that assesses differences in conversion to dementia and cognitive change in DEP-CI patients using a study design of open antidepressant medication plus add-on randomized, double-blind, placebo-controlled treatment with the acetylcholinesterase inhibitor donepezil. In Phase 1, DEP-CI patients receive optimized antidepressant treatment for 16 weeks. In Phase 2, antidepressant treatment is continued with the addition of randomized, double-blind treatment with donepezil or placebo. The total study duration for each patient is 78 weeks (18 months). Eighty DEP-CI outpatients (age 55 to 95 years) are recruited: 40 at New York State Psychiatric Institute/Columbia University and 40 at Duke University Medical Center. The primary outcome is conversion to a clinical diagnosis of dementia. The secondary outcomes are cognitive change scores in Selective Reminding Test (SRT) total recall and the modified Alzheimer’s Disease Assessment Scale (ADAS-cog). Other key assessments include the 24-item Hamilton Depression Rating Scale and antidepressant response; Clinical Global Impression (CGI) for depression, cognition, and global status; neuropsychological test battery for diagnosis; informant report of functional abilities (Pfeffer FAQ); Treatment Emergent Symptom Scale (TESS) for somatic side effects. Apolipoprotein E ε4 status, odor identification deficits, and MRI entorhinal/hippocampal cortex atrophy at baseline are evaluated as neurobiological moderators of donepezil treatment effects. PMID:24315979

  16. Protein Expression of BACE1 is Downregulated by Donepezil in Alzheimer's Disease Platelets.

    PubMed

    Sarno, Tamires Alves; Talib, Leda Leme; Joaquim, Helena Passarelli Giroud; Bram, Jessyka Maria de França; Gattaz, Wagner Farid; Forlenza, Orestes Vicente

    2017-01-01

    Abnormal amyloid-β protein precursor (AβPP) metabolism is a key feature of Alzheimer's disease (AD). Platelets contain most of the enzymatic machinery required for AβPP processing, and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. Thus, AβPP-related molecules in platelets may be regarded as peripheral markers of AD. We sought to determine the protein expression of the AβPP secretases (ADAM10, BACE1, and PSEN1) and AβPP ratio in platelets of patients with mild or moderate AD compared to healthy controls. We further determined whether the protein expression of these markers might be modified by chronic treatment with donepezil. Platelet samples were obtained from patients and controls at baseline and after 3 and 6 months of continuous treatment with therapeutic doses of donepezil. The protein expression of platelet markers was determined by western blotting. AD patients had a significant decrease in AβPP ratio, ADAM10, and PSEN1 compared to controls at baseline, but these differences were not modified by the treatment. Nonetheless, a significant reduction in the protein expression of BACE1 was observed in patients treated with donepezil for 6 months. Our results corroborate previous findings from our group and others of decreased AβPP ratio and protein expression of ADAM10 in AD. We further show that PSEN1 is decreased in AD platelets, and that the protein expression of BACE1 is downregulated by chronic treatment with donepezil. This effect may be interpreted as evidence of disease modification.

  17. Donepezil treatment of older adults with cognitive impairment and depression (DOTCODE study): clinical rationale and design.

    PubMed

    Pelton, Gregory H; Andrews, Howard; Roose, Steven P; Marcus, Sue M; D'Antonio, Kristina; Husn, Hala; Petrella, Jeffrey R; Zannas, Anthony S; Doraiswamy, P Murali; Devanand, D P

    2014-03-01

    Treatment strategies for patients with depression and cognitive impairment (DEP-CI), who are at high risk to develop a clinical diagnosis of dementia, are not established. This issue is addressed in the donepezil treatment of cognitive impairment and depression (DOTCODE) pilot clinical trial. The DOTCODE study is the first long-term treatment trial that assesses differences in conversion to dementia and cognitive change in DEP-CI patients using a study design of open antidepressant medication plus add-on randomized, double-blind, placebo-controlled treatment with the acetylcholinesterase inhibitor donepezil. In Phase 1, DEP-CI patients receive optimized antidepressant treatment for 16 weeks. In Phase 2, antidepressant treatment is continued with the addition of randomized, double-blind treatment with donepezil or placebo. The total study duration for each patient is 78 weeks (18 months). Eighty DEP-CI outpatients (age 55 to 95 years) are recruited: 40 at New York State Psychiatric Institute/Columbia University and 40 at Duke University Medical Center. The primary outcome is conversion to a clinical diagnosis of dementia. The secondary outcomes are cognitive change scores in Selective Reminding Test (SRT) total recall and the modified Alzheimer's Disease Assessment Scale (ADAS-cog). Other key assessments include the 24-item Hamilton Depression Rating Scale and antidepressant response; Clinical Global Impression (CGI) for depression, cognition, and global status; neuropsychological test battery for diagnosis; informant report of functional abilities (Pfeffer FAQ); and Treatment Emergent Symptom Scale (TESS) for somatic side effects. Apolipoprotein E ε4 status, odor identification deficits, and MRI entorhinal/hippocampal cortex atrophy at baseline are evaluated as neurobiological moderators of donepezil treatment effects.

  18. The protective role of tacrine and donepezil in the retina of acetylcholinesterase knockout mice

    PubMed Central

    Yi, Yun-Min; Cai, Li; Shao, Yi; Xu, Man; Yi, Jing-Lin

    2015-01-01

    AIM To determine the effect of different concentrations of the acetylcholinesterase (AChE) inhibitors tacrine and donepezil on retinal protection in AChE+/− mice (AChE knockout mice) of various ages. METHODS Cultured ARPE-19 cells were treated with hydrogen peroxide (H2O2) at concentrations of 0, 250, 500, 1000 and 2000 µmol/L and protein levels were measured using Western blot. Intraperitoneal injections of tacrine and donepezil (0.1 mg/mL, 0.2 mg/mL and 0.4 mg/mL) were respectively given to AChE+/− mice aged 2mo and 4mo and wild-type S129 mice for 7d; phosphate buffered saline (PBS) was administered to the control group. The mice were sacrificed after 30d by in vitro cardiac perfusion and retinal samples were taken. AChE-deficient mice were identified by polymerase chain reaction (PCR) analysis using specific genotyping protocols obtained from the Jackson Laboratory website. H&E staining, immunofluorescence and Western blot were performed to observe AChE protein expression changes in the retinal pigment epithelial (RPE) cell layer. RESULTS Different concentrations of H2O2 induced AChE expression during RPE cell apoptosis. AChE+/− mice retina were thinner than those in wild-type mice (P<0.05); the retinal structure was still intact at 2mo but became thinner with increasing age (P<0.05); furthermore, AChE+/− mice developed more slowly than wild-type mice (P<0.05). Increased concentrations of tacrine and donepezil did not significantly improve the protection of the retina function and morphology (P>0.05). CONCLUSION In vivo, tacrine and donepezil can inhibit the expression of AChE; the decrease of AChE expression in the retina is beneficial for the development of the retina. PMID:26558196

  19. Safety and efficacy of donepezil in African Americans with mild-to-moderate Alzheimer's disease.

    PubMed Central

    Griffith, Patrick; Lichtenberg, Peter; Goldman, Robert; Payne-Parrish, Jennifer

    2006-01-01

    BACKGROUND: African Americans have a higher incidence and prevalence of Alzheimer's disease (AD) than whites but have been underrepresented in clinical trials, including studies of cholinesterase inhibitors. PURPOSE: The purpose of this 12-week, open-label study was to evaluate the efficacy and safety of donepezil in African Americans with mild-to-moderate AD. METHODS: Efficacy was assessed via the Mini-Mental State Examination (MMSE), Clinician's Interview-Based Impression of Change-Plus interview with the patient and caregiver (CIBIC-Plus) and Fuld Object Memory Evaluation (FOME), a measure that has been validated for use with elderly African Americans. RESULTS: Significant improvements were observed in cognition (MMSE), global function (CIBIC-Plus) and memory (all four subscales of the FOME). Donepezil was well tolerated; 51% of patients experienced adverse events, most commonly diarrhea (5.6%), hypertension (5.6%) and urinary tract infection (4.8%). CONCLUSIONS: These results suggest that donepezil is effective and safe in treating African Americans with mild-to-moderate AD, and support the value of FOME in assessing efficacy in AD trials in diverse populations. PMID:17052048

  20. Safety and efficacy of donepezil in African Americans with mild-to-moderate Alzheimer's disease.

    PubMed

    Griffith, Patrick; Lichtenberg, Peter; Goldman, Robert; Payne-Parrish, Jennifer

    2006-10-01

    African Americans have a higher incidence and prevalence of Alzheimer's disease (AD) than whites but have been underrepresented in clinical trials, including studies of cholinesterase inhibitors. The purpose of this 12-week, open-label study was to evaluate the efficacy and safety of donepezil in African Americans with mild-to-moderate AD. Efficacy was assessed via the Mini-Mental State Examination (MMSE), Clinician's Interview-Based Impression of Change-Plus interview with the patient and caregiver (CIBIC-Plus) and Fuld Object Memory Evaluation (FOME), a measure that has been validated for use with elderly African Americans. Significant improvements were observed in cognition (MMSE), global function (CIBIC-Plus) and memory (all four subscales of the FOME). Donepezil was well tolerated; 51% of patients experienced adverse events, most commonly diarrhea (5.6%), hypertension (5.6%) and urinary tract infection (4.8%). These results suggest that donepezil is effective and safe in treating African Americans with mild-to-moderate AD, and support the value of FOME in assessing efficacy in AD trials in diverse populations.

  1. Donepezil delays progression to AD in MCI subjects with depressive symptoms

    PubMed Central

    Lu, P H.; Edland, S D.; Teng, E; Tingus, K; Petersen, R C.; Cummings, J L.

    2009-01-01

    Objective: To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship. Methods: The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD. Results: Cox proportional hazards regression, adjusted for age at baseline, gender, apolipoprotein genotype, and NYU paragraph delayed recall score, showed that higher BDI scores were associated with progression to AD (p = 0.03). The sample was stratified into depressed (BDI score ≥10; n = 208) and nondepressed (BDI <10; n = 548) groups. Kaplan-Meier analysis showed that among the depressed subjects, the proportion progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 years (p = 0.023), at 2.2 years (p = 0.025), and remained marginally lower at 2.7 years (p = 0.070). The survival curves among the three treatment groups did not differ within the nondepressed participants. Conclusions: Results suggest that depression is predictive of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and treatment with donepezil delayed progression to AD among depressed subjects with aMCI. Donepezil appears to modulate the increased risk of AD conferred by the presence of depressive symptoms. GLOSSARY AD = Alzheimer disease; ADCS = Alzheimer's Disease Cooperative Study; aMCI = amnestic mild cognitive impairment; BDI = Beck Depression Inventory; CDR = Clinical Dementia Rating; ChEI = cholinesterase inhibitors; DSM-IV = Diagnostic and Statistical Manual

  2. Changes in cerebral neurotransmitters and metabolites induced by acute donepezil and memantine administrations: a microdialysis study.

    PubMed

    Shearman, E; Rossi, S; Szasz, B; Juranyi, Z; Fallon, S; Pomara, N; Sershen, H; Lajtha, A

    2006-03-31

    Cholinesterase inhibitors including donepezil, rivastigmine, and galantamine and the N-methyl-D-aspartate (NMDA) antagonist, memantine are the medications currently approved for the treatment of Alzheimer's disease (AD). In addition to their beneficial effects on cognitive and functional domains typically disrupted in AD, these agents have also been shown to slow down the emergence of behavioral and psychotic symptoms associated with this disease. However, the underlying mechanisms for these therapeutic effects remain poorly understood and could involve effects of these medications on non-cholinergic or non-glutamatergic neurotransmitter systems respectively. These considerations prompted us to initiate a series of investigations to examine the acute and chronic effects of donepezil (Aricept (+/-)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-1 hydrochloride and memantine (1-amino-3,5-dimethyladamantane hydrochloride C12H21N.HCl)). The present study focuses on the acute effects of donepezil and memantine on brain extracellular levels of acetylcholine, dopamine, serotonin, norepinephrine and their metabolites. We assayed changes in the ventral and dorsal hippocampus and the prefrontal and medial temporal cortex by microdialysis. Memantine resulted in significant increases in extracellular dopamine (DA), norepinephrine (NE), and their metabolites, in the cortical regions, and in a reduction of DA in the hippocampus. Donepezil produced an increase in extracellular DA in the cortex and in the dorsal hippocampus. Norepinephrine increased in the cortex; with donepezil it increased in the dorsal hippocampus and the medial temporal cortex, and decreased in the ventral hippocampus. Interestingly both compounds decreased extracellular serotonin (5HT) levels. The metabolites of the neurotransmitters were increased in most areas. We also found an increase in extracellular acetylcholine (ACh) by memantine in the nucleus accumbens and the

  3. Subgroup analysis of US and non-US patients in a global study of high-dose donepezil (23 mg) in moderate and severe Alzheimer's disease.

    PubMed

    Salloway, Stephen; Mintzer, Jacobo; Cummings, Jeffrey L; Geldmacher, David; Sun, Yijun; Yardley, Jane; Mackell, Joan

    2012-09-01

    To better understand responses in the large number of US-based patients included in a global trial of donepezil 23 mg/d versus 10 mg/d for moderate-to-severe Alzheimer's disease (AD), post hoc exploratory analyses were performed to assess the efficacy and safety in US and non-US (rest of the world [RoW]) patient subgroups. In both subgroups, donepezil 23 mg/d was associated with significantly greater cognitive benefits than donepezil 10 mg/d. Significant global function benefits of donepezil 23 mg/d over 10 mg/d were also observed in the US subgroup only. Compared with RoW patients, US patients had relatively more severe AD, had been treated with donepezil 10 mg/d for longer periods prior to the start of the study, and a higher proportion took concomitant memantine. In both subgroups, donepezil had acceptable tolerability; overall incidence of treatment-emergent adverse events was higher in patients receiving donepezil 23 mg/d compared with donepezil 10 mg/d.

  4. Normal Hearing Ability but Impaired Auditory Selective Attention Associated with Prediction of Response to Donepezil in Patients with Alzheimer's Disease

    PubMed Central

    Ouchi, Yoshitaka; Meguro, Kenichi; Akanuma, Kyoko; Kato, Yuriko; Yamaguchi, Satoshi

    2015-01-01

    Background. Alzheimer's disease (AD) patients have a poor response to the voices of caregivers. After administration of donepezil, caregivers often find that patients respond more frequently, whereas they had previously pretended to be “deaf.” We investigated whether auditory selective attention is associated with response to donepezil. Methods. The subjects were40 AD patients, 20 elderly healthy controls (HCs), and 15 young HCs. Pure tone audiometry was conducted and an original Auditory Selective Attention (ASA) test was performed with a MoCA vigilance test. Reassessment of the AD group was performed after donepezil treatment for 3 months. Results. Hearing level of the AD group was the same as that of the elderly HC group. However, ASA test scores decreased in the AD group and were correlated with the vigilance test scores. Donepezil responders (MMSE 3+) also showed improvement on the ASA test. At baseline, the responders had higher vigilance and lower ASA test scores. Conclusion. Contrary to the common view, AD patients had a similar level of hearing ability to healthy elderly. Auditory attention was impaired in AD patients, which suggests that unnecessary sounds should be avoided in nursing homes. Auditory selective attention is associated with response to donepezil in AD. PMID:26161001

  5. Efficacy of Memantine, Donepezil, or Their Association in Moderate-Severe Alzheimer's Disease: A Review of Clinical Trials

    PubMed Central

    Molino, Ivana; Colucci, Luisa; Fasanaro, Angiola M.

    2013-01-01

    Background. Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer's disease (AD), respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage. Objectives. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD. Method. Double-blind, placebo-controlled randomized trials (RCTs) using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007–2012. Results and Conclusion. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of “adequacy and representativeness.” Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24–52 weeks), and the different cognitive assessment tools used did not allow comparing properly different trials. PMID:24288512

  6. Efficacy of memantine, donepezil, or their association in moderate-severe Alzheimer's disease: a review of clinical trials.

    PubMed

    Molino, Ivana; Colucci, Luisa; Fasanaro, Angiola M; Traini, Enea; Amenta, Francesco

    2013-01-01

    Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer's disease (AD), respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD. Double-blind, placebo-controlled randomized trials (RCTs) using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007-2012. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of "adequacy and representativeness." Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24-52 weeks), and the different cognitive assessment tools used did not allow comparing properly different trials.

  7. Concurrent administration of donepezil HCl and theophylline: assessment of pharmacokinetic changes following multiple-dose administration in healthy volunteers

    PubMed Central

    Tiseo, P J; Foley, K; Friedhoff, L T

    1998-01-01

    Aim The aim of the study was to evaluate the pharmacokinetics of theophylline administered alone, and in combination with donepezil HCl, following multiple-dose administration of both drugs in healthy volunteers. Methods This was an open-label, randomized, two-period crossover study in healthy male volunteers (n = 12). During each treatment period, subjects received either titrated-dose theophylline alone, or in combination with donepezil (5 mg, once daily) for 10 consecutive days. On day 10 of each treatment period, serial blood samples for the determination of theophylline concentrations in plasma were measured up to 24 h. Treatment periods were separated by a 3-week, drug-free washout. Plasma concentrations of theophylline were determined by HPLC with UV detection. Results No statistically significant differences in theophylline pharmacokinetics (Cmax, AUC or tmax) were observed between theophylline administered alone and in combination with donepezil. No clinically significant changes in vital signs, ECG parameters or clinical laboratory tests were observed in any subject during any treatment period. Conclusions Concurrent administration of donepezil HCl does not alter the pharmacokinetic profile of theophylline following multiple-dose administration of both drugs in healthy volunteers. These findings suggest that donepezil may be safely co-administered with theophylline without a need for dose modification or additional monitoring procedures. PMID:9839764

  8. Multi-Target Directed Donepezil-Like Ligands for Alzheimer's Disease

    PubMed Central

    Unzeta, Mercedes; Esteban, Gerard; Bolea, Irene; Fogel, Wieslawa A.; Ramsay, Rona R.; Youdim, Moussa B. H.; Tipton, Keith F.; Marco-Contelles, José

    2016-01-01

    HIGHLIGHTS ASS234 is a MTDL compound containing a moiety from Donepezil and the propargyl group from the PF 9601N, a potent and selective MAO B inhibitor. This compound is the most advanced anti-Alzheimer agent for preclinical studies identified in our laboratory.Derived from ASS234 both multipotent donepezil-indolyl (MTDL-1) and donepezil-pyridyl hybrids (MTDL-2) were designed and evaluated as inhibitors of AChE/BuChE and both MAO isoforms. MTDL-2 showed more high affinity toward the four enzymes than MTDL-1.MTDL-3 and MTDL-4, were designed containing the N-benzylpiperidinium moiety from Donepezil, a metal- chelating 8-hydroxyquinoline group and linked to a N-propargyl core and they were pharmacologically evaluated.The presence of the cyano group in MTDL-3, enhanced binding to AChE, BuChE and MAO A. It showed antioxidant behavior and it was able to strongly complex Cu(II), Zn(II) and Fe(III).MTDL-4 showed higher affinity toward AChE, BuChE.MTDL-3 exhibited good brain penetration capacity (ADMET) and less toxicity than Donepezil. Memory deficits in scopolamine-lesioned animals were restored by MTDL-3.MTDL-3 particularly emerged as a ligand showing remarkable potential benefits for its use in AD therapy. Alzheimer's disease (AD), the most common form of adult onset dementia, is an age-related neurodegenerative disorder characterized by progressive memory loss, decline in language skills, and other cognitive impairments. Although its etiology is not completely known, several factors including deficits of acetylcholine, β-amyloid deposits, τ-protein phosphorylation, oxidative stress, and neuroinflammation are considered to play significant roles in the pathophysiology of this disease. For a long time, AD patients have been treated with acetylcholinesterase inhibitors such as donepezil (Aricept®) but with limited therapeutic success. This might be due to the complex multifactorial nature of AD, a fact that has prompted the design of new Multi-Target-Directed Ligands

  9. Concurrent administration of donepezil HCl and sertraline HCl in healthy volunteers: assessment of pharmacokinetic changes and safety following single and multiple oral doses

    PubMed Central

    Nagy, Christa F; Kumar, Dinesh; Perdomo, Carlos A; Wason, Suman; Cullen, Edward I; Pratt, Raymond D

    2004-01-01

    Aim This study evaluated the safety and pharmacokinetics (PK) of donepezil HCl and sertraline HCl when administered separately and in combination. Methods This was a randomized, open-label, three-period crossover study. In consecutive dosing periods separated by washout periods of ≥3 weeks, healthy volunteers received either oral donepezil HCI 5 mg once daily for 15 days, oral sertraline HCl 50 mg once daily for 5 days followed by 10 days of once-daily sertraline HCl 100 mg, or the simultaneous administration of oral donepezil HCl and sertraline HCl. Plasma donepezil and sertraline concentrations were determined by high performance liquid chromatography/mass spectrometry. Safety was evaluated by physical and laboratory evaluations and the monitoring of adverse events (AEs). Results A total of 19 volunteers (16 male and three female) were enrolled. Three male subjects withdrew from the study prematurely due to AEs (one case of nausea/stomach cramps and one case of eosinophilia during combination treatment, and one upper respiratory tract infection during treatment with sertraline HCl alone). In subjects who completed all three treatment periods (n = 16), the concurrent administration of donepezil HCl and sertraline HCl did not alter the steady-state (day 15) PK parameters of donepezil HCl. A small (<12%) but statistically significant (P = 0.02) increase in donepezil Cmax was seen after single doses of sertraline HCl and donepezil HCl on day 1 but this was not thought to be clinically meaningful. No significant differences in the tmax or AUC0–24 h of donepezil were observed between the donepezil HCl only or donepezil HCl plus sertraline HCl groups on day 1. No significant changes in sertraline PK parameters were observed either on day 1 (single dose) or on day 15 (steady state) when sertraline HCl was co-administered with donepezil HCl. Generally, the concurrent administration of donepezil HCl and sertraline HCl was well tolerated, with no serious AEs reported

  10. Determination of donepezil in serum samples using molecularly imprinted polymer nanoparticles followed by high-performance liquid chromatography with ultraviolet detection.

    PubMed

    Khansari, Mehdi Rajabnia; Bikloo, Shahrzad; Shahreza, Sara

    2016-03-01

    A molecularly imprinted polymer designed for the selective extraction of donepezil from serum samples was synthesized using a noncovalent molecular imprinting approach. The molecularly imprinted polymer was evaluated chromatographically and then its affinity for donepezil was confirmed by solid-phase extraction. The optimal conditions for solid-phase extraction were provided by cartridge conditioning using acidified water purified from a Milli-Q system, sample loading under basic aqueous conditions, clean-up using acetonitrile, and elution with methanol/tetrahydrofuran. Desirable molecular recognition properties of the molecularly imprinted polymer led to good donepezil recoveries (90-102%). The data indicated that the imprinted polymer has a perfect selectivity and affinity for donepezil and could be used for selective extraction and analysis of donepezil in human serum.

  11. Procognitive effect of AC-3933 in aged mice, and synergistic effect of combination with donepezil in scopolamine-treated mice.

    PubMed

    Hashimoto, Takashi; Hatayama, Yuki; Nakamichi, Keiko; Yoshida, Naoyuki

    2014-12-15

    We have previously reported that AC-3933, a newly developed benzodiazepine receptor partial inverse agonist, facilitates acetylcholine release in the hippocampus and ameliorates scopolamine-induced memory deficits in rats. To further confirm the procognitive effect of AC-3933, we assessed in this study the beneficial effects of this compound in aged mice using the Y-maze and object recognition tests. In addition, we investigated the synergistic effect of AC-3933 and donepezil, a cholinesterase inhibitor, on scopolamine-induced memory impairment in mice. In aged mice, oral administration of AC-3933 at doses of 0.05-0.1 mg/kg and 0.05 mg/kg significantly improved spatial working memory and episodic memory, respectively. In scopolamine-treated mice, both AC-3933 and donepezil significantly ameliorated memory deficits in the Y-maze test at doses of 0.3-3 mg/kg and 10-15 mg/kg, respectively. The beneficial effect of AC-3933, but not that of donepezil, on scopolamine-induced memory impairment was antagonized by flumazenil, a benzodiazepine receptor antagonist, indicating that the procognitive action of AC-3933 arises via a mechanism different from that of donepezil. Co-administration of donepezil at the suboptimal dose of 3 mg/kg with AC-3933 at doses of 0.1-1 mg/kg significantly ameliorated scopolamine-induced memory impairment, suggesting that AC-3933 potentiates the effect of donepezil on memory impairment induced by cholinergic hypofunction. These findings indicate that AC-3933 not only has good potential as a cognitive enhancer by itself, but also is useful as a concomitant drug for the treatment of Alzheimer׳s disease.

  12. Donepezil as add-on treatment of psychotic symptoms in patients with dementia of the Alzheimer's type.

    PubMed

    Bergman, Joseph; Brettholz, Izidor; Shneidman, Michael; Lerner, Vladimir

    2003-01-01

    Traditionally, the neuropsychiatric symptoms of Alzheimer's disease (AD) have been managed with neuroleptics or benzodiazepines, which have serious side effects. Preliminary observations suggest the possible value of cholinesterase inhibitors in the amelioration of psychotic symptoms in patients with dementia of the Alzheimer's type, dementia with Lewy bodies, and in patients with Parkinson's disease. Twelve inpatients with AD with psychotic symptoms and lack of improvement of their delusions/hallucinations during perphenazine treatment (8 mg/day) for 3 weeks received random open-label donepezil 5 mg daily in addition to an ongoing treatment of 8 mg/day perphenazine or 16 mg/day perphenazine. Assessments conducted at baseline and after weeks 2 and 4 included the Mini-Mental State Examination, the Global Deterioration Scale, the Positive and Negative Symptoms Scale, and the Clinical Global Impressions scale. Frequency of extrapyramidal symptoms was measured according to the Abnormal Involuntary Movement Scale. The donepezil-perphenazine group exhibited substantially greater and clinical improvements in mental state. At the end of the trial (4 weeks), Positive and Negative Symptoms Scale scores revealed significant differences between both groups (p = 0.006). The Clinical Global Impressions scale and the Mini-Mental State Examination scores also showed significant differences between the donepezil-perphenazine group and the perphenazine group (p = 0.028 and p = 0.027 respectively). No significant differences were found in the Global Deterioration Scale scores. Abnormal Involuntary Movement Scale scores showed a significant deterioration in extrapyramidal symptoms in the perphenazine group compared with the donepezil-perphenazine group (p = 0.016). Donepezil augmentation of neuroleptics may be appropriate for those patients for whom neuroleptic monotherapy either does not lead to symptom remission or is associated with intolerable adverse effects. This was an open

  13. Design, Synthesis, and Evaluation of Donepezil-Like Compounds as AChE and BACE-1 Inhibitors

    PubMed Central

    2016-01-01

    An ecofriendly synthetic pathway for the synthesis of donepezil precursors is described. Alternative energy sources were used for the total synthesis in order to improve yields, regioselectively, and rate of each synthetic step and to reduce the coproduction of waste at the same time. For all products, characterized by an improved structural rigidity respect to donepezil, the inhibitor activity on AChE, the selectivity vs BuChE, the side-activity on BACE-1, and the effect on SHSY-5Y neuroblastoma cells viability were tested. Two potential new lead compounds for a dual therapeutic strategy against Alzheimer’s disease were envisaged. PMID:27190595

  14. Design, Synthesis, and Evaluation of Donepezil-Like Compounds as AChE and BACE-1 Inhibitors.

    PubMed

    Costanzo, Paola; Cariati, Luca; Desiderio, Doriana; Sgammato, Roberta; Lamberti, Anna; Arcone, Rosaria; Salerno, Raffaele; Nardi, Monica; Masullo, Mariorosario; Oliverio, Manuela

    2016-05-12

    An ecofriendly synthetic pathway for the synthesis of donepezil precursors is described. Alternative energy sources were used for the total synthesis in order to improve yields, regioselectively, and rate of each synthetic step and to reduce the coproduction of waste at the same time. For all products, characterized by an improved structural rigidity respect to donepezil, the inhibitor activity on AChE, the selectivity vs BuChE, the side-activity on BACE-1, and the effect on SHSY-5Y neuroblastoma cells viability were tested. Two potential new lead compounds for a dual therapeutic strategy against Alzheimer's disease were envisaged.

  15. Switching From Oral Donepezil to Rivastigmine Transdermal Patch in Alzheimer's Disease: 20-Week Extension Phase Results

    PubMed Central

    Dengiz, Alan; Meng, Xiangyi; Olin, Jason T.

    2010-01-01

    Objective: To evaluate the long-term safety, tolerability, and efficacy of 2 strategies for switching from donepezil to rivastigmine transdermal patches in patients with mild to moderate Alzheimer's disease. Method: This was a prospective, 25-week, randomized, open-label, parallel-group study to evaluate an immediate or delayed switch (7-day withdrawal) from donepezil (5 to 10 mg/d) to rivastigmine transdermal patches (4.6 mg/24 h). Participants included male and female patients, aged ≥ 50 years, with a DSM-IV-TR diagnosis of mild to moderate dementia of the Alzheimer's type, defined as a Mini-Mental State Examination score of 10–24, inclusive. Patients were enrolled between February 2007 and February 2008. The study was split into a 5-week core phase and a 20-week extension phase. Safety and efficacy results from the extension phase are presented. Results: Both switching strategies were well tolerated. Rates of discontinuation for any reason were similar between the groups. Discontinuations due to adverse events were also similar, and the incidence of gastrointestinal adverse events was low. Apart from Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale scores, at the end of the study, there was no statistically significant change from baseline in cognitive, behavioral, or global outcomes. Over half of the patients preferred rivastigmine transdermal patches to a tablet. Conclusions: This study suggests that the majority of patients receiving donepezil tablets can be safely switched to rivastigmine transdermal patches without significant deterioration in cognition, behavior, and global functioning. Trial Registration: clinicaltrials.gov Identifier: NCT00305903 PMID:21274364

  16. Evolution of a cost-utility model of donepezil for Alzheimer's disease.

    PubMed

    Peters, Jaime L; Anderson, Rob; Hoyle, Martin; Hyde, Chris

    2013-04-01

    The aim of this study was to describe the evolution of a cost-utility model used to inform the UK National Institute for Health and Clinical Excellence's (NICE) most recent decisions on the cost-utility of drug treatments for Alzheimer's disease (AD), and to explore the impact of structural assumptions on the cost-utility results. Changes informed by noted limitations of the decision model used in NICE's previous decisions (in 2006) were made cumulatively to the original decision model for donepezil compared with best supportive care (for patients with mild to moderate AD). Deterministic and probabilistic analyses were undertaken for each cumulative change of the model. The expected value of perfect information (EVPI) of parameter estimates and structural assumptions was also calculated. Cumulative changes to the decision model highlighted how the results of the original model (incremental cost-effectiveness ratio of £81,000 per quality-adjusted life-year gained) related to those of the new model (where donepezil was estimated to be cost-saving), mainly due to uncertainty in the incremental cost of donepezil treatment over best supportive care (ranging from -£600 to £3,000 per patient). The partial EVPI analysis reflected this finding where further information on treatment discontinuations and cost parameter estimates were shown to be valuable in terms of reducing decision uncertainty. Assessing the evolution of the cost-utility model helped to identify and explore structural differences between cohort-based models and is likely to be useful for decision models in other disease areas. This approach makes the structural uncertainty explicit, forcing decision makers to address structural uncertainty in addition to parameter uncertainty.

  17. Olfactory Deficits in MCI as Predictor of Improved Cognition on Donepezil

    DTIC Science & Technology

    2015-04-01

    those of the author( s ) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other...Improved Cognition on Donepezil. 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR( S ) Davangere Devanand, M.D. Betty Diamond 5d. PROJECT NUMBER...5e. TASK NUMBER E-Mail: dpd3@cumc.columbia.edu 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME( S ) AND ADDRESS(ES) AND ADDRESS(ES) 8

  18. Improvement in sundowning in dementia with Lewy bodies after treatment with donepezil.

    PubMed

    Skjerve, A; Nygaard, H A

    2000-12-01

    Sundowning, manifested as a recurring increase in restlessness and agitation in the evening, is described in a 71-year-old man with clinically diagnosed dementia with Lewy bodies. An objective measure of activity using the activity electronic monitoring technique indicated a marked increase in activity level during the evening compared to earlier in the day. After treatment with donepezil, a cholinesterase inhibitor, ratings of behavioural symptoms improved. In addition, there was a marked reduction in evening activity and an increase in daytime activity. Cognition and parkinsonism also improved. Possible explanations for this finding are discussed. Copyright 2000 John Wiley & Sons, Ltd.

  19. Relevance of donepezil in enhancing learning and memory in special populations: a review of the literature.

    PubMed

    Yoo, J Helen; Valdovinos, Maria G; Williams, Dean C

    2007-11-01

    This review discusses the laboratory and clinical research supporting the rationale for the efficacy of donepezil (Aricept USA) in enhancing cognition in autism, Alzheimer disease, Down syndrome, traumatic brain injury, Attention Deficit Hyperactivity Disorder (ADHD), and schizophrenia. While preliminary animal models have shown effective, human studies exclusive of Alzheimer disease are sparse. Although attention and memory are unlikely a sole operation of the cholinergic system, evidence indicates a promising direction for further examination of this hypothesis in autism. Studies that examine changes in operationally defined behaviors and reliable and valid measure of changes in attention and memory are needed.

  20. Treatment of post-electroconvulsive therapy delirium and agitation with donepezil.

    PubMed

    Logan, Christopher J; Stewart, Jonathan T

    2007-03-01

    Delirium and agitation are commonly encountered after administration of electroconvulsive therapy (ECT). Management is generally fairly straightforward, although some patients may have a severe, prolonged, or refractory course. We recently cared for a 65-year-old man who consistently developed severe and very prolonged post-ECT delirium that did not respond to typical pharmacological agents; the duration of delirium was dramatically shortened by the addition of donepezil. Cholinesterase inhibitors may have a place in mitigating severe and prolonged post-ECT delirium.

  1. Donepezil impairs memory in healthy older subjects: behavioural, EEG and simultaneous EEG/fMRI biomarkers.

    PubMed

    Balsters, Joshua H; O'Connell, Redmond G; Martin, Mary P; Galli, Alessandra; Cassidy, Sarah M; Kilcullen, Sophia M; Delmonte, Sonja; Brennan, Sabina; Meaney, Jim F; Fagan, Andrew J; Bokde, Arun L W; Upton, Neil; Lai, Robert; Laruelle, Marc; Lawlor, Brian; Robertson, Ian H

    2011-01-01

    Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise

  2. Donepezil in the Treatment of ADHD-Like Symptoms in Youths with Pervasive Developmental Disorder: A Case Series

    ERIC Educational Resources Information Center

    Doyle, Robert L.; Frazier, Jean; Spencer, Thomas J.; Geller, Daniel; Biederman, Joseph; Wilens, Timothy

    2006-01-01

    Background: Recent studies reported ADHD-like symptoms and cognitive deficits in pervasive developmental disorder (PDD). Because work in dementia documents improvement in executive function deficits with the acetylcholinesterase inhibitor donepezil, the authors reason that similar benefits could be obtained in PDD. Method: The authors describe…

  3. 7-MEOTA-donepezil like compounds as cholinesterase inhibitors: Synthesis, pharmacological evaluation, molecular modeling and QSAR studies.

    PubMed

    Korabecny, Jan; Dolezal, Rafael; Cabelova, Pavla; Horova, Anna; Hruba, Eva; Ricny, Jan; Sedlacek, Lukas; Nepovimova, Eugenie; Spilovska, Katarina; Andrs, Martin; Musilek, Kamil; Opletalova, Veronika; Sepsova, Vendula; Ripova, Daniela; Kuca, Kamil

    2014-07-23

    A novel series of 7-methoxytacrine (7-MEOTA)-donepezil like compounds was synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (EeAChE), human recombinant AChE (hAChE), equine serum butyrylcholinesterase (eqBChE) and human plasmatic BChE (hBChE). New hybrids consist of a 7-MEOTA unit, representing less toxic tacrine (THA) derivative, connected with analogues of N-benzylpiperazine moieties mimicking N-benzylpiperidine fragment from donepezil. 7-MEOTA-donepezil like compounds exerted mostly non-selective profile in inhibiting cholinesterases of different origin with IC50 ranging from micromolar to sub-micromolar concentration scale. Kinetic analysis confirmed mixed-type inhibition presuming that these inhibitors are capable to simultaneously bind peripheral anionic site (PAS) as well as catalytic anionic site (CAS) of AChE. Molecular modeling studies and QSAR studies were performed to rationalize studies from in vitro. Overall, 7-MEOTA-donepezil like derivatives can be considered as interesting candidates for Alzheimer's disease treatment. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  4. Effect of donepezil in Alzheimer disease can be measured by a computerized human analog of the Morris water maze.

    PubMed

    Hort, J; Andel, R; Mokrisova, I; Gazova, I; Amlerova, J; Valis, M; Coulson, E J; Harrison, J; Windisch, M; Laczó, J

    2014-01-01

    Drug development for Alzheimer disease (AD) is challenged by the success in animal models tested in the Morris water maze (MWM) and the subsequent failures to meet primary outcome measures in phase II or III clinical trials in patients. The human variant of MWM (hMWM) enables us to examine allocentric and egocentric navigation as in the MWM. It was the aim of this study to examine the utility of a computerized hMWM to assess the effects of donepezil in mild AD. Donepezil 5 mg/day was started after initial hMWM testing in the treated group (n = 12), and after 28 days, the dose was increased to 10 mg/day. The performance after 3 months was compared to that of a non-treated group (n = 12). Donepezil stabilized or improved the spatial navigation performance after 3 months, especially in the allocentric delayed recall subtask (p = 0.014). The computerized hMWM has the potential to measure the effects of donepezil in mild AD. It is a sensitive cognitive outcome measure in AD clinical trials.

  5. Donepezil in the Treatment of ADHD-Like Symptoms in Youths with Pervasive Developmental Disorder: A Case Series

    ERIC Educational Resources Information Center

    Doyle, Robert L.; Frazier, Jean; Spencer, Thomas J.; Geller, Daniel; Biederman, Joseph; Wilens, Timothy

    2006-01-01

    Background: Recent studies reported ADHD-like symptoms and cognitive deficits in pervasive developmental disorder (PDD). Because work in dementia documents improvement in executive function deficits with the acetylcholinesterase inhibitor donepezil, the authors reason that similar benefits could be obtained in PDD. Method: The authors describe…

  6. Donepezil-like multifunctional agents: Design, synthesis, molecular modeling and biological evaluation.

    PubMed

    Wu, Ming-Yu; Esteban, Gerard; Brogi, Simone; Shionoya, Masahi; Wang, Li; Campiani, Giuseppe; Unzeta, Mercedes; Inokuchi, Tsutomu; Butini, Stefania; Marco-Contelles, Jose

    2016-10-04

    Currently available drugs against Alzheimer's disease (AD) are only able to ameliorate the disease symptoms resulting in a moderate improvement in memory and cognitive function without any efficacy in preventing and inhibiting the progression of the pathology. In an effort to obtain disease-modifying anti-Alzheimer's drugs (DMAADs) following the multifactorial nature of AD, we have recently developed multifunctional compounds. We herein describe the design, synthesis, molecular modeling and biological evaluation of a new series of donepezil-related compounds possessing metal chelating properties, and being capable of targeting different enzymatic systems related to AD (cholinesterases, ChEs, and monoamine oxidase A, MAO-A). Among this set of analogues compound 5f showed excellent ChEs inhibition potency and a selective MAO-A inhibition (vs MAO-B) coupled to strong complexing properties for zinc and copper ions, both known to be involved in the progression of AD. Moreover, 5f exhibited moderate antioxidant properties as found by in vitro assessment. This compound represents a novel donepezil-hydroxyquinoline hybrid with DMAAD profile paving the way to the development of a novel class of drugs potentially able to treat AD.

  7. DOMINO-AD protocol: donepezil and memantine in moderate to severe Alzheimer's disease – a multicentre RCT

    PubMed Central

    Jones, Rob; Sheehan, Bart; Phillips, Patrick; Juszczak, Ed; Adams, Jessica; Baldwin, Ashley; Ballard, Clive; Banerjee, Sube; Barber, Bob; Bentham, Peter; Brown, Richard; Burns, Alistair; Dening, Tom; Findlay, David; Gray, Richard; Griffin, Mary; Holmes, Clive; Hughes, Alan; Jacoby, Robin; Johnson, Tony; Jones, Roy; Knapp, Martin; Lindesay, James; McKeith, Ian; McShane, Rupert; Macharouthu, Ajay; O'Brien, John; Onions, Caroline; Passmore, Peter; Raftery, James; Ritchie, Craig; Howard, Rob

    2009-01-01

    Background Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil. Method DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10 mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization

  8. Concentration of Donepezil in the Cerebrospinal Fluid of AD Patients: Evaluation of Dosage Sufficiency in Standard Treatment Strategy.

    PubMed

    Valis, Martin; Masopust, Jiri; Vysata, Oldrich; Hort, Jakub; Dolezal, Rafael; Tomek, Jiri; Misik, Jan; Kuca, Kamil; Karasova, Jana Zdarova

    2017-01-01

    Although some studies have described the pharmacokinetics and pharmacodynamics of donepezil in the peripheral compartment, studies focused on drug transport across the blood-brain barrier are still very rare. To our knowledge, the fluctuation in the cerebrospinal fluid concentration of donepezil after administration of the drug has not been described in the literature so far. We recruited 16 patients regularly taking a standard therapeutic dose of donepezil (10 mg per day). All patients (Caucasian race) were treated for at least three months with a stable dose of 10 mg per day prior to sample collection. Patients were divided into two groups depending on the time of plasma and cerebrospinal fluid sampling: 12 h (n = 9; 4 M/5F aged 78.68 ± 7.35 years) and 24 h (n = 7; 3 M/4F aged 77.14 ± 5.87 years) after donepezil administration. The cerebrospinal fluid sample was collected by standard lumbar puncture technique using a single-use traumatic needle. The samples were analysed on an Agilent 1260 Series liquid chromatograph comprising a degasser, a quaternary pump, a light-tight autosampler unit set, a thermostated column compartment, and a UV/VIS detector. Agilent ChemStation software, the statistical software Prism4, version 5.0 (GraphPad Software, USA), and IBM(®) SPSS(®) Statistics were used for the analysis of the results. The difference in plasma concentration of donepezil after 12 h (mean ± SEM; 39.99 ± 5.90 ng/ml) and after 24 h (29.38 ± 1.71 ng/ml) was nonsignificant. In contrast, the donepezil concentration in the cerebrospinal fluid was significantly higher in the 24-h interval (7.54 ± 0.55 ng/ml) compared with the 12-h interval (5.19 ± 0.83 ng/ml, which is ~70 % based on mean cerebrospinal fluid values). Based on these data, it is plausible to predict that donepezil might produce a stronger AChE inhibition in the brain at 24 h compared with 12 h following the administration. This information may help physicians

  9. Cognitive effects of the acetylcholinesterase inhibitor, donepezil, in healthy, non-treatment seeking smokers: A pilot feasibility study

    PubMed Central

    Ashare, Rebecca L.; Ray, Riju; Lerman, Caryn; Strasser, Andrew A.

    2012-01-01

    Background There is a need to identify medications to aid in smoking cessation. Reducing withdrawal-related cognitive deficits represents a pharmacological target for new pharmacotherapies. Endogenous acetylcholine levels, which are modulated by acetylcholinesterase inhibitors (AChEIs), play an important role in smoking behavior and cognition. This pilot feasibility study tested whether an AChEI, donepezil, enhanced cognitive performance among healthy smokers. Methods Eighteen non-treatment seeking daily smokers (6 female) received either donepezil (5mg q.d) or placebo (double-blind; 2:1 allocation ratio) for four weeks. Smoking rate, side effects, and neurocognitive measures of working memory (Letter-N-back) and sustained attention (Penn Continuous Performance Task) were assessed weekly. Results For the working memory task, there was a significant group × load × time interaction (p=0.03) indicating that the donepezil group demonstrated an increase in true positives from baseline to week 4 at the highest working memory load (3-back). The placebo group showed no change in accuracy. For the sustained attention task, there was a marginal effect in the same direction for discriminability, or d', p=0.08. There were no significant effects on reaction time during either task. There was also a reduction in cigarettes per day in the placebo group, but not the donepezil group. Conclusions AChEIs, such as donepezil, may have pro-cognitive effects among healthy smokers while they continue to smoke as usual. Given the association between cognitive deficits and relapse, AChEIs should be explored as potential therapeutics for smoking cessation. PMID:22595038

  10. Combined Memantine and Donepezil Treatment Improves Behavioral and Psychological Symptoms of Dementia-Like Behaviors in Olfactory Bulbectomized Mice.

    PubMed

    Yabuki, Yasushi; Matsuo, Kazuya; Hirano, Koga; Shinoda, Yasuharu; Moriguchi, Shigeki; Fukunaga, Kohji

    2017-01-01

    Memantine, an uncompetitive N-methyl-D-aspartate receptor antagonist, and the cholinesterase inhibitor, donepezil, are approved in most countries for treating moderate-to-severe Alzheimer's disease (AD). These drugs have different molecular targets; thus, it is expected that the effects of combined treatment would be synergistic. Some reports do show memantine/donepezil synergy in ameliorating cognition in AD model animals, but their combined effects on behavioral and psychological symptoms of dementia (BPSD)-like behaviors have not been addressed. Here, we investigate combined memantine/donepezil effects on cognitive impairment and BPSD-like behaviors in olfactory bulbectomized (OBX) mice. Interestingly, combined administration synergistically improved both depressive-like behaviors and impaired social interaction in OBX mice, whereas only weak synergistic effects on cognitive performance were seen. To address mechanisms underlying these effects, we used in vivo microdialysis study and observed impaired nicotine-induced serotonin (5-HT) release in OBX mouse hippocampus. Combined memantine/donepezil administration, but not single administration of either, significantly antagonized the decrease in nicotine-induced 5-HT release seen in OBX mouse hippocampus. Furthermore, decreased autophosphorylation of calcium/calmodulin dependent protein kinase II (CaMKII) was rescued in hippocampal CA1 and dentate gyrus of OBX mice by combined memantine/donepezil administration. These results suggest that improvement of BPSD-like behaviors by the co-administration of both drugs is in part mediated by enhanced 5-HT release and CaMKII activity in OBX mouse hippocampus. © 2016 S. Karger AG, Basel.

  11. Clinical Response to Donepezil in Mild and Moderate Dementia: Relationship to Drug Plasma Concentration and CYP2D6 and APOE Genetic Polymorphisms.

    PubMed

    Miranda, Luís F J R; Gomes, Karina B; Tito, Pedro A L; Silveira, Josianne N; Pianetti, Gerson A; Byrro, Ricardo M D; Peles, Patrícia R H; Pereira, Fernando H; Santos, Thiago R; Assini, Arthur G; Ribeiro, Valéria V; Moraes, Edgar N; Caramelli, Paulo

    2017-01-01

    The clinical response to donepezil in patients with mild and moderate dementia was investigated in relation to the drug plasma concentration and APOE and CYP2D6 polymorphisms. In a prospective naturalistic observational study, 42 patients with Alzheimer's disease (AD) and AD with cerebrovascular disease who took donepezil (10 mg) for 12 months were evaluated. Their DNA was genotyped, and the donepezil plasma concentrations were measured after 3, 6, and 12 months. Good responders scored ≥-1 on the Mini-Mental State Examination at 12 months in comparison to the baseline score. The study results indicated the good response pattern was influenced by the concentration of donepezil, but not by APOE and CYP2D6 polymorphisms.

  12. The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): design and baseline characteristics.

    PubMed

    Jones, Roy W; Kivipelto, Miia; Feldman, Howard; Sparks, Larry; Doody, Rachelle; Waters, David D; Hey-Hadavi, Judith; Breazna, Andrei; Schindler, Rachel J; Ramos, Harry

    2008-03-01

    Growing evidence suggests that elevated cholesterol levels in mid-life are associated with increased risk of developing Alzheimer's disease (AD), and that statins might have a protective effect against AD and dementia. The Lipitor's Effect in Alzheimer's Dementia (LEADe) study tests the hypothesis that a statin (atorvastatin 80 mg daily) will provide a benefit on the course of mild to moderate AD in patients receiving background therapy of a cholinesterase inhibitor (donepezil 10 mg daily). This is an international, multicenter, double-blind, randomized, parallel-group study with a double-blind randomized withdrawal phase of patients with mild to moderate AD (Mini-Mental State Examination [MMSE] score, 13 to 25). Inclusion criteria included age 50 to 90 years, receiving donepezil 10 mg for at least 3 months before randomization, and low-density lipoprotein cholesterol levels (LDL-C) 2.5 to 3.5 mmol/L (95 to 195 mg/dL). Co-primary end points are changes in AD Assessment Scale-cognitive subscale (ADAS-cog) and AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale scores. A confirmatory end point is rate of change in whole brain and hippocampal volumes in patients who enrolled in the magnetic resonance imaging substudy. Enrollment of 641 subjects is complete. The baseline mean data are age 74 +/- 8 years, 53% women, MMSE 22 +/- 3, ADAS-cog 23 +/- 10, AD Functional Assessment and Change Scale (ADFACS) 13 +/- 9, Neuropsychiatric Inventory (NPI) 10 +/- 11, and Clinical Dementia Rating-Sum of Boxes (CDR-SB) 6 +/- 3. Mean prior donepezil treatment was 409 +/- 407 days. Mean baseline lipid levels are total cholesterol 5.8 +/- 0.8 mmol/L (224 +/- 33 mg/dL), LDL-C 3.7 +/- 0.7 mmol/L (143 +/- 26 mg/dL), triglycerides 1.5 +/- 0.7 mmol/L (132 +/- 64 mg/dL), and high-density lipoprotein cholesterol 1.6 +/- 0.5 mmol/L (64 +/- 18 mg/dL). LEADe will report in 2008 and is expected to provide a more definitive evaluation of the potential for statins in the

  13. Donepezil 23 mg: a brief insight on efficacy and safety concerns.

    PubMed

    Nguyen, Minh D; Salbu, Rebecca L

    2013-12-01

    As life expectancy increases, it is imperative that health care providers recognize the importance of safe medication use within an aging geriatric population. Dealing with a cohort that has different biological and medical demands requires pharmacists to pay particular attention to details when treating this subset of individuals. In particular, this manuscript will focus on Alzheimer's disease (AD) and considerations when dealing with new treatment options. The Food and Drug Administration's recent approval of the increased dosage strength, donepezil 23 mg, previously only available in 5 mg and 10 mg strengths, has raised efficacy and safety concerns. Reservations stem from unproven superiority along with an increased incidence of adverse events. The purpose of the manuscript is to provide a brief insight into these concerns and provide readers the knowledge necessary to make a clinically sound decision when treating patients with moderate-to-severe AD.

  14. Donepezil Enhances Frontal Functional Connectivity in Alzheimer's Disease: A Pilot Study

    PubMed Central

    Griffanti, Ludovica; Wilcock, Gordon K.; Voets, Natalie; Bonifacio, Guendalina; Mackay, Clare E.; Jenkinson, Mark; Zamboni, Giovanna

    2016-01-01

    Background We have previously shown that increased resting-state functional magnetic resonance imaging (fMRI)-based functional connectivity (FC) within the frontal resting-state networks in Alzheimer's disease (AD) patients reflects residual, possibly compensatory, function. This suggests that symptomatic treatments should aim to enhance FC specifically in these networks. Methods 18 patients with probable AD underwent brain MRI and neuropsychological assessment at baseline and after 12 weeks of treatment with donepezil. We tested if changes in cognitive performance after treatment correlated with changes in FC in resting-state networks known to be altered in AD. Results We found increases in FC in the orbitofrontal network that correlated with cognitive improvement after treatment. The increased FC was greatest in patients who responded most to treatment. Conclusion This ‘proof of concept’ study suggests that changes in network-specific FC might be a biomarker of pharmacological intervention efficacy in AD. PMID:27920795

  15. Changes in cognitive domains during three years in patients with Alzheimer's disease treated with donepezil

    PubMed Central

    Persson, Cecilia M; Wallin, Åsa K; Levander, Sten; Minthon, Lennart

    2009-01-01

    Background The objective was to identify separate cognitive domains in the standard assessment tools (MMSE, ADAS-Cog) and analyze the process of decline within domains during three years in Alzheimer's disease (AD) patients with donepezil treatment. Method AD patients (n = 421) were recruited from a clinical multi-centre study program in Sweden. Patients were assessed every six months during three years. All patients received donepezil starting directly after study entry. After dropouts, 158 patients remained for analyses over three years. Data for the other patients were analysed until they dropped out (4 groups based on length in study). Results Factor analyses of all items suggested that there were three intercorrelated factors: a General, a Memory and a Spatial factor for which we constructed corresponding domains. Overall there was a cognitive improvement at six months followed by a linear drop over time for the three domains. Some group and domain differences were identified. Patients who remained longer in the study had better initial performance and a slower deterioration rate. The early dropouts showed no improvement at six months and many dropped out due to side effects. The other groups displayed a performance improvement at six months that was less pronounced in the Memory domain. Before dropping out, deterioration accelerated, particularly in the Spatial domain. Conclusion The course of illness in the three domains was heterogeneous among the patients. We were not able to identify any clinically relevant correlates of this heterogeneity. As an aid we constructed three algorithms corresponding to the cognitive domains, which can be used to characterize patients initially, identify rapid decliners and follow the course of the disease. PMID:19208247

  16. Acetylcholinesterase inhibitors for the treatment of Wernicke-Korsakoff syndrome--three further cases show response to donepezil.

    PubMed

    Cochrane, Murray; Cochrane, Ashley; Jauhar, Pramod; Ashton, Elizabeth

    2005-01-01

    Three patients diagnosed with Wernicke-Korsakoff syndrome were treated with the acetylcholinesterase inhibitor, donepezil, for periods of 6 to 8 months. Cognitive testing [Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), Mini-mental state examination (MMSE), Clock drawing test and six item 2 min recall] and carer questionnaires [Informant Questionnaire (IQ Code), Neuropsychiatric inventory scale (NPI)] were performed at baseline, mid- and endpoint of the treatment period and post-discontinuation. Progressive partial improvement occurred in cognitive measurements through the treatment period, some of which was sustained after discontinuing donepezil. Carer questionnaires also indicated improvement. Confounding factors necessitate caution when attributing improvements to the medication, but these cases suggest that this option merits further investigation.

  17. Efficacy and safety of donepezil in the treatment of executive dysfunction in Parkinson disease: a pilot study.

    PubMed

    Linazasoro, Gurutz; Lasa, Asier; Van Blercom, Nadége

    2005-01-01

    Cognitive disturbances in Parkinson's disease (PD) are dominated by troubles in executive functions which affects to a vast majority of parkinsonian patients since the onset of the disease. A common clinical observation is that parkinsonian patients, who eventually develop dementia, exhibit subtle cognitive disturbances quite earlier. The main biochemical substrate of cognitive dysfunction in PD, even of the early dysexecutive syndrome, might be a cholinergic deficiency. The aim of this pilot study was to determine the efficacy and safety of donepezil in the treatment of 10 patients with PD and dysexecutive alterations without dementia. All the items of the Clinical Global Impression were significantly improved. An improvement on both the modified Wisconsin Card Sorting Test and DIGIT Span was found. Parkinsonism remained unchanged during the study. Only 1 out of 10 patients experienced transient and mild gastrointestinal side effects. This study suggests that donepezil may be useful in the treatment of the dysexecutive syndrome associated with PD.

  18. Cognitive Results of CANTAB Tests and Their Change Due to the First Dose of Donepezil May Predict Treatment Efficacy in Alzheimer Disease

    PubMed Central

    Kuzmickienė, Jurgita; Kaubrys, Gintaras

    2015-01-01

    Background Ability to predict the efficacy of treatment in Alzheimer disease (AD) may be very useful in clinical practice. Cognitive predictors should be investigated alongside with the demographic, genetic, and other predictors of treatment efficacy. The aim of this study was to establish whether the baseline measures of CANTAB tests and their changes due to the first donepezil dose are able to predict the efficacy of treatment after 4 months of therapy. We also compared the predictive value of cognitive, clinical, and demographic predictors of treatment efficacy in AD. Material/Methods Seventy-two AD patients (62 treatment-naïve and 10 donepezil-treated) and 30 controls were enrolled in this prospective, randomized, rater-blinded, follow-up study. Treatment-naïve AD patients were randomized to 2 groups to take the first donepezil dose after the first or second CANTAB testing, separated by 4 hours. Follow-up Test 3 was performed 4 months after the initial assessment. Results The groups were similar in age, education, gender, Hachinski index, and depression. General Regression Models (GRM) have shown that cognitive changes after the first dose of donepezil in PAL (t-values for regression coefficients from 3.43 to 6.44), PRMd (t=4.33), SWM (t=5.85) test scores, and baseline results of PAL (t=2.57–2.86), PRM (t=3.08), and CRT (t=3.42) tests were significant predictors of long-term donepezil efficacy in AD (p<0.05). Conclusions The cognitive changes produced by the first donepezil dose in CANTAB PAL, PRM, and SWM test measures are able to predict the long-term efficacy of donepezil in AD. Baseline PAL, PRM, and CRT test results were significant predictors. PMID:26656642

  19. Cognitive Results of CANTAB Tests and Their Change Due to the First Dose of Donepezil May Predict Treatment Efficacy in Alzheimer Disease.

    PubMed

    Kuzmickienė, Jurgita; Kaubrys, Gintaras

    2015-12-14

    BACKGROUND Ability to predict the efficacy of treatment in Alzheimer disease (AD) may be very useful in clinical practice. Cognitive predictors should be investigated alongside with the demographic, genetic, and other predictors of treatment efficacy. The aim of this study was to establish whether the baseline measures of CANTAB tests and their changes due to the first donepezil dose are able to predict the efficacy of treatment after 4 months of therapy. We also compared the predictive value of cognitive, clinical, and demographic predictors of treatment efficacy in AD. MATERIAL AND METHODS Seventy-two AD patients (62 treatment-naïve and 10 donepezil-treated) and 30 controls were enrolled in this prospective, randomized, rater-blinded, follow-up study. Treatment-naïve AD patients were randomized to 2 groups to take the first donepezil dose after the first or second CANTAB testing, separated by 4 hours. Follow-up Test 3 was performed 4 months after the initial assessment. RESULTS The groups were similar in age, education, gender, Hachinski index, and depression. General Regression Models (GRM) have shown that cognitive changes after the first dose of donepezil in PAL (t-values for regression coefficients from 3.43 to 6.44), PRMd (t=4.33), SWM (t=5.85) test scores, and baseline results of PAL (t=2.57-2.86), PRM (t=3.08), and CRT (t=3.42) tests were significant predictors of long-term donepezil efficacy in AD (p<0.05). CONCLUSIONS The cognitive changes produced by the first donepezil dose in CANTAB PAL, PRM, and SWM test measures are able to predict the long-term efficacy of donepezil in AD. Baseline PAL, PRM, and CRT test results were significant predictors.

  20. Maintenance Treatment of Depression in Old Age: A Randomized, Double-blind, Placebo-Controlled Evaluation of the Efficacy and Safety of Donepezil Combined with Antidepressant Pharmacotherapy

    PubMed Central

    Reynolds, Charles F.; Butters, Meryl A.; Lopez, Oscar; Pollock, Bruce G.; Dew, Mary Amanda; Mulsant, Benoit H.; Lenze, Eric J.; Holm, Margo; Rogers, Joan C.; Mazumdar, Sati; Houck, Patricia R.; Begley, Amy; Anderson, Stewart; Karp, Jordan F.; Miller, Mark D.; Whyte, Ellen M.; Stack, Jacqueline; Gildengers, Ariel; Szanto, Katalin; Bensasi, Salem; Kaufer, Daniel I.; Kamboh, M. Ilyas; DeKosky, Steven T.

    2010-01-01

    Context Cognitive impairment in late-life depression is a core feature of the illness. Objective to test whether donepezil + antidepressant is superior to placebo + antidepressant in (1) improving cognitive performance and instrumental activities of daily living and (2) reducing recurrences of depression over two years of maintenance treatment. Design Randomized, double-blind, placebo controlled maintenance trial. Setting university clinic Main Outcome Measures global neuropsychological performance, cognitive instrumental ADL, and recurrent depression. Results Donepezil + antidepressant temporarily improved global cognition (treatment by time interaction F = 3.78, df = 2, 126, p = .03), but effect sizes were small (Cohen’s d = 0.27: group difference at 1 year). A marginal benefit to cognitive instrumental ADL was also observed (treatment by time interaction; F = 2.94; df = 2, 137, p = 0.06). The donepezil group was more likely to experience recurrent major depression: 35% [95% CI: 24%, 46%] versus 19% [95% CI: 9%, 29%] (log rank chi squared = 3.97, p = .05); hazard ratio = 2.09 [95% CI: 1.00, 4.41]. Post-hoc subgroup analyses showed that, of 57 participants with mild cognitive impairment, 3/30 on donepezil (10%; 95% CI: 0, 21%) and 9/27 on placebo (33%; 95% CI: 16%, 51%) converted to dementia over two years (Fisher exact p = 0.05). The MCI subgroup had a 44 percent recurrence rate of major depression on donepezil verses 12% on placebo (LR=4.91, p=.03). The subgroup with normal cognition (n = 73) showed no benefit on donepezil or increase in recurrence of major depression. Conclusion Whether ChEI should be used as augmentation in the maintenance treatment of late-life depression depends upon a careful weighing of risks and benefits in those with MCI. In cognitively intact patients, donepezil appears to have no clear benefit for preventing progression to MCI/dementia or recurrence of depression. PMID:21199965

  1. [Effectiveness of donepezil at six months in the treatment of cognition deterioration in patients with Alzheimer-type dementia].

    PubMed

    López-Pousa, S; Vilalta-Franch, J; Garre-Olmo, J; Turón-Estrada, A; Hernández-Ferrándiz, M; Cruz-Reina, M L

    We compared two groups of patients with cognitive deterioration secondary to Alzheimer's disease (AD) of minimal and slight degree (CAMDEX criteria), one treated with donepezil and the other without this drug (a case history sample) over a period of six months. Both groups received the CAMCOG battery of neuropsychological tests at basal (pretreatment) time and six months later. Those in the study sample who received donepezil (5-10 mg/day) were 91 patients (average age: 75.25, standard deviation = 6.01) of whom 28.6% were men. The control group, who did not receive anticholinesterase drugs (case history sample) consisted of 84 persons (average age: 75.98, standard deviation = 5.01) with 29.8% men. There were no significant differences with regard to age, sex, basal CAMCOG score or period of time between the two CAMCOG determinations. The averages of the differences between the basal CAMCOG scores and those six months later in the two groups was statistically significant (-1.5275 +/- 7.8458 against -6.7143 +/- 6.1234; p < 0.001). Multivariate analysis of repeat measurements corroborates these findings since significant differences were found between the two groups (p < 0.001) in the results of CAMCOG after six months. Donepezil was seen to be effective in that it delayed cognitive deterioration after six months in patients with minimal and slight degrees of AD.

  2. Efficacy and Tolerability of a Combination Treatment of Memantine and Donepezil for Alzheimer’s Disease: A Literature Review Evidence

    PubMed Central

    Riverol, Mario; Slachevsky, Andrea; López, Oscar L.

    2011-01-01

    INTRODUCTION Two types of drugs have been approved for the symptomatic treatment of Alzheimer’s disease (AD): the cholinesterase inhibitors (ChEIs) and memantine. There is a growing interest to know whether the combination of these drugs is safe and if it adds any clinical benefit to patients. OBJECTIVE To systematically review published medical literature assessing the efficacy and tolerability of a combination treatment of memantine and donepezil in AD patients. METHODS We searched PubMed for English and Spanish-language literature, using the terms “Alzheimer’s disease,” “cholinesterase inhibitors,” “donepezil,” and “memantine.” Our review focused on clinical trials and observational studies. RESULTS Eleven publications representing seven unique studies were selected for this review. Three were randomized double-blind, placebo-controlled trials and four were observational studies. CONCLUSIONS Available data revealed that the combination of memantine and donepezil slowed down cognitive decline, prolonged functional independence, and improved behavioral symptoms in patients with moderate to severe AD. The long-term use of the dual therapy decreased the risk of nursing home admission. More longitudinal studies are needed to further examine the role of combined therapy in the management of AD patients. PMID:25302109

  3. Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes.

    PubMed

    Sağlık, Begüm Nurpelin; Ilgın, Sinem; Özkay, Yusuf

    2016-11-29

    Donepezil (DNP), an acetylcholinesterase (AChE) inhibitor, is one of the most preferred choices in Alzheimer diseases (AD) therapy. In the present study, 38 new DNP analogues were synthesized. Structures of the synthesized compounds (1-38) were elucidated by IR, (1)H NMR, (13)C NMR and HRMS spectroscopic methods and elemental analysis. Inhibitory potential of the compounds on cholinesterase enzymes was investigated. None of the compounds displayed significant activity on butyrylcholinesterase (BChE) enzyme. On the other hand, compounds 26-29 indicated important inhibitory activity on AChE enzyme. Kinetic studies were performed in order to observe the effects of the most active compounds on substrate-enzyme relationship. Cytotoxicity studies and theoretical calculation of pharmacokinetic properties were also carried out to get an information about toxicity and pharmacokinetic profiles of the compounds. The compounds 26-29 were found to be nontoxic at their effective concentrations against AChE. A good pharmacokinetic profile was predicted for these compounds. Docking studies were performed for the most active compounds 26-29 and interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. Errorless practice as a possible adjuvant to donepezil in Alzheimer's disease.

    PubMed

    Rothi, Leslie J Gonzalez; Fuller, Renee; Leon, Susan A; Kendall, Diane; Moore, Anna; Wu, Samuel S; Crosson, Bruce; Heilman, Kenneth M; Nadeau, Stephen E

    2009-03-01

    Six individuals with probable Alzheimer's disease (AD) participated in a phase 1 study employing a repeated measures, parallel baseline design testing the hypothesis that error-free experience during word production practice combined with an acetyl cholinesterase inhibitor would improve confrontation naming ability. While acetyl cholinesterase inhibitors are safe and delay cognition decline associated with AD, improvement over baseline cognition is less evident; clinically significant cognitive deficits persist and progress. Both animal and clinical research strongly implicate acetylcholine in learning, a form of neuroplasticity. In clinical practice, however, people with AD are given cholinergic medications without concomitant systematic/targeted retraining. In this study six participants with probable AD and taking donepezil participated in targeted word production practice using an errorless learning strategy. Results showed that combining behavioral enrichment training and an acetyl cholinesterase inhibitor resulted in significant improvements in verbal confrontation naming of trained items for three of six participants. Differences in baseline dementia severity, living conditions, and medications may have influenced the training response. Detection of substantial treatment effects in 50% of subjects suggests further language treatment studies in AD in combination with an acetyl cholinesterase inhibitor are warranted and provide useful information on inclusion/exclusion criteria for use in subsequent studies.

  5. Effects of donepezil and serotonin reuptake inhibitor on acute regression during adolescence in Down syndrome.

    PubMed

    Tamasaki, Akiko; Saito, Yoshiaki; Ueda, Riyo; Ohno, Koyo; Yokoyama, Katsutoshi; Satake, Takahiro; Sakuma, Hiroshi; Takahashi, Yukitoshi; Kondoh, Tatsuro; Maegaki, Yoshihiro

    2016-01-01

    A 14-year-old boy with Down syndrome (DS) showed a gradual decline in his daily activities and feeding capacities, and a marked deterioration triggered by a streptococcal infection was observed at the age of 15 years. He became bedridden, accompanied by sleep disturbance, sustained upward gaze, and generalized rigidity. Magnetic resonance imaging showed unremarkable findings, but antiglutamate receptor autoantibodies were positive in his cerebrospinal fluid. Treatment with thiamine infusion and steroid pulse therapy showed little effect, but gross motor dysfunction and appetite loss were ameliorated by the administration of l-DOPA and serotonin reuptake inhibitors. Thereafter, autistic behaviors predominated, including loss of social interaction, oral tendency, water phobia, and aggressiveness. Initiation of donepezil, an acetylcholinesterase inhibitor, resulted in the disappearance of these symptoms and total recovery of the patient to his previous psychosocial levels. We hypothesize that the acute regression in adolescence represents a process closely related to the defects of serotonergic and cholinergic systems that are innate to DS brains and not just a nonspecific comorbidity of depression or limbic encephalitis.

  6. Genetic testing in combination with preventive donepezil treatment for patients with amnestic mild cognitive impairment: an exploratory economic evaluation of personalized medicine.

    PubMed

    Djalalov, Sandjar; Yong, Jean; Beca, Jaclyn; Black, Sandra; Saposnik, Gustavo; Musa, Zahra; Siminovitch, Katherine; Moretti, Myla; Hoch, Jeffrey S

    2012-12-01

    To evaluate the cost effectiveness of genetic screening for the apolipoprotein (APOE) ε4 allele in combination with preventive donepezil treatment in comparison with the standard of care for amnestic mild cognitive impairment (AMCI) patients in Canada. We performed a cost-effectiveness analysis using a Markov model with a societal perspective and a time horizon of 30 years. For each strategy, we calculated quality-adjusted life-years (QALYs), using utilities from the literature. Costs were also based on the literature and, when appropriate, Ontario sources. One-way and probabilistic sensitivity analyses were performed. Expected value of perfect information (EVPI) analysis was conducted to explore the value of future research. The base case results in our exploratory study suggest that the combination of genetic testing and preventive donepezil treatment resulted in a gain of 0.027 QALYs and an incremental cost of $1,015 (in 2009 Canadian dollars [Can$]), compared with the standard of care. The incremental cost-effectiveness ratio (ICER) for the base case was Can$38,016 per QALY. The ICER was sensitive to the effectiveness of donepezil in slowing the rate of progression to Alzheimer's disease (AD), utility in AMCI patients, and AD and donepezil treatment costs. EVPI analysis showed that additional information on these parameters would be of value. Using presently available clinical evidence, this exploratory study illustrates that genetic testing combined with preventive donepezil treatment for AMCI patients may be economically attractive. Since our results were based on a secondary post hoc analysis, our study alone is insufficient to warrant recommending APOE genotyping in AMCI patients. Future research on the effectiveness of preventive donepezil as a targeted therapy is recommended.

  7. Long-term safety and tolerability of donepezil 23 mg in patients with moderate to severe Alzheimer’s disease

    PubMed Central

    2012-01-01

    Background Donepezil (23 mg/day) is approved by the US Food and Drug Administration for the treatment of patients with moderate to severe Alzheimer’s disease (AD). Approval was based on results from a 24-week, randomized, double-blind study of patients who were stable on donepezil 10 mg/day and randomized 2:1 to either increase their donepezil dose to 23 mg/day or continue taking 10 mg/day. The objective of this study was to assess the long-term safety and tolerability of donepezil 23 mg/day in patients with moderate to severe AD. Methods Patients who completed the double-blind study and were eligible could enroll into a 12-month extension study of open-label donepezil 23 mg/day. Clinic visits took place at open-label baseline and at months 3, 6, 9, and 12. Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs); changes in weight, electrocardiogram, vital signs, and laboratory parameters; and discontinuation due to AEs. Results 915 double-blind study completers were enrolled in the open-label extension study and 902 comprised the safety population. Mean treatment duration in this study was 10.3 ± 3.5 months. In total, 674 patients (74.7%) reported at least one AE; in 320 of these patients (47.5%) at least one AE was considered to be possibly or probably study drug related. The majority of patients reporting AEs (81.9%) had AEs of mild or moderate severity. There were 268 patients (29.7%) who discontinued early, of which 123 (13.6%) were due to AEs. Patients increasing donepezil dose from 10 mg/day in the double-blind study to 23 mg/day in the extension study had slightly higher rates of AEs and SAEs than patients who were already receiving 23 mg (78.0% and 16.9% vs 72.8% and 14.0%, respectively). The incidence of new AEs declined rapidly after the first 2 weeks and remained low throughout the duration of the study. Conclusion This study shows that long-term treatment with

  8. Methyllycaconitine- and scopolamine-induced cognitive dysfunction: differential reversal effect by cognition-enhancing drugs

    PubMed Central

    Andriambeloson, Emile; Huyard, Bertrand; Poiraud, Etienne; Wagner, Stéphanie

    2014-01-01

    There is a growing body of evidence pointing to the pivotal role of alpha-7 nicotinic acetylcholine receptor (α7 nAchR) dysfunction in cognitive disorders such as Alzheimer’s disease or schizophrenia. This study was undertaken to establish and characterize an in vivo model for cognitive disorder secondary to the blockade of α7 nAChR by its specific antagonist, methyllycaconitine (MLA). The results show that MLA elicited cognitive dysfunction as assessed by reduced spontaneous alternation of mice in the T-maze. The maximal effect of MLA produced 25–30% reduction in the spontaneous alternation of mice, a level comparable with that induced by the muscarinic antagonism of scopolamine. Donepezil and galantamine fully reversed both MLA and scopolamine-induced cognitive dysfunction. However, the ED50 of donepezil and galantamine was significantly shifted to the left in the MLA- compared to scopolamine-treated mice (0.0005 and 0.002 mg/kg for donepezil; 0.0003 and 0.7 mg/kg for galantamine). Moreover, memantine elicited marked reversion of cognitive dysfunction (up to 70%) in MLA-treated mice while only a weak reversal effect at high dose of memantine (less than 20%) was observed in scopolamine-treated mice. The above findings indicate that MLA-induced cognitive dysfunction in the mouse is highly sensitive and more responsive to the current procognitive drugs than the traditional scopolamine-based assay. Thus, it can be of value for the preclinical screening and profiling of cognition-enhancing drugs. PMID:25505596

  9. Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic acid-induced animal model of autism.

    PubMed

    Kim, Ji-Woon; Seung, Hana; Kwon, Kyung Ja; Ko, Mee Jung; Lee, Eun Joo; Oh, Hyun Ah; Choi, Chang Soon; Kim, Ki Chan; Gonzales, Edson Luck; You, Jueng Soo; Choi, Dong-Hee; Lee, Jongmin; Han, Seol-Heui; Yang, Sung Min; Cheong, Jae Hoon; Shin, Chan Young; Bahn, Geon Ho

    2014-01-01

    Autism spectrum disorder (ASD) is a group of pervasive developmental disorders with core symptoms such as sociability deficit, language impairment, and repetitive/restricted behaviors. Although worldwide prevalence of ASD has been increased continuously, therapeutic agents to ameliorate the core symptoms especially social deficits, are very limited. In this study, we investigated therapeutic potential of donepezil for ASD using valproic acid-induced autistic animal model (VPA animal model). We found that prenatal exposure of valproic acid (VPA) induced dysregulation of cholinergic neuronal development, most notably the up-regulation of acetylcholinesterase (AChE) in the prefrontal cortex of affected rat and mouse offspring. Similarly, differentiating cortical neural progenitor cell in culture treated with VPA showed increased expression of AChE in vitro. Chromatin precipitation experiments revealed that acetylation of histone H3 bound to AChE promoter region was increased by VPA. In addition, other histone deacetyalse inhibitors (HDACIs) such as trichostatin A and sodium butyrate also increased the expression of AChE in differentiating neural progenitor cells suggesting the essential role of HDACIs in the regulation of AChE expression. For behavioral analysis, we injected PBS or donepezil (0.3 mg/kg) intraperitoneally to control and VPA mice once daily from postnatal day 14 all throughout the experiment. Subchronic treatment of donepezil improved sociability and prevented repetitive behavior and hyperactivity of VPA-treated mice offspring. Taken together, these results provide evidence that dysregulation of ACh system represented by the up-regulation of AChE may serve as an effective pharmacological therapeutic target against autistic behaviors in VPA animal model of ASD, which should be subjected for further investigation to verify the clinical relevance.

  10. Goal setting and attainment in Alzheimer's disease patients treated with donepezil

    PubMed Central

    Rockwood, K; Graham, J; Fay, S

    2002-01-01

    Objectives: To understand the treatment goals of Alzheimer's disease (AD) patients, carers, and physicians; to estimate whether clinically important goals are met during treatment with donepezil; and to compare a measure of goal attainment with standard measures used to evaluate AD treatment. Methods: In a 12 month phase IV trial, 108 patients with mild to moderate AD, their primary carers, and treating physicians set goals assigned to five domains, using Goal Attainment Scaling (GAS) as the primary outcome. Goal attainment was assessed quarterly. GAS scores were correlated with standard outcomes, including the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog), and the Clinician's Interview-Based Impression of Change-Plus (CIBIC-plus). Results: Physicians set fewer goals (342, mean (SD) per patient=3 (1)) than patients/carers (855, mean=9 (3)), particularly in leisure (20% by physicians compared with 76% by patients/carers), and social interaction (24% versus 49%). Physicians observed statistically significant improvement in global goal attainment for six months, and patients/carers for nine months. Patients/carers described consistent goal attainment, whereas physicians observed variable effects, such as decline in cognition but improved social interaction and behaviour. Physician global GAS scores correlated highly with the CIBIC-plus at weeks 12 (r= -0.82) and 52 (r=-0.80), but not with the ADAS-cog (r=0.12 and r=-0.45, respectively). Patient/carer global GAS scores correlated moderately with the physician's CIBIC-plus (week 12 r=-0.51; week 52 r=-0.56), and nominally with the ADAS-cog. Conclusions: Patients/carers and physicians differ in their expectations and impressions of treatment effects. Clinically important changes correlated only modestly with psychometric tests. Attainment of treatment goals does not accord with a simplistic model in which successful AD treatment means that all declines uniformly improve. PMID:12397141

  11. Synergistic Increase of Serum BDNF in Alzheimer Patients Treated with Cerebrolysin and Donepezil: Association with Cognitive Improvement in ApoE4 Cases

    PubMed Central

    Alvarez, Irene; Iglesias, Olalla; Crespo, Ignacio; Figueroa, Jesus; Aleixandre, Manuel; Linares, Carlos; Granizo, Elias; Garcia-Fantini, Manuel; Marey, Jose; Masliah, Eliezer; Winter, Stefan; Muresanu, Dafin; Moessler, Herbert

    2016-01-01

    Background: Low circulating brain derived neurotrophic factor may promote cognitive deterioration, but the effects of neurotrophic and combination drug therapies on serum brain derived neurotrophic factor were not previously investigated in Alzheimer’s disease. Methods: We evaluated the effects of Cerebrolysin, donepezil, and the combined therapy on brain derived neurotrophic factor serum levels at week 16 (end of Cerebrolysin treatment) and week 28 (endpoint) in mild-to-moderate Alzheimer’s disease patients. Results: Cerebrolysin, but not donepezil, increased serum brain derived neurotrophic factor at week 16, while the combination therapy enhanced it at both week 16 and study endpoint. Brain derived neurotrophic factor responses were significantly higher in the combination therapy group than in donepezil and Cerebrolysin groups at week 16 and week 28, respectively. Brain derived neurotrophic factor increases were greater in apolipoprotein E epsilon-4 allele carriers, and higher brain derived neurotrophic factor levels were associated with better cognitive improvements in apolipoprotein E epsilon-4 allele patients treated with Cerebrolysin and the combined therapy. Conclusion: Our results indicate a synergistic action of Cerebrolysin and donepezil to increase serum brain derived neurotrophic factor and delaying cognitive decline, particularly in Alzheimer’s disease cases with apolipoprotein E epsilon-4 allele. PMID:27207906

  12. Enhanced dendritic spine number of neurons of the prefrontal cortex, hippocampus and nucleus accumbens in old rats after chronic donepezil administration

    PubMed Central

    Alcantara-Gonzalez, Faviola; Juarez, Ismael; Solis, Oscar; Martinez-Tellez, Isaura; Camacho-Abrego, Israel; Masliah, Eliezer; Mena, Raul; Flores, Gonzalo

    2010-01-01

    In Alzheimer's disease brains morphological changes in the dendrites of pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been observed. These changes are particularly reflected in the decrement of both the dendritic tree and spine number. Donepezil is a potent and selective acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease. We have studied the effect of oral administration of this drug on the morphology of neuronal cells from the brain of aged rats. We examined dendrites of pyramidal neurons of the PFC, dorsal or ventral hippocampus and medium spiny neurons of the nucleus accumbens (NAcc). Donepezil (1 mg/Kg, vo) was administrated every day for 60 days to rats aged 10 and 18 months. Dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at 12 and 20 months ages, respectively. In all Donepezil treated-rats a significant increment of the dendritic spines number in pyramidal neurons of the PFC, dorsal hippocampus was observed. However, pyramidal neurons of the ventral hippocampus and medium spiny cells of the NAcc only showed an increase in the number of their spines in 12 months old-rats. Our results suggest that Donepezil prevents the alterations of the neuronal dendrite morphology caused by aging. PMID:20336627

  13. Rapid and sustained cognitive recovery in APP/PS1 transgenic mice by co-administration of EPPS and donepezil

    PubMed Central

    Kim, Hye Yun; Kim, Hyunjin Vincent; Lee, Dongkeun K.; Yang, Seung-Hoon; Kim, YoungSoo

    2016-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disease characterized by sequential progression of pathological events, such as aggregation of amyloid-β proteins, followed by outward symptoms of cognitive impairments. Given that a combination of different therapeutic strategies often provides more rapid and effective outcomes in diverse areas of clinical treatment, we hypothesized that administration of anti-amyloid drugs with cognitive enhancers would result in synergistic effects in AD treatment. Here, we co-administered 4-(2-hydroxyethyl)-1-piperazinepropane-sulphonic acid (EPPS), an amyloid-clearing chemical, and donepezil, an acetylcholinesterase inhibitor, to determine whether they could serve complementary roles for each other in regards to AD treatment. We found that oral administration of these two molecules led to a rapid and consistent cognitive improvement in APP/PS1 transgenic mice. Although there was no evidence for synergistic effects, our results indicated that EPPS and donepezil function complementary to each other without altering their individual effects. Thus, the combined use of disease-modifying and symptomatic relief drugs may be a promising approach in the treatment of AD. PMID:27796293

  14. Dose-dependent effect of donepezil administration on long-term enhancement of visually evoked potentials and cholinergic receptor overexpression in rat visual cortex.

    PubMed

    Chamoun, Mira; Groleau, Marianne; Bhat, Menakshi; Vaucher, Elvire

    2016-09-01

    Stimulation of the cholinergic system tightly coupled with periods of visual stimulation boosts the processing of specific visual stimuli via muscarinic and nicotinic receptors in terms of intensity, priority and long-term effect. However, it is not known whether more diffuse pharmacological stimulation with donepezil, a cholinesterase inhibitor, is an efficient tool for enhancing visual processing and perception. The goal of the present study was to potentiate cholinergic transmission with donepezil treatment (0.5 and 1mg/kg) during a 2-week visual training to examine the effect on visually evoked potentials and to profile the expression of cholinergic receptor subtypes. The visual training was performed daily, 10min a day, for 2weeks. One week after the last training session, visual evoked potentials were recorded, or the mRNA expression level of muscarinic (M1-5) and nicotinic (α/β) receptors subunits was determined by quantitative RT-PCR. The visual stimulation coupled with any of the two doses of donepezil produced significant amplitude enhancement of cortical evoked potentials compared to pre-training values. The enhancement induced by the 1mg/kg dose of donepezil was spread to neighboring spatial frequencies, suggesting a better sensitivity near the visual detection threshold. The M3, M4, M5 and α7 receptors mRNA were upregulated in the visual cortex for the higher dose of donepezil but not the lower one, and the receptors expression was stable in the somatosensory (non-visual control) cortex. Therefore, higher levels of acetylcholine within the cortex sustain the increased intensity of the cortical response and trigger the upregulation of cholinergic receptors.

  15. The influence of donepezil and EGb 761 on the innate immunity of human leukocytes: effect on the NF-κB system.

    PubMed

    Sochocka, Marta; Zaczyńska, Ewa; Taboł, Agnieszka; Czarny, Anna; Leszek, Jerzy; Sobczyński, Maciej

    2010-12-01

    Ginkgo biloba special extract EGb 761 and donepezil are drugs used in Alzheimer therapy. The influence of donepezil and EGb 761 on two mechanisms of innate immunity, natural antiviral resistance of human leukocytes ex vivo and NF-κB activation, was studied. Correlation between the innate immunity of leukocytes and NF-κB activation was investigated. The effect of the two drugs on resistance of human leukocytes to vesicular stomatitis virus (VSV) infection was also assessed. Two groups of healthy blood donors (n=30) were distinguished: one with resistant leukocytes (n=15) and one (n=15) with leukocytes sensitive to VSV. The degree of natural resistance of human peripheral blood leukocytes (PBLs) was determined by studying the kinetics of VSV replication. NF-κB activation was assayed by immunocytochemical staining. Efficiency of donepezil and EGb 761 was determined by a special regression model. The toxicity of the preparations to PBLs and the cell lines L(929) and A(549) and their effect on the different viruses was established. Results showed that donepezil used in concentrations of 10-50 μg/ml and EGb761 of 25-100 μg/ml stimulated resistance of human leukocytes. At the same concentrations both preparations decreased activation of transcriptional factor NF-κB. Correlation between innate immunity of PBLs and NF-κB activation was observed. Comparison of the effects of these two drugs showed that EGb 761 is more effective in stimulating leukocyte resistance. Donepezil and EGb 761 regulated innate immunity of human leukocytes by stimulating resistance and modulating NF-κB activation. The natural drug was more efficient in stimulating innate antiviral immunity of human leukocytes.

  16. The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates.

    PubMed

    Buccafusco, Jerry J; Terry, Alvin V; Webster, Scott J; Martin, Daniel; Hohnadel, Elizabeth J; Bouchard, Kristy A; Warner, Samantha E

    2008-08-01

    The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents. The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys. Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS). The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 microg/kg in the DMTS task. The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.

  17. The 5-HT6 receptor antagonist idalopirdine potentiates the effects of donepezil on gamma oscillations in the frontal cortex of anesthetized and awake rats without affecting sleep-wake architecture.

    PubMed

    Amat-Foraster, Maria; Leiser, Steven C; Herrik, Kjartan F; Richard, Nelly; Agerskov, Claus; Bundgaard, Christoffer; Bastlund, Jesper F; de Jong, Inge E M

    2017-02-01

    The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD). The high affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on cortical function using two in vivo electrophysiological methods. Neuronal network oscillations in the frontal cortex were measured during electrical stimulation of the brainstem nucleus pontis oralis (nPO) in the anesthetized rat and by an electroencephalogram (EEG) in the awake, freely moving rat. In conjunction with the EEG study, we investigated the effects of idalopirdine and donepezil on sleep-wake architecture using telemetric polysomnography. Idalopirdine (2 mg/kg i.v.) increased gamma power in the medial prefrontal cortex (mPFC) during nPO stimulation. Donepezil (0.3 and 1 mg/kg i.v.) also increased cortical gamma power and pretreatment with idalopirdine (2 mg/kg i.v.) potentiated and prolonged the effects of donepezil. Similarly, donepezil (1 and 3 mg/kg s.c.) dose-dependently increased frontal cortical gamma power in the freely moving rat and pretreatment with idalopirdine (10 mg/kg p.o.) augmented the effect of donepezil 1 mg/kg. Analysis of the sleep-wake architecture showed that donepezil (1 and 3 mg/kg s.c.) dose-dependently delayed sleep onset and decreased the time spent in both REM and non REM sleep stages. In contrast, idalopirdine (10 mg/kg p.o.) did not affect sleep-wake architecture nor the effects of donepezil. In summary, we show that idalopirdine potentiates the effects of donepezil on frontal cortical gamma oscillations, a pharmacodynamic biomarker associated with cognition, without modifying the effects of donepezil on sleep. The increased cortical excitability may contribute to the procognitive effects of idalopirdine in donepezil

  18. Effects of Donepezil on Extrapyramidal Symptoms in Patients with Dementia with Lewy Bodies: A Secondary Pooled Analysis of Two Randomized-Controlled and Two Open-Label Long-Term Extension Studies.

    PubMed

    Mori, Etsuro; Ikeda, Manabu; Nakagawa, Masaki; Miyagishi, Hideaki; Yamaguchi, Hideo; Kosaka, Kenji

    2015-01-01

    The aim of this study was to clarify the effects of donepezil on extrapyramidal symptoms in patients with dementia with Lewy bodies (DLB). Using pooled datasets from phase 2 and 3, 12-week randomized, placebo-controlled trials (RCT, n = 281) and 52-week open-label long-term extension trials (OLE, n = 241) of donepezil in DLB, the effects of donepezil on the incidence of extrapyramidal adverse events (AEs) and on the Unified Parkinson's Disease Rating Scale (UPDRS) part III were assessed, and potential baseline factors affecting the AEs were explored. The RCT analysis did not show significant differences between the placebo and active (3, 5, and 10 mg donepezil) groups in extrapyramidal AE incidence (3.8 and 6.5%, p = 0.569) and change in the UPDRS (mean ± SD: -0.2 ± 4.3 and -0.6 ± 6.5, p = 0.562). In the OLE analysis (5 and 10 mg donepezil), the incidence did not increase chronologically; all AEs leading to a dose reduction or discontinuation except one were relieved. The UPDRS was unchanged for 52 weeks. An exploratory multivariate logistic regression analysis of the RCTs revealed that donepezil treatment was not a significant factor affecting the AEs. Baseline severity of parkinsonism was a predisposing factor for worsening of parkinsonism without significant interactions between donepezil and baseline severity. DLB can safely be treated with donepezil without relevant worsening of extrapyramidal symptoms, but treatment requires careful attention to symptom progression when administered to patients with relatively severe parkinsonism. © 2015 The Author(s) Published by S. Karger AG, Basel.

  19. Effects of donepezil, galantamine and rivastigmine in 938 Italian patients with Alzheimer's disease: a prospective, observational study.

    PubMed

    Santoro, Aurelia; Siviero, Paola; Minicuci, Nadia; Bellavista, Elena; Mishto, Michele; Olivieri, Fabiola; Marchegiani, Francesca; Chiamenti, Andrea Maria; Benussi, Luisa; Ghidoni, Roberta; Nacmias, Benedetta; Bagnoli, Silvia; Ginestroni, Andrea; Scarpino, Osvaldo; Feraco, Emidio; Gianni, Walter; Cruciani, Guido; Paganelli, Roberto; Di Iorio, Angelo; Scognamiglio, Mario; Grimaldi, Luigi Maria Edoardo; Gabelli, Carlo; Sorbi, Sandro; Binetti, Giuliano; Crepaldi, Gaetano; Franceschi, Claudio

    2010-02-01

    Acetylcholinesterase inhibitors (AChEIs) have been used to improve cognitive status and disability in patients with mild to moderate Alzheimer's disease (AD). However, while the efficacy of AChEIs (i.e. how they act in randomized controlled trials) in this setting is widely accepted, their effectiveness (i.e. how they behave in the real world) remains controversial. To compare the effects of three AChEIs, donepezil (Aricept), galantamine (Reminyl) and rivastigmine (Exelon), in an Italian national, prospective, observational study representative of the 'real world' clinical practice of AChEI treatment for AD. 938 patients with mild to moderate AD collected within the framework of the Italian National Cronos Project (CP), involving several UVAs (AD Evaluation Units) spread over the entire national territory, who were receiving donepezil, galantamine or rivastigmine were followed for 36 weeks by measuring: (i) function, as determined by the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales; (ii) cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) [primary outcome measures]; and (iii) behaviour, as measured on the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR) scale. Moreover, all patients were genotyped for apolipoprotein E (apoE) genetic variants. No statistically significant improvement in the primary outcome measures (MMSE and ADAS-Cog) was observed with drug therapy at 36 weeks, at which point all groups had lost, on average, 1 point on the MMSE and gained 2-3 points on the ADAS-Cog scale compared with baseline. On the secondary outcome measures at week 36, all treatment groups showed a significant worsening on the ADL and IADL scales compared with baseline, while on the NPI scale there were no significant differences from baseline except for the galantamine-treated group which worsened significantly. Moreover

  20. Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease.

    PubMed

    Ismaili, Lhassane; Refouvelet, Bernard; Benchekroun, Mohamed; Brogi, Simone; Brindisi, Margherita; Gemma, Sandra; Campiani, Giuseppe; Filipic, Slavica; Agbaba, Danica; Esteban, Gerard; Unzeta, Mercedes; Nikolic, Katarina; Butini, Stefania; Marco-Contelles, José

    2017-04-01

    Alzheimer's disease is a multifactorial and fatal neurodegenerative disorder characterized by decline of cholinergic function, deregulation of other neurotransmitter systems, β-amyloid fibril deposition, and β-amyloid oligomers formation. Based on the involvement of a relevant number of biological systems in Alzheimer's disease progression, multitarget compounds may enable therapeutic efficacy. Accordingly, compounds possessing, besides anticholinergic activity and β-amyloid aggregation inhibition properties, metal chelating and/or nitric oxide releasing properties with additional antioxidant capacity were developed. Other targets relevant to Alzheimer's disease have also been considered in the last years for producing multitarget compounds such as β-secretase, monoamino oxidases, serotonin receptors and sigma 1 receptors. The purpose of this review will be to highlight recent reports on the development of multitarget compounds for Alzheimer's disease published within the last years focusing on multifunctional ligands characterized by tacrine-like and donepezil-like structures.

  1. Reversible dementias

    PubMed Central

    Tripathi, Manjari; Vibha, Deepti

    2009-01-01

    In recent years, more attention has been given to the early diagnostic evaluation of patients with dementia which is essential to identify patients with cognitive symptoms who may have treatable conditions. Guidelines suggest that all patients presenting with dementia or cognitive symptoms should be evaluated with a range of laboratory tests, and with structural brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI). While many of the disorders reported as ‘reversible dementias’ are conditions that may well be associated with cognitive or behavioral symptoms, these symptoms are not always sufficiently severe to fulfill the clinical criteria for dementia. Thus, while the etiology of a condition may be treatable it should not be assumed that the associated dementia is fully reversible. Potentially reversible dementias should be identified and treatment considered, even if the symptoms are not sufficiently severe to meet the clinical criteria for dementia, and even if partial or full reversal of the cognitive symptoms cannot be guaranteed. In the literature, the most frequently observed potentially reversible conditions identified in patients with cognitive impairment or dementia are depression, adverse effects of drugs, drug or alcohol abuse, space-occupying lesions, normal pressure hydrocephalus, and metabolic conditions land endocrinal conditions like hypothyroidism and nutritional conditions like vitamin B-12 deficiency. Depression is by far the most common of the potentially reversible conditions. The review, hence addresses the common causes of reversible dementia and the studies published so far. PMID:21416018

  2. A study of donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years following adjuvant chemotherapy

    PubMed Central

    Griffin, L.; Balcueva, E. P.; Groteluschen, D. L.; Samuel, T. A.; Lesser, G. J.; Naughton, M. J.; Case, L. D.; Shaw, E. G.; Rapp, S. R.

    2016-01-01

    Purpose Some breast cancer survivors report cognitive difficulties greater than 1 year after chemotherapy. Acetylcholinesterase inhibitors (AChEI) may improve cognitive impairment. We conducted a randomized, placebo-controlled, pilot study to assess the feasibility of using the AChEI, donepezil, to improve subjective and objective measures of cognitive function in breast cancer survivors. Methods Women who received adjuvant chemotherapy 1–5 years prior with current cognitive dysfunction symptoms were randomized to 5 mg of donepezil/day vs placebo for 6 weeks and if tolerated 10 mg/day for 18 weeks for a total of 24 weeks. A battery of validated measures of attention, memory, language, visuomotor skills, processing speed, executive function, and motor dexterity and speed was administered at baseline and at 24 and 36 weeks. Subjective cognitive function, fatigue, sleep, mood, and health-related quality of life were evaluated at baseline and at 12, 24, and 36 weeks. Results Sixty-two patients were enrolled, 76 % completed the study, self-reported compliance was 98 %, and toxicities were minimal. At the end of treatment, the donepezil group performed significantly better than the control group on two parameters of memory—the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall (p=0.033) and HVLT-R Discrimination (p=0.036). There were no significant differences on other cognitive variables or in subjective cognitive function or quality of life. Conclusion Accrual to this feasibility trial was robust, retention was good, compliance was excellent, and toxicities were minimal. Implications for Cancer Survivors Randomized clinical trials in breast cancer survivors to improve cognitive dysfunction are feasible. A phase III trial testing the efficacy of donepezil is warranted given these pilot results. PMID:26130292

  3. Predicting the neural effect of switching from donepezil to galantamine based on single-photon emission computed tomography findings in patients with Alzheimer's disease.

    PubMed

    Oka, Mizuki; Nakaaki, Shutaro; Negi, Atsushi; Miyata, Jun; Nakagawa, Atsuo; Hirono, Nobutsugu; Mimura, Masaru

    2016-03-01

    A number of neuroimaging studies have addressed the specific effect of treatment with cholinesterase inhibitors on the frontal lobe in patients with Alzheimer's disease (AD). However, the neural effects of cholinesterase inhibitors on both apathy and executive dysfunction remain unclear. We examined whether baseline regional cerebral blood flow, as determined by using single-photon emission computed tomography, is capable of predicting changes in apathy and executive dysfunction in response to AD patients switching from donepezil to galantamine therapy. We conducted a 24-week, prospective, open-label study of AD patients treated with galantamine who did not respond to previous treatment with donepezil. Single-photon emission computed tomography was performed at baseline, and behaviour and cognitive assessments including the Mini-Mental State Examination, the Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale, the Frontal Assessment Battery, the Neuropsychiatry Inventory Brief Questionnaire Form, and the Dysexecutive Questionnaire were conducted at three time points (baseline and after 12 and 24 weeks of galantamine therapy). After galantamine therapy, the Neuropsychiatry Inventory Brief Questionnaire Form scores (apathy, irritability, and aberrant motor symptoms) and the Dysexecutive Questionnaire score improved significantly. The single-photon emission computed tomography findings showed that lower baseline regional cerebral blood flow values in several frontal areas, including the dorsolateral and ventrolateral prefrontal cortex, the anterior cingulate, and the orbitofrontal cortex, predicted greater reductions in the score for apathy (distress) on the Neuropsychiatry Inventory Brief Questionnaire Form and the Dysexecutive Questionnaire score after patients switched from donepezil to galantamine therapy. Our study suggests that galantamine therapy, unlike donepezil, is characterized by a dual mechanism of action that may increase

  4. Recovery of Hippocampal Network Connectivity Correlates with Cognitive Improvement in Mild Alzheimer's Disease Patients Treated with Donepezil Assessed by Resting-State fMRI

    PubMed Central

    Goveas, Joseph S.; Xie, Chunming; Ward, B. Douglas; Wu, Zhilin; Li, Wenjun; Franczak, Malgorzata; Jones, Jennifer L.; Antuono, Piero G.; Li, Shi-Jiang

    2011-01-01

    Purpose To identify the neural correlates of cognitive improvement in mild AD subjects, following 12 weeks of donepezil treatment. Materials and Methods Resting-state functional connectivity MRI (R-fMRI) was used to measure the hippocampal functional connectivity (HFC) in 14 mild AD and 18 age-matched normal (CN) subjects. AD subjects were scanned at baseline and after donepezil treatment. CN subjects were scanned only at baseline as a reference to identify regions correlated or anticorrelated to the hippocampus. Before each scan, participants underwent cognitive, behavioral and functional assessments. Results After donepezil treatment, neural correlates of cognitive improvement measured by Mini-Mental State Examination scores were identified in the left parahippocampus, dorsolateral prefrontal cortex (DLPFC) and inferior frontal gyrus. Improvement in AD Assessment Scale-cognitive subscale scores correlated with the HFC changes in the left DLPFC and middle frontal gyrus. Stronger recovery in the network connectivity was associated with cognitive improvement. Conclusion R-fMRI may provide novel insight into the brain's functional responses to AD treatment in clinical pharmacological trials, and also may predict clinical response. PMID:21769962

  5. Age-Related Decline in Brain and Hepatic Clearance of Amyloid-Beta is Rectified by the Cholinesterase Inhibitors Donepezil and Rivastigmine in Rats.

    PubMed

    Mohamed, Loqman A; Qosa, Hisham; Kaddoumi, Amal

    2015-05-20

    In Alzheimer's disease (AD), accumulation of brain amyloid-β (Aβ) depends on imbalance between production and clearance of Aβ. Several pathways for Aβ clearance have been reported including transport across the blood-brain barrier (BBB) and hepatic clearance. The incidence of AD increases with age and failure of Aβ clearance correlates with AD. The cholinesterase inhibitors (ChEIs) donepezil and rivastigmine are used to ease the symptoms of dementia associated with AD. Besides, both drugs have been reported to provide neuroprotective and disease-modifying effects. Here, we investigated the effect of ChEIs on age-related reduced Aβ clearance. Findings from in vitro and in vivo studies demonstrated donepezil and rivastigmine to enhance (125)I-Aβ40 clearance. Also, the increase in brain and hepatic clearance of (125)I-Aβ40 was more pronounced in aged compared to young rats, and was associated with significant reduction in brain Aβ endogenous levels determined by ELISA. Furthermore, the enhanced clearance was concomitant with up-regulation in the expression of Aβ major transport proteins P-glycoprotein and LRP1. Collectively, our findings that donepezil and rivastigmine enhance Aβ clearance across the BBB and liver are novel and introduce an additional mechanism by which both drugs could affect AD pathology. Thus, optimizing their clinical use could help future drug development by providing new drug targets and possible mechanisms involved in AD pathology.

  6. Reversible Sterilization

    ERIC Educational Resources Information Center

    Largey, Gale

    1977-01-01

    Notes that difficult questions arise concerning the use of sterilization for alleged eugenic and euthenic purposes. Thus, how reversible sterilization will be used with relation to the poor, mentally ill, mentally retarded, criminals, and minors, is questioned. (Author/AM)

  7. Reversible Sterilization

    ERIC Educational Resources Information Center

    Largey, Gale

    1977-01-01

    Notes that difficult questions arise concerning the use of sterilization for alleged eugenic and euthenic purposes. Thus, how reversible sterilization will be used with relation to the poor, mentally ill, mentally retarded, criminals, and minors, is questioned. (Author/AM)

  8. Reversible Cardiomyopathies

    PubMed Central

    Patel, Harsh; Madanieh, Raef; Kosmas, Constantine E; Vatti, Satya K; Vittorio, Timothy J

    2015-01-01

    Cardiomyopathies (CMs) have many etiological factors that can result in severe structural and functional dysregulation. Fortunately, there are several potentially reversible CMs that are known to improve when the root etiological factor is addressed. In this article, we discuss several of these reversible CMs, including tachycardia-induced, peripartum, inflammatory, hyperthyroidism, Takotsubo, and chronic illness–induced CMs. Our discussion also includes a review on their respective pathophysiology, as well as possible management solutions. PMID:26052233

  9. Reversible Computing

    DTIC Science & Technology

    1980-02-01

    will have been introduced. 9. Reversible celular autemata We shall assume the reader to have some familiarity with the concept of cel- lular...10003 Mr. Kin B. Thcmpson 1 copy Technical Director Information Systems Divisia.i Naval Research Laboratory (OP-91T) Technical Information Division

  10. Reverse mortgages.

    PubMed

    Farnesi, D

    1995-09-01

    Elders and their families are often caught in a financial bind when it comes to paying for much-needed home care services. Reverse mortgages may offer a solution to elderly home care clients who own their homes but have a limited income with which to maintain their independence.

  11. REVERSE OSMOSIS,

    DTIC Science & Technology

    acetate membranes. Mechanisms of the process and porous cellulose acetate membrane technology are briefly reviewed. Based on a general capillary...The reverse osmosis process is discussed with particular reference to systems involving aqueous solutions and Loeb-Sourirajan-type porous cellulose

  12. Synthesis and evaluation of multi-target-directed ligands against Alzheimer's disease based on the fusion of donepezil and ebselen.

    PubMed

    Luo, Zonghua; Sheng, Jianfei; Sun, Yang; Lu, Chuanjun; Yan, Jun; Liu, Anqiu; Luo, Hai-Bin; Huang, Ling; Li, Xingshu

    2013-11-27

    A novel series of compounds obtained by fusing the cholinesterase inhibitor donepezil and the antioxidant ebselen were designed as multi-target-directed ligands against Alzheimer's disease. An in vitro assay showed that some of these molecules did not exhibit highly potent cholinesterase inhibitory activity but did have various other ebselen-related pharmacological effects. Among the molecules, compound 7d, one of the most potent acetylcholinesterase inhibitors (IC50 values of 0.042 μM for Electrophorus electricus acetylcholinesterase and 0.097 μM for human acetylcholinesterase), was found to be a strong butyrylcholinesterase inhibitor (IC50 = 1.586 μM), to possess rapid H2O2 and peroxynitrite scavenging activity and glutathione peroxidase-like activity (ν0 = 123.5 μM min(-1)), and to be a substrate of mammalian TrxR. A toxicity test in mice showed no acute toxicity at doses of up to 2000 mg/kg. According to an in vitro blood-brain barrier model, 7d is able to penetrate the central nervous system.

  13. Interaction study of aspirin or clopidogrel on pharmacokinetics of donepezil hydrochloride in rats by HPLC-fluorescence detection.

    PubMed

    Wada, Mitsuhiro; Nishiwaki, Junichiro; Yamane, Tomoko; Ohwaki, Yuichi; Aboul-Enein, Hassan Y; Nakashima, Kenichiro

    2007-06-01

    The present study aims to investigate the possibility of interaction of aspirin (Asp) or clopidogrel (CG) on donepezil (DP) hydrochloride in rats by HPLC-fluorescence detection. The separation of DP was achieved in ca. 13 min without interference of Asp and CG on the chromatogram. DP levels in rat plasma with a single administration of DP (5 mg/kg, i.p., group I) and those with a co-administration of Asp (200 mg/kg, p.o., group II or 200 mg/kg, i.p., group III) or CG (5 mg/kg, p.o., group IV) were monitored. The DP concentrations determined in rat plasma ranged from 25.0 to 336.1 ng/mL. Pharmacokinetic parameters for these groups were calculated and compared with one another. No significant difference was observed on the comparison of group I with other groups except for the mean resident time of group IV (p = 0.012). These basic findings may help clinical inference when DP is co-administered with Asp and CG to human. Copyright 2007 John Wiley & Sons, Ltd.

  14. Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer's disease.

    PubMed

    Dias, Kris Simone T; de Paula, Cynthia T; Dos Santos, Thiago; Souza, Isis N O; Boni, Marina S; Guimarães, Marcos J R; da Silva, Fernanda M R; Castro, Newton G; Neves, Gilda A; Veloso, Clarice C; Coelho, Márcio M; de Melo, Ivo Souza F; Giusti, Fabiana C V; Giusti-Paiva, Alexandre; da Silva, Marcelo L; Dardenne, Laurent E; Guedes, Isabella A; Pruccoli, Letizia; Morroni, Fabiana; Tarozzi, Andrea; Viegas, Claudio

    2017-04-21

    A novel series of feruloyl-donepezil hybrid compounds were designed, synthesized and evaluated as multitarget drug candidates for the treatment of Alzheimer's Disease (AD). In vitro results revealed potent acetylcholinesterase (AChE) inhibitory activity for some of these compounds and all of them showed moderate antioxidant properties. Compounds 12a, 12b and 12c were the most potent AChE inhibitors, highlighting 12a with IC50 = 0.46 μM. In addition, these three most promising compounds exhibited significant in vivo anti-inflammatory activity in the mice paw edema, pleurisy and formalin-induced hyperalgesy models, in vitro metal chelator activity for Cu(2+) and Fe(2+), and neuroprotection of human neuronal cells against oxidative damage. Molecular docking studies corroborated the in vitro inhibitory mode of interaction of these active compounds on AChE. Based on these data, compound 12a was identified as a novel promising drug prototype candidate for the treatment of AD with innovative structural feature and multitarget effects.

  15. Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse.

    PubMed

    Provensi, Gustavo; Costa, Alessia; Passani, M Beatrice; Blandina, Patrizio

    2016-10-01

    Histaminergic H3 receptors (H3R) antagonists enhance cognition in preclinical models and modulate neurotransmission, in particular acetylcholine (ACh) release in the cortex and hippocampus, two brain areas involved in memory processing. The cognitive deficits seen in aging and Alzheimer's disease have been associated with brain cholinergic deficits. Donepezil is one of the acetylcholinesterase (AChE) inhibitor approved for use across the full spectrum of these cognitive disorders. We addressed the question if H3R antagonists and donepezil require an intact histamine neuronal system to exert their procognitive effects. The effect of the H3R antagonist ABT-239 and donepezil were evaluated in the object recognition test (ORT), and on the level of glycogen synthase kinase 3 beta (GSK-3β) phosphorylation in normal and histamine-depleted mice. Systemic administration of ABT-239 or donepezil ameliorated the cognitive performance in the ORT. However, these compounds were ineffective in either genetically (histidine decarboxylase knock-out, HDC-KO) or pharmacologically, by means of intracerebroventricular (i.c.v.) injections of the HDC irreversible inhibitor a-fluoromethylhistidine (a-FMHis), histamine-deficient mice. Western blot analysis revealed that ABT-239 or donepezil systemic treatments increased GSK-3β phosphorylation in cortical and hippocampal homogenates of normal, but not of histamine-depleted mice. Furthermore, administration of the PI3K inhibitor LY294002 that blocks GSK-3β phosphorylation, prevented the procognitive effects of both drugs in normal mice. Our results indicate that both donepezil and ABT-239 require the integrity of the brain histaminergic system to exert their procognitive effects and strongly suggest that impairments of PI3K/AKT/GSK-3β intracellular pathway activation is responsible for the inefficacy of both drugs in histamine-deficient animals.

  16. Vasectomy reversal.

    PubMed

    Belker, A M

    1987-02-01

    A vasovasostomy may be performed on an outpatient basis with local anesthesia, but also may be performed on an outpatient basis with epidural or general anesthesia. Local anesthesia is preferred by most of my patients, the majority of whom choose this technique. With proper preoperative and intraoperative sedation, patients sleep lightly through most of the procedure. Because of the length of time often required for bilateral microsurgical vasoepididymostomy, epidural or general anesthesia and overnight hospitalization are usually necessary. Factors influencing the preoperative choice for vasovasostomy or vasoepididymostomy in patients undergoing vasectomy reversal are considered. The preoperative planned choice of vasovasostomy or vasoepididymostomy for patients having vasectomy reversal described herein does not have the support of all urologists who regularly perform these procedures. My present approach has evolved as the data reported in Tables 1 and 2 have become available, but it may change as new information is evaluated. However, it offers a logical method for planning choices of anesthesia and inpatient or outpatient status for patients undergoing vasectomy reversal procedures.

  17. A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer’s disease

    PubMed Central

    Deardorff, William James; Grossberg, George T

    2016-01-01

    Currently available therapies for the treatment of Alzheimer’s disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified. PMID:27757016

  18. Effectiveness of Donepezil, Rivastigmine, and (±)Huperzine A in Counteracting the Acute Toxicity of Organophosphorus Nerve Agents: Comparison with Galantamine

    PubMed Central

    Aracava, Yasco; Pereira, Edna F. R.; Akkerman, Miriam; Adler, Michael

    2009-01-01

    Galantamine, a centrally acting cholinesterase (ChE) inhibitor and a nicotinic allosteric potentiating ligand used to treat Alzheimer's disease, is an effective and safe antidote against poisoning with nerve agents, including soman. Here, the effectiveness of galantamine was compared with that of the centrally active ChE inhibitors donepezil, rivastigmine, and (±)huperzine A as a pre- and/or post-treatment to counteract the acute toxicity of soman. In the first set of experiments, male prepubertal guinea pigs were treated intramuscularly with one of the test drugs and 30 min later challenged with 1.5 × LD50 soman (42 μg/kg s.c.). All animals that were pretreated with galantamine (6–8 mg/kg), 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (±)huperzine A survived the soman challenge, provided that they were also post-treated with atropine (10 mg/kg i.m.). However, only galantamine was well tolerated. In subsequent experiments, the effectiveness of specific treatment regimens using 8 mg/kg galantamine, 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (±)huperzine A was compared in guinea pigs challenged with soman. In the absence of atropine, only galantamine worked as an effective and safe pretreatment in animals challenged with 1.0 × LD50 soman. Galantamine was also the only drug to afford significant protection when given to guinea pigs after 1.0 × LD50 soman. Finally, all test drugs except galantamine reduced the survival of the animals when administered 1 or 3 h after the challenge with 0.6 or 0.7 × LD50 soman. Thus, galantamine emerges as a superior antidotal therapy against the toxicity of soman. PMID:19741148

  19. A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer's disease.

    PubMed

    Deardorff, William James; Grossberg, George T

    2016-01-01

    Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified.

  20. Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments.

    PubMed

    Maurice, Tangui

    2016-01-01

    Drugs activating the sigma-1 (σ1) chaperone protein are anti-amnesic and neuroprotective in neurodegenerative pathologies like Alzheimer's disease (AD). Since these so-called σ1 receptor (σ1R) agonists modulate cholinergic and glutamatergic systems in a variety of physiological responses, we addressed their putative additive/synergistic action in combination with cholinergic or glutamatergic drugs. The selective σ1 agonist PRE-084, or the non-selective σ1 drug ANAVEX2-73 was combined with the acetylcholinesterase inhibitor donepezil or the NMDA receptor antagonist memantine in the nontransgenic mouse model of AD-like memory impairments induced by intracerebroventricular injection of oligomeric Aβ25-35 peptide. Two behavioral tests, spontaneous alternation and passive avoidance response, were used in parallel and both protective and symptomatic effects were examined. After determination of the minimally active doses for each compound, the combinations were tested and the combination index (CI) calculated. Combinations between the σ1 agonists and donepezil showed a synergic protective effect, with CI<1, whereas the combinations with memantine showed an antagonist effect, with CI>1. Symptomatic effects appeared only additive for all combinations, with CI=1. A pharmacological analysis of the PRE-084+donepezil combination revealed that the synergy could be due to an inter-related mechanism involving α7 nicotinic ACh receptors and σ1R. These results demonstrated that σ1 drugs do not only offer a protective potential alone but also in combination with other therapeutic agents. The nature of neuromodulatory molecular chaperone of the σ1R could eventually lead to synergistic combinations.

  1. Distinctive Effect of Donepezil Treatment on P300 and N200 Subcomponents of Auditory Event-Related Evoked Potentials in Alzheimer Disease Patients.

    PubMed

    Vaitkevičius, Arūnas; Kaubrys, Gintaras; Audronytė, Eglė

    2015-07-03

    Latency of P300 subcomponent of event-related potentials (ERPs) increases in Alzheimer disease (AD) patients, which correlate well with cognitive impairment. Cholinesterase inhibitors (ChEIs) reduce P300 latency in AD patients with parallel improvement in cognition. It is not known whether N200 response to ChEIs is similar to that of P300. The aim of this study was to evaluate and compare characteristics of P300 and N200 in AD patients, treatment-naïve and on stable donepezil treatment, matched by age, education, sex, and cognitive function. We recruited 22 consecutive treatment-naïve AD patients (AD-N group), 22 AD patients treated with a stable donepezil dose of 10 mg/day for at least 3 months (AD-T group), and 50 healthy controls were recruited. Neuropsychological testing (MMSE, ADAS-Cog, and additional tests) and ERP recording was performed and analyzed. All groups did not differ according to age, duration of education, or sex (p>0.05). AD-N and AD-T groups did not differ according to cognitive function. The AD-T group had longer duration of disease than the AD-N group (p<0.001). The AD-T and AD-N groups did not differ in P300 latencies (p=0.49). N200 latency was longer in the AD-T group (p<0.001). The general linear model showed that significant predictors of P300 latency were age (p=0.019) and AD treatment status (p<0.001). Duration of AD was a significant predictor of N200 latency (p=0.004). The response of N200 latency to donepezil treatment differs from the response of P300. P300 is a better marker of ChEI treatment-dependent cognitive functions. N200 is more dependent on the duration of AD.

  2. Impaired attention in the 3xTgAD mouse model of Alzheimer's disease: rescue by donepezil (Aricept).

    PubMed

    Romberg, Carola; Mattson, Mark P; Mughal, Mohamed R; Bussey, Timothy J; Saksida, Lisa M

    2011-03-02

    Several mouse models of Alzheimer's disease (AD) with abundant β-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V, and tauP301L mutations) and wild-type control mice on a newly developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild-type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects: first, although 3xTgAD mice initially responded as accurately as wild-type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD.

  3. Concurrent administration of thyroxine and donepezil induces plastic changes in the prefrontal cortex of adult hypothyroid rats.

    PubMed

    Wang, Fen; Wu, Zhangbi; Zha, Xiaoxue; Cai, Yaojun; Wu, Bo; Jia, Xuemei; Zhu, Defa

    2017-09-01

    The aim of the present study was to observe the effects of the concurrent administration of thyroxine (T4) and an acetylcholinesterase (AChE) inhibitor, donepezil (DON), on the hypothyroidism‑induced ultrastructural changes of the prefrontal cortex (PFC) in adult rats. The acetylcholine (ACh) content and AChE activity was assessed, as well as the expressions of synaptotagmin‑1 (syt‑1) and SNAP‑25 were analyzed in the rats. Adding 0.05% propylthiouracil to rats' drinking water induced a hypothyroid rat model. The animals were treated with T4 and DON administered separately or in combination from the fifth week. Transmission electron microscope analysis revealed that hypothyroidism induced marked ultrastructural changes, including the neurons, the synapses and the myelin sheath in the PFC. T4 or DON treatment improved the morphologic features of the PFC, and the performance of the T4 combined DON group was the closest to the control group. Moreover, hypothyroidism significantly decreased the content of ACh (29.8%) and activity of AChE (27.8%), which were restored to control values by T4 admi-nistration. In addition, DON treatment restored ACh content to normal. At the protein level, hypothyroidism increased the levels of syt‑1 and SNAP‑25 in the PFC, both of which were not restored to control values following T4 administration, while concurrent administration of T4 and DON was able to induce this effect. These results suggested that adult‑onset hypothyroidism induce morphological, biochemical and molecular alterations in the PFC, combined administration of T4 and DON induce plastic changes in the PFC, different from that of the standard T4 therapy, and that the DON treatment may facilitate the recovery of synaptic protein impairments induced by hypothyroidism.

  4. Donepezil-Based Central Acetylcholinesterase Inhibitors by Means of a "Bio-Oxidizable" Prodrug Strategy: Design, Synthesis, and in Vitro Biological Evaluation.

    PubMed

    Peauger, Ludovic; Azzouz, Rabah; Gembus, Vincent; Ţînţaş, Mihaela-Liliana; Sopková-de Oliveira Santos, Jana; Bohn, Pierre; Papamicaël, Cyril; Levacher, Vincent

    2017-07-13

    With the aim of reducing side effects of acetylcholinesterase inhibitors (AChEIs) during symptomatic treatment of Alzheimer's disease, we report herein a new class of donepezil-based "bio-oxidizable" prodrugs 1 designed to be converted into dual binding site AChEIs 2. While most of indanone-derived N-benzylpyridinium salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the standard drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines 1 were found to be inactive. Promisingly, whereas the selected prodrug 1r showed good permeability in the PAMPA-BBB model and high in vitro antioxidant activity, its conversion to AChEI 2r could be easily achieved under mild conditions when incubated in various oxidizing media. Lastly, both compounds 1r and 2r did not show genotoxicity in vitro and displayed high LD50 values in mice, making this prodrug 1r/drug 2r couple a good candidate for further in vivo biological experiments.

  5. Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study.

    PubMed

    Nahas, Ziad; George, Mark S; Horner, Michael D; Markowitz, John S; Li, Xingbao; Lorberbaum, Jeffrey P; Owens, Susan D; McGurk, Susan; DeVane, Lindsay; Risch, S Craig

    2003-06-01

    Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate's role in modulating cognition and neuronal connectivity in schizophrenia.

  6. Positive allosteric modulator of alpha 7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates

    PubMed Central

    Callahan, Patrick M.; Hutchings, Elizabeth J.; Kille, Nancy J.; Chapman, James M.; Terry, Alvin V.

    2012-01-01

    The development of novel therapeutic agents for disorders of cognition such as Alzheimer’s disease (AD) is of paramount importance given the ever-increasing elderly population, however; there is also considerable interest in any strategy that might enhance the clinical efficacy of currently available treatments. The purpose of this study was to evaluate an adjunctive treatment strategy to memory enhancement, namely combining the commonly prescribed acetylcholinesterase inhibitor (AChEI) donepezil, with a positive allosteric modulator (PAM) of α7 nicotinic-acetylcholine receptors (α7-nAChRs), PNU-120596. The treatment strategy was evaluated in a (non-spatial) spontaneous novel object recognition (NOR) task in young rats; a water maze spatial learning and recall procedure in aged, cognitively-impaired rats, and a delayed match to sample (working/short term memory) task in aged rhesus monkeys. In all three experiments a similar drug response was observed, namely that donepezil administered alone improved task performance in a dose-dependent manner; that PNU-120596 administered alone was without significant effect, but that the combination of PNU-120596 with a subthreshold dose of donepezil was effective. The positive effect of the drug combination appeared to be α7-nAChR mediated given that it was blocked in the NOR task by the selective α7-nAChR antagonist methyllycaconitine (MLA). Collectively, these data indicate that PNU-120596 increases the effective dose range of donepezil in learning/memory-related tasks in young and age-impaired animal models. The results suggest that α7-nAChR-selective PAMs like PNU-120596 have potential as adjunctive treatments with acetylcholinesterase inhibitors (e.g., donepezil) for age-related illnesses such as AD as well memory disorders not necessarily associated with advanced age. PMID:23168113

  7. Positive allosteric modulator of α7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates.

    PubMed

    Callahan, Patrick M; Hutchings, Elizabeth J; Kille, Nancy J; Chapman, James M; Terry, Alvin V

    2013-04-01

    The development of novel therapeutic agents for disorders of cognition such as Alzheimer's disease (AD) is of paramount importance given the ever-increasing elderly population, however; there is also considerable interest in any strategy that might enhance the clinical efficacy of currently available treatments. The purpose of this study was to evaluate an adjunctive treatment strategy to memory enhancement, namely combining the commonly prescribed acetylcholinesterase inhibitor (AChEI) donepezil, with a positive allosteric modulator (PAM) of α7 nicotinic-acetylcholine receptors (α7-nAChRs), PNU-120596. The treatment strategy was evaluated in a (non-spatial) spontaneous novel object recognition (NOR) task in young rats; a water maze spatial learning and recall procedure in aged, cognitively-impaired rats, and a delayed match to sample (working/short term memory) task in aged rhesus monkeys. In all three experiments a similar drug response was observed, namely that donepezil administered alone improved task performance in a dose-dependent manner; that PNU-120596 administered alone was without significant effect, but that the combination of PNU-120596 with a subthreshold dose of donepezil was effective. The positive effect of the drug combination appeared to be α7-nAChR mediated given that it was blocked in the NOR task by the selective α7-nAChR antagonist methyllycaconitine (MLA). Collectively, these data indicate that PNU-120596 increases the effective dose range of donepezil in learning/memory-related tasks in young and age-impaired animal models. The results suggest that α7-nAChR-selective PAMs like PNU-120596 have potential as adjunctive treatments with acetylcholinesterase inhibitors (e.g., donepezil) for age-related illnesses such as AD as well memory disorders not necessarily associated with advanced age. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Taste-masked and affordable donepezil hydrochloride orally disintegrating tablet as promising solution for non-compliance in Alzheimer's disease patients.

    PubMed

    Liew, Kai Bin; Tan, Yvonne Tze Fung; Peh, Kok Khiang

    2015-04-01

    Manufacturing process and superdisintegrants used in orally disintegrating tablet (ODT) formulation are often time discussed. However, the effect of suitable filler for ODT formulation is not explored thoroughly. The aim of this study was to develop a novel taste masked and affordable donepezil hydrochloride ODT with fast disintegration time and stable to improve medication compliance of Alzheimer's disease patient. The ODT was manufactured using simple wet-granulation method. Crospovidone XL-10 was used as superdisintegrant and optimization was done by comparing the effect of three grades of lactose monohydrate compound as filler: Starlac®, Flowlac® and Tablettose®. Formulations containing higher amount of colloidal silicon dioxide showed increase in hardness, weight, disintegration time and wetting time after stability study. Formulation E which containing 50% of Starlac® was found with shortest in vitro disintegration time (21.7 ± 1.67 s), in vivo disintegration time (24.0 ± 1.05 s) and in vitro disintegration time in artificial salvia (22.5 ± 1.67 s). Physical stability studies at 40 °C/75% RH for 6 months, Fourier transform infrared spectroscopy analysis and X-ray diffraction results showed that the formulation was stable. The drug-released profile showed that 80% of donepezil hydrochloride was released within 1 min. A single-dose, fasting, four-period, seven-treatment, double-blinded study involving 16 healthy human volunteers was performed to evaluate the palatability of ODT. Formulation VII containing 10 mg of ammonium glycyrrhizinate was able to mask the bitter taste of the drug. The product has the potential to be commercialized and it might serve as solution for non-compliance among the Alzheimer's disease patients.

  9. The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H3 Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice

    PubMed Central

    Sors, Aurore; Krazem, Ali; Kehr, Jan; Yoshitake, Takashi; Dominguez, Gaelle; Henkous, Nadia; Letondor, Claire; Mocaer, Elisabeth; Béracochéa, Daniel J.

    2016-01-01

    Donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer’s disease patients. An alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both histaminergic and cholinergic pathways, to create a synergistic effect. To that aim, 14 month old C57/Bl6 mice were administered per oesophagy during nine consecutive days with Donepezil (at 0.1 and 0.3 mg/kg) and S 38093 (at 0.1, 0.3, and 1.0 mg/kg), a H3 histaminergic antagonist developed by Servier, alone or in combination and tested for memory in a contextual memory task that modelized the age-induced memory dysfunction. The present study shows that the combination of Donepezil and S 38093 induced a dose-dependent synergistic memory-enhancing effect in middle-aged mice with a statistically higher size of effect never obtained with compounds alone and without any pharmacokinetic interaction between both compounds. We demonstrated that the memory-enhancing effect of the S 38093 and Donepezil combination is mediated by its action on the septo-hippocampal circuitry, since it canceled out the reduction of CREB phosphorylation (pCREB) observed in these brain areas in vehicle-treated middle-aged animals. Overall, the effects of drug combinations on pCREB in the hippocampus indicate that the synergistic promnesiant effects of the combination on memory performance in middle-aged mice stem primarily from an enhancement of neural activity in the septo-hippocampal system. PMID:28066242

  10. Reversible Thermoset Adhesives

    NASA Technical Reports Server (NTRS)

    Mac Murray, Benjamin C. (Inventor); Tong, Tat H. (Inventor); Hreha, Richard D. (Inventor)

    2016-01-01

    Embodiments of a reversible thermoset adhesive formed by incorporating thermally-reversible cross-linking units and a method for making the reversible thermoset adhesive are provided. One approach to formulating reversible thermoset adhesives includes incorporating dienes, such as furans, and dienophiles, such as maleimides, into a polymer network as reversible covalent cross-links using Diels Alder cross-link formation between the diene and dienophile. The chemical components may be selected based on their compatibility with adhesive chemistry as well as their ability to undergo controlled, reversible cross-linking chemistry.

  11. Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease.

    PubMed

    Wang, Li; Esteban, Gerard; Ojima, Masaki; Bautista-Aguilera, Oscar M; Inokuchi, Tsutomu; Moraleda, Ignacio; Iriepa, Isabel; Samadi, Abdelouahid; Youdim, Moussa B H; Romero, Alejandro; Soriano, Elena; Herrero, Raquel; Fernández Fernández, Ana Patricia; Ricardo-Martínez-Murillo; Marco-Contelles, José; Unzeta, Mercedes

    2014-06-10

    The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 μM; MAO B (IC50 = 10.2 ± 0.9 μM); AChE (IC50 = 1.8 ± 0.1 μM); BuChE (IC50 = 1.6 ± 0.25 μM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice.

  12. Use of a novel radiometric method to assess the inhibitory effect of donepezil on acetylcholinesterase activity in minimally diluted tissue samples

    PubMed Central

    Kikuchi, Tatsuya; Okamura, Toshimitsu; Arai, Takuya; Obata, Takayuki; Fukushi, Kiyoshi; Irie, Toshiaki; Shiraishi, Tetsuya

    2010-01-01

    Background and purpose: Cholinesterase inhibitors have been widely used for the treatment of patients with dementia. Monitoring of the cholinesterase activity in the blood is used as an indicator of the effect of the cholinesterase inhibitors in the brain. The selective measurement of cholinesterase with low tissue dilution is preferred for accurate monitoring; however, the methods have not been established. Here, we investigated the effect of tissue dilution on the action of cholinesterase inhibitors using a novel radiometric method with selective substrates, N-[14C]methylpiperidin-4-yl acetate ([14C]MP4A) and (R)-N-[14C]methylpiperidin-3-yl butyrate ([14C]MP3B_R), for AChE and butyrylcholinesterase (BChE) respectively. Experimental approach: We investigated the kinetics of hydrolysis of [14C]-MP4A and [14C]-MP3B_R by cholinesterases, and evaluated the selectivity of [14C]MP4A and [14C]MP3B_R for human AChE and BChE, respectively, compared with traditional substrates. Then, IC50 values of cholinesterase inhibitors in minimally diluted and highly diluted tissues were measured with [14C]MP4A and [14C]MP3B_R. Key results: AChE and BChE activities were selectively measured as the first-order hydrolysis rates of [14C]-MP4A and [14C]MP3B_R respectively. The AChE selectivity of [14C]MP4A was an order of magnitude higher than traditional substrates used for the AChE assay. The IC50 values of specific AChE and BChE inhibitors, donepezil and ethopropazine, in 1.2-fold diluted human whole blood were much higher than those in 120-fold diluted blood. In addition, the IC50 values of donepezil in monkey brain were dramatically decreased as the tissue was diluted. Conclusions and implications: This method would effectively monitor the activity of cholinesterase inhibitors used for therapeutics, pesticides and chemical warfare agents. PMID:20401964

  13. Tubal Ligation Reversal

    MedlinePlus

    ... seal off the fallopian tubes, such as the Essure or Adiana systems, generally aren't reversible. In ... electrocautery). Some types of sterilization, such as the Essure system, are not considered reversible. Even if tubal ...

  14. Vasectomy and its reversal.

    PubMed

    Belker, A M

    1985-12-01

    Techniques, results, complications, and medicolegal aspects of vasectomy are discussed in this article. Emphasis is placed on techniques that prevent spontaneous recanalization of the ends of the vas deferens after vasectomy. Factors that affect the reversibility of vasectomy are discussed. New microsurgical techniques of vasectomy reversal are described, and results of these new techniques are compared with results of nonmicrosurgical techniques of vasectomy reversal. Indications for bypass vasoepididymostomy during vasectomy reversal procedures, as well as techniques for performing vasoepididymostomy, are discussed.

  15. Reverse Correlation in Neurophysiology

    ERIC Educational Resources Information Center

    Ringach, Dario; Shapley, Robert

    2004-01-01

    This article presents a review of reverse correlation in neurophysiology. We discuss the basis of reverse correlation in linear transducers and in spiking neurons. The application of reverse correlation to measure the receptive fields of visual neurons using white noise and m-sequences, and classical findings about spatial and color processing in…

  16. Quantum Operation Time Reversal

    SciTech Connect

    Crooks, Gavin E.

    2008-03-25

    The dynamics of an open quantum system can be described by a quantum operation: A linear, complete positive map of operators. Here, I exhibit a compact expression for the time reversal of a quantum operation, which is closely analogous to the time reversal of a classical Markov transition matrix. Since open quantum dynamics are stochastic, and not, in general, deterministic, the time reversal is not, in general, an inversion of the dynamics. Rather, the system relaxes toward equilibrium in both the forward and reverse time directions. The probability of a quantum trajectory and the conjugate, time reversed trajectory are related by the heat exchanged with the environment.

  17. The effects of fluorine substitution on the chemical properties and inhibitory capacity of Donepezil anti-Alzheimer drug; density functional theory and molecular docking calculations.

    PubMed

    Khosravan, Azita; Marani, Safora; Sadeghi Googheri, Mohammad Sadegh

    2017-01-01

    Drug fluorination has the potential to reproduce useful drugs with decreasing the side effect of them. Identifying the effect of this improvement on the chemical properties and biological interactions of drug symbolizes a meaningful progress in drug design. Here the fluorination of Donepezil as an anti-Alzheimer drug, including 7 fluorinated derivatives of it, was investigated computationally. In the first part of our calculations, the most important chemical properties of drug that affects the drug efficiency were investigated by applying the M06/6-31g (d, p) and M062X/6-31g (d, p) levels of theories. Findings showed that the fluorine substitution changed the drug stability as altered the solubility and molecular polarity. Furthermore, the intramolecular hydrogen bonding, charge distribution and electron delocalization of the drug were affected by this replacement. In the second section, the effect of fluorination on the drug⋯enzyme interactions was evaluated by using two effective methods Based on the molecular docking and density functional theory (DFT) calculations fluorine substitution influenced the Donepezil⋯Acetylcholinesterase interactions. Calculated binding energies by two computational methods displayed that the fluorine replacement changed the binding affinity of drug. Finally, the most significant non-bonded interactions between drugs and involved residues were investigated by bond length data analysis.

  18. The effects of counseling spouse caregivers of people with Alzheimer disease taking donepezil and of country of residence on rates of admission to nursing homes and mortality.

    PubMed

    Brodaty, Henry; Mittelman, Mary; Gibson, Louisa; Seeher, Katrin; Burns, Alistair

    2009-09-01

    Does psychosocial intervention for caregivers whose spouses with Alzheimer disease (AD) are taking donepezil delay nursing home (NH) placement or death of patients? Randomized controlled trial with 2 years of active treatment and up to 8.5 years of follow-up (mean: 5.4 years, SD: 2.4). Outpatients of research clinics in Australia, the United Kingdom, and the United States. One hundred and fifty-five persons with AD and their spouses. Five sessions of individual and family counseling (+ prn ad hoc counseling) or usual care. Time to institutionalization and death using Cox proportional hazards methods. Over a mean of 5.4 years (SD: 2.4), there were no differences in NH placement or mortality by intervention group, but there were by country, with Australian patients admitted to NHs earlier than U.S. than U.K. patients. Earlier NH admission of Australian compared to U.K. and U.S. subjects may be due to differences in health care, NH systems, availability, and affordability.

  19. Synthesis and pharmacological evaluation of donepezil-based agents as new cholinesterase/monoamine oxidase inhibitors for the potential application against Alzheimer's disease.

    PubMed

    Li, Fan; Wang, Zhi-Min; Wu, Jia-Jia; Wang, Jin; Xie, Sai-Sai; Lan, Jin-Shuai; Xu, Wei; Kong, Ling-Yi; Wang, Xiao-Bing

    2016-01-01

    In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of donepezil-like compounds were designed, synthesized and evaluated. In vitro studies showed that most of the designed compounds displayed potent inhibitory activities toward AChE, BuChE, MAO-B and MAO-A. Among them, w18 was a promising agent with balanced activities, which exhibited a moderate cholinesterase inhibition (IC50, 0.220 μM for eeAChE; 1.23 μM for eqBuChE; 0.454 μM for hAChE) and an acceptable inhibitory activity against monoamine oxidases (IC50, 3.14 μM for MAO-B; 13.4 μM for MAO-A). Moreover, w18 could also be a metal-chelator, and able to cross the blood-brain barrier with low cell toxicity on PC12 cells. Taken together, these results suggested that w18 might be a promising multitargeted compound for AD treatment.

  20. The eyeglass reversal.

    PubMed

    Oh, Songjoo

    2011-07-01

    Some figures, such as the Necker cube, are spontaneously reversible between alternative percepts. Before learning those skilled reversals, how do people achieve reversals for the very first time? It has been known that, in the case of a first reversal, people can be expected to see the reversal when given specific information about how the figures are ambiguous. This point was confirmed by using drawing versions of reversible figures. To demonstrate how intention plays a role in the initial reversal of a real object, a pair of regular eyeglasses, reversible in perspective, were presented to naïve observers in monocular vision. When the eyeglasses were viewed inwardly and the observers were given information that the eyeglasses could be ambiguous, they were able to easily see the reversal. When the eyeglasses were viewed outwardly, observers saw it only after they had been informed of exactly what the two alternative percepts were.Interestingly, many observers often mistakenly saw the inwardly viewed eyeglasses as placed outwardly from the beginning of the observation, while they saw the outwardly viewed eyeglasses correctly. Taking these results together, for the first reversal of a real object, the specificity of intention varies with the ambiguity of the object.

  1. Reversible logic for supercomputing.

    SciTech Connect

    DeBenedictis, Erik P.

    2005-05-01

    This paper is about making reversible logic a reality for supercomputing. Reversible logic offers a way to exceed certain basic limits on the performance of computers, yet a powerful case will have to be made to justify its substantial development expense. This paper explores the limits of current, irreversible logic for supercomputers, thus forming a threshold above which reversible logic is the only solution. Problems above this threshold are discussed, with the science and mitigation of global warming being discussed in detail. To further develop the idea of using reversible logic in supercomputing, a design for a 1 Zettaflops supercomputer as required for addressing global climate warming is presented. However, to create such a design requires deviations from the mainstream of both the software for climate simulation and research directions of reversible logic. These deviations provide direction on how to make reversible logic practical.

  2. Perspective: reverse evolution.

    PubMed

    Teotónio, H; Rose, M R

    2001-04-01

    For some time, the reversibility of evolution was primarily discussed in terms of comparative patterns. Only recently has this problem been studied using experimental evolution over shorter evolutionary time frames. This has raised questions of definition, experimental procedure, and the hypotheses being tested. Experimental evolution has provided evidence for multiple population genetic mechanisms in reverse evolution, including pleiotropy and mutation accumulation. It has also pointed to genetic factors that might prevent reverse evolution, such as a lack of genetic variability, epistasis, and differential genotype-by-environment interactions. The main focus of this perspective is on laboratory studies and their relevance to the genetics of reverse evolution. We discuss reverse evolution experiments with Drosophila, bacterial, and viral populations. Field studies of the reverse evolution of melanism in the peppered moth are also reviewed.

  3. HIV-1 Reverse Transcription

    PubMed Central

    Hu, Wei-Shau; Hughes, Stephen H.

    2012-01-01

    Reverse transcription and integration are the defining features of the Retroviridae; the common name “retrovirus” derives from the fact that these viruses use a virally encoded enzyme, reverse transcriptase (RT), to convert their RNA genomes into DNA. Reverse transcription is an essential step in retroviral replication. This article presents an overview of reverse transcription, briefly describes the structure and function of RT, provides an introduction to some of the cellular and viral factors that can affect reverse transcription, and discusses fidelity and recombination, two processes in which reverse transcription plays an important role. In keeping with the theme of the collection, the emphasis is on HIV-1 and HIV-1 RT. PMID:23028129

  4. The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease (review of Technology Appraisal No. 111): a systematic review and economic model.

    PubMed

    Bond, M; Rogers, G; Peters, J; Anderson, R; Hoyle, M; Miners, A; Moxham, T; Davis, S; Thokala, P; Wailoo, A; Jeffreys, M; Hyde, C

    2012-01-01

    Alzheimer’s disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of

  5. Reverse Core Engine with Thrust Reverser

    NASA Technical Reports Server (NTRS)

    Suciu, Gabriel L. (Inventor); Chandler, Jesse M. (Inventor)

    2017-01-01

    An engine system has a gas generator, a bi-fi wall surrounding at least a portion of the gas generator, a casing surrounding a fan, and the casing having first and second thrust reverser doors which in a deployed position abut each other and the bi-fi wall.

  6. Quantum reverse hypercontractivity

    SciTech Connect

    Cubitt, Toby; Kastoryano, Michael; Montanaro, Ashley; Temme, Kristan

    2015-10-15

    We develop reverse versions of hypercontractive inequalities for quantum channels. By generalizing classical techniques, we prove a reverse hypercontractive inequality for tensor products of qubit depolarizing channels. We apply this to obtain a rapid mixing result for depolarizing noise applied to large subspaces and to prove bounds on a quantum generalization of non-interactive correlation distillation.

  7. Clocked Thrust Reversers

    NASA Technical Reports Server (NTRS)

    Suciu, Gabriel L. (Inventor); Chandler, Jesse M. (Inventor)

    2017-01-01

    An aircraft includes a fuselage including a propulsion system supported within an aft portion. A thrust reverser is mounted proximate to the propulsion system for directing thrust in a direction to slow the aircraft. The thrust reverser directs thrust at an angle relative to a vertical plane to reduce interference on control surfaces and reduce generation of underbody lift.

  8. Reverse Transfer Student Study.

    ERIC Educational Resources Information Center

    Slark, Julie

    After a preliminary study revealed that 21% of all credit students at Santa Ana College (SAC) had previously attended a four-year institution, a further study was conducted to determine the educational interests and matriculation patterns of these reverse transfer students. A sample of 360 reverse transfer students was selected for interviews,…

  9. Ultrasonic Time Reversal Mirrors

    NASA Astrophysics Data System (ADS)

    Fink, Mathias; Montaldo, Gabriel; Tanter, Mickael

    2004-11-01

    For more than ten years, time reversal techniques have been developed in many different fields of applications including detection of defects in solids, underwater acoustics, room acoustics and also ultrasound medical imaging and therapy. The essential property that makes time reversed acoustics possible is that the underlying physical process of wave propagation would be unchanged if time were reversed. In a non dissipative medium, the equations governing the waves guarantee that for every burst of sound that diverges from a source there exists in theory a set of waves that would precisely retrace the path of the sound back to the source. If the source is pointlike, this allows focusing back on the source whatever the medium complexity. For this reason, time reversal represents a very powerful adaptive focusing technique for complex media. The generation of this reconverging wave can be achieved by using Time Reversal Mirrors (TRM). It is made of arrays of ultrasonic reversible piezoelectric transducers that can record the wavefield coming from the sources and send back its time-reversed version in the medium. It relies on the use of fully programmable multi-channel electronics. In this paper we present some applications of iterative time reversal mirrors to target detection in medical applications.

  10. An HPLC-MS method for the quantification of new acetylcholinesterase inhibitor PC 48 (7-MEOTA-donepezil like compound) in rat plasma: Application to a pharmacokinetic study.

    PubMed

    Mzik, Martin; Korabecny, Jan; Nepovimova, Eugenie; Voříšek, Viktor; Palička, Vladimir; Kuca, Kamil; Zdarova Karasova, Jana

    2016-05-01

    A simple, rapid and sensitive method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated for the quantitative determination in rat plasma of a new candidate for AD treatment, namely PC 48 (a 7-MEOTA-donepezil like compound) in rat plasma. Sample preparation involved pH adjustment with sodium hydroxide followed by solvent extraction with ethyl acetate:dichloromethane (80:20, v/v). The chromatographic separation was achieved on an Ascentis Express RP-Amide column (75 mm × 2.1mm, 2.7 μm) with a gradient mobile phase consisting of 0.05 M aqueous formic acid and acetonitrile. Detection was carried out using positive-ion electrospray tandem mass spectrometry on an LTQ XL system using the MS/MS CID (collision-induced dissociation) mode. The method was linear in the range 0.1-1000 ng/ml (r(2)=0.999) with a lower limit of quantitation of 0.1 ng/mL. Extraction recovery was in the range 63.5-72.1% for PC 48 and 70.5% for reserpine (internal standard, IS). Intra- and inter-day precisions measured as relative standard deviation were below 10.8% and accuracy was from -7.2% to 7.4%. The method was successfully applied to a pharmacokinetic study involving intramuscular application of 3.86 mg/kg PC 48 to rats for the first time. Pharmacokinetic parameters for PC 48 include Cmax 39.09 ± 4.45 ng/mL,Tmax 5.00 ± 3.08 min, AUC0-t 23374 ± 4045 min ng/mL and t1/2 1065 ± 246 min.

  11. Impacts of thyroxine combined with donepezil on hippocampal ultrastructures and expressions of synaptotagmin-1 and SNAP-25 in adult rats with hypothyroidism

    PubMed Central

    Yang, Hao; Zha, Xiaoxue; Cai, Yaojun; Wang, Fen; Wu, Zhangbi; Wu, Bo; Jia, Xuemei; Zhu, Defa

    2015-01-01

    The study aims to observe the impacts of thyroxine (T4) combined with donepezil (DON) on hippocampal ultrastructures and expressions of synaptotagmin-1 and SNAP-25 in adult rats with hypothyroidism. All rats were randomly divided into five groups: the normal control group (CON), the hypothyroidism group (Hypo), the T4 treatment group (T4), the DON treatment group (DON) and the T4+DON combined treatment group (T4+DON). Technique of Electron Microscope (TEM) was used to observe the hippocampal ultrastructures of each group, Western blot and real-time RT-PCR were performed to analyze the protein and mRNA expressions of syt-1 and SNAP-25 in the hippocampus of each group. TEM revealed that the Hypo group exhibited the significant vacuolar degeneration of mitochondria in the hippocampal neurons, the free ribosomes were sparse, the synaptic structures were damaged, and the number of synaptic vesicles was reduced, the above injuries in the T4 or DON group were improved, and the performance of the T4+DON group was the most close to the CON group. From the protein and mRNA levels, the dorsal hippocampal syt-1 expression of the Hypo group was significantly reduced, while SNAP-25 was significantly increased, the expressions were partially recovered after the T4 treatment, and the T4+DON combined treatment made the expression return to normal. The adult hypothyroid rats exhibited pathological damages in the hippocampal ultrastructures, the expression of syt-1 was downregulated, while that of SNAP-25 was upregulated, the T4+DON combined therapy could repair the above injuries, and the roles were better than the single drug treatment. PMID:26770386

  12. Impaired Attention in the 3xTgAD Model of Alzheimer’s Disease Assessed Using a Translational Touchscreen Method for Mice: Rescue by Donepezil (Aricept)

    PubMed Central

    Romberg, Carola; Mattson, Mark P.; Mughal, Mohamed R.; Bussey, Timothy J.; Saksida, Lisa M.

    2011-01-01

    Several mouse models of Alzheimer’s Disease (AD) with abundant β-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V and tauP301L mutations) and wild type control mice on a newly-developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects; first, although 3xTgAD mice initially responded as accurately as wild type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD. PMID:21368062

  13. Impacts of thyroxine combined with donepezil on hippocampal ultrastructures and expressions of synaptotagmin-1 and SNAP-25 in adult rats with hypothyroidism.

    PubMed

    Yang, Hao; Zha, Xiaoxue; Cai, Yaojun; Wang, Fen; Wu, Zhangbi; Wu, Bo; Jia, Xuemei; Zhu, Defa

    2015-01-01

    The study aims to observe the impacts of thyroxine (T4) combined with donepezil (DON) on hippocampal ultrastructures and expressions of synaptotagmin-1 and SNAP-25 in adult rats with hypothyroidism. All rats were randomly divided into five groups: the normal control group (CON), the hypothyroidism group (Hypo), the T4 treatment group (T4), the DON treatment group (DON) and the T4+DON combined treatment group (T4+DON). Technique of Electron Microscope (TEM) was used to observe the hippocampal ultrastructures of each group, Western blot and real-time RT-PCR were performed to analyze the protein and mRNA expressions of syt-1 and SNAP-25 in the hippocampus of each group. TEM revealed that the Hypo group exhibited the significant vacuolar degeneration of mitochondria in the hippocampal neurons, the free ribosomes were sparse, the synaptic structures were damaged, and the number of synaptic vesicles was reduced, the above injuries in the T4 or DON group were improved, and the performance of the T4+DON group was the most close to the CON group. From the protein and mRNA levels, the dorsal hippocampal syt-1 expression of the Hypo group was significantly reduced, while SNAP-25 was significantly increased, the expressions were partially recovered after the T4 treatment, and the T4+DON combined treatment made the expression return to normal. The adult hypothyroid rats exhibited pathological damages in the hippocampal ultrastructures, the expression of syt-1 was downregulated, while that of SNAP-25 was upregulated, the T4+DON combined therapy could repair the above injuries, and the roles were better than the single drug treatment.

  14. Comparison of five benzodiazepine-receptor agonists on buprenorphine-induced mu-opioid receptor regulation.

    PubMed

    Poisnel, Géraldine; Dhilly, Martine; Le Boisselier, Reynald; Barre, Louisa; Debruyne, Danièle

    2009-05-01

    In this study, we compared the effects of five short-, medium-, or long-acting benzodiazepine-receptor agonists (BZDs) [alprazolam (APZ), clonazepam (CLZ), flunitrazepam (FLZ), loprazolam (LPZ), zolpidem (ZLP)], at two distinct doses, 0.2 and 2 mg/kg, on the cell surface regulation of mu-opioid receptor induced by 0.15 mg/kg buprenorphine (BPN) in specific regions of the rat brain. Using 0.312 - 5 nM [(3)H]-DAMGO concentrations and Scatchard plot analysis, B(max) (maximal receptor density) and K(d) (dissociation constant) were determined at different brain regions of interest (amygdala, cortex, hippocampus, hypothalamus, thalamus). Acute BPN induced an expected down-regulation and addition of each of the BZDs to BPN induced less down-regulation than did BPN alone, sometimes while altering affinity. Some significant differences in the intensity of these effects were observed between BZDs. FLZ that is widely abused and enlarges BPN toxicity appeared the most potent to increase mu-cell surface receptor density at the lowest dose of 0.2 mg/kg. Besides, LPZ for which the effect on mu-opioid-receptor regulation appeared lower is considered to have a low risk of dependence in the epidemiological data banks. CLZ and ZLP (2 mg/kg) induced the strongest modification on mu-opioid-receptor density, but a substantial decrease in affinity could minimize the functional consequences. The reported changes were maximal in the amygdala, hippocampus, and thalamus. Among people using BPN and BZDs, the effects described here are likely to influence addictive behaviors and induce toxic effects that could be quantitatively different due to the quality of the BZD.

  15. The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's disease mice

    PubMed Central

    2013-01-01

    Introduction Despite years of research, there are no disease-modifying drugs for Alzheimer's disease (AD), a fatal, age-related neurodegenerative disorder. Screening for potential therapeutics in rodent models of AD has generally relied on testing compounds before pathology is present, thereby modeling disease prevention rather than disease modification. Furthermore, this approach to screening does not reflect the clinical presentation of AD patients which could explain the failure to translate compounds identified as beneficial in animal models to disease modifying compounds in clinical trials. Clearly a better approach to pre-clinical drug screening for AD is required. Methods To more accurately reflect the clinical setting, we used an alternative screening strategy involving the treatment of AD mice at a stage in the disease when pathology is already advanced. Aged (20-month-old) transgenic AD mice (APP/swePS1ΔE9) were fed an exceptionally potent, orally active, memory enhancing and neurotrophic molecule called J147. Cognitive behavioral assays, histology, ELISA and Western blotting were used to assay the effect of J147 on memory, amyloid metabolism and neuroprotective pathways. J147 was also investigated in a scopolamine-induced model of memory impairment in C57Bl/6J mice and compared to donepezil. Details on the pharmacology and safety of J147 are also included. Results Data presented here demonstrate that J147 has the ability to rescue cognitive deficits when administered at a late stage in the disease. The ability of J147 to improve memory in aged AD mice is correlated with its induction of the neurotrophic factors NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor) as well as several BDNF-responsive proteins which are important for learning and memory. The comparison between J147 and donepezil in the scopolamine model showed that while both compounds were comparable at rescuing short term memory, J147 was superior at rescuing spatial

  16. An algebra of reversible computation.

    PubMed

    Wang, Yong

    2016-01-01

    We design an axiomatization for reversible computation called reversible ACP (RACP). It has four extendible modules: basic reversible processes algebra, algebra of reversible communicating processes, recursion and abstraction. Just like process algebra ACP in classical computing, RACP can be treated as an axiomatization foundation for reversible computation.

  17. Reversible shape memory

    NASA Astrophysics Data System (ADS)

    Sheiko, Sergei; Zhou, Jing; White, Sarah; Ashby, Valerie

    2012-02-01

    An ``Achilles' heel'' of shape memory materials is that shape transformations triggered by an external stimulus are usually irreversible. Here we present a new concept of reversible transitions between two well-defined shapes by controlling hierarchic crystallization of a dual-network elastomer. The reversibility was demonstrated for different types of shape transformations including rod bending, winding of a helical coil, and widening an aperture. The distinct feature of the reversible shape alterations is that both counter-shapes are infinitely stable at a temperature of exploitation. Shape reversibility is highly desirable property in many practical applications such as non-surgical removal of a previously inserted catheter and handfree wrapping up of an earlier unraveled solar sail on a space shuttle.

  18. Reversing the arms race

    SciTech Connect

    von Hippel, F. ); Sagdeev, R.Z. )

    1992-01-01

    This paper contains proceedings of Reversing The Arms Race. Topics covered include: Verifying Reductions of Nuclear Warheads; Verifying Limits on Nuclear-Armed Cruise Missiles; and The Technical Basis for Warhead Detection.

  19. On thermodynamic and microscopic reversibility

    SciTech Connect

    Crooks, Gavin E.

    2011-07-12

    The word 'reversible' has two (apparently) distinct applications in statistical thermodynamics. A thermodynamically reversible process indicates an experimental protocol for which the entropy change is zero, whereas the principle of microscopic reversibility asserts that the probability of any trajectory of a system through phase space equals that of the time reversed trajectory. However, these two terms are actually synonymous: a thermodynamically reversible process is microscopically reversible, and vice versa.

  20. Distribution of intravenously administered acetylcholinesterase inhibitor and acetylcholinesterase activity in the adrenal gland: 11C-donepezil PET study in the normal rat.

    PubMed

    Watabe, Tadashi; Naka, Sadahiro; Ikeda, Hayato; Horitsugi, Genki; Kanai, Yasukazu; Isohashi, Kayako; Ishibashi, Mana; Kato, Hiroki; Shimosegawa, Eku; Watabe, Hiroshi; Hatazawa, Jun

    2014-01-01

    Acetylcholinesterase (AChE) inhibitors have been used for patients with Alzheimer's disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered (11)C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands. The distribution of (11)C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight  = 220 ± 8.9 g). A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of (11)C-DNP (45.0 ± 10.7 MBq). The whole-body distribution of the (11)C-DNP PET was evaluated based on the Vt (total distribution volume) by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs. The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of (11)C-DNP in the body (following the liver) (13.33 ± 1.08 and 19.43 ± 1.29 ml/cm(3), respectively), indicating that the distribution of (11)C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach) (24.9 ± 1.6, 83.1 ± 3.0, and 38.5 ± 8.1 mU/mg, respectively), indicating high activity of AChE in the adrenal glands. We demonstrated the whole-body distribution of (11)C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of (11)C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors.

  1. Distribution of Intravenously Administered Acetylcholinesterase Inhibitor and Acetylcholinesterase Activity in the Adrenal Gland: 11C-Donepezil PET Study in the Normal Rat

    PubMed Central

    Watabe, Tadashi; Naka, Sadahiro; Ikeda, Hayato; Horitsugi, Genki; Kanai, Yasukazu; Isohashi, Kayako; Ishibashi, Mana; Kato, Hiroki; Shimosegawa, Eku; Watabe, Hiroshi; Hatazawa, Jun

    2014-01-01

    Purpose Acetylcholinesterase (AChE) inhibitors have been used for patients with Alzheimer's disease. However, its pharmacokinetics in non-target organs other than the brain has not been clarified yet. The purpose of this study was to evaluate the relationship between the whole-body distribution of intravenously administered 11C-Donepezil (DNP) and the AChE activity in the normal rat, with special focus on the adrenal glands. Methods The distribution of 11C-DNP was investigated by PET/CT in 6 normal male Wistar rats (8 weeks old, body weight  = 220±8.9 g). A 30-min dynamic scan was started simultaneously with an intravenous bolus injection of 11C-DNP (45.0±10.7 MBq). The whole-body distribution of the 11C-DNP PET was evaluated based on the Vt (total distribution volume) by Logan-plot analysis. A fluorometric assay was performed to quantify the AChE activity in homogenized tissue solutions of the major organs. Results The PET analysis using Vt showed that the adrenal glands had the 2nd highest level of 11C-DNP in the body (following the liver) (13.33±1.08 and 19.43±1.29 ml/cm3, respectively), indicating that the distribution of 11C-DNP was the highest in the adrenal glands, except for that in the excretory organs. The AChE activity was the third highest in the adrenal glands (following the small intestine and the stomach) (24.9±1.6, 83.1±3.0, and 38.5±8.1 mU/mg, respectively), indicating high activity of AChE in the adrenal glands. Conclusions We demonstrated the whole-body distribution of 11C-DNP by PET and the AChE activity in the major organs by fluorometric assay in the normal rat. High accumulation of 11C-DNP was observed in the adrenal glands, which suggested the risk of enhanced cholinergic synaptic transmission by the use of AChE inhibitors. PMID:25225806

  2. Reversible collisionless magnetic reconnection

    SciTech Connect

    Ishizawa, A.; Watanabe, T.-H.

    2013-10-15

    Reversible magnetic reconnection is demonstrated for the first time by means of gyrokinetic numerical simulations of a collisionless magnetized plasma. Growth of a current-driven instability in a sheared magnetic field is accompanied by magnetic reconnection due to electron inertia effects. Following the instability growth, the collisionless reconnection is accelerated with development of a cross-shaped structure of current density, and then all field lines are reconnected. The fully reconnected state is followed by the secondary reconnection resulting in a weakly turbulent state. A time-reversed simulation starting from the turbulent state manifests that the collisionless reconnection process proceeds inversely leading to the initial state. During the reversed reconnection, the kinetic energy is reconverted into the original magnetic field energy. In order to understand the stability of reversed process, an external perturbation is added to the fully reconnected state, and it is found that the accelerated reconnection is reversible when the deviation of the E × B streamlines due to the perturbation is comparable with or smaller than a current layer width.

  3. Reversibility of liver fibrosis.

    PubMed

    Sun, Mengxi; Kisseleva, Tatiana

    2015-09-01

    Liver fibrosis is a serious health problem worldwide, which can be induced by a wide spectrum of chronic liver injuries. However, until today, there is no effective therapy available for liver fibrosis except the removal of underlying etiology or liver transplantation. Recent studies indicate that liver fibrosis is reversible when the causative agent(s) is removed. Understanding of mechanisms of liver fibrosis regression will lead to the identification of new therapeutic targets for liver fibrosis. This review summarizes recent research progress on mechanisms of reversibility of liver fibrosis. While most of the research has been focused on HSCs/myofibroblasts and inflammatory pathways, the crosstalk between different organs, various cell types and multiple signaling pathways should not be overlooked. Future studies that lead to fully understanding of the crosstalk between different cell types and the molecular mechanism underlying the reversibility of liver fibrosis will definitely give rise to new therapeutic strategies to treat liver fibrosis.

  4. Dynamics of magnetization reversal

    NASA Astrophysics Data System (ADS)

    Safonov, Vladimir L.

    2000-03-01

    Advanced magnetic recording systems are designed for extremely high areal densities and data rate. These two aspects require both magnetization reversal at very short times (< 1 ns) and long term ( ~ 5-10 years) stability against thermal fluctuations. There are two basic physics problems associated with these requirements. The first is a characterization of thermal-dynamic reversal over very wide time range. The second is an understanding of the physics of the relaxation mechanisms. Both these subjects will be reviewed in this talk. Thermal dynamic reversal requires solution of the Landau-Lifshitz equation with fluctuations. We have solved this problem in terms of the ``random walk" dynamics of a nonlinear oscillator [1,2]. The expressions for the switching field versus pulse time are analytic and show good agreement with measurements on CrO_2. Our studies of fundamental relaxation mechanisms have involved a two step approach. First the results of computer simulations of magnetization reversal without phenomenological damping will be discussed. In this case coherent rotation of the magnetization excites spin waves during which an excess of Zeeman energy is transformed to anisotropy and exchange energies. However, for fine grains whose size is sufficiently small so that the grain magnetization is virtually uniform, non-linear spin waves cannot assist reversal [3]. A new analytic model of reversal that couples coherent rotation to impurity ions by an anisotropic exchange mechanism will be discussed. These impurity ions are assumed to relax at a very high rate to the lattice. [1] V.L.Safonov, JMMM 195, 523 (1999); J.Appl.Phys. 85, 4370 (1999). [2] V.L.Safonov, H.N.Bertram, MMM'99, CU-09. [3] V.L.Safonov, H.N.Bertram, J.Appl.Phys. 85, 5072 (1999); MMM'99, CD-11.

  5. Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids

    PubMed Central

    Bautista-Aguilera, Oscar M; Esteban, Gerard; Chioua, Mourad; Nikolic, Katarina; Agbaba, Danica; Moraleda, Ignacio; Iriepa, Isabel; Soriano, Elena; Samadi, Abdelouahid; Unzeta, Mercedes; Marco-Contelles, José

    2014-01-01

    The design, synthesis, and biochemical evaluation of donepezil-pyridyl hybrids (DPHs) as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential treatment of Alzheimer’s disease (AD) is reported. The 3D-quantitative structure-activity relationship study was used to define 3D-pharmacophores for inhibition of MAO A/B, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) enzymes and to design DPHs as novel multi-target drug candidates with potential impact in the therapy of AD. DPH14 (Electrophorus electricus AChE [EeAChE]: half maximal inhibitory concentration [IC50] =1.1±0.3 nM; equine butyrylcholinesterase [eqBuChE]: IC50 =600±80 nM) was 318-fold more potent for the inhibition of AChE, and 1.3-fold less potent for the inhibition of BuChE than the reference compound ASS234. DPH14 is a potent human recombinant BuChE (hBuChE) inhibitor, in the same range as DPH12 or DPH16, but 13.1-fold less potent than DPH15 for the inhibition of human recombinant AChE (hAChE). Compared with donepezil, DPH14 is almost equipotent for the inhibition of hAChE, and 8.8-fold more potent for hBuChE. Concerning human monoamine oxidase (hMAO) A inhibition, only DPH9 and 5 proved active, compound DPH9 being the most potent (IC50 [MAO A] =5,700±2,100 nM). For hMAO B, only DPHs 13 and 14 were moderate inhibitors, and compound DPH14 was the most potent (IC50 [MAO B] =3,950±940 nM). Molecular modeling of inhibitor DPH14 within EeAChE showed a binding mode with an extended conformation, interacting simultaneously with both catalytic and peripheral sites of EeAChE thanks to a linker of appropriate length. Absortion, distribution, metabolism, excretion and toxicity analysis showed that structures lacking phenyl-substituent show better druglikeness profiles; in particular, DPHs13–15 showed the most suitable absortion, distribution, metabolism, excretion and toxicity properties. Novel donepezil-pyridyl hybrid DPH14 is a potent, moderately selective h

  6. Reverse shoulder arthroplasty.

    PubMed

    Jarrett, Claudius D; Brown, Brandon T; Schmidt, Christopher C

    2013-07-01

    The reverse shoulder arthroplasty is considered to be one of the most significant technological advancements in shoulder reconstructive surgery over the past 30 years. It is able to successfully decrease pain and improve function for patients with rotator cuff-deficient shoulders. The glenoid is transformed into a sphere that articulates with a humeral socket. The current reverse prosthesis shifts the center of rotation more medial and distal, improving the deltoid's mechanical advantage. This design has resulted in successful improvement in both active shoulder elevation and in quality of life. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Sequential Polarity-Reversing Circuit

    NASA Technical Reports Server (NTRS)

    Labaw, Clayton C.

    1994-01-01

    Proposed circuit reverses polarity of electric power supplied to bidirectional dc motor, reversible electro-mechanical actuator, or other device operating in direction depending on polarity. Circuit reverses polarity each time power turned on, without need for additional polarity-reversing or direction signals and circuitry to process them.

  8. Sequential Polarity-Reversing Circuit

    NASA Technical Reports Server (NTRS)

    Labaw, Clayton C.

    1994-01-01

    Proposed circuit reverses polarity of electric power supplied to bidirectional dc motor, reversible electro-mechanical actuator, or other device operating in direction depending on polarity. Circuit reverses polarity each time power turned on, without need for additional polarity-reversing or direction signals and circuitry to process them.

  9. Histamine reverses a memory deficit induced in rats by early postnatal maternal deprivation.

    PubMed

    Benetti, Fernando; da Silveira, Clarice Kras Borges; da Silva, Weber Cláudio; Cammarota, Martín; Izquierdo, Iván

    2012-01-01

    Early partial maternal deprivation causes long-lasting neurochemical, behavioral and brain structural effects. In rats, it causes a deficit in memory consolidation visible in adult life. Some of these deficits can be reversed by donepezil and galantamine, which suggests that they may result from an impairment of brain cholinergic transmission. One such deficit, representative of all others, is an impairment of memory consolidation, clearly observable in a one-trial inhibitory avoidance task. Recent data suggest a role of brain histaminergic systems in the regulation of behavior, particularly inhibitory avoidance learning. Here we investigate whether histamine itself, its analog SKF-91844, or various receptor-selective histamine agonists and antagonists given into the CA1 region of the hippocampus immediately post-training can affect retention of one-trial inhibitory avoidance in rats submitted to early postnatal maternal deprivation. We found that histamine, SKF-91844 and the H2 receptor agonist, dimaprit enhance consolidation on their own and reverse the consolidation deficit induced by maternal deprivation. The enhancing effect of histamine was blocked by the H2 receptor antagonist, ranitidine, but not by the H1 receptor antagonist pyrilamine or by the H3 antagonist thioperamide given into CA1 at doses known to have other behavioral actions, without altering locomotor and exploratory activity or the anxiety state of the animals. The present results suggest that the memory deficit induced by early postnatal maternal deprivation in rats may in part be due to an impairment of histamine mediated mechanisms in the CA1 region of the rat hippocampus.

  10. Time reversal communication system

    DOEpatents

    Candy, James V.; Meyer, Alan W.

    2008-12-02

    A system of transmitting a signal through a channel medium comprises digitizing the signal, time-reversing the digitized signal, and transmitting the signal through the channel medium. The channel medium may be air, earth, water, tissue, metal, and/or non-metal.

  11. Reversible Chemochromic Hydrogen Detectors

    NASA Technical Reports Server (NTRS)

    2008-01-01

    The Florida Solar Energy Center (FSEC), affiliated with the University of Central Florida, has invented a reversible pigment that changes from light beige to blue when exposed to hydrogen and back to light beige when exposed to atmospheric oxygen. In laboratory and environmental studies, the FSEC pigment in its tape form failed to change color adequately when exposed to hydrogen after one day of exposure at Kennedy Space Center's Beach Corrosion Test Facility. The reversible hydrogen-detecting tape also lost its ability to change color after being placed in an environmental chamber at 45 C for one day. The first attempts at extruding the reversible pigment into various polymers were unsuccessful because of the pigment's poor thermal stability. The goal of this project was to formulate a pigment with improved thermal and environmental stability for extrusion into a variety of appropriate polymer matrices. The formulation of the reversible hydrogen-detecting pigment was modified by removing one reagent and chemically modifying the hydrogen sensitive ingredient. This was intended to improve the hydrophobicity of the pigment and alter the thermal degradation mechanism.

  12. Engineering Encounters: Reverse Engineering

    ERIC Educational Resources Information Center

    McGowan, Veronica Cassone; Ventura, Marcia; Bell, Philip

    2017-01-01

    This column presents ideas and techniques to enhance your science teaching. This month's issue shares information on how students' everyday experiences can support science learning through engineering design. In this article, the authors outline a reverse-engineering model of instruction and describe one example of how it looked in our fifth-grade…

  13. Reversing Discrimination: A Perspective

    ERIC Educational Resources Information Center

    Pati, Gopal; Reilly, Charles W.

    1977-01-01

    Examines the debate over affirmative action and reverse discrimination, and discusses how and why the present dilemma has developed. Suggests that organizations can best address the problem through an honest, in-depth analysis of their organizational structure and management practices. (JG)

  14. Reversing Flow Test Facility

    NASA Astrophysics Data System (ADS)

    Roach, P. D.

    1986-04-01

    The Reversing Flow Test Facility (RFTF) is intended for the study of fluid flow and heat transfer under the reversing-flow conditions that occur in Stirling engines. The facility consists of four major parts: (1) Mechanical Drive - two cylinders with cam-driven pistons which generate the reversing gas flow, (2) Test Section - a U-shaped section containing instrumented test pieces, (3) Instruments -l high-speed transducers for measuring gas pressure and temperature, piston positions, and other system parameters, and (4) Data Acquisition System - a computer-based system able to acquire, store, display and analyze the data from the instruments. The RFTF can operate at pressures up to 8.0 MPa, hot-side temperatures to 800 deg. C, and flow-reversal frequencies to 50 Hz. Operation to data has used helium as the working gas at pressures of 3.0 and 6.0 MPa, at ambient temperature, and at frequencies from 1 to 50 Hz. The results show that both frictional and inertial parts of the pressure drop are significant in the heater, coolers and connecting tubes; the inertial part is negligible in the regenerators. In all cases, the frictional part of the pressure drop is nearly in phase with the mass flow.

  15. Reversible cerebral vasoconstriction syndrome.

    PubMed

    Lee, R; Ramadan, H; Bamford, J

    2013-01-01

    Reversible cerebral vasoconstriction syndrome (RCVS) is an underdiagnosed condition which usually presents as severe headache with or without neurological deficit. We report the case of a 55-year-old woman who presented with headache and multifocal intracerebral haemorrhage. We review the literature regarding the presentation, pathophysiology and management of RCVS and discuss how to differentiate it from cerebral vasculitis.

  16. Language Reversion Revisited.

    ERIC Educational Resources Information Center

    De Bot, Kees; Clyne, Michael

    1989-01-01

    A longitudinal study on language maintenance and loss among Dutch-English bilinguals in Australia revealed little loss in both languages over the years. This leads to the hypothesis of a "critical threshold" that must be reached to retain the second language. First language reversion appears commonly among immigrants who did not reach this…

  17. A reverse transcriptase ribozyme.

    PubMed

    Joyce, Gerald F; Samanta, Biswajit

    2017-09-26

    A highly evolved RNA polymerase ribozyme was found to also be capable of functioning as a reverse transcriptase, an activity that has never been demonstrated before for RNA. This activity is thought to have been crucial for the transition from RNA to DNA genomes during the early history of life on Earth, when it similarly could have arisen as a secondary function of an RNA-dependent RNA polymerase. The reverse transcriptase ribozyme can incorporate all four dNTPs and can generate products containing up to 32 deoxynucleotides. It is likely that this activity could be improved through evolution, ultimately enabling the synthesis of complete DNA genomes. DNA is much more stable compared to RNA and thus provides a larger and more secure repository for genetic information.

  18. Gridded electron reversal ionizer

    NASA Technical Reports Server (NTRS)

    Chutjian, Ara (Inventor)

    1993-01-01

    A gridded electron reversal ionizer forms a three dimensional cloud of zero or near-zero energy electrons in a cavity within a filament structure surrounding a central electrode having holes through which the sample gas, at reduced pressure, enters an elongated reversal volume. The resultant negative ion stream is applied to a mass analyzer. The reduced electron and ion space-charge limitations of this configuration enhances detection sensitivity for material to be detected by electron attachment, such as narcotic and explosive vapors. Positive ions may be generated by generating electrons having a higher energy, sufficient to ionize the target gas and pulsing the grid negative to stop the electron flow and pulsing the extraction aperture positive to draw out the positive ions.

  19. Reversible Aggregation of Albumin

    NASA Astrophysics Data System (ADS)

    Colby, Ralph H.; Oates, Katherine M. N.; Krause, Wendy E.; Jones, Ronald L.

    2004-03-01

    We explore the interactions in synovial fluid involving the polyelectrolyte sodium hyaluronate (NaHA) and plasma proteins in their native state (albumin and globulins). Rheological measurements on synovial fluid show it to be highly viscoelastic and also rheopectic (stress increases with time in steady shear). Equilibrium dialysis confirms the findings of Ogston and Dubin that there is no association between NaHA and albumin at physiological pH and salt. What we find instead is a reversible aggregation of albumin, with an association energy of order 3kT and commensurate association lifetime of order microseconds. Certain anti-inflammatory drugs are shown to prevent this reversible aggregation. The implications of these findings for synovial fluid and blood rheology are discussed.

  20. Reversing Glass Wettability

    NASA Technical Reports Server (NTRS)

    Frazier, D. O.; Smith, J. E., Jr.; Kaukler, W. F.

    1985-01-01

    Treatment reverses wettability of glassware: Liquids that normally wet glass no longer do, and those that do not wet glass are made to do so. Useful in research on container effects in nucleation and growth of secondary phase from solution. Treatment consists of spreading 3 percent (by weight) solution of silicone oil in hexane isomers over glass, drying in air, and curing at 300 degrees C in vacuum for one hour.

  1. URCHIN: Reverse ray tracer

    NASA Astrophysics Data System (ADS)

    Altay, Gabriel; Theuns, Tom

    2014-12-01

    URCHIN is a Smoothed Particle Hydrodynamics (SPH) reverse ray tracer (i.e. from particles to sources). It calculates the amount of shielding from a uniform background that each particle experiences. Preservation of the adaptive density field resolution present in many gas dynamics codes and uniform sampling of gas resolution elements with rays are two of the benefits of URCHIN; it also offers preservation of Galilean invariance, high spectral resolution, and preservation of the standard uniform UV background in optically thin gas.

  2. [Reversible cerebral vasoconstriction syndrome].

    PubMed

    Laakso, Elina; Pekkola, Johanna; Soinne, Lauri; Putaala, Jukka

    2014-01-01

    Reversible cerebral vasoconstriction syndrome (RCVS) is increasingly recognized. The condition is characterized by multifocal vasoconstriction lesions in cerebral arteries. Headache is the central symptom, with an acute onset and paroxysmal occurrence. Some of the patients develop intracranial hemorrhage, ischemic disturbance of the cerebral circulation, hypertensive encephalopathy (PRES) or epileptic seizures as complications. The disease is most common in middle-aged women. Most patients have an underlying predisposing factor, most commonly vasoactive medications, drugs or puerperium. There is no evidence-based practice.

  3. 49 CFR 230.89 - Reverse gear.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Reversing Gear § 230.89 Reverse gear. (a) General provisions. Reverse gear, reverse levers, and quadrants shall be maintained in a safe and suitable condition for service. Reverse lever latch shall be so...

  4. 49 CFR 230.89 - Reverse gear.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Reversing Gear § 230.89 Reverse gear. (a) General provisions. Reverse gear, reverse levers, and quadrants shall be maintained in a safe and suitable condition for service. Reverse lever latch shall be so...

  5. 49 CFR 230.89 - Reverse gear.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Reversing Gear § 230.89 Reverse gear. (a) General provisions. Reverse gear, reverse levers, and quadrants shall be maintained in a safe and suitable condition for service. Reverse lever latch shall be so...

  6. 49 CFR 230.89 - Reverse gear.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Reversing Gear § 230.89 Reverse gear. (a) General provisions. Reverse gear, reverse levers, and quadrants shall be maintained in a safe and suitable condition for service. Reverse lever latch shall be so...

  7. 49 CFR 230.89 - Reverse gear.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Reversing Gear § 230.89 Reverse gear. (a) General provisions. Reverse gear, reverse levers, and quadrants shall be maintained in a safe and suitable condition for service. Reverse lever latch shall be so...

  8. Time reversal interactive objects

    NASA Astrophysics Data System (ADS)

    Ing, Ros Ki; Quieffin, Nicolas; Catheline, Stefan; Fink, Mathias

    2001-05-01

    Time reversal has shown to be a fruitful concept in nondestructive testing in underwater acoustic or in ultrasonic imaging. In this paper this technique is adapted in the audible range to transform every day objects into tactile sensitive interfaces. A quick historical background is presented in the ultrasonic field and specially in chaotic cavity. In all time reversal experiments, it is demonstrated that a wave field spatially and temporally recorded is able to back propagate to its source. In other words, the field contains all the information on the location of the source. In the interactive experiments, it is shown that touching an object like a window, a table or a world globe generates an acoustic field easily detectable with one or two acoustic sensors. Using the concept of time reversal, the source location is deduced in real time. Then, touching objects at specific locations (virtual switches) is used to activate devices. Such devices are for example lights, stereo volume, or computer software. From a technical point of view, all these interactive experiments just use some computation easily performed with a standard personnel computer.

  9. Reversible hysteresis loop tuning

    NASA Astrophysics Data System (ADS)

    Berger, A.; Binek, Ch.; Margulies, D. T.; Moser, A.; Fullerton, E. E.

    2006-02-01

    We utilize antiferromagnetically coupled bilayer structures to magnetically tune hysteresis loop properties. Key element of this approach is the non-overlapping switching field distribution of the two magnetic layers that make up the system: a hard magnetic CoPtCrB layer (HL) and a soft magnetic CoCr layer (SL). Both layers are coupled antiferromagnetically through an only 0.6-nm-thick Ru interlayer. The non-overlapping switching field distribution allows the measurement of magnetization reversal in the SL at low fields while keeping the magnetization state of the HL unperturbed. Applying an appropriate high field or high field sequence changes the magnetic state of the HL, which then influences the SL magnetization reversal due to the interlayer coupling. In this way, the position and shape of the SL hysteresis loop can be changed or tuned in a fully reversible and highly effective manner. Here, we study specifically how the SL hysteresis loop characteristics change as we move the HL through an entire high field hysteresis loop sequence.

  10. Utility of (11)C-methionine and (11)C-donepezil for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model: comparison to autologous (111)In-labelled leukocytes, (99m) Tc-DPD, and (18)F-FDG.

    PubMed

    Afzelius, Pia; Alstrup, Aage Ko; Schønheyder, Henrik C; Borghammer, Per; Jensen, Svend B; Bender, Dirk; Nielsen, Ole L

    2016-01-01

    The aim of this study was to compare (11)C-methionine and (11)C-donepezil positron emission tomography (PET) with (111)In-labeled leukocyte and (99m) Tc-DPD (Tc-99m 3,3-diphosphono-1,2-propanedicarboxylic acid) single-photon emission computed tomography (SPECT), and (18)F-fluorodeoxyglucose ((18)F-FDG) PET to improve detection of osteomyelitis. The tracers' diagnostic utility where tested in a juvenile porcine hematogenously induced osteomyelitis model comparable to osteomyelitis in children. Five 8-9 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus. The sequential scan protocol included Computed Tomography, (11)C-methionine and (11)C-donepezil PET, (99m) Tc-DPD and (111)In-labelled leukocytes scintigraphy, and (18)F-FDG PET. This was followed by necropsy of the pigs and gross pathology, histopathology, and microbial examination. The pigs developed a total of 24 osteomyelitic lesions, 4 lesions characterized as contiguous abscesses and pulmonary abscesses (in two pigs). By comparing the 24 osteomyelitic lesions, (18)F-FDG accumulated in 100%, (111)In-leukocytes in 79%, (11)C-methionine in 79%, (11)C-donepezil in 58%, and (99m) Tc-DPD in none. Overall, (18)F-FDG PET was superior to (111)In-leukocyte SPECT and (11)C-methionine in marking infectious lesions.

  11. Utility of 11C-methionine and 11C-donepezil for imaging of Staphylococcus aureus induced osteomyelitis in a juvenile porcine model: comparison to autologous 111In-labelled leukocytes, 99mTc-DPD, and 18F-FDG

    PubMed Central

    Afzelius, Pia; Alstrup, Aage KO; Schønheyder, Henrik C; Borghammer, Per; Jensen, Svend B; Bender, Dirk; Nielsen, Ole L

    2016-01-01

    The aim of this study was to compare 11C-methionine and 11C-donepezil positron emission tomography (PET) with 111In-labeled leukocyte and 99mTc-DPD (Tc-99m 3,3-diphosphono-1,2-propanedicarboxylic acid) single-photon emission computed tomography (SPECT), and 18F-fluorodeoxyglucose (18F-FDG) PET to improve detection of osteomyelitis. The tracers’ diagnostic utility where tested in a juvenile porcine hematogenously induced osteomyelitis model comparable to osteomyelitis in children. Five 8-9 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus. The sequential scan protocol included Computed Tomography, 11C-methionine and 11C-donepezil PET, 99mTc-DPD and 111In-labelled leukocytes scintigraphy, and 18F-FDG PET. This was followed by necropsy of the pigs and gross pathology, histopathology, and microbial examination. The pigs developed a total of 24 osteomyelitic lesions, 4 lesions characterized as contiguous abscesses and pulmonary abscesses (in two pigs). By comparing the 24 osteomyelitic lesions, 18F-FDG accumulated in 100%, 111In-leukocytes in 79%, 11C-methionine in 79%, 11C-donepezil in 58%, and 99mTc-DPD in none. Overall, 18F-FDG PET was superior to 111In-leukocyte SPECT and 11C-methionine in marking infectious lesions. PMID:28078182

  12. [Reversible cerebral vasoconstriction syndrome].

    PubMed

    Néel, A; Guillon, B; Auffray-Calvier, E; Hello, M; Hamidou, M

    2012-10-01

    The reversible cerebral vasoconstriction syndrome (RCVS) is an under-estimated transient acute cerebrovascular disorder. It has long been mistaken as central nervous system vasculitis whereas it is now believed to result from an acute but prolonged vasospasm of cerebral arteries. This disorder can be precipitated by postpartum or vasoactive drug. However, it occurs spontaneously in a significant number of cases. The characteristic clinico-radiological presentation and disease course of the RCVS has been delineated only recently. Mean age at onset is 40-45 years, with a female predominance. A provocative factor can be identified in 12-60% out of the patients. Clinical presentation is predominantly marked by recurrent thunderclap headaches, but can be complicated with focal neurological deficit or seizures. Brain imaging is normal in most cases, but can reveal hemorrhagic or ischemic complications. Cortical subarachnoid hemorrhage is a suggestive finding. A posterior reversible encephalopathy syndrome (PRES) can be seen occasionally. Cerebral angiography reveals multifocal arterial narrowing with string and bead appearance. Cerebrospinal fluid reveals no or mild abnormalities. The disease resumes spontaneously within several days to weeks, whereas vasoconstriction reverses within 1 to 3 months. This clinico-radiological presentation should be promptly recognized in order to avoid unnecessary investigations and aggressive treatment, and lead to search for a triggering factor. Further studies are required in order to clarify the precipitating role of several drugs, and clinical trials are needed to reduce the occurrence of strokes. Copyright © 2012 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  13. Reversible brazing process

    SciTech Connect

    Pierce, J.D.; Stephens, J.J.; Walker, C.A.

    1999-09-14

    A method of reversibly brazing surfaces together is disclosed. An interface is affixed to each surface. The interfaces can be affixed by processes such as mechanical joining, welding, or brazing. The two interfaces are then brazed together using a brazing process that does not defeat the surface to interface joint. Interfaces of materials such as Ni-200 can be affixed to metallic surfaces by welding or by brazing with a first braze alloy. The Ni-200 interfaces can then be brazed together using a second braze alloy. The second braze alloy can be chosen so that it minimally alters the properties of the interfaces to allow multiple braze, heat and disassemble, rebraze cycles.

  14. Reversible brazing process

    DOEpatents

    Pierce, Jim D.; Stephens, John J.; Walker, Charles A.

    1999-01-01

    A method of reversibly brazing surfaces together. An interface is affixed to each surface. The interfaces can be affixed by processes such as mechanical joining, welding, or brazing. The two interfaces are then brazed together using a brazing process that does not defeat the surface to interface joint. Interfaces of materials such as Ni-200 can be affixed to metallic surfaces by welding or by brazing with a first braze alloy. The Ni-200 interfaces can then be brazed together using a second braze alloy. The second braze alloy can be chosen so that it minimally alters the properties of the interfaces to allow multiple braze, heat and disassemble, rebraze cycles.

  15. Reversal bending fatigue testing

    DOEpatents

    Wang, Jy-An John; Wang, Hong; Tan, Ting

    2014-10-21

    Embodiments for apparatuses for testing reversal bending fatigue in an elongated beam are disclosed. Embodiments are configured to be coupled to first and second end portions of the beam and to apply a bending moment to the beam and create a pure bending condition in an intermediate portion of the beam. Embodiments are further configured to cyclically alternate the direction of the bending moment applied to the beam such that the intermediate portion of the beam cyclically bends in opposite directions in a pure bending condition.

  16. Reversal of sterilisation.

    PubMed

    Cartwright, A

    1977-09-03

    It is difficult to know what conclusions one can reach in a study of 103 women who asked for reversal of sterilization (Mr. R.M.L. Winston, July 30, p. 305) when there are no data about the numbers and characteristics of the women who were sterilized and have not asked for reversal. And Mr. Winston's conclusion that it "seems unwise to sterilise women under 30 particularly immediately after pregnancy or if their marriage is in jeopardy" is therefore difficult to justify and has a disconcertingly paternalistic ring. It also implies that the stability or otherwise of a marriage should be a prime concern of obstetricians when women request sterilization. But what distrubed me most about Mr. Winston's article was his statement that "most women in this survey had been told that termination would not be undertaken without sterilisation." I wonder if this form of ultimatum, which Mr. Winston condemns, is likely to increase now that this operation is performed under a fee-for-service system?

  17. Reverse Engineering Molecular Hypergraphs

    PubMed Central

    Rahman, Ahsanur; Poirel, Christopher L.; Badger, David J.; Estep, Craig; Murali, T.M.

    2014-01-01

    Analysis of molecular interaction networks is pervasive in systems biology. This research relies almost entirely on graphs for modeling interactions. However, edges in graphs cannot represent multiway interactions among molecules, which occur very often within cells. Hypergraphs may be better representations for networks having such interactions, since hyperedges can naturally represent relationships among multiple molecules. Here, we propose using hypergraphs to capture the uncertainty inherent in reverse engineering gene-gene networks. Some subsets of nodes may induce highly varying subgraphs across an ensemble of networks inferred by a reverse engineering algorithm. We provide a novel formulation of hyperedges to capture this uncertainty in network topology. We propose a clustering-based approach to discover hyperedges. We show that our approach can recover hyperedges planted in synthetic data sets with high precision and recall, even for moderate amount of noise. We apply our techniques to a data set of pathways inferred from genetic interaction data in S. cerevisiae related to the unfolded protein response. Our approach discovers several hyperedges that capture the uncertain connectivity of genes in relevant protein complexes, suggesting that further experiments may be required to precisely discern their interaction patterns. We also show that these complexes are not discovered by an algorithm that computes frequent and dense subgraphs. PMID:24384702

  18. Reverse engineering molecular hypergraphs.

    PubMed

    Rahman, Ahsanur; Poirel, Christopher L; Badger, David J; Estep, Craig; Murali, T M

    2013-01-01

    Analysis of molecular interaction networks is pervasive in systems biology. This research relies almost entirely on graphs for modeling interactions. However, edges in graphs cannot represent multiway interactions among molecules, which occur very often within cells. Hypergraphs may be better representations for networks having such interactions, since hyperedges can naturally represent relationships among multiple molecules. Here, we propose using hypergraphs to capture the uncertainty inherent in reverse engineering gene-gene networks. Some subsets of nodes may induce highly varying subgraphs across an ensemble of networks inferred by a reverse engineering algorithm. We provide a novel formulation of hyperedges to capture this uncertainty in network topology. We propose a clustering-based approach to discover hyperedges. We show that our approach can recover hyperedges planted in synthetic data sets with high precision and recall, even for moderate amount of noise. We apply our techniques to a data set of pathways inferred from genetic interaction data in S. cerevisiae related to the unfolded protein response. Our approach discovers several hyperedges that capture the uncertain connectivity of genes in relevant protein complexes, suggesting that further experiments may be required to precisely discern their interaction patterns. We also show that these complexes are not discovered by an algorithm that computes frequent and dense subgraphs.

  19. Reversible cerebral vasoconstriction syndrome.

    PubMed

    Ducros, Anne

    2012-10-01

    Recurrent thunderclap headaches, seizures, strokes, and non-aneurysmal subarachnoid haemorrhage can all reveal reversible cerebral vasoconstriction syndrome. This increasingly recognised syndrome is characterised by severe headaches, with or without other symptoms, and segmental constriction of cerebral arteries that resolves within 3 months. Reversible cerebral vasoconstriction syndrome is supposedly due to a transient disturbance in the control of cerebrovascular tone. More than half the cases occur post partum or after exposure to adrenergic or serotonergic drugs. Manifestations have a uniphasic course, and vary from pure cephalalgic forms to rare catastrophic forms associated with several haemorrhagic and ischaemic strokes, brain oedema, and death. Diagnosis can be hampered by the dynamic nature of clinicoradiological features. Stroke can occur a few days after initial normal imaging, and cerebral vasoconstriction is at a maximum on angiograms 2-3 weeks after clinical onset. The calcium channel blocker nimodipine seems to reduce thunderclap headaches within 48 h of administration, but has no proven effect on haemorrhagic and ischaemic complications. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Reversible cerebral vasoconstriction syndrome.

    PubMed

    Calic, Z; Cappelen-Smith, C; Zagami, A S

    2015-06-01

    Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical-radiological syndrome characterised by severe thunderclap headaches with or without other neurological symptoms and multifocal constriction of cerebral arteries that usually resolves spontaneously within 3 months. Most patients recover completely, but up to 10% have a permanent neurological disability and some even die. Previously RCVS has been described in many clinical contexts and under different names with the term RCVS first being suggested in 2007 to unify the group. The condition may be spontaneous, but in up to 60% of cases it is secondary to another cause, including vasoactive substances (medications and illicit drugs), blood products and the post-partum state. It is believed to have a similar pathophysiological mechanism to the posterior reversible encephalopathy syndrome (PRES), and both can occur in similar clinical contexts and are frequently associated. Treatment options include calcium channel antagonists. RCVS occurs in a broad range of clinical situations making it an increasingly recognised condition about which doctors in various specialties need to be aware. © 2014 Royal Australasian College of Physicians.

  1. A reversible molecular valve

    PubMed Central

    Nguyen, Thoi D.; Tseng, Hsian-Rong; Celestre, Paul C.; Flood, Amar H.; Liu, Yi; Stoddart, J. Fraser; Zink, Jeffrey I.

    2005-01-01

    In everyday life, a macroscopic valve is a device with a movable control element that regulates the flow of gases or liquids by blocking and opening passageways. Construction of such a device on the nanoscale level requires (i) suitably proportioned movable control elements, (ii) a method for operating them on demand, and (iii) appropriately sized passageways. These three conditions can be fulfilled by attaching organic, mechanically interlocked, linear motor molecules that can be operated under chemical, electrical, or optical stimuli to stable inorganic porous frameworks (i.e., by self-assembling organic machinery on top of an inorganic chassis). In this article, we demonstrate a reversibly operating nanovalve that can be turned on and off by redox chemistry. It traps and releases molecules from a maze of nanoscopic passageways in silica by controlling the operation of redox-activated bistable [2]rotaxane molecules tethered to the openings of nanopores leading out of a nanoscale reservoir. PMID:16006520

  2. Reverse photoacoustic standoff spectroscopy

    DOEpatents

    Van Neste, Charles W [Kingston, TN; Senesac, Lawrence R [Knoxville, TN; Thundat, Thomas G [Knoxville, TN

    2011-04-12

    A system and method are disclosed for generating a reversed photoacoustic spectrum at a greater distance. A source may emit a beam to a target and a detector measures signals generated as a result of the beam being emitted on the target. By emitting a chopped/pulsed light beam to the target, it may be possible to determine the target's optical absorbance by monitoring the intensity of light collected at the detector at different wavelengths. As the wavelength of light is changed, the target may absorb or reject each optical frequency. Rejection may increase the intensity at the sensing element and absorption may decrease the intensity. Accordingly, an identifying spectrum of the target may be made with the intensity variation of the detector as a function of illuminating wavelength.

  3. Reverse slapper detonator

    DOEpatents

    Weingart, Richard C.

    1990-01-01

    A reverse slapper detonator (70), and methodology related thereto, are provided. The detonator (70) is adapted to be driven by a pulse of electric power from an external source (80). A conductor (20) is disposed along the top (14), side (18), and bottom (16) surfaces of a sheetlike insulator (12). Part of the conductor (20) comprises a bridge (28), and an aperture (30) is positioned within the conductor (20), with the bridge (28) and the aperture (30) located on opposite sides of the insulator (12). A barrel (40) and related explosive charge (50) are positioned adjacent to and in alignment with the aperture (30), and the bridge (28) is buttressed with a backing layer (60). When the electric power pulse vaporizes the bridge (28), a portion of the insulator (12) is propelled through the aperture (30) and barrel (40), and against the explosive charge (50), thereby detonating it.

  4. Reversible fluctuation rectifier

    NASA Astrophysics Data System (ADS)

    Sokolov, I. M.

    1999-10-01

    The analysis of a Feynman's ratchet system [J. M. R. Parrondo and P. Español, Am. J. Phys. 64, 1125 (1996)] and of its electrical counterpart, a diode engine [I. M. Sokolov, Europhys. Lett. 44, 278 (1998)] has shown that ``fluctuation rectifiers'' consisting of a nonlinear element (ratchet, diode) and a linear element (vane, resistor) kept at different temperatures always show efficiency smaller than the Carnot value, thus indicating the irreversible mode of operation. We show that this irreversibility is not intrinsic for a system in simultaneous contact with two heat baths at different temperatures and that a fluctuation rectifier can work reversibly. This is illustrated by a model with two diodes switched in opposite directions, where the Carnot efficiency is achieved when backward resistivity of the diodes tends to infinity.

  5. Reverse Osmosis Optimization

    SciTech Connect

    2013-08-01

    This technology evaluation was prepared by Pacific Northwest National Laboratory on behalf of the U.S. Department of Energy’s Federal Energy Management Program (FEMP). The technology evaluation assesses techniques for optimizing reverse osmosis (RO) systems to increase RO system performance and water efficiency. This evaluation provides a general description of RO systems, the influence of RO systems on water use, and key areas where RO systems can be optimized to reduce water and energy consumption. The evaluation is intended to help facility managers at Federal sites understand the basic concepts of the RO process and system optimization options, enabling them to make informed decisions during the system design process for either new projects or recommissioning of existing equipment. This evaluation is focused on commercial-sized RO systems generally treating more than 80 gallons per hour.

  6. Reverse Osmosis Optimization

    SciTech Connect

    McMordie Stoughton, Kate; Duan, Xiaoli; Wendel, Emily M.

    2013-08-26

    This technology evaluation was prepared by Pacific Northwest National Laboratory on behalf of the U.S. Department of Energy’s Federal Energy Management Program (FEMP). ¬The technology evaluation assesses techniques for optimizing reverse osmosis (RO) systems to increase RO system performance and water efficiency. This evaluation provides a general description of RO systems, the influence of RO systems on water use, and key areas where RO systems can be optimized to reduce water and energy consumption. The evaluation is intended to help facility managers at Federal sites understand the basic concepts of the RO process and system optimization options, enabling them to make informed decisions during the system design process for either new projects or recommissioning of existing equipment. This evaluation is focused on commercial-sized RO systems generally treating more than 80 gallons per hour.¬

  7. Sex Reversal in Amphibians.

    PubMed

    Flament, Stéphane

    2016-01-01

    Amphibians have been widely used to study developmental biology due to the fact that embryo development takes place independently of the maternal organism and that observations and experimental approaches are easy. Some amphibians like Xenopus became model organisms in this field. In the first part of this article, the differentiation of the gonads in amphibians and the mechanisms governing this process are reviewed. In the second part, the state of the art about sex reversal, which can be induced by steroid hormones in general and by temperature in some species, is presented. Also information about pollutants found in the environment that could interfere with the development of the amphibian reproductive apparatus or with their reproductive physiology is given. Such compounds could play a part in the amphibian decline, since in the wild, many amphibians are endangered species. © 2016 S. Karger AG, Basel.

  8. Reverse shoulder arthroplasty.

    PubMed

    Smithers, Christopher J; Young, Allan A; Walch, Gilles

    2011-12-01

    The reverse shoulder arthroplasty emerged as a potential solution for those patients who could not be managed effectively with a conventional total shoulder arthroplasty. Grammont revolutionized the design by medializing and distalizing the center of rotation and utilizing a large convex glenoid surface and concave humeral component with a neck-shaft angle of 155°. This design has been highly successful in cuff deficient shoulders, and indications continue to broaden. Many mid-term studies have improved upon the early encouraging results. Long-term studies are starting to emerge, demonstrating good survivorship, but progressive functional and radiographic deterioration continue to be concerning. Careful patient selection and attention to appropriate technique are required to reduce the current high rate of complications. New prosthesis designs are continuing to develop to address some of these limitations.

  9. Biochemical Reversal of Aging

    NASA Astrophysics Data System (ADS)

    Ely, John T. A.

    2006-03-01

    We cite our progress on biochemical reversal of aging. However, it may be circa 2 years before we have necessary substances at low cost. Meanwhile, without them, a number of measures can be adopted providing marked improvement for the problems of aging in modern societies. For example, enzymes are needed to excrete toxins that accelerate aging; Hg is the ultimate toxin that disables all enzymes (including those needed to excrete Hg itself). Low Hg level in the urine, due to loss of excretory ability, causes the diagnosis of Hg toxicity to almost always be missed. Hg sources must be removed from the body! Another example is excess sugar; hyperglycemia decreases intracellular ascorbic acid (AA) by competitively inhibiting the insulin- mediated active transport of AA into cells. Thus, immunity is impaired by low leucocyte AA. AA is needed for new proteins in aging tissues. Humans must supplement AA; their need same as in AA-synthesizing mammals.

  10. Reversed-polarity regions

    NASA Technical Reports Server (NTRS)

    Tang, F.

    1982-01-01

    It is found by a statistical study of 58 reversed-polarity regions (RPRs) covering the 11-year period 1969-1979 that RPRs (1) have a lifespan comparable to normal active regions, (2) do not show a tendency to rotate toward a more normal alignment, and (3) have stable configurations that do not suggest stress due to their anomalous magnetic alignment. As in normal regions, RPR magnetic complexity is found to be the primary factor in flare productivity. Weak-field RPRs produce no flares, and regions with complex spots produce more flares than regions with non-complex spots by a factor of five. The main difference between RPRs and normal regions lies in complex spot frequency, with less that 17% of normal active regions having such spots and fewer than 1.8% having long-lived complex ones, while 41% of RPRs have complex spots and 24% have long-lived complex spots.

  11. Reversed-polarity regions

    NASA Technical Reports Server (NTRS)

    Tang, F.

    1982-01-01

    It is found by a statistical study of 58 reversed-polarity regions (RPRs) covering the 11-year period 1969-1979 that RPRs (1) have a lifespan comparable to normal active regions, (2) do not show a tendency to rotate toward a more normal alignment, and (3) have stable configurations that do not suggest stress due to their anomalous magnetic alignment. As in normal regions, RPR magnetic complexity is found to be the primary factor in flare productivity. Weak-field RPRs produce no flares, and regions with complex spots produce more flares than regions with non-complex spots by a factor of five. The main difference between RPRs and normal regions lies in complex spot frequency, with less that 17% of normal active regions having such spots and fewer than 1.8% having long-lived complex ones, while 41% of RPRs have complex spots and 24% have long-lived complex spots.

  12. Multiple stimulus reversible hydrogels

    DOEpatents

    Gutowska, Anna; Krzyminski, Karol J.

    2003-12-09

    A polymeric solution capable of gelling upon exposure to a critical minimum value of a plurality of environmental stimuli is disclosed. The polymeric solution may be an aqueous solution utilized in vivo and capable of having the gelation reversed if at least one of the stimuli fall below, or outside the range of, the critical minimum value. The aqueous polymeric solution can be used either in industrial or pharmaceutical environments. In the medical environment, the aqueous polymeric solution is provided with either a chemical or radioisotopic therapeutic agent for delivery to a specific body part. The primary advantage of the process is that exposure to one environmental stimuli alone will not cause gelation, thereby enabling the therapeutic agent to be conducted through the body for relatively long distances without gelation occurring.

  13. Multiple stimulus reversible hydrogels

    DOEpatents

    Gutowska, Anna; Krzyminski, Karol J.

    2006-04-25

    A polymeric solution capable of gelling upon exposure to a critical minimum value of a plurality of environmental stimuli is disclosed. The polymeric solution may be an aqueous solution utilized in vivo and capable of having the gelation reversed if at least one of the stimuli fall below, or outside the range of, the critical minimum value. The aqueous polymeric solution can be used either in industrial or pharmaceutical environments. In the medical environment, the aqueous polymeric solution is provided with either a chemical or radioisotopic therapeutic agent for delivery to a specific body part. The primary advantage of the process is that exposure to one environmental stimuli alone will not cause gelation, thereby enabling the therapeutic agent to be conducted through the body for relatively long distances without gelation occurring.

  14. Advanced structure-activity relationships applied to Mentha spicata L. subsp. spicata essential oil compounds as AChE and NMDA ligands, in comparison with donepezil, galantamine and memantine - new approach in brain disorders pharmacology.

    PubMed

    Avram, Speranta; Maria, Mernea; Bagci, Eyup; Hritcu, Lucian; Borcan, Livia-Cristina; Mihailescu, Dan

    2017-01-13

    Alzheimer's disease (AD) therapy is based on several natural and synthetic compounds that act as acetylcholinesterase (AChE) and N-methyl-D-aspartate receptor (NMDA) ligands that have limited efficiency in relieving AD symptoms. Recent studies show that inhibitors isolated from Mentha spicata L. subsp. spicata are promising for AD therapy. We aimed to identify novel and more potent phytopharmaceutical compounds for AD treatment by taking into account the compounds from Mentha spicata L. subsp. spicata essential oil. We generated structure-activity relationship (SAR) models that predict the biological activities of 14 Mentha spicata L. subsp. spicata compounds on AChE and NMDA by comparing their molecular features with those of the three conventional ligands: donepezil, galantamine and memantine. The most relevant descriptors for predicting the biological activities of considered compounds are solvent accessible area and their subdivided, hydrophobicity, energy of frontier molecular orbitals and counts of the aromatic ring and rotatable bounds. 1,8-cineole, the main compound from Mentha spicata L. subsp. spicata essential oil, resulted to be similar with memantine and dissimilar with donepezil in respect to hidrophobicity (logP1,8-cineole=2.95, logPmemantine=2.81, logPdonepezil=4.11), the energy of LUMO (eLUMO1,8-cineole=3.01 eV, eLUMOmemantine=3.35 eV, eLUMOdonepezil=-0.35 eV) and the solvent accessible surface areas over all hydrophobic (SA_H1,8-cineole= 350 Å2, SA_Hmemantine= 358 Å2, SA_Hdonepezil= 655 Å2) or polar atoms (SA_P1,8-cineole= 4 Å2, SA_Pmemantine=10 Å2, SA_Pdonepezil=44.62 Å2). Our results point towards 1,8-cineole as a good candidate for NMDA antagonism, with a weaker AChE inhibitory effect. Our results may be useful in establishing new therapeutic strategies for neurological disorders.

  15. Discrete symmetries in dynamo reversals

    NASA Astrophysics Data System (ADS)

    Bandyopadhyay, Riddhi; Verma, Mahendra K.

    2017-06-01

    Quantification of the velocity and magnetic field reversals in dynamo remains an interesting challenge. In this paper, using group-theoretic analysis, we classify the reversing and non-reversing Fourier modes during a dynamo reversal in a Cartesian box. Based on odd-even parities of the wavenumber indices, we categorise the velocity and magnetic Fourier modes into eight classes each. Then, using the properties of the nonlinear interactions in magnetohydrodynamics, we show that these 16 elements form Klein 16-group Z 2 × Z 2 × Z 2 × Z 2 . We demonstrate that field reversals in a class of Taylor-Green dynamo, as well as the reversals in earlier experiments and models, belong to one of the classes predicted by our group-theoretic arguments.

  16. Magnetic reversals and mass extinctions

    NASA Technical Reports Server (NTRS)

    Raup, D. M.

    1985-01-01

    The results of a study of reversals of the earth's magnetic field over the past 165 Myr are presented. A stationary periodicity of 30 Myr emerges which predicts pulses of increased reversal activity centered at 10, 40, 70, . . . Myr before the present. The correlation between the reversal intensity and biological extinctions is examined, and a nontrivial discrepancy is found between the magnetic and extinction periodicity.

  17. Magnetic reversals and mass extinctions

    NASA Technical Reports Server (NTRS)

    Raup, D. M.

    1985-01-01

    The results of a study of reversals of the earth's magnetic field over the past 165 Myr are presented. A stationary periodicity of 30 Myr emerges which predicts pulses of increased reversal activity centered at 10, 40, 70, . . . Myr before the present. The correlation between the reversal intensity and biological extinctions is examined, and a nontrivial discrepancy is found between the magnetic and extinction periodicity.

  18. [Posterior reversible encephalopathy syndrome].

    PubMed

    Petrović, Branko; Kostić, Vladimir; Sternić, Nadezda; Kolar, Jovo; Tasić, Nebojsa

    2003-01-01

    Reversible Posterior Leukoencephalopathy Syndrome was introduced into clinical practice in 1996 in order to describe unique syndrome, clinically expressed during hypertensive and uremic encephalopathy, eclampsia and during immunosuppressive therapy [1]. First clinical investigations showed that leucoencephalopathy is major characteristic of the syndrome, but further investigations showed no significant destruction in white cerebral tissue [2, 3, 4]. In majority of cases changes are localise in posterior irrigation area of the brain and in the most severe cases anterior region is also involved. Taking into consideration all above mentioned facts, the suggested term was Posterior Reversible Encephalopathy Syndrome (PRES) for the syndrome clinically expressed by neurological manifestations derived from cortical and subcortical changes localised in posterior regions of cerebral hemispheres, cerebral trunk and cerebellum [5]. Patient, aged 53 years, was re-hospitalized in Cardiovascular Institute "Dediwe" two months after successful aorto-coronary bypass performed in June 2001 due to the chest bone infection. During the treatment of the infection (according to the antibiogram) in September 2001, patient in evening hours developed headache and blurred vision. The recorded blood pressure was 210/120 mmHg so antihypertensive treatment was applied (Nifedipin and Furosemid). After this therapy there was no improvement and intensive headache with fatigue and loss of vision developed. Neurological examination revealed cortical blindness and left hemiparesis. Manitol (20%, 60 ccm every 3 hours) and i.v. Nytroglicerin (high blood pressure). Brain CT revealed oedema of parieto-occipital regions of both hemispheres, more emphasized on the right. (Figure 1a, b, c). There was no sign of focal ischemia even in deeper sections (Figure 1d, e, f). Following three days enormous high blood pressure values were registered. On the fourth day the significant clinical improvement occurred

  19. Reversibility in nucleocytoplasmic transport

    PubMed Central

    Kopito, Ronen Benjamine; Elbaum, Michael

    2007-01-01

    Nucleocytoplasmic exchange of proteins and RNAs is mediated by receptors that usher their cargo through the nuclear pores. Peptide localization signals on each cargo determine the receptors with which it will interact. Those interactions are normally regulated by the small GTPase Ran. Hydrolysis of GTP provides the chemical energy required to create a bona fide thermodynamic pump that selectively and directionally accumulates its substrates across the nuclear envelope. A common perception is that cargo delivery is irreversible, e.g., a protein imported to the nucleus does not return to the cytoplasm except perhaps via a specific export receptor. Quantitative measurements using cell-free nuclei reconstituted in Xenopus egg extract show that nuclear accumulation follows first-order kinetics and reaches steady state at a level that follows a Michaelis–Menten function of the cytoplasmic cargo concentration. This saturation suggests that receptor-mediated translocation across the nuclear pore occurs bidirectionally. The reversibility of accumulation was demonstrated directly by exchange of the cytosolic medium and by fluorescence recovery after photobleaching. Based on our results, we offer a simple biophysical model that predicts the observed behavior. A far-reaching consequence is that the nuclear localization signal dictates the fate of a protein population rather than that of the individual molecules that bear it, which remain free to shuttle back and forth. This implies an open communication between the nucleus and cytoplasm and a ubiquitous mechanism for signaling in both directions. PMID:17646647

  20. Reverse Phase Protein Microarrays.

    PubMed

    Baldelli, Elisa; Calvert, Valerie; Hodge, Alex; VanMeter, Amy; Petricoin, Emanuel F; Pierobon, Mariaelena

    2017-01-01

    While genes and RNA encode information about cellular status, proteins are considered the engine of the cellular machine, as they are the effective elements that drive all cellular functions including proliferation, migration, differentiation, and apoptosis. Consequently, investigations of the cellular protein network are considered a fundamental tool for understanding cellular functions.Alteration of the cellular homeostasis driven by elaborate intra- and extracellular interactions has become one of the most studied fields in the era of personalized medicine and targeted therapy. Increasing interest has been focused on developing and improving proteomic technologies that are suitable for analysis of clinical samples. In this context, reverse-phase protein microarrays (RPPA) is a sensitive, quantitative, high-throughput immunoassay for protein analyses of tissue samples, cells, and body fluids.RPPA is well suited for broad proteomic profiling and is capable of capturing protein activation as well as biochemical reactions such as phosphorylation, glycosylation, ubiquitination, protein cleavage, and conformational alterations across hundreds of samples using a limited amount of biological material. For these reasons, RPPA represents a valid tool for protein analyses and generates data that help elucidate the functional signaling architecture through protein-protein interaction and protein activation mapping for the identification of critical nodes for individualized or combinatorial targeted therapy.

  1. Time Reversal Violation

    SciTech Connect

    Quinn, H; /SLAC

    2009-01-27

    This talk briefly reviews three types of time-asymmetry in physics, which I classify as universal, macroscopic and microscopic. Most of the talk is focused on the latter, namely the violation of T-reversal invariance in particle physics theories. In sum tests of microscopic T-invariance, or observations of its violation, are limited by the fact that, while we can measure many processes, only in very few cases can we construct a matched pair of process and inverse process and observe it with sufficient sensitivity to make a test. In both the cases discussed here we can achieve an observable T violation making use of flavor tagging, and in the second case also using the quantum properties of an antisymmetric coherent state of two B mesons to construct a CP-tag. Both these tagging properties depend only on very general properties of the flavor and/or CP quantum numbers and so provide model independent tests for T-invariance violations. The microscopic laws of physics are very close to T-symmetric. There are small effects that give CP- and T-violating processes in three-generation-probing weak decays. Where a T-violating observable can be constructed we see the relationships between T-violation and CP-violation expected in a CPT conserving theory. These microscopic effects are unrelated to the 'arrow of time' that is defined by increasing entropy, or in the time direction defined by the expansion of our Universe.

  2. Reversible cerebral vasoconstriction syndrome.

    PubMed

    Ducros, Anne

    2014-01-01

    Reversible cerebral vasoconstriction syndrome is characterized by severe headaches with or without focal neurologic deficits and/or seizures, and segmental constriction of cerebral arteries that resolves within 3 months. This increasingly recognized syndrome is supposedly due to a transient disturbance in the control of cerebral vascular tone with sympathetic overactivity. It can cause stroke in the young. It affects mainly middle-aged women. More than half the cases occur after exposure to vasoactive substances or during postpartum. The manifestations have a monophasic course, without new clinical symptom after 4 weeks, and range from pure cephalalgic forms with recurrent thunderclap headaches over 1-2 weeks to rare catastrophic forms with multiple hemorrhagic and ischemic strokes, brain edema and death. Diagnosis may be hampered by the dynamic nature of clinicoradiological features. Convexity subarachnoid hemorrhage or stroke may occur a few days after initial normal imaging, and cerebral vasoconstriction is maximal on angiography 2-3 weeks after clinical onset. Symptomatic treatment includes rest and removal of vasoactive substances. Nimodipine has been proposed to reduce thunderclap headaches within 48 hours, but has no proven effect on the hemorrhagic and ischemic complications. © 2014 Elsevier B.V. All rights reserved.

  3. Reversible cerebral vasoconstriction syndrome.

    PubMed

    Sampaio Rocha Filho, Pedro Augusto; Santos Barbosa, Janayna; Melo Correa-Lima, Ana Rosa

    2010-08-01

    Reversible cerebral vasoconstriction syndrome is characterized by thunderclap headache associated with multifocal vasoconstriction of cerebral arteries in patients without aneurysmal subarachnoid hemorrhage (SAH). The vasoconstriction reverts within three months. We report a 44-year-old man who had a thunderclap headache during sexual intercourse. A similar episode occurred at rest 36 hours later. The patient had already experienced a thunderclap headache 10 years earlier, during coitus. There were no abnormalities on examination. His brain computed tomography scan was normal and cerebrospinal fluid analysis showed no xanthochromia, 15 WBC/mm³ and 10 RBC/mm³. Lumbar puncture was repeated two days later (WBC = 3/mm³ and RBC = 43/mm³). An initial digital cerebral angiography showed a diffuse segmental intracerebral vasospasm. A new angiography after 15 days was normal. He remains headache-free after twenty six months. In conclusion, patients who have thunderclap headache with normal brain CT and cerebrospinal fluid without xantochromia should be investigated for this syndrome.

  4. Reversible micromachining locator

    DOEpatents

    Salzer, L.J.; Foreman, L.R.

    1999-08-31

    This invention provides a device which includes a locator, a kinematic mount positioned on a conventional tooling machine, a part carrier disposed on the locator and a retainer ring. The locator has disposed therein a plurality of steel balls, placed in an equidistant position circumferentially around the locator. The kinematic mount includes a plurality of magnets which are in registry with the steel balls on the locator. In operation, a blank part to be machined is placed between a surface of a locator and the retainer ring (fitting within the part carrier). When the locator (with a blank part to be machined) is coupled to the kinematic mount, the part is thus exposed for the desired machining process. Because the locator is removably attachable to the kinematic mount, it can easily be removed from the mount, reversed, and reinserted onto the mount for additional machining. Further, the locator can likewise be removed from the mount and placed onto another tooling machine having a properly aligned kinematic mount. Because of the unique design and use of magnetic forces of the present invention, positioning errors of less than 0.25 micrometer for each machining process can be achieved. 7 figs.

  5. Reversible micromachining locator

    DOEpatents

    Salzer, Leander J.; Foreman, Larry R.

    1999-01-01

    This invention provides a device which includes a locator, a kinematic mount positioned on a conventional tooling machine, a part carrier disposed on the locator and a retainer ring. The locator has disposed therein a plurality of steel balls, placed in an equidistant position circumferentially around the locator. The kinematic mount includes a plurality of magnets which are in registry with the steel balls on the locator. In operation, a blank part to be machined is placed between a surface of a locator and the retainer ring (fitting within the part carrier). When the locator (with a blank part to be machined) is coupled to the kinematic mount, the part is thus exposed for the desired machining process. Because the locator is removably attachable to the kinematic mount, it can easily be removed from the mount, reversed, and reinserted onto the mount for additional machining. Further, the locator can likewise be removed from the mount and placed onto another tooling machine having a properly aligned kinematic mount. Because of the unique design and use of magnetic forces of the present invention, positioning errors of less than 0.25 micrometer for each machining process can be achieved.

  6. Preference Reversal in Multiattribute Choice

    ERIC Educational Resources Information Center

    Tsetsos, Konstantinos; Usher, Marius; Chater, Nick

    2010-01-01

    A central puzzle for theories of choice is that people's preferences between options can be reversed by the presence of decoy options (that are not chosen) or by the presence of other irrelevant options added to the choice set. Three types of reversal effect reported in the decision-making literature, the attraction, compromise, and similarity…

  7. Preference Reversal in Multiattribute Choice

    ERIC Educational Resources Information Center

    Tsetsos, Konstantinos; Usher, Marius; Chater, Nick

    2010-01-01

    A central puzzle for theories of choice is that people's preferences between options can be reversed by the presence of decoy options (that are not chosen) or by the presence of other irrelevant options added to the choice set. Three types of reversal effect reported in the decision-making literature, the attraction, compromise, and similarity…

  8. Reverse Transfer Project, Summer 1986.

    ERIC Educational Resources Information Center

    Reis, Elizabeth

    In 1986, a Reverse Transfer Project was initiated at Moraine Valley Community College (MVCC) in order to promote the summer school attendance at MVCC of "reverse transfer" students (i.e., students who attended another institution during the regular academic year). A mailing, containing a cover letter, informational brochure, summer catalog, and…

  9. Play: The Reversal Theory Perspective.

    ERIC Educational Resources Information Center

    Kerr, J. H.

    The intention of this theoretical paper is to present a reversal theory interpretation of play phenomena. Reversal theory, a developing theory in psychology, concerns the complex relationship between experience and motivation. One of the central charactieristics of the theory is that it attempts to understand why so much of human behavior is…

  10. The effects of counseling spouse caregivers of people with Alzheimer’s disease taking donepezil and of country of residence on rates of admission to nursing homes and mortality

    PubMed Central

    Brodaty, Henry; Mittelman, Mary; Gibson, Louisa; Seeher, Katrin; Burns, Alistair

    2009-01-01

    Objective Does psychosocial intervention for caregivers whose spouses with Alzheimer’s disease (AD) are taking donepezil delay nursing home (NH) placement or death of patients? Design Randomized controlled trial with 2 years of active treatment and up to 8.5 years of follow-up (M = 5.4 years, SD = 2.4) was conducted. Setting Outpatients of research clinics in Australia, United Kingdom (UK) and the United States (US). Participants 155 persons with AD and their spouses. Intervention 5 sessions of individual and family counseling (+ prn ad hoc counseling) or usual care. Measurements Time to institutionalization and death using Cox proportional hazards methods. Results Over a mean of 5.4 years (SD = 2.4), there were no differences in NH placement or mortality by intervention group but there were by country, with Australian patients admitted to NHs earlier than US and UK patients. Conclusion Earlier NH admission of Australian than UK and US subjects may be due to differences in health care, NH systems, availability and affordability. PMID:19705519

  11. Enzymatic and solid-phase synthesis of new donepezil-based L- and d-glutamic acid derivatives and their pharmacological evaluation in models related to Alzheimer's disease and cerebral ischemia.

    PubMed

    Monjas, Leticia; Arce, Mariana P; León, Rafael; Egea, Javier; Pérez, Concepción; Villarroya, Mercedes; López, Manuela G; Gil, Carmen; Conde, Santiago; Rodríguez-Franco, María Isabel

    2017-04-21

    Previously, we have described N-Bz-L-Glu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution. The lipase-catalysed amidation of L- and D-Glu diesters with N-benzyl-4-(2-aminoethyl)piperidine has been studied, using Candida antarctica and Mucor miehei lipases. In all cases, the α-amidated compound was obtained as the main product, pointing out that regioselectivity was independent of the reacting Glu enantiomer and the nature of the lipase. An efficient solid-phase route has been used to produce new donepezil-based L- and D-Glu derivatives, resulting in good yield. At micromolar concentrations, the new compounds inhibited human cholinesterases and protected neurons against toxic insults related to Alzheimer's disease and cerebral ischemia. The CNS-permeable compounds N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-3) and L-1 blocked the voltage-dependent calcium channels and L-3 protected rat hippocampal slices against oxygen-glucose deprivation, becoming promising anti-Alzheimer and anti-stroke lead compounds. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Reversible Cerebral Vasoconstriction Syndrome.

    PubMed

    Bernard, Kenneth R L; Rivera, Morris

    2015-07-01

    Reversible cerebral vasoconstriction syndrome (RCVS) is an underappreciated and poorly understood cause of thunderclap headache (TCH). Although self-limited in the majority of patients, incidence is increasing, with presentations overlapping considerably with life-threatening conditions, such as aneurysmal subarachnoid hemorrhage and stroke. In addition, radiographic findings seen in RCVS are also present in primary angiitis of the central nervous system (PACNS). Misdiagnosis of RCVS might subject patients to unnecessary invasive testing and immunosuppressive therapy. Furthermore, the recommended treatment of glucocorticoids used in PACNS can be harmful in RCVS. RCVS is not a benign condition, as patients can have ischemic or hemorrhagic complications leading to persistent neurologic deficits and even death. Current treatments, guided only by expert consensus, have no proven effect on these complications, which argues the need for accurate identification of patients with RCVS and prospective studies to validate treatment and inform prognoses. We describe a previously healthy male who presented to the emergency department after 2 episodes of TCH and angiography consistent with RCVS. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: RCVS is a common but underappreciated cause of TCH. The likelihood of misdiagnosing RCVS following the accepted diagnostic algorithm of acute headache in the emergency department is high due to a lack of clinical awareness and common features shared with other headache syndromes. Emergency department physicians must broaden the differential in patients presenting to the emergency department with TCH to include RCVS and be familiar with the accepted treatments and appropriate follow-up. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. PHAGOCYTOSIS INHIBITION AND REVERSAL I.

    PubMed Central

    Sbarra, Anthony J.; Shirley, William

    1963-01-01

    Sbarra, Anthony J. (St. Margaret's Hospital, Boston, Mass.) and William Shirley. Phagocytosis inhibition and reversal. I. Effect of glycolytic intermediates and nucleotides on particle uptake. J. Bacteriol. 86:259–265. 1963.—By microscopically monitoring phagocytosis and following the biochemical changes associated with this process, the inhibition of phagocytosis by fluoride or iodoacetate was shown to be partially reversed by pyruvate. This reversal occurred with both inhibitors, either aerobically or anaerobically. Nicotinamide adenine dinucleotide (NAD) apparently increased the degree of pyruvate reversal when fluoride, but not iodoacetate, was the inhibitory agent. Lactate under some conditions was also shown to reverse the inhibition. It is suggested that pyruvate and NAD are key compounds for the phagocytic process. PMID:14058950

  14. Classical Analog to Entanglement Reversibility

    NASA Astrophysics Data System (ADS)

    Chitambar, Eric; Fortescue, Ben; Hsieh, Min-Hsiu

    2015-08-01

    In this Letter we study the problem of secrecy reversibility. This asks when two honest parties can distill secret bits from some tripartite distribution pX Y Z and transform secret bits back into pX Y Z at equal rates using local operation and public communication. This is the classical analog to the well-studied problem of reversibly concentrating and diluting entanglement in a quantum state. We identify the structure of distributions possessing reversible secrecy when one of the honest parties holds a binary distribution, and it is possible that all reversible distributions have this form. These distributions are more general than what is obtained by simply constructing a classical analog to the family of quantum states known to have reversible entanglement. An indispensable tool used in our analysis is a conditional form of the Gács-Körner common information.

  15. Reverse osmosis reverses conventional wisdom with Superfund cleanup success

    SciTech Connect

    Collins, M. ); Miller, K. )

    1994-09-01

    Although widely recognized as the most efficient means of water purification, reverse osmosis has not been considered effective for remediating hazardous wastewater. Scaling and fouling, which can cause overruns and downtime, and require membrane replacement, have inhibited success in high-volume wastewater applications. Despite this background, a reverse osmosis technology developed in Europe recently was used successfully to treat large volumes of contaminated water at a major Superfund site in Texas. The technology's success there may increase the chances for reverse osmosis to find wider use in future cleanups and other waste treatment applications.

  16. The Geomagnetic Field During a Reversal

    NASA Technical Reports Server (NTRS)

    Heirtzler, James R.

    2003-01-01

    By modifying the IGRF it is possible to learn what may happen to the geomagnetic field during a geomagnetic reversal. If the entire IGRF reverses then the declination and inclination only reverse when the field strength is zero. If only the dipole component of the IGRF reverses a large geomagnetic field remains when the dipole component is zero and he direction of the field at the end of the reversal is not exactly reversed from the directions at the beginning of the reversal.

  17. Reversible simulation of irreversible computation

    NASA Astrophysics Data System (ADS)

    Li, Ming; Tromp, John; Vitányi, Paul

    1998-09-01

    Computer computations are generally irreversible while the laws of physics are reversible. This mismatch is penalized by among other things generating excess thermic entropy in the computation. Computing performance has improved to the extent that efficiency degrades unless all algorithms are executed reversibly, for example by a universal reversible simulation of irreversible computations. All known reversible simulations are either space hungry or time hungry. The leanest method was proposed by Bennett and can be analyzed using a simple ‘reversible’ pebble game. The reachable reversible simulation instantaneous descriptions (pebble configurations) of such pebble games are characterized completely. As a corollary we obtain the reversible simulation by Bennett and, moreover, show that it is a space-optimal pebble game. We also introduce irreversible steps and give a theorem on the tradeoff between the number of allowed irreversible steps and the memory gain in the pebble game. In this resource-bounded setting the limited erasing needs to be performed at precise instants during the simulation. The reversible simulation can be modified so that it is applicable also when the simulated computation time is unknown.

  18. Supercritical fluid reverse micelle separation

    DOEpatents

    Fulton, John L.; Smith, Richard D.

    1993-01-01

    A method of separating solute material from a polar fluid in a first polar fluid phase is provided. The method comprises combining a polar fluid, a second fluid that is a gas at standard temperature and pressure and has a critical density, and a surfactant. The solute material is dissolved in the polar fluid to define the first polar fluid phase. The combined polar and second fluids, surfactant, and solute material dissolved in the polar fluid is maintained under near critical or supercritical temperature and pressure conditions such that the density of the second fluid exceeds the critical density thereof. In this way, a reverse micelle system defining a reverse micelle solvent is formed which comprises a continuous phase in the second fluid and a plurality of reverse micelles dispersed in the continuous phase. The solute material is dissolved in the polar fluid and is in chemical equilibrium with the reverse micelles. The first polar fluid phase and the continuous phase are immiscible. The reverse micelles each comprise a dynamic aggregate of surfactant molecules surrounding a core of the polar fluid. The reverse micelle solvent has a polar fluid-to-surfactant molar ratio W, which can vary over a range having a maximum ratio W.sub.o that determines the maximum size of the reverse micelles. The maximum ratio W.sub.o of the reverse micelle solvent is then varied, and the solute material from the first polar fluid phase is transported into the reverse micelles in the continuous phase at an extraction efficiency determined by the critical or supercritical conditions.

  19. Supercritical fluid reverse micelle separation

    DOEpatents

    Fulton, J.L.; Smith, R.D.

    1993-11-30

    A method of separating solute material from a polar fluid in a first polar fluid phase is provided. The method comprises combining a polar fluid, a second fluid that is a gas at standard temperature and pressure and has a critical density, and a surfactant. The solute material is dissolved in the polar fluid to define the first polar fluid phase. The combined polar and second fluids, surfactant, and solute material dissolved in the polar fluid is maintained under near critical or supercritical temperature and pressure conditions such that the density of the second fluid exceeds the critical density thereof. In this way, a reverse micelle system defining a reverse micelle solvent is formed which comprises a continuous phase in the second fluid and a plurality of reverse micelles dispersed in the continuous phase. The solute material is dissolved in the polar fluid and is in chemical equilibrium with the reverse micelles. The first polar fluid phase and the continuous phase are immiscible. The reverse micelles each comprise a dynamic aggregate of surfactant molecules surrounding a core of the polar fluid. The reverse micelle solvent has a polar fluid-to-surfactant molar ratio W, which can vary over a range having a maximum ratio W[sub o] that determines the maximum size of the reverse micelles. The maximum ratio W[sub o] of the reverse micelle solvent is then varied, and the solute material from the first polar fluid phase is transported into the reverse micelles in the continuous phase at an extraction efficiency determined by the critical or supercritical conditions. 27 figures.

  20. Reverse mortgage decision-making.

    PubMed

    Leviton, R

    2001-01-01

    Reverse mortgages have been suggested as a promising financial tool to help low-income older homeowners who want to remain in their houses. However, actual use of this option has been much below early estimates of potential demand. This study explored response to the new option through open-ended interviews of homeowners who had received reverse mortgage counseling. Decision-making was influenced by attachment to home, family input, and financial attitudes, including desire to leave a legacy. In general, homeowners took reverse mortgages only as a "last resort" that enabled them to maintain their independence.

  1. Dielectrophoresis of reverse phase emulsions.

    PubMed

    Flores-Rodriguez, N; Bryning, Z; Markx, G H

    2005-08-01

    Reverse miniemulsions, emulsions of droplets of size 200 nm-1 microm of a polar liquid dispersed in an apolar continuous liquid phase, exhibit strong electrokinetic responses in low-frequency electric fields. The electrokinetic behaviour of a reverse miniemulsion, previously developed for use as electronic paper, has been investigated under static and flow conditions, in uniform and non-uniform electric fields. Results reveal that when using frequencies lower than 10 Hz strong aggregation of the droplets occurs. In uniform electric fields, under static conditions, droplets reversibly aggregate into honeycomb-like or irregular aggregates. Under flow conditions, droplets aggregate into approximately equidistant streams. In non-uniform electric fields the droplets reversibly aggregate in high-field regions, and can be guided along regions of high field strength in a flow. The potential of the technique for the formation of structured materials is discussed.

  2. Reverse engineering quantum field theory

    NASA Astrophysics Data System (ADS)

    Oeckl, Robert

    2012-12-01

    An approach to the foundations of quantum theory is advertised that proceeds by "reverse engineering" quantum field theory. As a concrete instance of this approach, the general boundary formulation of quantum theory is outlined.

  3. Deciphering records of geomagnetic reversals

    NASA Astrophysics Data System (ADS)

    Valet, Jean-Pierre; Fournier, Alexandre

    2016-06-01

    Polarity reversals of the geomagnetic field are a major feature of the Earth's dynamo. Questions remain regarding the dynamical processes that give rise to reversals and the properties of the geomagnetic field during a polarity transition. A large number of paleomagnetic reversal records have been acquired during the past 50 years in order to better constrain the structure and geometry of the transitional field. In addition, over the past two decades, numerical dynamo simulations have also provided insights into the reversal mechanism. Yet despite the large paleomagnetic database, controversial interpretations of records of the transitional field persist; they result from two characteristics inherent to all reversals, both of which are detrimental to an ambiguous analysis. On the one hand, the reversal process is rapid and requires adequate temporal resolution. On the other hand, weak field intensities during a reversal can affect the fidelity of magnetic recording in sedimentary records. This paper is aimed at reviewing critically the main reversal features derived from paleomagnetic records and at analyzing some of these features in light of numerical simulations. We discuss in detail the fidelity of the signal extracted from paleomagnetic records and pay special attention to their resolution with respect to the timing and mechanisms involved in the magnetization process. Records from marine sediments dominate the database. They give rise to transitional field models that often lead to overinterpret the data. Consequently, we attempt to separate robust results (and their subsequent interpretations) from those that do not stand on a strong observational footing. Finally, we discuss new avenues that should favor progress to better characterize and understand transitional field behavior.

  4. Reverse Current in Solar Flares

    NASA Technical Reports Server (NTRS)

    Knight, J. W., III

    1978-01-01

    An idealized steady state model of a stream of energetic electrons neutralized by a reverse current in the pre-flare solar plasma was developed. These calculations indicate that, in some cases, a significant fraction of the beam energy may be dissipated by the reverse current. Joule heating by the reverse current is a more effective mechanism for heating the plasma than collisional losses from the energetic electrons because the Ohmic losses are caused by thermal electrons in the reverse current which have much shorter mean free paths than the energetic electrons. The heating due to reverse currents is calculated for two injected energetic electron fluxes. For the smaller injected flux, the temperature of the coronal plasma is raised by about a factor of two. The larger flux causes the reverse current drift velocity to exceed the critical velocity for the onset of ion cyclotron turbulence, producing anomalous resistivity and an order of magnitude increase in the temperature. The heating is so rapid that the lack of ionization equilibrium may produce a soft X-ray and EUV pulse from the corona.

  5. Reversible Rings with Involutions and Some Minimalities

    PubMed Central

    Fakieh, W. M.; Nauman, S. K.

    2013-01-01

    In continuation of the recent developments on extended reversibilities on rings, we initiate here a study on reversible rings with involutions, or, in short, ∗-reversible rings. These rings are symmetric, reversible, reflexive, and semicommutative. In this note we will study some properties and examples of ∗-reversible rings. It is proved here that the polynomial rings of ∗-reversible rings may not be ∗-reversible. A criterion for rings which cannot adhere to any involution is developed and it is observed that a minimal noninvolutary ring is of order 4 and that a minimal noncommutative ∗-reversible ring is of order 16. PMID:24489510

  6. Effects of acute administration of donepezil or memantine on sleep-deprivation-induced spatial memory deficit in young and aged non-human primate grey mouse lemurs (Microcebus murinus).

    PubMed

    Rahman, Anisur; Lamberty, Yves; Schenker, Esther; Cella, Massimo; Languille, Solène; Bordet, Régis; Richardson, Jill; Pifferi, Fabien; Aujard, Fabienne

    2017-01-01

    The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)-induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.

  7. Reversal Transition Records from Intrusions: Implications for the Reversal Process.

    NASA Astrophysics Data System (ADS)

    Fuller, M. D.; Williams, I. S.

    2014-12-01

    The nature of reversals of the geomagnetic field and the details of the transition fields remain controversial. However, reversal records from the Agno batholith and Tatoosh intrusion confirm the suggestion of Valet et al., (2012) from studies of lava records, that there is a threefold division in reversal transition directions. In the Agno, the first phase, or precursor, consists of a CCW loop of the VGP moving from high southerly latitude reverse poles to reach North America. The second phase takes the VGP along a half CCW loop from the tip of South America to northern latitudes at the intensity minimum. The third phase, or rebound is a smaller CCW loop and the main intensity recovery begins. The first and third phases appear to be paleosecular variation loops analogous to present London-Paris secular variation loops. The Tatoosh intrusion gives a similar, but less complete record with the VGPs again confined to the East Pacific and the Americas. Away from the reversal region, secular variation loops in the Tatoosh were shown to be comparable in duration to the precursor in the transition record, consistent with the first phase being a paleosecular variation loop in the Agno. Using westward drift estimates from the present field, this should last about1800 years. This gives ~3300 for phase 2, in an intensity low of >16,000 years. A feature of R to N reversal field models is a low latitude magnetic field flux concentration of the same sign as the polar vortex of the south geographic pole. This is followed by northward flux flow, e.g. Shao et al., (1999). The reversal is achieved by northward motion of this flux feature. The feature is locked in longitudinal mantle coordinates and similarly the VGPs in the Agno and Tatoosh records are confined to the longitudes of the eastern Pacific and the Americas. Whether we are approaching a reversal remains to be seen, although judging by these intrusion records the field intensity would need to decrease much further before

  8. Thrust reverser with variable nozzle

    NASA Technical Reports Server (NTRS)

    Butler, Lawrence (Inventor)

    1997-01-01

    A thrust reverser is provided for both modulating and reversing bypass flow discharged from a fan through a bypass duct of a turbofan gas turbine engine. The reverser includes an aft cowl joined to a forward cowl and having an aft end surrounding a core engine to define a discharge fan nozzle of minimum flow throat area. The aft cowl is axially translatable relative to the forward cowl from a first position fully retracted against the forward cowl, to a second position partially extended from the forward cowl, and to a third position fully extended from the forward cowl. A plurality of cascade turning vanes are disposed between the forward and aft cowls, and a plurality of thrust reversing deflector doors are pivotally mounted to the aft cowl and bound the bypass duct. The deflector doors are selectively deployed from a stowed position corresponding with the first and second positions of the aft cowl for allowing unrestricted flow of the bypass flow through the fan nozzle. The doors also have a deployed position corresponding with the third position of the aft cowl for substantially deflecting the bypass flow from discharging through the fan nozzle to discharging through the cascade vanes for effecting thrust reverse. Axial translation of the aft cowl between the first and second positions varies flow area of the fan nozzle to vary thrust effected by the discharged bypass flow.

  9. Reverse shift mechanism for automotive manual transmission

    SciTech Connect

    Inui, M.; Ogawa, S.

    1987-03-03

    A reverse shift mechanism is described for an automotive manual transmission of a type having a reverse idler gear which is movable to selectively complete a reverse gear train, the reverse shift mechanism comprising: a reverse shift arm having a portion disposed adjacent the reverse idler gear and pivotally carried with respect to a transmission casing so that the portion rocks along a direction of axis of the reverse idler gear in response to shifting operation. The portion of the reverse shift arm is provided with a blind hole which is open at a first end toward the reverse idler gear and is closed at a second end away from the reverse idler gear; and a shift arm shoe carried by the portion of the reverse shift arm adjacent the reverse idler gear for pushing the reverse idler gear. The shift arm shoe has an end adapted to engage with a circumferential groove formed in the reverse idler gear and an opposing end shaped to fit in the blind hole of the reverse shift arm; whereby the shift arm shoe is prevented from coming off during assembly by virtue of a vacuum effect created by air confined in the blind hole by fitting engagement between the opposing end and the blind hole, and is held in place after assembly by being clamped between the groove of the reverse idler gear and the blind hole of the reverse shift arm.

  10. Ice ages and geomagnetic reversals

    NASA Technical Reports Server (NTRS)

    Wu, Patrick

    1992-01-01

    There have been speculations on the relationship between climatic cooling and polarity reversals of the earth's magnetic field during the Pleistocene. Two of the common criticisms on this relationship have been the reality of these short duration geomagnetic events and the accuracy of their dates. Champion et al. (1988) have reviewed recent progress in this area. They identified a total of 10 short-duration polarity events in the last 1 Ma and 6 of these events have been found in volcanic rocks, which also have K-Ar dates. Supposing that the speculated relationship between climatic cooling and geomagnetic reversals actually exist, two mechanisms that assume climatic cooling causes short period magnetic reversals will be investigated. These two methods are core-mantle boundary topography and transfer of the rotational energy to the core.

  11. The posterior reversible encephalopathy syndrome.

    PubMed

    Sanjay, K Mandal; Partha, P Chakraborty

    2008-09-01

    The posterior/potentially reversible encephalopathy syndrome is a unique syndrome encountered commonly in hypertensive encephalopathy. A 13-year-old boy presented with of intermittent high grade fever, throbbing headache and non-projective vomiting for 5 days. The patient had a blood pressure of 120/80 mmHg but fundoscopy documented grade 3 hypertensive retinopathy. The patient improved symptomatically following conservative management. However, on the 5(th) post-admission day headache reappeared, and blood pressure measured at that time was 240/120 mmHg. Neuroimaging suggested white matter abnormalities. Search for the etiology of secondary hypertension led to the diagnosis of pheochromocytoma. Repeated MRI after successful surgical excision of the tumor patient showed reversal of white matter abnormalities. Reversible leucoencephalopathy due to pheochromocytoma have not been documented in literature previously.

  12. Ultrafast Dynamics in Reverse Micelles

    NASA Astrophysics Data System (ADS)

    Levinger, Nancy E.; Swafford, Laura A.

    2009-05-01

    Recent advances in ultrafast laser technology have spurred investigations of microheterogeneous solutions. In particular, researchers have explored details of reverse micelles (RMs), which present isolated droplets of polar solvent sequestered from a continuous nonpolar phase by a surfactant layer. This review explores recent studies utilizing a variety of ultrafast laser techniques to uncover details about structure and dynamics in various RMs. Using ultrafast vibrational spectroscopy, researchers have probed hydrogen-bond dynamics and vibrational energy relaxation in RMs. These studies have developed our understanding of reverse micellar structure, identifying varying water environments in the RMs. In a plethora of experiments employing probe molecules, researchers have explored the confined environment presented by RMs and their impact on a range of chemical reactions. These studies have shown that confinement, rather than the specific interactions with surfactants, is an important factor determining the impact of the reverse micellar environment on the chemistry.

  13. Time-reversed, flow-reversed ballistics simulations

    SciTech Connect

    Zernow, L.; Chapyak, E. J.; Scheffler, D. R.

    2001-01-01

    Two-dimensional simulations of planar sheet jet formation are studied to examine the hydrodynamic issues involved when simulations are carried out in the inverse direction, that is, with reversed time and flow. Both a realistic copper equation of state and a shockless equation of state were used. These studies are an initial step in evaluating this technique as a ballistics design tool.

  14. Reversible Switching of Cooperating Replicators

    NASA Astrophysics Data System (ADS)

    Urtel, Georg C.; Rind, Thomas; Braun, Dieter

    2017-02-01

    How can molecules with short lifetimes preserve their information over millions of years? For evolution to occur, information-carrying molecules have to replicate before they degrade. Our experiments reveal a robust, reversible cooperation mechanism in oligonucleotide replication. Two inherently slow replicating hairpin molecules can transfer their information to fast crossbreed replicators that outgrow the hairpins. The reverse is also possible. When one replication initiation site is missing, single hairpins reemerge from the crossbreed. With this mechanism, interacting replicators can switch between the hairpin and crossbreed mode, revealing a flexible adaptation to different boundary conditions.

  15. Marburg Virus Reverse Genetics Systems.

    PubMed

    Schmidt, Kristina Maria; Mühlberger, Elke

    2016-06-22

    The highly pathogenic Marburg virus (MARV) is a member of the Filoviridae family and belongs to the group of nonsegmented negative-strand RNA viruses. Reverse genetics systems established for MARV have been used to study various aspects of the viral replication cycle, analyze host responses, image viral infection, and screen for antivirals. This article provides an overview of the currently established MARV reverse genetic systems based on minigenomes, infectious virus-like particles and full-length clones, and the research that has been conducted using these systems.

  16. Stagnation point reverse flow combustor

    NASA Technical Reports Server (NTRS)

    Zinn, Ben T. (Inventor); Neumeier, Yedidia (Inventor); Seitzman, Jerry M. (Inventor); Jagoda, Jechiel (Inventor); Weksler, Yoav (Inventor)

    2008-01-01

    A method for combusting a combustible fuel includes providing a vessel having an opening near a proximate end and a closed distal end defining a combustion chamber. A combustible reactants mixture is presented into the combustion chamber. The combustible reactants mixture is ignited creating a flame and combustion products. The closed end of the combustion chamber is utilized for directing combustion products toward the opening of the combustion chamber creating a reverse flow of combustion products within the combustion chamber. The reverse flow of combustion products is intermixed with combustible reactants mixture to maintain the flame.

  17. Marburg Virus Reverse Genetics Systems

    PubMed Central

    Schmidt, Kristina Maria; Mühlberger, Elke

    2016-01-01

    The highly pathogenic Marburg virus (MARV) is a member of the Filoviridae family and belongs to the group of nonsegmented negative-strand RNA viruses. Reverse genetics systems established for MARV have been used to study various aspects of the viral replication cycle, analyze host responses, image viral infection, and screen for antivirals. This article provides an overview of the currently established MARV reverse genetic systems based on minigenomes, infectious virus-like particles and full-length clones, and the research that has been conducted using these systems. PMID:27338448

  18. Long-acting reversible contraception.

    PubMed

    Peck, Susan A

    2013-10-01

    Although short-acting reversible hormonal contraceptives, such as oral contraceptives and the contraceptive patch and vaginal ring, remain the most commonly used contraceptive methods in the United States, they are also associated with the highest failure rates. Long-acting reversible contraception (LARC) methods, such as intrauterine devices and contraceptive implants, offer high continuation rates and very low failure rates, and are safe for use in most women. The provision of LARC methods to adolescent, young adult and nulliparous women is a relatively new concept that offers an innovative option for these populations.

  19. Nickel-hydrogen cell reversal characteristics

    NASA Technical Reports Server (NTRS)

    Lurie, Charles

    1994-01-01

    Nickel-hydrogen cell reversal characteristics are being studied as part of a TRW program directed towards development of a high current battery cell bypass switch. The following are discussed: cell bypass switch; nickel-hydrogen cell reversal characteristics; and nickel-hydrogen cell chemistry: discharge/reversal and overdischarge (reversal) with nickel and hydrogen precharge.

  20. Reversible logic gate using adiabatic superconducting devices

    PubMed Central

    Takeuchi, N.; Yamanashi, Y.; Yoshikawa, N.

    2014-01-01

    Reversible computing has been studied since Rolf Landauer advanced the argument that has come to be known as Landauer's principle. This principle states that there is no minimum energy dissipation for logic operations in reversible computing, because it is not accompanied by reductions in information entropy. However, until now, no practical reversible logic gates have been demonstrated. One of the problems is that reversible logic gates must be built by using extremely energy-efficient logic devices. Another difficulty is that reversible logic gates must be both logically and physically reversible. Here we propose the first practical reversible logic gate using adiabatic superconducting devices and experimentally demonstrate the logical and physical reversibility of the gate. Additionally, we estimate the energy dissipation of the gate, and discuss the minimum energy dissipation required for reversible logic operations. It is expected that the results of this study will enable reversible computing to move from the theoretical stage into practical usage. PMID:25220698

  1. Reversible logic gate using adiabatic superconducting devices

    NASA Astrophysics Data System (ADS)

    Takeuchi, N.; Yamanashi, Y.; Yoshikawa, N.

    2014-09-01

    Reversible computing has been studied since Rolf Landauer advanced the argument that has come to be known as Landauer's principle. This principle states that there is no minimum energy dissipation for logic operations in reversible computing, because it is not accompanied by reductions in information entropy. However, until now, no practical reversible logic gates have been demonstrated. One of the problems is that reversible logic gates must be built by using extremely energy-efficient logic devices. Another difficulty is that reversible logic gates must be both logically and physically reversible. Here we propose the first practical reversible logic gate using adiabatic superconducting devices and experimentally demonstrate the logical and physical reversibility of the gate. Additionally, we estimate the energy dissipation of the gate, and discuss the minimum energy dissipation required for reversible logic operations. It is expected that the results of this study will enable reversible computing to move from the theoretical stage into practical usage.

  2. Reversible logic gate using adiabatic superconducting devices.

    PubMed

    Takeuchi, N; Yamanashi, Y; Yoshikawa, N

    2014-09-15

    Reversible computing has been studied since Rolf Landauer advanced the argument that has come to be known as Landauer's principle. This principle states that there is no minimum energy dissipation for logic operations in reversible computing, because it is not accompanied by reductions in information entropy. However, until now, no practical reversible logic gates have been demonstrated. One of the problems is that reversible logic gates must be built by using extremely energy-efficient logic devices. Another difficulty is that reversible logic gates must be both logically and physically reversible. Here we propose the first practical reversible logic gate using adiabatic superconducting devices and experimentally demonstrate the logical and physical reversibility of the gate. Additionally, we estimate the energy dissipation of the gate, and discuss the minimum energy dissipation required for reversible logic operations. It is expected that the results of this study will enable reversible computing to move from the theoretical stage into practical usage.

  3. REVERSING THE SPIRAL TOWARD FUTILITY.

    ERIC Educational Resources Information Center

    PROCTOR, SAMUEL D.

    CONDITIONS THAT ENGENDER FUTILITY AND HOSTILITY AMONG NEGROES CAN BE REVERSED BY COMPETENT, DEDICATED TEACHERS. FACTORS LEADING TO NEGRO ATTITUDES OF DEFEAT ARE ANALYZED. EXPERIENCE OF REJECTION AND AWARENESS OF BEING DIFFERENT AND INFERIOR ARE AMONG THE FIRST REALIZATIONS OF THE NEGRO. FROM REJECTION GROWS FEAR OF WHITE INSTITUTIONS AND OF…

  4. CAPSULE REPORT: REVERSE OSMOSIS PROCESS

    EPA Science Inventory

    A failure analysis has been completed for the reverse osmosis (RO) process. The focus was on process failures that result in releases of liquids and vapors to the environment. The report includes the following: 1) A description of RO and coverage of the principles behind the proc...

  5. CAPSULE REPORT: REVERSE OSMOSIS PROCESS

    EPA Science Inventory

    A failure analysis has been completed for the reverse osmosis (RO) process. The focus was on process failures that result in releases of liquids and vapors to the environment. The report includes the following: 1) A description of RO and coverage of the principles behind the proc...

  6. Reversible energy quenching and conservation

    NASA Astrophysics Data System (ADS)

    Fedorenko, S. G.; Burshtein, A. I.

    2010-05-01

    The kinetics of reversible energy transfer from photo-excited donors to energy acceptors is studied at arbitrary concentrations of both and any relationship between the decay-times of the reactants. The backward reaction of transfer products in a bulk is included in the consideration. Its contribution to delayed fluorescence, resulting from the energy conservation on the long-lived acceptors, is specified.

  7. Response Reversals in Recognition Memory

    ERIC Educational Resources Information Center

    Van Zandt, Trisha; Maldonado-Molina, Mildred M.

    2004-01-01

    Using a dynamic sequential sampling model and a recently proposed model for confidence judgments in recognition memory (T. Van Zandt, 2000b), the authors examine the tendency for rememberers to reverse their responses after a primary decision. In 4 experiments, speeded "old"-"new" decisions were made under bias followed by a 2nd response', either…

  8. Reversible colour change in Arthropoda.

    PubMed

    Umbers, Kate D L; Fabricant, Scott A; Gawryszewski, Felipe M; Seago, Ainsley E; Herberstein, Marie E

    2014-11-01

    The mechanisms and functions of reversible colour change in arthropods are highly diverse despite, or perhaps due to, the presence of an exoskeleton. Physiological colour changes, which have been recorded in 90 arthropod species, are rapid and are the result of changes in the positioning of microstructures or pigments, or in the refractive index of layers in the integument. By contrast, morphological colour changes, documented in 31 species, involve the anabolism or catabolism of components (e.g. pigments) directly related to the observable colour. In this review we highlight the diversity of mechanisms by which reversible colour change occurs and the evolutionary context and diversity of arthropod taxa in which it has been observed. Further, we discuss the functions of reversible colour change so far proposed, review the limited behavioural and ecological data, and argue that the field requires phylogenetically controlled approaches to understanding the evolution of reversible colour change. Finally, we encourage biologists to explore new model systems for colour change and to engage scientists from other disciplines; continued cross-disciplinary collaboration is the most promising approach to this nexus of biology, physics, and chemistry.

  9. Reversible simulations of elastic collisions

    SciTech Connect

    Perumalla, Kalyan S.; Protopopescu, Vladimir A.

    2013-05-01

    Consider a system of N identical hard spherical particles moving in a d-dimensional box and undergoing elastic, possibly multi-particle, collisions. We develop a new algorithm that recovers the pre-collision state from the post-collision state of the system, across a series of consecutive collisions, \\textit{with essentially no memory overhead}. The challenge in achieving reversibility for an n-particle collision (where, in general, n<< N) arises from the presence of nd-d-1 degrees of freedom (arbitrary angles) during each collision, as well as from the complex geometrical constraints placed on the colliding particles. To reverse the collisions in a traditional simulation setting, all of the particular realizations of these degrees of freedom (angles) during the forward simulation must be tracked. This requires memory proportional to the number of collisions, which grows very fast with N and d, thereby severely limiting the \\textit{de facto} applicability of the scheme. This limitation is addressed here by first performing a pseudo-randomization of angles, which ensures determinism in the reverse path for any values of n and d. To address the more difficult problem of geometrical and dynamic constraints, a new approach is developed which correctly samples the constrained phase space. Upon combining the pseudo-randomization with correct phase space sampling, perfect reversibility of collisions is achieved, as illustrated for n<=3, d=2, and n=2, d=3. This result enables, for the first time, reversible simulations of elastic collisions with essentially zero memory accumulation. In principle, the approach presented here could be generalized to larger values of n, which would be of definite interest for molecular dynamics simulations at high densities.

  10. Reversion phenomena of Cu-Cr alloys

    NASA Technical Reports Server (NTRS)

    Nishikawa, S.; Nagata, K.; Kobayashi, S.

    1985-01-01

    Cu-Cr alloys which were given various aging and reversion treatments were investigated in terms of electrical resistivity and hardness. Transmission electron microscopy was one technique employed. Some results obtained are as follows: the increment of electrical resistivity after the reversion at a constant temperature decreases as the aging temperature rises. In a constant aging condition, the increment of electrical resistivity after the reversion increases, and the time required for a maximum reversion becomes shorter as the reversion temperature rises. The reversion phenomena can be repeated, but its amount decreases rapidly by repetition. At first, the amount of reversion increases with aging time and reaches its maximum, and then tends to decrease again. Hardness changes by the reversion are very small, but the hardness tends to soften slightly. Any changes in transmission electron micrographs by the reversion treatment cannot be detected.

  11. Molecular Simulation of Reverse Micelles

    NASA Astrophysics Data System (ADS)

    Chowdhary, Janamejaya; Ladanyi, Branka

    2009-03-01

    Reverse micelles (RM) are surfactant assemblies containing a nanosized water pool dissolved in a hydrophobic solvent. Understanding their properties is crucial for insight into the effect of confinement on aqueous structure, dynamics as well as physical processes associated with solutes in confinement. We perform molecular dynamics simulations for the RM formed by the surfactant Aerosol-OT (AOT) in isooctane (2,2,4-trimethyl pentane) in order to study the effect of reverse micelle size on the aqueous phase. The structure of the RM is quantified in terms of the radial and pair density distributions. Dynamics are studied in terms of the mean squared displacements and various orientational time correlation functions in different parts of the RM so as to understand the effect of proximity to the interface on aqueous dynamics. Shape fluctuations of the RM are also analyzed.

  12. Reversing the Brazil Nut Effect

    NASA Astrophysics Data System (ADS)

    Ludewig, F.; Vandewalle, N.

    2005-12-01

    We propose a lattice model for studying the Brazil Nut Effect (BNE), i.e. the phase segregation occuring when a granular material is vertically shaked. The model considers the tap intensity and the mobility μ of the grains as the main physical parameters. Different mobilities for different grain species lead to segregation (BNE) patterns, reverse segregation (RBNE) patterns, “sandwhich" layered structures or vertical domains. A phase diagram (decompaction χ, mobility difference between both species Δ μ) is obtained in which the different phases are emphasized. In a narrow region of the diagram, different phases coexist. It is shown that the BNE segregation could be reversed by increasing the tap intensity or the characteristics of the grains. Numerical results are compared with earlier experimental works.

  13. Reverse osmosis water purification system

    NASA Technical Reports Server (NTRS)

    Ahlstrom, H. G.; Hames, P. S.; Menninger, F. J.

    1986-01-01

    A reverse osmosis water purification system, which uses a programmable controller (PC) as the control system, was designed and built to maintain the cleanliness and level of water for various systems of a 64-m antenna. The installation operates with other equipment of the antenna at the Goldstone Deep Space Communication Complex. The reverse osmosis system was designed to be fully automatic; with the PC, many complex sequential and timed logic networks were easily implemented and are modified. The PC monitors water levels, pressures, flows, control panel requests, and set points on analog meters; with this information various processes are initiated, monitored, modified, halted, or eliminated as required by the equipment being supplied pure water.

  14. Reverse Current in Solar Flares

    NASA Technical Reports Server (NTRS)

    Knight, J. W.; Sturrock, P. A.

    1976-01-01

    The theory that impulsive X ray bursts are produced by high energy electrons streaming from the corona to the chromosphere is investigated. Currents associated with these streams are so high that either the streams do not exist or their current is neutralized by a reverse current. Analysis of a simple model indicates that the primary electron stream leads to the development of an electric field in the ambient corona which decelerates the primary beam and produces a neutralizing reverse current. It appears that, in some circumstances, this electric field could prevent the primary beam from reaching the chromosphere. In any case, the electric field acts as an energy exchange mechanism, extracting kinetic energy from the primary beam and using it to heat the ambient plasma. This heating is typically so rapid that it must be expected to have important dynamical consequences.

  15. [Pneumothorax after "reversed" bungee jump].

    PubMed

    Pedersen, M N; Jensen, B N

    1999-10-04

    We here present a case of pneumothorax in a 24 year-old previously healthy man who had performed an uncomplicated "reversed" bungee jump a few hours before. A high resolution CT scan of the thorax taken three weeks later was normal. The high energy produced during a "reversed" bungee jump, up to 7-8 g corresponds to the threshold value for NASA astronauts, and can cause injuries in healthy persons. In this case we believe that there is a correlation between the pneumothorax and the high energy jump. Bungee jumping is a very popular amusement, millions of jumps have been carried out since 1979, when the sport was introduced. No register and therefore no ratio of risk exists.

  16. A reversible nanoconfined chemical reaction.

    PubMed

    Nielsen, Thomas K; Bösenberg, Ulrike; Gosalawit, Rapee; Dornheim, Martin; Cerenius, Yngve; Besenbacher, Flemming; Jensen, Torben R

    2010-07-27

    Hydrogen is recognized as a potential, extremely interesting energy carrier system, which can facilitate efficient utilization of unevenly distributed renewable energy. A major challenge in a future "hydrogen economy" is the development of a safe, compact, robust, and efficient means of hydrogen storage, in particular, for mobile applications. Here we report on a new concept for hydrogen storage using nanoconfined reversible chemical reactions. LiBH4 and MgH2 nanoparticles are embedded in a nanoporous carbon aerogel scaffold with pore size Dmax approximately 21 nm and react during release of hydrogen and form MgB2. The hydrogen desorption kinetics is significantly improved compared to bulk conditions, and the nanoconfined system has a high degree of reversibility and stability and possibly also improved thermodynamic properties. This new scheme of nanoconfined chemistry may have a wide range of interesting applications in the future, for example, within the merging area of chemical storage of renewable energy.

  17. A reversible cerebral vasoconstriction syndrome

    PubMed Central

    Ba, Fang; Giuliani, Fabrizio; Camicioli, Richard; Saqqur, Maher

    2012-01-01

    Reversible cerebral vasoconstriction syndrome (RCVS) is typically presented with severe headaches where, vascular imaging demonstrates multiple intracranial arterial narrowing. Variable triggers are related to RCVS, such as serotonin agents and bromocriptine. Thus, a detailed medication history is important. Subarachnoid haemorrhage (SAH) is not uncommon in RCVS. Repeat vascular imaging at 2–3 months with complete reversal of the narrowed vessels confirms the diagnosis of RCVS. The authors present a case where use of triptan along with multiple psychotropic medications, was associated with RVCS. Neuroimaging demonstrated focal SAH and diffuse beaded appearance involving the intracranial vasculature. The patient improved clinically with oral nimodipine treatment. Repeat angiography and a follow-up transcranial Doppler showed complete resolution of vasoconstriction. In the setting of acute severe headache, with any ‘red flags’, it is important to evaluate the medication use and other precipitating risks for RVCS. Vascular imaging is the key for diagnosis. PMID:22787186

  18. Reverse engineering of integrated circuits

    DOEpatents

    Chisholm, Gregory H.; Eckmann, Steven T.; Lain, Christopher M.; Veroff, Robert L.

    2003-01-01

    Software and a method therein to analyze circuits. The software comprises several tools, each of which perform particular functions in the Reverse Engineering process. The analyst, through a standard interface, directs each tool to the portion of the task to which it is most well suited, rendering previously intractable problems solvable. The tools are generally used iteratively to produce a successively more abstract picture of a circuit, about which incomplete a priori knowledge exists.

  19. Inference of reversible tree languages.

    PubMed

    López, Damián; Sempere, José M; García, Pedro

    2004-08-01

    In this paper, we study the notion of k-reversibility and k-testability when regular tree languages are involved. We present an inference algorithm for learning a k-testable tree language that runs in polynomial time with respect to the size of the sample used. We also study the tree language classes in relation to other well known ones, and some properties of these languages are proven.

  20. Reversal agents in anaesthesia and critical care

    PubMed Central

    Pani, Nibedita; Dongare, Pradeep A; Mishra, Rajeeb Kumar

    2015-01-01

    Despite the advent of short and ultra-short acting drugs, an in-depth knowledge of the reversal agents used is a necessity for any anaesthesiologist. Reversal agents are defined as any drug used to reverse the effects of anaesthetics, narcotics or potentially toxic agents. The controversy on the routine reversal of neuromuscular blockade still exists. The advent of newer reversal agents like sugammadex have made the use of steroidal neuromuscular blockers like rocuronium feasible in rapid sequence induction situations. We made a review of the older reversal agents and those still under investigation for drugs that are regularly used in our anaesthesia practice. PMID:26644615

  1. Reversible Seeding in Storage Rings

    SciTech Connect

    Ratner, Daniel; Chao, Alex; /SLAC

    2011-12-14

    We propose to generate steady-state microbunching in a storage ring with a reversible seeding scheme. High gain harmonic generation (HGHG) and echo-enabled harmonic generation (EEHG) are two promising methods for microbunching linac electron beams. Because both schemes increase the energy spread of the seeded beam, they cannot drive a coherent radiator turn-by-turn in a storage ring. However, reversing the seeding process following the radiator minimizes the impact on the electron beam and may allow coherent radiation at or near the storage ring repetition rate. In this paper we describe the general idea and outline a proof-of-principle experiment. Electron storage rings can drive high average power light sources, and free-electron lasers (FELs) are now producing coherent light sources of unprecedented peak brightness While there is active research towards high repetition rate FELs (for example, using energy recovery linacs), at present there are still no convenient accelerator-based sources of high repetition rate, coherent radiation. As an alternative avenue, we recently proposed to establish steady-state microbunching (SSMB) in a storage ring. By maintaining steady-state coherent microbunching at one point in the storage ring, the beam generates coherent radiation at or close to the repetition rate of the storage ring. In this paper, we propose a method of generating a microbunched beam in a storage ring by using reversible versions of linac seeding schemes.

  2. Reversible Oxidative Addition at Carbon.

    PubMed

    Eichhorn, Antonius F; Fuchs, Sonja; Flock, Marco; Marder, Todd B; Radius, Udo

    2017-04-07

    The reactivity of N-heterocyclic carbenes (NHCs) and cyclic alkyl amino carbenes (cAACs) with arylboronate esters is reported. The reaction with NHCs leads to the reversible formation of thermally stable Lewis acid/base adducts Ar-B(OR)2 ⋅NHC (Add1-Add6). Addition of cAAC(Me) to the catecholboronate esters 4-R-C6 H4 -Bcat (R=Me, OMe) also afforded the adducts 4-R-C6 H4 Bcat⋅cAAC(Me) (Add7, R=Me and Add8, R=OMe), which react further at room temperature to give the cAAC(Me) ring-expanded products RER1 and RER2. The boronate esters Ar-B(OR)2 of pinacol, neopentylglycol, and ethyleneglycol react with cAAC at RT via reversible B-C oxidative addition to the carbene carbon atom to afford cAAC(Me) (B{OR}2 )(Ar) (BCA1-BCA6). NMR studies of cAAC(Me) (Bneop)(4-Me-C6 H4 ) (BCA4) demonstrate the reversible nature of this oxidative addition process.

  3. Rapid evaluation of reverse-osmosis membranes

    NASA Technical Reports Server (NTRS)

    Hollahan, J. R.; Wydeven, T.

    1972-01-01

    Simultaneous reverse-osmosis tests conducted with centrifuges having multiple compartment heads are discussed. Equipment for retaining reverse-osmosis membrane is illustrated. Method of conducting tests is described.

  4. Ancient Magnetic Reversals: Clues to the Geodynamo.

    ERIC Educational Resources Information Center

    Hoffman, Kenneth A.

    1988-01-01

    Discusses the question posed by some that the earth's magnetic field may reverse. States that rocks magnetized by ancient fields may offer clues to the underlying reversal mechanism in the earth's core. (TW)

  5. Ancient Magnetic Reversals: Clues to the Geodynamo.

    ERIC Educational Resources Information Center

    Hoffman, Kenneth A.

    1988-01-01

    Discusses the question posed by some that the earth's magnetic field may reverse. States that rocks magnetized by ancient fields may offer clues to the underlying reversal mechanism in the earth's core. (TW)

  6. Novel Design for Reversible Arithmetic Logic Unit

    NASA Astrophysics Data System (ADS)

    Zhou, Rigui; Li, Yancheng; Zhang, Manqun; Hu, BenQiong

    2015-02-01

    Reversible logic circuits are of high interests to calculate with minimum energy consumption having applications in low-power CMOS design, optical computing and nanotechnology, especially in quantum computer. Quantum computer requires quantum arithmetic. A new design of a reversible arithmetic logic unit (reversible ALU) for quantum arithmetic has been proposed in this article. As we known, ALU is an important part of central processing unit (CPU) as the execution unit. So this article provides explicit construction of reversible ALU effecting basic arithmetic operations. By provided the corresponding control unit, the proposed reversible ALU can combine the classical arithmetic and logic operation in a reversible integrated system. This article provides a new more powerful ALU which contains more functions and it will make contribute to the realization of reversible Programmable Logic Device (RPLD) in future using reversible ALU.

  7. 14 CFR 23.933 - Reversing systems.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... systems. (a) For turbojet and turbofan reversing systems. (1) Each system intended for ground operation only must be designed so that, during any reversal in flight, the engine will produce no more than..., or from any failure, or likely combination of failures, of the reversing system under any operating...

  8. 14 CFR 23.933 - Reversing systems.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... systems. (a) For turbojet and turbofan reversing systems. (1) Each system intended for ground operation only must be designed so that, during any reversal in flight, the engine will produce no more than..., or from any failure, or likely combination of failures, of the reversing system under any operating...

  9. 14 CFR 23.933 - Reversing systems.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... systems. (a) For turbojet and turbofan reversing systems. (1) Each system intended for ground operation only must be designed so that, during any reversal in flight, the engine will produce no more than..., or from any failure, or likely combination of failures, of the reversing system under any operating...

  10. 14 CFR 23.933 - Reversing systems.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... systems. (a) For turbojet and turbofan reversing systems. (1) Each system intended for ground operation only must be designed so that, during any reversal in flight, the engine will produce no more than..., or from any failure, or likely combination of failures, of the reversing system under any operating...

  11. 14 CFR 23.933 - Reversing systems.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... systems. (a) For turbojet and turbofan reversing systems. (1) Each system intended for ground operation only must be designed so that, during any reversal in flight, the engine will produce no more than..., or from any failure, or likely combination of failures, of the reversing system under any operating...

  12. 14 CFR 25.933 - Reversing systems.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Reversing systems. 25.933 Section 25.933... STANDARDS: TRANSPORT CATEGORY AIRPLANES Powerplant General § 25.933 Reversing systems. (a) For turbojet reversing systems— (1) Each system intended for ground operation only must be designed so that during any...

  13. Cleaning Our World through Reverse Graffiti

    ERIC Educational Resources Information Center

    Randazzo, Gabe; LaJevic, Lisa

    2013-01-01

    Over the last decade artists have begun to experiment with "reverse pollution" techniques, such as reverse graffiti, which focuses on cleaning environmental surfaces. Having recently been introduced to the works of Moose, the artist known for inventing the reverse graffiti technique, the authors decided to design a curriculum to increase…

  14. Statistical Learning, Letter Reversals, and Reading

    ERIC Educational Resources Information Center

    Treiman, Rebecca; Gordon, Jessica; Boada, Richard; Peterson, Robin L.; Pennington, Bruce F.

    2014-01-01

    Reversal errors play a prominent role in theories of reading disability. We examined reversal errors in the writing of letters by 5- to 6-year-old children. Of the 130 children, 92 had a history of difficulty in producing speech sounds, a risk factor for reading problems. Children were more likely to reverse letter forms that face left, such as…

  15. 14 CFR 25.933 - Reversing systems.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Reversing systems. 25.933 Section 25.933... STANDARDS: TRANSPORT CATEGORY AIRPLANES Powerplant General § 25.933 Reversing systems. (a) For turbojet reversing systems— (1) Each system intended for ground operation only must be designed so that during any...

  16. 14 CFR 25.933 - Reversing systems.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 1 2013-01-01 2013-01-01 false Reversing systems. 25.933 Section 25.933... STANDARDS: TRANSPORT CATEGORY AIRPLANES Powerplant General § 25.933 Reversing systems. (a) For turbojet reversing systems— (1) Each system intended for ground operation only must be designed so that during any...

  17. Cleaning Our World through Reverse Graffiti

    ERIC Educational Resources Information Center

    Randazzo, Gabe; LaJevic, Lisa

    2013-01-01

    Over the last decade artists have begun to experiment with "reverse pollution" techniques, such as reverse graffiti, which focuses on cleaning environmental surfaces. Having recently been introduced to the works of Moose, the artist known for inventing the reverse graffiti technique, the authors decided to design a curriculum to increase…

  18. Remote Whispering Applying Time Reversal

    SciTech Connect

    Anderson, Brian Eric

    2015-07-16

    The purpose of this project was to explore the use of time reversal technologies as a means for communication to a targeted individual or location. The idea is to have the privacy of whispering in one’s ear, but to do this remotely from loudspeakers not located near the target. Applications of this work include communicating with hostages and survivors in rescue operations, communicating imaging and operational conditions in deep drilling operations, monitoring storage of spent nuclear fuel in storage casks without wires, or clandestine activities requiring signaling between specific points. This technology provides a solution in any application where wires and radio communications are not possible or not desired. It also may be configured to self calibrate on a regular basis to adjust for changing conditions. These communications allow two people to converse with one another in real time, converse in an inaudible frequency range or medium (i.e. using ultrasonic frequencies and/or sending vibrations through a structure), or send information for a system to interpret (even allowing remote control of a system using sound). The time reversal process allows one to focus energy to a specific location in space and to send a clean transmission of a selected signal only to that location. In order for the time reversal process to work, a calibration signal must be obtained. This signal may be obtained experimentally using an impulsive sound, a known chirp signal, or other known signals. It may also be determined from a numerical model of a known environment in which the focusing is desired or from passive listening over time to ambient noise.

  19. Reversible Photoswitching of Carbon Dots

    PubMed Central

    Khan, Syamantak; Verma, Navneet Chandra; Gupta, Abhishek; Nandi, Chayan Kanti

    2015-01-01

    We present a method of reversible photoswitching in carbon nanodots with red emission. A mechanism of electron transfer is proposed. The cationic dark state, formed by the exposure of red light, is revived back to the bright state with the very short exposure of blue light. Additionally, the natural on-off state of carbon dot fluorescence was tuned using an electron acceptor molecule. Our observation can make the carbon dots as an excellent candidate for the super-resolution imaging of nanoscale biomolecules within the cell. PMID:26078266

  20. Lower lateral crural reverse plasty.

    PubMed

    Kubilay, Utku; Azizli, Elad; Erdoğdu, Suleyman

    2013-11-01

    The lateral crus plays a significant role in the aesthetic appearance of the nose. Excessive concavities of the lower lateral crura can lead to heavy aesthetic disfigurement of the nasal tip and to insufficiencies of the external nasal valve. The lateral crus of the alar cartilage may also cause a concavity of the alar rim and even collapse of the alar rim in severe cases. Surgical techniques performed on the lateral crus help to treat both functional and aesthetic deformities of the lateral nasal tip. We present a reverse plasty technique for the lateral crus, and we evaluated the advantages and disadvantages of the technique.

  1. Theta, time reversal and temperature

    DOE PAGES

    Gaiotto, Davide; Kapustin, Anton; Komargodski, Zohar; ...

    2017-05-17

    SU(N) gauge theory is time reversal invariant at θ = 0 and θ = π. We show that at θ = π there is a discrete ’t Hooft anomaly involving time reversal and the center symmetry. This anomaly leads to constraints on the vacua of the theory. It follows that at θ = π the vacuum cannot be a trivial non-degenerate gapped state. (By contrast, the vacuum at θ = 0 is gapped, non-degenerate, and trivial.) Due to the anomaly, the theory admits nontrivial domain walls supporting lower-dimensional theories. Depending on the nature of the vacuum at θ = π,more » several phase diagrams are possible. Assuming area law for space-like loops, one arrives at an inequality involving the temperatures at which CP and the center symmetry are restored. We also analyze alternative scenarios for SU(2) gauge theory. The underlying symmetry at θ = π is the dihedral group of 8 elements. If deconfined loops are allowed, one can have two O(2)-symmetric fixed points. In conclusion, it may also be that the four-dimensional theory around θ = π is gapless, e.g. a Coulomb phase could match the underlying anomalies.« less

  2. Steganography using reversible texture synthesis.

    PubMed

    Wu, Kuo-Chen; Wang, Chung-Ming

    2015-01-01

    We propose a novel approach for steganography using a reversible texture synthesis. A texture synthesis process resamples a smaller texture image, which synthesizes a new texture image with a similar local appearance and an arbitrary size. We weave the texture synthesis process into steganography to conceal secret messages. In contrast to using an existing cover image to hide messages, our algorithm conceals the source texture image and embeds secret messages through the process of texture synthesis. This allows us to extract the secret messages and source texture from a stego synthetic texture. Our approach offers three distinct advantages. First, our scheme offers the embedding capacity that is proportional to the size of the stego texture image. Second, a steganalytic algorithm is not likely to defeat our steganographic approach. Third, the reversible capability inherited from our scheme provides functionality, which allows recovery of the source texture. Experimental results have verified that our proposed algorithm can provide various numbers of embedding capacities, produce a visually plausible texture images, and recover the source texture.

  3. Exercise prescription to reverse frailty.

    PubMed

    Bray, Nick W; Smart, Rowan R; Jakobi, Jennifer M; Jones, Gareth R

    2016-10-01

    Frailty is a clinical geriatric syndrome caused by physiological deficits across multiple systems. These deficits make it challenging to sustain homeostasis required for the demands of everyday life. Exercise is likely the best therapy to reverse frailty status. Literature to date suggests that pre-frail older adults, those with 1-2 deficits on the Cardiovascular Health Study-Frailty Phenotype (CHS-frailty phenotype), should exercise 2-3 times a week, for 45-60 min. Aerobic, resistance, flexibility, and balance training components should be incorporated but resistance and balance activities should be emphasized. On the other hand, frail (CHS-frailty phenotype ≥ 3 physical deficits) older adults should exercise 3 times per week, for 30-45 min for each session with an emphasis on aerobic training. During aerobic, balance, and flexibility training, both frail and pre-frail older adults should work at an intensity equivalent to a rating of perceived exertion of 3-4 ("somewhat hard") on the Borg CR10 scale. Resistance-training intensity should be based on a percentage of 1-repetition estimated maximum (1RM). Program onset should occur at 55% of 1RM (endurance) and progress to higher intensities of 80% of 1RM (strength) to maximize functional gains. Exercise is the medicine to reverse or mitigate frailty, preserve quality of life, and restore independent functioning in older adults at risk of frailty.

  4. Theta, time reversal and temperature

    NASA Astrophysics Data System (ADS)

    Gaiotto, Davide; Kapustin, Anton; Komargodski, Zohar; Seiberg, Nathan

    2017-05-01

    SU( N ) gauge theory is time reversal invariant at θ = 0 and θ = π. We show that at θ = π there is a discrete 't Hooft anomaly involving time reversal and the center symmetry. This anomaly leads to constraints on the vacua of the theory. It follows that at θ = π the vacuum cannot be a trivial non-degenerate gapped state. (By contrast, the vacuum at θ = 0 is gapped, non-degenerate, and trivial.) Due to the anomaly, the theory admits nontrivial domain walls supporting lower-dimensional theories. Depending on the nature of the vacuum at θ = π, several phase diagrams are possible. Assuming area law for space-like loops, one arrives at an inequality involving the temperatures at which CP and the center symmetry are restored. We also analyze alternative scenarios for SU(2) gauge theory. The underlying symmetry at θ = π is the dihedral group of 8 elements. If deconfined loops are allowed, one can have two O(2)-symmetric fixed points. It may also be that the four-dimensional theory around θ = π is gapless, e.g. a Coulomb phase could match the underlying anomalies.

  5. Preference reversal in multiattribute choice.

    PubMed

    Tsetsos, Konstantinos; Usher, Marius; Chater, Nick

    2010-10-01

    A central puzzle for theories of choice is that people's preferences between options can be reversed by the presence of decoy options (that are not chosen) or by the presence of other irrelevant options added to the choice set. Three types of reversal effect reported in the decision-making literature, the attraction, compromise, and similarity effects, have been explained by a number of theoretical proposals. Yet a major theoretical challenge is capturing all 3 effects simultaneously. We review the range of mechanisms that have been proposed to account for decoy effects and analyze in detail 2 computational models, decision field theory (Roe, Busemeyer, & Townsend, 2001) and leaky competing accumulators (Usher & McClelland, 2004), that aim to combine several such mechanisms into an integrated account. By simulating the models, we examine differences in the ways the decoy effects are predicted. We argue that the LCA framework, which follows on Tversky's relational evaluation with loss aversion (Tversky & Kahneman, 1991), provides a more robust account, suggesting that common mechanisms are involved in both high-level decision making and perceptual choice, for which LCA was originally developed.

  6. Reversing invasion in bistable systems.

    PubMed

    Alzahrani, Ebraheem O; Davidson, Fordyce A; Dodds, Niall

    2012-12-01

    In this paper, we discuss a class of bistable reaction-diffusion systems used to model the competitive interaction of two species. The interactions are assumed to be of classic "Lotka-Volterra" type and we will consider a particular problem with relevance to applications in population dynamics: essentially, we study under what conditions the interplay of relative motility (diffusion) and competitive strength can cause waves of invasion to be halted and reversed. By establishing rigorous results concerning related degenerate and near-degenerate systems, we build a picture of the dependence of the wave speed on system parameters. Our results lead us to conjecture that this class of competition model has three "zones of response". In the central zone, varying the motility can slow, halt and reverse invasion. However, in the two outer zones, the direction of invasion is independent of the relative motility and is entirely determined by the relative competitive strengths. Furthermore, we conjecture that for a large class of competition models of the type studied here, the wave speed is an increasing function of the relative motility.

  7. Pronoun reversals: who, when, and why?

    PubMed

    Dale, P S; Crain-Thoreson, C

    1993-10-01

    Seventeen of a sample of 30 precocious talkers aged 1;8 produced at least one pronoun reversal (I/you) during unstructured play. This finding led to an examination of the role of cognitive and linguistic individual differences as well as contextual factors and processing complexity as determinants of pronoun reversal. Contrary to predictions derived from previous hypotheses, there were few differences between reversers and non-reversers, other than higher use of second person forms by reversers. Reversals were more likely to occur in certain contexts: semantically reversible predicates with two noun phrases, and in imitations (though the rate of imitation was lower overall in reversers). We propose that pronoun reversals commonly result from a failure to perform a deictic shift, which is especially likely when children's psycholinguistic processing resources are taxed. Children who did not produce any pronoun reversals tended to avoid pronoun use, especially second person forms. Overt reversal may thus reflect a risk-taking approach to language acquisition, which may be particularly characteristic of precocious children.

  8. Time reversal for modified oscillators

    NASA Astrophysics Data System (ADS)

    Cordero-Soto, R.; Suslov, S. K.

    2010-03-01

    We consider a new completely integrable case of the time-dependent Schrödinger equation in ®n with variable coefficients for a modified oscillator that is dual (with respect to time reversal) to a model of the quantum oscillator. We find a second pair of dual Hamiltonians in the momentum representation. The examples considered show that in mathematical physics and quantum mechanics, a change in the time direction may require a total change of the system dynamics to return the system to its original quantum state. We obtain particular solutions of the corresponding nonlinear Schrödinger equations. We also consider a Hamiltonian structure of the classical integrable problem and its quantization.

  9. Reversible Watermarking Surviving JPEG Compression.

    PubMed

    Zain, J; Clarke, M

    2005-01-01

    This paper will discuss the properties of watermarking medical images. We will also discuss the possibility of such images being compressed by JPEG and give an overview of JPEG compression. We will then propose a watermarking scheme that is reversible and robust to JPEG compression. The purpose is to verify the integrity and authenticity of medical images. We used 800x600x8 bits ultrasound (US) images in our experiment. SHA-256 of the image is then embedded in the Least significant bits (LSB) of an 8x8 block in the Region of Non Interest (RONI). The image is then compressed using JPEG and decompressed using Photoshop 6.0. If the image has not been altered, the watermark extracted will match the hash (SHA256) of the original image. The result shown that the embedded watermark is robust to JPEG compression up to image quality 60 (~91% compressed).

  10. Reversible optical doping of graphene

    PubMed Central

    Tiberj, A.; Rubio-Roy, M.; Paillet, M.; Huntzinger, J. -R.; Landois, P.; Mikolasek, M.; Contreras, S.; Sauvajol, J. -L.; Dujardin, E.; Zahab, A. -A.

    2013-01-01

    The ultimate surface exposure provided by graphene monolayer makes it the ideal sensor platform but also exposes its intrinsic properties to any environmental perturbations. In this work, we demonstrate that the charge carrier density of graphene exfoliated on a SiO2/Si substrate can be finely and reversibly tuned between hole and electron doping with visible photons. This photo-induced doping happens under moderate laser power conditions but is significantly affected by the substrate cleaning method. In particular, it requires hydrophilic substrates and vanishes for suspended graphene. These findings suggest that optically gated graphene devices operating with a sub-second time scale can be envisioned and that Raman spectroscopy is not always as non-invasive as generally assumed. PMID:23912707

  11. Multiple genome rearrangement by reversals.

    PubMed

    Wu, Shiquan; Gu, Xun

    2002-01-01

    In this paper, we discuss a multiple genome rearrangement problem: Given a collection of genomes represented by permutations, we generate the collection from some fixed genome, e.g., the identity permutation, in a minimum number of signed reversals. It is NP-hard, so efficient heuristics is important for finding its optimal solution. We at first discuss how to generate two and three genomes from a fixed genome by polynomial algorithms for some special cases. Then based on the polynomial algorithms, we obtain some approximation algorithms for generating two and three genomes in general, respectively. Finally, we apply these approximation algorithms to design a new approximation algorithm for generating more genomes. We also show by some experimental examples that the algorithms are efficient.

  12. Fluorescence-based reversible immunosensors

    NASA Astrophysics Data System (ADS)

    Issachar, David; Rao, Srivasta V.; Ho, Winston; Kempen, Lothar U.; Wang, Allan Z.; Gasca, Rebecca; Lieberman, Robert A.

    1999-02-01

    All immunosensors currently described in literature are irreversible. Intelligent Optical Systems, Inc. has developed a revolutionary method for producing reversible immunosensors. In this method, the antibody and a labeled analog (structurally and functionally similar to the antigen) are coimmobilized on the sensor surface. Under equilibrium conditions, the labeled analog interacts with immobilized antibody to produce a sensor response. However, in the presence of antigen (analyte), the equilibrium is disturbed as the analyte competes for the binding sites of the immobilized antibody. This produces a measurable sensor response. The equilibrium is shifted back by washing the analyte away with a wash buffer, and the bound analog interacts with the immobilized antibody. Polarization and intensity based measurements are used to design the analog. Photoinduced electron transfer is used to create fluorescent analogs that provide enhancements in fluorescence intensity that can be measured. This principle can be extended to the detection of bacteria.

  13. Reversible airflow obstruction in lymphangioleiomyomatosis.

    PubMed

    Taveira-DaSilva, Angelo M; Steagall, Wendy K; Rabel, Antoinette; Hathaway, Olanda; Harari, Sergio; Cassandro, Roberto; Stylianou, Mario; Moss, Joel

    2009-12-01

    We previously reported that approximately one-fourth of patients with lymphangioleiomyomatosis (LAM) may respond to therapy with bronchodilators. However, the validity of those observations has been questioned. The aims of the present study were to determine the prevalence of reversible airflow obstruction in patients with LAM and to identify associated clinical and physiologic parameters. First, the clinical and physiologic characteristics of 235 patients were analyzed to determine the frequency of the response to albuterol during a total of 2,307 visits. Second, we prospectively evaluated the response to albuterol (2.5 mg) and ipratropium (500 mug) in 130 patients, and correlated their responses with their clinical and physiologic characteristics. In the retrospective study, 51% of the patients responded at least once to bronchodilators; of these, 12% responded >/= 50% of the time. A higher frequency of positive bronchodilator responses was associated with greater rates of decline in FEV(1) and diffusing capacity of the lung for carbon monoxide (Dlco). In the prospective study, 39 patients (30%) responded to bronchodilators, including 12 to ipratropium, 9 to albuterol, and 18 to both. The prevalence of asthma and smoking in the 39 responders was not different from that seen in the 91 nonresponders. Patients who responded to ipratropium, albuterol, or both had significantly (p < 0.02) lower FEV(1) and Dlco, and a greater rate of FEV(1) decline (p = 0.044) and Dlco decline (p = 0.039) than patients who did not respond to these bronchodilators. After adjusting for FEV(1)/FVC ratio, Dlco decline also was greater in responders than in nonresponders (p = 0.009). Patients with LAM may have partially reversible airflow obstruction. A positive response to bronchodilators is associated with an accelerated rate of decline in pulmonary function.

  14. Process of forming compounds using reverse micelle or reverse microemulsion systems

    DOEpatents

    Linehan, John C.; Fulton, John L.; Bean, Roger M.

    1998-01-01

    The present invention is directed to a process for producing a nanometer-sized metal compound. The process comprises forming a reverse micelle or reverse microemulsion system comprising a polar fluid in a non-polar or low-polarity fluid. A first reactant comprising a multi-component, water-soluble metal compound is introduced into the polar fluid in a non-polar or low-polarity fluid. This first reactant can be introduced into the reverse micelle or reverse microemulsion system during formation thereof or subsequent to the formation of the reverse micelle or microemulsion system. The water-soluble metal compound is then reacted in the reverse micelle or reverse microemulsion system to form the nanometer-sized metal compound. The nanometer-sized metal compound is then precipitated from the reverse micelle or reverse microemulsion system.

  15. Reverse Pressure Capable Finger Seal (Preprint)

    DTIC Science & Technology

    2012-01-01

    Currently, the typical solution for locations requiring reverse capable sealing are labyrinth seals which can exhibit significantly higher leakage...AFRL-RX-WP-TP-2012-0215 REVERSE PRESSURE CAPABLE FINGER SEAL (PREPRINT) Nathan Gibson and Joe Yanof Honeywell International, Inc...AND SUBTITLE REVERSE PRESSURE CAPABLE FINGER SEAL (PREPRINT) 5a. CONTRACT NUMBER FA8650-09-D-2925-0003 5b. GRANT NUMBER 5c. PROGRAM ELEMENT

  16. Reverse polarization in conjugated heterocycle polythiophene

    NASA Astrophysics Data System (ADS)

    Wang, Lu-Xia; Liu, De-Sheng; Zhang, Da-Cheng; Xie, Shi-Jie; Han, Sheng-Hao; Mei, Liang-Mo

    2005-01-01

    Reverse polarization in polythiophene under an applied electric field has been studied in the framework of the tight-binding model. It is found that the applied electronic field has a great influence on the excited states of polythiophene. The effect of the heteroatoms on the polarization has been calculated and analysed carefully. It is indicated that a reverse polarization of biexcitons in polythiophene will be observed more easily. The heteroatoms increase this reversed polarization strength apparently.

  17. Reversibility of a Symmetric Linear Cellular Automata

    NASA Astrophysics Data System (ADS)

    Del Rey, A. Martín; Sánchez, G. Rodríguez

    The characterization of the size of the cellular space of a particular type of reversible symmetric linear cellular automata is introduced in this paper. Specifically, it is shown that those symmetric linear cellular with 2k + 1 cells, and whose transition matrix is a k-diagonal square band matrix with nonzero entries equal to 1 are reversible. Furthermore, in this case the inverse cellular automata are explicitly computed. Moreover, the reversibility condition is also studied for a general number of cells.

  18. Gravity controlled anti-reverse rotation device

    DOEpatents

    Dickinson, Robert J.; Wetherill, Todd M.

    1983-01-01

    A gravity assisted anti-reverse rotation device for preventing reverse rotation of pumps and the like. A horizontally mounted pawl is disposed to mesh with a fixed ratchet preventing reverse rotation when the pawl is advanced into intercourse with the ratchet by a vertically mounted lever having a lumped mass. Gravitation action on the lumped mass urges the pawl into mesh with the ratchet, while centrifugal force on the lumped mass during forward, allowed rotation retracts the pawl away from the ratchet.

  19. Reversibility of Sympathectomy for Primary Hyperhidrosis.

    PubMed

    Hynes, Conor F; Marshall, M Blair

    2016-11-01

    Endoscopic thoracic sympathectomy (ETS) is an effective treatment of primary hyperhidrosis of the face, upper extremities, and axillae. The major limitation is the side effect of compensatory sweating severe enough that patients request reversal in up to 10% of cases. When ETS is performed by cutting the sympathetic chain, reversal requires nerve grafting. However, for ETS done with clips, reversal is a simple thoracoscopic outpatient procedure of removing the clips. Subsequent reversal of the sympathectomy, ie, nerve regeneration, is successful in many cases. However, follow-up is short. Factors contributing to success rates require further study. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Reversal of liver cirrhosis in autoimmune hepatitis.

    PubMed

    Shah, Anish M; Malhotra, Ashish; Kothari, Shivangi; Baddoura, Walid; Depasquale, Joseph; Spira, Robert

    2011-01-01

    Liver cirrhosis is generally considered irreversible but there are reports in which there is documented reversal of fibrosis/cirrhosis in various clinical conditions like Wilson's disease, hemochromatosis, primary biliary cirrhosis and autoimmune hepatitis. The subgroup of patients with autoimmune hepatitis that will have reversal of cirrhosis is not known. We present two cases with documented liver cirrhosis that had reversal of cirrhosis after treatment with immunosuppressive agents. We postulate that patients presenting with acute hepatitis and no other fibrogenic factors have higher chances of reversal of liver cirrhosis as compared to those presenting as chronic liver injury.

  1. On the regimes of charge reversal.

    PubMed

    Jiménez-Angeles, Felipe; Lozada-Cassou, Marcelo

    2008-05-07

    Charge reversal of the planar electrical double layer is studied by means of a well known integral equation theory. By a numerical analysis, a diagram is constructed with the onset points of charge reversal in the space of the fundamental variables of the system. Within this diagram, two regimes of charge reversal are identified, which are referred to as oscillatory and nonoscillatory. We found that these two regimes can be distinguished through a simple formula. Furthermore, a symmetry between electrostatic and size correlations in charge reversal is exhibited. Agreement of our results with other theories and molecular simulations data is discussed.

  2. Profile of women undergoing reversal of sterilisation.

    PubMed

    Desai, P; Barbhaya, M; Desai, M; Modi, D

    1998-04-01

    Two hundred twenty women who were subjected to reversal of female sterilisation over 7 years were analysed. It was found that death of the male child was the strongest reason for seeking a reversal. This was coupled with the parity of these subjects being two or less in 70% instances at the time of primary sterilisation surgery. Nearly 85.9% reversal were sought in the higher age groups clubbed together. This has an adverse bearing on success of reversal surgery as the fertility potential of a woman declines physiologically as age advances.

  3. Reverse ethnopharmacology and drug discovery.

    PubMed

    Leonti, Marco; Stafford, Gary I; Cero, Maja Dal; Cabras, Stefano; Castellanos, Maria Eugenia; Casu, Laura; Weckerle, Caroline S

    2017-02-23

    Ethnopharmacological investigations of traditional medicines have made significant contributions to plant-derived drugs, as well as the advancement of pharmacology. Drug discovery from medicinal flora is more complex than generally acknowledged because plants are applied for different therapeutic indications within and across cultures. Therefore we propose the concept of "reverse ethnopharmacology" and compare biomedical uses of plant taxa with their ethnomedicinal and popular uses and test the effect of these on the probability of finding biomedical and specifically anticancer drugs. For this analysis we use data on taxonomy and medical indications of plant derived biomedical drugs, clinical trial, and preclinical trial drug candidates published by Zhu et al. (2011) and compare their therapeutic indications with their ethnomedicinal and popular uses as reported in the NAPRALERT(®) database. Specifically, we test for increase or decrease of the probability of finding anticancer drugs based on ethnomedicinal and popular reports with Bayesian logistic regression analyses. Anticancer therapy resulted as the most frequent biomedicinal indication of the therapeutics derived from the 225 drug producing higher plant taxa and showed an association with ethnomedicinal and popular uses in women's medicine, which was also the most important popular use-category. Popular remedies for dysmenorrhoea, and uses as emmenagogues, abortifacients and contraceptives showed a positive effect on the probability of finding anticancer drugs. Another positive effect on the probability of discovering anticancer therapeutics was estimated for popular herbal drugs associated with the therapy of viral and bacterial infections, while the highest effect was found for popular remedies used to treat cancer symptoms. However, this latter effect seems to be influenced by the feedback loop and divulgence of biomedical knowledge on the popular level. We introduce the concept of reverse

  4. The Reverse Statistical Disclosure Attack

    NASA Astrophysics Data System (ADS)

    Mallesh, Nayantara; Wright, Matthew

    Statistical disclosure is a well-studied technique that an attacker can use to uncover relations between users in mix-based anonymity systems. Prior work has focused on finding the receivers to whom a given targeted user sends. In this paper, we investigate the effectiveness of statistical disclosure in finding all of a users' contacts, including those from whom she receives messages. To this end, we propose a new attack called the Reverse Statistical Disclosure Attack (RSDA). RSDA uses observations of all users sending patterns to estimate both the targeted user's sending pattern and her receiving pattern. The estimated patterns are combined to find a set of the targeted user's most likely contacts. We study the performance of RSDA in simulation using different mix network configurations and also study the effectiveness of cover traffic as a countermeasure. Our results show that that RSDA outperforms the traditional SDA in finding the user's contacts, particularly as the amounts of user traffic and cover traffic rise.

  5. Reverse engineering adverse outcome pathways.

    PubMed

    Perkins, Edward J; Chipman, J Kevin; Edwards, Stephen; Habib, Tanwir; Falciani, Francesco; Taylor, Ronald; Van Aggelen, Graham; Vulpe, Chris; Antczak, Philipp; Loguinov, Alexandre

    2011-01-01

    The toxicological effects of many stressors are mediated through unknown, or incompletely characterized, mechanisms of action. The application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, metabolic, signaling) can be used to overcome these limitations. This approach was used to characterize adverse outcome pathways (AOPs) for chemicals that disrupt the hypothalamus-pituitary-gonadal endocrine axis in fathead minnows (FHM, Pimephales promelas). Gene expression changes in FHM ovaries in response to seven different chemicals, over different times, doses, and in vivo versus in vitro conditions, were captured in a large data set of 868 arrays. Potential AOPs of the antiandrogen flutamide were examined using two mutual information-based methods to infer gene regulatory networks and potential AOPs. Representative networks from these studies were used to predict network paths from stressor to adverse outcome as candidate AOPs. The relationship of individual chemicals to an adverse outcome can be determined by following perturbations through the network in response to chemical treatment, thus leading to the nodes associated with the adverse outcome. Identification of candidate pathways allows for formation of testable hypotheses about key biological processes, biomarkers, or alternative endpoints that can be used to monitor an AOP. Finally, the unique challenges facing the application of this approach in ecotoxicology were identified and a road map for the utilization of these tools presented.

  6. Entropic uncertainty and measurement reversibility

    NASA Astrophysics Data System (ADS)

    Berta, Mario; Wehner, Stephanie; Wilde, Mark M.

    2015-11-01

    The entropic uncertainty relation with quantum side information (EUR-QSI) from [Berta et al., Nat. Phys. 6, 659 (2010)] is a unifying principle relating two distinctive features of quantum mechanics: quantum uncertainty due to measurement incompatibility, and entanglement. In these relations, quantum uncertainty takes the form of preparation uncertainty where one of two incompatible measurements is applied. In particular, the "uncertainty witness" lower bound in the EUR-QSI is not a function of a post-measurement state. An insightful proof of the EUR-QSI from [Coles et al., Phys. Rev. Lett. 108, 210405 (2012)] makes use of a fundamental mathematical consequence of the postulates of quantum mechanics known as the non-increase of quantum relative entropy under quantum channels. Here, we exploit this perspective to establish a tightening of the EUR-QSI which adds a new state-dependent term in the lower bound, related to how well one can reverse the action of a quantum measurement. As such, this new term is a direct function of the post-measurement state and can be thought of as quantifying how much disturbance a given measurement causes. Our result thus quantitatively unifies this feature of quantum mechanics with the others mentioned above. We have experimentally tested our theoretical predictions on the IBM Quantum Experience and find reasonable agreement between our predictions and experimental outcomes.

  7. Reverse Genetics in Ecological Research

    PubMed Central

    Schwachtje, Jens; Kutschbach, Susan; Baldwin, Ian T.

    2008-01-01

    By precisely manipulating the expression of individual genetic elements thought to be important for ecological performance, reverse genetics has the potential to revolutionize plant ecology. However, untested concerns about possible side-effects of the transformation technique, caused by Agrobacterium infection and tissue culture, on plant performance have stymied research by requiring onerous sample sizes. We compare 5 independently transformed Nicotiana attenuata lines harboring empty vector control (EVC) T-DNA lacking silencing information with isogenic wild types (WT), and measured a battery of ecologically relevant traits, known to be important in plant-herbivore interactions: phytohormones, secondary metabolites, growth and fitness parameters under stringent competitive conditions, and transcriptional regulation with microarrays. As a positive control, we included a line silenced in trypsin proteinase inhibitor gene (TPI) expression, a potent anti-herbivore defense known to exact fitness costs in its expression, in the analysis. The experiment was conducted twice, with 10 and 20 biological replicates per genotype. For all parameters, we detected no difference between any EVC and WT lines, but could readily detect a fitness benefit of silencing TPI production. A statistical power analyses revealed that the minimum sample sizes required for detecting significant fitness differences between EVC and WT was 2–3 orders of magnitude larger than the 10 replicates required to detect a fitness effect of TPI silencing. We conclude that possible side-effects of transformation are far too low to obfuscate the study of ecologically relevant phenotypes. PMID:18253491

  8. Reversing expectations during discourse comprehension

    PubMed Central

    Xiang, Ming; Kuperberg, Gina

    2014-01-01

    In two ERP experiments, we asked whether comprehenders used the concessive connective, even so, to predict upcoming events. Participants read coherent and incoherent scenarios, with and without even so, e.g. “Elizabeth had a history exam on Monday. She took the test and aced/failed it. (Even so), she went home and celebrated wildly.”, as they rated coherence (Experiment 1) or simply answered intermittent comprehension questions (Experiment 2). The semantic function of even so was used to reverse real-world knowledge predictions, leading to an attenuated N400 to coherent versus incoherent target words (“celebrated”). Moreover, its pragmatic communicative function enhanced predictive processing, leading to more N400 attenuation to coherent targets in scenarios with than without even so. This benefit however, did not come for free: the detection of failed event predictions triggered a later posterior positivity and/or an anterior negativity effect, and costs of maintaining alternative likelihood relations manifest as a sustained negativity effect on sentence-final words. PMID:25914891

  9. Reverse Engineering Adverse Outcome Pathways

    SciTech Connect

    Perkins, Edward; Chipman, J.K.; Edwards, Stephen; Habib, Tanwir; Falciani, Francesco; Taylor, Ronald C.; Van Aggelen, Graham; Vulpe, Chris; Antczak, Philipp; Loguinov, Alexandre

    2011-01-30

    The toxicological effects of many stressors are mediated through unknown, or poorly characterized, mechanisms of action. We describe the application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, metabolic, signaling) to characterize adverse outcome pathways (AOPs) for chemicals that disrupt the hypothalamus-pituitary-gonadal endocrine axis in fathead minnows. Gene expression changes in fathead minnow ovaries in response to 7 different chemicals, over different times, doses, and in vivo versus in vitro conditions were captured in a large data set of 868 arrays. We examined potential AOPs of the antiandrogen flutamide using two mutual information theory methods, ARACNE and CLR to infer gene regulatory networks and potential adverse outcome pathways. Representative networks from these studies were used to predict a network path from stressor to adverse outcome as a candidate AOP. The relationship of individual chemicals to an adverse outcome can be determined by following perturbations through the network in response to chemical treatment leading to the nodes associated with the adverse outcome. Identification of candidate pathways allows for formation of testable hypotheses about key biologic processes, biomarkers or alternative endpoints, which could be used to monitor an adverse outcome pathway. Finally, we identify the unique challenges facing the application of this approach in ecotoxicology, and attempt to provide a road map for the utilization of these tools. Key Words: mechanism of action, toxicology, microarray, network inference

  10. Entropic uncertainty and measurement reversibility

    NASA Astrophysics Data System (ADS)

    Berta, Mario; Wehner, Stephanie; Wilde, Mark M.

    2016-07-01

    The entropic uncertainty relation with quantum side information (EUR-QSI) from (Berta et al 2010 Nat. Phys. 6 659) is a unifying principle relating two distinctive features of quantum mechanics: quantum uncertainty due to measurement incompatibility, and entanglement. In these relations, quantum uncertainty takes the form of preparation uncertainty where one of two incompatible measurements is applied. In particular, the ‘uncertainty witness’ lower bound in the EUR-QSI is not a function of a post-measurement state. An insightful proof of the EUR-QSI from (Coles et al 2012 Phys. Rev. Lett. 108 210405) makes use of a fundamental mathematical consequence of the postulates of quantum mechanics known as the non-increase of quantum relative entropy under quantum channels. Here, we exploit this perspective to establish a tightening of the EUR-QSI which adds a new state-dependent term in the lower bound, related to how well one can reverse the action of a quantum measurement. As such, this new term is a direct function of the post-measurement state and can be thought of as quantifying how much disturbance a given measurement causes. Our result thus quantitatively unifies this feature of quantum mechanics with the others mentioned above. We have experimentally tested our theoretical predictions on the IBM quantum experience and find reasonable agreement between our predictions and experimental outcomes.

  11. Reversible temperature exchange upon thermal contact

    NASA Astrophysics Data System (ADS)

    Mishchenko, Eugene G.; Pshenichka, Paul F.

    2017-01-01

    According to a well-known principle of thermodynamics, the transfer of heat between two bodies is reversible when their temperatures are infinitesimally close. As we demonstrate, a little-known alternative exists: two bodies with temperatures different by an arbitrary amount can completely exchange their temperatures in a reversible way if split into infinitesimal parts that are brought into thermal contact sequentially.

  12. Reversible logic gates on Physarum Polycephalum

    SciTech Connect

    Schumann, Andrew

    2015-03-10

    In this paper, we consider possibilities how to implement asynchronous sequential logic gates and quantum-style reversible logic gates on Physarum polycephalum motions. We show that in asynchronous sequential logic gates we can erase information because of uncertainty in the direction of plasmodium propagation. Therefore quantum-style reversible logic gates are more preferable for designing logic circuits on Physarum polycephalum.

  13. Reversible logic circuits made of DNA.

    PubMed

    Genot, Anthony J; Bath, Jonathan; Turberfield, Andrew J

    2011-12-21

    We report reversible logic circuits made of DNA. The circuits are based on an AND gate that is designed to be thermodynamically and kinetically reversible and to respond nonlinearly to the concentrations of its input molecules. The circuits continuously recompute their outputs, allowing them to respond to changing inputs. They are robust to imperfections in their inputs. © 2011 American Chemical Society

  14. Szilard engine reversibility as quantum gate function

    NASA Astrophysics Data System (ADS)

    Mihelic, F. Matthew

    2012-06-01

    A quantum gate is a logically and thermodynamically reversible situation that effects a unitary transformation of qubits of superimposed information, and essentially constitutes a situation for a reversible quantum decision. A quantum decision is a symmetry break, and the effect of the function of a Szilard engine is a symmetry break. A quantum gate is a situation in which a reversible quantum decision can be made, and so if a logically and thermodynamically reversible Szilard engine can be theoretically constructed then it would function as a quantum gate. While the traditionally theorized Szilard engine is not thermodynamically reversible, if one of the bounding walls of a Szilard engine were to be constructed out of the physical information by which it functions in such a manner as to make that information available to both sides of the wall simultaneously, then such a Szilard engine would be both logically and thermodynamically reversible, and thus capable of function as a quantum gate. A theoretical model of the special case of a reversible Szilard engine functioning as a quantum gate is presented and discussed, and since a quantum decision is made when the shutter of a Szilard engine closes, the coherence of linked reversible Szilard engines should be considered as a state during which all of the shutters of linked Szilard engines are open simultaneously.

  15. Reversing Africa's Decline. Worldwatch Paper 65.

    ERIC Educational Resources Information Center

    Brown, Lester R.; Wolf, Edward C.

    This paper highlights some of the themes that any successful strategy to reverse the decline of Africa must embrace. Africa is a continent experiencing a breakdown in the relationship between people and their natural support systems. Famine and the threat of famine are among the manifestations of this breakdown. This decline can be reversed. To do…

  16. Reverse design of the automatic transmission case

    NASA Astrophysics Data System (ADS)

    Li, Yuan; Li, Yuan; Wu, Jiao; Jiang, Wangping; Zhang, Zhou

    2017-04-01

    The 3D point cloud data of the AT case are achieved by 3D scanning, and the 3D model are set up by multi-curve-surface reverse design method. The free modal FEM model of the case is built, the modal frequencies and the modes of first 6 orders show that the reverse design model meets the design requirements.

  17. Multiple Reversal Olfactory Learning in Honeybees

    PubMed Central

    Mota, Theo; Giurfa, Martin

    2010-01-01

    In multiple reversal learning, animals trained to discriminate a reinforced from a non-reinforced stimulus are subjected to various, successive reversals of stimulus contingencies (e.g. A+ vs. B−, A− vs. B+, A+ vs. B−). This protocol is useful to determine whether or not animals “learn to learn” and solve successive discriminations faster (or with fewer errors) with increasing reversal experience. Here we used the olfactory conditioning of proboscis extension reflex to study how honeybees Apis mellifera perform in a multiple reversal task. Our experiment contemplated four consecutive differential conditioning phases involving the same odors (A+ vs. B− to A− vs. B+ to A+ vs. B− to A− vs. B+). We show that bees in which the weight of reinforced or non-reinforced stimuli was similar mastered the multiple olfactory reversals. Bees which failed the task exhibited asymmetric responses to reinforced and non-reinforced stimuli, thus being unable to rapidly reverse stimulus contingencies. Efficient reversers did not improve their successive discriminations but rather tended to generalize their choice to both odors at the end of conditioning. As a consequence, both discrimination and reversal efficiency decreased along experimental phases. This result invalidates a learning-to-learn effect and indicates that bees do not only respond to the actual stimulus contingencies but rather combine these with an average of past experiences with the same stimuli. PMID:20700501

  18. Remendable Polymeric Materials Using Reversible Covalent Bonds

    DTIC Science & Technology

    2008-12-01

    Novel Polymeric Dienes and Dienophiles: Synthesis of Reversibly Cross- Linked Elastomers . Macromolecules, 35, 7246- 7253. Goiti, E., M. Huglin, and J...Materials and Nanotechnology in Engineering. Edited by Du, 6423, 112. Liu, Y., and Y. Chen, 2007: Thermally Reversible Cross- Linked Polyamides with...High Toughness and Self- Repairing Ability from Maleimide- and Furan- Functionalized Aromatic Polyamides . Macromolecular Chemistry and Physics, 208

  19. Reversed flow above a plate with suction

    NASA Technical Reports Server (NTRS)

    Lin, S. P.; Tobak, M.

    1986-01-01

    A minor extension is developed for Kovasznay's (1948) solution, and an exact solution is presented for Navier-Stokes equations that may represent the reversed flow about a flat plate with suction. This exact solution is the result of a search for a solution that may serve as an exact basic flow for a model stability analysis of nonparallel flows involving flow reversal.

  20. Magnetic reversals from planetary dynamo waves.

    PubMed

    Sheyko, Andrey; Finlay, Christopher C; Jackson, Andrew

    2016-11-24

    A striking feature of many natural dynamos is their ability to undergo polarity reversals. The best documented example is Earth's magnetic field, which has reversed hundreds of times during its history. The origin of geomagnetic polarity reversals lies in a magnetohydrodynamic process that takes place in Earth's core, but the precise mechanism is debated. The majority of numerical geodynamo simulations that exhibit reversals operate in a regime in which the viscosity of the fluid remains important, and in which the dynamo mechanism primarily involves stretching and twisting of field lines by columnar convection. Here we present an example of another class of reversing-geodynamo model, which operates in a regime of comparatively low viscosity and high magnetic diffusivity. This class does not fit into the paradigm of reversal regimes that are dictated by the value of the local Rossby number (the ratio of advection to Coriolis force). Instead, stretching of the magnetic field by a strong shear in the east-west flow near the imaginary cylinder just touching the inner core and parallel to the axis of rotation is crucial to the reversal mechanism in our models, which involves a process akin to kinematic dynamo waves. Because our results are relevant in a regime of low viscosity and high magnetic diffusivity, and with geophysically appropriate boundary conditions, this form of dynamo wave may also be involved in geomagnetic reversals.

  1. 14 CFR 25.933 - Reversing systems.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... reversing systems— (1) Each system intended for ground operation only must be designed so that during any... of the thrust reverser. (2) Each system intended for inflight use must be designed so that no unsafe... systems— (1) Each system intended for ground operation only must be designed so that no single failure...

  2. The New Reverse Transfer: A National Landscape

    ERIC Educational Resources Information Center

    Friedel, Janice Nahra; Wilson, Sarah L.

    2015-01-01

    For decades, higher education professionals and researchers have used the term reverse transfer to describe a specific group of students. A current review of community college literature and higher education policy reflects a contextual change of the term, and today reverse transfer has grown to include students who transfer from a two-year…

  3. The Rate Laws for Reversible Reactions.

    ERIC Educational Resources Information Center

    King, Edward L.

    1986-01-01

    Provides background information for teachers on the rate laws for reversible reactions. Indicates that although prediction of the form of the rate law for a reverse reaction given the rate law for the forward reaction is not certain, the number of possibilities is limited because of relationships described. (JN)

  4. Neuronal Activation for Semantically Reversible Sentences

    ERIC Educational Resources Information Center

    Richardson, Fiona M.; Thomas, Michael S. C.; Price, Cathy J.

    2010-01-01

    Semantically reversible sentences are prone to misinterpretation and take longer for typically developing children and adults to comprehend; they are also particularly problematic for those with language difficulties such as aphasia or Specific Language Impairment. In our study, we used fMRI to compare the processing of semantically reversible and…

  5. 14 CFR 33.97 - Thrust reversers.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Thrust reversers. 33.97 Section 33.97 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: AIRCRAFT ENGINES Block Tests; Turbine Aircraft Engines § 33.97 Thrust reversers. (a) If...

  6. Laparoscopic reversal of Hartmann's procedure.

    PubMed

    Fiscon, Valentino; Portale, Giuseppe; Mazzeo, Antonio; Migliorini, Giovanni; Frigo, Flavio

    2014-12-01

    Reestablishing continuity after a Hartmann's procedure is considered a major surgical procedure with high morbidity/mortality. The aim of this study was to assess the short-/long-term outcome of laparoscopic restoration of bowel continuity after HP. A prospectively collected database of colorectal laparoscopic procedures (>800) performed between June 2005 and June 2013 was used to identify 20 consecutive patients who had undergone laparoscopic reversal of Hartmann's procedure (LHR). Median age was 65.4. Ten patients (50 %) had undergone surgery for perforated diverticulitis, 3 (15 %) for cancer, and 7 (35 %) for other reasons (volvulus, posttraumatic perforation, and sigmoid perforation from foreign body). Previous HP had been performed laparoscopically in only 3 patients. Median operative time was 162.5 min. All the procedures were completed laparoscopically. Intraoperative complication rate was nil. Post-operative mortality and morbidity were respectively 0 and 10 % (1 pneumonia, 1 bowel obstruction from post-anastomotic stenosis which required resection and redo of the anastomosis). Median time to first flatus was 3 days, to normal diet 5 days. Median hospital stay was 9 days without readmissions. We followed up the patients for a median of 44 months: when asked, all 20 (100 %) said they would undergo the operation (LHR) again; 3 (15 %) had been re-operated of laparoscopic mesh repair for incisional hernia. When performed by experienced surgeons, LHR is a feasible, safe, reproducible operation, which allows early return of bowel function, early discharge and fast return to work for the patient. It has a low morbidity rate.

  7. Parkinson’s disease managing reversible neurodegeneration

    PubMed Central

    Hinz, Marty; Stein, Alvin; Cole, Ted; McDougall, Beth; Westaway, Mark

    2016-01-01

    Traditionally, the Parkinson’s disease (PD) symptom course has been classified as an irreversible progressive neurodegenerative disease. This paper documents 29 PD and treatment-induced systemic depletion etiologies which cause and/or exacerbate the seven novel primary relative nutritional deficiencies associated with PD. These reversible relative nutritional deficiencies (RNDs) may facilitate and accelerate irreversible progressive neurodegeneration, while other reversible RNDs may induce previously undocumented reversible pseudo-neurodegeneration that is hiding in plain sight since the symptoms are identical to the symptoms being experienced by the PD patient. Documented herein is a novel nutritional approach for reversible processes management which may slow or halt irreversible progressive neurodegenerative disease and correct reversible RNDs whose symptoms are identical to the patient’s PD symptoms. PMID:27103805

  8. Three component vibrational time reversal communication

    DOE PAGES

    Anderson, Brian E.; Ulrich, Timothy J.; Ten Cate, James A.

    2015-01-01

    Time reversal provides an optimal prefilter matched signal to apply to a communication signal before signal transmission. Time reversal allows compensation for wave speed dispersion and can function well in reverberant environments. Time reversal can be used to focus elastic energy to each of the three components of motion independently. A pipe encased in concrete was used to demonstrate the ability to conduct communications of information using three component time reversal. Furthermore, the ability of time reversal to compensate for multi-path distortion (overcoming reverberation) will be demonstrated and the rate of signal communication will be presented. [The U.S. Department ofmore » Energy, through the LANL/LDRD Program, is gratefully acknowledged for supporting this work.]« less

  9. Periodic reversals allow bacteria to swarm

    NASA Astrophysics Data System (ADS)

    Wu, Yilin; Kaiser, Dale; Jiang, Yi; Alber, Mark

    2009-03-01

    Many bacteria can rapidly traverse surfaces from which they are extracting nutrient for growth. They generate flat, spreading colonies, called swarms because they resemble swarms of insects. We seek to understand how members of any dense swarm track their neighbors while interfering minimally with the motion of others'. We choose myxobacteria as our model system. Individual myxobacteria cells regularly reverse their gliding directions. With a cell- and behavior-based computational model, we show that reversals of gliding direction are essential for swarming and that reversals increase the outflow of cells across the edge of the swarm. We also find that the reversal period predicted to maximize the outflow of cells is the same (within the errors of measurement) as the period observed in experiments with normal myxobacteria cells. This coincidence suggests that the circuit regulating reversals evolved to its current sensitivity under selection for growth achieved by swarming. Our work suggests a crucial componentin the general behavioral algorithm governing bacterial swarming.

  10. Three component vibrational time reversal communication

    SciTech Connect

    Anderson, Brian E.; Ulrich, Timothy J.; Ten Cate, James A.

    2015-01-01

    Time reversal provides an optimal prefilter matched signal to apply to a communication signal before signal transmission. Time reversal allows compensation for wave speed dispersion and can function well in reverberant environments. Time reversal can be used to focus elastic energy to each of the three components of motion independently. A pipe encased in concrete was used to demonstrate the ability to conduct communications of information using three component time reversal. Furthermore, the ability of time reversal to compensate for multi-path distortion (overcoming reverberation) will be demonstrated and the rate of signal communication will be presented. [The U.S. Department of Energy, through the LANL/LDRD Program, is gratefully acknowledged for supporting this work.

  11. Uncommon Indications for Reverse Total Shoulder Arthroplasty

    PubMed Central

    Hyun, Yoon Suk; Huri, Gazi; Garbis, Nickolas G.

    2013-01-01

    Total shoulder arthroplasty and shoulder hemiarthroplasty have been the traditional method for treating a variety of shoulder conditions, including arthritis, cuff tear arthropathy, and some fracture types. However, these procedures did not provide consistently good results for patients with torn rotator cuffs. The development of the reverse prosthesis by Grammont in the late 20th century revolutionized the treatment of the rotator-cuff-deficient shoulder with arthritis. The main indication for the reverse prosthesis remains the patient with cuff tear arthropathy who has pain and loss of motion. Because the reverse total shoulder arthroplasty produced such good results in these patients, the indications for the reverse prosthesis have expanded to include other shoulder conditions that have previously been difficult to treat successfully and predictably. This review discusses and critically reviews these newer indications for the reverse total shoulder arthroplasty. PMID:24340143

  12. Uncommon indications for reverse total shoulder arthroplasty.

    PubMed

    Hyun, Yoon Suk; Huri, Gazi; Garbis, Nickolas G; McFarland, Edward G

    2013-12-01

    Total shoulder arthroplasty and shoulder hemiarthroplasty have been the traditional method for treating a variety of shoulder conditions, including arthritis, cuff tear arthropathy, and some fracture types. However, these procedures did not provide consistently good results for patients with torn rotator cuffs. The development of the reverse prosthesis by Grammont in the late 20th century revolutionized the treatment of the rotator-cuff-deficient shoulder with arthritis. The main indication for the reverse prosthesis remains the patient with cuff tear arthropathy who has pain and loss of motion. Because the reverse total shoulder arthroplasty produced such good results in these patients, the indications for the reverse prosthesis have expanded to include other shoulder conditions that have previously been difficult to treat successfully and predictably. This review discusses and critically reviews these newer indications for the reverse total shoulder arthroplasty.

  13. Observation of the reversed Cherenkov radiation

    NASA Astrophysics Data System (ADS)

    Duan, Zhaoyun; Tang, Xianfeng; Wang, Zhanliang; Zhang, Yabin; Chen, Xiaodong; Chen, Min; Gong, Yubin

    2017-03-01

    Reversed Cherenkov radiation is the exotic electromagnetic radiation that is emitted in the opposite direction of moving charged particles in a left-handed material. Reversed Cherenkov radiation has not previously been observed, mainly due to the absence of both suitable all-metal left-handed materials for beam transport and suitable couplers for extracting the reversed Cherenkov radiation signal. In this paper, we develop an all-metal metamaterial, consisting of a square waveguide loaded with complementary electric split ring resonators. We demonstrate that this metamaterial exhibits a left-handed behaviour, and we directly observe the Cherenkov radiation emitted predominantly near the opposite direction to the movement of a single sheet electron beam bunch in the experiment. These observations confirm the reversed behaviour of Cherenkov radiation. The reversed Cherenkov radiation has many possible applications, such as novel vacuum electronic devices, particle detectors, accelerators and new types of plasmonic couplers.

  14. Observation of the reversed Cherenkov radiation

    PubMed Central

    Duan, Zhaoyun; Tang, Xianfeng; Wang, Zhanliang; Zhang, Yabin; Chen, Xiaodong; Chen, Min; Gong, Yubin

    2017-01-01

    Reversed Cherenkov radiation is the exotic electromagnetic radiation that is emitted in the opposite direction of moving charged particles in a left-handed material. Reversed Cherenkov radiation has not previously been observed, mainly due to the absence of both suitable all-metal left-handed materials for beam transport and suitable couplers for extracting the reversed Cherenkov radiation signal. In this paper, we develop an all-metal metamaterial, consisting of a square waveguide loaded with complementary electric split ring resonators. We demonstrate that this metamaterial exhibits a left-handed behaviour, and we directly observe the Cherenkov radiation emitted predominantly near the opposite direction to the movement of a single sheet electron beam bunch in the experiment. These observations confirm the reversed behaviour of Cherenkov radiation. The reversed Cherenkov radiation has many possible applications, such as novel vacuum electronic devices, particle detectors, accelerators and new types of plasmonic couplers. PMID:28332487

  15. Estimation and uncertainty of reversible Markov models

    NASA Astrophysics Data System (ADS)

    Trendelkamp-Schroer, Benjamin; Wu, Hao; Paul, Fabian; Noé, Frank

    2015-11-01

    Reversibility is a key concept in Markov models and master-equation models of molecular kinetics. The analysis and interpretation of the transition matrix encoding the kinetic properties of the model rely heavily on the reversibility property. The estimation of a reversible transition matrix from simulation data is, therefore, crucial to the successful application of the previously developed theory. In this work, we discuss methods for the maximum likelihood estimation of transition matrices from finite simulation data and present a new algorithm for the estimation if reversibility with respect to a given stationary vector is desired. We also develop new methods for the Bayesian posterior inference of reversible transition matrices with and without given stationary vector taking into account the need for a suitable prior distribution preserving the meta-stable features of the observed process during posterior inference. All algorithms here are implemented in the PyEMMA software — http://pyemma.org — as of version 2.0.

  16. Gastric bypass reversal: a 7-year experience.

    PubMed

    Pernar, Luise I M; Kim, Julie J; Shikora, Scott A

    After gastric bypass, some patients develop conditions that ultimately require reversal of the bypass. There are currently few publications on the topic to guide clinicians. To describe the indications, techniques, and outcomes for gastric bypass reversal. Two academic medical centers. We conducted a retrospective chart review of all patients who underwent gastric bypass reversal at our institutions between 2008 and 2015. Information regarding the original operation, the indications for reversal, procedures performed, and the postoperative outcomes were collected and analyzed. Nineteen patients underwent gastric bypass reversal. All but 4 reversal operations were performed laparoscopically. The indications for reversal were malnutrition or excessive weight loss (6 patients); chronic nausea, vomiting, and abdominal pain (5); neuroglycopenia (4); massive small bowel loss due to internal hernia (3); and need for surveillance gastric endoscopy (1). In the perioperative period, 4 patients had a complication that required intervention. Five patients required additional delayed procedures. One patient was lost to follow-up. The remaining patients' mean follow-up was 22±18 months. Symptoms that prompted reversal of the gastric bypass resolved in the majority of patients. However, 1 patient's hypoglycemia did not resolve and 2 continued to have diarrhea. Six patients were weaned off of total parenteral nutrition. Laparoscopic gastric bypass reversal is feasible and well tolerated. The procedure can be employed to treat a variety of conditions that may occur after gastric bypass and the majority of patients benefit, with resolution of symptoms. In a carefully selected patient population, gastric bypass reversal should be considered if conservative approaches to adverse conditions fail. Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

  17. Why Contextual Preference Reversals Maximize Expected Value

    PubMed Central

    2016-01-01

    Contextual preference reversals occur when a preference for one option over another is reversed by the addition of further options. It has been argued that the occurrence of preference reversals in human behavior shows that people violate the axioms of rational choice and that people are not, therefore, expected value maximizers. In contrast, we demonstrate that if a person is only able to make noisy calculations of expected value and noisy observations of the ordinal relations among option features, then the expected value maximizing choice is influenced by the addition of new options and does give rise to apparent preference reversals. We explore the implications of expected value maximizing choice, conditioned on noisy observations, for a range of contextual preference reversal types—including attraction, compromise, similarity, and phantom effects. These preference reversal types have played a key role in the development of models of human choice. We conclude that experiments demonstrating contextual preference reversals are not evidence for irrationality. They are, however, a consequence of expected value maximization given noisy observations. PMID:27337391

  18. Chemical reactions in reverse micelle systems

    DOEpatents

    Matson, Dean W.; Fulton, John L.; Smith, Richard D.; Consani, Keith A.

    1993-08-24

    This invention is directed to conducting chemical reactions in reverse micelle or microemulsion systems comprising a substantially discontinuous phase including a polar fluid, typically an aqueous fluid, and a microemulsion promoter, typically a surfactant, for facilitating the formation of reverse micelles in the system. The system further includes a substantially continuous phase including a non-polar or low-polarity fluid material which is a gas under standard temperature and pressure and has a critical density, and which is generally a water-insoluble fluid in a near critical or supercritical state. Thus, the microemulsion system is maintained at a pressure and temperature such that the density of the non-polar or low-polarity fluid exceeds the critical density thereof. The method of carrying out chemical reactions generally comprises forming a first reverse micelle system including an aqueous fluid including reverse micelles in a water-insoluble fluid in the supercritical state. Then, a first reactant is introduced into the first reverse micelle system, and a chemical reaction is carried out with the first reactant to form a reaction product. In general, the first reactant can be incorporated into, and the product formed in, the reverse micelles. A second reactant can also be incorporated in the first reverse micelle system which is capable of reacting with the first reactant to form a product.

  19. Novel Designs of Quantum Reversible Counters

    NASA Astrophysics Data System (ADS)

    Qi, Xuemei; Zhu, Haihong; Chen, Fulong; Zhu, Junru; Zhang, Ziyang

    2016-11-01

    Reversible logic, as an interesting and important issue, has been widely used in designing combinational and sequential circuits for low-power and high-speed computation. Though a significant number of works have been done on reversible combinational logic, the realization of reversible sequential circuit is still at premature stage. Reversible counter is not only an important part of the sequential circuit but also an essential part of the quantum circuit system. In this paper, we designed two kinds of novel reversible counters. In order to construct counter, the innovative reversible T Flip-flop Gate (TFG), T Flip-flop block (T_FF) and JK flip-flop block (JK_FF) are proposed. Based on the above blocks and some existing reversible gates, the 4-bit binary-coded decimal (BCD) counter and controlled Up/Down synchronous counter are designed. With the help of Verilog hardware description language (Verilog HDL), these counters above have been modeled and confirmed. According to the simulation results, our circuits' logic structures are validated. Compared to the existing ones in terms of quantum cost (QC), delay (DL) and garbage outputs (GBO), it can be concluded that our designs perform better than the others. There is no doubt that they can be used as a kind of important storage components to be applied in future low-power computing systems.

  20. Mirror reversal: empirical tests of competing accounts.

    PubMed

    Takano, Yohtaro; Tanaka, Akihiro

    2007-11-01

    In a mirror, left and right are said to look reversed. Surprisingly, this very familiar phenomenon, mirror reversal, has still no agreed-upon account to date. This study compared a variety of accounts in the light of empirical data. In Experiment 1, 102 students judged whether the mirror image of a person or a character looked reversed or not in 15 settings and also judged the directional relation between its components. In Experiment 2, 52 students made the reversal judgements in 13 settings. It was found for the first time that a substantial proportion of people denied the left-right mirror reversal of a person, whereas virtually all of them did recognize that of a character. This discrepancy strongly suggested that these two kinds of mirror reversal are produced by different processes, respectively. A number of findings including this discrepancy clearly contradicted two accounts that are currently active: the one based on the priority of the up-down and front-back axes over the left-right axis, and the one based on the physical rotation of an object. All the findings were consistent with an account that considered mirror reversal a complex of three different phenomena produced by three different processes, respectively.

  1. GALVANOTROPISM AND "REVERSAL OF INHIBITION" BY STRYCHNINE

    PubMed Central

    Crozier, W. J.

    1927-01-01

    The cathodically galvanotropic orientation of nemerteans, Lineus, and the anodic orientation of the gephyrean Echiurus, are reversed by the action of strychnine under conditions such that the typical "reversal of inhibition" induced by this substance is apparent. Nicotine does not give this result. Since it is necessary to assume that the strychnine effect is due to action upon the central ganglia, and since the galvanotropic effect depends upon action of the current on nerve cell bodies of the central ganglia, it must be assumed that the locus of reversal by strychnine is not perikaryal, but presumably synaptic. PMID:19872331

  2. Reverse logistics in the Brazilian construction industry.

    PubMed

    Nunes, K R A; Mahler, C F; Valle, R A

    2009-09-01

    In Brazil most Construction and Demolition Waste (C&D waste) is not recycled. This situation is expected to change significantly, since new federal regulations oblige municipalities to create and implement sustainable C&D waste management plans which assign an important role to recycling activities. The recycling organizational network and its flows and components are fundamental to C&D waste recycling feasibility. Organizational networks, flows and components involve reverse logistics. The aim of this work is to introduce the concepts of reverse logistics and reverse distribution channel networks and to study the Brazilian C&D waste case.

  3. Magnetization reversal in cobalt-phosphorus films

    NASA Astrophysics Data System (ADS)

    Hughes, Gordon F.

    1983-09-01

    A brief review is given of preparation, structure, and magnetization reversal in Co-P thin films for digital recording. From this, a magnetization reversal theory is developed which correctly predicts a number of observed facts about Co-P. Among these are &mA0.1 (conventional theory predicts 0.64 and 0.51, respectively), avalanche and cluster reversal mechanisms, transverse ripple, and sawtooth structure in recorded bits. Limitations to high bit and track density recording are discussed. It is suggested that lower Mr/Ms remanent squareness values may alleviate these density limiting mechanisms.

  4. Time reversibility in the quantum frame

    SciTech Connect

    Masot-Conde, Fátima

    2014-12-04

    Classic Mechanics and Electromagnetism, conventionally taken as time-reversible, share the same concept of motion (either of mass or charge) as the basis of the time reversibility in their own fields. This paper focuses on the relationship between mobile geometry and motion reversibility. The goal is to extrapolate the conclusions to the quantum frame, where matter and radiation behave just as elementary mobiles. The possibility that the asymmetry of Time (Time’s arrow) is an effect of a fundamental quantum asymmetry of elementary particles, turns out to be a consequence of the discussion.

  5. Methane Screening in JET Reverse Field Experiments

    SciTech Connect

    J.D. Strachan; B. Alper; G. Corrigan; S.K. Erents; C. Giroud; A. Korotkov; H. Leggate; G.F. Mathews; R.A. Pitts; M. Stamp; J. Spence

    2004-05-17

    JET plasmas with reverse magnetic field feature a different SOL flow than those with normal field. The observed carbon fueling efficiency from injecting methane gas was similar in reverse and normal field. EDGE2D modeling used an externally applied force to create the SOL flows, without specifying the origin of the force. The resulting flow agreed reasonably with the experimental values between the separatrix and 4 cm mid-plane depth in the SOL. The effect of the flow on the calculated carbon screening was 5 to 15% higher carbon fueling efficiency for the low flow velocity with reverse field.

  6. Biomechanics of reverse total shoulder arthroplasty.

    PubMed

    Berliner, Jonathan L; Regalado-Magdos, Ashton; Ma, C Benjamin; Feeley, Brian T

    2015-01-01

    Reverse total shoulder arthroplasty is an effective procedure for treatment of glenohumeral joint disease among patients with severe rotator cuff deficiency. Improvements in prosthetic design are the result of an evolved understanding of both shoulder and joint replacement biomechanics. Although modern generations of the reverse shoulder prosthesis vary in specific design details, they continue to adhere to Grammont's core principles demonstrated by his original Delta III prosthesis. This review article discusses the biomechanics of reverse total shoulder arthroplasty with a focus on elements of implant design and surgical technique that may affect stability, postoperative complications, and functional outcomes.

  7. Time reversibility in the quantum frame

    NASA Astrophysics Data System (ADS)

    Masot-Conde, Fátima

    2014-12-01

    Classic Mechanics and Electromagnetism, conventionally taken as time-reversible, share the same concept of motion (either of mass or charge) as the basis of the time reversibility in their own fields. This paper focuses on the relationship between mobile geometry and motion reversibility. The goal is to extrapolate the conclusions to the quantum frame, where matter and radiation behave just as elementary mobiles. The possibility that the asymmetry of Time (Time's arrow) is an effect of a fundamental quantum asymmetry of elementary particles, turns out to be a consequence of the discussion.

  8. Reverse osmosis desalination: Modeling and experiment

    NASA Astrophysics Data System (ADS)

    Fraidenraich, Naum; Vilela, Olga C.; Lima, Gilmário A.; Gordon, Jeffrey M.

    2009-03-01

    An analytic model for the performance of reverse osmosis desalination systems is derived. Predictions are shown to agree well with extensive measurements conducted on a commercial multistage reverse osmosis desalination unit over a broad range of operating conditions. The model allows a transparent understanding of the dependence of system performance on key design and operating variables. Identifying the characteristic flow rate and length scale of reverse osmosis systems allows a universal description of the variation of the permeate flow rate and recovery factor with the salinity, flow rate, and pressure of the feedwater.

  9. Cheaper Adjoints by Reversing Address Computations

    DOE PAGES

    Hascoët, L.; Utke, J.; Naumann, U.

    2008-01-01

    The reverse mode of automatic differentiation is widely used in science and engineering. A severe bottleneck for the performance of the reverse mode, however, is the necessity to recover certain intermediate values of the program in reverse order. Among these values are computed addresses, which traditionally are recovered through forward recomputation and storage in memory. We propose an alternative approach for recovery that uses inverse computation based on dependency information. Address storage constitutes a significant portion of the overall storage requirements. An example illustrates substantial gains that the proposed approach yields, and we show use cases in practical applications.

  10. Extending the boundaries of reverse engineering

    NASA Astrophysics Data System (ADS)

    Lawrie, Chris

    2002-04-01

    In today's market place the potential of Reverse Engineering as a time compression tool is commonly lost under its traditional definition. The term Reverse Engineering was coined way back at the advent of CMM machines and 3D CAD systems to describe the process of fitting surfaces to captured point data. Since these early beginnings, downstream hardware scanning and digitising systems have evolved in parallel with an upstream demand, greatly increasing the potential of a point cloud data set within engineering design and manufacturing processes. The paper will discuss the issues surrounding Reverse Engineering at the turn of the millennium.

  11. NARCOSIS AND EMULSION REVERSAL BY INERT GASES

    PubMed Central

    Sears, Dewey F.; Fenn, Wallace O.

    1957-01-01

    Investigations of the effect of high pressures of Na (100 to 130 atmospheres) and of Ar (60 to 80 atmospheres) showed that these gases are effective in reversing the phases of an oil in water emulsion. Nitrous oxide did not cause reversal at pressures as high as 53 atmospheres nor did helium as high as 107 atmospheres. We found CO2 most effective in reversing the emulsions and attributed this to its chemical properties. It is suggested that these observations may help to explain the narcotic effects of inert gases. PMID:13416527

  12. Reversible cerebral vasoconstriction syndrome induced by adrenaline.

    PubMed

    Palma, Jose-Alberto; Fontes-Villalba, Ariadna; Irimia, Pablo; Garcia-Eulate, Reyes; Martinez-Vila, Eduardo

    2012-04-01

    Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by acute severe thunderclap headaches and evidence of multifocal, segmental, reversible vasoconstrictions of the cerebral arteries. Several precipitating factors have been identified and reported, including the use of recreational substances or sympathomimetic drugs and the postpartum state. Here we present the case of a woman who developed RCVS after the administration of adrenaline (epinephrine) in the setting of an anaphylactic reaction during antibiotic allergy testing. To our knowledge, this is the first reported case of RCVS following the administration of exogenous adrenaline. This case contributes to the understanding of the physiopathological mechanisms underlying reversible cerebral vasoconstriction.

  13. Performance of the reverse Helmbold universal portfolio

    NASA Astrophysics Data System (ADS)

    Tan, Choon Peng; Kuang, Kee Seng; Lee, Yap Jia

    2017-04-01

    The universal portfolio is an important investment strategy in a stock market where no stochastic model is assumed for the stock prices. The zero-gradient set of the objective function estimating the next-day portfolio which contains the reverse Kullback-Leibler order-alpha divergence is considered. From the zero-gradient set, the explicit, reverse Helmbold universal portfolio is obtained. The performance of the explicit, reverse Helmbold universal portfolio is studied by running them on some stock-price data sets from the local stock exchange. It is possible to increase the wealth of the investor by using these portfolios in investment.

  14. Constraining the reversing and non-reversing modes of the geodynamo. New insights from magnetostratigraphy.

    NASA Astrophysics Data System (ADS)

    Gallet, Y.; Pavlov, V.; Shatsillo, A.; Hulot, G.

    2015-12-01

    Constraining the evolution in the geomagnetic reversal frequency over hundreds of million years is not a trivial matter. Beyond the fact that there are long periods without reversals, known as superchrons, and periods with many reversals, the way the reversal frequency changes through time during reversing periods is still debated. A smooth evolution or a succession of stationary segments have both been suggested to account for the geomagnetic polarity time scale since the Middle-Late Jurassic. Sudden changes from a reversing mode to a non-reversing mode of the geodynamo may also well have happened, the switch between the two modes having then possibly been controlled by the thermal conditions at the core-mantle boundary. There is, nevertheless, a growing set of magnetostratigraphic data, which could help decipher a proper interpretation of the reversal history, in particular in the early Paleozoic and even during the Precambrian. Although yielding a fragmentary record, these data reveal the occurrence of both additional superchrons and periods characterized by extremely high, not to say extraordinary, magnetic reversal frequencies. In this talk, we will present a synthesis of these data, mainly obtained from Siberia, and discuss their implication for the magnetic reversal behavior over the past billion years.

  15. Reverse Racism: The Great White Hoax

    ERIC Educational Resources Information Center

    Zitron, Celia

    1975-01-01

    The controversy around quotas, school integration, open admissions, and reverse racism indicates a serious problem for equal educational opportunities and employment for minorities. United action of all people for effective integrated education is stressed. (Author/AM)

  16. Template definition by Tetrahymena telomerase reverse transcriptase.

    PubMed

    Miller, M C; Liu, J K; Collins, K

    2000-08-15

    The ribonucleoprotein enzyme telomerase extends chromosome ends by copying a specific template sequence within its integral RNA component. An active recombinant telomerase RNP is minimally composed of this RNA and the telomerase reverse transcriptase (TERT) protein, which contains sequence motifs conserved among viral reverse transcriptases (RTs), flanked by N- and C-terminal extensions specific to TERTs. We have used site-directed mutagenesis to explore the roles of Tetrahymena TERT in determining features of telomerase activity in general and in establishing the boundaries and use of an internal RNA template in specific. We identify a new ciliate-specific motif in the TERT N-terminus required for template definition. Moreover, several residues in reverse transcriptase motifs 1, 2, A and D are critical for specific aspects of internal template use. Our results indicate that the unique specificity of telomerase activity is conferred to a reverse transcriptase active site by TERT residues both within and beyond the RT motif region.

  17. Local heating realization by reverse thermal cloak.

    PubMed

    Hu, Run; Wei, Xuli; Hu, Jinyan; Luo, Xiaobing

    2014-01-08

    Transformation thermodynamics, as one of the important branches among the extensions of transformation optics, has attracted plentiful attentions and interests recently. The result of transformation thermodynamics, or called as "thermal cloak", can realize isothermal region and hide objects from heat. In this paper, we presented the concept of "reverse thermal cloak" to correspond to the thermal cloak and made a simple engineering definition to identify them. By full-wave simulations, we verified that the reverse thermal cloak can concentrate heat and realize local heating. The performance of local heating depends on the anisotropic dispersion of the cloaking layer's thermal conductivity. Three-dimensional finite element simulations demonstrated that the reverse thermal cloak can be used to heat up objects. Besides pre-engineered metamaterials, such reverse thermal cloak can even be realized with homogenous materials by alternating spoke-like structure or Hashin coated-sphere structure.

  18. Reverse-osmosis membranes by plasma polymerization

    NASA Technical Reports Server (NTRS)

    Hollahan, J. R.; Wydeven, T.

    1972-01-01

    Thin allyl amine polymer films were developed using plasma polymerization. Resulting dry composite membranes effectively reject sodium chloride during reverse osmosis. Films are 98% sodium chloride rejective, and 46% urea rejective.

  19. Reverse Fluid Transport Due to Boundary Pulsations

    NASA Astrophysics Data System (ADS)

    Coloma, Mikhail; Schaffer, David; Chiarot, Paul; Huang, Peter

    2016-11-01

    We investigate a reverse fluid transport mechanism consisting of peristaltic flow and boundary wave reflections. The reverse flow occurs in a rectangular conduit aligned in parallel between two cylindrical channels embedded in an elastic PDMS medium. The pulsating flow in the cylindrical channels, driven by a peristaltic pump, deform the PDMS medium and induce a pulsating flow in the rectangular conduit. Waveforms along the conduit boundaries, and their transmission and reflections, can be controlled by changing the PDMS rigidity. Our results show that while the overall wave propagation direction is in the forward direction, a reverse flow in the rectangular conduit can be preferentially induced by varying the elastic rigidity in one of the cylindrical channels. We study the overall flow velocity and direction under various PDMS rigidities. The identified set of experimental parameters that leads to a reverse flow will provide insights in understanding metabolic waste transport within the arterial walls in the brain.

  20. Gas hydrate formation in reversed micelles

    SciTech Connect

    Nguyen, H.; Rao, A.M.; Phillips, J.B.; John, V.T.; Reed, W.F.

    1991-12-31

    We describe a technique to modify protein solubility and optimize enzyme activity in reversed micellar solutions. The technique is based on the ability of hydrates of natural gas to form in the microaqueous phase. Clathrate hydrates are crystalline inclusions of water and gas, and their formation in bulk water has traditionally been studied with relevance to natural gas recovery. We have found that hydrates can form in the environment of the microaqueous pools of reversed micelles, and that their extent of formation can be well controlled through the thermodynamic variables of temperature and pressure. Additionally, formation of hydrates affects the size and aggregation number of the micelles, and thus influences the solubility and conformation of encapsulated proteins. We demonstrate how the concept can be used in two applications: (1) protein extraction into reversed micelles and subsequent recovery, and (2) optimization of enzyme activity in reversed micelles.

  1. Chain friction system gives positive, reversible drive

    NASA Technical Reports Server (NTRS)

    Davidsen, J. S.

    1964-01-01

    By cementing a strip of an elastomer to the smooth metal rim of the pulley and neoprene covered idlers providing suitable tension to the chain around the pulley, a positive reversible drive is accomplished more quietly and with less vibration.

  2. The reverse laser drilling of transparent materials

    NASA Technical Reports Server (NTRS)

    Anthony, T. R.; Lindner, P. A.

    1980-01-01

    Within a limited range of incident laser-beam intensities, laser drilling of a sapphire wafer initiates on the surface of the wafer where the laser beam exits and proceeds upstream in the laser beam to the surface where the laser beam enters the wafer. This reverse laser drilling is the result of the constructive interference between the laser beam and its reflected component on the exit face of the wafer. Constructive interference occurs only at the exit face of the sapphire wafer because the internally reflected laser beam suffers no phase change there. A model describing reverse laser drilling predicts the ranges of incident laser-beam intensity where no drilling, reverse laser drilling, and forward laser drilling can be expected in various materials. The application of reverse laser drilling in fabricating feed-through conductors in silicon-on-sapphire wafers for a massively parallel processer is described.

  3. Reverse Engineering Adverse Outcome Pathways in Ecotoxicology

    EPA Science Inventory

    The toxicological effects of many stressors are mediated through unknown, or incompletely characterized, mechanisms of action. We describe the application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, meabolic, signaling) t...

  4. Improving patient care after stoma reversal.

    PubMed

    Taylor, Claire

    This article will examine the current service provision for patients who have had a temporary stoma reversal. Findings of a patient survey will be presented, highlighting the support and information received by 27 patients following a stoma reversal operation. Associated literature (Camilleri-Brennan and Steele, 2000; Sailer at al, 2000; Desnoo and Faithfull, 2006; Siassi et al, 2008; Chow et al, 2009) has confirmed a high likelihood of altered bowel function after stoma reversal, but makes less reference to the care that these patients require during the follow-up period. It is recommended that colorectal teams discuss the care implications for patients requiring stoma reversal, and appraise their care delivery to ensure patient needs are met.

  5. Reversible Oxygenation of Oxygen Transport Proteins.

    ERIC Educational Resources Information Center

    Drain, C. M.; Corden, Barry B.

    1987-01-01

    Describes a lecture demonstration which illustrates changes in the visible spectra of oxygen transport proteins upon reversible oxygen binding. Provides a comparison of the physical characteristics of oxygen storage and transport proteins. Reviews essentials for preparation of the materials. (ML)

  6. Low Cost Reversible fuel cell systems

    SciTech Connect

    Technology Management Inc.

    2003-12-30

    This final report summarizes a 3-phase program performed from March 2000 through September 2003 with a particular focus on Phase III. The overall program studied TMI's reversible solid oxide stack, system concepts, and potential applications. The TMI reversible (fuel cell-electrolyzer) system employs a stack of high temperature solid-oxide electrochemical cells to produce either electricity (from a fuel and air or oxygen) or hydrogen (from water and supplied electricity). An atmospheric pressure fuel cell system operates on natural gas (or other carbon-containing fuel) and air. A high-pressure reversible electrolyzer system is used to make high-pressure hydrogen and oxygen from water and when desired, operates in reverse to generate electricity from these gases.

  7. Reverse Engineering Adverse Outcome Pathways in Ecotoxicology

    EPA Science Inventory

    The toxicological effects of many stressors are mediated through unknown, or incompletely characterized, mechanisms of action. We describe the application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, meabolic, signaling) t...

  8. Heterotopic Pregnancy Following Reversal of Tubal Ligation.

    PubMed

    Eschenbach, Stephanie; Entzian, Dirk; Baumgarten, Deborah A

    2008-01-01

    We describe the case of a 37-year-old woman who had undergone reversal of tubal ligation with subsequent heterotopic pregnancy. We review the initial radiological evaluation of heterotopic pregnancies and the subsequent radiologic findings following appropriate therapy.

  9. Reversibility of hyperhidrosis post axillary depilatory laser.

    PubMed

    Helou, Josiane; Habre, Maya; Soutou, Boutros; Maatouk, Ismael; Ibrahim, Tony; Tomb, Roland

    2014-03-01

    Hyperhidrosis and bromhidrosis were lately reported as novel side effects of laser-assisted removal of axillary hair. The goal of our study was to evaluate the reversibility of these two side effects. An observational, single-center cohort study included over a 30-month screening period 30 patients with newly reported hyperhidrosis and/or bromhidrosis related to axillary depilatory laser. After 26 weeks of follow-up, each patient was assessed for spontaneous reversibility. A 12-week duration treatment with topical aluminum chloride was evaluated in patients with persisting hyperhidrosis. Hyperhidrosis was assessed using the Hyperhidrosis Disease Severity Scale (HDSS). Spontaneous reversibility was observed in 20% of patients. In total, 23 out of 30 patients recovered normal axillary transpiration either spontaneously or after treatment. Mean HDSS score was significantly lower in the treated group. It appears that axillary hyperhidrosis and bromhidrosis, secondary to laser depilation, reverse either spontaneously or after using topical antiperspirant.

  10. Galen: developer of the reversal design?

    PubMed

    Brown, Robert T

    2007-01-01

    Galen, known to psychologists largely for his personality theory of the four temperaments, diagnosed the cause of a patient's symptoms with a form of reversal design long before its formal description (e.g., Sidman, 1960).

  11. Galen: Developer of the Reversal Design?

    PubMed Central

    Brown, Robert T

    2007-01-01

    Galen, known to psychologists largely for his personality theory of the four temperaments, diagnosed the cause of a patient's symptoms with a form of reversal design long before its formal description (e.g., Sidman, 1960). PMID:22478486

  12. RNA Virus Reverse Genetics and Vaccine Design

    PubMed Central

    Stobart, Christopher C.; Moore, Martin L.

    2014-01-01

    RNA viruses are capable of rapid spread and severe or potentially lethal disease in both animals and humans. The development of reverse genetics systems for manipulation and study of RNA virus genomes has provided platforms for designing and optimizing viral mutants for vaccine development. Here, we review the impact of RNA virus reverse genetics systems on past and current efforts to design effective and safe viral therapeutics and vaccines. PMID:24967693

  13. RNA virus reverse genetics and vaccine design.

    PubMed

    Stobart, Christopher C; Moore, Martin L

    2014-06-25

    RNA viruses are capable of rapid spread and severe or potentially lethal disease in both animals and humans. The development of reverse genetics systems for manipulation and study of RNA virus genomes has provided platforms for designing and optimizing viral mutants for vaccine development. Here, we review the impact of RNA virus reverse genetics systems on past and current efforts to design effective and safe viral therapeutics and vaccines.

  14. Miniature Reversal Electron-Attachment Detector

    NASA Technical Reports Server (NTRS)

    Chutjian, Ara

    1994-01-01

    Miniature reversal electron-attachment detector (miniREAD) enables direct injection of air or vapor at atmospheric pressure from monitored area into mass-spectrometric instrument to detect explosives, narcotics, or other substances, vapors of which suspected of being present in low concentrations. In comparison with older reversal electron-attachment detector, miniREAD simpler in design; more rugged; and easier to build, repair, and maintain. In addition, probably more sensitive.

  15. Reverse Shoulder Arthroplasty – A Literature Review

    PubMed Central

    Mahmood, Aatif; Malal, Joby Jacob George; Waseem, Mohammed

    2013-01-01

    Professor Grammont revolutionised shoulder surgery with his reverse shoulder arthroplasty design. Patients who had poor results from a conventional shoulder replacement because of cuff deficiency can now be treated effectively. Although designed for cuff tear arthropathy, indications continue to evolve and broaden. The initial results look very promising and the implant has gained much popularity over the years. The article provides an extensive literature review of the indications, results and complications for reverse shoulder arthroplasty. PMID:24082977

  16. Reverse shoulder arthroplasty - a literature review.

    PubMed

    Mahmood, Aatif; Malal, Joby Jacob George; Waseem, Mohammed

    2013-01-01

    Professor Grammont revolutionised shoulder surgery with his reverse shoulder arthroplasty design. Patients who had poor results from a conventional shoulder replacement because of cuff deficiency can now be treated effectively. Although designed for cuff tear arthropathy, indications continue to evolve and broaden. The initial results look very promising and the implant has gained much popularity over the years. The article provides an extensive literature review of the indications, results and complications for reverse shoulder arthroplasty.

  17. How the geomagnetic field vector reverses polarity

    USGS Publications Warehouse

    Prevot, M.; Mankinen, E.A.; Gromme, C.S.; Coe, R.S.

    1985-01-01

    A highly detailed record of both the direction and intensity of the Earth's magnetic field as it reverses has been obtained from a Miocene volcanic sequence. The transitional field is low in intensity and is typically non-axisymmetric. Geomagnetic impulses corresponding to astonishingly high rates of change of the field sometimes occur, suggesting that liquid velocity within the Earth's core increases during geomagnetic reversals. ?? 1985 Nature Publishing Group.

  18. Streamwise Oscillation of Airfoils into Reverse Flow

    NASA Astrophysics Data System (ADS)

    Granlund, Kenneth; Jones, Anya; Ol, Michael

    2015-11-01

    An airfoil in freestream is oscillated in streamwise direction to cyclically enter reverse flow. Measured lift is compared to analytical blade element theories. Advance ratio, reduced frequency and angle of attack is varied within those typical for helicopters. Experimental results reveal that lift does not become negative in the flow reversal part, contradicting one theory and supported by another. Flow visualization reveal the leading edge vortex advecting against the freestream to a point in front of the leading edge.

  19. MODIFIED BOROHYDRIDES FOR REVERSIBLE HYDROGEN STORAGE

    SciTech Connect

    Au, Ming

    2006-05-10

    This paper reports the results in the effort to destabilize lithium borohydride for reversible hydrogen storage. A number of metals, metal hydrides, metal chlorides and complex hydrides were selected and evaluated as the destabilization agents for reducing dehydriding temperature and generating dehydriding-rehydriding reversibility. It is found that some additives are effective. The Raman spectroscopic analysis shows the change of B-H binding nature.

  20. Vasectomy and vasectomy reversal: An update

    PubMed Central

    Ramasamy, Ranjith; Schlegel, Peter N.

    2011-01-01

    Vasectomy is an elective surgical sterilization procedure for men that is intended to obstruct or remove a portion of both vas deferens, thereby preventing sperm from moving from the testes to the ejaculatory ducts. Although intended for permanent sterilization, vasectomy can be reversed in most men seeking to restore their fertility due to a change in marital status or reproductive goals. The purpose of this document is to provided a synopsis of the latest techniques used in vasectomy and reversal. PMID:21716894

  1. Emerging Indications for Reverse Shoulder Arthroplasty.

    PubMed

    Urch, Ekaterina; Dines, Joshua S; Dines, David M

    2016-01-01

    Historically, reverse shoulder arthroplasty was reserved for older, low-demand patients in whom rotator cuff arthropathy was diagnosed. Other common indications included sequelae of previously treated proximal humerus fractures, failed anatomic total shoulder arthroplasty, tumor resection, and rheumatoid arthritis in the elderly population. Unpredictable implant durability and high complication rates have limited the use of reverse shoulder arthroplasty to a narrow group of patients. Over the past decade, however, research has led to an improved understanding of the biomechanics behind reverse shoulder prostheses, which has improved implant design and surgical techniques. Consequently, orthopaedic surgeons have slowly begun to expand the indications for reverse shoulder arthroplasty to include a wider spectrum of shoulder pathologies. Recent studies have shown promising results for patients who undergo reverse shoulder arthroplasty for the treatment of acute proximal humerus fractures, massive rotator cuff tears without arthropathy, primary osteoarthritis, and chronic anterior dislocation, as well as for younger patients who have rheumatoid arthritis. These data suggest that, with judicious patient selection, reverse shoulder arthroplasty can be an excellent treatment option for a growing patient cohort.

  2. Rotating Reverse-Osmosis for Water Purification

    NASA Technical Reports Server (NTRS)

    Lueptow, RIchard M.

    2004-01-01

    A new design for a water-filtering device combines rotating filtration with reverse osmosis to create a rotating reverse- osmosis system. Rotating filtration has been used for separating plasma from whole blood, while reverse osmosis has been used in purification of water and in some chemical processes. Reverse- osmosis membranes are vulnerable to concentration polarization a type of fouling in which the chemicals meant not to pass through the reverse-osmosis membranes accumulate very near the surfaces of the membranes. The combination of rotating filtration and reverse osmosis is intended to prevent concentration polarization and thereby increase the desired flux of filtered water while decreasing the likelihood of passage of undesired chemical species through the filter. Devices based on this concept could be useful in a variety of commercial applications, including purification and desalination of drinking water, purification of pharmaceutical process water, treatment of household and industrial wastewater, and treatment of industrial process water. A rotating filter consists of a cylindrical porous microfilter rotating within a stationary concentric cylindrical outer shell (see figure). The aqueous suspension enters one end of the annulus between the inner and outer cylinders. Filtrate passes through the rotating cylindrical microfilter and is removed via a hollow shaft. The concentrated suspension is removed at the end of the annulus opposite the end where the suspension entered.

  3. Role of reversible susceptibility in ferromagnetic hysteresis

    NASA Astrophysics Data System (ADS)

    Schneider, Carl S.

    2002-05-01

    An equation of state based upon saturation magnetization, Ms, coercive field, Hc, and the reversible susceptibility function of magnetization is proposed for ferromagnetic hysteresis. Reversible susceptibility divided by the initial susceptibility is the anisotropy function of magnetization, χr, ranging from one in the demagnetized state to zero at saturation, and varying with magnetic history. Its dependence on scaled magnetization, m=M/Ms on the interval (-1,1) varies with material, allowing characterization of anisotropy classes. Precise measurements have been made of reversible susceptibility, initial and saturate magnetization curves, and loops for Orthonol™, annealed 3% nickel steel and as-received 1018 steel, representing crystals, isotropic polycrystals and composite ferromagnets, respectively. Magnetization change is the product of the reversible susceptibility, change in the applied field and the cooperative function due to domain interactions. This function is 1+βm for the virgin curve with half this slope from any reversal, where β=Ms/XiHc is the hysteresis coefficient. Variation of β for 1018 steel is due to distributed coercivities, and causes sigmoid B(H) curves. In the scaled field representation, where h=H/Hc, the cooperative function is 1/(1-hχr), a hyperbolic field dependence smeared by the anisotropy function. Constant anisotropy causes closed hysteresis loops, while variable anisotropy causes creeping of cycled asymmetric loops. In ferromagnetism, 1/χ=1/χr-h, normal scaled reluctivity is reduced from its reversible value by the scaled field.

  4. A detailed analysis of simulated magnetic reversals

    NASA Astrophysics Data System (ADS)

    Wicht, J.; Olson, P.

    2003-04-01

    Field reversals are the most spectacular feature of the Earth's magnetic field but are only little understood. Paläomagnetism can provide an estimate of the involved time scales but has no means of exploring the internal mechanism behind this phenomenon. Numerical simulations, on the other hand, deliver a complete picture of the reversal dynamics but may not model all relevant geophysical aspects. We focus on simulations of reversals at modest parameters. While these relatively simple models reproduce many features of the geomagnetic field their relatively large scale field does still allow a detailed analysis of the 3d dynamics. However, the visualisation remains challanging and we use animations of different fields in various surfaces to understand the reversal sequence and mechanism. Rising plumes in or close to the tangent cylinder are the main sources of inverse magnetic field. Inverse field produced inside the tangent cylinder is unlikey to cross this barrier. However, inverse field produced near the CMB by plumes that rise close to but outside the tangent cylinder can be distributed through the outer core by meridional circulation. The duration of a reversal is thus determined by the time scale of this circulation. Using the west-ward drift as an estimat this would suggest a duration of about 2000 years, which is compatible with paläomagnetic findings. The reversal frequency depends on the detailed dynamics of the plumes and their ability to produce magnetic field, properties that are much harder to estimate.

  5. Reversal of neuromuscular block in companion animals.

    PubMed

    Jones, Ronald S; Auer, Ulrike; Mosing, Martina

    2015-09-01

    To review the evidence regarding the reversal of neuromuscular block (NMB) in companion animals with emphasis on the development and use of newer agents. Data sources include scientific reviews and original research publications in both human and veterinary literature using Pubmed and Scopus as search data bases. Unpublished and locally published data on reversal of NMB are presented. Residual NMB has been shown to increase morbidity and mortality in humans and needs to be avoided. It can be detected only by adequate neuromuscular monitoring. The proper use of reversal agents avoids residual NMB and recurarization should not occur. Anticholinesterase inhibitors, such as edrophonium and neostigmine have been used to reverse NMB when the need for this has been established. Reversal is influenced by several factors and a number of undesirable side- effects of these drugs have been reported. Sugammadex, a γ-cyclodextrin, which was designed specifically to encapsulate rocuronium, is more rapid in its actions, has fewer side effects and can reverse profound NMB induced by aminosteroidal muscle relaxants. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  6. Designing novel reversible BCD adder and parallel adder/subtraction using new reversible logic gates

    NASA Astrophysics Data System (ADS)

    Zhou, Rigui; Zhang, Manqun; Wu, Qian; Shi, Yang

    2012-10-01

    Reversible logic has received much attention in recent years when calculation with minimum energy consumption is considered. Especially, interest is sparked in reversible logic by its applications in some technologies, such as quantum computing, low-power CMOS design, optical information processing and nanotechnology. This article proposes two new reversible logic gates, ZRQ and NC. The first gate ZRQ not only implements all Boolean functions but also can be used to design optimised adder/subtraction architectures. One of the prominent functionalities of the proposed ZRQ gate is that it can work by itself as a reversible full adder/subtraction unit. The second gate NC can complete overflow detection logic of Binary Coded Decimal (BCD) adder. This article proposes two approaches to design novel reversible BCD adder using new reversible gates. A comparative result which is presented shows that the proposed designs are more optimised in terms of number of gates, garbage outputs, quantum costs and unit delays than the existing designs.

  7. Time reversal acoustics for small targets using decomposition of the time reversal operator

    NASA Astrophysics Data System (ADS)

    Simko, Peter C.

    The method of time reversal acoustics has been the focus of considerable interest over the last twenty years. Time reversal imaging methods have made consistent progress as effective methods for signal processing since the initial demonstration that physical time reversal methods can be used to form convergent wave fields on a localized target, even under conditions of severe multipathing. Computational time reversal methods rely on the properties of the so-called 'time reversal operator' in order to extract information about the target medium. Applications for which time reversal imaging have previously been explored include medical imaging, non-destructive evaluation, and mine detection. Emphasis in this paper will fall on two topics within the general field of computational time reversal imaging. First, we will examine previous work on developing a time reversal imaging algorithm based on the MUltiple SIgnal Classification (MUSIC) algorithm. MUSIC, though computationally very intensive, has demonstrated early promise in simulations using array-based methods applicable to true volumetric (three-dimensional) imaging. We will provide a simple algorithm through which the rank of the time reversal operator subspaces can be properly quantified so that the rank of the associated null subspace can be accurately estimated near the central pulse wavelength in broadband imaging. Second, we will focus on the scattering from small acoustically rigid two dimensional cylindrical targets of elliptical cross section. Analysis of the time reversal operator eigenmodes has been well-studied for symmetric response matrices associated with symmetric systems of scattering targets. We will expand these previous results to include more general scattering systems leading to asymmetric response matrices, for which the analytical complexity increases but the physical interpretation of the time reversal operator remains unchanged. For asymmetric responses, the qualitative properties of the

  8. Time reversal transfer: Exploring the robustness of time reversed acoustics in media with geometry perturbations.

    PubMed

    Kober, Jan; Dvorakova, Zuzana; Prevorovsky, Zdenek; Krofta, Josef

    2015-07-01

    In this letter, fundamentals of transferring a time reversal experiment between similar objects are discussed. The time reversal experiment consists of two steps: forward propagation, when a source excites the medium and a complex wave field is created, and back propagation, resulting in time reversal focusing. Here the procedure of performing the first step on one specimen and the second step on another is investigated. The theory of time reversal transfer is explained on an example of object shape variations. However, conclusions of the theoretical analysis are applicable universally. The feasibility of the proposed procedure is validated in experiments modeling conditions in practice.

  9. What is inside a nonionic reverse micelle? Probing the interior of Igepal reverse micelles using decavanadate.

    PubMed

    Sedgwick, M A; Crans, D C; Levinger, N E

    2009-05-19

    The interiors of reverse micelles formed using nonionic surfactants to sequester water droplets in a nonpolar environment have been investigated using the decavanadate molecule as a probe. Chemical shifts and line widths of the three characteristic signals in the 51V NMR spectrum of decavanadate, corresponding to vanadium atoms in equatorial peripheral, equatorial interior, and axial locations, measure the local proton concentration and characteristics of the reverse micellar interior near the decavandate probe. All samples investigated indicate deprotonation of the vanadate probe in the reverse micelle environment. However, the relative mobility of the decavanadate molecule depends on the reverse micellar components. Specifically, the 51V NMR signals of the decavandate in reverse micelles formed using only the Igepal CO-520 surfactant display sharp signals indicating that the decavandate molecule tumbles relatively freely while reverse micelles formed from a mixture of Igepal CO-610 and -430 present a more viscous environment for the decavanadate molecule; the nature of the interior of the nonionic reverse water pool varies significantly depending on the specific Igepal. The 51V NMR spectra also indicate that the interior core water pool of the reverse micelles is less acidic than the bulk aqueous solution from which the samples were created. Together, these data provide a description that allows for a comparison of the water pools in these different nonionic reverse micelles.

  10. Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease.

    PubMed

    Bolea, Irene; Juárez-Jiménez, Jordi; de Los Ríos, Cristóbal; Chioua, Mourad; Pouplana, Ramón; Luque, F Javier; Unzeta, Mercedes; Marco-Contelles, José; Samadi, Abdelouahid

    2011-12-22

    A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2±1.1 nM) and MAO-B (IC50=43±8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35±0.01 μM) and BuChE (IC50=0.46±0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.

  11. Performance Characteristics of Cylindrical Target-type Thrust Reversers

    NASA Technical Reports Server (NTRS)

    Steffen, Fred W; Mcardle, Jack G

    1956-01-01

    From tests on cylindrical target-type thrust reversers, it was found that the reverser frontal area, lip angle, end-plate angle, and end-plate depth had important effects on reverse-thrust performance. Frontal area, reverser depth, lip angle, and end-plate angele had important effects on the spacing required for unrestricted nozzle flow. For reverse-thrust ratios greater than 64 percent, the reversed flow attached to the 7 degree cowl in quiescent air. Swept-type cylindrical reversers were generally unstable. The thrust-modulation characteristics of a cylindrical target-type thrust reverser were found to be satisfactory.

  12. Reversible Lithium Neurotoxicity: Review of the Literature

    PubMed Central

    Netto, Ivan

    2012-01-01

    Objective: Lithium neurotoxicity may be reversible or irreversible. Reversible lithium neurotoxicity has been defined as cases of lithium neurotoxicity in which patients recovered without any permanent neurologic sequelae, even after 2 months of an episode of lithium toxicity. Cases of reversible lithium neurotoxicity differ in clinical presentation from those of irreversible lithium neurotoxicity and have important implications in clinical practice. This review aims to study the clinical presentation of cases of reversible lithium neurotoxicity. Data Sources: A comprehensive electronic search was conducted in the following databases: MEDLINE (PubMed), 1950 to November 2010; PsycINFO, 1967 to November 2010; and SCOPUS (EMBASE), 1950 to November 2010. MEDLINE and PsycINFO were searched by using the OvidSP interface. Study Selection: A combination of the following search terms was used: lithium AND adverse effects AND central nervous system OR neurologic manifestation. Publications cited include articles concerned with reversible lithium neurotoxicity. Data Extraction: The age, sex, clinical features, diagnostic categories, lithium doses, serum lithium levels, precipitating factors, and preventive measures of 52 cases of reversible lithium neurotoxicity were extracted. Data Synthesis: Among the 52 cases of reversible lithium neurotoxicity, patients ranged in age from 10 to 80 years and a greater number were female (P = .008). Most patients had affective disorders, schizoaffective disorders, and/or depression (P < .001) and presented mainly with acute organic brain syndrome. In most cases, the therapeutic serum lithium levels were less than or equal to 1.5 mEq/L (P < .001), and dosage regimens were less than 2,000 mg/day. Specific drug combinations with lithium, underlying brain pathology, abnormal tissue levels, specific diagnostic categories, and elderly populations were some of the precipitating factors reported for reversible lithium neurotoxicity. The

  13. Effects of thrust reversing in ground proximity

    NASA Technical Reports Server (NTRS)

    Joshi, P. B.; Hughes, R. V.

    1987-01-01

    The changes in stability and control characteristics encountered by a thrust reversing aircraft during its final approach, landing, and ground roll are described. These changes include a strong pitch-up accompanied by the loss of horizontal tail and aileron control effectiveness. The magnitude of reverser induced changes in ground effect are much larger than corresponding changes in free air. Some unexpected unsteady motions exhibited in wind tunnel by an aircraft model with reversers operating in ground proximity are also described. The cause of this oscillatory behavior was determined to be an unsteady interaction between the wall jets formed by impingement of reverser jets on the ground and the on-coming free stream. Time histories of rolling moments measured by the wind tunnel balance or support system were removed and frequencies were scaled by Strouhal number to full scale. Corrected time series were used to simulate the motion of a fighter aircraft with thrust reversers in ground effect. The simulation predicted large roll angles and nose down attitude at touchdown. Some phenomena of jet attachment to solid surfaces are discussed and areas for future research are recommended.

  14. "Reversed" alamethicin conductance in lipid bilayers.

    PubMed Central

    Taylor, R J; de Levie, R

    1991-01-01

    Alamethicin at a concentration of 2 micrograms/ml on one side of a lipid bilayer, formed at the tip of a patch clamp pipette from diphytanoyl phosphatidylcholine and cholesterol (2:1 mol ratio) in aqueous 0.5 M KCl, 5 mM Hepes, pH 7.0, exhibits an asymmetric current-voltage curve, only yielding alamethicin currents when the side to which the peptide has been added is made positive. Below room temperature, however, single alamethicin channels created in such membranes sometimes survive a sudden reversal of the polarity. These "reversed" channels are distinct from transiently observed states displayed as the channel closes after a polarity reversal. Such "reversed" channels can be monitored for periods up to several minutes, during which time we have observed them to fluctuate through more than 20 discrete conductance states. They are convenient for the study of isolated ion-conducting alamethicin aggregates because, after voltage reversal, no subsequent incorporation of additional ion-conducting aggregates takes place. PMID:1712238

  15. Polar Solvents Trigger Formation of Reverse Micelles.

    PubMed

    Khoshnood, Atefeh; Firoozabadi, Abbas

    2015-06-09

    We use molecular dynamics simulations and molecular thermodynamics to investigate the formation of reverse micelles in a system of surfactants and nonpolar solvents. Since the early observation of reverse micelles, the question has been whether the existence of polar solvent molecules such as water is the driving force for the formation of reverse micelles in nonpolar solvents. In this work, we use a simple coarse-grained model of surfactants and solvents to show that a small number of polar solvent molecules triggers the formation of large permanent aggregates. In the absence of polar molecules, both the thermodynamic model and molecular simulations show that small aggregates are more populated in the solution and larger ones are less frequent as the system evolves over time. The size and shape of reverse micelles depend on the size of the polar core: the shape is spherical for a large core and ellipsoidal for a smaller one. Using the coarse-grained model, we also investigate the effect of temperature and surfactant tail length. Our results reveal that the number of surfactant molecules in the micelle decreases as the temperature increases, but the average diameter does not change because the size of the polar core remains invariant. A reverse micelle with small polar core attracts fewer surfactants when the tail is long. The uptake of solvent particles by a micelle of longer surfactant tail is less than shorter ones when the polar solvent particles are initially distributed randomly.

  16. Reverse Transcription of Retroviruses and LTR Retrotransposons.

    PubMed

    Hughes, Stephen H

    2015-04-01

    The enzyme reverse transcriptase (RT) was discovered in retroviruses almost 50 years ago. The demonstration that other types of viruses, and what are now called retrotransposons, also replicated using an enzyme that could copy RNA into DNA came a few years later. The intensity of the research in both the process of reverse transcription and the enzyme RT was greatly stimulated by the recognition, in the mid-1980s, that human immunodeficiency virus (HIV) was a retrovirus and by the fact that the first successful anti-HIV drug, azidothymidine (AZT), is a substrate for RT. Although AZT monotherapy is a thing of the past, the most commonly prescribed, and most successful, combination therapies still involve one or both of the two major classes of anti-RT drugs. Although the basic mechanics of reverse transcription were worked out many years ago, and the first high-resolution structures of HIV RT are now more than 20 years old, we still have much to learn, particularly about the roles played by the host and viral factors that make the process of reverse transcription much more efficient in the cell than in the test tube. Moreover, we are only now beginning to understand how various host factors that are part of the innate immunity system interact with the process of reverse transcription to protect the host-cell genome, the host cell, and the whole host, from retroviral infection, and from unwanted retrotransposition.

  17. Mantle flow reversals in cylindrical Earth models

    NASA Astrophysics Data System (ADS)

    Ghias, Sanaz R.; Jarvis, Gary T.

    2007-12-01

    We employ a two-dimensional model of mantle convection in a cylindrical shell to study the influence of curvature on the phenomenon of spontaneous flow reversal, which has been found previously only in plane layer models in Cartesian geometry. Our model includes rigidly moving plates, with weak zones at each end, and uniformly distributed internal heat sources. Surface plates in this model are passive in that their lateral velocities reflect the overall buoyancy in the underlying mantle and, at each time step, match the average surface velocity that would occur in the absence of plates. Our principal finding is that flow reversals, similar to those in plane layers, are also found in our cylindrical shell models, thereby attesting to the robustness of this feature. We conduct systematic investigations of the impact on the flow reversal behavior of varying degree of curvature, plate thickness, internal heating rate and aspect ratio of the convection cells. Flow reversals are driven by a build-up of internally heated material adjacent to a major mantle downwelling. When thermal instabilities develop in the upper boundary layer they develop into intermediate sinking plumes which disrupt the build-up of hot material near sinking plumes. Accordingly, parameter values which tend to stabilize the upper thermal boundary layer (low degree of curvature, high plate thickness, small aspect ratio and intermediate internal heating rate) favor regular flow reversals.

  18. Reversing anticoagulants both old and new.

    PubMed

    Warkentin, Theodore E; Crowther, Mark A

    2002-01-01

    Reversal of pharmacologic anticoagulation is an issue that arises when an anticoagulated patient has major bleeding or when a patient on chronic anticoagulant therapy requires urgent reversal of anticoagulation, for example, for surgery. We reviewed the literature to determine what strategies are available to reverse anticoagulation caused by older agents, such as warfarin or unfractionated heparin (UFH), as well as newer agents, for example, low-molecular-weight heparin, danaparoid, fondaparinux, lepirudin, and argatroban. Specific "antidotes" exist for the "classic" anticoagulant agents: protamine sulfate for UFH, and vitamin K for warfarin. However, vitamin K only begins to reverse warfarin's anticoagulant effect by four to six hours, so urgent situations additionally require blood products, such as plasma (fresh frozen or cryosupermatant plasma), prothrombin complex concentrates, or, possibly, recombinant factor VIIa. A growing problem arises from the increasing use of new anticoagulants that lack specific antidotes. For example, protamine sulfate reverses only about 60% of the anti-factor Xa activity of low-molecular-weight heparin, has negligible effects on danaparoid (a mixture of anticoagulant glycosaminoglycans used to treat heparin-induced thrombocytopenia) and fondaparinux (a novel synthetic antithrombin-binding pentasaccharide with exclusive anti-factor Xa activity approved in the United States for antithrombotic prophylaxis following orthopedic surgery). The new direct thrombin inhibitors (e.g., lepirudin, bivalirudin, argatroban) also have no specific antidote. Newer anticoagulant agents generally lack specific antidotes. Thus, careful choice of an anticoagulant agent and laboratory monitoring where appropriate are needed to minimize risk of bleeding complications.

  19. Time reversal for damage detection in pipes

    NASA Astrophysics Data System (ADS)

    Ying, Yujie; Harley, Joel; Garrett, James H., Jr.; Jin, Yuanwei; Moura, José M. F.; O'Donoughue, Nicholas; Oppenheim, Irving J.; Soibelman, Lucio

    2010-04-01

    Monitoring the structural integrity of vast natural gas pipeline networks requires continuous and economical inspection technology. Current approaches for inspecting buried pipelines require periodic excavation of sections of pipe to assess only a couple of hundred meters at a time. These inspection systems for pipelines are temporary and expensive. We propose to use guided-wave ultrasonics with Time Reversal techniques to develop an active sensing and continuous monitoring system. Pipe environments are complex due to the presence of multiple modes and high dispersion. These are treated as adverse effects by most conventional ultrasonic techniques. However, Time Reversal takes advantage of the multi-modal and dispersive behaviors to improve the spatial and temporal wave focusing. In this paper, Time Reversal process is mathematically described and experimentally demonstrated through six laboratory experiments, providing comprehensive and promising results on guided wave focusing in a pipe with/without welded joint, with/without internal pressure, and detection of three defects: lateral, longitudinal and corrosion-like. The experimental results show that Time Reversal can effectively compensate for multiple modes and dispersion in pipes, resulting in an enhanced signal-to-noise ratio and effective damage detection ability. As a consequence, Time Reversal shows benefits in long-distance and lowpower pipeline monitoring, as well as potential for applications in other infrastructures.

  20. Evolution of the reverse total shoulder prosthesis.

    PubMed

    Jazayeri, Reza; Kwon, Young W

    2011-01-01

    Over the last decade, reverse total shoulder arthroplasty has gained significant popularity due to its ability to address difficult reconstructive shoulder problems that could not be adequately treated in the past. The concept of the reverse shoulder prosthesis was introduced in the 1970s, but the initial attempts were associated with high complication and implant failure rates. The pioneering work of Paul Grammont (shifting the center of rotation medially and distally) and the development of the DELTA prosthesis have been fundamental to all subsequent reverse shoulder arthroplasty systems. These semiconstrained prostheses utilize the deltoid to improve function and stability of the shoulder joint by coupling a convex glenoid with a concave humeral component. Modern generations of reverse shoulder prosthesis continue to evolve on the fundamentals of Grammont. Though results of these new prosthesis demonstrate promising outcomes, many controversies and challenges continue to be refined. An historical review of the evolution of reverse shoulder arthroplasty is presented, as well as the currently expanding indications for its application.

  1. How common are ALS plateaus and reversals?

    PubMed

    Bedlack, Richard S; Vaughan, Timothy; Wicks, Paul; Heywood, Jamie; Sinani, Ervin; Selsov, Roger; Macklin, Eric A; Schoenfeld, David; Cudkowicz, Merit; Sherman, Alex

    2016-03-01

    To determine the frequency of amyotrophic lateral sclerosis (ALS) plateaus and reversals in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. We analyzed Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) and ALSFRS-revised (ALSFRS-R) data from PRO-ACT participants. The frequencies of participants experiencing plateaus (periods where scores did not change) were calculated over 6-, 12-, and 18-month epochs. The percentage of participants ever experiencing reversals (periods where scores improved) of different lengths were also calculated and plotted. Over 6 months, 25% of 3,132 participants did not decline. Over 12 months, 16% of 2,105 participants did not decline. Over 18 months, 7% of 1,218 participants did not decline. Small ALS reversals were also common, especially over shorter follow-up intervals; 14% of 1,343 participants had a 180-day interval where their ALSFRS-R slope was greater than zero. Fewer than 1% of participants ever experienced improvements of 4 or more ALSFRS-R points lasting at least 12 months. ALS plateaus and small reversals are common, especially over brief intervals. In light of these data, stable disease, especially for a short period of time, should not be interpreted as an ALS treatment effect. Large sustained ALS reversals, on the other hand, are rare, potentially important, and warrant further study. © 2015 American Academy of Neurology.

  2. Republic F-84 Thunderjet with Reverse Thruster

    NASA Image and Video Library

    1954-06-21

    The US Air Force loaned a Republic F-84 Thunderjet to the National Advisory Committee for Aeronautics (NACA) Lewis Flight Propulsion Laboratory in the spring of 1954. NACA researchers soon modified the aircraft for the first demonstration of a reverse thruster. Republic built over 4000 Thunderjets between 1947 and 1953 for the military as a successor to the Lockheed F-80 Shooting Star. TheF-84s became successful multi-use aircraft during the Korean War. The use of traditional wheel brakes on high speed aircraft was problematic because the required braking system would weigh too much. The reverse thruster was developed as a method for stopping these aircraft without increasing the overall weight. Panels in the tail section near the jet engine’s nozzle opened up during a landing. These extended flaps not only caused resistance to the airstream but also reversed the engine’s thrust. In June 1964 Irving Pinkel, head of the Lewis Physics Division, oversaw a demonstration of this technology on an F-84 at the NACA laboratory. The side fuselage panels around the engine nozzle, seen closed in this photograph, opened up like wings and deflected the engine’s thrust towards the front of the aircraft, thus producing reverse thrust. The F-84 activated the reverse thruster and the aircraft moved backwards across the runway.

  3. Reverse logistics in the construction industry.

    PubMed

    Hosseini, M Reza; Rameezdeen, Raufdeen; Chileshe, Nicholas; Lehmann, Steffen

    2015-06-01

    Reverse logistics in construction refers to the movement of products and materials from salvaged buildings to a new construction site. While there is a plethora of studies looking at various aspects of the reverse logistics chain, there is no systematic review of literature on this important subject as applied to the construction industry. Therefore, the objective of this study is to integrate the fragmented body of knowledge on reverse logistics in construction, with the aim of promoting the concept among industry stakeholders and the wider construction community. Through a qualitative meta-analysis, the study synthesises the findings of previous studies and presents some actions needed by industry stakeholders to promote this concept within the real-life context. First, the trend of research and terminology related with reverse logistics is introduced. Second, it unearths the main advantages and barriers of reverse logistics in construction while providing some suggestions to harness the advantages and mitigate these barriers. Finally, it provides a future research direction based on the review. © The Author(s) 2015.

  4. Investigation into reversion of polyurethane encapsulants

    NASA Technical Reports Server (NTRS)

    Lynch, C. R.

    1973-01-01

    The effect of high humidity (95% RH) at 60 C, 70 C, 85 C and 100 C on the solid-to-liquid reversion of polyurethane elastomers (used for potting electrical connectors and conformal coating printed circuit boards) was investigated. Hardness measurements were conducted on eleven elastomers to track reversion for a 101-day period. The primary purpose of the tests was to provide data to predict service life for the polyurethane elastomers. This was not accomplished as the hardness did not deteriorate rapidly enough at the lower test temperatures. The tests did determine that the potting and coating materials most widely used on the S-1C Program are susceptible to reversion but appear adequate for service in the S-1C environment.

  5. Magnetization Reversal of Individual Co Nanoislands

    NASA Astrophysics Data System (ADS)

    Ouazi, S.; Wedekind, S.; Rodary, G.; Oka, H.; Sander, D.; Kirschner, J.

    2012-03-01

    We investigate the magnetization reversal of individual Co islands on Cu(111) in the size range of N=700 to 18 000 atoms by spin-polarized scanning tunneling microscopy at 8 K. The switching field Hsw changes with island size in a nonmonotonic manner: it increases with island size and reaches a maximum value of 2.4 T at N=5500 atoms, and it decreases for larger islands. We extract the energy barrier for magnetization reversal as a function of island size. The maximum Hsw corresponds to an energy barrier of 1 eV. Our results elucidate a crossover of the magnetization reversal from an exchange-spring behavior to domain wall formation with increasing size at around 7500 atoms.

  6. The thermodynamics of reversible thermoelectric nanomaterials

    NASA Astrophysics Data System (ADS)

    Humphrey, Tammy; Linke, Heiner

    2005-03-01

    Irreversible effects in thermoelectric materials limit their efficiency and economy for applications in power generation and refrigeration. While electron transport is unavoidably irreversible in bulk materials, here we derive conditions under which reversible diffusive electron transport can be achieved in nanostructured thermoelectric materials via the same physical mechanism utilized in the three-level amplifier (thermally pumped laser) and idealized thermophotovoltaic and thermionic devices. From a broader physical perspective, the most interesting aspect of this work is that it suggests that all of the above-mentioned solid-state devices may be unified as a single `type' of heat engine which achieves reversibility when heat transfer via particle exchange between reservoirs is isentropic (but non-isothermal), in contrast to heat engines such as Carnot, Otto or Brayton cycles, which achieve reversibility when heat transfer between the working gas and heat reservoirs is isothermal.

  7. Optimal design of reverse osmosis module networks

    SciTech Connect

    Maskan, F.; Wiley, D.E.; Johnston, L.P.M.; Clements, D.J.

    2000-05-01

    The structure of individual reverse osmosis modules, the configuration of the module network, and the operating conditions were optimized for seawater and brackish water desalination. The system model included simple mathematical equations to predict the performance of the reverse osmosis modules. The optimization problem was formulated as a constrained multivariable nonlinear optimization. The objective function was the annual profit for the system, consisting of the profit obtained from the permeate, capital cost for the process units, and operating costs associated with energy consumption and maintenance. Optimization of several dual-stage reverse osmosis systems were investigated and compared. It was found that optimal network designs are the ones that produce the most permeate. It may be possible to achieve economic improvements by refining current membrane module designs and their operating pressures.

  8. Total laparoscopic reversal of Hartmann's procedure.

    PubMed

    Masoni, Luigi; Mari, Francesco Saverio; Nigri, Giuseppe; Favi, Francesco; Pindozzi, Fioralba; Dall'Oglio, Anna; Pancaldi, Alessandra; Brescia, Antonio

    2013-01-01

    Hartmann's procedure is still performed in those cases in which colorectal anastomosis might be unsafe. Reversal of Hartmann's procedure (HR) is considered a major surgical procedure with a high morbidity (55 to 60%) and mortality rate (0 to 4%). To decrease these rates, laparoscopic Hartmann's reversal procedure was successfully experienced. We report our totally laparoscopic Hartmann's reversal technique. Between 2004 and 2010 we performed 27 HRs with a totally laparoscopic approach. The efficacy and safety of this technique were demonstrated evaluating the operative data, postoperative complications, and the outcome of the patients. There were no open conversions or major intraoperative complications. Anastomotic leaking occurred in one patient requiring an ileostomy; one patient needed a blood transfusion and one had a nosocomial pneumonia. The mean postoperative hospitalization was 5.7 days. Laparoscopic HR is a feasible and safe procedure and can be considered a valid alternative to open HR.

  9. Origin of reversed vortex ratchet motion.

    PubMed

    Gillijns, W; Silhanek, A V; Moshchalkov, V V; Reichhardt, C J Olson; Reichhardt, C

    2007-12-14

    We experimentally demonstrate that the origin of multiply reversed rectified vortex motion in an asymmetric pinning landscape not only is a consequence of the vortex-vortex interactions but also essentially depends on the ratio between the characteristic interaction distance and the period of the asymmetric pinning potential. We study four samples with different periods d of the asymmetric potential. For large d the dc voltage V(dc) recorded under a ac excitation indicates that the average vortex drift is from bigger to smaller dots for all explored positive fields. As d is reduced, a series of sign reversals in the dc response are observed as a function of field. We show that the number of sign reversals increases as d decreases. These findings are in agreement with recent computer simulations and illustrate the relevance of the different characteristic lengths for the vortex rectification effects.

  10. Time reversal signal processing for communication.

    SciTech Connect

    Young, Derek P.; Jacklin, Neil; Punnoose, Ratish J.; Counsil, David T.

    2011-09-01

    Time-reversal is a wave focusing technique that makes use of the reciprocity of wireless propagation channels. It works particularly well in a cluttered environment with associated multipath reflection. This technique uses the multipath in the environment to increase focusing ability. Time-reversal can also be used to null signals, either to reduce unintentional interference or to prevent eavesdropping. It does not require controlled geometric placement of the transmit antennas. Unlike existing techniques it can work without line-of-sight. We have explored the performance of time-reversal focusing in a variety of simulated environments. We have also developed new algorithms to simultaneously focus at a location while nulling at an eavesdropper location. We have experimentally verified these techniques in a realistic cluttered environment.

  11. Importance of reversibility in the quantum formalism.

    PubMed

    David, François

    2011-10-28

    In this Letter I stress the role of causal reversibility (time symmetry), together with causality and locality, in the justification of the quantum formalism. First, in the algebraic quantum formalism, I show that the assumption of reversibility implies that the observables of a quantum theory form an abstract real C^{⋆} algebra, and can be represented as an algebra of operators on a real Hilbert space. Second, in the quantum logic formalism, I emphasize which axioms for the lattice of propositions (the existence of an orthocomplementation and the covering property) derive from reversibility. A new argument based on locality and Soler's theorem is used to derive the representation as projectors on a regular Hilbert space from the general quantum logic formalism. In both cases it is recalled that the restriction to complex algebras and Hilbert spaces comes from the constraints of locality and separability.

  12. Reversible evanescent wave sensors for hydrazine

    NASA Astrophysics Data System (ADS)

    Carter, Michael T.; Smith, Jimmy R.; Mowry, Donald R.; Patel, Jay G.

    1999-02-01

    We report recent progress on development of evanescent wave fiber optic sensors for hydrazine (HZ), monomethylhydrazine (MMH) and unsymmetrical dimethylhydrazine (UDMH). Chemically reversible evanescent sensors capable of detection below 10 ppb were prepared by removing cladding from commercial multimode fiber and coating the exposed core with a hydrazine-sensitive triphenylmethane dye immobilized in an inert polymer matrix, typically poly(vinylchloride). Triphenylmethane dyes bleach reversibly in the presence of hydrazines, enabling colorimetric sensing. The linear dynamic range was typically 0 - 300 ppb and overall dynamic range up to ca. 5 ppm. Sensors optimized for HZ were as much as a factor of 45 less sensitive to MMH and UDMH, suggesting that the sensor film would require optimization for each analyte. Saturation response and relaxation times were on the order of 5 - 8 min, but measurable signals for 10 ppb HZ could be obtained in under 30 s. These sensors demonstrate a novel route to reversible sensing of these highly toxic compounds.

  13. Importance of Reversibility in the Quantum Formalism

    NASA Astrophysics Data System (ADS)

    David, François

    2011-10-01

    In this Letter I stress the role of causal reversibility (time symmetry), together with causality and locality, in the justification of the quantum formalism. First, in the algebraic quantum formalism, I show that the assumption of reversibility implies that the observables of a quantum theory form an abstract real C⋆ algebra, and can be represented as an algebra of operators on a real Hilbert space. Second, in the quantum logic formalism, I emphasize which axioms for the lattice of propositions (the existence of an orthocomplementation and the covering property) derive from reversibility. A new argument based on locality and Soler’s theorem is used to derive the representation as projectors on a regular Hilbert space from the general quantum logic formalism. In both cases it is recalled that the restriction to complex algebras and Hilbert spaces comes from the constraints of locality and separability.

  14. Conditional reversibility in nonequilibrium stochastic systems

    NASA Astrophysics Data System (ADS)

    Bonança, Marcus V. S.; Jarzynski, Christopher

    2016-02-01

    For discrete-state stochastic systems obeying Markovian dynamics, we establish the counterpart of the conditional reversibility theorem obtained by Gallavotti for deterministic systems [Ann. de l'Institut Henri Poincaré (A) 70, 429 (1999)]. Our result states that stochastic trajectories conditioned on opposite values of entropy production are related by time reversal, in the long-time limit. In other words, the probability of observing a particular sequence of events, given a long trajectory with a specified entropy production rate σ , is the same as the probability of observing the time-reversed sequence of events, given a trajectory conditioned on the opposite entropy production, -σ , where both trajectories are sampled from the same underlying Markov process. To obtain our result, we use an equivalence between conditioned ("microcanonical") and biased ("canonical") ensembles of nonequilibrium trajectories. We provide an example to illustrate our findings.

  15. Conditional reversibility in nonequilibrium stochastic systems.

    PubMed

    Bonança, Marcus V S; Jarzynski, Christopher

    2016-02-01

    For discrete-state stochastic systems obeying Markovian dynamics, we establish the counterpart of the conditional reversibility theorem obtained by Gallavotti for deterministic systems [Ann. de l'Institut Henri Poincaré (A) 70, 429 (1999)]. Our result states that stochastic trajectories conditioned on opposite values of entropy production are related by time reversal, in the long-time limit. In other words, the probability of observing a particular sequence of events, given a long trajectory with a specified entropy production rate σ, is the same as the probability of observing the time-reversed sequence of events, given a trajectory conditioned on the opposite entropy production, -σ, where both trajectories are sampled from the same underlying Markov process. To obtain our result, we use an equivalence between conditioned ("microcanonical") and biased ("canonical") ensembles of nonequilibrium trajectories. We provide an example to illustrate our findings.

  16. Sorting by reciprocal translocations via reversals theory.

    PubMed

    Ozery-Flato, Michal; Shamir, Ron

    2007-05-01

    The understanding of genome rearrangements is an important endeavor in comparative genomics. A major computational problem in this field is finding a shortest sequence of genome rearrangements that transforms, or sorts, one genome into another. In this paper we focus on sorting a multi-chromosomal genome by translocations. We reveal new relationships between this problem and the well studied problem of sorting by reversals. Based on these relationships, we develop two new algorithms for sorting by reciprocal translocations, which mimic known algorithms for sorting by reversals: a score-based method building on Bergeron's algorithm, and a recursive procedure similar to the Berman-Hannenhalli method. Though their proofs are more involved, our procedures for reciprocal translocations match the complexities of the original ones for reversals.

  17. On the reliability of reverse engineering results.

    PubMed

    Amotchkina, Tatiana V; Trubetskov, Michael K; Pervak, Vladimir; Romanov, Boris; Tikhonravov, Alexander V

    2012-08-01

    Determination of actual parameters of manufactured optical coatings (reverse engineering of optical coatings) provides feedback to the design-production chain and thus plays an important role in raising the quality of optical coatings production. In this paper, the reliability of reverse engineering results obtained using different types of experimental data is investigated. Considered experimental data include offline normal incidence transmittance data, offline ellipsometric data, and online transmittance monitoring data recorded during depositions of all coating layers. Experimental data are obtained for special test quarter-wave mirrors with intentional errors in some layers. These mirrors were produced by a well-calibrated magnetron-sputtering process. The intentional errors are several times higher than estimated errors of layer thickness monitoring, and the reliability of their detection is used as a measure of reliability of reverse engineering results. It is demonstrated that the most reliable results are provided by online transmittance data.

  18. Analysis of Ten Reverse Engineering Tools

    NASA Astrophysics Data System (ADS)

    Koskinen, Jussi; Lehmonen, Tero

    Reverse engineering tools can be used in satisfying the information needs of software maintainers. Especially in case of maintaining large-scale legacy systems tool support is essential. Reverse engineering tools provide various kinds of capabilities to provide the needed information to the tool user. In this paper we analyze the provided capabilities in terms of four aspects: provided data structures, visualization mechanisms, information request specification mechanisms, and navigation features. We provide a compact analysis of ten representative reverse engineering tools for supporting C, C++ or Java: Eclipse Java Development Tools, Wind River Workbench (for C and C++), Understand (for C++), Imagix 4D, Creole, Javadoc, Javasrc, Source Navigator, Doxygen, and HyperSoft. The results of the study supplement the earlier findings in this important area.

  19. Polar Field Reversals and Active Region Decay

    NASA Astrophysics Data System (ADS)

    Petrie, Gordon; Ettinger, Sophie

    2015-07-01

    We study the relationship between polar field reversals and decayed active region magnetic flux. Photospheric active region flux is dispersed by differential rotation and turbulent diffusion, and is transported poleward by meridional flows and diffusion. We summarize the published evidence from observation and modeling of the influence of meridional flow variations and decaying active region flux's spatial distribution, such as the Joy's law tilt angle. Using NSO Kitt Peak synoptic magnetograms covering cycles 21-24, we investigate in detail the relationship between the transport of decayed active region flux to high latitudes and changes in the polar field strength, including reversals in the magnetic polarity at the poles. By means of stack plots of low- and high-latitude slices of the synoptic magnetograms, the dispersal of flux from low to high latitudes is tracked, and the timing of this dispersal is compared to the polar field changes. In the most abrupt cases of polar field reversal, a few activity complexes (systems of active regions) are identified as the main cause. The poleward transport of large quantities of decayed trailing-polarity flux from these complexes is found to correlate well in time with the abrupt polar field changes. In each case, significant latitudinal displacements were found between the positive and negative flux centroids of the complexes, consistent with Joy's law bipole tilt with trailing-polarity flux located poleward of leading-polarity flux. The activity complexes of the cycle 21 and 22 maxima were larger and longer-lived than those of the cycle 23 and 24 maxima, and the poleward surges were stronger and more unipolar and the polar field changes larger and faster. The cycle 21 and 22 polar reversals were dominated by only a few long-lived complexes whereas the cycle 23 and 24 reversals were the cumulative effects of more numerous, shorter-lived regions. We conclude that sizes and lifetimes of activity complexes are key to

  20. Efficacy of a reverse cardioid directional microphone.

    PubMed

    Kuk, Francis; Keenan, Denise

    2012-01-01

    Directional microphones have been shown to improve a listener's ability to communicate in noise by improving the signal to noise ratio. However, their efficacy may be questioned in situations where the listener needs to understand speech originating from the back. The goal of the study was to examine the performance of a directional microphone mode that has an automatic reverse cardioid polar pattern. A single-blinded, factorial repeated-measures design was used to study the effect of microphone modes (reverse cardioid, omnidirectional, and front hypercardioid) and stimulus azimuths (front and back) on three outcome variables (aided thresholds, nonsense syllable identification in quiet, and sentence recognition in noise). Twenty adults with a mild-to-severe bilaterally symmetrical (±5 dB) sensorineural hearing loss participated. Audibility in quiet was evaluated by obtaining aided sound field thresholds and speech identification at an input level of 50 dB SPL presented at 0 and 180° azimuths. In addition, speech understanding in noise was also assessed with the Hearing In Noise Test (HINT) sentences presented at both azimuths (0 and 180°) with a diffuse noise. Repeated-measures analyses of variance (ANOVAs) were conducted to examine the effects of microphone mode (omnidirectional, front hypercardioid, reverse cardioid) and stimulus azimuth (0°, 180°) on aided thresholds, nonsense syllable identification, and HINT performance. Results with the reverse cardioid directional microphone in both quiet conditions were similar to the omnidirectional microphone. The results of the reverse cardioid microphone in noise were significantly better than the omnidirectional microphone and front hypercardioid microphone when speech was presented from the back (p < 0.001). These results support the possible benefits of a reverse cardioid directional microphone when used in specific listening situations. American Academy of Audiology.