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Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

65 publications regarding Central Nervous System
  • Author:
    Mizuno Y; Yamamoto M; Kuno S; Hasegawa K; Hattori N; Kagimura T; Sarashina A; Rascol O; Schapira AHV; Barone P; Hauser RA; Poewe W
    Title:
    Efficacy and safety of extended-versus immediate-release pramipexole in Japanese patients with advanced L-dopa-undertreated Parkinson disease: A double-blind, randomized trial.
    Source:
    Clin Neuropharmacol 35 (4), 174-181 (2012)
    Abstract:
    OBJECTIVES: To compare the efficacy, safety, tolerability, and trough plasma levels of pramipexole extended-release (ER) and pramipexole immediate-release (IR), and to assess the effects of overnight switching from an IR to an ER formulation, in L-dopa-treated patients with Parkinson disease (PD). METHODS: After a 1- to 4-week screening/enrollment, 112 patients who had exhibited L-dopa-related problems or were receiving suboptimal L-dopa dosage were randomized in double-blind, double-dummy, 1:1 fashion to pramipexole ER once daily or pramipexole IR 2 to 3 times daily for 12 weeks, both titrated to a maximum daily dose of 4.5 mg. Successful completers of double-blind treatment were switched to open-label pramipexole ER, beginning with a 4-week dose-adjustment phase. RESULTS: Among the double-blind treatment patients (n = 56 in each group), Unified Parkinson's Disease Rating Scale Parts II+III total scores decreased significantly from baseline and to a similar degree with pramipexole ER and IR formulations. In each group, 47 double-blind patients (83.9%) reported adverse events (AEs), requiring withdrawal of 3 ER patients (5.4%) and 2 IR patients (3.6%). Trough plasma levels at steady state (at the same doses and dose-normalized concentrations) were also similar with both formulations. Among open-label treatment patients (n = 53 from IR to ER), 83% were successfully switched (no worsening of PD symptoms) to pramipexole ER. CONCLUSIONS: In L-dopa-treated patients, pramipexole ER and pramipexole IR demonstrated similar efficacy, safety, tolerability, and trough plasma levels. Patients can be safely switched overnight from pramipexole IR to pramipexole ER with no impact on efficacy.
  • Author:
    Yassine N; Lazaris A; Dorner-Ciossek C; Despres O; Meyer L; Maitre M; Mensah-Nyagan AG; Cassel JC; Mathis C
    Title:
    Detecting spatial memory deficits beyond blindness in tg2576 Alzheimer mice.
    Source:
    Neurobiol Aging 34 (3), 716-730 (2012)
    Abstract:
    The retinal degeneration Pde6b rd1 (rd) mutation can be a major pitfall in behavioral studies using tg2576 mice bred on a B6:SJL genetic background, 1 of the most widely used models of Alzheimer's disease. After a pilot study in wild type mice, performance of 8- and 16-month-old tg2576 mice were assessed in several behavioral tasks with the challenge of selecting 1 or more task(s) showing robust memory deficits on this genetic background. Water maze acquisition was impossible in rd homozygotes, whereas Y-maze alternation, object recognition, and olfactory discrimination were unaffected by both the transgene and the rd mutation. Spatial memory retention of 8- and 16-month-old tg2576 mice, however, was dramatically affected independently of the rd mutation when mice had to recognize a spatial configuration of objects or to perform the Barnes maze. Thus, the latter tasks appear extremely useful to evaluate spatial memory deficits and to test cognitive therapies in tg2576 mice and other mouse models bred on a background susceptible to visual impairment.
  • Author:
    Aubert Y; Bohl MA; Lange JR; Diol NR; Allers KA; Sommer B; Datson NA; Abbott DH
    Title:
    Chronic systemic administration of serotonergic ligands flibanserin and 8-OH-DPAT enhance HPA axis responses to restraint in female marmosets
    Source:
    Psychoneuroendocrinology 38 (1), 145-154 (2012)
    Abstract:
    Background: Flibanserin, a novel serotonin (5-HT) 1A agonist and 5-HT 2A antagonist, has been shown to increase sexual desire and reduce distress in women with Hypoactive Sexual Desire Disorder (HSDD). In marmoset monkeys, flibanserin has demonstrated pro-social effects on male-female pairmates, while the classic 5-HT 1A agonist 8-OH-DPAT suppresses female sexual behavior and increases aggressive interactions between pairmates. Activation of 5-HT 1A and 5-HT 2A receptors is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. This study aims to characterize the effects of repeated flibanserin and 8-OH-DPAT administration on the marmoset HPA axis and to elucidate endocrine correlates of altered marmoset pair behavior. Methods: Adrenocorticotropic hormone (ACTH) and cortisol were examined at baseline and during 5-HT 1A agonist and restraint challenges in 8 female marmoset monkeys receiving daily flibanserin (15 mg/kg) and an additional 8 female marmosets receiving 8-OH-DPAT (0.1 mg/kg) for 15-16 weeks. Corresponding vehicle treatments were administered in a counterbalanced, within-subject design. All females were housed in stable male-female pairs. Treatment-induced changes in ACTH and cortisol levels were correlated with previously assessed marmoset pair behavior. Results: While morning basal cortisol levels and HPA responses to a 5-HT 1A agonist challenge were not altered by chronic flibanserin or 8-OH-DPAT, both treatments increased the responsiveness of the marmoset HPA axis to restraint. Enhanced ACTH responses to restraint correlated with reduced sexual receptivity and increased aggression in 8-OH-DPAT-, but not in flibanserin-treated female marmosets. Conclusions: Unaltered HPA responses to a 5-HT 1A agonist challenge after chronic flibanserin and 8-OH-DPAT treatments indicate little or no de-sensitization of the HPA axis to repeated 5-HT 1A manipulation. Chronic 8-OH-DPAT, but not flibanserin, leads to aggravated ACTH responses to stress that may contribute to anti-sexual and anti-social behavior between 8-OH-DPAT-treated females and their male pairmates. Despite similar flibanserin and 8-OH-DPAT induced ACTH responses to restraint stress, flibanserin-treated females show unchanged cortisol profiles. This is possibly due to flibanserin's regional selectivity in 5-HT 1A activation and concurrent 5-HT 2A inhibition. The contrasting restraint-related cortisol responses emulate contrasting behavioral phenotypes of diminished pair-bond of 8-OH-DPAT-treated females compared to the more affiliative pair-bond of flibanserin-treated females.
  • Author:
    Saleem F; Ametaj B N; Deiana S
    Title:
    Medical use of cannabis. Cannabidiol: A new light for schizophrenia?
    Abstract:
    The medical properties of cannabis have been known for many centuries; its first documented use dates back to 2800 BC when it was described for its hallucinogenic and pain-relieving properties. In the first half of the twentieth century, a number of pharmaceutical companies marked cannabis for indications such as asthma and pain, but since then its use has sharply declined, mainly due to its unpredictable effects, but also for socio-political issues. Recently, great attention has been directed to the medical properties of phytocannabinoids present in the cannabis plant alongside the main constituent ? 9-Tetrahydrocannabinol (THC); these include cannabinoids such as cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabivarin (THCV). Evidence suggests an association between cannabis and schizophrenia: schizophrenics show a higher use of marijuana as compared to the healthy population. Additionally, the use of marijuana can trigger psychotic episodes in schizophrenic patients, and this has been ascribed to THC. Given the need to reduce the side effects of marketed antipsychotics, and their weak efficacy on some schizophrenic symptoms, cannabinoids have been suggested as a possible alternative treatment for schizophrenia. CBD, a non-psychoactive constituent of the Cannabis sativa plant, has been receiving growing attention for its anti-psychotic-like properties. Evidence suggests that CBD can ameliorate positive and negative symptoms of schizophrenia. Behavioural and neurochemical models suggest that CBD has a pharmacological profile similar to that of atypical anti-psychotic drugs and a clinical trial reported that this cannabinoid is a well-tolerated alternative treatment for schizophrenia. © 2012 John Wiley & Sons, Ltd.
  • Author:
    Rosen RC; Connor MK; Miyasato G; Link C; Shifren JL; Fisher WA; Derogatis LR; Schobelock MJ
    Title:
    Sexual desire problems in women seeking healthcare: A novel study design for ascertaining prevalence of hypoactive sexual desire disorder in clinic-based samples of U.S. women.
    Source:
    J Womens Health 21 (5), 505-515 (2012)
    Abstract:
    Background: Hypoactive sexual desire disorder (HSDD) has been estimated to occur in 10%-15% of adult women in large population-representative and community-based studies. However, none of these studies have used in-person diagnostic interview assessment to rule out alternative diagnoses, nor has the impact of other health conditions or help-seeking experiences been investigated. The current study aimed to determine the prevalence of generalized acquired HSDD in women aged =18 who attended primary care or obstetrics and gynecology clinics for nonurgent clinic visits in the United States. Methods: A total of 701 women were enrolled at 20 clinical sites across the United States between June 11, 2010, and October 15, 2010. Participants completed a two-part self-administered questionnaire, and a validated, structured, in-person diagnostic interview, conducted by a trained health professional was used for diagnosing HSDD according to DSM-IV-TR criteria. Results: Fifty-two women (7.4%) were assigned a diagnosis of generalized acquired HSDD. Prevalence was lower in minority and postmenopausal women. Level of education and other sociodemographic factors did not appear to differentiate between women with and without HSDD. A marked increase in HSDD prevalence was noted in the perimenopausal (i.e., 40-49 years) and immediate postmenopausal (i.e., 50-59) age groups. Of the women diagnosed with HSDD, 53% had sought care from a health professional for HSDD. Conclusions: In this sample of women recruited in the clinical care setting, we observed an overall prevalence rate of 7.4% of acquired, generalized HSDD, with markedly increased prevalence in midlife women.
  • Author:
    Hansmann F; Herder V; Kalkuhl A; Haist V; Zhang N; Schaudien D; Deeschl U; Baumgaertner W; Ulrich R
    Title:
    Matrix metalloproteinase-12 deficiency ameliorates the clinical course and demyelination in Theiler's murine encephalomyelitis.
    Source:
    Acta Neuropathol 124 (1), 127-142 (2012)
    Abstract:
    Matrix metalloproteinases (MMPs) are a family of extracellular proteases involved in the pathogenesis of demyelinating diseases like multiple sclerosis (MS). The aim of the present study was to investigate whether MMPs induce direct myelin degradation, leukocyte infiltration, disruption of the blood-brain barrier (BBB), and/or extracellular matrix remodeling in the pathogenesis of Theiler's murine encephalomyelitis (TME), a virus-induced model of MS. During the demyelinating phase of TME, the highest transcriptional upregulation was detected for Mmp12, followed by Mmp3. Mmp12 -/- mice showed reduced demyelination, macrophage infiltration, and motor deficits compared with wild-type- and Mmp3 knock-out mice. However, BBB remained unaltered, and the amount of extracellular matrix deposition was similar in knock-out mice and wild-type mice. Furthermore, stereotaxic injection of activated MMP-3, -9, and -12 into the caudal cerebellar peduncle of adult mice induced a focally extensive primary demyelination prior to infiltration of inflammatory cells, as well as a reduction in the number of oligodendrocytes and a leakage of BBB. All these results demonstrate that MMP-12 plays an essential role in the pathogenesis of TME, most likely due to its primary myelin- or oligodendrocyte-toxic potential and its role in macrophage extravasation, whereas there was no sign of BBB damage or alterations to extracellular matrix remodeling/deposition. Thus, interrupting the MMP-12 cascade may be a relevant therapeutic approach for preventing chronic progressive demyelination. © 2012 Springer-Verlag.
  • Author:
    Schapira AHV; Barone P; Hauser RA; Mizuno Y; Rascol O; Busse M; Debieuvre C; Fraessdorf M; Poewe W
    Title:
    Patient-reported convenience of once-daily versus three-times-daily dosing during long term studies of pramipexole in early and advanced Parkinson's disease.
    Source:
    Eur J Neurol Article in Press (2012)
  • Author:
    Mar J; Avarez-Sabin J; Oliva J; Becerra V; Casado M A; Yebenes M; Gonzáles-Rojas N; Arenillas J F; Martinez Zabaleta M T; Rebello M; Lago A; Segura T; Castillo J; Gállego J; Jiménez-Martinez C; López-Gastón J I; Moniche F; Casado-Naranjo I; López-Fernàndez J C; González-Rodriguez C; Escribano B; Masjuan J
    Title:
    The costs of stroke in Spain by aetiology: the CONOCES study protocol [Los costes del ictus en España según su etiología. El protocolo del estudio CONOCES]
    Source:
    Neurologia Article in Press (2012)
    Abstract:
    Introduction: Patients with stroke associated with non-valvular atrial fibrillation (NVAF) are a specific group, and their disease has a considerable social and economic impact. The primary objective of the CONOCES study, the protocol of which is presented here, is to compare the costs of stroke in NVAF patients to those of patients without NVAF in Spanish stroke units from a social perspective. Materials and methods: CONOCES is an epidemiological, observational, naturalistic, prospective, multicentre study of the cost of the illness in a sample of patients who have suffered a stroke and were admitted to a Spanish stroke unit. During a 12-month of follow-up period, we record sociodemographic and clinical variables, score on the NIH stroke scale, level of disability, degree of functional dependency according to the modified Rankin scale, and use of healthcare resources (hospitalisation at the time of the first episode, readmissions, outpatient rehabilitation, orthotic and/or prosthetic material, medication for secondary prevention, medical check-ups, nursing care and formal social care services). Estimated monthly income, lost work productivity and health-related quality of life with the generic EQ-5D questionnaire are also recorded. We also administer a direct interview to the caregiver to determine loss of productivity, informal care, and caregiver burden. Results and conclusions: The contribution of the CONOCES study will help to set the economic and clinical impact of stroke on the basis of its association with NVAF. © 2012 Sociedad Española de Neurología.
  • Author:
    Revicki DA; Margolis MK; Fisher W; Rosen RC; Kuppermann M; Hannes V; Sand M
    Title:
    Evaluation of the sexual desire relationship distress scale (SDRDS) in women with hypoactive sexual desire disorder.
    Source:
    J Sex Med 9 (5), 1344-1354 (2012)
  • Author:
    Vlad C; Iurascu MI; Slamnoiu S; Hengerer B; Przbylski M
    Title:
    Characterization of oligomerization-aggregation products of neurodegenerative target proteins by ion mobility mass spectrometry
    Source:
    Methods Mol Biol 896, 399-412 (2012)
    Abstract:
    Protein amyloidogenesis is generally considered to be a major cause of two most severe neurodegenerative disorders, Parkinson's disease (PD) and Alzheimer's disease (AD). Formation and accumulation of fibrillar aggregates and plaques derived from ?-synuclein (?-Syn) and ß-amyloid (Aß) polypeptide in brain have been recognized as characteristics of Parkinson's disease and Alzheimer's disease. Oligomeric aggregates of ?-Syn and Aß are considered as neurotoxic intermediate products leading to progressive neurodegeneration. However, molecular details of the oligomerization and aggregation pathway(s) and the molecular structure details are still unclear. We describe here the application of ion-mobility mass spectrometry (IMS-MS) to the identification of ?-Syn and Aß oligomerization-aggregation products, and to the characterization of different conformational forms. IMS-MS is an analytical technique capable of separating gaseous ions based on their size, shape, and topography. IMS-MS studies of soluble ?-Syn and Aß-aggregates prepared by in vitro incubation over several days were performed on a quadrupole time of flight mass spectrometer equipped with a "travelling wave" ion mobility cell, and revealed the presence of different conformational states and, remarkably, truncation and proteolytic products of high aggregating reactivity. These results suggest that different polypeptide sequences may contribute to the formation of oligomeric aggregates of heterogeneous composition and distinct biochemical properties. © 2012 Springer Science+Business Media New York.
  • Author:
    Nakatsuji Y; Okuno T; Moriya M; Sugimoto T; Kinoshita M; Takamatsu H; Nojima S; Kimura T; Kanbg S; Ito D; Nakagawa Y; Toyofuku T; Takata K; Nakano M; Kubo M; Suzuki S; Mantsui-Hasumi A; Uto-Konomi A; Ogata A; Mochizuki H; Sakoda S; Kumangoh A
    Title:
    Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-beta therapy in multiple skerosis.
    Source:
    J Immunol 188 (10), 4858-4865 (2012)
  • Author:
    Riether D
    Title:
    Selective cannabinoid receptor 2 modulators: A patent review 2009 present.
    Source:
    Expert Opin Ther Pat 22 (5), 495-510 (2012)
    Abstract:
    Introduction: The activation of the cannabinoid receptor 2 (CB2) affects a myriad of immune responses from inflammation to neuroprotection, demonstrates analgesic effects and suppresses responses in many animal models of pain. Questions around the involvement of CB1 activation in these effects remain, but efforts have been directed toward the discovery of highly selective CB2 modulators lacking the psychotropic effects of cannabinoids, which are mediated by the CB1 receptor.Areas covered: This review covers the patent literature which was published since April 2009 on CB2 selective modulators. It provides a general summary of the CB2 biology supporting the interest in CB2 as a drug target, new potential therapeutic indications and the development status of selective CB2 agonists.Expert opinion: There is a continuous interest in the CB2 receptor as a drug target. Many highly selective compounds of various chemotypes have been identified and their analgesic effects in animal models further support the potential of this mechanism in pain therapy. Several companies have initiated clinical trials. While some of these have been terminated for various reasons, one can anticipate the emergence of new drugs from CB2 modulation once a better understanding around the cannabinoid receptors is gained. © 2012 Informa UK, Ltd.
  • Author:
    Schapira A H V; Barone P; Hauser R A; Mizuno Y; Rascol O; Busse M; Debieuvre C; Fraessdorf M; Poewe W
    Title:
    Success rate, efficacy, and safety/tolerability of overnight switching from immediate- to extended-release pramipexole in advanced Parkinson's disease
    Abstract:
    Background: For Parkinson's disease (PD), an extended-release (ER) pramipexole formulation taken once daily, has shown efficacy, safety, and tolerability resembling those of immediate-release (IR) pramipexole taken three times daily. The present study assessed, in advanced PD, the success of an overnight switch from adjunctive IR to ER. Methods: Levodopa users experiencing motor fluctuations were randomized to adjunctive double-blind (DB) placebo, IR, or ER. Amongst completers of ?18 weeks, ER recipients were kept on DB ER, whilst IR recipients were switched overnight to DB ER at unchanged daily dosage. After a DB week, switch success was assessed. During the next 5 weeks, all patients underwent ER titration to optimal open-label maintenance dosage. Results: One week post-switch, 86.2% of 123 IR-to-ER and 83.8% of 105 ER-to-ER patients had ?15% (or ?3-point, for pre-switch scores ?20) increase on UPDRS Parts II + III, and 77.9% (of 122) and 70.2% (of 104) had ?1-h increase in daily OFF-time. At 32 weeks, the groups showed comparable improvements from DB baseline (pramipexole inception), including, on UPDRS II + III, adjusted mean (SE) changes of -14.8 (1.5) for IR-to-ER and -13.3 (1.6) for ER-to-ER. Rates of premature discontinuation owing to adverse events were 6.5% for IR-to-ER and 4.9% for ER-to-ER. Conclusions: By OFF-time and UPDRS criteria, majorities of patients with advanced PD were successfully switched overnight from pramipexole IR to ER at unchanged daily dosage. During subsequent maintenance, pramipexole showed sustained efficacy, safety, and tolerability, regardless of formulation (IR or ER) in the preceding DB trial. European Journal of Neurology © 2012 EFNS.
  • Author:
    Kroker KS; Rast G; Giovannini R; Marti A; Dorner-Ciossek C; Rosenbrock H
    Title:
    Inhibition of acetylcholinterase and phosphodiesterase-9A has differential effects on hippocampal erly and late LTP.
    Source:
    Neuropharmacology 62 (5-6), 1964-1974 (2012)
  • Author:
    Derogatis L; Rosen RC; Goldstein I; Werneburg B; Kemthorne-Rawson J; Sand M
    Title:
    Characterization of hypoactive sexual disire disorder (HSDD) in men.
    Source:
    J Sex Med 9 (3), 812-820 (2012)
  • Author:
    Aubert Y; Gustison ML; Gardner LA; Bohl MA; Lange JR; Allers KA; Sommer B; Datson NA; Abbott DH
    Title:
    Flibanserin and 8-OH-DPAT implicate serotonin in association between female marmoset monkey sexual behavior and changes in pair-bond quality.
    Source:
    J Sex Med 9 (3), 694-707 (2012)
  • Author:
    Oeckl P; Steinacker P; Lehnert S; Jesse S; Kretzschmar HA; Ludolph AC; Otto M; Ferger B
    Title:
    Csf concentrations of camp and cgmp are lower in patients with creutzfeldt-jacob disease but not parkinson's disease and amyotrophic lateral sclerosis.
    Source:
    PLoS ONE 7 (3) art.no.32664 (2012)
  • Author:
    Lehnert S; Jesse S; Steinacker P; Rist W; Soininen H; Henukka S-K; Tumani H; Lenter M; Oeckel P; Ferger B; Hengerer B; Otto M
    Title:
    ITRAQ and multiple reaction monitoring as proteomic tools for biomarker search in cerebrospinal fluid of patients with Parkinson's disease dementia.
    Source:
    Exp Neurol 234 (2), 499-505 (2012)
  • Author:
    Gillardon F; Schmid R; Draheim H
    Title:
    Parkinson's disease-linked leucine-rich repeat-kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity.
    Source:
    Neuroscience 208, 41-48 (2012)
  • Author:
    Huynh HK; Beers C; Willemsen A; Lont E; Laan E; Dierckx R; Jansen M; Sand M; Weijmar Schultz W; Holstege G
    Title:
    High-intensity erotic visual stimuli de-activate the primary visual cortex in women.
    Source:
    J Sex Med 9 (6), 1579-1587 (2012)
    Abstract:
    Introduction. The primary visual cortex, Brodmann's area (BA 17), plays a vital role in basic survival mechanisms in humans. In most neuro-imaging studies in which the volunteers have to watch pictures or movies, the primary visual cortex is similarly activated independent of the content of the pictures or movies. However, in case the volunteers perform demanding non-visual tasks, the primary visual cortex becomes de-activated, although the amount of incoming visual sensory information is the same. Aim. Do low- and high-intensity erotic movies, compared to neutral movies, produce similar de-activation of the primary visual cortex? Methods. Brain activation/de-activation was studied by Positron Emission Tomography scanning of the brains of 12 healthy heterosexual premenopausal women, aged 18-47, who watched neutral, low- and high-intensity erotic film segments. Main Outcome Measures. We measured differences in regional cerebral blood flow (rCBF) in the primary visual cortex during watching neutral, low-intensity erotic, and high-intensity erotic film segments. Results. Watching high-intensity erotic, but not low-intensity erotic movies, compared to neutral movies resulted in strong de-activation of the primary (BA 17) and adjoining parts of the secondary visual cortex. Conclusions. The strong de-activation during watching high-intensity erotic film might represent compensation for the increased blood supply in the brain regions involved in sexual arousal, also because high-intensity erotic movies do not require precise scanning of the visual field, because the impact is clear to the observer. Huynh HK, Beers C, Willemsen A, Lont E, Laan E, Dierckx R, Jansen M, Sand M, Weijmar Schultz W, and Holstege G. High-intensity erotic visual stimuli de-activate the primary visual cortex in women. J Sex Med 2012;9:1579-1587. © 2012 International Society for Sexual Medicine. Reaxys Database Information
  • Author:
    Bantscheff M; Hobson S; Kuster B
    Title:
    Affinity purification of proteins binding to kinase inhibitors immobilized on self-assembling monolayers.
    Source:
    Methods Mol Biol 795, 149-160 (2012)
  • Author:
    Aicher B; Peil H; Peil B; Diener H-C
    Title:
    Pain measurement: Visual analogue scale (VAS) and verbal rating scale (VRS) in clinical trials with OTC analgesics in headache.
    Source:
    Cephalalgia 32 (3), 185-197 (2012)
  • Author:
    Demyttenaere K; Desaiah D; Petit C; Brecht S; Croenlein J
    Title:
    Time course of improvement of different symptom clusters in patients with major depression and pain treated with duloxetine or placebo.
    Source:
    Curr Med Res Opin 28 (1), 41-48 (2012)
    Abstract:
    Objective: This post hoc analysis assessed improvements in a broad range of psychopathological dimensions and in interference of pain with functioning as well as the time course of these improvements in patients with major depressive disorder (MDD) and pain treated with duloxetine versus placebo. Research design and methods: Data were derived from an 8-week, double-blind, placebo-controlled study in adult outpatients with MDD and non-specific physical pain. Mean times between improvement in Brief Pain Inventory (BPI) pain severity and interference of pain with functioning, depression severity, and dimensions of the Symptom Checklist-90 Revised (SCL-90-R) subscales were evaluated by responder analysis. Results: For all SCL-90-R subscores, a higher percentage of duloxetine-treated patients reached responder status (50% improvement) as compared to placebo, of these anger/hostility and interpersonal sensitivity had the highest response rates. In the duloxetine-treated group, response for anger/hostility, phobic anxiety, psychoticism, and most items assessing interference of pain with functioning was reached earlier than response for pain severity. The times to response for MontgomeryAsberg Depression Rating Scale (MADRS) and for pain severity were similar. In the placebo-treated group, times to response for depression, anxiety, and MADRS were longer than response for pain severity. Conclusions: Duloxetine, and to a lesser degree placebo, not only improved depressive symptomatology and pain severity but also a much broader range of psychopathological symptoms. Time courses of improvements were different for duloxetine and placebo, in that depression and interference of pain with functioning improved earlier than pain severity in duloxetine-treated patients but not in placebo-treated patients. These results suggest that time to response is a valuable means of characterizing treatment effects. Limitations: Pain was only assessed as a symptom and no further clinical diagnosis for pain syndromes were performed.
  • Author:
    Converse AK; Aubert Y; Farhoud M; Weichert JP; Rowland IJ; Ingrisano NM; Allers KA; Sommer B; Abbott DH
    Title:
    Positron emission tomography assessment of 8-OH-DPAT-mediated changes in an index of cerebral glucose metabolism in female marmosets.
    Source:
    Neuroimage 60 (1), 447-455 (2012)
  • Author:
    Demyttenaere K; Dessaiah D; Petit C; Croenlein J; Brecht St
    Title:
    Time course of improvement of different symtom clusters in patients with major depression and pain treated with duloxetine or placebo.
    Source:
    Curr Med Res Opin 28 (1), 41-48 (2012)
  • Author:
    Kreutzer M; Seehusen F; Kreutzer R; Pringproa K; Kummerfeld M; Claus P; Deschl U; Kalkul A; Beineke A; Baumgaertner W; Ulricn R
    Title:
    Axonopathy is associated with complex axonal transport defects in a model of multiple sclerosis.
    Source:
    Brain Pathol 22 (4), 454-471 (2012)
    Abstract:
    Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized by myelin and axonal pathology. In a viral model of MS, we tested whether axonopathy initiation and development are based on an impaired transport of neurofilaments. Spinal cords of Theiler's murine encephalomyelitis virus (TMEV)-infected and mock-infected mice and TMEV infected neuroblastoma N1E-115 cells were analyzed by microarray analysis, light microscopy and electron and laser confocal microscopy. In vivo axonal accumulation of non-phosphorylated neurofilaments after TMEV infection revealed a temporal development caused by the impairments of the axonal traffic consisting of the downregulation of kinesin family member 5A, dynein cytoplasmic heavy chain 1, tau-1 and ß-tubulin III expression. In addition, alterations of the protein metabolism were also noticed. In vitro, the TMEV-infected N1E-115 cells developed tandem-repeated swellings similar to in vivo alterations. Furthermore, the hypothesis of an underlying axonal self-destruction program involving nicotinamide adenine dinucleotide depletion was supported by molecular findings. The obtained data indicate that neurofilament accumulation in TME is mainly the result of dysregulation of their axonal transport machinery and impairment of neurofilament phosphorylation and protein metabolism. The present findings allow a more precise understanding of the complex interactions responsible for initiation and development of axonopathies in inflammatory degenerative diseases.
  • Author:
    Picchietti DL; Arbuckle RA; Abetz L; Durmer JS; Ivanenko A; Owens JA; Croenlein J; Allen RP; Walters AS
    Title:
    Pediatric restless legs syndrome: Analysis of symptom description and drawings.
    Source:
    J Child Neurol 26 (11), 1365-376 (2011)
  • Author:
    Diener HC; Peil H; Aicher B
    Title:
    The effiacy and tolerability of a fixed combination of acetylsalicylic acid, paracetamol and caffeine in patients with severe headache: A post-hoc subgroup analysis from a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study.
    Source:
    Cephalalgia 31 (14), 1466-1476 (2011)
  • Author:
    Lund SS; Tarnow L; Frandsen M; Smidt UM; Pedersen O; Parving HH; Vaag AA
    Title:
    Impact of metformin versus the prandial insulin secretagogue, repaglinide, on fasting and postprandial glucose glucose and lipid responses in non-obese patients with type 2 diabetes (Vol 158, pg 35, 2008).
    Source:
    Eur J Endocrinol 165 (5), 831 (2011)
  • Author:
    Edwards A; Pidsley R; Huang G-J; Cleak J; Flint J; Treiber CD; Breuss M; Oliver PL; Keays DA
    Title:
    Cytoarchitectural distribution of the superior colliculus and an enlarged acoustic startle response in the tubala mutant mouse.
    Source:
    Neuroscience 195, 191-200 (2011)
  • Author:
    Kroker KS; Rast G; Rosenbrock H
    Title:
    Differential effects of subtype-specific nicotinic acetylcholine receptor agonists on early and late hippocampal LTP.
    Source:
    Eur J Pharmacol 671 (1-3), 26-32 (2011)
    Abstract:
    Brain nicotinic acetylcholine receptors are involved in several neuropsychiatric disorders, e.g. Alzheimer's and Parkinson's diseases, Tourette's syndrome, schizophrenia, depression, autism, attention deficit hyperactivity disorder, and anxiety. Currently, approaches selectively targeting the activation of specific nicotinic acetylcholine receptors are in clinical development for treatment of memory impairment of Alzheimer's disease patients. These are ?4?2 and ?7 nicotinic acetylcholine receptor agonists which are believed to enhance cholinergic and glutamatergic neurotransmission, respectively. In order to gain a better insight into the mechanistic role of these two nicotinic acetylcholine receptors in learning and memory, we investigated the effects of the ?4?2 nicotinic acetylcholine receptor agonist TC-1827 and the ?7 nicotinic acetylcholine receptor partial agonist SSR180711 on hippocampal long-term potentiation (LTP), a widely accepted cellular experimental model of memory formation. Generally, LTP is distinguished in an early and a late form, the former being protein-synthesis independent and the latter being protein-synthesis dependent. TC-1827 was found to increase early LTP in a bell-shaped dose dependent manner, but did not affect late LTP. In contrast, the ?7 nicotinic acetylcholine receptor partial agonist SSR180711 showed enhancing effects on both early and late LTP in a bell-shaped manner. Furthermore, SSR180711 not only increased early LTP, but also transformed it into late LTP, which was not observed with the ?4?2 nicotinic acetylcholine receptor agonist. Therefore, based on these findings ?7 nicotinic acetylcholine receptor (partial) agonists appear to exhibit stronger efficacy on memory improvement than ?4?2 nicotinic acetylcholine receptor agonists.
  • Author:
    Oeckl P; Ferger B
    Title:
    Simultaneous LC-MS/MS analysis of the biomarkers cAMP and cGMP in plasma. CSF and brain tissue.
    Source:
    J Neurosci Methods 203 (2), 338-343 (2012)
    Abstract:
    The cyclic nucleotides cyclic adenosine-3',5'-monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) are important second messengers. They are useful biomarkers to indicate biological activity of drugs such as phosphodiesterase (PDE) inhibitors which block the degradation of these nucleotides. Here, we established a fast and sensitive method for the simultaneous analysis of cAMP and cGMP by LC-MS/MS with broad applicability. The limit of detection is 50. pM. Linearity is given in a range of 0.5-500. nM for both nucleotides, with a high intra- and inter-assay precision and accuracy and an analysis time of 3.5. min. We validated the suitability of the method by pharmacological modulation of cAMP or cGMP concentrations in mice with the PDE4 inhibitor rolipram and the PDE5 inhibitor zaprinast. Rolipram significantly increased cAMP concentrations in plasma, CSF and brain tissue. Zaprinast increased cGMP concentrations in plasma but not in brain tissue, which is in accordance with its blood brain barrier permeability. In conclusion, the LC-MS/MS method described here could be a valuable analytical tool for investigating pharmacodynamic effects of PDE inhibitors and to monitor disease-related changes of cAMP and cGMP in the periphery as well as in the central nervous system.
  • Author:
    Vlad C; Lindner K; Karreman C; Schicknecht S; Leist M; Tomczyk N; Rontree J; Langridge J; Danzer K; Ciossek T; Petre A; Gross ML; Hengerer B; Przybylski M
    Title:
    Autoproteolytic fragments are intermediates in the oligomerization/aggregation of the Parkinson's disease protein alpha-synuclein as revealed by ion mobility mass spectrometry.
    Source:
    ChemBioChem 12 (18), 2740-2744 (2011)
  • Author:
    Schneider E; Linden M; Weigmann H; Wagner T; Quail D; Hundemer H-P; Hegerl U
    Title:
    Early reduction in painful physical symptoms is associated with improvements in long-term depression outcomes in patients treated with duloxetine.
    Source:
    BMC Psychiatry 11 art.no.150 (2011)
    Abstract:
    Background: To investigate the association of the change of painful physical symptoms (PPS) after 4 weeks, with the 6-month treatment outcomes of depressive symptoms in patients treated with duloxetine in clinical practice.Methods: Multicenter, prospective, 6-month, non-interventional study in adult outpatients with a depressive episode and starting treatment with duloxetine. Depression severity was assessed by the clinician (Inventory for Depressive Symptomatology [IDS-C]) and patient (Kurz-Skala Stimmung/Aktivierung [KUSTA]). Somatic symptoms and PPS were assessed using the patient-rated Somatic Symptom Inventory (SSI) and visual analog scales (VAS) for pain items. Association of change in PPS with outcomes of depressive symptoms was analyzed based on mean KUSTA scores (mean of items mood, activity, tension/relaxation, sleep) and achievement of a 50% reduction in the total IDS-C score after 6 months using linear and logistic regression models, respectively.Results: Of the 4,517 patients enrolled (mean age: 52.2 years, 71.8% female), 3,320 patients (73.5%) completed the study. 80% of the patients had moderate to severe overall pain (VAS > 30 mm) at baseline. A 50% VAS overall pain reduction after 4 weeks was associated with a 13.32 points higher mean KUSTA score after 6 months, and a 50% pain reduction after 2 weeks with a 6.33 points improvement. No unexpected safety signals were detected in this naturalistic study.Conclusion: Pain reduction after 2 and 4 weeks can be used to estimate outcomes of long-term treatment with duloxetine. PPS associated with depression have a potential role in predicting remission of depressive symptoms in clinical practice.
  • Author:
    Haist V; Ulrich R; Kalkuhl A; Deschl U; Baumgaertner W
    Title:
    Distinct spatio-temporal extracellular matrix accumulation within demyelinated spinal cord lesions in theiler's murine encephalomyelitis.
    Source:
    Brain Pathol 22 (2), 188-204 (2012)
    Abstract:
    The accumulation of extracellular matrix (ECM) and glial scar formation are considered important factors for the failure of regeneration in central nervous system (CNS) injury and multiple sclerosis. Theiler's murine encephalomyelitis (TME) as a model of multiple sclerosis served to evaluate the spatio-temporal course of ECM alterations in demyelinating conditions. Microarray analysis revealed only mildly upregulated gene expression of ECM molecules, their biosynthesis pathways and pro-fibrotic factors, while upregulation of matrix remodeling enzymes was more prominent. Immunohistochemistry demonstrated progressive accumulation of chondroitin sulfate proteoglycans, glycoproteins and collagens within demyelinated TME lesions, paralleling the development of astrogliosis. Deposition of collagen IV, laminin, perlecan and tenascin-C started 28 days postinfection (dpi), collagen I, decorin, entactin and neurocan accumulated from 56dpi on, and fibronectin from 98dpi on. The basement membrane (BM) molecules collagen IV, entactin, fibronectin, laminin and perlecan showed perivascular and parenchymal deposition, while the non-BM components collagen I, decorin, neurocan and tenascin-C only accumulated in a nonvascular pattern in demyelinated areas. Contrary, phosphacan expression progressively decreased during TME. The immunoreactivity of aggrecan and brevican remained unchanged. The spatio-temporal association of matrix accumulation with astrogliosis suggests a mainly astrocytic origin of ECM deposits, which in turn may contribute to remyelination failure in TME.
  • Author:
    Sand M
    Title:
    Errata by Fabre et al. in gepirone-ER treatment of hypoactive sexual desire disorder associated with depression in women.
    Source:
    J Sex Med 8 (10), 2954 (2011)
  • Author:
    Fornaro M; Maremmani I; Canonico PL; Carbonatto P; Mencacci C; Muscettola G; Pani L; Torta R; Vampini C; Parazzini F; Dumitriu A; Perugi G
    Title:
    Prevalence and diagnostic distribution of medically unexplained painful somatic symptoms across 571 major depressed outpatients.
    Source:
    Neuropsychiatr Dis Treat 7, 217-221 (2011)
    Abstract:
    To assess the prevalence and distribution of medically unexplained painful somatic symptoms (PSSs) versus nonpainful somatic symptoms (NPSSs) in patients diagnosed with major depressive episode (MDE). Method: A total of 571 outpatients diagnosed with MDE according to DSM-IV-TR criteria were consecutively enrolled into a cross-sectional, multicentric, observational study over a period of 7 months. Subjects were evaluated by means of the ad hoc validated 30-item Somatic Symptoms Checklist (SSCL-30) and Zung's questionnaires for depression and anxiety. The 32-item Hypomania Checklist (HCL-32) was also administered in order to explore any eventual association of PSSs or NPSSs with sub-threshold (DSM-IV-TR [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision] not recognized) bipolar disorder (BD). Results: In our sample, just 183 patients (32%) did not report painful somatic symptoms (NPSSs). Of these, 90 patients (15.76%) had no somatic symptoms at all. The remaining 388 (68%) had at least one PSS being subdivided as follows: 248 (43%) had one or two PSSs, while 140 (25%) experienced two or more. Patients with at least one PSS also reported a greater number of nonpainful somatic symptoms than NPSS. Bipolar patients (associated with higher HCL-32 scores) were less represented across PSS cases than NPSS subjects. Conversely, females were more prone to having a higher number of total somatic symptoms (and bipolar features). Conclusion: PSSs are common in patients with MDE, especially among those patients reporting fewer somatic symptoms in general as opposed to those patients who exhibit more somatic symptoms (both PSSs and NPSSs) with lower relative number of PSSs. A major therapeutic implication is that antidepressant monotherapy could be used with more confidence in unexplained PSS patients than in NPSS patients because of the latter group's lower frequency of (sub)-threshold bipolar features.
  • Author:
    Brecht St; Desaiah D; Marechal ES; Santini AM; Podhorna J; Guelfi JD
    Title:
    Efficacy and safety of duloxetine 60 mg and 120 mg daily in patients hospitalized for serve depression: a double-blind randomized trial.
    Source:
    J Clin Psychiatry 72 (8), 1086-1094 (2011)
    Abstract:
    OBJECTIVE: To assess whether hospitalized patients with severe depression and potential suicidal ideation/behavior have earlier and better response to duloxetine 120 mg daily than 60 mg daily. METHOD: Adults from 34 sites in 4 countries with severe major depressive disorder, defined by DSM-IV criteria, who were demonstrating Montgomery-Asberg Depression Rating Scale (MADRS) scores .gtoreq. 30, 6-item Hamilton Depression Rating Scale (HDRS-6) scores .gtoreq. 12, and Clinical Global Impressions-Severity of Illness scale (CGI-S) .gtoreq. 4 and hospitalized .gtoreq. 2 weeks underwent double-blind treatment with either duloxetine 60 mg (n = 167) or 120 mg (n = 171) daily for 8 weeks. Patients treated with 60 mg/d who did not respond had their doses titrated up to 120 mg/d. Primary outcome was the difference in baseline to week 4 change in MADRS scores between the groups. Secondary outcomes were baseline to week 8 changes in MADRS and HDRS-6 scores, response and remission, CGI-S scores, CGI-Improvement scores, Patient Global Impressions-Improvement, Hamilton Anxiety Rating Scale scores, and Reasons For Living inventory results. Safety was also assessed. The study was conducted between February 9, 2007, and August 26, 2008. RESULTS: There was no significant difference in mean baseline to week 4 MADRS score change between the 60-mg (-20.1) and 120-mg (-19.9) groups (P = .88). At week 4, 96/166 (60 mg) and 106/170 (120 mg) patients responded and maintained responses at week 8 by further decreasing mean MADRS scores to 5.8 (60 mg) and 5.6 (120 mg). At week 8, 226/336 (67.3%) patients achieved remission, with no difference demonstrated between groups. Most secondary efficacy measures were significantly reduced from baseline to week 8 within each group and did not differ between groups. Treatment-emergent adverse events observed with > 10% frequency in both groups were headache and nausea. CONCLUSIONS: Duloxetine 60-mg and 120-mg doses were equally effective and demonstrated no significant differences in treating severe depressive symptoms in hospitalized patients. The safety and tolerability profile of duloxetine in both dosages did not differ and was similar to those reported in previous duloxetine studies.
  • Author:
    Graefe-Mody U; Friedrich C; Port A; Ring A; Retlich S; Heise T; Halabi A; Woerle H-J
    Title:
    Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin(+).
    Source:
    Diabetes Obes Metab 13 (10), 939-946 (2011)
    Abstract:
    Aim: This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily non-renal route of excretion, in subjects with type 2 diabetes mellitus (T2DM). Methods: Linagliptin pharmacokinetics was studied under single-dose and steady-state conditions in subjects with mild, moderate and severe renal impairment (with and without T2DM) and end-stage renal disease and compared with the pharmacokinetics in subjects with normal renal function (with and without T2DM). Results: Renal excretion of unchanged linagliptin was <7% in all groups. Under single-dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration-time profiles. These showed a similar decline and almost identical plasma concentrations 24 h postdosing in subjects with mild, moderate or severe renal impairment and in subjects with T2DM with and without renal impairment. Although there was a tendency towards slightly higher (20-60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady-state AUC and C-max values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half-life of linagliptin ranged from 14-15 h in subjects with normal renal function to 18 h in severe renal impairment. Only a weak correlation (r(2) = 0.18) was seen between creatinine clearance and steady-state exposure. Conclusions: Renal impairment has only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM. - DERWENT Abstract - The Authors assessed the influence of various degrees of renal impairment on exposure to linagliptin, a dipeptidyl peptidase-4 inhibitor with a primarily nonrenal route of excretion, in a parallel-group open-label study of 34 subjects with mild, moderate, and severe renal impairment with and without type 2 diabetes mellitus (T2DM) and end-stage renal disease and 17 subjects with normal renal function with and without T2DM. Renal impairment had only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM. 34 Subjects with mild (n=6, mean age 65.2 yr, 4 male), moderate (n=6, mean age 60.3 yr, 3 male), and severe (n=6, mean age 57.3 yr, 4 male) renal impairment with (severe renal impairment, n=10, mean age 60.8 yr, 6 male) and without T2DM and end-stage renal disease (requiring hemodialysis, n=6, mean age 41.7 yr, 4 male) and 17 subjects with normal renal function with (n=11, mean age 60.6 yr, 5 male) and without T2DM (n=6, mean age 60.2 yr, 4 male) were stratified into groups according to the degree of renal impairment. Renal excretion of unchanged linagliptin was less than 7% in all groups. Under single-dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration-time profiles. These showed a similar decline and almost identical plasma concentrations 24 hr postdosing in subjects with mild, moderate, or severe renal impairment and in subjects with T2DM with an without renal impairment. Although there was a tendency toward slightly higher (20%-60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady-state AUC and Cmax values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half-life of linagliptin ranged from 14-15 hr in subjects with normal renal function to 18 hr in severe renal impairment. Only a weak correlation was seen between creatinine clearance and steady-state exposure.
  • Author:
    Poewe W; Rascokl O; Barone P; Hauser RA; Mizuno Y; Haaksma M; Salin L; Juhel N; Schapira AHV
    Title:
    Extended-release pramipexole in early Parkinson disease A 33-week randomized controlled trial.
    Source:
    Neurology 77 (8), 759-766 (2011)
    Abstract:
    Objective: To assess the clinical efficacy of a novel once-daily extended-release (ER) formulation of the dopamine agonist pramipexole as monotherapy in patients with early Parkinson disease (PD) and establish its noninferiority vs standard immediate-release (IR) pramipexole. Methods: This was a multicenter, double-blind, parallel study of patients with early PD not receiving levodopa or dopamine agonists, randomly assigned to pramipexole IR, pramipexole ER, or placebo. Seven-week flexible titration was followed by 26-week maintenance, with levodopa permitted as rescue medication. The primary analysis was to test pramipexole ER noninferiority to pramipexole IR based on a change in the Unified Parkinson's Disease Rating Scale (UPDRS) part II+III score at 33 weeks, with noninferiority predefined as a treatment group difference for which the lower bound of the 95% confidence interval (CI) did not exceed -3 points. Results: Among 213 ER and 207 IR recipients, the adjusted mean 33-week UPDRS II+III change (excluding levodopa rescue effects) was -8.2 for ER and -8.7 for IR, a difference of -0.5 with a 95% CI of -2.3 to 1.3. Compared with placebo (n = 103), pramipexole ER and pramipexole IR were significantly superior on UPDRS II+III score, all key secondary outcomes, and almost all other endpoints. On the 39-item Parkinson Disease Questionnaire, superiority of pramipexole ER failed to reach statistical significance. Both formulations were equally safe and well-tolerated. Conclusions: As monotherapy for early PD, pramipexole ER was noninferior to pramipexole IR and significantly more effective than placebo. Tolerability and safety did not differ between the formulations. - DERWENT Abstract - This phase 3, multicenter, double-blind, parallel, placebo-controlled, randomized study (NCT00479401) evaluated efficacy, safety and tolerability of new once-daily extended-release (ER) formulation of pramipexole (PX) as monotherapy in 539 patients with early Parkinson disease and established its non-inferiority vs. standard immediate release (IR) PX. Compared with placebo, PX ER and PX IR were superior on Unified Parkinson's Disease Rating Scale II + III score, all key secondary outcomes, and almost all other endpoints. On 39-item Parkinson Disease Questionnaire, superiority of PX ER failed to reach significance. Both formulations were equally safe and well-tolerated. Adverse events noted more frequently in PX were somnolence, nausea, constipation, dizziness and dry mouth. As monotherapy for early Parkinson disease, PX ER was non-inferior to PX IR and more effective than placebo. Methods 539 Patients with early Parkinson disease were randomly assigned in a 2:2:1 ratio to receive PX ER (0.375, 0.75, 1.5, 2.25, 3, 3.75, or 4.5 mg/day) (n=223, mean age 61.3 yr), PX IR (0.125, 0.25, 0.50, 0.75, 1, 1.25 or 1.5 mg t.i.d.) (n=213, mean age 61.7 yr) or matching placebo (n=103, mean age 62 yr) in a double-blind fashion. Results 98 Patients discontinued before completing 33 wk (11.7% in placebo, 22% in ER arm, and 17.4% in IR arm). At wk 33, 15/213 ER recipients and 9/207 IR recipients vs. 22/103 placebo recipients had received adjunct levodopa. The adjusted mean decrease in Unified Parkinson's Disease Rating Scale II + III score at 33 wk was -8.2 for ER and -8.7 for IR. Both PX formulations showed a significant difference from placebo on the adjusted mean changes in Unified Parkinson's Disease Rating Scale II + III score. Superiority of both formulations was also observed in all key secondary outcomes. The mean duration of exposure to study drug was 199 days for ER and 208.2 days for IR compared with 215.2 days for placebo. The final mean study medication dosage was 2.9 mg/day in PX ER group and 2.9 mg/day in PX IR group compared with 3.2 mg/day of matched placebo in placebo group. Overall, 88.3% of subjects in placebo, 78% of subjects in PX ER group and 82.6% in PX IR group completed the study. The percentages of patients with adverse events leading to discontinuation were 3.9% in placebo group, 10.8% in ER group and 9.4% in IR group. Adverse events reported more frequently in PX group than in placebo group were somnolence, nausea, constipation, dizziness and dry mouth. There were no reports of drug-induced dyskinesias or motor fluctuations.
  • Author:
    Schapira AHV; Barone P; Hauser RA; Mizuno Y; Rascol O; Busse M; Salin L; Juhel N; Poewe W
    Title:
    Extended-release pramipexole in advanced Parkinson disease a randomized controlled trial.
    Source:
    Neurology 77 (8), 767-774 (2011)
    Abstract:
    Background: In advanced Parkinson disease (PD), immediate-release pramipexole, taken 3 times daily, improves symptoms and quality of life. A once-daily extended-release formulation may be an effective and simple alternative therapy. Methods: For a multicenter randomized, double-blind, parallel trial of extended-and immediate-release pramipexole vs placebo, patients experiencing motor fluctuations while taking levodopa underwent flexible study drug titration and then maintenance at optimized dosage (0.375-4.5 mg/day). The primary endpoint was a change in the Unified Parkinson's Disease Rating Scale (UPDRS) part II+III score at 18 weeks, with further assessments at 33 weeks in a subset of patients. Adverse events were recorded throughout. Results: Among 507 patients in the 18-week analyses, UPDRS II+III scores decreased (from baseline means of 40.0-41.7) by an adjusted mean of -11.0 for extended-release pramipexole and -12.8 for immediate-release pramipexole vs -6.1 for placebo (p = 0.0001 and p < 0.0001) and off-time decreased (from baseline means of 5.8-6.0 hours/day) by an adjusted mean of -2.1 and -2.5 vs -1.4 hours/day (p = 0.0199 and p < 0.0001). Other outcomes were largely corroborative, including a significant improvement in early morning off symptoms. Among 249 pramipexole patients completing 33 weeks, UPDRS II+III and off-time findings showed <= 10.1% change from 18-week values. Both formulations were well-tolerated. Conclusions: Extended-release pramipexole significantly improved UPDRS score and off-time compared with placebo, with similar efficacy, tolerability, and safety of immediate-release pramipexole compared with placebo. Classification of evidence: This study provides Class I evidence that the extended-release form of pramipexole, taken once daily, is efficacious as an adjunct to levodopa in advanced PD. - DERWENT Abstract - This phase III, multicenter, randomized, placebo-controlled, double-blind, parallel study (NCT00466167) evaluated efficacy, safety and tolerability of extended-release (ER) pramipexole (PX, Sifrol, Mirapex, Mirapexin, Pexola, Boehr.Ingelheim) in 517 patients experiencing motor fluctuations with levodopa for advanced Parkinson disease, and compared it with immediate-release (IR) PX and placebo. Among 507/517 patients in efficacy analyses, UPDRS II + III score decreased for ER PX and IR PX vs. placebo. Other outcomes were largely corroborative, including improvement in early morning off symptoms. ER PX improved UPDRS II + III score and off-time compared with placebo, with similar efficacy, tolerability, and safety of IR PX compared with placebo. Adverse events noted were dyskinesia, somnolence, nausea, constipation, headache, hallucination, dizziness and vomiting. Methods 517 Patients experiencing motor fluctuations with levodopa for advanced Parkinson disease randomly received (in a 1:1: ratio) placebo (n=178, mean age 60.9 yr), ER PX (0.375, 0.75, 1.5, 2.25, 3, 3.75 or 4.5 mg once daily) (n=164, mean age 61.6 yr) and IR PX (0.125, 0.25, 0.50, 0.75, 1, 1.25 or 1.5 mg t.i.d.) (n=175, mean age 62 yr). Results Among them, 11.8% of placebo recipients, 11.6% of PX ER recipients and 6.9% of PX IR recipients discontinued before completing 18 wk, most often due to adverse events. Of 517 patients, 507 provided postbaseline data for the study's 18 wk efficacy analyses. In full-analysis set at 18 wk, the adjusted mean decrease in UPDRS II + III score was -11 for PX ER and -12.8 for PX IR vs. -6.1 for placebo. Off-time decreased by an adjusted mean -2.1 hr/day for PX ER and -2.5 hr/day for PX IR vs. -1.4 hr/day for placebo. Of 337 patients who completed the study up to 33 wk, 308 patients had an evaluable UPDRS II + III score, permitting descriptive evaluation of 33 wk mean change from baseline vs. 18 wk mean change from baseline with no use of last observation carried forward. Among all treated patients, the proportion reporting any adverse events while taking PX ER, as of wk 18, resembled the proportion for placebo (at 54.9% and 55.6%) and was lower than the proportion for PX IR (64%). The frequency of severe adverse events was similar in each PX group and the frequency of serious adverse events and adverse events leading to premature discontinuation was similar in all groups. Adverse events reported by the patients were dyskinesia, somnolence, nausea, constipation, headache, hallucination, dizziness, and vomiting.
  • Author:
    Meyers JL; Davis KL; Yu YF
    Title:
    Stroke and transient ischemic attack in the long-term care setting: Patient characteristics, medication treatment and length of stay.
    Source:
    Consultant Pharm 26 (3), 170-181 (2011)
    Abstract:
    Objective: To examine the percentage of patients treated with antiplatelet or anticoagulant therapy among patients with stroke or transient ischemic attack (TIA) in the long-term care setting. Design: Data were taken from the Minimum Data Set. Information regarding medications was derived from a linked pharmacy-claims database. Setting: Long-term care facilities. Patients, participants: Residents of long-term care facilities with stroke or TIA as indicated in the database between January 1, 2007, and December 31, 2008, were selected; 14,469 patients with stroke and 833 patients with TIA were identified. Interventions: None. Main study variables: Demographics, admission and payer source, residential history, quality measures, comorbidities, and antiplatelet and anticoagulant therapies received. Results: Approximately 48% of stroke patients and 53% of TIA patients received any antiplatelet or anticoagulant medication. Stroke patients had a mean (standard deviation [SD]) of 19.5 (73.2) days from their first assessment to their first medication, and they received therapy for a mean (SD) of 112.3 (258.3) days. TIA patients had a mean (SD) of 13.7 (54.9) days from their first assessment to their first medication, and they received therapy for a mean (SD) of 67.0 (165.7) days. In both cohorts, clopidogrel was the most common therapy received (22.5% of stroke patients and 24.6% of TIA patients). Conclusions: Health care providers treating patients in the long-term care setting should be aware of the population characteristics and high rate of undertreatment observed in this analysis. This study may help inform optimal decisionmaking by physicians and other health care practitioners.
  • Author:
    Gerlach M; Maetzler W; Broich K; Hampel H; Rems L; Reum T; Riederer P; Stoeffler A; Streffer J; Berg D
    Title:
    Biomarker candidates of neurogeneration in Parkinson's disease for the evaluation of disease-modifying therapeutics.
    Source:
    J Neural Transm 119 (1), 39-52 (2012)
    Abstract:
    Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson's disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of ?-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies.
  • Author:
    Horie Y; Kanada Sh; Watada H; Sarashina A; Taniguchi A; Hayashi N; Graefe-Mody EU; Woerle H-J; Dugi KA
    Title:
    Pharmacokinetic, pharmacodynamic and tolerability profiles of the dipeptidyl peptidase-4 inhibitor Linagliptin: A 4-week multicenter, randomized, double-blind, placebo-controlled phase IIa study in Japanese type 2 diabetes patients.
    Source:
    Clin Ther 33 (7), 973-989 (2011)
    Abstract:
    BACKGROUND: The dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin is under clinical development for treatment of type 2 diabetes mellitus (T2DM). In previous studies in white populations it showed potential as a once-daily oral antidiabetic drug. OBJECTIVES: In compliance with regulatory requirements for new drugs intended for use in the Japanese population, this study investigated the pharmacokinetics, pharmacodynamics, and tolerability of multiple oral doses of linagliptin in Japanese patients with T2DM. METHODS: In this randomized, double-blind, placebo-controlled multiple dose study, 72 Japanese patients with T2DM were assigned to receive oral doses of linagliptin 0.5, 2.5, or 10 mg or placebo (1:1:1:1 ratio) once daily for 28 days. For analysis of pharmacokinetic properties, linagliptin concentrations were determined from plasma and urinary samples obtained throughout the treatment phase, with more intensive samplings on days 1 and 28. DPP-4 inhibition, glycosylated hemoglobin A1c (HbA(1c)) levels, and plasma glucose and glucagon-like peptide-1 (GLP-1) levels were compared by mixed effect model. Tolerability was assessed throughout the study by physical examination, including blood pressure and pulse rate measurements, 12-lead ECG, and laboratory analysis. RESULTS: Baseline demographic characteristics were well balanced across the 4 treatment groups (mean [SD] age, 59.7 [6.4] years in the placebo group, 60.8 [9.2] years in the 0.5 mg group, 60.2 [6.4] years in the 2.5 mg group, and 59.1 [8.6] years in the 10 mg group; mean [SD] weight, 67.2 [10.0] kg in the placebo group, 64.5 [9.0] kg in the 0.5 mg group, 69.6 [9.4] kg in the 2.5 mg group, and 63.5 [12.2] kg in the 10 mg group; mean [SD] duration of T2DM diagnosis, 5.1 [4.2] years in the placebo group, 5.2 [4.7] years in the 0.5 mg group, 5.9 [4.8] years in the 2.5 mg group, and 2.6 [2.3] years in the 10 mg group). The majority of the patients treated were male (76.4%). Use of previous antidiabetic medication was more common in the 2.5 mg linagliptin group (44%) than in the 0.5 or 10 mg linagliptin (15.8% and 22.2%, respectively) or placebo groups (35.3%). Total systemic exposure in terms of linagliptin AUC and C(max) (which occurred at 1.25-1.5 hours) increased in a less than dose-proportional manner. The terminal half-life was long (223-260 hours) but did not reflect the accumulation half-life (10.0-38.5 hours), resulting in a moderate accumulation ratio of <2.9 that decreased with increasing dose. Urinary excretion increased with linagliptin doses but was <7% at steady state for all dose groups. Inhibition of plasma DPP-4 at 24 hours after the last dose on day 28 was approximately 45.8%, 77.8%, and 89.7% after linagliptin 0.5, 2.5, and 10 mg, respectively. At steady state, linagliptin was associated with dose-dependent increases in plasma GLP-1 levels, and the postprandial GLP-1 response was enhanced. Statistically significant dose-dependent reductions were observed in fasting plasma glucose levels at day 29 for all linagliptin groups (-11.5, -13.6, and -25.0 mg/dL for the 0.5, 2.5, and 10 mg groups, respectively; P < 0.05 for all linagliptin groups). Linagliptin also produced statistically significant dose-dependent reductions from baseline for glucose area under the effect curve over 3 hours after meal tolerance tests (-29.0 to -68.1 mg .times. h/dL; P < 0.05 for all 3 linagliptin groups). For the 0.5 and 10 mg linagliptin-treated groups, there were statistically significant reductions in HbA(1c) from baseline compared with placebo, despite the relatively low baseline HbA(1c) (7.2%) and small sample size (P < 0.01 for both groups). The greatest reduction in HbA(1c) (-0.44%) was seen in the highest linagliptin dose group (10 mg). On dosing for up to 28 days, linagliptin was well tolerated with no reported serious adverse events or symptoms suggestive of hypoglycemia. Overall, fewer adverse events were reported by patients after linagliptin than after placebo (11 of 55 [20%] vs 6 of 17 [35%]). CONCLUSIONS: Linagliptin demonstrated a nonlinear pharmacokinetic profile in these Japanese patients with T2DM consistent with the findings of previous studies in healthy Japanese and white patients. Linagliptin treatment resulted in statistically significant and clinically relevant reductions in HbA(1c) as soon as 4 weeks after starting therapy in these Japanese patients with T2DM, suggesting that clinical studies of longer duration in Japanese T2DM patients are warranted. - DERWENT Abstract - This multicenter, randomized, double-blind, placebo-controlled, phase IIa study examined the pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 (DPP-4) inhibitor p.o. linagliptin (LIN) in 72 Japanese patients with type 2 diabetes. Total systemic exposure in terms of AUC and Cmax increased in a less than dose-proportional manner. The terminal half-life was long but did not reflect the accumulation half-life. LIN dose-dependently inhibited DPP-4, increased plasma glucagon-like peptide (GLP)-1 levels, decreased glucose AUC over 3 hr after meal tolerance tests, and decreased HbA1c. LIN was well tolerated. These findings suggest that LIN has a nonlinear pharmacokinetic profile in these patients. 72 Japanese patients with type 2 diabetes randomly received p.o. LIN (0.5, 2.5, or 10.0 mg/day) (n=19, 18, and 18, mean age 60.8, 60.2, and 59.1 yr, 15, 14, and 13 male, respectively) or placebo (17, mean age 59.7 yr, 13 male) for 28 days. LIN was rapidly absorbed in all patients, with a Tmax of 1.5 hr across doses. A less than proportional increase of LIN Cmax was seen between 0.5 and 2.5 mg, while a dose-proportional increase of Cmax was seen between 2.5 and 10.0 mg. The total exposure on day 1 of LIN increased dose-dependently, but less than dose proportionally from 0.5 to 2.5 mg and from 2.5 to 10.0 mg. In the statistical analysis for dose proportionally using a power model for the pharmacokinetic parameters AUC after the 1st dose, AUC at steady-state, Cmax after the 1st dose, and Cmax at steady-state of LIN, none of these parameters showed dose proportionality. LIN oral clearance at steady-state and Vd increased with dose. The renal excretion of the parent compound appeared to be only a minor route of elimination. The terminal half-life was long (223-260 hr) but did not reflect the accumulation half-life (10.0-38.5 hr). LIN resulted in 45.8%, 77.8%, and 89.7% inhibition of plasma DPP-4 at 24 hr after the last dose on day 28. LIN dose-dependently decreased fasting plasma glucose at day 29, being -11.5, -13.6, and -25.0 mg/l for the 0.5, 2.5, and 10.0 mg groups, respectively. LIN dose-dependently decreased glucose AUC over 3 hr after meal tolerance tests (-29.0 to -68.1 mg x hr/dl). The greatest reduction in HbA1c was seen with LIN (10.0 mg) (-0.44%). LIN was well tolerated. Overall, fewer adverse events were seen with LIN than with placebo (20% vs. 35%).
  • Author:
    Edwards PJ
    Title:
    The solution-phase design and synthesis of libraries for the discovery of CNS active substances.
    Source:
    Drug Discov Today 16 (15-16), 742-744 (2011)
  • Author:
    Loewenstein Y; Kuras A; Rumpel S
    Title:
    Multiplicative dynamics underlie the emergence of the log-normal distribution of spine sizes in the neocortex in vivo.
    Source:
    J Neurosci 31 (26), 9481-9488 (2011)
    Abstract:
    What fundamental properties of synaptic connectivity in the neocortex stem from the ongoing dynamics of synaptic changes? In this study, we seek to find the rules shaping the stationary distribution of synaptic efficacies in the cortex. To address this question, we combined chronic imaging of hundreds of spines in the auditory cortex of mice in vivo over weeks with modeling techniques to quantitatively study the dynamics of spines, the morphological correlates of excitatory synapses in the neocortex. We found that the stationary distribution of spine sizes of individual neurons can be exceptionally well described by a log-normal function. We furthermore show that spines exhibit substantial volatility in their sizes at timescales that range from days to months. Interestingly, the magnitude of changes in spine sizes is proportional to the size of the spine. Such multiplicative dynamics are in contrast with conventional models of synaptic plasticity, learning, and memory, which typically assume additive dynamics. Moreover, we show that the ongoing dynamics of spine sizes can be captured by a simple phenomenological model that operates at two timescales of days and months. This model converges to a log-normal distribution, bridging the gap between synaptic dynamics and the stationary distribution of synaptic efficacies.
  • Author:
    Voon V; Sohr M; Lang AE; Potenza MN; Siderowf AD; Whetteckey J; Weintraub D; WunderliCh GR; Stacy M
    Title:
    Impulse control disorders in Parkinson disease: A multicenter case-control study.
    Source:
    Ann Neurol 69 (6), 986-996 (2011)
    Abstract:
    Objective: To assess factors associated with impulse control disorders (ICDs) in Parkinson disease (PD) using a multicenter case-control design. Methods: Patients enrolled in the DOMINION study, a multicenter study assessing the cross-sectional frequency of ICDs in PD, were eligible to participate in the case-control study. PD patients with and without an ICD (n = 282 each) (compulsive gambling, buying, sexual behavior, and eating) were matched individually on age, gender, and dopamine agonist treatment. Subjects were assessed with a comprehensive neurological, psychiatric, and cognitive assessment battery. Results: ICD patients reported more functional impairment (p < 0.001); greater depressive (p < 0.0001), state (p < 0.0001), and trait (p < 0.0001) anxiety; greater obsessive-compulsive symptoms (p < 0.0001); higher novelty-seeking (p < 0.001) and impulsivity (p < 0.001); and differences in reward preference reflecting greater choice impulsivity (p < 0.05). Patients with multiple ICDs had greater dyskinesia scores compared to those with single ICDs. Interpretation: ICDs in PD are associated with multiple psychiatric and cognitive impairments, including affective and anxiety symptoms, as well as elevated obsessionality, novelty seeking, and impulsivity. These results highlight the importance of assessing multiple mental health domains in individuals with PD and ICDs, and suggest possible pathophysiological mechanisms and risk indicators for these disorders.
  • Author:
    Valldeoriola F; Coronell C; Pont C; Buongiomo MT; Camara A; Gaig C; Compta Y
    Title:
    Socio-demographic and clinical factors influencing the adherence to treatment in Parkinson's disease: The ADHESON study.
    Source:
    Eur J Neurol 18 (7), 980-987 (2011)
    Abstract:
    Background: Symptoms of Parkinson's disease (PD) are usually controlled by a continuous titration of medication and addition of multiple therapies over the course of the disease. Therapeutic complex schemes, polymedication, comorbidities and the number of medications required contribute to non-adherence. Methods: This cross-sectional survey was performed in 418 patients with PD on treatment with any antiparkinsonian medication. Patient adherence was assessed through physicians' subjective perception and the Morisky-Green test (MGT). Several social, demographic and clinical features were correlated through bivariate and multivariate analyses. Results: According to the physician's opinion 93.7%, and according to the MGT 60.4% of patients were adherent to parkinsonian therapy. The bivariate analysis showed greater adherence in patients with a high level of knowledge about the disease (62.8%), good clinical control (63.6%), a spouse or life partner (63%) and higher incomes (66%). Negative correlation with psychiatric symptoms was found. In relation to the MGT, the logistic regression model showed a negative correlation between cognitive deterioration and psychiatric pathology and adherence to therapy. Conclusions: The physician's impression overestimated the compliance of patients when compared with an objective evaluation such as the MGT. Cognitive impairment and psychiatric symptoms are the clinical variables associated with a lower level of adherence.
  • Author:
    Kirillova I; Teliban A; Gorodetskaya N; Grossmann L; Bartsch F; Rausch VH; Struck M; Tode J; Baron R; Jaenig W
    Title:
    Effect of local and intravenous lidocaine on ongoing activity in injured afferent nerve fibers.
    Source:
    Pain 152 (7), 1562-1571 (2011)
    Abstract:
    Lidocaine applied systemically or locally attenuates neuropathic pain in patients. Here we tested the hypothesis that ectopic activity in injured afferent A- or C-fibers is suppressed by lidocaine. In rats the sural nerve (skin nerve) or lateral gastrocnemius-soleus nerve (muscle nerve) was crushed. Four to 11 days after crush lesion afferent fibers were isolated from the lesioned nerves in bundles rostral to the injury site. Ongoing ectopic activity was recorded from 75 A-fibers (muscle N = 43, skin N = 32) and 69 C-fibers (muscle N = 30, skin N = 39). Most afferent fibers were functionally characterized by their responses to mechanical and thermal (mostly heat) stimuli applied at or distal to the nerve injury site. Low-threshold cold-sensitive cutaneous C-fibers were excluded from the analysis [34,35]. Lidocaine was either applied to the nerve at or distal to the injury site in concentrations of 1 to 1000 ?g/mL or injected i.v. in doses of 0.09 to 9 mg/kg (skin) or 0.047 to 4.7 mg/kg (muscle). Local application of lidocaine depressed ectopic activity in A- and C-fibers dose-dependently. Depression was weaker in C- than in A-fibers. Intravenous application of lidocaine depressed ongoing ectopic activity in A- and C-fibers dose-dependently. Responses to heat or mechanical stimulation of the injured nerve were not suppressed at the highest concentrations of lidocaine. The results support the hypothesis that decrease of neuropathic pain following local or systemic application of a local anesthetic is related to decrease of ectopic ongoing activity in injured afferent nerve fibers.
  • Author:
    Schulz C; Paus M; Frey K; Schmid R; Kohl Z; Mennerich D; Winkler J; Gillardon F
    Title:
    Leucine-rich repeat kinase 2 modulates retinoic acid-induced neuronal differentiation of murine embryonic stem cells.
    Source:
    PLoS ONE 6 (6) art.no. e20820 (2011)
    Abstract:
    Background: Dominant mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent cause of Parkinson's disease, however, little is known about the biological function of LRRK2 protein. LRRK2 is expressed in neural precursor cells suggesting a role in neurodevelopment. Methodology/Principal Findings: In the present study, differential gene expression profiling revealed a faster silencing of pluripotency-associated genes, like Nanog, Oct4, and Lin28, during retinoic acid-induced neuronal differentiation of LRRK2-deficient mouse embryonic stem cells compared to wildtype cultures. By contrast, expression of neurotransmitter receptors and neurotransmitter release was increased in LRRK2+/- cultures indicating that LRRK2 promotes neuronal differentiation. Consistently, the number of neural progenitor cells was higher in the hippocampal dentate gyrus of adult LRRK2-deficient mice. Alterations in phosphorylation of the putative LRRK2 substrates, translation initiation factor 4E binding protein 1 and moesin, do not appear to be involved in altered differentiation, rather there is indirect evidence that a regulatory signaling network comprising retinoic acid receptors, let-7 miRNA and downstream target genes/mRNAs may be affected in LRRK2-deficient stem cells in culture. Conclusion/Significance: Parkinson's disease-linked LRRK2 mutations that associated with enhanced kinase activity may affect retinoic acid receptor signaling during neurodevelopment and/or neuronal maintenance as has been shown in other mouse models of chronic neurodegenerative diseases.
  • Author:
    Kroker KS; Rast G; Rosenbrock H
    Title:
    Differential effect of the mGlu5 receptor positive allosteric modulator ADX-47273 on early and late hippocampal LTP.
    Source:
    Neuropharmacology 61 (4), 707-714 (2011)
    Abstract:
    Conflicting findings are reported in the literature about the involvement of the mGlu5 receptor in hippocampal long-term potentiation (LTP), which might be a consequence of different sub-types of LTP induced by the investigators due to the specific experimental conditions used. A comparable controversy came up in the past concerning the influence of different experimental conditions on the involvement of L-type voltage dependent calcium channels (L-VDCCs) and NMDA receptors in hippocampal LTP. In this study, two stimulation protocols with otherwise identical conditions were used to probe modulatory effects of mGlu5 receptor activation in NMDA receptor and L-VDCCs dependent CA1 LTP: weak high frequency stimulation (20 stimuli at 100 Hz) to induce early LTP and repeated strong high frequency stimulation (3 times 100 stimuli at 100 Hz with 5 min interval) to induce late LTP, which - in contrast to early LTP - was shown to be protein-synthesis dependent. Using the NMDA receptor antagonist MK-801 and the L-type calcium channel blocker nifedipine, early LTP was shown to be dependent on NMDA receptors only, whereas late LTP was demonstrated to be dependent on NMDA receptors and L-VDCCs in about equal parts. Moreover, late LTP, but not early LTP, was increased by the mGlu5 receptor positive allosteric modulator ADX-47273, indicating that artificial augmentation of mGlu5 receptor activation by endogenous glutamate may boost the protein-synthesis dependent form of LTP but not the protein-synthesis independent form.
  • Author:
    Fulton RL; Lees KR; Senn S; Bluhmki E; Biegert G; Albers GK; Davis St; Donnan GK; Grotta JC; Hacke W; Kaste M; von Kummer R; Shuaib A; Toni D
    Title:
    Selection for delayed intravenous alteplase treatment based on prognostic score.
    Source:
    Stroke 42 (3), E112 (2011)
  • Author:
    Huels S; Hoegen T; Vassallo N; Danzer KM; Hengerer B; Giese A; Herms J
    Title:
    AMPA-receptor-mediated excitatory synaptic transmission is enhanced by iron-induced .alpha.-synuclein oligmers.
    Source:
    J Neurochem 117 (5), 868-878 (2011)
    Abstract:
    Aggregated .alpha.-synuclein (.alpha.-syn) is a characteristic pathological finding in Parkinson's disease and related disorders, such as dementia with Lewy bodies. Recent evidence suggests that .alpha.-syn oligomers represent the principal neurotoxic species; however, the pathophysiological mechanisms are still not well understood. Here, we studied the neurophysiological effects of various biophysically-characterized preparations of .alpha.-syn aggregates on excitatory synaptic transmission in autaptic neuronal cultures. Nanomolar concentrations of large .alpha.-syn oligomers, generated by incubation with organic solvent and Fe(3+) ions, were found to selectivity enhance evoked .alpha.-amino-3-hydroxy-5-methylisoxazole-4- propionate (AMPA)-receptor, but not NMDA-receptor, mediated synaptic transmission within minutes. Moreover, the analysis of spontaneous AMPA-receptor-mediated miniature synaptic currents revealed an augmented frequency. These results collectively indicate that large .alpha.-syn oligomers alter both pre- and post-synaptic mechanisms of AMPA-receptor-mediated synaptic transmission. The augmented excitatory synaptic transmission may directly contribute to nerve cell death in synucleinopathies. Indeed, already low micromolar glutamate concentrations were found to be toxic in primary cultured neurons incubated with large .alpha.-syn oligomers. In conclusion, large .alpha.-syn oligomers enhance both pre- and post-synaptic AMPA-receptor-mediated synaptic transmission, thereby aggravating intracellular calcium dyshomeostasis and contributing to excitotoxic nerve cell death in synucleinopathies.
  • Author:
    Taskinen M-R; Rosenstock J; Tamminen I; Kubiak R; Patel S; Woerle H-J; Dugi KA; Tocque-le Goussee E
    Title:
    Efficacy and safety of linagliptine in combination with metformin in patients with type 2 diabetes uncontrolled on metformin monotherapy.
    Source:
    Diabetes Metab 37 (Sp.iss. 1), A107-A108 (2011)
  • Author:
    Graefe-Mody U; Friederich C; Port A; Ring A; Woedel H-J; Heise T; Halabi A; Tocque-le Gousse A
    Title:
    Linagliptine, a new inhibitor of DPP-4: no need for dosage adjustment in patients with renal failure.
    Source:
    Diabetes Metab 37 (Sp.iss,. 1), A108 (2011)
  • Author:
    Del Prato SO; Barnett A; Huismann H; Neubacher D; Woerle H-J; Tocque-Le-Gousse E; Dugi KA
    Title:
    Linagliptine monotherapy improves glycemic control and surrogate markers cell function in type 2 diabetes.
    Source:
    Diabetes Metab 37 (Sp.iss. 1), A108 (2011)
  • Author:
    Straube A; Aicher B; Fiebich BL; Haag G
    Title:
    Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics? - art. no. 43.
    Source:
    BMC Neurol 11, 43 (2011)
    Abstract:
    Background: Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. Discussion: In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect. As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Summary: Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.
  • Author:
    Weintraub D; Siderowf AD; Fraessdorf M; Potenza MN; Stacy M; Voon V; Whetteckey J; Wunderlich GR; Lang AE
    Title:
    Dopamine agonists vs Levodopa in impulse control disorders reply.
    Source:
    Arch Neurol 68 (4), 545-546 (2011)
  • Author:
    Diener H-Ch; Barbanti P; Dahloef C; Reuter U; Habeck J; Padhorna J
    Title:
    BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: Results from a phase II study.
    Source:
    Cephalalgia 31 (5), 573-584 (2011)
    Abstract:
    Methods: Four hundred and sixty-one adult subjects with migraine were randomised to one of five treatments, the oral antagonist at the calcitonin gene-related peptide (CGRP) receptor BI 44370 TA (50 mg, 200 mg, 400 mg), active comparator eletriptan 40 mg or placebo. The analysis included 341 subjects who took study medication. Results: The primary endpoint, pain-free after two hours, was reached by significantly more subjects in the BI 44370 TA 400 mg (20/73=27.4%) and eletriptan 40 mg (24/69=34.8%) groups compared to placebo (6/70=8.6%, p=.0016), but not by subjects in the BI 44370 TA 200 mg group (14/65=21.5%). The effect of 50 mg BI 44370 TA (5/64=7.8%) was similar to that of placebo. Analysis of secondary endpoints supported the conclusion from the primary analysis. The frequency of adverse events was low in all groups. Conclusion: Efficacy of BI 44370 TA was shown in a dose-dependent manner in the treatment of acute migraine attacks. - DERWENT Avstract - 2011-18683 DRUGU T S <<LOGINID:SSSWISFTS:20110610>> AB This randomized, double-blind, double-dummy, placebo- and active-controlled, parallel-group, outpatient, phase II study (NCT00751803) investigated the efficacy and safety of p.o. BI-44370TA, a calcitonin gene-related peptide antagonist, in 341 adult subjects with migraine. The highest dose of BI-44370TA tested as well as the active control p.o. eletriptan (ELE) resulted in more subjects being pain-free at 2 hr vs. placebo. The overall incidence of adverse events was low in all groups. The most common adverse events were fatigue and diarrhea. These findings suggest that the efficacy of BI-44370TA is dose-dependent in this patient population. Methods 341 Adult subjects (mean age 40.2 yr, 284 female) with migraine were randomized to either p.o. BI-44370TA (50, 200, or 400 mg) (n=64, 65, and 73, respectively), p.o. ELE (40 mg) (n=69), or placebo (n=70). Results Pain-free after 2 hr was reached by more subjects given BI-44370TA (400 mg) (20/73, 27.4%) and ELE (40 mg) (24/69, 34.8%) groups vs. placebo (6/70, 8.6%), but not by subjects in the BI-44370TA (200 mg) group (14/65, 21.5%). The effect of BI-44370TA (50 mg) was similar to that of placebo. The frequency of adverse events was low in all groups. No adverse event occurred with an incidence of greater than 5% during the treatment period. Overall, 42/341 subjects (12.3%) experienced at least 1 adverse event. The highest overall incidence (5/341, 1.5%) was found for diarrhea and fatigue. No dose-dependent increase of adverse event frequency was observed for treatment with BI-44370TA. No changes of clinical relevance were noted during the trial for ECG results, mean pulse rate, and B.P. Abnormalities of laboratory value were rare and there were no clinically relevant differences among treatment groups.
  • Author:
    Hoegl B; Garcia-Borreguero D; Trenkwalder C; Ferini-Strambi L; Hening W; Poewe W; Brenner SS; Fraessdorf M; Busse M; Albrecht S; Allen RP
    Title:
    Efficacy and augmentation during 6 months of double-blind pramipexole for restless legs syndrome.
    Source:
    Sleep Med 12 (4), 351-360 (2011)
    Abstract:
    Background: Pramipexole is an effective treatment for restless legs syndrome (RLS), but no controlled studies have lasted >12 weeks. Methods: RLS patients (N = 331) with pretreatment serum ferritin >30 ng/mL were randomly assigned to take double-blind optimized pramipexole (0.125-0.75 mg/d) or placebo for 26 weeks. The primary efficacy endpoint was change in International RLS Study Group Rating Scale (IRLS) score. Other endpoints assessed global change, symptoms, and QoL. Patients maintained symptom diaries. Cases meeting predefined criteria for suspected augmentation were reviewed by a blinded expert panel, which used a predefined algorithm. Results: Among 321 patients providing post-baseline data, of whom 234 completed 26 weeks, pramipexole was more effective than placebo by multiple endpoints, including an adjusted mean IRLS score change of -13.7 vs. -11.1 (p = 0.0077) and an IRLS responder rate (?50% score reduction) of 58.6% vs. 42.8% (p = 0.0044). Efficacy showed considerable country-to-country variability. Six-month incidence of confirmed augmentation was 9.2% for pramipexole and 6.0% for placebo. The rate increased with treatment duration for pramipexole but not placebo. Treatment-related adverse events (AEs) were more likely for pramipexole than for placebo, but discontinuation due to AEs was less likely. Conclusions: During a 6-month period, pramipexole was effective, safe, and generally well tolerated. Because risk of augmentation may have increased over 6 months, it should be studied in longer trials. Beginning or mild augmentation is difficult to distinguish from natural RLS fluctuation, at least in a non-iron-deficient population.
  • Author:
    Perugi G; Canonico PL; Carbonato P; Mencacci C; Muscettola G; Pani L; Torta R; Vampini C; Fornaro M; Parazzini F; Dumitriu A
    Title:
    Unexplained somatic symptoms during major depression: Prevalence and clinical impact in a national sample of Italian psychiatric outpatients.
    Source:
    Psychopathology 44 (2), 116-124 (2011)
    Abstract:
    Background: The aim of this study was to explore the prevalence and impact of unexplained somatic symptoms during major depression. Sampling and Methods: A total of 560 consecutive outpatients with a major depressive episode according to the DSM-IV (text revision) were evaluated in 30 psychiatric facilities throughout Italy. 'Unexplained' somatic symptoms were evaluated using the 30-item Somatic Symptoms Checklist (SSCL-30). Somatic symptoms were considered explained if they were best accounted for as coming from a concomitant physical illness or side effects. Patients evaluated their own mood symptomatology using the Zung questionnaires for depression and anxiety and the Hypomania Checklist-32. Results: According to the SSCL-30, only 90 subjects (16.1%) had no unexplained somatic symptoms, while 231 (41.3%) had 1-5 unexplained symptoms and 239 (42.7%) had more than 5. Asthenia was the most commonly observed unexplained somatic symptom (53% of patients). Unexplained somatic symptoms were more common in females and among those suffering from major depression and depression not otherwise specified rather than in patients with recurrent major depression and bipolar disorders. No relationship between unexplained somatic symptoms and hypomanic features was observed. Conclusions: The presence of a large number of unexplained somatic symptoms is associated with more severe depression and higher rates of misdiagnosis and inappropriate treatment.
  • Author:
    Hornyak M; Sohr M; Busse M
    Title:
    Evaluation of painful sensory symptoms in restless legs syndrome: Experience from two clinical trials.
    Source:
    Sleep Med 12 (2), 186-189 (2011)
    Abstract:
    Background: Although " uncomfortable and unpleasant" limb sensations are a core symptom of restless legs syndrome (RLS), change in sensory symptomatology is usually not evaluated as a treatment outcome. Methods: In two double-blind trials, patients with idiopathic RLS (n= 357 in trial 615 and 398 in trial 604) were randomized to placebo or pramipexole (optimized at 0.125, 0.25, 0.50, or 0.75. mg/day). For entry, trial 604 also required at least moderate mood disturbance. In both trials, 12-week change in RLS-related limb pain was assessed using a 100-mm visual analogue scale (VAS). Results: At baseline, approximately 75% of patients had limb-pain scores >30. Treatment with pramipexole yielded significant score reduction as early as day 5. At week 12, median score reduction for pramipexole relative to placebo was -33.5 vs. -11.0 (p< 0.0001) in trial 615 and -31.0 vs. -11.0 (p< 0.0001) in trial 604. Conclusions: Painful sensations may be more frequent in RLS than has previously been appreciated, and their amelioration may be a facet of pramipexole's benefit even in patients with concurrent mood disturbance. Limb pain assessment, e.g., by a VAS, is a useful measure of change in RLS symptom severity.
  • Author:
    Kroker KS; Rosenbrock H; Rast G
    Title:
    A multi-slice recording system for stable late phase hippocampal long-term potentiation experiments.
    Source:
    J Neurosci Methods 194 (2), 394-401 (2011)
    Abstract:
    A major challenge in neuroscience is identifying the cellular and molecular processes underlying learning and memory formation. In the past decades, significant progress has been made in understanding cellular and synaptic mechanisms underlying hippocampal learning and memory using long-term potentiation (LTP) experiments in brain slices as a model system. To expedite LTP measurements it is helpful to further optimize such recording systems. Here, we describe a modification of a multi-slice recording system (SliceMaster, Scientifica Limited, East Sussex, UK) that allows absolutely stable measurements of field excitatory postsynaptic potentials (fEPSPs) for up to 8h in up to eight slices simultaneously. The software Notocord.RTM. was used for on-line data acquisition and to control the digital pattern generator which can generate different patterns for slice stimulation, inducing different types of LTP. Moreover, in contrast to common gravity-driven perfusion systems, a Pumped Perfusion System was employed to recycle drug solutions applied to the hippocampal slice. In addition, slices were positioned on two stacked grids for optimal recording of fEPSPs. These two stacked grids were placed in the measuring chambers allowing recordings for several hours without any perturbances. In summary, this modified slice-recording system improves throughput and allows for better statistical design, increases number of used slices per animal and enables very robust LTP measurements for up to 7h. Hence, this system is suitable not only to investigate molecular mechanisms underlying the late phase of LTP, but also to screen candidate compounds in the context of drug discovery.
  • Author:
    Inoue Y; Kagimra T; Kuroda K; Hirata K; Uchimura N; Shimizu T
    Title:
    Efficacy, safety and dose response of pramipexole in Japanese patients with primary restless legs syndrome: randomized trial.
    Source:
    Neuropsychobiology 63 (1), 35-42 (2011)
    Abstract:
    Aims: To assess the safety and efficacy of pramipexole in Japanese patients with restless legs syndrome (RLS) and to investigate factors predictive of early treatment response. Methods: Patients with primary RLS and the International Restless Legs Syndrome Study Group rating scale (IRLS) total score of >15 were randomized to receive pramipexole 0.25, 0.5 or 0.75 mg/day for 6 weeks. Results: A total of 154 patients were recruited. Following treatment, the mean adjusted change in IRLS score in the 0.25, 0.5 and 0.75 mg/day groups was -12.3, -12.5 and -11.8, respectively. The proportion of IRLS responders at week 2, when all patients were receiving pramipexole at a dose of 0.25 mg/day, was 34.0-37.7%. At 6 weeks, when the patients were on 0.25, 0.5 or 0.75 mg/day, IRLS responders defined as those having a >= 50% reduction in IRLS score accounted for 60.4, 58.5 and 49.1%, respectively. Older age above the median value (>= 55 years) and low IRLS score at baseline (<21.5 points) were significantly associated with early response to low-dose pramipexole therapy. The type and frequency of adverse events were consistent with the known safety profile for dopamine agonists in RLS. Conclusions: Pramipexole at 0.25-0.75 mg/day is efficacious, safe and well tolerated in Japanese patients with primary RLS.
  • Author:
    Montagna P; Hornyak M; Ulfberg J; Hong SB; Koester J; Crespi G; Albrecht S
    Title:
    Randomized trial of pramipexole for patients with restless legs syndrome (RLS) and RLS-related impairment of mood.
    Source:
    Sleep Med 12 (1), 34-40 (2011)
    Abstract:
    Objectives: Patients with restless legs syndrome (RLS) have an elevated prevalence of mood disorders compared with the general population. We investigated the change of RLS-related mood impairment during treatment of RLS with pramipexole, a dopamine D<sub>3</sub>/D<sub>2</sub> agonist. Methods: Adults with moderate to very severe RLS were enrolled in a 12-week, double-blind, placebo-controlled Phase IV pramipexole trial. A moderate to very severe RLS-related mood disturbance at baseline (score ?2 on Item 10 of the International RLS Study Group Rating Scale [IRLS]) was also required. Pramipexole (0.125 to 0.75. mg once daily) was flexibly titrated over the first 4. weeks. Results: The intent-to-treat population comprised 199 patients on placebo and 203 on pramipexole. At week 12, adjusted mean total-score changes on IRLS were -14.2 ± 0.7 for pramipexole and -8.1 ± 0.7 for placebo (p&lt;0.0001), and on the Beck Depression Inventory version II, -7.3 ± 0.4 for pramipexole and -5.8 ± 0.5 for placebo (p=0.0199). For IRLS item 10, the 12-week responder rate (reduction to no or mild mood disturbance) was 75.9% for pramipexole and 57.3% for placebo (p&lt;0.0001). Study withdrawal rates were higher for placebo (20.5%) than for pramipexole (12.8%). Conclusions: In patients with RLS-related mood disturbance, pramipexole improved RLS while also improving RLS-related mood impairment. Tolerability of pramipexole was similar to that in previous studies.
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