Koch H.,University of Leipzig |
Bespalov A.,AbbVie Deutschland GmbH and Co KG |
Drescher K.,AbbVie Deutschland GmbH and Co KG |
Franke H.,University of Leipzig |
Krugel U.,University of Leipzig
Neuropsychopharmacology | Year: 2015
We hypothesize that cortical ATP and ADP accumulating in the extracellular space, eg during prolonged network activity, contribute to a decline in cognitive performance in particular via stimulation of the G protein-coupled P2Y1 receptor (P2Y1 R) subtype. Here, we report first evidence on P2Y1 R-mediated control of cognitive functioning in rats using bilateral microinfusions of the selective agonist MRS2365 into medial prefrontal cortex (mPFC). MRS2365 attenuated prepulse inhibition of the acoustic startle reflex while having no impact on startle amplitude. Stimulation of P2Y1 Rs deteriorated performance accuracy in the delayed non-matching to position task in a delay dependent manner and increased the rate of magazine entries consistent with both working memory disturbances and impaired impulse control. Further, MRS2365 significantly impaired performance in the reversal learning task. These effects might be related to MRS2365-evoked increase of dopamine observed by microdialysis to be short-lasting in mPFC and long-lasting in the nucleus accumbens. P2Y1 Rs were identified on pyramidal cells and parvalbumin-positive interneurons, but not on tyrosine hydroxylase-positive fibers, which argues for an indirect activation of dopaminergic afferents in the cortex by MRS2365. Collectively, these results suggest that activation of P2Y1 Rs in the mPFC impairs inhibitory control and behavioral flexibility mediated by increased mesocorticolimbic activity and local disinhibition. © 2015 American College of Neuropsychopharmacology. All rights reserved.
Wohr M.,University of Marburg |
Rippberger H.,University of Marburg |
Schwarting R.K.W.,University of Marburg |
Van Gaalen M.M.,AbbVie Deutschland GmbH and Co. KG
Psychopharmacology | Year: 2015
Rationale: Rats emit various distinct types of ultrasonic vocalizations (USV), with high-frequency 50-kHz USV typically occurring in appetitive situations being elicited by administering drugs of abuse, most notably amphetamine (AMPH), possibly reflecting drug wanting/craving and/or liking. Objectives: Because 50-kHz USV emission is, at least in part, dopamine (DA) dependent and 5-HT2C agonists inhibit DA neurotransmission, we hypothesized that AMPH-induced 50-kHz USV can be attenuated by pretreatment with a 5-HT2C agonist. Methods: In experiments I and II, a dose-response curve for AMPH-induced 50-kHz USV was established, and the partial dependency of AMPH-induced 50-kHz USV on DA neurotransmission was validated by pretreatment with the D2-antagonist eticlopride. In experiment III, rats were pretreated with the 5-HT2C agonist CP 809,101 (0.0, 0.3, 1.0, 3.0, and 10 mg/kg), while in experiment IV, CP 809,101 (3.0 mg/kg), the 5-HT2C antagonist SB 242084 (1.0 mg/kg), or the combination of the two, was applied before AMPH administration (2.0 mg/kg). Finally, in experiment V, rats were treated with SB 242084 (0.0, 0.1, 0.3, and 1.0 mg/kg) only, i.e., in absence of AMPH. Results: The 5-HT2C agonist CP 809,101 dose-dependently blocked AMPH-induced 50-kHz USV, most notably trills, a call subtype that is considered to exclusively reflect a positive affective state, while the 5-HT2C antagonist SB 242084 induced opposite effects. Moreover, SB 242084 induced 50-kHz USV by its own. Conclusions: 5-HT2C receptors are critically involved in AMPH-induced 50-kHz USV, with 5-HT2C antagonism resulting in a stimulant-like effect. Attenuation of drug wanting/craving and/or liking by coadministration of a 5-HT2C agonist could be a translational pharmacodynamic biomarker. © 2014 Springer-Verlag Berlin Heidelberg.
Feagan B.G.,University of Western Ontario |
Sandborn W.J.,University of California at San Diego |
Lazar A.,AbbVie Deutschland GmbH and Co. KG |
Thakkar R.B.,Abbvie Inc. |
And 7 more authors.
Gastroenterology | Year: 2014
Background & Aims Adalimumab is effective for induction and maintenance of remission in patients with moderate to severe ulcerative colitis (UC). We assessed whether adalimumab, in addition to standard UC therapy, reduced the risk for hospitalization (from all causes, from complications of UC, or from complications of UC or the drugs used to treat it) and colectomy in patients with moderate to severe UC compared with placebo. Methods Data were combined from patients that received induction therapy (a 160-mg dose followed by an 80-mg dose of adalimumab) or placebo in 2 trials (ULTRA 1 and ULTRA 2; n = 963). The risks of hospitalization and colectomy were compared between groups using unadjusted rates during the 8-week induction period, and patient-year-adjusted rates during 52 weeks. Statistical differences between groups were determined using the χ2 method and Z score normal approximations. Numbers of hospitalizations were compared using Poisson regression with time offset. Results Significant reductions in risk of all-cause, UC-related, and UC- or drug-related hospitalizations (by 40%, 50%, and 47%, respectively; P <.05 for all comparisons) were observed within the first 8 weeks of adalimumab therapy compared with placebo. Significantly lower incidence rates for all-cause (0.18 vs 0.26; P =.03), UC-related (0.12 vs 0.22; P =.002), and UC- or drug-related (0.14 vs 0.24; P =.005) hospitalizations were observed during 52 weeks of adalimumab therapy compared with placebo. Rates of colectomy did not differ significantly between patients given adalimumab vs placebo. Conclusions In patients with moderate to severe UC, the addition of adalimumab to standard of care treatment reduced the number of hospitalizations for any cause, as well as for UC-related and UC- or drug-related complications, compared with placebo. ClinicalTrials.gov numbers, NCT00385736 and NCT00408629. © 2014 by the AGA Institute.
Mease P.J.,Swedish Medical Center |
Mease P.J.,University of Washington |
Heckaman M.,Abbvie Inc. |
Kary S.,AbbVie Deutschland GmbH and Co. KG |
Kupper H.,AbbVie Deutschland GmbH and Co. KG
Journal of Rheumatology | Year: 2013
Objective. This posthoc analysis evaluated the percentage of patients with psoriatic arthritis (PsA) who achieved minimal disease activity (MDA) and compared the results with a modified MDA substituting the physician global assessment (PGA) for the Psoriasis Activity and Severity Index (PASI) using data from the ADalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT; NCT00646386). Methods. Patients with active PsA were randomized to receive adalimumab 40 mg or placebo every other week for 24 weeks. MDA was defined as achieving ≥ 5 of the following criteria: tender joint count ≤ 1; swollen joint count ≤ 1; PASI ≤ 1 or body surface area ≤ 3%; patient pain score ≤ 15 [1-100 mm visual analog scale (VAS)]; patient global assessment (PGA) of disease activity ≤ 20 (1-100 mm VAS); Health Assessment Questionnaire ≤ 0.5; and tender entheseal points ≤ 1 (only heels assessed). For modification of the MDA, PASI ≤ 1 was substituted with PGA "Clear" as MDA PGA1 and PGA "Clear" or "Almost clear" as MDAPGA2. Results. Sixty-seven patients were treated with adalimumab and 69 with placebo. At Week 24, MDA, MDAPGA1, and MDAPGA2 were achieved by 39%, 37%, and 39%, respectively, of patients treated with adalimumab versus 7%, 5%, and 8% of patients on placebo (p < 0.001). Kappa coefficients indicated good agreement between PASI and PGA at Week 24. Conclusion. ADEPT results indicated that significantly more patients treated with adalimumab achieved MDA by Week 24 compared with placebo. Modification of the MDA by replacing PASI ≤ 1 with PGA assessments did not alter the results, which may improve feasibility of practical use of the index. The Journal of Rheumatology Copyright © 2013. All rights reserved.
Wicke K.,AbbVie Deutschland GmbH and Co KG |
Haupt A.,AbbVie Deutschland GmbH and Co KG |
Bespalov A.,AbbVie Deutschland GmbH and Co KG
Expert Opinion on Investigational Drugs | Year: 2015
Introduction: There are significant efforts invested into the discovery and development of novel treatments for Alzheimers disease. While current discovery efforts and most scientific discussions seem to focus on disease-modifying therapy, there are several symptomatic therapy approaches that are being actively pursued. The goal of this review is to summarize the recent developments in the field of 5-HT6 receptor antagonists, a principle that has been extensively characterized preclinically and is now undergoing critical phases of clinical development. Areas covered: The article covers the current status of 5-HT6 receptor antagonists in clinical development. It also discusses the underlying mechanisms for the observed procognitive effects. The article is based on a search for investigational drugs using the key words '5-HT6', 'cognition', 'dementia', 'Alzheimer's disease', 'Phase II' and 'Phase III' in various databases and from conference abstracts. Expert opinion: After some period of little or no development activities, the field of 5-HT6 receptor antagonists attracted a lot of attention with three companies (GSK, Pfizer and Lundbeck) confirming aggressive development plans and initiating pivotal Phase II and III studies. These studies will be critical to prove that 5-HT6 receptor antagonists have a symptomatic efficacy profile that can be differentiated from that of currently used agents (cholinesterase inhibitors and the NMDA-antagonist memantine). Furthermore, there are several sets of data that point at a disease-modifying potential of this class of agents and these effects are likely to receive critical exploration if the ongoing symptomatic trials bring 5-HT6 antagonists closer to clinical use. © 2015 Taylor & Francis.
Thaci D.,University of Lübeck |
Unnebrink K.,AbbVie Deutschland GmbH and Co. KG |
Sundaram M.,Abbvie Inc. |
Sood S.,Abbvie Inc. |
Yamaguchi Y.,Abbvie Inc.
Journal of the European Academy of Dermatology and Venereology | Year: 2015
Background/Objective: This post hoc analysis examined the effects of adalimumab in patients with scalp and/or nail psoriasis from BELIEVE (a randomized, controlled, multicentre phase 3 safety and efficacy trial). Methods: Efficacy was assessed in the pooled treatment group (adalimumab with or without calcipotriol plus betamethasone dipropionate) by Psoriasis Area and Severity Index (75% improvement; PASI 75), Psoriasis Scalp Severity Index (PSSI), Nail Psoriasis Severity Index (NAPSI), Dermatology Life Quality Index (DLQI) and a visual analog scale (VAS) for pain. Results: Of the 730 enrolled patients, 663 (91.3%), 457 (63.1%) and 433 (60.1%) had psoriasis of the scalp, nails, or both, respectively. Similar proportions of patients with (68.2%) and without (63.5%) scalp involvement achieved a PASI 75 response at week 16 [adjusted odds ratio (OR), 1.34; P = 0.320]. PASI 75 response rates were lower in patients with nail psoriasis compared with patients without nail psoriasis at week 8 (53.0% vs. 62.9%; OR, 0.68; P = 0.019) and week 16 (65.0% vs. 73.0%; OR, 0.70; P = 0.052). PASI 75 response rates were 66.1% in patients with scalp and nail involvement and 70.8% in patients without both scalp and nail involvement at week 16 (OR, 0.87; P = 0.423). Patients in all scalp and nail subgroups reported improvements in DLQI and VAS pain scores throughout the study. Patients with scalp psoriasis exhibited large improvements in scalp symptoms demonstrated by a median (mean ± SD) decrease from baseline PSSI at week 16 of 100% (77.2 ± 96.9%). Patients with nail psoriasis improved, demonstrated by a median (mean ± SD) decrease from baseline NAPSI at week 16 of 39.5% (9.4 ± 164.5%). Conclusion: Our results indicate that adalimumab improves overall psoriasis and scalp and nail symptoms in this patient population with scalp psoriasis and/or nail involvement. In addition, similar PASI 75 response rates are achieved in patients with and without scalp involvement, whereas patients with nail involvement demonstrate a moderate (perhaps delayed) PASI 75 response rate. © 2014 European Academy of Dermatology and Venereology.
Burmester G.-R.,Charité - Medical University of Berlin |
Kivitz A.J.,Altoona Center for Clinical Research |
Kupper H.,AbbVie Deutschland GmbH and Co. KG |
Arulmani U.,Abbvie Inc. |
And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2015
Objective: CONCERTO was a randomised, double-blind, parallel-armed study of methotrexate (MTX) in combination with adalimumab to assess whether an increasing trend of efficacy and decreased safety exists when increasing MTX dose in patients with early rheumatoid arthritis (RA). Methods: Early, biologic and MTX-naive RA patients (N=395) were evenly randomised to open-label adalimumab (40 mg every other week) plus weekly blinded 2.5, 5, 10 or 20 mg MTX for 26 weeks. Clinical, radiographic and functional outcomes were analysed using two-sided linear trend tests or one-way analysis of covariance. Results: Statistically significant increasing trends were observed in the proportion of patients achieving the primary endpoint, 28-joint count disease activity score with C reactive protein (DAS28(CRP)) <3.2 (42.9%, 44.0%, 56.6% and 60.2% for 2.5, 5, 10 or 20 mg/week MTX, respectively), DAS28(CRP) <2.6 and American College of Rheumatology 50/70/90 responses with increasing doses of MTX in combination with adalimumab. No statistical differences in minimal clinically important differences in physical function were detected. Statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose by validated clinical indices; differences comparing 10 and 20 mg MTX were minimal. Adalimumab serum concentrations increased with ascending dose up to 10 mg MTX. More patients experienced infectious adverse events with increasing MTX dose. Conclusions: Increasing doses of MTX in combination with adalimumab demonstrated a statistically significant trend in improved clinical outcomes that mimicked the adalimumab pharmacokinetic profile. In early RA patients initiating adalimumab combination therapy, efficacy of 10 and 20 mg/week MTX appeared equivalent. © 2015, BMJ Publishing Group. All rights reserved.
Barsegyan A.,Radboud University Nijmegen |
Atsak P.,Radboud University Nijmegen |
Hornberger W.B.,AbbVie Deutschland GmbH and Co KG |
Jacobson P.B.,Integrated science and Technology |
And 2 more authors.
Neuropsychopharmacology | Year: 2015
Stress-induced activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and high circulating glucocorticoid levels are well known to impair the retrieval of memory. Vasopressin can activate the HPA axis by stimulating vasopressin 1b (V1b) receptors located on the pituitary. In the present study, we investigated the effect of A-988315, a selective and highly potent non-peptidergic V1b-receptor antagonist with good pharmacokinetic properties, in blocking stress effects on HPA-axis activity and memory retrieval. To study cognitive performance, male Sprague-Dawley rats were trained on an object-discrimination task during which they could freely explore two identical objects. Memory for the objects and their location was tested 24 h later. A-988315 (20 or 60 mg/kg) or water was administered orally 90 min before retention testing, followed 60 min later by stress of footshock exposure. A-988315 dose-dependently dampened stress-induced increases in corticosterone plasma levels, but did not significantly alter HPA-axis activity of non-stressed control rats. Most importantly, A-988315 administration prevented stress-induced impairment of memory retrieval on both the object-recognition and the object-location tasks. A-988315 did not alter the retention of non-stressed rats and did not influence the total time spent exploring the objects or experimental context in either stressed or non-stressed rats. Thus, these findings indicate that direct antagonism of V1b receptors is an effective treatment to block stress-induced activation of the HPA axis and the consequent impairment of retrieval of different aspects of recognition memory. © 2015 American College of Neuropsychopharmacology.
Van Den Bosch F.,Ghent University |
Kavanaugh A.,University of California at San Diego |
Kron M.,Swedish Medical Center |
Kupper H.,Swedish Medical Center |
Mease P.J.,AbbVie Deutschland GmbH and Co KG
Journal of Rheumatology | Year: 2015
Objective. Adalimumab (ADA) was evaluated for its efficacy in patients with moderate to severely active psoriatic arthritis (PsA) and for the presence of correlations in disease change variables. Methods. Patients with inadequate response to standard PsA therapy were given 40 mg of ADA every other week for up to 12 weeks or 20 weeks. Outcome variables encompassed tender joint count (TJC), swollen joint count (SJC), physician's global assessment (PGA) of psoriasis, Health Assessment Questionnaire (HAQ), patient's global assessment (PtGA) of disease activity and pain, C-reactive protein, as well as composite measures of disease activity. Patients with inactive skin disease symptoms at baseline were excluded from the remission analyses. Results. Of 268 patients with active baseline joint and skin disease and data available at Week 12 following open-label ADA therapy, 73 achieved joint remission (27.2%, TJC ? 1 + SJC ? 1) and 144 achieved skin remission criteria (53.7%, PGA = clear/almost clear). Simultaneous joint and skin remission criteria were achieved in 16.0% and 24.8% of patients at weeks 12 and 20, respectively. In patients who did not achieve skin and/or joint remission, 12-week ADA treatment improved mean clinical and functional scores. Joint remission was more frequently associated with achieving clinically relevant outcomes including HAQ, PtGA disease activity, and PtGA pain compared to skin remission. No correlation between improvement in skin and joint disease was observed. Conclusion. ADA was effective in achieving strict criteria for remission in joint or skin disease in many patients with active PsA within 12 weeks and sustained through 20 weeks. Copyright © 2015. All rights reserved.
Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: The randomised controlled OPTIMA trial
Smolen J.S.,Medical University of Vienna |
Smolen J.S.,Hietzing Hospital |
Emery P.,University of Leeds |
Emery P.,Leeds Teaching Hospitals NHS Trust |
And 9 more authors.
The Lancet | Year: 2014
Background Biological agents offer good control of rheumatoid arthritis, but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear. The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining (or not) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy. Methods This trial was done at 161 sites worldwide. Patients with early (<1 year duration) rheumatoid arthritis naive to methotrexate were randomly allocated (by interactive voice response system, in a 1:1 ratio, block size four) to adalimumab (40 mg every other week) plus methotrexate (initiated at 7 · 5 mg/week, increased by 2 · 5 mg every 1-2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks (period 1). Patients in the adalimumab plus methotrexate group who completed period 1 and achieved the stable low disease activity target (28-joint disease activity score with C-reactive protein [DAS28] (<3 · 2 at weeks 22 and 26) were randomised to adalimumabcontinuation or adalimumab-withdrawal for an additional 52 weeks (period 2). Patients achieving the target with initial methotrexate continued methotrexate-monotherapy. Inadequate responders were offered adalimumab plus methotrexate. All patients and investigators were masked to treatment allocation in period 1. During period 2, treatment reallocation of patients who achieved the target was masked to patients and investigators; patients who did not achieve the target remained masked to original randomisation, but were aware of the subsequent assignment. The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78, compared between adalimumab-continuation and methotrexate-monotherapy. Adverse events were monitored throughout period 2. This trial is registered with ClinicalTrials.gov, number NCT00420927. Findings The study was done between Dec 28, 2006, and Aug 3, 2010. 1636 patients were assessed and 1032 were randomised in period 1 (515 to adalimumab plus methotrexate; 517 to placebo plus methotrexate). 466 patients in the adalimumab plus methotrexate group completed period 1; 207 achieved the stable low disease activity target, of whom 105 were rerandomised to adalimumab-continuation. 460 patients in the placebo plus methotrexate group completed period 1; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy. 73 of 105 (70%) patients in the adalimumab-continuation group and 61 of 112 (54%) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 (mean difference 15% [95% CI 2-28%], p=0·0225). Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses. Overall, 706 of 926 patients in period 2 had an adverse event, of which 82 were deemed serious; however, distribution of adverse events did not differ between groups. Interpretation Treatment to a stable low disease activity target resulted in improved clinical, functional, and structural outcomes, with both adalimumab-continuation and methotrexate-monotherapy. However, a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone. Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate.