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Sinha B.,Free University of Berlin | Muller R.H.,Free University of Berlin | Moschwitzer J.P.,Free University of Berlin | Moschwitzer J.P.,AbbVie Deutschland GmbH and Co. KG
International Journal of Pharmaceutics | Year: 2013

The solubility dependent bioavailability problem has become a major hurdle in drug development processes. Drug nanocrystals have been widely accepted by the pharmaceutical industry to improve the bioavailability of poorly water-soluble compounds. Top-down and bottom-up technologies are the two primary technical approaches of drug nanocrystal production. Though the top-down approach has been hugely successful on the commercial front, it has some inherent drawbacks that necessitate the emergence of alternate approaches. The bottom-up approach has not yet been established as a successful commercial technology. However, it has the potential to produce small size drug nanocrystals with less energy demanding processes. The bottom-up approach is commonly known as precipitation technique. It would be possible to stabilize particles at an early stage of precipitation and to generate drug nanocrystals. In the first part of this review article, we have discussed various bottom-up technologies that are currently in use. This has been followed by description and analysis of various process parameters that can affect the final particle size of the drug nanocrystals. © 2013 Elsevier B.V. All rights reserved.


Bespalov A.,AbbVie Deutschland GmbH and Co KG | Bespalov A.,University of London | Muller R.,AbbVie Deutschland GmbH and Co KG | Relo A.-L.,AbbVie Deutschland GmbH and Co KG | Hudzik T.,Abbvie Inc.
Trends in Pharmacological Sciences | Year: 2016

In neuropsychiatric drug development, the rate of successful translation of preclinical to clinical efficacy has been disappointingly low. Tolerance, defined as a loss of efficacy with repeated drug exposure, is rarely addressed as a potential source of clinical failures. In this review, we argue that preclinical methods of tolerance development may have predictive validity and, therefore, inclusion of studies using repeated drug exposure early during the drug discovery and development process should serve to mitigate a proportion of clinical failures. Our analysis indicates that many published preclinical efficacy studies in the neuropsychiatry arena are conducted with acute drug administration only. Furthermore, specifically in the field of schizophrenia, there are several examples where tolerance development may be suspected as a factor contributing to translational failures. These and other examples highlight the need for built-for-purpose tolerance studies to be conducted, regardless of the target interaction mode of the drugs (i.e., agonist or antagonist, allosteric or orthosteric). We suggest that, for compounds that have failed in clinical studies, preclinical efficacy data sets need to be revisited to estimate the potential impact of tolerance development, one of the most significant known unknowns in the preclinical-to-clinical translation. © 2016 Elsevier Ltd. All rights reserved.


Delille H.K.,Abbott Laboratories | Mezler M.,AbbVie Deutschland GmbH and Co KG | Marek G.J.,AbbVie
Neuropharmacology | Year: 2013

Important functional interactions between the metabotropic glutamate 2 (mGlu2) and 5-hydroxytryptamine2A (5-HT2A) neurotransmitter receptors have been established based on electrophysiological, biochemical and behavioral evidence. Over the last several years, dimerization between 5-HT2A and mGlu2 receptors has been proposed to account for the functional cross-talk between these two receptors in the prefrontal cortex. The pros and cons for the existence of a heteromeric complex between 5-HT2A and mGlu2 receptors will be reviewed here. First, the fundamental criteria needing to establish evidence for heteromeric complexes will be reviewed. Then, the in vitro evidence for and against heteromeric complexes between 5-HT2A and mGlu2 receptors will be discussed in regard to physical and functional interactions. Finally, the data with native in situ mGlu2 and 5-HT2A receptors will be discussed with respect to whether heteromeric complexes or a simple functional interaction between two distinct GPCRs based on brain network activity is the more simple explanation for a range of in vivo data. © 2013 Elsevier Ltd. All rights reserved.


Salazar J.,Free University of Berlin | Muller R.H.,Free University of Berlin | Moschwitzer J.P.,Free University of Berlin | Moschwitzer J.P.,AbbVie Deutschland GmbH and Co. KG
European Journal of Pharmaceutical Sciences | Year: 2013

Standard particle size reduction techniques such as high pressure homogenization or wet bead milling are frequently used in the production of nanosuspensions. The need for micronized starting material and long process times are their evident disadvantages. Combinative particle size reduction technologies have been developed to overcome the drawbacks of the standard techniques. The H 42 combinative technology consists of a drug pre-treatment by means of spray-drying followed by standard high pressure homogenization. In the present paper, spray-drying process parameters influencing the diminution effectiveness, such as drug and surfactant concentration, were systematically analyzed. Subsequently, the untreated and pre-treated drug powders were homogenized for 20 cycles at 1500 bar. For untreated, micronized glibenclamide, the particle size analysis revealed a mean particle size of 772 nm and volume-based size distribution values of 2.686 μm (d50%) and 14.423 μm (d90%). The use of pre-treated material (10:1 glibenclamide/docusate sodium salt ratio spray-dried as ethanolic solution) resulted in a mean particle size of 236 nm and volume-based size distribution values of 0.131 μm (d50%) and 0.285 μm (d90%). These results were markedly improved compared to the standard process. The nanosuspensions were further transferred into tablet formulations. Wet granulation, freeze-drying and spray-drying were investigated as downstream methods to produce dry intermediates. Regarding the dissolution rate, the rank order of the downstream processes was as follows: Spray-drying > freeze-drying > wet granulation. The best drug release (90% within 10 min) was obtained for tablets produced with spray-dried nanosuspension containing 2% mannitol as matrix former. In comparison, the tablets processed with micronized glibenclamide showed a drug release of only 26% after 10 min. The H 42 combinative technology could be successfully applied in the production of small drug nanocrystals. A nanosuspension transfer to tablets that maintained the fast dissolution properties of the drug nanocrystals was successfully achieved. © 2013 Elsevier B.V.


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.


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.


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.


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.

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