Pharmacokinetics of a Modified-Release Dexamphetamine Sulfate Formulation Following Single and Multiple Dosing in Healthy Adults: Comparative Bioavailability with Immediate-Release Dexamphetamine Sulfate, between Strengths, Assessment of Food and Meal Composition Effects.

Background: A modified-release dexamphetamine sulfate formulation (DEX-MR) is under development for the treatment of attention-deficit/hyperactivity disorder. Objective: We investigated the bioequivalence of once-daily DEX-MR to twice-daily immediate-release dexamphetamine sulfate (DEX-IR) after single and multiple dosing and between strengths, and effects of food and meal types. Method: Three randomized, open-label, crossover studies in healthy males were conducted. In the single-dose study, participants received DEX-MR 20 mg, DEX-MR 10 mg (20 mg dose), and twice-daily DEX-IR 10 mg under fasted conditions and after a high-fat, high-calorie breakfast. In the breakfast study, participants received DEX-MR 20 mg and twice-daily DEX-IR 10 mg after a normocaloric and a high-fat, high-calorie breakfast. In the multiple-dose study, participants received DEX-MR 20 mg and twice-daily DEX-IR 10 mg for seven days each. In the run-in period (five days), participants consumed a normocaloric breakfast; on profile days, participants consumed a normocaloric breakfast (day 6) or a high-fat, high-calorie breakfast (day 7). Results: Once-daily DEX-MR at a dose of 20 mg was bioequivalent to twice-daily DEX-IR 10 mg after single dosing under fasted and fed conditions and after multiple dosing under fed conditions. DEX-MR 10 mg and DEX-MR 20 mg were bioequivalent when administered as a single 20 mg dose. Food slightly reduced the rate and extent of absorption of DEX-MR and delayed the time to peak plasma concentration (tmax) by approximately two hours compared to the fasted state. Bioavailability of DEX-MR was comparable under different meal conditions (normocaloric vs. high-fat, high-calorie breakfast) both after single and multiple dosing. Conclusions: Bioequivalence of once-daily DEX-MR and twice-daily DEX-IR was established. 1×2 DEX-MR 10 mg was bioequivalent to 1×1 DEX-MR 20 mg. DEX-MR should be administered with/after a meal to achieve the targeted pharmacokinetic profile (delayed tmax). Bioavailability of DEX-MR is not affected by meal composition (i.e., fat and caloric content).

Keratolytics and emollients and their role in the therapy of psoriasis: a systematic review.

INTRODUCTION: Psoriasis is a common chronic disease with significant impairment in quality of life. As there is no cure, it often requires lifelong disease control to minimize the development of skin lesions and to relieve symptoms. The aim of this publication is to systematically review the role of currently used emollients and keratolytics in the treatment of psoriasis. METHODS: A systematic literature search was conducted in Medline via PubMed regarding reviews, meta-analyses, and trials published from January 1983 to December 2013 dealing with topical administration of emollients and keratolytics in patients with psoriasis. A subsequent search in EMBASE regarding clinical trials published from 1983 to 2013 was performed to complement the findings. RESULTS: A total of 60 publications met the inclusion criteria for full-text evaluation. While current reviews, meta-analyses, and guidelines state that adjuvant therapy with emollients and keratolytics should be an obligatory part in the therapy of psoriasis to facilitate descaling and/or penetration enhancement, comprehensive trials on these agents are missing, with the exception of combination products containing salicylic acid and corticosteroids. In the mentioned trials, addition of salicylic acid was beneficial in inducing a more rapid onset of action as well as a reduction of severity parameters and the area affected. However, its use has substantial limitations in young children, in patients with renal/hepatic impairment, with widespread psoriasis, those undergoing phototherapy, or those concomitantly treated with calcipotriene/systemic salicylates. CONCLUSION: In view of these shortcomings, there is a need for well-designed studies on suitable keratolytic alternatives to salicylic acid offering an indisputable positive benefit-risk ratio.

Angiogenically stimulated alternative monocytes maintain their pro-angiogenic and non-inflammatory phenotype in long-term co-cultures with HUVEC.

Angiogenically stimulated alternative monocytes (aMO2) could be established as cellular release system accelerating the endothelialization of polymers rendering their surfaces hemocompatibility in a short-term study. However, for their clinical application it is essential that aMO2 do not switch back to the MO1 state sustaining their capability as cellular release system over an extended period of time. We explored whether aMO2 can maintain their differentiation state over 21 days in a mono- and in a co-culture with HUVEC. In comparison, the influence of recombinant VEGF-A165 on the endothelialization of biomaterials was assessed including endothelial cell (HUVEC) density, organisation of the endothelial cytoskeleton, cytokine secretion profile and release of prostacyclin, thromboxane A2 and matrix metalloproteinases. In mono-culture aMO2 secreted high amounts of VEGF and other growth factors/cytokines. Co-cultured with HUVEC, aMO2 accelerated the formation of a confluent HUVEC monolayer. Furthermore, no pro-inflammatory cytokines were found, neither in aMO2-mono, nor in co-cultures with HUVEC indicating that the majority of the aMO2 remained stable in their aMO2 state during the 21 days of cultivation. In contrast, the addition of recombinant VEGF-A165 instead of the co-culture with aMO2 resulted in the formation of stress fibres, dissociated marginal filament bands, and a detachment of HUVEC. In addition, the profile of bioactive agents of HUVEC (e.g. prostacyclin, thromboxane A2, matrix metalloproteinases, IFN-γ and TNF-α) was influenced by the VEGF-A165 treatment inducing the detachment of HUVEC. In conclusion, in co-culture with HUVEC aMO2 remained stable in their type 2 state over 21 days confirming the suitability of aMO2 as biological release system for the endothelialization of biomaterial surfaces with constant release of angiogenic factors but without secretion of pro-inflammatory cytokines over three weeks. Therefore, this endothelialization approach seems to be appropriate to improve the hemocompatibility of cardiovascular implant materials in vitro, and proved to be superior to the use of recombinant VEGF-A165.

Pro-angiogenic CD14(++) CD16(+) CD163(+) monocytes accelerate the in vitro endothelialization of soft hydrophobic poly (n-butyl acrylate) networks.

As the majority of the polymers used as cardiovascular grafts so far do not match the elasticity of human arteries (100-1000kPa) and the required endothelialization, a multifunctional material approach is needed to allow the adjustment of the mechanical properties while at the same time exhibiting a haemocompatible surface. Recently soft poly(n-butyl acrylate) networks (cPnBA) with adjustable mechanical properties were introduced as candidate materials with a surface that can be endothelialized. In this study, angiogenically stimulated intermediate CD163(+) monocytes/macrophages (aMO2) were utilized as a cellular cytokine release system to realize the functional endothelialization of the hydrophobic cPnBA surface. We investigated the influence of co-cultured aMO2 on the morphology, density and cytokine secretion of human umbilical venous endothelial cells (HUVEC) seeded on cPnBA with an elastic modulus of around 250kPa (cPnBA0250). A functional confluent HUVEC monolayer could be developed in the co-culture within 3days. In contrast, the HUVEC in the monoculture exhibited stress fibres, broadened marginal filament bands and significantly more and larger cell-free areas in the monolayer, indicating incomplete cell-substrate binding. Remarkably, a functional confluent monolayer formation could only be achieved in co-cultures; it did not develop with the sole supplementation of recombinant VEGF-A(165) to the HUVEC monocultures (unpublished data). The study demonstrated the multifunctional potential of cPnBA in combination with aMO2 as a cellular cytokine release system, adapting their secretion to the demand of HUVEC. In this way, a functional confluent monolayer could be generated within 3days.

Interaction of angiogenically stimulated intermediate CD163+ monocytes/macrophages with soft hydrophobic poly(n-butyl acrylate) networks with elastic moduli matched to that of human arteries.

The cell population of peripheral blood monocytes/macrophages (MO) is heterogeneous: The majority of the MO are CD14++ CD16- and named "classical" (= MO1). Furthermore, two other subpopulations were described: CD14++ CD16+ ("intermediate" = MO2) and CD14+ CD16++ ("non-classical" = MO3). It is reported that MO2 possess anti-inflammatory properties and express the MO lineage marker CD163. On a hydrophilic neutrally charged acrylamide-based hydrogel human intermediate (CD14++ CD16+ ), angiogenically stimulated CD163++ monocytes/macrophages (aMO2) maintained a proangiogenic and noninflammatory status for at least 14 days. Here, we explored whether this aMO2 subset adhered to hydrophobic poly(n-butyl acrylate) networks (cPnBA) and also remained in its proangiogenic and noninflammatory status. Because substrate elasticity can impact adherence, morphology, and function of cells, cPnBAs with different Young's modulus (250 and 1100 kPa) were investigated, whereby their elasticity was tailored by variation of the cross-linker content and matched to the elasticity of human arteries. The cPnBAs exhibited similar surface properties (e.g., surface roughness), which were maintained after ethylene oxide sterilization and exposure in serum-free cell culture medium for 18 h at 37°C. aMO2 were seeded on cPnBA samples (1.7 × 10(5) cells/1.33 cm(2) ) in Dulbecco's modified Eagle medium (DMEM high glucose) supplemented with vascular endothelial growth factor 165 (VEGF-A(165) , 10 ng/mL) and fetal calf serum (10 vol%) for 3 and 72 h. On both polymeric samples (n = 3 each), the numbers of adherent cells per unit area were significantly higher (P < 0.01; cPnBA0250: 3 h 13 ± 5 cells/mm(2) , 72 h 234 ± 106 cells/mm(2) ; cPnBA1100: 3 h 14 ± 3 cells/mm(2) , 72 h 198 ± 113 cells/mm(2) ) compared to control cultures (glass, 3 h: 6 ± 3 cells/mm(2) , 72 h: 130 ± 83 cells/mm(2) ) and showed a typically spread morphology. The mRNA expression profile of the aMO2 was not influenced by the substrate elasticity. In the supernatant of aMO2 on cPnBA0250, significantly less VEGF-A(165) product was found than expected based on the mRNA level measured (P < 0.01). Tests with recombinant VEGF-A(165) then demonstrated that significantly more VEGF-A(165) was adhered on cPnBA0250 than on cPnBA1100 (P < 0.01). Seeded on cPnBA, aMO2-unaffected by the elastic moduli of both substrates-seemed to remain in their subset status and secreted VEGF-A(165) without release of proinflammatory cytokines. These in vitro results might indicate that this MO subset can be used as cellular delivery system for proangiogenic and noninflammatory mediators to support the endothelialization of cPnBA.