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Wolfgang H Jost,1 Reiner Benecke,2 Dieter Hauschke,3 Joseph Jankovic,4 Petr Kaňovský,5 Peter Roggenkämper,6 David M Simpson,7 Cynthia L Comella81Department of Neurology, University of Freiburg, Freiburg, Germany; 2Clinic and Policlinic for Neurology, University of Rostock, Rostock, Germany; 3Institute of Medical Biometry and Medical Informatics, University of Freiburg, Freiburg, Germany; 4Department of Neurology, Baylor College of Medicine, Houston, TX, USA; 5Department of Neurology, Palacky University Olomouc, Faculty of Medicine and Dentistry and University Hospital, Olomouc, Czech Republic; 6University Eye Clinic of Bonn, Bonn, Germany; 7Icahn School of Medicine at Mount Sinai, New York, NY, USA; 8Rush University Medical Center, Chicago, IL, USABackground: IncobotulinumtoxinA (Xeomin®) is a purified botulinum neurotoxin type A formulation, free from complexing proteins, with proven efficacy and good tolerability for the treatment of neurological conditions such as blepharospasm, cervical dystonia (CD), and post-stroke spasticity of the upper limb. This article provides a comprehensive overview of incobotulinumtoxinA based on randomized controlled trials and prospective clinical studies.Summary: IncobotulinumtoxinA provides clinical efficacy in treating blepharospasm, CD, and upper-limb post-stroke spasticity based on randomized, double-blind, placebo-controlled trials with open-label extension periods (total study duration up to 89 weeks). Adverse events were generally mild or moderate. The most frequent adverse events, probably related to the injections, included eyelid ptosis and dry eye in the treatment of blepharospasm, dysphagia, neck pain, and muscular weakness in patients with CD, and injection site pain and muscular weakness when used for treating spasticity. In blepharospasm and CD, incobotulinumtoxinA was investigated in clinical trials permitting flexible intertreatment intervals based on the individual patient’s clinical need; the safety profile of intervals shorter than 12 weeks was comparable to intervals of 12 weeks and longer. There were no cases of newly formed neutralizing antibodies during the Phase III and IV incobotulinumtoxinA trials. Phase III head-to-head trials of incobotulinumtoxinA versus onabotulinumtoxinA for the treatment of blepharospasm and CD have demonstrated therapeutic equivalence of both formulations. Additional Phase III trials of incobotulinumtoxinA in conditions such as lower-limb spasticity, spasticity in children with cerebral palsy, and sialorrhea in various neurological disorders are ongoing.Conclusion: IncobotulinumtoxinA is an effective, well-tolerated botulinum neurotoxin type A formulation. Data from randomized clinical trials and further observational studies are expected to help physicians to optimize treatment by tailoring the choice of formulation, dose, and treatment intervals to the patient’s clinical needs.Keywords: blepharospasm, botulinum toxin, cervical dystonia, incobotulinumtoxinA, spasticity, Xeomin

This open, randomized, single-dose crossover study investigated effects of a high-fat meal on the pharmacokinetics of roflumilast and its major active N-oxide metabolite. Twelve healthy subjects received oral roflumilast 500 mug (2 x 250 mug) after overnight fasting and after breakfast. Blood was sampled up to 54 hours for pharmacokinetic profiling of roflumilast and N-oxide. Geometric mean ratios (fed/fasted) for point estimates (PE) and 90% confidence intervals (CI) were calculated for AUC(0-last), AUC(0-infinity), and C(max) of both compounds. After the meal, roflumilast C(max) (PE, 0.59; 90% CI, 0.49-0.70) was modestly reduced; N-oxide C(max) (PE, 0.95; 90% CI, 0.90-1.01) was unchanged. Roflumilast t(max) was delayed in fed state (2.0 +/- 0.4 hours) versus fasted state (1.0 +/- 0.2 hours); N-oxide t(max) was unaltered. No significant food effect on roflumilast AUC(0-last) (PE, 1.04; 90% CI, 0.90-1.21), AUC(0-infinity) (PE, 1.12; 90% CI, 1.00-1.25), and respective N-oxide AUCs (PE, 0.91; 90% CI, 0.79-1.04; PE, 0.99; 90% CI, 0.92-1.06) occurred. Because roflumilast N-oxide is the major contributor to roflumilast's overall pharmacologic effects, these findings suggest that roflumilast can be taken with or without food. [ABSTRACT FROM AUTHOR]

ᅟ: We analyze one-year costs and savings of a telemedically supported case management program after kidney transplantation from the perspective of the German Healthcare System. Recipients of living donor kidney transplantation (N = 46) were randomly allocated to either (1) standard aftercare or (2) standard aftercare plus additional telemedically supported case management. A range of cost figures of each patient's medical service utilization were calculated at month 3, 6 and 12 and analyzed using two-part regression models. In comparison to standard aftercare, patients receiving telemedically supported case management are associated with substantial lower costs related to unscheduled hospitalizations (mean difference: €3,417.46 per patient for the entire one-year period, p = 0.003). Taking all cost figures into account, patients receiving standard aftercare are associated, on average, with one-year medical service utilization costs of €10,449.28, while patients receiving telemedically supported case management are associated with €5,504.21 of costs (mean difference: € 4,945.07 per patient, p < 0.001). With estimated expenditures of €3,001.5 for telemedically supported case management of a single patient, we determined a mean difference of €1,943.57, but this result is not statistically significant (p = 0.128). Sensitivity analyses show that the program becomes cost-neutral at around ten participating patients, and was beneficial starting at 15 patients. Routine implementation of telemedically supported case management in German medium and high-volume transplant centers would result in annual cost savings of €791,033 for the German healthcare system. Patients with telemedically supported case management showed a lower utilization of medical services as well as better medical outcomes. Therefore, such programs should be implemented in medium and high-volume transplant centers., Trial Registration: DRKS00007634 ( http://www.drks.de/DRKS00007634 ).

Background: We evaluated breast cancer (BC) core biopsies taken before neoadjuvant chemotherapy (NACT) by immunohistochemistry using anti-phosphohistone H3 (PHH3) antibody to determine mitosis, and correlated the results to clinicopathological data and histopathological regression of resected tumor specimens after NACT., Methods: 72 patients with either triple-negative (TN) or luminal type BC received NACT with epirubicin/cyclophosphamide (EC) and Taxotere®. Tumor regression was analyzed in resected specimens; pathological complete response (pCR) was achieved in 22.2%. Immunohistochemistry with PHH3 was performed on biopsy samples taken before treatment, and mitotic figures were evaluated in 10 high-power fields (HPF)., Results: PHH3-detected mitoses correlated significantly with tumor grading (p = 0.001). TNBC showed > 10 PHH3-positive mitoses/10 HPF significantly more frequently than luminal type BC (p = 0.003). Tumors with > 10 PHH3-positive mitoses/10 HPF achieved pCR significantly more often than those with ≤ 10 PHH3-positive mitoses/10 HPF (p = 0.031). Even luminal type BC with > 10 PHH3-positive mitoses/10 HPF was associated significantly with pCR compared to luminal type BC with ≤ 10 PHH3-positive mitoses/10 HPF (p = 0.016)., Conclusion: NACT with EC and Taxotere is suitable for strong proliferating TNBC and luminal BC (> 10 PHH3-positive mitoses/10 HPF). Immunohistochemical determination of mitoses using anti-PHH3 antibody is a simple and robust method for predicting therapy response to NACT in BC tissue.