Romanski M.,Poznan University of Medical Sciences |
Baumgart J.,Medac GmbH |
Bohm S.,Medac GmbH |
Glowka F.K.,Poznan University of Medical Sciences
Drug Metabolism and Disposition | Year: 2015
Treosulfan (TREO) is currently investigated as an alternative treatment of busulfan in conditioning before hematopoietic stem cell transplantation. The knowledge of the blood-brain barrier penetration of the drug is still scarce. In this paper, penetration of TREO and its active monoepoxide (S, S-EBDM) and diepoxide (S, S-DEB) into the CNS was studied in juvenile (JR) andyoungadult rats (YAR) for the first time. CD rats of both sexes (n = 96) received an intravenous dose of TREO 500 mg/kg b.wt. Concentrations of TREO, S, S-EBDM, and S, S-DEB in rat plasma, brain, and cerebrospinal fluid (CSF, in YAR only) were determined by validated bioanalytical methods. Pharmacokinetic calculations were performed in WinNonlin using a noncompartmental analysis and statistical evaluation was done in Statistica software. In male JR, female JR, male YAR, and female YAR, the brain/plasma area under the curve (AUC) ratio for unbound TREOwas 0.14, 0.17, 0.10, and 0.07 and for unbound S, S-EBDM, it was 0.52, 0.48, 0.28, and 0.22, respectively. The CSF/plasma AUC ratio in male and female YAR was 0.12 and 0.11 for TREO and 0.66 and 0.64 for S, S-EBDM, respectively. Elimination rate constants of TREO and S, S-EBDM in all the matrices were sex-independent with a tendency to be lower in the JR. No quantifiable levels of S, S-DEB were found in the studied samples. TREO and S, S-EBDM demonstrated poor and sex-independent penetration into CNS. However, the brain exposure was greater in juvenile rats, so very young children might potentially be more susceptible to high-dose TREO-related CNS exposure than young adults. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
van der Sluis I.,Erasmus MC Sophia Childrens Hospital |
Moricke A.,University of Kiel |
Escherich G.,University of Hamburg |
von Stackelberg A.,Charité - Medical University of Berlin |
And 10 more authors.
Haematologica | Year: 2013
The pharmacokinetics, pharmacodynamics, efficacy and safety of a new recombinant E. coli-asparaginase preparation were evaluated in infants (<1 year of age) with de novo acute lymphoblastic leukemia. Twelve patients were treated according to the INTERFANT-06 protocol and received up to 10,000 U/m2 recombinant asparaginase as intravenous infusions on days 15, 18, 22, 25, 29 and 33 of remission induction treatment. The asparaginase dose was individually adjusted by protocol to 67% of the calculated dose for infants <6 months, and to 75% of the calculated dose for infants aged 6-12 months. The trough serum asparaginase activities observed were above 20, 50, and 100 U/L in 86%, 71%, and 51% of measured samples, respectively. Looking only at the data assessed 3 days after asparaginase infusion these percentages were 91%, 84%, and 74%, respectively. Asparagine was completely depleted in serum in all but one patient who was the youngest in the study. No anti-asparaginase antibodies were detected during this treatment phase. Observed adverse reactions are known to be possible and are labeled side effects of asparaginase treatment and chemotherapy. We conclude that the asparaginase dose regimen used in infants is safe and provides complete asparagine depletion for the desired time period in nearly all patients. Measured asparaginase trough serum levels justify the higher doses used in infants compared to in older children and show that 3-day intervals are preferred over 4-day intervals. (This trial was registered at www.clinicaltrialsregister.eu as EudraCT number 2008-006300-27). © 2013 Ferrata Storti Foundation.
Gyurkocza B.,Fred Hutchinson Cancer Research Center |
Gutman J.,University of Colorado at Denver |
Nemecek E.R.,Oregon Health And Science University |
Bar M.,Fred Hutchinson Cancer Research Center |
And 14 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014
Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial, we assessed the efficacy and toxicity of treosulfan, fludarabine, and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n=36: 15 refractory cytopenia with multilineage dysplasia, 10 refractory anemia with excess blasts type 1, 10 refractory anemia with excess blasts type 2, 1 chronic myelomonocytic leukemia type 1) or AML (n=60: 35 first complete remission [CR], 18second CR, 3 advanced CR, 4 refractory relapse) were enrolled; median age was 51 (range, 1 to 60) years. Twelve patients had undergone a prior HCT with high-intensity conditioning. Patients received 14g/m2/day treosulfan i.v. on days-6 to-4, 30mg/m2/day fludarabine i.v. on days-6 to-2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n=27) or unrelated (n=69) donors. Graft-versus-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30months, the 2-year overall survival (OS), relapse incidence, and nonrelapse mortality were 73%, 27%, and 8%, respectively. The incidences of grades II to IV (III to IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor-risk and good/intermediate-risk cytogenetics (69% and 85%, respectively) or between AML patients with unfavorable and favorable/intermediate-risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n=10) at the time of HCT predicted higher relapse incidence (70% versus 18%) and lower OS (41% versus 79%) at 2years, when compared with patients without MRD. In conclusion, treosulfan, fludarabine, and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML and resulted in low relapse incidence, regardless of cytogenetic risk. In patients with AML, MRD at the time of HCT remained a risk factor for post-HCT relapse. © 2014 American Society for Blood and Marrow Transplantation.
Neumann L.,German Cancer Research Center |
Neumann L.,University of Heidelberg |
Pforr C.,German Cancer Research Center |
Beaudouin J.,German Cancer Research Center |
And 8 more authors.
Molecular Systems Biology | Year: 2010
This study explores the dilemma in cellular signaling that triggering of CD95 (Fas/APO-1) in some situations results in cell death and in others leads to the activation of NF-κB. We established an integrated kinetic mathematical model for CD95-mediated apoptotic and NF-κB signaling. Systematic model reduction resulted in a surprisingly simple model well approximating experimentally observed dynamics. The model postulates a new link between c-FLIP(L) cleavage in the death-inducing signaling complex (DISC) and the NF-κB pathway. We validated experimentally that CD95 stimulation resulted in an interaction of p43-FLIP with the IKK complex followed by its activation. Furthermore, we showed that the apoptotic and NF-κB pathways diverge already at the DISC. Model and experimental analysis of DISC formation showed that a subtle balance of c-FLIP(L) and procaspase-8 determines life/death decisions in a nonlinear manner. We present an integrated model describing the complex dynamics of CD95-mediated apoptosis and NF-κB signaling. © 2010 EMBO and Macmillan Publishers Limited All rights reserved.
Nestler U.,Justus Liebig University |
Nestler U.,University of Leipzig |
Lutz K.,Justus Liebig University |
Pichlmeier U.,medac GmbH |
And 5 more authors.
Acta Neurochirurgica | Year: 2015
Background: Many reports on glioblastoma multiforme discuss the prognostic impact of anatomical features such as cysts, necrotic changes, extent of edema or subependymal spread of tumor cells. In the present study, we examined different growth patterns and their possible relations to patient survival.Methods: To analyze whether anatomical characteristics are related to prognosis, we reviewed the prospectively collected pre- and postoperative MRIs of 83 patients in the 5-ALA study, provided by the 5-ALA Glioma Study Group. Following a standardized analytic work flow, the tumor volume and site, presence of necrosis or cysts, and perifocal edema were assessed preoperatively. In the same way, postoperative MRI and the MRI at first recurrence were analyzed. In addition, survival time of the patients was documented.Results: Median survival time of all 83 patients was 15.1 months (range 1.5 to 70.1, mean 18). The site or volume of glioblastoma, as well as the presence of intratumoral necrosis or cysts, did not exert a significant effect on survival time; 96.4 % of recurrences occurred within the former resection margin. Tumors with initial contact with the subependymal zone had multifocal or ventricular recurrences significantly more often. In patients with residual tumor on early postoperative MRI, the follow-up images displayed enlargement of the remnants in 91.9 % of these cases.Conclusions: A merely anatomical analysis of the glioblastoma growth pattern cannot reliably provide prognostic information. The occurrence of most recurrences next to the resection margin and the high percentage of growing residual tumors underline the importance of complete resections. © 2014, Springer-Verlag Wien.
Pichlmeier U.,Medac GmbH |
Heuer K.-U.,Medac GmbH
Clinical and Experimental Rheumatology | Year: 2014
Objective: Methotrexate (MTX) is recognised as the cornerstone of treatment for rheumatoid arthritis. For some patients, oral MTX demonstrates variable bioavailability, especially at higher doses. Such concerns may be mitigated by subcutaneous (SC) MTX administration. This study investigated the relative bioavailability, safety, and tolerability of MTX administered either by SC injection with a prefilled autoinjector pen (MTX pen) or orally. Methods: This single-centre, open-label, randomised, 2-period, 2-sequence, single-dose, crossover study enrolled healthy subjects aged 18 to 55 years into 1 of 4 dose groups (7.5 mg, 15 mg, 22.5 mg, and 30 mg), where they received a single dose of SC MTX and of the oral MTX tablets. Blood samples were collected from subjects predose and at prespecified time points postdose for pharmacokinetic analyses. Adverse events (AEs) were recorded to assess differences in safety and tolerability. Results: Bioavailability, as measured by maximum plasma concentrations (Cmax) and area under the plasma-concentration curves (AUC0-t), was generally higher with the SC MTX pen compared with oral administration for all dose groups. AUC0-t ratios increased with ascending doses; Cmax ratios did not increase. A total of 80 AEs were reported in 35/62 subjects; none were severe. Differences in the safety profiles were related to the route of administration. Single administrations with the MTX pen were well tolerated at the injection site. Conclusion: Single-dose administration with the SC MTX pen resulted in a higher relative bioavailability compared with oral administration. SC MTX pen administration was associated with fewer gastrointestinal AEs than oral MTX. © Clinical and Experimental Rheumatology 2014.
Willer A.,University Childrens Hospital of Muenster |
Gerss J.,University of Munster |
Konig T.,medac GmbH |
Franke D.,medac GmbH |
And 7 more authors.
Blood | Year: 2011
Hypersensitivity reactions limit the use of the antileukemic enzyme asparaginase (ASE). We evaluated Ab levels against Escherichia coli ASE and ASE activity in 1221 serum samples from 329 patients with acute lymphoblastic leukemia who had received ASE treatment according to the ALL-BFM 2000 or the ALL-REZ BFM 2002 protocol for primary or relapsed disease. ASE activity during first-line treatment with native E coli ASE and second- line treatment with pegylated E coli ASE was inversely related to anti-E coli ASE Ab levels (P < .0001; Spearman rank order correlation). An effect on ASE activity during second-line treatment with pegylated E coli ASE was, however, only observed when anti-E coli ASE Ab levels were high (> 200 AU/mL). In the presence of moderate or intermediate Ab levels (6.25-200 AU/mL) the switch from native to pegylated E coli ASE resulted in a significant increase of ASE activity above the threshold of 100 U/L (P < .05). Erwinia chrysanthemi ASE activity was not correlated with anti-E coli ASE Ab levels. Erwinia ASE was found to be the best ASE alternative if Ab levels against E coli ASE exceed 200 AU/mL. This retrospective analysis is the first to describe the relationship between the level of anti-E coli ASE Abs and serum activity of pegylated E coli ASE used second-line after native E coli ASE. These studies are registered at http://clinicaltrials.org as NTC00430118 and NCT00114348. © 2011 by The American Society of Hematology.
Pappa A.,Medac GmbH |
Current Signal Transduction Therapy | Year: 2010
The posttranslational modification of proteins by a single O-linked N-acetylglucosamine (O-GlcNAc) is an intracellular biochemical reaction which is ubiquitous in eukaryotic cells. Two enzymes regulate the process: O-linked Nacetylglucosaminyltransferase (OGT), which attaches O-GlcNAc to serine/threonine residues of proteins, and a β-Nacetylglucosaminidase (O-GlcNAcase), that removes the O-GlcNAc group. The serine or threonine targeted by OGlcNAc can occur at sites modified by other enzymes such as protein kinases. There have been many indications that OGlcNAc modifications are actively involved in the regulation of the immune system and recent results have begun to shed light on possible mechanisms. This review summarizes recent advances in the field of O-GlcNAc modification, with a special attention to its role in the activation of lymphocytes. © 2010 Bentham Science Publishers Ltd.
Shatnyeva O.M.,German Cancer Research Center |
Kubarenko A.V.,German Cancer Research Center |
Kubarenko A.V.,University of Bonn |
Weber C.E.M.,German Cancer Research Center |
And 6 more authors.
PLoS ONE | Year: 2011
Protein modifications of death receptor pathways play a central role in the regulation of apoptosis. It has been demonstrated that O-glycosylation of TRAIL-receptor (R) is essential for sensitivity and resistance towards TRAIL-mediated apoptosis. In this study we ask whether and how glycosylation of CD95 (Fas/APO-1), another death receptor, influences DISC formation and procaspase-8 activation at the CD95 DISC and thereby the onset of apoptosis. We concentrated on N-glycostructure since O-glycosylation of CD95 was not found. We applied different approaches to analyze the role of CD95 N-glycosylation on the signal transduction: in silico modeling of CD95 DISC, generation of CD95 glycosylation mutants (at N136 and N118), modulation of N-glycosylation by deoxymannojirimycin (DMM) and sialidase from Vibrio cholerae (VCN). We demonstrate that N-deglycosylation of CD95 does not block DISC formation and results only in the reduction of the procaspase-8 activation at the DISC. These findings are important for the better understanding of CD95 apoptosis regulation and reveal differences between apoptotic signaling pathways of the TRAIL and CD95 systems. © 2011 Shatnyeva et al.
Hahn S.U.,SCRATCH Pharmacovigilance GmbH |
Stoffers K.L.,Medac GmbH
Zeitschrift fur Allgemeinmedizin | Year: 2014
All active ingredients can also cause adverse events. As clinical trials are performed on a relatively small and strictly selected group of subjects, adverse drug reactions (ADR) are frequently detected after the active substance or drug has been approved. For drug monitoring authorities it is crucial that physicians report suspected ADR and/or ineffective drugs. As an example the Federal Institute for Drugs and Medical Devices (BfArM), the Paul-Ehrlich-lnstitut (PEI) and the Drug Commission of the German Medical Association (AKdÄ) have ADR reporting forms available on their homepages. In fact, physicians are obliged to report ADR by their professional code. As physicians are the first contact person for patients they are the most important source of information for drug monitoring. For reporting a suspected ADR a causality assessment is not required; it is sufficient, if the physician recognizes that a temporal relationship to the suspected drug exists or no other possible causes are known. It is of particular importance to report ADR of drugs which have the black triangle ▼ in their product information. ADR from all over the European Economic Area (EEA) - EU member states and Island, Liechtenstein and Norway - are recorded and evaluated centrally in the EudraVigilance database. Based on the collected data, the risk-benefit profile and therefore the prerequisite for the approval of drugs, is constantly monitored. The success of this system depends essentially on the effective cooperation of pharmaceutical companies, physicians, health professionals and authorities. © Deutscher Ärzte-Verlag.