TY  - JOUR
A1  - Mc Laughlin, Anna M.
A1  - Schmulenson, Eduard
A1  - Teplytska, Olga
A1  - Zimmermann, Sebastian
A1  - Opitz, Patrick
A1  - Groenland, Stefanie L.
A1  - Huitema, Alwin D. R.
A1  - Steeghs, Neeltje
A1  - Müller, Lothar
A1  - Fuxius, Stefan
A1  - Illerhaus, Gerald
A1  - Joerger, Markus
A1  - Mayer, Frank
A1  - Fuhr, Uwe
A1  - Holdenrieder, Stefan
A1  - Hempel, Georg
A1  - Scherf-Clavel, Oliver
A1  - Jaehde, Ulrich
A1  - Kloft, Charlotte
T1  - Developing a nationwide infrastructure for therapeutic drug monitoring of targeted oral anticancer drugs: the ON-TARGET study protocol
JF  - Cancers
N2  - Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs.
KW  - therapeutic drug monitoring
KW  - oral anticancer drugs
KW  - renal cell carcinoma
KW  - volumetric absorptive microsampling
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252196
SN  - 2072-6694
VL  - 13
IS  - 24
ER  - 
TY  - JOUR
A1  - Mantel, Frederick
A1  - Müller, Elena
A1  - Kleine, Philip
A1  - Zimmermann, Marcus
A1  - Exner, Florian
A1  - Richter, Anne
A1  - Weick, Stefan
A1  - Ströhle, Serge
A1  - Polat, Bülent
A1  - Höcht, Stefan
A1  - Flentje, Michael
T1  - Chemoradiotherapy by intensity-modulated radiation therapy with simultaneous integrated boost in locally advanced or oligometastatic non-small-cell lung cancer-a two center experience
JF  - Strahlentherapie und Onkologie
N2  - Purpose
Integrating moderate hypofractionation to the macroscopic tumor with elective nodal irradiation while sparing the organs at risk (OAR) in chemoradiotherapy of locally advanced non-small-cell lung cancer.
Methods
From 2010-2018, treatment, patient and tumor characteristics of 138 patients from two radiation therapy centers were assessed. Chemoradiotherapy by intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) to the primary tumor and macroscopic lymph node metastases was used.
Results
A total of 124 (90%) patients received concurrent chemotherapy. 106 (76%) patients had UICC (Union for International Cancer Control) stage ≥IIIB and 21 (15%) patients had an oligometastatic disease (UICC stage IV). Median SIB and elective total dose was 61.6 and 50.4 Gy in 28 fractions, respectively. Furthermore, 64 patients (46%) had an additional sequential boost to the primary tumor after the SIB-IMRT main series: median 6.6 Gy in median 3 fractions. The median cumulative mean lung dose was 15.6 Gy (range 6.2-29.5 Gy). Median follow-up and radiological follow-up for all patients was 18.0 months (range 0.6-86.9) and 16.0 months (range 0.2-86.9), respectively. Actuarial local control rates at 1, 2 and 3 years were 80.4, 68.4 and 57.8%. Median overall survival and progression-free survival was 30.0 months (95% confidence interval [CI] 23.5-36.4) and 12.1 months (95% CI 8.2-16.0), respectively. Treatment-related toxicity was moderate. Radiation-induced pneumonitis grade 2 and grade 3 occurred in 13 (9.8%) and 3 (2.3%) patients.
Conclusions
Chemoradiotherapy using SIB-IMRT showed promising local tumor control rates and acceptable toxicity in patients with locally advanced and in part oligometastatic lung cancer. The SIB concept, resulting in a relatively low mean lung dose, was associated with low numbers of clinically relevant pneumonitis. The overall survival appears promising in the presence of a majority of patients with UICC stage ≥IIIB disease.
KW  - local control
KW  - image-guided radiation therapy
KW  - thoracic cancer
KW  - hypofractionation
KW  - multimodal therapy
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264821
SN  - 1439-099X
VL  - 197
IS  - 5
ER  - 
TY  - JOUR
A1  - Welker, Armin
A1  - Kersten, Christian
A1  - Müller, Christin
A1  - Madhugiri, Ramakanth
A1  - Zimmer, Collin
A1  - Müller, Patrick
A1  - Zimmermann, Robert
A1  - Hammerschmidt, Stefan
A1  - Maus, Hannah
A1  - Ziebuhr, John
A1  - Sotriffer, Christoph
A1  - Schirmeister, Tanja
T1  - Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2
JF  - ChemMedChem
N2  - Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PL\(^{pro}\)) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor (R)‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PL\(^{pro}\). Moreover, we report the discovery of isoindolines as a new class of potent PL\(^{pro}\) inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS‐CoV PL\(^{pro}\) are valuable starting points for the development of new pan‐coronaviral inhibitors.
KW  - antiviral agents
KW  - computational chemistry
KW  - drug design
KW  - protease inhibitors
KW  - structure-activity relationships
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225700
VL  - 16
IS  - 2
SP  - 340
EP  - 354
ER  - 
TY  - JOUR
A1  - Mühlberg, Eric
A1  - Umstätter, Florian
A1  - Domhan, Cornelius
A1  - Hertlein, Tobias
A1  - Ohlsen, Knut
A1  - Krause, Andreas
A1  - Kleist, Christian
A1  - Beijer, Barbro
A1  - Zimmermann, Stefan
A1  - Haberkorn, Uwe
A1  - Mier, Walter
A1  - Uhl, Philipp
T1  - Vancomycin-lipopeptide conjugates with high antimicrobial activity on vancomycin-resistant enterococci
JF  - Pharmaceuticals
N2  - Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented. Here, a strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed. This study especially focuses on the structure–activity relationship, depending on the modification site and fatty acid chain length. The synthesized conjugates showed high antimicrobial potential on vancomycin-resistant enterococci. We were able to demonstrate that the antimicrobial activity of the vancomycin-lipopeptide conjugates depends on the chain length of the attached fatty acid. All conjugates showed good cytocompatibility in vitro and in vivo. Radiolabeling enabled the in vivo determination of pharmacokinetics in Wistar rats by molecular imaging and biodistribution studies. An improved biodistribution profile in comparison to unmodified vancomycin was observed. While vancomycin is rapidly excreted by the kidneys, the most potent conjugate shows a hepatobiliary excretion profile. In conclusion, these results demonstrate the potential of the structural modification of already established antibiotics to provide highly active compounds for tackling multidrug-resistant bacteria.
KW  - antibiotics
KW  - multidrug-resistant bacteria
KW  - enterococci
KW  - vancomycin
KW  - structural modification
KW  - fatty acids
KW  - polycationic peptides
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-205879
SN  - 1424-8247
VL  - 13
IS  - 6
ER  - 
TY  - JOUR
A1  - Umstätter, Florian
A1  - Werner, Julia
A1  - Zerlin, Leah
A1  - Mühlberg, Eric
A1  - Kleist, Christian
A1  - Klika, Karel D.
A1  - Hertlein, Tobias
A1  - Beijer, Barbro
A1  - Domhan, Cornelius
A1  - Zimmermann, Stefan
A1  - Ohlsen, Knut
A1  - Haberkorn, Uwe
A1  - Mier, Walter
A1  - Uhl, Philipp
T1  - Impact of linker modification and PEGylation of vancomycin conjugates on structure-activity relationships and pharmacokinetics
JF  - Pharmaceuticals
N2  - As multidrug-resistant bacteria represent a concerning burden, experts insist on the need for a dramatic rethinking on antibiotic use and development in order to avoid a post-antibiotic era. New and rapidly developable strategies for antimicrobial substances, in particular substances highly potent against multidrug-resistant bacteria, are urgently required. Some of the treatment options currently available for multidrug-resistant bacteria are considerably limited by side effects and unfavorable pharmacokinetics. The glycopeptide vancomycin is considered an antibiotic of last resort. Its use is challenged by bacterial strains exhibiting various types of resistance. Therefore, in this study, highly active polycationic peptide-vancomycin conjugates with varying linker characteristics or the addition of PEG moieties were synthesized to optimize pharmacokinetics while retaining or even increasing antimicrobial activity in comparison to vancomycin. The antimicrobial activity of the novel conjugates was determined by microdilution assays on susceptible and vancomycin-resistant bacterial strains. VAN1 and VAN2, the most promising linker-modified derivatives, were further characterized in vivo with molecular imaging and biodistribution studies in rodents, showing that the linker moiety influences both antimicrobial activity and pharmacokinetics. Encouragingly, VAN2 was able to undercut the resistance breakpoint in microdilution assays on vanB and vanC vancomycin-resistant enterococci. Out of all PEGylated derivatives, VAN:PEG1 and VAN:PEG3 were able to overcome vanC resistance. Biodistribution studies of the novel derivatives revealed significant changes in pharmacokinetics when compared with vancomycin. In conclusion, linker modification of vancomycin-polycationic peptide conjugates represents a promising strategy for the modulation of pharmacokinetic behavior while providing potent antimicrobial activity.
KW  - glycopeptide antibiotics
KW  - antimicrobial resistance
KW  - vancomycin
KW  - polycationic peptides
KW  - linker influence
KW  - pharmacokinetics
KW  - PEGylation
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255197
SN  - 1424-8247
VL  - 15
IS  - 2
ER  - 
TY  - JOUR
A1  - Fabritius, Matthias Philipp
A1  - Wölfer, Teresa A.
A1  - Herzberg, Moriz
A1  - Tiedt, Steffen
A1  - Puhr-Westerheide, Daniel
A1  - Grosu, Sergio
A1  - Maurus, Stefan
A1  - Geyer, Thomas
A1  - Curta, Adrian
A1  - Kellert, Lars
A1  - Küpper, Clemens
A1  - Liebig, Thomas
A1  - Ricke, Jens
A1  - Dimitriadis, Konstantinos
A1  - Kunz, Wolfgang G.
A1  - Zimmermann, Hanna
A1  - Reidler, Paul
T1  - Course of early neurologic symptom severity after endovascular treatment of anterior circulation large vessel occlusion stroke: association with baseline multiparametric CT imaging and clinical parameters
JF  - Diagnostics
N2  - Background: Neurologic symptom severity and deterioration at 24 hours (h) predict long-term outcomes in patients with acute large vessel occlusion (LVO) stroke of the anterior circulation. We aimed to examine the association of baseline multiparametric CT imaging and clinical factors with the course of neurologic symptom severity in the first 24 h after endovascular treatment (EVT). Methods: Patients with LVO stroke of the anterior circulation were selected from a prospectively acquired consecutive cohort of patients who underwent multiparametric CT, including non-contrast CT, CT angiography and CT perfusion before EVT. The symptom severity was assessed on admission and after 24 h using the 42-point National Institutes of Health Stroke Scale (NIHSS). Clinical and imaging data were compared between patients with and without early neurological deterioration (END). END was defined as an increase in ≥4 points, and a significant clinical improvement as a decrease in ≥4 points, compared to NIHSS on admission. Multivariate regression analyses were used to determine independent associations of imaging and clinical parameters with NIHSS score increase or decrease in the first 24 h. Results: A total of 211 patients were included, of whom 38 (18.0%) had an END. END was significantly associated with occlusion of the internal carotid artery (odds ratio (OR), 4.25; 95% CI, 1.90–9.47) and the carotid T (OR, 6.34; 95% CI, 2.56–15.71), clot burden score (OR, 0.79; 95% CI, 0.68–0.92) and total ischemic volume (OR, 1.01; 95% CI, 1.00–1.01). In a comprehensive multivariate analysis model including periprocedural parameters and complications after EVT, carotid T occlusion remained independently associated with END, next to reperfusion status and intracranial hemorrhage. Favorable reperfusion status and small ischemic core volume were associated with clinical improvement after 24 h. Conclusions: The use of imaging parameters as a surrogate for early NIHSS progression in an acute LVO stroke after EVT reached limited performance with only carotid T occlusion as an independent predictor of END. Reperfusion status and early complications in terms of intracranial hemorrhage are critical factors that influence patient outcome in the acute stroke phase after EVT.
KW  - stroke
KW  - large vessel occlusion
KW  - multiparametric CT
KW  - CT perfusion
KW  - CT angiography
KW  - NIHSS
KW  - EVT
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242681
SN  - 2075-4418
VL  - 11
IS  - 7
ER  - 
TY  - JOUR
A1  - Umstätter, Florian
A1  - Domhan, Cornelius
A1  - Hertlein, Tobias
A1  - Ohlsen, Knut
A1  - Mühlberg, Eric
A1  - Kleist, Christian
A1  - Zimmermann, Stefan
A1  - Beijer, Barbro
A1  - Klika, Karel D.
A1  - Haberkorn, Uwe
A1  - Mier, Walter
A1  - Uhl, Philipp
T1  - Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides
JF  - Angewandte Chemie International Edition
N2  - Multidrug‐resistant bacteria represent one of the biggest challenges facing modern medicine. The increasing prevalence of glycopeptide resistance compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant bacteria. To reestablish its activity, polycationic peptides were conjugated to vancomycin. By site‐specific conjugation, derivatives that bear the peptide moiety at four different sites of the antibiotic were synthesized. The most potent compounds exhibited an approximately 1000‐fold increased antimicrobial activity and were able to overcome the most important types of vancomycin resistance. Additional blocking experiments using d‐Ala‐d‐Ala revealed a mode of action beyond inhibition of cell‐wall formation. The antimicrobial potential of the lead candidate FU002 for bacterial infection treatments could be demonstrated in an in vivo study. Molecular imaging and biodistribution studies revealed that conjugation engenders superior pharmacokinetics.
KW  - antibiotics
KW  - bacterial resistance
KW  - glycopeptide antibiotics
KW  - peptide conjugates
KW  - vancomycin
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215550
VL  - 59
IS  - 23
SP  - 8823
EP  - 8827
ER  - 
TY  - JOUR
A1  - Zimmermann, Marcus
A1  - Richter, Anne
A1  - Weick, Stefan
A1  - Exner, Florian
A1  - Mantel, Frederick
A1  - Diefenhardt, Markus
A1  - Fokas, Emmanouil
A1  - Kosmala, Rebekka
A1  - Flentje, Michael
A1  - Polat, Bülent
T1  - Acute toxicities of patients with locally advanced rectal cancer treated with intensified chemoradiotherapy within the CAO/ARO/AIO-12 trial: comparing conventional versus VMAT planning at a single center
JF  - Scientific Reports
N2  - In locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is regarded as standard treatment. We assessed acute toxicities in patients receiving conventional 3D-conformal radiotherapy (3D-RT) and correlated them with dosimetric parameters after re-planning with volumetric modulated arc therapy (VMAT). Patients were randomized within the multicenter CAO/ARO/AIO-12 trial and received 50.4 Gy in 28 fractions and simultaneous chemotherapy with fluorouracil and oxaliplatin. Organs at risk (OAR) were contoured in a standardized approach. Acute toxicities and dose volume histogram parameters of 3D-RT plans were compared to retrospectively calculated VMAT plans. From 08/2015 to 01/2018, 35 patients with LARC were treated at one study center. Thirty-four patients were analyzed of whom 1 (3%) was UICC stage II and 33 (97%) patients were UICC stage III. Grade 3 acute toxicities occurred in 5 patients (15%). Patients with acute grade 1 cystitis (n = 9) had significantly higher D\(_{mean}\) values for bladder (29.4 Gy vs. 25.2 Gy, p < 0.01) compared to patients without bladder toxicities. Acute diarrhea was associated with small bowel volume (grade 2: 870.1 ccm vs. grade 0–1: 647.3 ccm; p < 0.01) and with the irradiated volumes V5 to V50. Using VMAT planning, we could reduce mean doses and irradiated volumes for all OAR: D\(_{mean}\) bladder (21.9 Gy vs. 26.3 Gy, p < 0.01), small bowel volumes V5–V45 (p < 0.01), D\(_{mean}\) anal sphincter (34.6 Gy vs. 35.6 Gy, p < 0.01) and D\(_{mean}\) femoral heads (right 11.4 Gy vs. 25.9 Gy, left 12.5 Gy vs. 26.6 Gy, p < 0.01). Acute small bowel and bladder toxicities were dose and volume dependent. Dose and volume sparing for all OAR could be achieved through VMAT planning and might result in less acute toxicities.
KW  - radiotherapy
KW  - rectal cancer
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301255
VL  - 12
ER  -