@article{ShahBulittaKinzigetal.2019,
  author    = {Shah, Nirav R. and Bulitta, J{\"u}rgen B. and Kinzig, Martina and Landersdorfer, Cornelia B. and Jiao, Yuanyuan and Sutaria, Dhruvitkumar S. and Tao, Xun and H{\"o}hl, Rainer and Holzgrabe, Ulrike and Kees, Frieder and Stephan, Ulrich and S{\"o}rgel, Fritz},
  title     = {Novel population pharmacokinetic approach to explain the differences between cystic fibrosis patients and healthy volunteers via protein binding},
  series = {Pharmaceutics},
  volume    = {11},
  journal   = {Pharmaceutics},
  number    = {6},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics11060286},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196934},
  year      = {2019},
  abstract  = {The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3\% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50\% in male and estimated as 54.5\% in female healthy volunteers as well as 56.3\% in male and 74.4\% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.},
  language  = {en}
}
@article{SchumannEberleinMuhtadietal.2018,
  author    = {Schumann, Sarah and Eberlein, Uta and Muhtadi, Razan and Lassmann, Michael and Scherthan, Harry},
  title     = {DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223},
  series = {Scientific Reports},
  volume    = {8},
  journal   = {Scientific Reports},
  number    = {2286},
  doi       = {10.1038/s41598-018-20364-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175596},
  year      = {2018},
  abstract  = {Irradiation with high linear energy transfer α-emitters, like the clinically used Ra-223 dichloride, severely damages cells and induces complex DNA damage including closely spaced double-strand breaks (DSBs). As the hematopoietic system is an organ-at-risk for the treatment, knowledge about Ra-223-induced DNA damage in blood leukocytes is highly desirable. Therefore, 36 blood samples from six healthy volunteers were exposed ex-vivo (in solution) to different concentrations of Ra-223. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the decay, ranging from 0 to 142 mGy. γ-H2AX + 53BP1 co-staining and analysis was performed in leukocytes isolated from the irradiated blood samples. For DNA damage quantification, leukocyte samples were screened for occurrence of α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of β-irradiation was similar to baseline values, being in agreement with a negligible β-contribution (3.7\%) to the total absorbed dose to the blood. Our calibration curve will contribute to the biodosimetry of Ra-223-treated patients and early after incorporation of α-emitters.},
  language  = {en}
}
@article{HechtErberHarreretal.2015,
  author    = {Hecht, Markus and Erber, Sonja and Harrer, Thomas and Klinker, Hartwig and Roth, Thomas and Parsch, Hans and Fiebig, Nora and Fietkau, Rainer and Distel, Luitpold V.},
  title     = {Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells},
  series = {PLoS ONE},
  volume    = {10},
  journal   = {PLoS ONE},
  number    = {6},
  doi       = {10.1371/journal.pone.0130277},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151694},
  pages     = {e0130277},
  year      = {2015},
  abstract  = {Background Cancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI) Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo. Methods Cytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays. The 50\% effective cytotoxic concentrations (EC50) were calculated and compared to the blood levels in our patients and published data. Results The in vitro EC50 of the different drugs in the BxPC-3 pancreatic cancer cells were: Efavirenz 31.5\(\mu\)mol/l (= 9944ng/ml), Nevirapine 239\(\mu\)mol/l (= 63786ng/ml), Etravirine 89.0\(\mu\)mol/l (= 38740ng/ml), Lersivirine 543\(\mu\)mol/l (= 168523ng/ml), Delavirdine 171\(\mu\)mol/l (= 78072ng/ml), Rilpivirine 24.4\(\mu\)mol/l (= 8941ng/ml). As Efavirenz and Rilpivirine had the highest cytotoxic potential and Nevirapine is frequently used in HIV-1 positive patients, the results of these three drugs were further studied in Panc-1 pancreatic cancer cells and confirmed with colony formation assays. 205 patient blood levels of Efavirenz, 127 of Rilpivirine and 31 of Nevirapine were analyzed. The mean blood level of Efavirenz was 3587ng/ml (range 162-15363ng/ml), of Rilpivirine 144ng/ml (range 0-572ng/ml) and of Nevirapine 4955ng/ml (range 1856-8697ng/ml). Blood levels from our patients and from published data had comparable Efavirenz levels to the in vitro toxic EC50 in about 1 to 5\% of all patients. Conclusion All studied NNRTIs were toxic against cancer cells. A low percentage of patients taking Efavirenz reached in vitro cytotoxic blood levels. It can be speculated that in HIV-1 positive patients having high Efavirenz blood levels pancreatic cancer incidence might be reduced. Efavirenz might be a new option in the treatment of cancer.},
  language  = {en}
}
@article{BulittaJiaoLandersdorferetal.2019,
  author    = {Bulitta, J{\"u}rgen B. and Jiao, Yuanyuan and Landersdorfer, Cornelia B. and Sutaria, Dhruvitkumar S. and Tao, Xun and Shin, Eunjeong and H{\"o}hl, Rainer and Holzgrabe, Ulrike and Stephan, Ulrich and S{\"o}rgel, Fritz},
  title     = {Comparable Bioavailability and Disposition of Pefloxacin in Patients with Cystic Fibrosis and Healthy Volunteers Assessed via Population Pharmacokinetics},
  series = {Pharmaceutics},
  volume    = {11},
  journal   = {Pharmaceutics},
  number    = {7},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics11070323},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197221},
  pages     = {323},
  year      = {2019},
  abstract  = {Quinolone antibiotics present an attractive oral treatment option in patients with cystic fibrosis (CF). Prior studies have reported comparable clearances and volumes of distribution in patients with CF and healthy volunteers for primarily renally cleared quinolones. We aimed to provide the first pharmacokinetic comparison for pefloxacin as a predominantly nonrenally cleared quinolone and its two metabolites between both subject groups. Eight patients with CF (fat-free mass [FFM]: 36.3 ± 6.9 kg, average ± SD) and ten healthy volunteers (FFM: 51.7 ± 9.9 kg) received 400 mg pefloxacin as a 30 min intravenous infusion and orally in a randomized, two-way crossover study. All plasma and urine data were simultaneously modelled. Bioavailability was complete in both subject groups. Pefloxacin excretion into urine was approximately 74\% higher in patients with CF compared to that in healthy volunteers, whereas the urinary excretion of metabolites was only slightly higher in patients with CF. After accounting for body size and composition via allometric scaling by FFM, pharmacokinetic parameter estimates in patients with CF divided by those in healthy volunteers were 0.912 for total clearance, 0.861 for nonrenal clearance, 1.53 for renal clearance, and 0.916 for volume of distribution. Nonrenal clearance accounted for approximately 90\% of total pefloxacin clearance. Overall, bioavailability and disposition were comparable between both subject groups.},
  language  = {en}
}