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Ulmer A.,University Hospital Carl Gustav Caruso | Tabea Tauer J.,University Hospital Carl Gustav Caruso | Glauche I.,Institute for Medical Informatics and Biometry | Jung R.,Medical Faculty Carl Gustav Caruso Experimental Center | Suttorp M.,University Hospital Carl Gustav Caruso
Klinische Padiatrie | Year: 2013

Background: Long-term treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) exerts off-target effects on bone growth by either impaired growth hormone (GH) action or osseous modelling impairment. Methods: Body height and the GH-related parameters insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3(IGFBP-3) were determined repetitively 3-monthly over 2 years in 21 pediatric CML-patients on standardized imatinib treatment. In an animal model 4-week-old male Wistar rats were exposed over 10 weeks to imatinib, dasatinib, or bosutinib at varying concentrations via the drinking water. Blood was collected at prepubertal age, pubertal age, and at adult age, respectively, and animals' serum levels of IGFBP-3 were measured. Results: Independent from treatment duration patients exhibited IGF-1 and IGFBP-3 levels almost exclusively in the very low range when compared to age-matched references. No clear pattern of rising or falling IGF-1 and IGFBP-3 levels was observed. In rats, compared to controls, serum IGFBP-3 was significantly lowered for all TKIs tested, at all concentrations applied, and at all ages under investigation. Conclusion: Besides direct off-target effects on the growing skeleton, TKI treatment also results in lowered blood levels of IGF-1 and IGFBP-3. A juvenile rat model predicts this side effect for dasatinib and bosutinib. Thus, growth and GH- related parameters should be monitored regularly in pediatric patients with CML on TKIs. © Georg Thieme Verlag KG Stuttgart, New York.

Pistrosch F.,University Hospital Carl Gustav Caruso | Passauer J.,University Hospital Carl Gustav Caruso | Herbrig K.,University Hospital Carl Gustav Caruso | Schwanebeck U.,TU Dresden | And 2 more authors.
Hormone and Metabolic Research | Year: 2012

Proteinuria in diabetic nephropathy predicts the progressive loss of glomerular filtration rate (GFR) and serves as independent predictor for mortality. We performed the present study (ClinicalTrials.gov identifier: NCT 00324675) to clarify whether the activation of PPARγ receptor by thiazolidinediones was able to improve proteinuria and preserve renal function in advanced diabetic nephropathy. A total of 28 type 2 diabetic patients (4 women and 24 men, mean age 66.1±9.1 years) with urinary albumin excretion >300mg/24h and an estimated GFR <60ml/min were included into this prospective double blind trial to receive either rosiglitazone (RSG) 4mg b.i.d or matching placebo (PLC) for 52 weeks in addition to their concomitant antidiabetic background therapy. At baseline and after 26 and 52 weeks, renal plasma flow (RPF) and GFR were determined before and after blockade of nitric oxide (NO) by intravenous administration of N-monomethyl-l-arginine acetate. RSG treatment resulted in a significant reduction of proteinuria (2.4±1.1; 1.2±0.6; 1.5±0.7g/d at baseline, 26 weeks and 52 weeks; respectively, p<0.05) whereas PLC did not influence proteinuria (1.6±0.6; 1.6±0.8; 1.7±0.8g/d). GFR and RPF did not change significantly during the study, however, RSG improved the intrarenal NO bioavailability. RSG treatment was generally well tolerated and the major adverse event - development of edema - could be controlled by dose adjustment of the study drug and diuretic agents. In conclusion, we demonstrated a possible renoprotective effect of RSG in patients with advanced diabetic nephropathy. © Georg Thieme Verlag KG Stuttgart - New York.

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