Doris Röthlein

Evaluation of implementation of a fully automated algorithm (enhanced model predictive control) in an interacting infusion pump system for establishment of tight glycemic control in medical intensive care unit patients.

Background: The objective of this study was to investigate the performance of a newly developed decision support system for the establishment of tight glycemic control in medical intensive care unit (ICU) patients for a period of 72 hours. Methods: This was a single-center, open, non-controlled feasibility trial including 10 mechanically ventilated ICU patients. The CS-1 decision support system (interacting infusion pumps with integrated enhanced model predictive control algorithm and user interface) was used to adjust the infusion rate of administered insulin to normalize blood glucose. Efficacy and safety were assessed by calculating the percentage of values within the target range (80–110 mg/dl), hyperglycemic index, mean glucose, and hypoglycemic episodes (<40 mg/dl). Results: The percentage of values in time in target was 47.0% (±13.0). The average blood glucose concentration and hyperglycemic index were 109 mg/dl (±13) and 10 mg/dl (±9), respectively. No hypoglycemic episode (<40 mg/dl) was detected. Eleven times (1.5% of all given advice) the nurses did not follow and, thus, overruled the advice of the CS-1 system. Several technical malfunctions of the device (repetitive error messages and missing data in the data log) due to communication problems between the new hardware components are shortcomings of the present version of the device. As a consequence of these technical failures of system integration, treatment had to be stopped ahead of schedule in three patients. Conclusions: Despite technical malfunctions, the performance of this prototype CS-1 decision support system was, from a clinical point of view, already effective in maintaining tight glycemic control. Accordingly, and with technical improvement required, the CS-1 system has the capacity to serve as a reliable tool for routine establishment of glycemic control in ICU patients.

Synthesis of 5-fluorouridine nucleolipid derivatives and their cytostatic/cytotoxic activities on human HT-29 colon carcinoma cells.

One of the major drawbacks of chemotherapeutics is their insufficient penetration through cell membranes due to a high hydrophobicity. Thus, we have synthesized a series of selected nucleolipid derivatives of 5‐fluorouridine (5‐FUrd; 2a), carrying lipophilic moieties at N(3) and/or in the 2′,3′‐O‐position (i.e., 3a–7a and 3c), and tested their cytostatic/cytotoxic activities using HT‐29 human colon carcinoma cells, in comparison with, e.g., 5‐FU (1) and 5‐FUrd (2a). Incorporation and intracellular localization of the substances under test were performed after conjugation with the fluorochrome Atto 425. We showed that all 5′‐O‐labelled Atto 425 derivatives were incorporated by the human HT‐29 cells and accumulated in their cytoplasm. Moreover, after 24‐h treatment of HT‐29 human colon carcinoma cells, 1 or 2a (10, 20, 40, or 80 μM) revealed a significant (14–23 or 33–45%, resp.) decrease of the viability in comparison with the (negative) control. Interestingly, derivatives 3a and 3c (40 and 80 μM) led to a significant (77–95 or 89–96%, resp.) inhibition of survival of human HT29 cells, i.e., these two substances were ca. 63–72% or ca. 75%, respectively more effective than 5‐FU (1; positive control). Furthermore, derivative 5a showed a significant, i.e., 30 and 86%, inhibition of the survival at 40 and 80 μM, respectively in comparison with the (negative) control. Some synthesized 5‐FUrd derivatives turned out to be more effective than 5‐FU (1) or 5‐FUrd (2a).

Cytostatic/Cytotoxic Effects of 5-Fluorouridine Nucleolipids on Colon, Hepatocellular, and Renal Carcinoma Cells: in vitro Identification of a Potential Cytotoxic Multi-Anticancer Drug

The insufficient penetration through the cell membranes is one of the major drawbacks of chemotherapeutics such as 5‐fluorouracil (5‐FU; 1). To improve the penetration, a useful strategy is the attachment of lipophilic moieties. Thus, we have synthesized a series of nucleolipid derivatives of 5‐fluorouridine (5‐FUrd; 2a), carrying lipophilic moieties at N(3) and/or at the 2′,3′‐O position, i.e., 3a, 3b, 4–7, and tested their cytostatic/cytotoxic activities towards three carcinoma cell lines (colon (HT‐29), hepatocellular (HepG2), and renal (RENCA)) in comparison with 5‐FU (1) and 5‐FUrd (2a). After 48 h of incubation, four derivatives, 3a, 3b, 5, and 7, showed inhibitory effects on the survival of HT‐29, HepG2, and RENCA cells. Additionally, to differentiate between anticancer and side‐effects, we tested the cytotoxicity of the derivatives in human macrophages. Interestingly, the derivatives 4, 5, and 6 did not exhibit any effects on survival of THP‐1 macrophages. Furthermore, we investigated the apoptosis induction of compound 1 and 2a, and the above‐mentioned derivatives in HT‐29 cells. Derivative 5 showed the highest significant (p<0.05; p<0.01) increase of the apoptosis at 80 μM after 2‐h or 4‐h treatment, as well as after 6‐h incubation at 40 μM (p<0.05). Real‐time PCR revealed that 40‐μM derivative 5 showed a 1.8‐fold increase of the pro‐apoptotic caspase‐3 gene and a twofold significant increase (p<0.01 and p<0.05 vs. control and 1, resp.) of the tumor suppressor TP53 gene, whereas the other compounds did not show any effect. We demonstrated that some 5‐FUrd derivatives such as compound 5 are more effective than 5‐FU or 5‐FUrd concerning a cytotoxic (vs. cytostatic (5‐FU, 5‐FUrd)) effect on different cancer cell lines, but without cytotoxic side‐effects on differentiated macrophages. Thus, compound 5 is suggested as a novel potent cytotoxic multi‐anti‐cancer drug.

Cytoprotection by omega-3 fatty acids as a therapeutic drug vehicle when combined with nephrotoxic drugs in an intravenous emulsion: Effects on intraglomerular mesangial cells

Highlights • Distinct concentrations of Ketorolac/Gentamicin are toxic to mesangial (MES 13) cells.• Omega-3 fatty acids protect intraglomerular mesangial cells against nephrotoxic drugs.• Omega-6 fatty acids do not protect MES 13 cells against nephrotoxic drugs.• Cytoprotection by n-3 PUFA may be due to increased intracellular redox state.