Multiple-dose pharmacokinetics of anidulafungin during continuous venovenous haemofiltration

Background: Clinical studies support a role for anidulafungin as first-line treatment of invasive candidiasis in critically ill patients and postulate no need for dose adjustments in mild to severe renal failure. Although intensive care patients requiring renal replacement therapy are at particular risk of invasive fungal infection, no pharmacokinetic data on anidulafungin during continuous venovenous haemofiltration (CVVHF) are available. Patients and methods: Ten patients with CVVHF due to acute renal failure were included. Anidulafungin was infused on 3 consecutive days starting with a loading dose of 200 mg on day 1, followed by doses of 100 mg on each of days 2 and 3. During the 72 h study phase of CVVHF, blood and ultrafiltrate samples were collected at corresponding times. Anidulafungin concentrations were determined by HPLC. Results: Peak plasma concentrations were reached 3 h after the start of infusion and were 8.5 +/- 3.6 mg/L at the pre-filter port. The mean arterial area under the curve (AUC(0-24)) of the study population was 109.9 +/- 49.82 mg.h/L, the total clearance was 1.08 +/- 0.41 L/h, the volume of distribution was 41.97 +/- 22.64 L and the elimination half-life was 28.78 +/- 10.40 h. Anidulafungin was not filtered, but CVVHF resulted in a substance loss of similar to 20%, due to adherence to synthetic surfaces. Conclusions: Pharmacokinetics of anidulafungin during CVVHF resembled findings in healthy adults and adults with fungal infections. Therefore we recommend a loading dose of 200 mg intravenous anidulafungin on the first day and 100 mg on consecutive treatment days in patients during CVVHF

Plasma protein binding may reduce antimicrobial activity by preventing intra-bacterial uptake of antibiotics, for example clindamycin

Although plasma protein binding (PPB) is accepted to be an essential factor in reducing antimicrobial activity, little is known about the underlying mechanisms. One possibility includes impaired penetration of an antimicrobial into bacterial cells in the presence of PPB. As a prerequisite for testing this hypothesis an optimized medium displaying high protein binding without impairing bacterial growth had to be identified for our model compound clindamycin. Determination of PPB, bacterial growth and antimicrobial killing was performed in Mueller-Hinton broth (MHB) containing various amounts of human albumin or serum. [(3)H]clindamycin was used to investigate clindamycin penetration into Staphylococcus aureus. Of all investigated media only MHB(50%serum) and MHB(70%serum) achieved protein binding comparable to pure serum. In contrast, MHB(20%serum) and most media containing only albumin demonstrated considerably lower protein binding. Pure serum resulted in bacterial growth inhibition compared with MHB while MHB(16%albumin) and MHB(50%serum) did not result in significant differences in bacterial count after 24 h. However, in both MHB(16%albumin) and MHB(50%serum) the antimicrobial activity of clindamycin was reduced by > 2 log(10) cfu/mL compared with pure MHB. The radioactive signal after administration of [(3)H]clindamycin to S. aureus was significantly decreased in pure serum as well as in MHB(16%albumin) and MHB(50%serum), while no significant difference was observed for MHB(4%albumin) and MHB(20%serum). Reduction of the intracellular radioactive signal in the presence of serum proteins correlated both with the degree of protein binding and reduction of antimicrobial activity supporting the hypothesis of impairment of activity by PPB by reducing intra-bacterial antimicrobial concentrations

Diagnostic Performance of Urinary Resveratrol Metabolites as a Biomarker of Moderate Wine Consumption

Background: Nutritional biomarkers may be better measures of dietary exposure than self-reported dietary data. We evaluated resveratrol metabolites, potential biomarkers of wine consumption, in humans after moderate consumption of sparkling, white, or red wines. Methods: We performed 2 randomized, crossover trials and a cohort study. In the first study, 10 healthy men consumed 30 g of ethanol/day as sparkling wine or gin for 28 days. In the second trial, 10 healthy women consumed 20 g of ethanol/day as white or red wine for 28 days. We also evaluated 52 participants in a study on the effects of a Mediterranean diet on primary prevention of cardiovascular disease (the PREDIMED Study). We used liquid chromatography-tandem mass spectrometry to analyze urinary total resveratrol metabolites (TRMs) and predictive values and ROC curve analyses to assess the diagnostic accuracy. Results: We observed significant increases in TRMs [72.4 (95% confidence interval, 48.5-96.2; P = 0.005), 211.5 (166.6-256.3; P = 0.005), and 560.5 nmol/g creatinine (244.9-876.1; P = 0.005)] after consumption of sparkling, white, or red wine, respectively, but no changes after the washout or gin periods. In the cohort study, the reported daily dose of wine consumption correlated directly with TRMs (r = 0.654; P <0.001). Using a cutoff of 90 nmol/g, we were able to use TRMs to differentiate wine consumers from abstainers with a sensitivity of 72% (60%-84%); and a specificity of 94% (87%-100%). Conclusions: Resveratrol metabolites in urine may be useful biomarkers of wine intake in epidemiologic and intervention studies. 2006 American Association for Clinical Chemistry

Involvement of UDP-Glucuronosyltransferases and Sulfotransferases in the Excretion and Tissue Distribution of Resveratrol in Mice

Resveratrol is a naturally occurring polyphenolic compound with various pharmacological activities. It is unknown whether the expression of metabolizing enzymes correlates with resveratrol levels in organs and tissues. Therefore, we investigated the metabolism and tissue distribution of resveratrol in mice and assessed its association with the expression of UDP-glucuronosyltransferase (Ugt) and sulfotransferase (Sult) genes. Plasma, urine, feces, and various organs were analyzed using high-performance liquid chromatography at up to 8 h after intragastric resveratrol administration. The metabolism of resveratrol was pronounced, leading to the formation of resveratrol glucuronides and sulfates. Concentrations of resveratrol and its metabolites were high in the gastrointestinal organs, urine, and feces, but low in the liver and kidneys. In lung, heart, thymus, and brain tissues, parent resveratrol levels exceeded the sulfate and glucuronide concentrations. The formation of resveratrol conjugates correlated with the expression of certain Ugt and Sult genes. Reverse transcription quantitative PCR (RT-qPCR) analysis revealed high mRNA expression of Ugt1a1 and Ugt1a6a in the liver, duodenum, jejunum, ileum, and colon, leading to high concentrations of resveratrol-3-O-glucuronide in these organs. Strong correlations of resveratrol-3-O-sulfate and resveratrol-3-O-4′-O-disulfate formation with Sult1a1 mRNA expression were also observed, particularly in the liver and colon. In summary, our data revealed organ-specific expression of Sults and Ugts in mice that strongly affects resveratrol concentrations; this may also be predictive in humans following oral uptake of dietary resveratrol.© 2017 by the author

Resveratrol Inhibits Key Steps of Steroid Metabolism in a Human Estrogen-Receptor Positive Breast Cancer Model: Impact on Cellular Proliferation

The role of resveratrol (RES) in preventing breast cancer is controversial, as low concentrations may stimulate the proliferation of estrogen-receptor alpha positive (ERα+) breast cancer cells. As metabolism is the key factor in altering cellular estrogens, thereby influencing breast tumor growth, we investigated the effects of RES on the formation of estrogen metabolites, namely 4-androstene-3,17-dione (AD), dehydroepiandrosterone (DHEA), dehydroepiandrosterone-3-O-sulfate (DHEA-S), estrone (E1), estrone-3-sulfate (E1-S), 17β-estradiol (E2), 17β-estradiol-3-O-(β-D-glucuronide) (E2-G), 17β-estradiol-3-O-sulfate (E2-S), 16α-hydroxy-17β-estradiol (estriol, E3), and testosterone (T) in ERα- MDA-MB-231 and ERα+ MCF-7 cells. Incubation of both of the cell lines with the hormone precursors DHEA and E1 revealed that sulfation and glucuronidation were preferred metabolic pathways for DHEA, E1 and E2 in MCF-7 cells, compared with in MDA-MB-231 cells, as the Vmax values were significantly higher (DHEA-S: 2873.0 ± 327.4 fmol/106 cells/h, E1-S: 30.4 ± 2.5 fmol/106 cells/h, E2-S: 24.7 ± 4.9 fmol/106 cells/h, E2-G: 7.29 ± 1.36 fmol/106 cells/h). RES therefore significantly inhibited DHEA-S, E1-S, E2-S and E2-G formation in MCF-7, but not in MDA-MB-231 cells (Kis: E2-S, 0.73 ± 0.07 μM < E1-S, 0.94 ± 0.03 μM < E2-G, 7.92 ± 0.24 μM < DHEA-S, 13.2 ± 0.2 μM). Suppression of these metabolites subsequently revealed twofold higher levels of active E2, concomitant with an almost twofold increase in MCF-7 cell proliferation, which was the most pronounced upon the addition of 5 μM RES. As the content of RES in food is relatively low, an increased risk of breast cancer progression in women is likely to only be observed following the continuous consumption of high-dose RES supplements. Further long-term human studies simultaneously monitoring free estrogens and their conjugates are therefore highly warranted to evaluate the efficacy and safety of RES supplementation, particularly in patients diagnosed with ERα+ breast cancer.© 2018 Poschner, Maier-Salamon, Zehl, Wackerlig, Dobusch, Meshcheryakova, Mechtcheriakova, Thalhammer, Pachmann and Jäge

Different expression patterns of organic anion transporting polypeptides in osteosarcomas, bone metastases and aneurysmal bone cysts

Organic anion transporting polypeptides (OATP) were identified as transmembrane transporters for various endo- and exogenous organic compounds (hormones, prostaglandins, anticancer drugs). OATP expression had been shown in different tissues, but not in bone tumors. Therefore, the expression pattern of all known eleven human OATPs was analyzed by quantitative RT-PCR in 21 human bone tumor specimens (osteosarcomas, bone metastases and benign aneurysmal bone cysts). Transcriptional expression of OATP1A2, 1C1, 2A1, 2B1, 3A1, 4A1, 4C1 and 5A1, but not of OATP1B1, 1B3 and 6A1 was observed in malignant and non-malignant tumor specimens at varying level. Importantly, OATP3A1, 4A1, 2B1 and 1C1 mRNA levels were significantly higher in aneurysmal bone cysts as compared to osteosarcomas. Elevated mRNA levels of OATP2A1, 1A2, and 4C1 in metastases from kidney cancer and of OATP5A1 in prostate cancer suggest that the OATP expression pattern in metastases is comparable to that of the primary tumors. Different to tissue, OATP expression in osteosarcoma cell lines HOS and MG-63, normal human osteoblast outgrowth cells (hOB) and bone marrow stromal cells (BMSC) is limited to OATP3A1 and OATP4A1. High OATP expression levels, particularly in benign bone tumors, suggest an important role of these transporters for providing hormones, their conjugates, prostaglandins and drugs in bone cells. Thereby, they may influence bone resorption and formation

Novel Oncology Therapeutics: Targeted Drug Delivery for Cancer

No abstract availabl