Biomedical subjects

Jurgen Venitz

Publications and source records attributed to Jurgen Venitz.

7 recordsLinked to original sources

PubMed2006

Factors affecting the pharmacokinetic profile of MS-275, a novel histone deacetylase inhibitor, in patients with cancer.

AIMS: To evaluate elimination pathways of the histone deacetylase inhibitor MS-275 in vitro and screen for relationships between demographic factors that may affect its pharmacokinetics in vivo. PATIENTS AND METHODS: Substrate specificity of MS-275 for the liver-specific organic anion transporting polypeptides (OATPs) was assessed using Xenopus laevis oocytes, and in vitro metabolism was evaluated using human liver microsomes. In vivo pharmacokinetic data were obtained from 64 adult patients (36 male/28 female; median age, 57 years) receiving MS-275 orally (dose range, 2 to 12 mg/m2). RESULTS: Accumulation of [G-3H]MS-275 by oocytes expressing OATP1B1 or OATP1B3 was not significantly different from water-injected controls (p = 0.82). Furthermore, no metabolites could be detected after incubation of MS-275 in human liver microsomes, suggesting that hepatic metabolism is a minor pathway of elimination. The mean (+/- SD) apparent oral clearance of MS-275 was 38.5 +/- 18.7 L/h, with a coefficient of variation (%CV) of 48.7%. When clearance was adjusted for body-surface area (BSA), the inter-individual variability was similar (%CV = 50.1%). In addition, in a linear-regression analysis, except for adjusted ideal body weight (p = 0.02, |r| = 0.29), none of the studied measures (BSA, lean-body mass, ideal body weight, body-mass index, height, weight, age, and sex) was a significant covariate (p > 0.13; |r| < 0.11) for oral clearance. CONCLUSIONS: The current analysis has eliminated a number of candidate covariates from further consideration as important determinants of MS-275 absorption and disposition. Furthermore, MS-275 can be added to the list of cancer drugs where BSA-based dosing is not more accurate than fixed dosing.

Adult↗

PubMed2005

Interspecies differences in plasma protein binding of MS-275, a novel histone deacetylase inhibitor.

MS-275 (MS-27-275; 3-pyridylmethyl-N-[4-[(2-aminophenyl)-carbamoyl]-benzyl-carbamate) is a histone deacetylase inhibitor under clinical development as an anticancer agent. Here, we examined the role of protein binding as a possible determinant of the pharmacokinetic behavior of MS-275. The distribution of MS-275 in plasma was studied in vitro using equilibrium dialysis and ex vivo in five cancer patients receiving the drug orally at a dose of 10 mg/m(2). The dialysis method uses a tracer amount of [G-(3)H]MS-275 on a 96-well microdialysis plate with a 5-kDa cut-off membrane, and requires 250 microl sample. The time to equilibrium was established to be within 5 h, and the mean unbound fraction of MS-275 (f (u)) over a presumed therapeutic concentration range in healthy volunteer human plasma was 0.188 +/- 0.0075 as compared to 0.168 +/- 0.0144 in cancer patients. The binding was concentration-independent, indicating a low affinity, possibly non-specific and non-saturable process. MS-275 was found to bind in decreasing order to plasma > alpha(1)-acid glycoprotein > albumin. Among 19 tested drugs, a slightly increased f (u) was observed in the presence of only ibuprofen (f (u), 0.236 +/- 0.001) and metoclopramide (f (u), 0.270 +/- 0.042), suggesting weakly competitive displacement from protein-binding sites (P < 0.01). Compared to humans, f (u) was significantly higher in plasma from mouse (0.376), rat (0.393), rabbit (0.355), dog (0.436), and pig (0.439) (P < 0.01), which may explain, in part, the species-dependent pharmacokinetic profile of MS-275 observed previously.

Animals↗

PubMed2003

Comparison of neural network and multiple linear regression as dissolution predictors.

The predictive performance of an artificial neural network (NN) was compared with the first-order multiple linear regression (MLR) using mean dissolution data of 28 diltiazem immediate release tablet formulations. The performance was evaluated using "Weibull" function parameters alpha and beta. Weibull parameters were used as dissolution markers of the eight principal, mainly compositional, variables. The parameters were obtained by fitting the Weibull function to the mean (n = 12) dissolution profiles of 28 diltiazem hydrochloride tablet formulations. The generated set of 28 pairs of Weibull function parameters was evaluated for internal and external predictability using both the MLR and the artificial NN. A three-layered 8-5-2 feedforward NN was found to be an adequate descriptor of the dissolution data. Internal predictions were based on the data of 24 products. External predictions used the 24 product data to test four products not used in the training phase. The predictive performances of the two techniques were evaluated using bias (mean prediction error; MPE) and precision (mean absolute error; MAE). The study results suggested that, for the studied data set, NN is a superior internal and external predictor to MLR. The artificial NN predicted order of the formulation composition variables, influencing the dissolution parameters as follows: hydrogenated oil > microcrystallinecellulose > ethyl cellulose > eudragit > hydroxypropylcellulose > coat > hydroxypropylmethylcellulose > Speed.

Chemistry, Pharmaceutical↗

PubMed2003

2-Methoxyestradiol, a promising anticancer agent.

Estrogens occurring naturally in the body are metabolized to catecholestrogens (2- and 4-hydroxyestradiol) by the cytochrome P450 enzymes. 2-Hydroxy catecholestrogens are further metabolized by catechol-O-methyltransferase to 2-methoxyestradiol, which is known to be protective against tumor formation. 2-Methoxyestradiol exhibits potent apoptotic activity against rapidly growing tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the colchicine-binding site, have been reported. The exact mechanism of action of 2-methoxyestradiol is still unclear, but it has been shown to be effective in preventing tumor growth in a variety of cell lines. 2-Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for estrogen receptor alpha compared with that of estradiol, and its affinity for estrogen receptor beta is even lower than that of estrogen receptor alpha, thus it has minimal estrogenic activity. 2-Methoxyestradiol is distinct because of its inability to engage estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of estrogen receptors alpha and beta. A phase I clinical trial of 2-methoxyestradiol 200, 400, 600, 800, and 1,000 mg/day in 15 patients with breast cancer showed significant reduction in bone pain and analgesic intake in some patients, with no significant adverse effects. Another phase I study of 2-methoxyestradiol 200-1,000 mg/day in combination with docetaxel 35 mg/m2/week for 4-6 weeks performed in 15 patients with advanced refractory metastatic breast cancer showed no serious drug-related adverse effects. A phase II randomized, double-blind trial of 2-methoxyestradiol 400 and 1,200 mg/day in 33 patients with hormone-refractory prostate cancer showed that it was well tolerated and showed prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1,000 mg/day.

2-Methoxyestradiol↗

PubMed2002

A theoretical model for the effects of reduced hemoglobin-oxygen affinity on tumor oxygenation.

PURPOSE: To develop a theoretical model for oxygen delivery to tumors, and to use the model to simulate the effects of changing the affinity of hemoglobin for oxygen on tumor oxygenation. METHODS AND MATERIALS: Hemoglobin affinity is expressed in terms of P(50), the partial pressure of oxygen (Po(2)) at half saturation. Effects of changing P(50) on arterial Po(2) are predicted using an effective vessel approach to describe diffusive oxygen transport in the lungs, assuming fixed systemic oxygen demand and fixed blood flow rate. The decline in oxygen content of blood as it flows through normal tissue before entering the tumor region is assumed fixed. The hypoxic fraction of the tumor region is predicted using a three-dimensional simulation of diffusion from a network of vessels whose geometry is derived from observations of tumor microvasculature in the rat. RESULTS: In air-breathing rats, predicted hypoxic fraction decreases with moderate increases in P(50), but increases with further increases of P(50), in agreement with previous experimental results. In rats breathing hyperoxic gases, and in humans breathing either normoxic or hyperoxic gases, increased P(50) is predicted to improve tumor oxygenation. CONCLUSIONS: The results support the administration of synthetic agents to increase P(50) during radiation treatment of tumors.

Animals↗

PubMed2002

Solute disposition in the rat lung in vivo and in vitro: determining regional absorption kinetics in the presence of mucociliary escalator.

Solute absorption from the airways was compared and modeled in vivo and in vitro isolated perfused rat lung (IPRL), and its regional kinetic descriptors in the presence of competing mucociliary escalator were estimated. 7.4 kDa fluorophore-labeled polyhydroxyethylaspartamide (F-PHEA), FITC-labeled dextran 40 (FD-4) and sodium fluorescein (F-Na) were used as model solutes. They were reproducibly administered into the airways in a range of doses in vivo and in vitro IPRL, and their initial deposition and subsequent absorption profiles compared. Each of the absorption data was fitted across doses to a kinetic model in which rate constants for Michaelis-Menten-type active (V(max,P) and K(m,P)) and/or first-order passive (k(a,P)) absorption and mucociliary escalator (k(E)) were estimated simultaneously. Statistically indistinguishable initial solute distribution was ensured in vivo and in vitro. The absorption profiles for F-PHEA were kinetically identical in vivo and in vitro, and their modeling analysis revealed the presence of competing, solute-independent pulmonary-to-bronchial mucociliary escalator with a half-life of 28.9 min. F-PHEA's active absorption was found to be 77 times faster than its passive absorption, yet this was present only in the pulmonary region. Passive solute absorption was inversely related to solute molecular weight [F-PHEA < FD-4 < F-Na]. Bronchial absorption was shown for F-Na in vivo and its rate indistinguishable from that from the pulmonary region. Thus, a single kinetic model was developed, enabling regional absorption kinetic analysis both in vivo and in vitro, in the presence of competing, solute-independent mucociliary escalator.

Absorption↗

PubMed2002

Antiangiogenesis therapeutic strategies in prostate cancer.

It is now well documented that tumor progression from its early stages to an advanced metastatic state requires the recruitment of new vasculature. The reliance on angiogenesis by tumors renders them susceptible to agents that can interfere with the angiogenic process. Recent interest in the therapeutic potential of using angiogenesis as a target mechanism for anticancer therapy has led to the identification of various antiangiogenic agents that interfere at various stages of the process. This review is a summary of recent progress in the identification and characterization of antiangiogenesis agents with a focus on their utility with respect to prostate cancer. Though we focus on prostate cancer, this knowledge is relevant to any cancer that involves angiogenesis.

Angiogenesis Inhibitors↗