Abstract only
614
Background: Hypertension (HT) is the most common toxicity associated with bevacizumab (BV). Angiotensin converting enzyme inhibitors, calcium channel blockers (CCB), beta-blockers ...or diuretics are frequently chosen to control BV-associated HT. However, optimal use of these antihypertensive (AHT) agents for each grade of HT remains to be determined. Furthermore, the AHT agent to be used must be carefully chosen to avoid increasing risk for BV-associated cardiovascular adverse events.
Methods: Seventy-five consecutive patients with metastatic colorectal cancer who received first-line FOLFOX4 plus BV 5 mg/kg were included in the study. Treatment continued until progression of disease or unmanageable toxicity occurred. Blood pressure was measured prior to treatment in each cycle and graded using the NCI–CTC, version 3.0. The management protocol was as follows: 8-12 mg candesartan cilexetil (an angiotensin II receptor antagonist) as the first choice for grade 2 HT; 2.5 mg ≤ additional amlodipine besylate (a CCB) when grade 3 HT occurred; BV was discontinued if HT remained uncontrolled with use of both these agents. Stable blood pressure < 150/100mmHg during treatment was defined as manageable.
Results: Twenty patients (26.7%) had a history of HT. Grades 2-3 HT developed in 53 patients (70.7%) and grade 3 in 24 (32%). Median number of treatment cycles until onset of grades 2 and 3 HT was 3 and 4.5, respectively. Comparing patients with a history of HT to those without, the incidence of grade 3 was greater in the former (85 vs. 12.7%, respectively), and the median number of treatment cycles until onset of grade 3 was shorter (4 vs. 12 cycles, respectively); blood pressure was considered manageable in both groups (90 vs. 91%, respectively), and no difference in total duration of chemotherapy was observed. No AHT approach-related severe adverse events were observed.
Conclusions: Grade 3 HT was manageable during BV treatment, regardless of prior hypertensive history. However, to ensure improved survival, especially in patients with a history of HT, appropriate management is needed in BV-associated grade 3 HT. These data suggest that use of AHT agents is an effective and safe strategy in the management of BV-associated HT.
No significant financial relationships to disclose.
CYP3A4 exhibits unusual kinetic characteristics that result from the metabolism of multiple substrate including endogenous steroids and some drugs that coexist at the active site. To clarify the ...mechanism of the effect of endogenous steroids on the drug metabolism, the interaction between substrates, nevirapine (NVP) and carbamazepine (CBZ), and endogenous steroids was investigated by theoretical calculations. When the activities of NVP 2-hydroxylation and CBZ 10,11-epoxidation by expressed CYP3A4 were measured in the presence of steroids, NVP 2-hydroxylation was found to be remarkably increased by aldosterone and inhibited by estradiol. CBZ 10,11-epoxidation was increased by androstenedione. Three-dimensional computer modeling has shown that the active site of CYP3A4 is especially large, permitting access of two substrate molecules. The interactions between NVP and aldosterone and between CBZ and androstenedione were estimated by theoretical calculations assuming the substrate and steroids to be present in the active site at the same time. It was shown that NVP or CBZ would be stably fixed close to the oxygen atom at the sixth ligand of heme by interaction with steroids, suggesting that NVP and CBZ may be hydroxylated more easily due to the interaction with steroids. Estradiol was also expected to interact with NVP via a π/π interaction between a benzene ring, in which the NVP hydroxylation site is located, and a benzene ring of estradiol, suggested to inhibit the reaction. From these results, interactions between the substrate and endogenous steroids in the active site may change the activity of CYP3A4.
The surface charge distribution of disc-type (diameter, 23 mm; thickness, 5 mm) alumina YSA 998 and UHA 99 insulator were measured after impulse voltage application. The measurement of the surface ...charge distribution was carried out using an in situ electrostatic probe connected to an electrometer. The electrode configuration included needle and back-side electrodes that made it possible to measure trapped charge over the whole area of the insulator surface. For non-flashover conditions (positive polarity) the surface charge density is dependent on the applied voltage, and that the highest surface charge density occurs at an anode position decaying toward the cathode. Up to the critical voltage which caused a flashover, no charge was detected at the cathode region. On the other hand, for a flashover, the entire sample surfaces were charged positively, and generally, the highest surface charge density occurred at the cathode region. For negative polarity (non-flashover) the cathode region is charged positively, and a small positive charge is detected on the other part of the anode region.
Neuropeptides have important roles in modulating behavioral patterns such as social interaction. With the aim to determine the presence of neuropeptides known to be involved in social interaction as ...well as novel peptides, we used MALDI-TOF/MS to analyze neuropeptide profiles in some medaka brain regions. In the telencephalon, hypothalamus, and pituitary gland, 3, 6, and 10 peaks, respectively, were identified as neuropeptides (Arg-vasotocin AVT, growth hormone-releasing hormone GHRH, neuropeptide FF, substance P SP, somatostatin-1 and -2, melanin-concentrating hormone MCH, MCH gene-related peptide Mgrp, melanocyte-stimulating hormone MSH, corticotropin-like intermediate lobe peptide CLIP, and b-endorphin). The neuropeptide profile of telencephalon similar to that of the hypothalamus, but completely different from that of pituitary gland. For the future genetic analysis, we identified cDNAs encoding precursor proteins for the identified peptides. We also detect its expression of g-prepro-tachykinin gene encoding a SP precursor protein in both the telencephalon and hypothalamus. Our results indicated that the medaka brain contains some neuropeptides (AVT, SP, and somatostatins) that may be involved in modulating medaka behaviors such as social interaction.
