Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII 890 CL

We have synthesized a new benzomorphan derivative, 2R-[2alpha,3(S*), 6alpha]-1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-3-[2-(phenylmethoxy)propyl]-2, 6-methano-3-benzazocin-10-ol hydrochloride (BIII 890 CL), which displaced [(3)H]batrachotoxinin A-20alpha-benzoate from neurotoxin receptor site 2 of the Na(+) channel in rat brain synaptosomes (IC(50) = 49 nM), but exhibited only low affinity for 65 other receptors and ion channels. BIII 890 CL inhibited Na(+) channels in cells transfected with type IIA Na(+) channel alpha subunits and shifted steady-state inactivation curves to more negative potentials. The IC(50) value for the inactivated Na(+) channel was much lower (77 nM) than for Na(+) channels in the resting state (18 microM). Point mutations F1764A and Y1771A in transmembrane segment S6 in domain IV of the alpha subunit reduced the voltage- and frequency-dependent block, findings which suggest that BIII 890 CL binds to the local anesthetic receptor site in the pore. BIII 890 CL inhibited veratridine-induced glutamate release in brain slices, as well as glutamate release and neurotoxicity in cultured cortical neurons. BIII 890 CL (3-30 mg/kg s.c.) reduced lesion size in mice and rats when administered 5 min after permanent focal cerebral ischemia at doses that did not impair motor coordination. In contrast to many other agents, BIII 890 CL was neuroprotective in both cortical and subcortical regions of the rat brain. Our results demonstrate that BIII 890 CL is a potent, selective, and highly use-dependent Na(+) channel blocker that protects brain tissue from the deleterious effects of focal cerebral ischemia in rodents.     

Secondary acute leukaemias with 11q23 rearrangement: clinical, cytogenetic, FISH and FICTION studies

Three patients with secondary acute leukaemia after treatment with topoisomerase II inhibitor agents are described. Two patients had acute myeloid leukaemia (AML), FAB M5a, one had pro-B-acute lymphoblastic leukaemia (ALL). The interval between initiation of chemotherapy and the onset of secondary acute leukaemia was 19–20 months. 11q23 rearrangements were detected in all cases. They were due to translocations t(11;19) (q23;p13.3), t(11;16)(q23;p13) and t(4;11)(q21;q23), respectively. Fluorescence in situ hybridization (FISH) with Yeast Artificial Chromosome (YAC) probe 13HH4 spanning the ALL-1 gene on 11q23 confirmed that in each case the ALL-1 gene had been disrupted by the translocations. The study underlined the relationship between the development of secondary acute leukaemias with 11q23 rearrangement and previous chemotherapy with topoisomerase II inhibitor agents. So far, however, only six adult patients with secondary ALL with t(4;11) after treatment with topoisomerase II inhibitor agents have been reported. ALL with t(4;11) mostly occurs in infants or young children. Our patient received epirubicin continuously for >19 months. This indicates that both myeloid and lymphoid leukaemias with involvement of the ALL-1 gene can be induced by exogenous agents, especially topoisomerase II inhibitors. Thus they may have a common biological background. This hypothesis was substantiated by means of combined immunophenotyping and FISH (FICTION). In the case of AML M5a with t(11;19), the tumour cells with ALL-1 rearrangement expressed CD34. Moreover, the pro-B-ALL with t(4;11) was CD34 positive. These findings suggest that the cell of origin of secondary AML and ALL with 11q23 rearrangement is an immature haemopoietic progenitor cell.     

Aprepitant for the control of delayed nausea and vomiting associated with the use of high-dose melphalan for autologous peripheral blood stem cell transplants in patients with multiple myeloma: a phase II study

Study objective

The aim of this study is to evaluate the efficacy of aprepitant as part of the antiemetic regimen for high-dose melphalan conditioning in multiple myeloma patients.

Design

This is a prospective, single-arm study.

Setting

The study was conducted at an Academic Medical Facility.

Subjects

Twenty-six patients receiving high-dose melphalan with autologous stem cell support were included in this study.

Intervention

Eligible patients were >18 years with a diagnosis of MM undergoing high-dose melphalan followed by autologous peripheral blood stem cell transplantation (PBSCT). All patients had serum aminotransferases and total bilirubin less than 2× upper limit of normal. Treatment consisted of aprepitant 125 mg orally on day 1, followed by 80 mg orally 24 and 48 h after the initial dose; ondansetron 16 mg orally day 1; dexamethasone 12 mg orally day 1, and 8 mg orally days 2–4 with breakthrough medications as needed.

Measurements and main results

Patients were evaluated for the frequency of emetic episodes, the need for breakthrough antiemetic medication, and the mean nausea score in 24-h increments beginning 24 h after chemotherapy and continuing until 120 h. Nausea score was determined using a linear analog scale (0–10). Complete response (CR) was defined as no more than one (1) emetic episode during the evaluation period. A total of 26 patients (17 male, 9 female) were enrolled in the study. Of these, 25 (96 %) were complete responders and 24 (92 %) had no documented emetic episodes during the study period. One patient (4 %) had 1 emetic episode and one patient (4 %) had 2 emetic episodes. Some degree of nausea was reported by 23/26 patients, and the mean nausea score for the entire group over the study period was 0.7 (range 0–10).

Conclusions

Addition of aprepitant to standard antiemetics resulted in low rates of delayed nausea/vomiting associated with high-dose melphalan and PBSCT, and has now become standard practice in this patient population at our institution.     

IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol

IKZF1 gene deletions have been associated with a poor outcome in pediatric precursor B-cell acute lymphoblastic leukemia. To assess the prognostic relevance of IKZF1 deletions for patients treated on Berlin-Frankfurt-Münster Study Group trial ALL-BFM 2000, we screened 694 diagnostic acute lymphoblastic leukemia samples by Multiplex Ligation-dependent Probe Amplification. Patients whose leukemic cells bore IKZF1 deletions had a lower 5-year event-free survival (0.69±0.05 vs. 0.85±0.01; P<0.0001) compared to those without, mainly due to a higher cumulative incidence of relapses (0.21±0.04 vs. 0.10±0.01; P=0.001). Although IKZF1 deletions were significantly associated with the P2RY8-CRLF2 rearrangement, their prognostic value was found to be independent from this association. Thus, IKZF1 deletion is an independent predictor of treatment outcome and a strong candidate marker for integration in future treatment stratification strategies on ALL-BFM protocols.Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00430118","term_id":"NCT00430118"}}NCT00430118     

NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia

Despite improvements in treatment results for pediatric T-cell acute lymphoblastic leukemia, approximately 20% of patients relapse with dismal prognosis. PTEN inactivation and NOTCH1 activation are known frequent leukemogenic events but their effect on outcome is still controversial. We analyzed the effect of PTEN inactivation and its interaction with NOTCH1 activation on treatment response and long-term outcome in 301 ALL-BFM treated children with T-cell acute lymphoblastic leukemia. We identified PTEN mutations in 52 of 301 (17.3%) of patients. In univariate analyses this was significantly associated with increased resistance to induction chemotherapy and a trend towards poor long-term outcome. By contrast, patients with inactivating PTEN and activating NOTCH1 mutations showed marked sensitivity to induction treatment and excellent long-term outcome, which was similar to patients with NOTCH1 mutations only, and more favorable than in patients with PTEN mutations only. Notably, in the subgroup of patients with a prednisone- and minimal residual disease (MRD)-response based medium risk profile, PTEN-mutations without co-existing NOTCH1-mutations represented an MRD-independent highly significant high-risk biomarker. Mutations of PTEN highly significantly indicate a poor prognosis in T-ALL patients who have been stratified to the medium risk group of the BFM-protocol. This effect is clinically neutralized by NOTCH1 mutations. Although these results have not yet been explained by an obvious molecular mechanism, they contribute to the development of new molecularly defined stratification algorithms. Furthermore, these data have unexpected potential implications for the development of NOTCH1 inhibitors in the treatment of T-cell acute lymphoblastic leukemia in general, and in those with a combination of PTEN and NOTCH1 mutations in particular.     

Electrochemical characterization of cobalt-based alloys using the mini-cell system.

OBJECTIVES: The aim of this work was to investigate the electrochemical behavior of cobalt-based alloys of different compositions using the mini-cell system (MCS) and to test the sensitivity of this technique in the detection of variations in the electrochemical behavior caused by the different compositions of cobalt-based alloys. METHODS: The electrochemical measurements were performed on two cobalt-based alloys, having a small content of gold (B?rlight and Gold Core); one cobalt-platinum-ruthenium alloy (Porta Smart) and one classical Co-based alloy (Wironit), in two different electrolytes, 1% NaCl and phosphate buffered solution (PBS). RESULTS: Based on I versus E curves, enhanced pitting corrosion capability was observed for the cobalt-based alloys, especially for those with lower chromium content and with the addition of a small amount of gold. The alloying of Co with Pt and Ru (Porta Smart), and the standard Co-based alloy do not show any critical instability; in contrast, a small addition of Au enhanced the pitting corrosion activity and reduced the corrosion stability. For higher alloy stability, a minimum 30% atomic ratio of chromium in the alloy composition is necessary. Furthermore, it was shown that MCS has sensitivity for the qualitative comparison of the alloys as well as in the electrochemical characterization of each alloy. SIGNIFICANCE: Electrochemical measurements are essential to assess the quality of an alloy. MCS might help in understanding the role the elements play in the electrochemical behavior of the alloys and at the same time contribute to the selection of the alloys in terms of their quality, even before more complex tests in vitro or in vivo are applied, and might reduce the costs for materials research.     

Intraindividual variability of paracetamol absorption kinetics after a semi-solid meal in healthy volunteers

Objective: The absorption kinetics of paracetamol is dependent on gastric emptying and its measurement was proposed as a non-invasive method to estimate gastric emptying rate. The objective of this study was to evaluate the intraindividual variability of paracetamol absorption kinetics after a semi-solid meal. Methods: The pharmacokinetics of paracetamol was studied on two occasions in 15 healthy volunteers without Helicobacter pylori antibodies. A 1-g dose of paracetamol was given as a solution together with a standardised semi-solid meal and the subjects stayed in the supine position. Results: For most of the subjects, the time course of paracetamol concentrations was similar on the two occasions. The intraindividual variability was low, with coefficients of variation of 38.3%, 8.0% and 3.8% for time to maximum plasma concentration, maximum concentration and area under the plasma concentration – time curve until 6 h, respectively. Conclusion: The assessment of paracetamol absorption kinetics is reproducible when the drug is given together with a semi-solid meal in Helicobacter pylori-negative healthy subjects. Received: 21 July 1997 / Accepted in revised form: 14 October 1997     

自体肺动脉瓣替换主动脉瓣手术226例临床分析

自体肺动脉瓣替换病变主动脉瓣(Ross)手术自1967年被首次应用于临床并取得了长期效果。本研究对吕贝克医科大学心脏外科11年来Ross手术临床经验进行总结。     

Particle formation in emulsion polymerization, 1. Oligomers in emulsion polymerization of vinyl acetate

The oligomers formed in the beginning of the emulsion polymerization of vinyl acetate were characterized by surface tension measurements, analysis of molecular weight distribution and light scattering. The results indicate that primary particle formation in the emulsion polymerization of vinyl acetate is due to an oligomeric micellization. Additionally, these oligomers are strongly adsorbed onto highly dispersed silica particles in the aqueous phase. This effect leads to a disaggregation of the filler particles during the beginning of the emulsion polymerization.