Evaluation of the factors affecting the quality of life and total costs in epilepsy patients on monotherapy with carbamazepine and valproate

OBJECTIVES: To evaluate the effect of different demographic and clinical factors on the quality of life and cost of treatment of epilepsy patients on monotherapy with carbamazepine and valproate. PATIENTS AND METHODS: A total of 146 patients (67 male, 79 female, age range 18-80 years) with focal and generalized seizures were studied for one year. The patients were allocated into two groups depending on the drug they received: group one--46 patients on carbamazepine, and group two--100 patients on valproate. Quality of life (QOL) and total costs per patient per year were calculated. QOL was assessed using a questionnaire--Quality of Life in Epilepsy Inventory (QOLIE-31). Costs included direct medical, non-medical and indirect costs related to either epilepsy or its treatment. The assessed demographic and clinical factors were: age, gender, type of seizures, number of registered adverse events (AE) per three months, interval between seizures and seizure reduction percentage. RESULTS AND CONCLUSIONS: In both groups, age, gender and type of seizures didn't cause significant differences in the formation of QOL and costs. In the carbamazepine patients costs were influenced by the incidence of AEs, the time between seizures and seizure reduction percentage. In the valproate patients costs were mainly influenced by the time period between seizures while QOL by the incidence of AEs.     

Inhibitory effect of imatinib on normal progenitor cells in vitro

Imatinib is a novel tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome-positive leukemias and other malignancies. Side effects are mostly moderate; however, a dose-dependent hematologic toxicity affecting all hematopoietic lineages is observed clinically. The aim of this study was to investigate the effect of imatinib on normal hematopoietic stem and progenitor cells in vitro. A dose-dependent decrease in proliferation potential was found when CD34+ cells were expanded in serum-free medium supplemented with 6 growth factors and imatinib. Functionally, a decrease in colony-forming capacity was observed under increasing doses of imatinib. However, no such effect on more primitive cobblestone area-forming cells was detectable. Both withdrawal of stem cell factor from our expansion cultures or functional inhibition of c-kit led to a similar degree of inhibition of expansion, whereas the effect of imatinib was substantially greater at all dose levels tested. These data suggest a significant inhibitory effect of imatinib on normal CD34+ progenitor (but not stem) cells that is largely independent of c-kit signaling.     

PHA-680626 exhibits anti-proliferative and pro-apoptotic activity on Imatinib-resistant chronic myeloid leukemia cell lines and primary CD34+ cells by inhibition of both Bcr-Abl tyrosine kinase and Aurora kinases

Emergence of resistance to Imatinib complicates the treatment of chronic myeloid leukemia (CML). Second-generation Bcr-Abl inhibitors are capable to overcome resistance mediated by most mutations except T315I. As this mutation is causative for 20% of clinically observed resistances, the need for novel treatment strategies becomes obvious.Here, we report on a novel kinase inhibitor PHA-680626 exhibiting strong inhibitory activity on both Bcr-Abl and Aurora kinases. Significant anti-proliferative and pro-apoptotic effects were observed in human BCR-ABL positive cell lines and murine BaF3 cells ectopically expressing wt BCR-ABL or the Imatinib-resistant BCR-ABL mutants M351T, E255K and, T315I. Treatment with PHA-680626 decreased phosphorylation of CrkL and histone H3. As CrkL represents a typical downstream target of Bcr-Abl while histone H3 phosphorylation is an indicator for Aurora kinase B activity, these findings indicate that effects of PHA-680626 are mediated via inhibition of both pathways. Moreover, high anti-proliferative activity of PHA-680626 was observed in primary CD34+ cells derived from CML patients at diagnosis or in blast crisis as well as from an individual harbouring the T315I mutation.Thus, both Bcr-Abl and Aurora kinase inhibition contribute to the efficacy of PHA-680626 against Imatinib-resistant BCR-ABL positive leukemias, particularly those harbouring the T315I mutation.     

Aurora Kinase Inhibitor PHA-739358 Suppresses Growth of Hepatocellular Carcinoma In Vitro and in a Xenograft Mouse Model

Patients with advanced stages of hepatocellular carcinoma (HCC) face a poor prognosis. Although encouraging clinical results have been obtained with multikinase inhibitor sorafenib, the development of improved therapeutic strategies for HCC remains an urgent goal. Aurora kinases are key regulators of the cell cycle, and their uncontrolled expression promotes aneuploidy and tumor development. In tissue microarray analyses, we detected aurora-A kinase expression in all of the examined 93 human HCC samples, whereas aurora-B kinase expression levels significantly correlated with the proliferation index of HCCs. In addition, two human HCC cell lines (Huh-7 and HepG2) were tested positive for aurora-A and -B and revealed Ser10 phosphorylation of histone H3, indicating an increased aurora-B kinase activity. The antiproliferative features of a novel aurora kinase inhibitor, PHA-739358, currently under investigation in phase 2 clinical trials for other solid tumors, were examined in vitro and in vivo. At concentrations exceeding 50nM, PHA-739358 completely suppressed tumor cell proliferation in cell culture experiments and strongly decreased histone H3 phosphorylation. Cell cycle inhibition and endoreduplication were observed at 50 nM, whereas higher concentrations led to a complete G₂/M-phase arrest. In vivo, administration of PHA-739358 resulted in significant tumor growth inhibition at a well-tolerated dose. In combination with sorafenib, additive effects were observed. Remarkably, when tumors restarted to grow under sorafenib monotherapy, subsequent treatment with PHA-739358 induced tumor shrinkage by up to 81%. Thus, targeting aurora kinases with PHA-739358 is a promising therapeutic strategy administered alone or in combination with sorafenib for patients with advanced stages of HCC.     

Glabellar flap technique in oculoplastic surgery

Facial skin defect reconstruction in medial-canthal area of the lids can be a challenge even when performed by a skilled surgeon. The excision of large tumors in this area leads to significant surgical defects that cannot be repaired by merely closing the wound. The glabellar area provides a source of redundant skin with similar characteristics to that of the medial-canthal lid area. The purpose show the possibility of the glabellar flap technique surgery in patients after tumor excision in the medial canthal area with the formation of a large surgical defect and especially those with defect under the medial canthal tendon. We selected 15 well-documented retrospective cases of patients operated over 2 years and followed up for a minimum of 36 months, who underwent surgery with a glabellar flap technique. Patients were operated with V-Y glabellar rotation, advancement, or combined transposition flap techniques. According to the defect’s location, we divided the patients into three groups: upper, medial, and lower surgical defects. A satisfactory functional result was obtained in all the patients. In most of them, the cosmetic results were also good. No additional surgical procedures were required in any of the patients. Our experience showed excellent results with the glabellar flap technique in all three types of lesions in the medial canthal zone—upper, medial, and especially lower which until recently was thought to be inappropriate.     

Role of the CNS microvascular pericyte in the blood-brain barrier

Pericytes are a very important cellular constituent of the blood-brain barrier. They play a regulatory role in brain angiogenesis, endothelial cell tight junction formation, blood-brain barrier differentiation, as well as contribute to the microvascular vasodynamic capacity and structural stability. Central nervous system pericytes express macrophage functions and are actively involved in the neuroimmune network operating at the blood-brain barrier. They exhibit unique functional characteristics critical for the pathogenesis of a number of cerebrovascular, neurodegenerative, and neuroimmune diseases. J. Neurosci. Res. 53:637–644, 1998. © 1998 Wiley-Liss, Inc.