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Sample records for high-dose imatinib mesylate

  1. LAM Pilot Study with Imatinib Mesylate (LAMP-1)

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-14-1-0132 TITLE: LAM Pilot Study with Imatinib Mesylate (LAMP-1) PRINCIPAL INVESTIGATOR: Charlie Strange, MD...regarding imatinib mesylate (imatinib) in the treatment of Lymphangioleiomyomatosis ( LAM ) sufficient to power and design a phase 3 imatinib vs. placebo...clinical trial. The hypothesis is that imatinib will be equivalent to rapamycin in short term efficacy and safety. Currently, most LAM patients are

  2. Imatinib mesylate--gold standards and silver linings.

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    Peggs, K

    2004-09-01

    Imatinib mesylate represents the first of a new generation of molecularly targeted therapies engineered to disrupt signal transduction pathways. It is a tyrosine kinase inhibitor with relatively selective activity against the Abelson (ABL) proto-oncogene, platelet-derived growth factor receptor, and c-KIT receptor. Deregulated tyrosine kinase activity has been implicated as a central pathogenic event in a number of human malignancies, most notably chronic myeloid leukemia. In this myeloproliferative disorder the t(9;22) reciprocal translocation results in the generation of a novel fusion oncoprotein, BCR-ABL, with constitutive tyrosine kinase activity. Imatinib inhibits this activity, inducing remarkable rates of hematological and cytogenetic remission in excess of those seen with alternative medical therapies. Following a large phase III study comparing its efficacy with the combination of interferon alpha and low-dose cytarabine, it has emerged as the current gold standard therapy for patients with chronic-phase disease without a potential bone marrow donor and those considered unsuitable for bone marrow transplantation. Its integration into the management of those patients who might be considered for transplantation, which has historically been considered the only potentially curative approach, remains a major challenge. The increasing recognition and subsequent molecular characterization of resistance mechanisms has reinforced the need to exercise caution against deferring a proven curative therapy in favor of a treatment approach that is still investigational, with the spectre of increased numbers of patients progressing to sudden-onset blast crisis remaining the potential dark cloud in the silver lining for imatinib.

  3. Successful Treatment For Chronic Eosinophilic Leukemia (CEL With Imatinib Mesylate

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    Rayane da Silva Souza

    2017-12-01

    Full Text Available We report a case of a patient with Chronic Eosinophilic Leukemia (CEL with mutation in alfa PDGFR gene exhibiting a satisfactory response to treatment with imatinib mesylate. A 25-year-old man presented in a hematology service with a persistent cough and hemogram alterations. His blood count showed a hemoglobin level of 12.5 g/dL and a white blood cell count of 94,030/mm3, eosinophils were 68% of all cells. Bone marrow aspiration and biopsy showed hypercellularity with marked eosinophilia (77% and erythroid differentiation series was hypocellular with normoblast maturation. The immunohistochemically of the bone biopsy was positive for myeloperoxidase and negative for CD34/CD99, consistent with CEL. Fluorescence in situ hybridization (FISH for the beta-fraction of platelet-derived growth factor (PDGFRβ and Philadelphia chromosome (Ph 1 were negative and the alfa PDGFR (Platelet-Derived Growth Factor was positive and showed heterozygosis in c.2531T>C on 18 Exon and homozygous in C.2562+1G>A at the region of the splicing site at the 18 intron. Treatment was initiated and maintained by administering 400mg/day imatinib mesylate. Laboratory findings returned to normal ranges, with clinical improvement and a hematological response observed after the second month of therapy. Currently, the patient’s blood count shows the white blood cell count (5,400 total leukocytes, eosinophils (8.6/mm3, hemoglobin (15.5 g/dl, hematocrit (45.4% and platelets (298,000/mm3 within normal ranges. The mutation search was negative in in peripheral blood one year after the initial treatment. Our work corroborates other studies on the efficacy of imatinib mesylate in the treatment of patients with CSF PDGFR alpha positive. We emphasize the importance of molecular studies, considering its relevance for the correct staging of the disease. Since CEL is a rare disease, it is important to define its etiology and anticipate its treatment, thus minimizing the damage induced by

  4. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.

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    Reardon, David A; Egorin, Merrill J; Quinn, Jennifer A; Rich, Jeremy N; Rich, Jeremy N; Gururangan, Sridharan; Gururangan, Idharan; Vredenburgh, James J; Desjardins, Annick; Sathornsumetee, Sith; Provenzale, James M; Herndon, James E; Dowell, Jeannette M; Badruddoja, Michael A; McLendon, Roger E; Lagattuta, Theodore F; Kicielinski, Kimberly P; Dresemann, Gregor; Sampson, John H; Friedman, Allan H; Salvado, August J; Friedman, Henry S

    2005-12-20

    We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

  5. In vitro effects of imatinib mesylate on radiosensitivity and chemosensitivity of breast cancer cells

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    Weigel, Marion T; Maass, Nicolai; Mundhenke, Christoph; Dahmke, Linda; Schem, Christian; Bauerschlag, Dirk O; Weber, Katrin; Niehoff, Peter; Bauer, Maret; Strauss, Alexander; Jonat, Walter

    2010-01-01

    Breast cancer treatment is based on a combination of adjuvant chemotherapy followed by radiotherapy effecting intracellular signal transduction. With the tyrosine kinase inhibitors new targeted drugs are available. Imatinib mesylate is a selective inhibitor of bcr-abl, PRGFR alpha, beta and c-kit. The purpose of this study was to determine whether Imatinib has an influence on the effectiveness of radiotherapy in breast cancer cell lines and if a combination of imatinib with standard chemotherapy could lead to increased cytoreduction. Colony-forming tests of MCF 7 and MDA MB 231 were used to study differences in cell proliferation under incubation with imatinib and radiation. Changes in expression and phosphorylation of target receptors were detected using western blot. Cell proliferation, migration and apoptosis assays were performed combining imatinib with doxorubicin. The combination of imatinib and radiotherapy showed a significantly stronger inhibition of cell proliferation compared to single radiotherapy. Differences in PDGFR expression could not be detected, but receptor phosphorylation was significantly inhibited when treated with imatinib. Combination of imatinib with standard chemotherapy lead to an additive effect on cell growth inhibition compared to single treatment. Imatinib treatment combined with radiotherapy leads in breast cancer cell lines to a significant benefit which might be influenced through inhibition of PDGFR phosphorylation. Combining imatinib with chemotherapy enhances cytoreductive effects. Further in vivo studies are needed to evaluate the benefit of Imatinib in combination with radiotherapy and chemotherapy on the treatment of breast cancer

  6. Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.

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    Bérengère Gobin

    Full Text Available Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma, a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1. Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma and POS-1 (undifferentiated osteosarcoma. Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R, appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor

  7. Imatinib mesylate induces responses in patients with liver metastases from gastrointestinal stromal tumor failing intra-arterial hepatic chemotherapy

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    Fiorentini Giammaria

    2006-01-01

    Full Text Available Background: Imatinib mesylate represents a real major paradigm shift in cancer therapy, targeting the specific molecular abnormalities, crucial in the etiology of tumor. Intra-arterial hepatic chemotherapy (IAHC followed by embolization, has been considered an interesting palliative option for patients with liver metastases from gastrointestinal stromal tumor (GIST, due to the typically hypervascular pattern of the tumor. Aims: We report our experience with IAHC followed by Imatinib mesylate, in order to show the superiority of the specific molecular approach in liver metastases from GIST. Materials and Methods: Three patients (pts with pretreated massive liver metastases from GIST, received IAHC with Epirubicin 50 mg/mq, every 3 weeks for 6 cycles. At the evidence of progression, they received Imatinib mesylate. Results: We observed progressive diseases in all cases. In 1998, one patient underwent Thalidomide at 150 mg orally, every day for 4 months, with evidence of stable disease and clinical improvement. In 2001, two patients received Imatinib mesylate at 400 mg orally, every day, with evidence of partial response lasting 18+ months and 16 months. One of them had grade 3 neutropenia, with suspension of therapy for 3 weeks. Conclusion: No patient treated with IAHC, reported objective responses, but two of them obtained partial response after the assumption of Imatinib mesylate and one showed temporary stabilization with thalidomide. Imatinib mesylate represents a new opportunity in GIST therapy, targeting the specific molecular alteration. It seems to be superior to conventional intra arterial hepatic chemotherapy.

  8. Management of CML in the Pediatric Age Group: Imatinib Mesylate or SCT.

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    El-Alfy, Mohsen S; Al-Haddad, Alaa M; Hamed, Ahmed A

    2010-12-01

    Management of CML has changed markedly since the introduction of tyrosine kinase inhibitors (TKIs). However stem cell transplantation (SCT) remains a valid therapeutic modality especially in developing countries due to its relatively lower cost. We aim to compare between imatinib mesylate and SCT as regard outcome in CML in the pediatric age group. Forty-eight patients with newly diagnosed CML in the chronic phase, aged 3 to 18 years were enrolled in this prospective study. Patients without a matched donor (Group I; N=30) were assigned to receive imatinib mesylate at a dose of 340mg÷m2÷day, while patients with a fully matched related donor (Group II; N=18), were offered SCT. Response (hematologic, cytogenetic and molecular), side effects and survival were analyzed. Complete hematologic response was obtained in 97% of the patients in group I and 94% in group II. Major cytogenetic response (CyR) was obtained in 80% of patients in group I and 100% in group II. Complete CyR was 57% in group I and 64% in group II. Major molecular response (MMR) was 36% in group I and 50% in group II with no significant difference between both groups. Six years overall survival (OS) was 87% in the 1st group and 61% in the 2nd group (pSCT group (55% had GVHD and 78% had infection). Imatinib mesylate has a superior OS and EFS than SCT in children. It is generally safe and well tolerated. Imatinib mesylate should be the 1st line treatment of pediatric patients with CML in the chronic phase. CML- Imatinib- SCT- Pediatrics.

  9. Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes.

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    Stagno, Fabio; Stella, Stefania; Spitaleri, Antonio; Pennisi, Maria Stella; Di Raimondo, Francesco; Vigneri, Paolo

    2016-01-01

    The tyrosine kinase inhibitor Imatinib Mesylate has dramatically improved the clinical outcome of chronic myeloid leukemia (CML) patients in the chronic phase of the disease, generating unprecedented rates of complete hematologic and cytogenetic responses and sustained reductions in BCR-ABL transcripts. Here, we present an overview on the efficacy and safety of Imatinib and describe the most important clinical studies employing this drug for the frontline treatment of chronic phase CML. We also discuss recent reports describing the long-term outcome of patients receiving Imatinib for their disease. The imminent availability of generic forms of Imatinib coupled with the approval of expensive second-generation tyrosine kinase inhibitors underlines an unmet need for early molecular parameters that may distinguish CML patients likely to benefit from the drug from those that should receive alternative forms of treatment.

  10. Platelet Dysfunction in Patients with Chronic Myeloid Leukemia: Does Imatinib Mesylate Improve It?

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    Olga Meltem Akay

    2016-05-01

    Full Text Available Objective: The aim of this study was to investigate the effects of imatinib mesylate on platelet aggregation and adenosine triphosphate (ATP release in chronic myeloid leukemia patients. Materials and Methods: Platelet aggregation and ATP release induced by 5.0 mM adenosine diphosphate, 0.5 mM arachidonic acid, 1.0 mg/ mL ristocetin, and 2 µg/mL collagen were studied by whole blood platelet lumi-aggregometer in 20 newly diagnosed chronic myeloid leukemia patients before and after imatinib mesylate treatment. Results: At the time of diagnosis, 17/20 patients had abnormal platelet aggregation results; 8 (40% had hypoactivity, 6 (30% had hyperactivity, and 3 (15% had mixed hypo- and hyperactivity. Repeat platelet aggregation studies were performed after a mean of 19 months (min: 5 months-max: 35 months in all patients who received imatinib mesylate during this period. After therapy, 18/20 (90% patients had abnormal laboratory results; 12 (60% had hypoactive platelets, 4 (20% had mixed hypo- and hyperactive platelets, and 2 (10% had hyperactive platelets. Three of the 8 patients with initial hypoactivity remained hypoactive, while 2 developed a mixed picture, 2 became hyperactive, and 1 normalized. Of the 6 patients with initial hyperactivity, 4 became hypoactive and 2 developed a mixed pattern. All of the 3 patients with initial hypo- and hyperactivity became hypoactive. Finally, 2 of the 3 patients with initial normal platelets became hypoactive while 1 remained normal. There was a significant decrease in ristocetin-induced platelet aggregation after therapy (p0.05. Conclusion: These findings indicate that a significant proportion of chronic myeloid leukemia patients have different patterns of platelet function abnormalities and imatinib mesylate has no effect on these abnormalities, with a significant impairment in ristocetin-induced platelet aggregation.

  11. Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas.

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    Desjardins, Annick; Quinn, Jennifer A; Vredenburgh, James J; Sathornsumetee, Sith; Friedman, Allan H; Herndon, James E; McLendon, Roger E; Provenzale, James M; Rich, Jeremy N; Sampson, John H; Gururangan, Sridharan; Dowell, Jeannette M; Salvado, August; Friedman, Henry S; Reardon, David A

    2007-05-01

    Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1-7) and the median number of prior treatment regimens was 3 (range, 1-8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.

  12. Concurrent Male Gynecomastia and Testicular Hydrocele after Imatinib Mesylate Treatment of a Gastrointestinal Stromal Tumor

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    Kim, Hawk; Chang, Heung-Moon; Ryu, Min-Hee; Kim, Tae-Won; Sohn, Hee-Jung; Kim, So-Eun; Kang, Hye-Jin; Park, Sarah; Lee, Jung-Shin

    2005-01-01

    We report a gastrointestinal stromal tumor (GIST) patient with male gynecomastia and testicular hydrocele after treatment with imatinib mesylate. A 42 yr-old male patient presented for management of hepatic masses. Two years earlier, he had undergone a small bowel resection to remove an intraabdominal mass later shown to be a GIST, followed by adjuvant radiation therapy. At presentation, CT scan revealed multiple hepatic masses, which were compatible with metastatic GIST, and he was prescribed imatinib 400 mg/day. During treatment, he experienced painful enlargement of the left breast and scrotal swelling. Three months after cessation of imatinib treatment, the tumors recurred, and, upon recommencing imatinib, he experienced painful enlargement of the right breast and scrotal swelling. He was diagnosed with male gynecomastia caused by decreased testosterone and non-communicative testicular hydrocele. He was given androgen support and a hydrocelectomy, which improved his gynecomastia. The mechanism by which imatinib induces gynecomastia and hydrocele is thought to be associated with an inhibition of c-KIT and platelet-derive growth factor. This is the first report, to our knowledge, describing concurrent male gynecomastia and testicular hydrocele after imatinib treatment of a patient with GIST. PMID:15953881

  13. Imatinib mesylate in chronic myelogenous leukemia: a Congolese ...

    African Journals Online (AJOL)

    Major cytogenetic response was noticed in 87.18%. After a median follow up of 12 months, chronic myeloid leukemia had not progressed to the accelerated or blastic phase in an estimated 91.8% of patients and 86.6% were alive. Conclusion: Imatinib is effective in newly chronic phase chronic myeloid leukemia patient ...

  14. Formulation and In Vitro, In Vivo Evaluation of Effervescent Floating Sustained-Release Imatinib Mesylate Tablet

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    Kadivar, Ali; Kamalidehghan, Behnam; Javar, Hamid Akbari; Davoudi, Ehsan Taghizadeh; Zaharuddin, Nurul Dhania; Sabeti, Bahareh; Chung, Lip Yong; Noordin, Mohamed Ibrahim

    2015-01-01

    Introduction Imatinib mesylate is an antineoplastic agent which has high absorption in the upper part of the gastrointestinal tract (GIT). Conventional imatinib mesylate (Gleevec) tablets produce rapid and relatively high peak blood levels and requires frequent administration to keep the plasma drug level at an effective range. This might cause side effects, reduced effectiveness and poor therapeutic management. Therefore, floating sustained-release Imatinib tablets were developed to allow the tablets to be released in the upper part of the GIT and overcome the inadequacy of conventional tablets. Methodology Floating sustained-release Imatinib mesylate tablets were prepared using the wet granulation method. Tablets were formulated using Hydroxypropyl Methylcellulose (HPMC K4M), with Sodium alginate (SA) and Carbomer 934P (CP) as release-retarding polymers, sodium bicarbonate (NaHCO3) as the effervescent agent and lactose as a filler. Floating behavior, in vitro drug release, and swelling index studies were conducted. Initial and total drug release duration was compared with a commercial tablet (Gleevec) in 0.1 N HCl (pH 1.2) at 37 ± 0.5°C for 24 hours. Tablets were then evaluated for various physical parameters, including weight variation, thickness, hardness, friability, and drug content. Consequently, 6 months of physical stability studies and in vitro gastro-retentive studies were conducted. Results and Discussion Statistical data analysis revealed that tablets containing a composition of 14.67% w/w HPMC K4M, 10.67%, w/w Na alginate, 1.33%, w/w Carbomer 934P and 9.33%, w/w NaHCO3 produced the most favorable formulation to develop 24-hour sustained-release tablets with optimum floating behavior and satisfactory physicochemical characteristics. Furthermore, in vitro release study revealed that the formulated SR tablet had significantly lower Cmax and higher Tmax compared to the conventional tablet (Gleevec). Thus, formulated SR tablets preserved persistent

  15. Formulation and in vitro, in vivo evaluation of effervescent floating sustained-release imatinib mesylate tablet.

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    Ali Kadivar

    Full Text Available Imatinib mesylate is an antineoplastic agent which has high absorption in the upper part of the gastrointestinal tract (GIT. Conventional imatinib mesylate (Gleevec tablets produce rapid and relatively high peak blood levels and requires frequent administration to keep the plasma drug level at an effective range. This might cause side effects, reduced effectiveness and poor therapeutic management. Therefore, floating sustained-release Imatinib tablets were developed to allow the tablets to be released in the upper part of the GIT and overcome the inadequacy of conventional tablets.Floating sustained-release Imatinib mesylate tablets were prepared using the wet granulation method. Tablets were formulated using Hydroxypropyl Methylcellulose (HPMC K4M, with Sodium alginate (SA and Carbomer 934P (CP as release-retarding polymers, sodium bicarbonate (NaHCO3 as the effervescent agent and lactose as a filler. Floating behavior, in vitro drug release, and swelling index studies were conducted. Initial and total drug release duration was compared with a commercial tablet (Gleevec in 0.1 N HCl (pH 1.2 at 37 ± 0.5°C for 24 hours. Tablets were then evaluated for various physical parameters, including weight variation, thickness, hardness, friability, and drug content. Consequently, 6 months of physical stability studies and in vitro gastro-retentive studies were conducted.Statistical data analysis revealed that tablets containing a composition of 14.67% w/w HPMC K4M, 10.67%, w/w Na alginate, 1.33%, w/w Carbomer 934P and 9.33%, w/w NaHCO3 produced the most favorable formulation to develop 24-hour sustained-release tablets with optimum floating behavior and satisfactory physicochemical characteristics. Furthermore, in vitro release study revealed that the formulated SR tablet had significantly lower Cmax and higher Tmax compared to the conventional tablet (Gleevec. Thus, formulated SR tablets preserved persistent concentration of plasma up to 24 hours

  16. Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults.

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    Menon-Andersen, Divya; Mondick, John T; Jayaraman, Bhuvana; Thompson, Patrick A; Blaney, Susan M; Bernstein, Mark; Bond, Mason; Champagne, Martin; Fossler, Michael J; Barrett, Jeffrey S

    2009-01-01

    Imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor approved for use in the management of chronic myeloid leukemia in adults and children and in gastrointestinal stromal tumors in adults. Population pharmacokinetic (PPK) studies evaluating the effect of population covariates on the pharmacokinetics of imatinib and its active metabolite have been developed in adults with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, this still remains to be described in children. The objectives of the analysis were to develop a PPK model of imatinib and its active metabolite, CGP74588, to describe exposure in children and young adults and to identify covariates that are predictors of variability in disposition. Plasma concentrations from 26 subjects with Philadelphia (Ph+) leukemia (Phase I study) and 15 subjects with refractory solid tumors (Phase II study), who received oral imatinib at doses ranging from 260 to 570 mg/m(2), were available for the PPK analysis in NONMEM. Blood samples were drawn prior to dosing and over 24-48 h on days 1 and 8 of the studies. Covariates studied included weight, age, albumin, alanine aminotransferase and the study population. The pharmacokinetics of imatinib and CGP 74588 were well described by one and two compartment models, respectively. Total body weight was the only covariate found to significantly affect Cl/F and V/F. The final imatinib-CGP 74588 model is summarized as follows: CL/F (imatinib) (L/h) = 10.8 x (WT/70)(0.75), V/F (imatinib) (L) = 284 x (WT/70) and D1(duration of zero order absorption,imatinib) (h) = 1.67 and CL/F (CGP 74588) (L/h) = 9.65 x (WT/70)(0.75), V1/F (CGP 74588) (L) = 11.6 x (WT/70), Q (CGP 74588) (L/h) = 2.9 x (WT/70)(0.75) and V2/F (CGP 74588) (L) = 256*(WT/70). Model evaluation indicated that the final model was robust and satisfactory. Current imatinib dosing guidelines in pediatrics is based on the achievement of exposures consistent with doses known to be

  17. Gynecomastia during imatinib mesylate treatment for gastrointestinal stromal tumor: a rare adverse event

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    Yan ZhongShu

    2011-11-01

    Full Text Available Abstract Background Imatinib mesylate has been the standard therapeutic treatment for chronic myeloid leukemia, advanced and metastatic gastrointestinal stromal tumor (GIST. It is well tolerated with mild adverse effects. Gynecomastia development during the course of treatment has been rarely reported. Methods Ninety-eight patients with advanced or recurrent GIST were treated with imatinib mesylate. Among the fifty-seven male patients six developed gynecomastia during the treatment. The lesions were confirmed by sonography. Sex hormone levels were determined in six patients with and without the presence of gynecomastia respectively. The patients with gynecomatia were treated with tamoxifene and the sex hormones were assayed before and after tamoxifene treatment. Results In patients with gynecomastia the lump underneath the bilateral nipples was 2.5 to 5 centimeters in diameter. Their serum free testosterone levels ranged between 356.61 and 574.60 ng/dl with a mean ± SD of 408.64 ± 82.06 ng/dl (95% CI 343.03~474.25 ng/dl, which is within the normal range. The level of serum estradiol was 42.89 ± 16.54 pg/ml (95% CI 29.66~56.12 pg/ml. Three patients had higher levels (43.79~71.21 pg/ml and the others' were within normal range of 27.00~34.91 pg/ml. Six patients without the development of gynecomastia had normal free testosterone. One patient died because of large tumor burden. The sex hormones had no significant changes before and after tamoxifene treatment.(P > 0.05 Conclusions Testosterone levels were not decreased in the six GIST patients with gynecomastia. Three patients had increased serum estradiol level which suggests that imbalance of sex hormones may be the cause of gynecomastia during treatment with imatinib mesylate.

  18. Imatinib mesylate inhibits Leydig cell tumor growth: evidence for in vitro and in vivo activity.

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    Basciani, Sabrina; Brama, Marina; Mariani, Stefania; De Luca, Gabriele; Arizzi, Mario; Vesci, Loredana; Pisano, Claudio; Dolci, Susanna; Spera, Giovanni; Gnessi, Lucio

    2005-03-01

    Leydig cell tumors are usually benign tumors of the male gonad. However, if the tumor is malignant, no effective treatments are currently available. Leydig cell tumors express platelet-derived growth factor (PDGF), kit ligand and their respective receptors, PDGFR and c-kit. We therefore evaluated the effects of imatinib mesylate (imatinib), a selective inhibitor of the c-kit and PDGFR tyrosine kinases, on the growth of rodent Leydig tumor cell lines in vivo and in vitro, and examined, in human Leydig cell tumor samples, the expression of activated PDGFR and c-kit and the mutations in exons of the c-kit gene commonly associated with solid tumors. Imatinib caused concentration-dependent decreases in the viability of Leydig tumor cell lines, which coincided with apoptosis and inhibition of proliferation and ligand-stimulated phosphorylation of c-kit and PDGFRs. Mice bearing s.c. allografts of a Leydig tumor cell line treated with imatinib p.o., had an almost complete inhibition of tumor growth, less tumor cell proliferation, increased apoptosis, and a lesser amount of tumor-associated mean vessel density compared with controls. No drug-resistant tumors appeared during imatinib treatment but tumors regrew after drug withdrawal. Human Leydig cell tumors showed an intense expression of the phosphorylated form of c-kit and a less intense expression of phosphorylated PDGFRs. No activating mutations in common regions of mutation of the c-kit gene were found. Our studies suggest that Leydig cell tumors might be a potential target for imatinib therapy.

  19. Cerebral relapse of metastatic gastrointestinal stromal tumor during treatment with imatinib mesylate: Case report

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    Waring Paul

    2004-10-01

    Full Text Available Abstract Background The management of unresectable or metastatic gastrointestinal stromal tumors (GISTs has previously been difficult as they are resistant to conventional chemotherapy and radiation. The development of imatinib mesylate has made a major impact on the management of advanced GISTs. It is apparent that there are sanctuary sites such as the central nervous system where imatinib does not achieve adequate concentrations. We describe the case of a man with metastatic GIST who experienced multiple cerebral relapses of disease while systemic disease progression appeared to be controlled by imatinib. Case presentation A 47-year-old man presented in July 1999 with a jejunal GIST with multiple hepatic metastases. The jejunal primary was resected and after unsuccessful cytoreductive chemotherapy, the liver metastases were also resected in December 1999. The patient subsequently relapsed in August 2001 with symptomatic hepatic, subcutaneous gluteal, left choroidal and right ocular metastases all confirmed on CT and PET scanning. Biopsy confirmed recurrent GIST. MRI and lumbar puncture excluded central nervous system involvement. The patient was commenced on imatinib 400 mg bd in September 2001 through a clinical trial. The symptoms improved with objective PET and CT scan response until December 2002 when the patient developed a right-sided foot drop. MRI scan showed a left parasagittal tumor which was resected and confirmed histologically to be metastatic GIST. Imatinib was ceased pre-operatively due to the trial protocol but recommenced in February 2003 on a compassionate use program. The left parasagittal metastasis recurred and required subsequent re-excision in September 2003 and January 2004. Control of the systemic GIST was temporarily lost on reduction of the dose of imatinib (due to limited drug supply but on increasing the dose back to 800 mg per day, systemic disease was stabilized for a period of time before generalised progression

  20. Cerebral relapse of metastatic gastrointestinal stromal tumor during treatment with imatinib mesylate: Case report

    International Nuclear Information System (INIS)

    Hughes, Brett; Yip, Desmond; Goldstein, David; Waring, Paul; Beshay, Victoria; Chong, Guan

    2004-01-01

    The management of unresectable or metastatic gastrointestinal stromal tumors (GISTs) has previously been difficult as they are resistant to conventional chemotherapy and radiation. The development of imatinib mesylate has made a major impact on the management of advanced GISTs. It is apparent that there are sanctuary sites such as the central nervous system where imatinib does not achieve adequate concentrations. We describe the case of a man with metastatic GIST who experienced multiple cerebral relapses of disease while systemic disease progression appeared to be controlled by imatinib. A 47-year-old man presented in July 1999 with a jejunal GIST with multiple hepatic metastases. The jejunal primary was resected and after unsuccessful cytoreductive chemotherapy, the liver metastases were also resected in December 1999. The patient subsequently relapsed in August 2001 with symptomatic hepatic, subcutaneous gluteal, left choroidal and right ocular metastases all confirmed on CT and PET scanning. Biopsy confirmed recurrent GIST. MRI and lumbar puncture excluded central nervous system involvement. The patient was commenced on imatinib 400 mg bd in September 2001 through a clinical trial. The symptoms improved with objective PET and CT scan response until December 2002 when the patient developed a right-sided foot drop. MRI scan showed a left parasagittal tumor which was resected and confirmed histologically to be metastatic GIST. Imatinib was ceased pre-operatively due to the trial protocol but recommenced in February 2003 on a compassionate use program. The left parasagittal metastasis recurred and required subsequent re-excision in September 2003 and January 2004. Control of the systemic GIST was temporarily lost on reduction of the dose of imatinib (due to limited drug supply) but on increasing the dose back to 800 mg per day, systemic disease was stabilized for a period of time before generalised progression occurred. This case illustrates that the brain can be a

  1. Long-term remission in BCR/ABL-positive AML-M6 patient treated with Imatinib Mesylate.

    Science.gov (United States)

    Pompetti, Franca; Spadano, Antonio; Sau, Antonella; Mennucci, Antonio; Russo, Rosa; Catinella, Virginia; Franchi, Paolo Guanciali; Calabrese, Giuseppe; Palka, Giandomenico; Fioritoni, Giuseppe; Iacone, Antonio

    2007-04-01

    BCR/ABL-positive acute myeloid leukemia (AML) is a rare disease, characterized by a poor prognosis, with resistance to induction chemotherapy and frequent relapses in responsive patients. Here we report a case of BCR/ABL-positive AML-M6 who, after relapse, was treated with Imatinib Mesylate (600 mg/die) and within 4 months achieved a cytogenetic and molecular complete response. After more than 4 years of continuous Imatinib therapy, nested RT-PCR for BCR/ABL is persistently negative. The case reported shows that the response obtained with Imatinib Mesylate in BCR/ABL-positive AML may be long lasting, offering a chance of successful treatment for this poor prognosis group of patients.

  2. Falla cardiaca asociada con el uso de imatinib mesilato: Reporte de un caso Heart failure associated to imatinib mesylate use: Case report

    Directory of Open Access Journals (Sweden)

    Clara Saldarriaga

    2008-12-01

    Full Text Available La cardiotoxicidad por medicamentos es un evento cada vez más frecuente en la práctica clínica diaria. Inhibidores de la proteína de fusión Brc/Abl como el imatinib mesilato, son una nueva herramienta para el tratamiento de algunas neoplasias hematológicas, en especial de la leucemia mieloide crónica. Sin embargo, en la literatura se reporta desarrollo de cardiotoxicidad a causa de este medicamento. Se presenta el caso de una mujer joven con corazón de estructura sana quien desarrolla cardiotoxicidad por imatinib pocas semanas después de iniciarlo.Cardiotoxicity due to drugs has become a frequent event in the daily clinical practice. Fusion protein Brc/Abl inhibitors such as imatinib mesylate constitute a new tool for the treatment of some hematogical neoplasias, especially chronic myeloid leukemia. Nevertheless, there have been reports in the literature regarding imatinib mesylate toxicity. We present the case of a young woman with a structurally healthy heart who developed cardiotoxicity with imatinib few weeks after its initiation.

  3. Cytoprotective effect of imatinib mesylate in non-BCR-ABL-expressing cells along with autophagosome formation

    International Nuclear Information System (INIS)

    Ohtomo, Tadashi; Miyazawa, Keisuke; Naito, Munekazu; Moriya, Shota; Kuroda, Masahiko; Itoh, Masahiro; Tomoda, Akio

    2010-01-01

    Treatment with imatinib mesylate (IM) results in an increased viable cell number of non-BCR-ABL-expressing cell lines by inhibiting spontaneous apoptosis. Electron microscopy revealed an increase of autophagosomes in response to IM. IM attenuated the cytotoxic effect of cytosine arabinoside, as well as inhibiting cell death with serum-deprived culture. Cytoprotection with autophagosome formation by IM was observed in various leukemia and cancer cell lines as well as normal murine embryonic fibroblasts (MEFs). Complete inhibition of autophagy by knockdown of atg5 in the Tet-off atg5 -/- MEF system attenuated the cytoprotective effect of IM, indicating that the effect is partially dependent on autophagy. However, cytoprotection by IM was not mediated through suppression of ROS production via mitophagy, ER stress via ribophagy, or proapoptotic function of ABL kinase. Although the target tyrosine kinase(s) of IM remains unclear, our data provide novel therapeutic possibilities of using IM for cytoprotection.

  4. O tratamento da Leucemia Mielóide Crônica com mesilato de imatinibe Therapy of Chronic Myeloid Leukemia with imatinib mesylate

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    Vaneuza M. Funke

    2008-04-01

    Full Text Available O mesilato de imatinibe é atualmente o tratamento de escolha para pacientes com Leucemia mielóide Crônica (LMC recém-diagnosticados. Desde os primeiros estudos clínicos em 1998 até o estudo IRIS, que comparou o uso em primeira linha de imatinibe com interferon + ara-C, esta droga vem se consolidando em segurança e eficácia. Ainda há, entretanto questionamentos sobre a melhor dose inicial, a identificação dos pacientes que mais se beneficiariam e a melhor abordagem frente a respostas sub-ótimas e resistência. Os principais estudos clínicos publicados com mesilato de imatinibe são revisados no presente artigo, e discutidos sob a perspectiva da realidade brasileira.Imatinib mesylate is currently the gold-standard therapy for patients with newly diagnosed Chronic Myelogenous Leukemia. From the clinical trials in 1998 to the IRIS study, which compared first line imatinib treatment with interferon and low dose ara-C, this drug has been consolidated in regards to its safety and efficacy. There are still some questions to answer. Which would be the best initial dose? Are there any patients who benefit more than others? What is the best approach to suboptimal response and resistance? The most important published clinical studies are reviewed in the current article and discussed from a Brazilian perspective.

  5. Up regulation of K A I 1 gene expression and apoptosis effect of imatinib mesylate in gastric adenocarcinoma (AGS cell line

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    eyed Ataollah Sadat Shandiz

    2016-02-01

    Full Text Available Objective: To evaluate the effect of imatinib mesylate on KAI1 gene expression and apoptosis properties in human gastric carcinoma AGS cell line. Methods: Cell viability was assessed by MTT assay and quantitative real time PCR method was applied for investigation of Bax, Bcl-2, and KAI1 gene expression in AGS cells. The quantity of KAI1, Bax, and Bcl-2 compared to GAPDH gene expressions were examined using the formula 2-∆∆Ct. Furthermore, cell apoptosis/necrosis was carried out by annexin V/PI staining and quantified with flow cytometry after treatment with imatinib. Results: Imatinib mesylate was showed to have a dose-dependent toxicity effect against AGS cells. KAI1/GAPDH gene expression ratios were 1.07 ± 0.02 (P > 0.05, 1.68 ± 0.19 (P > 0.05, 3.60 ± 0.55 (P < 0.05, 6.54 ± 0.27 (P < 0.001 for 20, 50, 80 and 100 μmol/L of imatinib concentrations. The mRNA levels of Bax detected by real-time PCR after treatment with imatinib mesylate were significantly increased. Also, the number of apoptotic cells was increased from 3.72% (statistically significant; P < 0.05 in untreated AGS cells to 21.72%, 83.04% and 85.80%, respectively, following treatment with 20, 40, and 60 μmol/L imatinib mesylate. Conclusions: The results suggest that imatinib mesylate can induce apoptosis pathway in a dose-dependent mode and might modulate metastasis by up regulating KAI1 gene expression in human gastric carcinoma AGS cell line.

  6. "Antifibrotic effect after low-dose imatinib mesylate treatment in patients with nephrogenic systemic fibrosis: An open-label non-randomized, uncontrolled clinical trial"

    DEFF Research Database (Denmark)

    Elmholdt, Tina Rask; Olesen, Anne Braae

    2011-01-01

    Background Nephrogenic systemic fibrosis is a disease affecting the connective tissue of the skin and internal organs in patients with renal failure. No effective treatments are available. Objectives To investigate if the tyrosine kinase inhibitor, imatinib mesylate was effective in patients...... Imatinib mesylate may be an effective drug in the treatment of skin fibrosis in moderate to severe NSF cases, even at reduced doses. We found a positive clinical effect on the skin, but no convincing improvement of the joint mobility. Only few patients could be recruited limiting the interpretation...

  7. In vitro inhibitory effects of imatinib mesylate on stromal cells and hematopoietic progenitors from bone marrow

    Directory of Open Access Journals (Sweden)

    P.B. Soares

    2013-01-01

    Full Text Available Imatinib mesylate (IM is used to treat chronic myeloid leukemia (CML because it selectively inhibits tyrosine kinase, which is a hallmark of CML oncogenesis. Recent studies have shown that IM inhibits the growth of several non-malignant hematopoietic and fibroblast cells from bone marrow (BM. The aim of the present study was to evaluate the effects of IM on stromal and hematopoietic progenitor cells, specifically in the colony-forming units of granulocyte/macrophage (CFU-GM, using BM cultures from 108 1.5- to 2-month-old healthy Swiss mice. The results showed that low concentrations of IM (1.25 µM reduced the growth of CFU-GM in clonogenic assays. In culture assays with stromal cells, fibroblast proliferation and α-SMA expression by immunocytochemistry analysis were also reduced in a concentration-dependent manner, with a survival rate of approximately 50% with a dose of 2.5 µM. Cell viability and morphology were analyzed using MTT and staining with acrydine orange/ethidium bromide. Most cells were found to be viable after treatment with 5 µM IM, although there was gradual growth inhibition of fibroblastic cells while the number of round cells (macrophage-like cells increased. At higher concentrations (15 µM, the majority of cells were apoptotic and cell growth ceased completely. Oil red staining revealed the presence of adipocytes only in untreated cells (control. Cell cycle analysis of stromal cells by flow cytometry showed a blockade at the G0/G1 phases in groups treated with 5-15 µM. These results suggest that IM differentially inhibits the survival of different types of BM cells since toxic effects were achieved.

  8. The tyrosine kinase inhibitor imatinib mesylate suppresses uric acid crystal-induced acute gouty arthritis in mice.

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    Laurent L Reber

    Full Text Available Gouty arthritis is caused by the deposition of monosodium urate (MSU crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated. Here we demonstrate that treatment with the tyrosine kinase inhibitor imatinib mesylate (imatinib can suppress inflammation induced by injection of MSU crystals into subcutaneous air pouches or into the ankle joint of wild type mice. Moreover, imatinib treatment also largely abolished the lower levels of inflammation which developed in IL-1R1-/- or KitW-sh/W-sh mice, indicating that this drug can inhibit IL-1-independent pathways, as well as mast cell-independent pathways, contributing to pathology in this model. Imatinib treatment not only prevented ankle swelling and synovial inflammation when administered before MSU crystals but also diminished these features when administrated after the injection of MSU crystals, a therapeutic protocol more closely mimicking the clinical situation in which treatment occurs after the development of an acute gout flare. Finally, we also assessed the efficiency of local intra-articular injections of imatinib-loaded poly(lactic-co-glycolic acid (PLGA nanoparticles in this model of acute gout. Treatment with low doses of this long-acting imatinib:PLGA formulation was able to reduce ankle swelling in a therapeutic protocol. Altogether, these results raise the possibility that tyrosine kinase inhibitors might have utility in the treatment of acute gout in humans.

  9. An economic analysis of high-dose imatinib, dasatinib, and nilotinib for imatinib-resistant chronic phase chronic myeloid leukemia in China: A CHEERS-compliant article.

    Science.gov (United States)

    Wu, Bin; Liu, Maobai; Li, Te; Lin, Houwen; Zhong, Hua

    2017-07-01

    The aim of the study was to test the cost-effectiveness of dasatinib compared to high-dose imatinib and nilotinib in Chinese patients who were diagnosed with imatinib-resistant chronic myeloid leukemia in the chronic phase (CML-CP). A Markov model combined with clinical effectiveness, utility, and cost data was used. The sensitivity analyses were conducted to determine the robustness of the model outcomes. The impact of patient assistance programs (PAPs) was assessed. Treatment with dasatinib is expected to produce 3.65, 0.59, and 0.15 more quality-adjusted life years (QALYs) in comparison with high-dose imatinib (600 and 800 mg) and nilotinib, respectively. When a PAP was available, dasatinib yielded an incremental cost of $16,417 per QALY compared to imatinib (600 mg) and was cost-saving compared to imatinib (800 mg) and nilotinib. When PAP is available in the Chinese setting, dasatinib is likely to be a cost-effective strategy for patients with CML-CP standard-dose imatinib resistance. The results should be carefully explained due to the assumptions and limitations used in the study.

  10. Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation

    NARCIS (Netherlands)

    Millot, F; Guilhot, J; Nelken, B; Leblanc, T; De Bont, ES; Bekassy, AN; Gadner, H; Sufliarska, S; Stary, J; Gschaidmeier, H; Guilhot, F; Suttorp, M

    A multicentric phase 2 study was conducted to determine the efficiency and the tolerance of imatinib mesylate in children with chronic myelogenous leukemia (CML) in advanced phase of the disease, in relapse after stem cell transplantation, or in case of failure to an interferon a-based regimen. In

  11. Dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia: a systematic review and economic evaluation.

    Science.gov (United States)

    Loveman, E; Cooper, K; Bryant, J; Colquitt, J L; Frampton, G K; Clegg, A

    2012-01-01

    The present report was commissioned as a supplement to an existing technology assessment report produced by the Peninsula Technology Assessment Group (PenTAG), which evaluated the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in patients who are either resistant or intolerant to standard-dose imatinib. This report evaluates the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and high-dose imatinib within their licensed indications for the treatment of people with chronic myeloid leukaemia (CML) who are resistant to standard-dose imatinib. Bibliographic databases were searched from inception to January 2011, including The Cochrane Library, MEDLINE (Ovid), EMBASE (Ovid), and MEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were screened, key conferences were searched, and experts were contacted to identify additional published and unpublished references. This report includes systematic reviews of clinical effectiveness and cost-effectiveness studies, an independent appraisal of information submitted by drug manufacturers to the National Institute for Health and Clinical Excellence (NICE), an independent appraisal of the PenTAG economic evaluation, and new economic analyses adapting the PenTAG economic model. Standard systematic procedures involving two reviewers to maintain impartiality and transparency, and to minimise bias, were conducted. Eleven studies met the inclusion criteria. Four of these studies included new data published since the PenTAG report; all of these were in chronic-phase CML. No relevant studies on the clinical effectiveness of nilotinib were found. The clinical effectiveness studies on dasatinib [one arm of a randomised controlled trial (RCT)] and high-dose imatinib (one arm of a RCT and three single-arm cohort studies) had major methodological limitations. These limitations precluded a comparison of the different arms within the RCT. Data from the studies are

  12. [Disappearance of a Philadelphia chromosome-positive clone and appearance of a -negative clone following treatment with imatinib mesylate in acute myelomonocytic leukemia].

    Science.gov (United States)

    Takahashi, Wataru; Arai, Yukihiro; Tadokoro, Jiro; Takeuchi, Kengo; Yamagata, Tetsuya; Mitani, Kinuko

    2006-02-01

    A 63-year-old female was diagnosed as having Philadelphia chromosome-positive acute myelomonocytic leukemia in June 2002. The patient received monotherapy with imatinib mesylate or combination therapy with DCM and idarubicin/cytarabine, both of which failed in attaining disease remission. However, the second imatinib administration plus CAG therapy resulted in disappearance of the Philadelphia chromosome-positive clone and increase of Philadelphia chromosome-negative cells. During a therapy-withholding period due to fungal infection, the Philadelphia chromosome-positive clone expanded and the patient died of cerebral hemorrhage in February 2003. The transient suppression of the Philadelphia chromosome-positive clone may have brought about amplification of the Philadelphia chromosome-negative cells after the secondary imatinib treatment.

  13. The Effects of Imatinib Mesylate on Cellular Viability, Platelet Derived Growth Factor and Stem Cell Factor in Mouse Testicular Normal Leydig Cells.

    Science.gov (United States)

    Kheradmand, Fatemeh; Hashemnia, Seyyed Mohammad Reza; Valizadeh, Nasim; Roshan-Milani, Shiva

    2016-01-01

    Growth factors play an essential role in the development of tumor and normal cells like testicular leydig cells. Treatment of cancer with anti-cancer agents like imatinib mesylate may interfere with normal leydig cell activity, growth and fertility through failure in growth factors' production or their signaling pathways. The purpose of the study was to determine cellular viability and the levels of, platelet derived growth factor (PDGF) and stem cell factor (SCF) in normal mouse leydig cells exposed to imatinib, and addressing the effect of imatinib on fertility potential. The mouse TM3 leydig cells were treated with 0 (control), 2.5, 5, 10 and 20 μM imatinib for 2, 4 and 6 days. Each experiment was repeated three times (15 experiments in each day).The cellular viability and growth factors levels were assessed by MTT and ELISA methods, respectively. For statistical analysis, one-way ANOVA with Tukey's post hoc and Kruskal-Wallis test were performed. A p-value less than 0.05 was considered statistically significant. With increasing drug concentration, cellular viability decreased significantly (pcellular viability, PDGF and SCF levels. Imatinib may reduce fertility potential especially at higher concentrations in patients treated with this drug by decreasing cellular viability. The effect of imatinib on leydig cells is associated with PDGF stimulation. Of course future studies can be helpful in exploring the long term effects of this drug.

  14. Myeloid neoplasm with prominent eosinophilia and PDGFRA rearrangement treated with imatinib mesylate

    DEFF Research Database (Denmark)

    Rathe, Mathias; Kielsgaard Kristensen, Thomas; Møller, Michael Boe

    2010-01-01

    of FIP1L1-PDGFRA positive disease has been reported. We report a 2-year-old female with a myeloid neoplasm associated with eosinophilia and rearrangement of PDGFRA. Treatment with imatinib resulted in complete and durable clinical, hematological, and molecular remission within 3 months after starting...

  15. Chronic Myeloid Leukemia with Variant Chromosomal Translocations: Results of Treatment with Imatinib Mesylate

    Directory of Open Access Journals (Sweden)

    Rohan Bhise

    2013-01-01

    Full Text Available Objective: To evaluate the efficacy of imatinib in chronic myeloid leukemia patients with variant translocations. Methods: Forty eight chronic myeloid leukemia patients carrying variant translocations and treated with imatinib at our institute were considered for the study. Survival and response rates were evaluated. Results: The median follow up was 48 months(m. Forty three (89.58% patients achieved complete hematologic response. Thirty one (64.58% patients achieved complete cytogenetic response and 19(39.58% achieved major molecular response anytime during their follow up period. Only 18.75% of the patients achieved complete cytogenetic response and major molecular response within the stipulated time frames.The estimated overall survival at 48 m median follow up was 81.2%.The progression free survival was also 81.2% and the event free survival was 79.1%.There was no significant survival difference between low vs intermediate and high risk sokal group. Conclusion: We report suboptimal responses to imatinib in chronic myeloid leukemia with variant translocations. Further studies with imatinib and the newer more active drugs dasatinib and nilotinib are justified.

  16. Evaluation of the Safety of Imatinib Mesylate in 200 Iraqi Patients with Chronic Myeloid Leukemia in the Chronic Phase: Single-Center Study

    Directory of Open Access Journals (Sweden)

    Bassam Francis Matti

    2013-12-01

    Full Text Available OBJECTIVE: Imatinib mesylate, a tyrosine kinase inhibitor, is presently the drug of choice for chronic myeloid leukemia (CML. During therapy, a few patients may develop hematological and non-hematological adverse effects. METHODS: The aim of this study was to evaluate the safety of imatinib therapy in patients with CML. Between December 2007 and October 2009 two hundred patients with CML in chronic phase were included in the study. Written informed consent was obtained from all patients prior to the start of the study. Imatinib was started at 400 mg orally daily. Patients were monitored carefully for any adverse effects. Complete blood count, liver, and renal function tests were done once in 2 weeks during the first month and on a monthly basis during follow-up. Toxicities that encountered were graded as per the National Cancer Institute common toxicity criteria version 2. Both hematologic and non-hematologic toxicities were managed with short interruptions of treatment and supportive measures, but the daily dose of imatinib was not reduced below 300 mg/day. RESULTS: Two hundred CML patients in chronic phase were included in this study; the male: female ratio was 0.7: 1 with mean age 39.06±13.21 years (ranged from 15-81 years. The study showed that the commonest hematological side effects were grade 2 anemia (12.5% followed by leukopenia (8% and thrombocytopenia (4%, while the most common non-hematological adverse effects were superficial edema and weight gain (51.5%, followed by musculoskeletal pain (35.5%, then gastro-intestinal symptoms (vomiting, diarrhea (19%. Fluid retention was the commonest side effect, which responded to low-dose diuretics. The drug was safe and well tolerated. There were no deaths due to toxicity. CONCLUSION: Imatinib mesylate a well-tolerated drug, and all undesirable effects could be ameliorated easily. The most common hematological and non-hematological side effects were anemia and fluid retention, respectively.

  17. Chronic myeloid leukemia: an overview of the determinants of effectiveness and therapeutic response in the first decade of treatment with imatinib mesylate in a Brazilian hospital

    Directory of Open Access Journals (Sweden)

    Danielle Maria Camelo Cid

    2013-01-01

    Full Text Available Background: In the last decade, there has been a revolution in chronic myeloid leukemia treatment with the introduction of tyrosine kinase inhibitors with imatinib mesylate becoming the frontline therapy. Objective: To evaluate the therapeutic efficacy of imatinib mesylate in treating chronic myeloid leukemia patients and to identify factors related to therapeutic efficacy. Methods: This retrospective study was based on information obtained from patients'records in the Hematology Service of Hospital Universitário Walter Cantídio of the Universidade Federal do Ceará (HUWC / UFC. All patients diagnosed with chronic myeloid leukemia that took imatinib mesylate for a minimum of 12 months in the period from January 2001 to January 2011 were included. From a population of 160 patients, 100 were eligible for analysis. Results: The study population consisted of 100 patients who were mostly male (51% with ages rangingbetween 21 and 40 years (42%, from the countryside (59%, in the chronic phase (95%, with high-riskprognostic factors (40%; the prognosis of high risk was not associated with complete hematologic responseor complete cytogenetic response, but correlated to complete molecular response or major molecularresponse. Reticulin condensation was associated with complete hematologic response and completecytogenetic response. It was found that 53% of patients had greater than 90% adherence to treatment. Thehigh adherence was correlated to attaining complete cytogenetic response in less than 12 months. Moreover,20% of patients had good response. Conclusion: Significant changes are indispensable in the monitoring of patients with chronic myeloid leukemia. Thus, the multidisciplinary team is important as it provides access to the full treatment and not just to medications.

  18. Prolonged treatment with imatinib mesylate in patients with advanced chronic myeloid leukemia causes a reduction of bcr/abl mRNA levels independent of cytogenetic response.

    Science.gov (United States)

    Cariani, E; Capucci, M; Micheletti, M; Spalenza, F; Zanella, I; Albertini, A; Rossi, G

    2003-06-01

    Bcr/abl mRNA levels were monitored in 13 patients with chronic myeloid leukemia receiving imatinib mesylate over a period of 78 weeks. During treatment median bcr/abl mRNA levels progressively declined from 77.2 normalized dose (nD) at baseline to 11.28 nD after 13 weeks ( P<0.05) and to 1.28 nD after 78 weeks ( P<0.05). After 13 weeks, bcr/abl mRNA levels were significantly lower in cytogenetic responders compared to nonresponders ( P<0.05), but subsequent decrease in the transcript levels caused the loss of any correlation to the cytogenetic status. These results suggest that bcr/abl mRNA levels may reflect cytogenetic response only during the early phases of imatinib therapy.

  19. Maximizing the Therapeutic Efficacy of Imatinib Mesylate-Loaded Niosomes on Human Colon Adenocarcinoma Using Box-Behnken Design.

    Science.gov (United States)

    Kassem, Mohammed A; El-Sawy, Hossam S; Abd-Allah, Fathy I; Abdelghany, Tamer M; El-Say, Khalid M

    2017-01-01

    This research purposed to formulate an optimized imatinib mesylate (IM)-loaded niosomes to improve its chemotherapeutic efficacy. The influence of 3 formulation factors on niosomal vesicular size (Y 1 ), zeta potential (Y 2 ), entrapment capacity percentage (Y 3 ), the percentage of initial drug release after 2 h (Y 4 ), and the percentage of cumulative drug release after 24 h (Y 5 ) were studied and optimized using Box-Behnken design. Optimum desirability was specified and the optimized formula was prepared, stability tested, morphologically examined, checked for vesicular bilayer formation and evaluated for its in vitro cytotoxicity on 3 different cancer cell lines namely MCF-7, HCT-116, and HepG-2 in addition to 1 normal cell line to ensure its selectivity against cancer cells. The actual responses of the optimized IM formulation were 425.36 nm, -62.4 mV, 82.96%, 18.93%, and 89.45% for Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 , respectively. The optimized IM-loaded niosomes confirmed the spherical vesicular shape imaged by both light and electron microscopes and further proven by differential scanning calorimetry. Moreover, the optimized formula exhibited improved stability on storage at 4 ± 2°C and superior efficacy on MCF7, HCT-116, and HepG2 as IC 50 values were 6.7, 16.4, and 7.3 folds less than those of free drug, respectively. Interestingly, IC 50 of the optimized formula against normal cell line was ranged from 3 to 11 folds higher than in different cancer cells indicating a higher selectivity of the optimized formula to cancer cells. In conclusion, the incorporation of IM in niosomes enhanced its efficacy and selectivity toward cancer cells, presenting a promising tool to fight cancer using this approach. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  20. Simultaneous regression of Philadelphia chromosome and multiple nonrecurrent clonal chromosomal abnormalities with imatinib mesylate in a patient autografted 22 years before for chronic myelogenous leukemia.

    Science.gov (United States)

    Van Den Akker, J; Coppo, P; Portnoï, M F; Barbu, V; Bories, D; Gorin, N C

    2007-09-01

    A 31-year-old patient developed chronic myelogenous leukemia (CML) in November, 1983. In November 1984, following a diagnosis of acceleration, he received an autologous hemopoietic transplant after conditioning with cyclophosphamide and total body irradiation. The autologous marrow was purged with mafosfamide. Over 20 years, the patient remained in chronic phase of CML. Multiple nonrecurrent clonal chromosomal abnormalities appeared leading to a very complex karyotype, including among others involvement of chromosomes 1, 7, 9, 13, 19, and X. Fluorescent in situ hybridization showed that the two chromosomes 9 were involved. Acute myeloid crisis was diagnosed in February, 2004. Treatment with imatinib mesylate resulted within 6 months in a total disappearance of all chromosomal abnormalities with a complete cytogenetic and molecular response, which persists 3 years later. We question whether the ex vivo purging procedure with mafosfamide has favored the occurrence of these particular cytogenetic abnormalities (with no independent oncogenic potential) within the original leukemic stem cell pool. It remains unclear whether the autologous transplantation has indeed resulted into some prolongation of the duration of the chronic phase, which lasted for 20 years. At time of acute crisis, the dramatic response to imatinib mesylate leading to a complete cytogenetic and molecular response is noteworthy.

  1. Effects of imatinib mesylate on the pharmacokinetics of paracetamol (acetaminophen) in Korean patients with chronic myelogenous leukaemia.

    Science.gov (United States)

    Kim, Dong-Wook; Tan, Eugene Y; Jin, Yu; Park, Sahee; Hayes, Michael; Demirhan, Eren; Schran, Horst; Wang, Yanfeng

    2011-02-01

    The major objective of the present study was to investigate the effect of imatinib on the pharmacokinetics of paracetamol in patients with chronic myelogenous leukaemia (CML). Patients (n = 12) received a single oral dose of acetaminophen 1000 mg on day 1 (control). On days 2-8, imatinib 400 mg was administered daily. On day 8 (treatment), another 1000 mg dose of paracetamol was administered 1 h after the morning dose of imatinib 400 mg. Blood and urine samples were collected for bioanalytical analyses. The area under the plasma concentration-time curve (AUC) for paracetamol, paracetamol glucuronide and paracetamol sulphate under control conditions was similar to that after treatment with imatinib; the 90% confidence interval of the log AUC ratio was within 0.8 to 1.25. Urinary excretion of paracetamol, paracetamol glucuronide and paracetamol sulphate was also unaffected by imatinib. The pharmacokinetics of paracetamol and imatinib in Korean patients with CML were similar to previous pharmacokinetic results in white patients with CML. Co-administration of a single dose of paracetamol and multiple doses of imatinib was well tolerated and safety profiles were similar to those of either drug alone. The pharmacokinetics of paracetamol and its major metabolites in the presence of imatinib were similar to those of the control conditions and the combination was well tolerated. These findings suggest that imatinib can be safely administered with paracetamol without dose adjustment of either drug. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

  2. Marrow signal changes observed in follow-up whole-body MRI studies in children and young adults with neurofibromatosis type 1 treated with imatinib mesylate (Gleevec) for plexiform neurofibromas

    Energy Technology Data Exchange (ETDEWEB)

    Karmazyn, Boaz; Cohen, Mervyn D. [Riley Hospital for Children, Indiana University Health, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN (United States); Jennings, Samuel Gregory [Indiana University School of Medicine, Department of Radiology and Imaging Sciences, Indianapolis, IN (United States); Robertson, Kent A. [Riley Hospital for Children, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN (United States)

    2012-10-15

    We observed bone marrow signal changes (BMSC) in patients with plexiform neurofibromas after treatment with imatinib mesylate (Gleevec). To evaluate the pattern and natural history of BMSC. The data were obtained from a pilot study of imatinib mesylate in patients with plexiform neurofibromas. All patients underwent baseline and sequential whole-body STIR 1.5-T MRI after treatment. The bone marrow signal on MRI was evaluated for abnormalities, location and pattern, and any change on follow-up studies. The study group included 16 patients (8 males) with a median age of 14 years (range 4 to 25 years). The mean whole-body MRI follow-up duration was 1.9 years. Of the 16 patients, 14 (88%) developed BMSC. The signal change was asymmetrical in 9 of the 14 patients (64%). The appendicular skeleton was involved in all 14 patients and the axial skeleton in 3 patients (21%). BMSC was followed in 13 patients and decreased signal was seen in 9 patients (69%) after a mean duration of 1.3 years of treatment (range 0.6 to 2.9 years); no complications were observed. BMSC appeared in most patients with neurofibromatosis type 1 following treatment with imatinib mesylate. BMSC was unusually asymmetrical and involved the lower extremities. On follow-up, BMSC often showed a decrease without complications. (orig.)

  3. Penetrable silica microspheres for immobilization of bovine serum albumin and their application to the study of the interaction between imatinib mesylate and protein by frontal affinity chromatography.

    Science.gov (United States)

    Ma, Liyun; Li, Jing; Zhao, Juan; Liao, Han; Xu, Li; Shi, Zhi-guo

    2016-01-01

    In the current study, novel featured silica, named penetrable silica, simultaneously containing macropores and mesopores, was immobilized with bovine serum albumin (BSA) via Schiff base method. The obtained BSA-SiO2 was employed as the high-performance liquid chromatographic (HPLC) stationary phase. Firstly, D- and L-tryptophan were used as probes to investigate the chiral separation ability of the BSA-SiO2 stationary phase. An excellent enantioseparation factor was obtained up to 4.3 with acceptable stability within at least 1 month. Next, the BSA-SiO2 stationary phase was applied to study the interaction between imatinib mesylate (IM) and BSA by frontal affinity chromatography. A single type of binding site was found for IM with the immobilized BSA, and the hydrogen-bonding and van der Waals interactions were expected to be contributing interactions based on the thermodynamic studies, and this was a spontaneous process. Compared to the traditional silica for HPLC stationary phase, the proposed penetrable silica microsphere possessed a larger capacity to bond more BSA, minimizing column overloading effects and enhancing enantioseparation ability. In addition, the lower running column back pressure and fast mass transfer were meaningful for the column stability and lifetime. It was a good substrate to immobilize biomolecules for fast chiral resolution and screening drug-protein interactions.

  4. Administration of imatinib mesylate in rats impairs the neonatal development of intramuscular interstitial cells in bladder and results in altered contractile properties.

    Science.gov (United States)

    Gevaert, Thomas; Hutchings, Graham; Everaerts, Wouter; Prenen, Hans; Roskams, Tania; Nilius, Bernd; De Ridder, Dirk

    2014-04-01

    The KIT receptor is considered as a reliable marker for a subpopulation of interstitial cells (IC), and by persistent neonatal inhibition of KIT we have investigated the role of this receptor in the development of IC-networks in bladder and we have observed the functional consequences of this inhibition. Newborn rat pups were treated daily with the KIT inhibitor imatinib mesylate (IM). After 7 days animals were sacrificed and bladder samples were dissected for morphological and functional studies. Morphological research consisted of immunohistochemistry with IC specific antigens (KIT and vimentin) and electron microscopy. The functional studies were based on isolated bladder strips in organ baths, in which spontaneous bladder contractility and the response to a non-subtype selective muscarinic agonist was evaluated. Suburothelial and intramuscular IC were found and characterized in neonatal rat bladder. IM-treatment induced a significant decrease in numbers of IC based on specific immunohistochemical markers, and electron microscopy revealed evidence of IC cell injury. These morphological alterations were observed on intramuscular IC only and not on IC in the suburothelium. Isolated muscle strips from IM-treated animals had a lower contractile frequency and an altered response to muscarinic agonists. The present study shows the presence of regional subpopulations of IC in neonatal rat bladder, provides evidence for a dependence on KIT of the development of intramuscular IC and supports the hypothesis that a poor development of networks of intramuscular IC might have repercussions on spontaneous and muscarinic-induced bladder contractility. © 2013 Wiley Periodicals, Inc.

  5. Carbonic anhydrase inhibition boosts the antitumor effects of Imatinib mesylate via potentiating the antiangiogenic and antimetastatic machineries

    Energy Technology Data Exchange (ETDEWEB)

    Abd-El Fattah, Amal A. [Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562 (Egypt); Darwish, Hebatallah A. [Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562 (Egypt); Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University, Cairo (Egypt); Fathy, Nevine, E-mail: nevine.abdallah@pharma.cu.edu.eg [Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562 (Egypt); Shouman, Samia A. [Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11796 (Egypt)

    2017-02-01

    Carbonic anhydrase inhibitors have emerged in the past few years as an interesting candidate for the development of novel unconventional strategies. Despite their effect in tumor regression via inhibition of tumor acidification, their potential role is not yet fully elucidated. Herein, we investigated whether acetazolamide (AZ) could modulate imatinib (IM) anticancer activity, both in breast cancer cells (T47D) and in isolated tumor specimens of Ehrlich ascites carcinoma (EAC). The impact of this combination on angiogenesis was evidenced by decreasing PDGF-A expression and enhancing that of TSP-1. In the meantime, AZ significantly suppressed IM-induced attenuation of VEGF secretion in T47D cells, most probably due to NO inhibition. The combination also dramatically decreased the metastatic activity of T47D cells by mitigating the protein levels of MMP-2 and -9 and phosphorylation of p38 MAPK, while increasing the expression of TIMP-1 and -2. In addition, a strong proapoptotic effect was observed in T47D cells after combining AZ and IM in terms of increased caspase-9 and -3 activities. Interestingly, these results were confirmed by the reduction in the isolated tumor volume, MVD, Ki-67 and VEGF expression. Eventually, the study provides a new therapeutic strategy for treating cancer. - Highlights: • A novel combination of imatinib and a carbonic anhydrase was studied. • The impact was evaluated in T47D cells and EAC-bearing mice. • The interaction suppressed PDGF-A and VEGF while enhanced TSP-1. • MMPs and p38 MAPK phosphorylation were suppressed while TIMPs were enhanced. • The interaction triggered caspase-9 and -3 activation.

  6. Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with imatinib mesylate against chronic myelogenous leukemia cell lines

    Directory of Open Access Journals (Sweden)

    Xin P

    2017-04-01

    Full Text Available Pengliang Xin, Chuntuan Li, Yan Zheng, Qunyi Peng, Huifang Xiao, Yuanling Huang, Xiongpeng Zhu Department of Haematology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Licheng, Quanzhou, Fujian Province, China Background: Phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR pathway is a therapy target of cancer. We aimed to confirm the effect of dual PI3K/mTOR inhibitor NVP-BEZ235 on proliferation, apoptosis, and autophagy of chronic myelogenous leukemia (CML cells and sensitivity of tyrosine kinase inhibitor in vitro.Methods: Two human CML cell lines, K562 and KBM7R (T315I mutant strain, were used. The proliferation of CML cells was detected by MTS (Owen’s reagent assay. Cell cycle and apoptosis assay were examined by flow cytometric analysis. The phosphorylation levels and the expression levels were both evaluated by Western blot analysis. NVP-BEZ235 in combination with imatinib was also used to reveal the effect on proliferation and apoptosis.Results: NVP-BEZ235 significantly inhibited the proliferation in a time- and dose-dependent manner, and the half-maximal inhibitory concentration values of NVP-BEZ235 inhibiting the proliferation of K562 and KBM7R were 0.37±0.21 and 0.43±0.27 µmol/L, respectively, after 48 h. Cell apoptosis assay showed that NVP-BEZ235 significantly increased the late apoptotic cells. Cell cycle analysis indicated that the cells were mostly arrested in G1/G0 phase after treatment by NVP-BEZ235. In addition, results also found that, after treatment by NVP-BEZ235, phosphorylation levels of Akt kinase and S6K kinase significantly reduced, and the expression levels of cleaved caspase-3 significantly increased; meanwhile, the expression levels of caspase-3, B-cell lymphoma-2, cyclin D1, and cyclin D2 significantly decreased, and the ratio of LC3II/LC3I was significantly increased with increased LC3II expression level. Moreover, imatinib in combination with NVP-BEZ235

  7. Tratamento da recidiva da leucemia mielóide crônica após transplante de medula óssea alogênico utilizando mesilato de imatinibe: relato de três casos Treatment of chronic myelogenous leukemia relapse after allogeneic bone marrow transplantation with imatinib mesylate: report of three cases

    Directory of Open Access Journals (Sweden)

    Ronald Pallotta

    2006-06-01

    Full Text Available O mesilato de imatinibe (MI, inibidor seletivo da tirosinoquinase envolvido na patogênese da leucemia mielóide crônica (LMC, tem se constituído como terapia farmacológica de primeira linha para o tratamento desta doença. A infusão de linfócitos do doador (DLI tem sido considerada como tratamento padrão para recidiva da LMC após transplante de medula óssea (TMO alogênico, apesar de estar freqüentemente associado à ocorrência de doença do enxerto contra hospedeiro e mielossupressão. Por apresentar resultados satisfatórios e boa tolerabilidade no tratamento da LMC, os autores empregaram o mesilato de imatinib como terapêutica alternativa à DLI em pacientes que sofreram recidiva após o TMO. Obtiveram sucesso em dois casos, sendo que em um houve retorno comprovado do quimerismo do doador. No terceiro caso houve progressão da doença e o paciente foi encaminhado para segundo TMO. Desta forma, devido ao caráter recente do tema, este estudo descritivo sugere que esta opção terapêutica possa ser estudada como alternativa na recaída pós-TMO.Imatinib mesylate (MI, a selective tyrosine kinase inhibitor involved in the pathogenesis of chronic myelogenous leukemia (CML, has become the first-line treatment for this disease. Donor lymphocyte infusion (DLI has been considered as the standard treatment for relapse after allogeneic bone marrow transplantation (BMT, even though it is frequently associated with graft versus host disease and myelosuppression. Because of the satisfactory results and tolerance of the treatment of CML, the authors used MI as an alternative therapy for DLI in patients that relapsed after BMT. They obtained cytogenetic remission in two cases, with, in one case, proven conversion to the donor chimera. The third case evolved with progression of the disease and a second BMT was required. Since this is a new alternative, this descriptive study suggests it should be considered as an alternative therapy for relapse

  8. The long-term clinical implications of clonal chromosomal abnormalities in newly diagnosed chronic phase chronic myeloid leukemia patients treated with imatinib mesylate.

    Science.gov (United States)

    Lee, Sung-Eun; Choi, Soo Young; Bang, Ju-Hee; Kim, Soo-Hyun; Jang, Eun-Jung; Byeun, Ji-Young; Park, Jin Eok; Jeon, Hye-Rim; Oh, Yun Jeong; Kim, Myungshin; Kim, Dong-Wook

    2012-11-01

    The aim of this study was to evaluate the long-term clinical significance of an additional chromosomal abnormality (ACA), variant Philadelphia chromosome (vPh) at diagnosis, and newly developed other chromosomal abnormalities (OCA) in patients with chronic myeloid leukemia (CML) on imatinib (IM) therapy. Sequential cytogenetic data from 281 consecutive new chronic phase CML patients were analyzed. With a median follow-up of 78.6 months, the 22 patients with vPh (P = 0.034) or ACA (P = 0.034) at diagnosis had more events of IM failure than did the patients with a standard Ph. The 5-year overall survival (OS), event-free survival (EFS), and failure-free survival (FFS) rates for patients with vPh at diagnosis were 77.8%, 75.0%, and 53.3%, respectively; for patients with ACA at diagnosis, 100%, 66.3%, and 52.1%, respectively; and for patients with a standard Ph, 96.0%, 91.3%, and 83.7%, respectively. During IM therapy, eight patients developed an OCA, which had no impact on outcomes as a time-dependent covariate in our Cox proportional hazards regression models. This study showed that vPh was associated with poor OS and FFS and that ACA had adverse effects on EFS and FFS. In addition, no OCA, except monosomy 7, had any prognostic impact, suggesting that the development of OCA may not require a change in treatment strategy. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Results of plasma N-terminal pro B-type natriuretic peptide and cardiac troponin monitoring in GIST patients do not support the existence of imatinib-induced cardiotoxicity

    NARCIS (Netherlands)

    Perik, P. J.; Rikhof, B.; de Jong, F. A.; Verweij, J.; Gietema, J. A.; van der Graaf, W. T. A.

    Background: Recently, case reports of patients treated with imatinib (imatinib mesylate; Gleevec (R); Glvec (R)) indicated that this tyrosine kinase inhibitor may induce cardiomyopathy. Consequently, careful cardiac monitoring was advocated for clinical studies. The purpose of this study was to

  10. Acompanhamento farmacoterapêutico dos pacientes com leucemia mieloide crônica em uso de mesilato de imatinibe na Universidade Federal do Ceará The pharmacotherapeutic follow- up of patients with chronic myeloid leukemia (CML on imatinib mesylate therapy

    Directory of Open Access Journals (Sweden)

    Sterfen S. Aquino

    2009-01-01

    unregulated growth of myeloid precursor cells in the bone marrow. CML is associated with a characteristic chromosomal translocation known as the Philadelphia chromosome. This is a descriptive observational study of CML patients in the Walter Cantídio University Hospital, Federal University of Ceará, Brazil. The aim of the study was to investigate the efficacy and common side effects of imatinib mesylate therapy. Twenty- six patients were included in the study: 9 in the chronic phase (34.61%, 6 in the accelerated phase (23.08% and 11 in blast crises (42.31 %. The cases in the chronic phase had previous intolerance to interferon alpha (IFN- α. Complete hematological responses were observed in 7 patients: 5 in the chronic phase, 1 in the accelerated phase and 1 in blast crisis. During the first year of treatment, 4 patients in the chronic phase presented complete cytogenetic responses. One of these patients subsequently lost response. No patient in the accelerated phase or blast crisis showed complete cytogenetic response. Complete molecular response was confirmed in 1 patient in the chronic phase. Among the 18 patients who were alive at the end of the study, only 4 patients (22.22% had no complaint. The most commonly reported adverse events were: edema (50%, adynamia (33.33%, bone and / or joint pain (33.33%, headaches (27.78%, cramps (16,67%, diarrhea (16.67%, insomnia (16.67%, itching (16.67%, ecchymosis (11.11%, nauseas (11.11%, epigastric pain (5.55%, erythema (5.55%, shedding of tears (5.55%, dehydration of the skin and lips (5.55%, rush (5.55%, and sweating (5.55%. A minority of patients evolved with imatinib resistance. Newer drugs and trials are being developed to overcome resistance and to increase responsiveness to tyrosine- kinase inhibitors.

  11. Imatinib-induced postoperative periorbital purpura: GASP (Gleevec-Associated Surgical Purpura) in a woman with imatinib-treated chronic myelogenous leukemia.

    Science.gov (United States)

    Anzalone, C Lane; Cohen, Philip R; Kurzrock, Razelle; Cortes, Jorge E

    2014-01-15

    Imatinib mesylate is a selective tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia. Ocular side effects of imatinib include periorbital edema, which may become so severe as to obstruct the visual field. The purpose of this case study is to describe the clinical characteristics of imatinib- induced postoperative periorbital purpura. We retrospectively reviewed the medical literature using PubMed, searching the terms edema, Gleevec, imatinib, periorbital, postoperative and purpura. Patient reports and previous reviews of the subject were critically assessed and the salient features are presented. Three patients have undergone surgery to reduce the imatinib-induced periorbital edema; two of these individuals have developed imatinib-induced postoperative periorbital purpura. We recommend discontinuing imatinib usage one week prior to periorbital surgery and not resuming therapy until the eighth postoperative day.

  12. Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: a randomized, open-label, single-dose, fasting, two-period, two-sequence crossover comparison in healthy male South American volunteers.

    Science.gov (United States)

    Parrillo-Campiglia, Susana; Ercoli, Mónica Cedres; Umpierrez, Ofelia; Rodríguez, Patricia; Márquez, Sara; Guarneri, Carolina; Estevez-Parrillo, Francisco T; Laurenz, Marilena; Estevez-Carrizo, Francisco E

    2009-10-01

    Imatinib is a tyrosine kinase inhibitor that has been established as a highly effective therapy for chronic myelogenous leukemia and gastrointestinal stromal tumors. A new generic, once-daily 400-mg tablet of imatinib has been developed by a pharmaceutical company in Argentina, where the regulatory standard for marketing authorization of an imatinib generic is in vitro dissolution testing. The aim of this study was to assess the bioequivalence of a new generic film-coated test tablet formulation versus a film-coated reference tablet formulation of imatinib 400 mg. The local manufacturer seeks to validate the in vitro performance of this new formulation with a bioequivalence study. A randomized, open-label, single-dose, fasting, 2-period, 2-sequence crossover design with a 2-week washout period was used in this study. The study population consisted of healthy male South American (Uruguayan) volunteers, who were assigned in a 1:1 ratio to a randomized sequence (test-reference or reference-test). In each period, the test or reference formulation was administered after an overnight fast. During the 72-hour follow-up period, participants were monitored for vital signs and symptoms. Blood samples were collected at 15 time points, including baseline, until 72 hours. Physical examination and laboratory tests (blood, urine) were repeated 1 week after study completion. A noncompartmental model was used to determine the pharmacokinetic parameters of imatinib. The 90% CIs of the test/reference ratios for AUC(0-infinity) and C(max) were determined; the test and reference formulations were considered bioequivalent if the 90% CIs were between 0.80 and 1.25. Adverse events were assessed by a nurse who administered a questionnaire while the healthy volunteers were admitted in the unit. The bioequivalence study was conducted in 30 Uruguayan male volunteers. Demographic characteristics (mean [SD]) included age, 27.8 (6.5) years; weight, 71.2 (9.8) kg; height, 1.71 (0.09) m; and body

  13. Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

    NARCIS (Netherlands)

    D.A. Reardon; G. Dresemann; S. Taillibert; M. Campone (Mario); M.J. van den Bent (Martin); P.M.J. Clement (Paul); E. Blomquist; L. Gordower; H. Schultz; J. Raizer; P. Hau (Peter); J. Easaw; M. Gil (Miguel); J. Tonn; A. Gijtenbeek; U. Schlegel; P. Bergström (Per); S. Green; A.E. Weir (Angela); Z. Nikolova

    2009-01-01

    textabstractBackground: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). Methods: A total of 231 patients with GBM at first recurrence from 21

  14. Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma.

    NARCIS (Netherlands)

    Reardon, D.A.; Dresemann, G.; Taillibert, S.; Campone, M.; Bent, M. van den; Clement, P.; Blomquist, E.; Gordower, L.; Schultz, H.; Raizer, J.; Hau, P.; Easaw, J.; Gil, M.; Tonn, J.; Gijtenbeek, A.; Schlegel, U.; Bergstrom, P.; Green, S.; Weir, A.; Nikolova, Z.

    2009-01-01

    BACKGROUND: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). METHODS: A total of 231 patients with GBM at first recurrence from 21 institutions in 10

  15. Determination of trace level of palladium and platinum content in anticancer drug Imatinib base by ICP-MS

    International Nuclear Information System (INIS)

    Yadav, Ravi; Salunke-Gawali, Sunita

    2013-01-01

    Metal impurities in Pharmaceutical drug substance is of great concern not only because of the intrinsic toxicity of certain contaminants but also due to the opposite effect that the contaminants which may have on drug stability and shelf life. Therefore it is necessary to monitor the organic as well as inorganic impurities throughout the process of manufacturing process at every stage from raw material, intermediate and finished products. An Inductively Coupled Plasma - Mass Spectrometry (ICP-MS) method has been developed for Palladium and Platinum content in the anticancer drug, Imatinib mesylate. Rhodium (Rh) was used as internal standard for determination of Palladium and Platinum content on in Imatinib mesylate. (author)

  16. Epigenetic Silencing and Resistance to Imatinib Mesylate in CML

    National Research Council Canada - National Science Library

    Issa, Jean-Pierre

    2004-01-01

    ...). In this project, we are exploring the hypothesis that epigenetic silencing associated with promoter DNA methylation mediates resistance in selected cases, and that reversal of silencing by decitabine...

  17. Epigenetic Silencing and Resistance to Imatinib Mesylate in CML

    National Research Council Canada - National Science Library

    Issa, Jean-Pierre

    2005-01-01

    ...). In this project, we are exploring the hypothesis that epigenetic silencing associated with promoter DNA methylation mediates resistance in selected cases, and that reversal of silencing by decitabine...

  18. Epigenetic Silencing and Resistance to Imatinib Mesylate in CML

    National Research Council Canada - National Science Library

    Issa, Jean-Pierre

    2006-01-01

    ...). In this project we are exploring the hypothesis that epigenetic silencing associated with promoter DNA methylation mediates resistance in selected cases and that reversal of silencing by decitabine...

  19. LAM Pilot Study with Imatinib Mesylate (LAMP 1)

    Science.gov (United States)

    2016-10-01

    purchase generic drug from Canada; however, all drug purchases inside the Medical University of South Carolina must occur through the MUSC pharmacy who...decline to purchase international drug. We do have an accepted IND plan to overencapsulate Gleevec and manufacture placebo at MUSC that was approved by... Journal publications. List peer-reviewed articles or papers appearing in scientific, technical, or professional journals . Identify for each publication

  20. Celecoxib sensitizes imatinib-resistant K562 cells to imatinib by inhibiting MRP1-5, ABCA2 and ABCG2 transporters via Wnt and Ras signaling pathways.

    Science.gov (United States)

    Dharmapuri, Gangappa; Doneti, Ravinder; Philip, Gundala Harold; Kalle, Arunasree M

    2015-07-01

    Imatinib mesylate, a tyrosine kinase inhibitor, is very effective in the treatment of chronic myeloid leukemia (CML). However, development of resistance to imatinib therapy is also a very common mechanism observed with long-term administration of the drug. Our previous studies have highlighted the role of cyclooxygenase-2 (COX-2) in regulating the expression of multidrug resistant protein-1 (MDR1), P-gp, in imatinib-resistant K562 cells (IR-K562) via PGE2-cAMP-PKC-NF-κB pathway and inhibition of COX-2 by celecoxib, a COX-2 specific inhibitor, inhibits this pathway and reverses the drug resistance. Studies have identified that not only MDR1 but other ATP-binding cassette transport proteins (ABC transporters) are involved in the development of imatinib resistance. Here, we tried to study the role of COX-2 in the regulation of other ABC transporters such as MRP1, MRP2, MRP3, ABCA2 and ABCG2 that have been already implicated in imatinib resistance development. The results of the study clearly indicated that overexpression of COX-2 lead to upregulation of MRP family proteins in IR-K562 cells and celecoxib down-regulated the ABC transporters through Wnt and MEK signaling pathways. The study signifies that celecoxib in combination with the imatinib can be a good alternate treatment strategy for the reversal of imatinib resistance. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

    OpenAIRE

    Reardon, D A; Dresemann, G; Taillibert, S; Campone, M; van den Bent, M; Clement, P; Blomquist, E; Gordower, L; Schultz, H; Raizer, J; Hau, P; Easaw, J; Gil, M; Tonn, J; Gijtenbeek, A

    2009-01-01

    textabstractBackground: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). Methods: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIA...

  2. Imatinib induced severe skin reactions and neutropenia in a patient with gastrointestinal stromal tumor

    International Nuclear Information System (INIS)

    Hwang, Jun-Eul; Yoon, Ju-Young; Bae, Woo-Kyun; Shim, Hyun-Jeong; Cho, Sang-Hee; Chung, Ik-Joo

    2010-01-01

    Imatinib mesylate has been used for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST). The current recommended dose of imatinib is 400 mg/day that is increased to 800 mg/day in cases with disease progression. However, imatinib can be associated with diverse adverse events, which has limited its use. We report a case of severe adverse skin reactions with neutropenic fever during imatinib treatment in a patient with GIST. A 71-year-old man was admitted with a one month history of epigastric pain and a palpable mass in the right upper quadrant. An abdominal CT scan revealed a 20 × 19 cm intraabdominal mass with tumor invasion into the peritoneum. Needle biopsy was performed and the results showed spindle shaped tumor cells that were positive for c-KIT. The patient was diagnosed with unresectable GIST. Imatinib 400 mg/day was started. The patient tolerated the first eight weeks of treatment. However, about three months later, the patient developed a grade 4 febrile neutropenia and a grade 3 exfoliative skin rash. The patient recovered from this serious adverse events after discontinuation of imatinib with supportive care. However, the skin lesions recurred whenever the patient received imatinib over 100 mg/day. Therefore, imatinib 100 mg/day was maintained. Despite the low dose imatinib, follow up CT showed a marked partial response without grade 3 or 4 toxicities. The recommended dose of imatinib for the treatment of GIST is 400 mg/day but patients at risk for adverse drug reaction may benefit from lower doses. Individualized treatment is needed for such patients, and we may also try sunitinib as a alternative drug

  3. Bioinspired co-crystals of Imatinib providing enhanced kinetic solubility.

    Science.gov (United States)

    Reggane, Maude; Wiest, Johannes; Saedtler, Marco; Harlacher, Cornelius; Gutmann, Marcus; Zottnick, Sven H; Piechon, Philippe; Dix, Ina; Müller-Buschbaum, Klaus; Holzgrabe, Ulrike; Meinel, Lorenz; Galli, Bruno

    2018-05-04

    Realizing the full potential of co-crystals enhanced kinetic solubility demands a comprehensive understanding of the mechanisms of dissolution, phase conversion, nucleation and crystal growth, and of the complex interplay between the active pharmaceutical ingredient (API), the coformer and co-existing forms in aqueous media. One blueprint provided by nature to keep poorly water-soluble bases in solution is the complexation with phenolic acids. Consequently, we followed a bioinspired strategy for the engineering of co-crystals of a poorly water-soluble molecule - Imatinib - with a phenolic acid, syringic acid (SYA). The dynamics of dissolution and solution-mediated phase transformations were monitored by Nuclear Magnetic Resonance (NMR) spectroscopy, providing mechanistic insights into the 60 fold-increased long lasting concentrations achieved by the syringate co-crystals as compared to Imatinib base and Imatinib mesylate. This lasting effect was linked to SYA's ability to delay the formation and nucleation of Imatinib hydrate - the thermodynamically stable form in aqueous media - through a metastable association of SYA with Imatinib in solution. Results from permeability studies evidenced that SYA did not impact Imatinib's permeability across membranes while suggesting improved bioavailability through higher kinetic solubility at the biological barriers. These results reflect that some degree of hydrophobicity of the coformer might be key to extend the kinetic solubility of co-crystals with hydrophobic APIs. Understanding how kinetic supersaturation can be shaped by the selection of an interactive coformer may help achieving the needed performance of new forms of poorly water-soluble, slowly dissolving APIs. Copyright © 2018. Published by Elsevier B.V.

  4. [Watermelon stomach: Chronic renal failure and/or imatinib?].

    Science.gov (United States)

    Montagnac, Richard; Blaison, Dominique; Brahimi, Saïd; Schendel, Adeline; Levasseur, Thomas; Takin, Romulus

    2015-11-01

    Watermelon stomach or gastric antral vascular ectasia (GAVE) syndrome is an uncommon cause of sometimes severe upper gastro-intestinal bleeding. Essentially based on a pathognomonic endoscopic appearance, its diagnosis may be unrecognised because mistaken with portal hypertensive gastropathy, while treatment of these two entities is different. Its etiopathogeny remains still unclear, even if it is frequently associated with different systemic illnesses as hepatic cirrhosis, autoimmune disorders and chronic renal failure. The mechanism inducing these vascular ectasia may be linked with mechanical stress on submucosal vessels due to antropyloric peristaltic motility dysfunction modulated by neurohormonal vasoactive alterations. Because medical therapies are not very satisfactory, among the endoscopic modalities, argon plasma coagulation seems to be actually the first-line treatment because the most effective and safe. However, surgical antrectomy may be sometimes necessary. Recently GAVE syndrome appeared as a new adverse reaction of imatinib mesylate, one of the tyrosine kinase inhibitors used in chronic myeloid leukemia, and we report here the observation of such a pathology in one patient treated at the same time by haemodialysis and by imatinib mesylate for chronic myeloid leukemia. Copyright © 2015 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

  5. Positron emission tomography in patients with aggressive fibromatosis/desmoid tumours undergoing therapy with imatinib

    Energy Technology Data Exchange (ETDEWEB)

    Kasper, Bernd; Hohenberger, Peter [University of Heidelberg, Sarcoma Unit, ITM - Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, Mannheim (Germany); Dimitrakopoulou-Strauss, Antonia; Strauss, Ludwig G. [German Cancer Research Center, Clinical Cooperation Unit Nuclear Medicine, Heidelberg (Germany)

    2010-10-15

    We used {sup 18}F-FDG PET to evaluate the FDG uptake in patients with aggressive fibromatosis (AF, also known as desmoid tumours) undergoing therapy with imatinib (imatinib mesylate, Glivec). The pilot study included nine patients with progressive AF receiving oral treatment with imatinib at a daily dose of 800 mg. Patients were examined using PET prior to the start of therapy and during imatinib treatment. Restaging according to the Response Evaluation Criteria in Solid Tumors (RECIST) was performed in parallel using CT and/or MRI and served as reference. The clinical outcomes in nine evaluable patients were as follows: seven patients with stable disease, and two patients with progressive disease. A 27% decrease in the median average standardized uptake value (SUV) of the sequential PET examinations was demonstrated in all evaluable patients with three patients (33%) showing a decrease in SUV of more than 40% (48%, 52% and 54%, respectively); no patient showed a substantial increase in SUV. To our knowledge, this is the first series of AF patients undergoing treatment with imatinib and monitored using sequential PET imaging, that allows detection of SUV changes after imatinib induction, thus helping to decide whether treatment should be continued or not. (orig.)

  6. Synthesis and positron emission tomography studies of carbon-11-labeled imatinib (Gleevec)

    Energy Technology Data Exchange (ETDEWEB)

    Kil, Kun-Eek [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States); Ding Yushin [Department of Radiology, Yale University School of Medicine, New Haven, CT 06520-8048 (United States); Lin Kuoshyan [Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Alexoff, David [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Kim, Sung Won [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States); Shea, Colleen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Xu Youwen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Muench, Lisa [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Fowler, Joanna S. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States) and Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400 (United States)]. E-mail: fowler@bnl.gov

    2007-02-15

    Introduction: Imatinib mesylate (Gleevec) is a well known drug for treating chronic myeloid leukemia and gastrointestinal stromal tumors. Its active ingredient, imatinib ([4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl) -2-pyrimidinyl]amino]phenyl]benzamide), blocks the activity of several tyrosine kinases. Here we labeled imatinib with carbon-11 as a tool for determining the drug distribution and pharmacokinetics of imatinib, and we carried out positron emission tomography (PET) studies in baboons. Methods: [N-{sup 11}C-methyl]imatinib was synthesized from [{sup 11}C]methyl iodide and norimatinib was synthesized by the demethylation of imatinib (isolated from Gleevec tablets) according to a patent procedure [Collins JM, Klecker RW Jr, Anderson LW. Imaging of drug accumulation as a guide to antitumor therapy. US Patent 20030198594A1, 2003]. Norimatinib was also synthesized from the corresponding amine and acid. PET studies were carried out in three baboons to measure pharmacokinetics in the brain and peripheral organs and to determine the effect of a therapeutic dose of imatinib. Log D and plasma protein binding were also measured. Results: [N-{sup 11}C-methyl]imatinib uptake in the brain is negligible (consistent with P-glycoprotein-mediated efflux); it peaks and clears rapidly from the heart, lungs and spleen. Peak uptake and clearance occur more slowly in the liver and kidneys, followed by accumulation in the gallbladder and urinary bladder. Pretreatment with imatinib did not change uptake in the heart, lungs, kidneys and spleen, and increased uptake in the liver and gallbladder. Conclusions: [N-{sup 11}C-methyl]imatinib has potential for assessing the regional distribution and kinetics of imatinib in the human body to determine whether the drug targets tumors and to identify other organs to which the drug or its labeled metabolites distribute. Paired with tracers such as 2'deoxy-2'-[{sup 18}F]fluoro-D-glucose ({sup 18}FDG) and 3&apos

  7. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study

    DEFF Research Database (Denmark)

    Baccarani, Michele; Rosti, Gianantonio; Castagnetti, Fausto

    2009-01-01

    Imatinib mesylate (IM), 400 mg daily, is the standard treatment of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML). Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. To investigate whether the systematic...

  8. Adherence to treatment with imatinib in chronic myeloid leukemia: a study of the first decade of responses obtained at a Brazilian hospital

    Directory of Open Access Journals (Sweden)

    Samuel Roosevelt Campos dos Reis

    2013-06-01

    Full Text Available Objetive: The aim of this study was to identify the reasons for failure in adherence to imatinib mesylate treatment in chronic myeloid leukemia. Methods: A retrospective review was performed of 100 non-electronic records of patients with Ph+ chronic myeloid leukemia treated with imatinib mesylate. The study period was from January 2001 to January2011. Data were analyzed by Chi-Square and Correspondence analysis using the Statistical Analysis System software package. Results: At the beginning of treatment 41% of patients were in advanced stages of the disease. The unavailability of the drug (44.8% and myelotoxicity (25.7% were the most frequent reasons for interruption. The adherence rate was 95% induced complete cytogenetic response, major cytogenetic response and major molecular response. Conclusion: The population of this study obtained lower-than-expected therapeutic responses compared to other studies.

  9. Quantification of imatinib in human serum: validation of a high-performance liquid chromatography-mass spectrometry method for therapeutic drug monitoring and pharmacokinetic assays

    OpenAIRE

    Rezende, Vinicius Marcondes; Rivellis, Ariane; Novaes, Mafalda Megumi Yoshinaga; de Alencar Fisher Chamone, Dalton; Bendit, Israel

    2013-01-01

    Vinicius Marcondes Rezende,1 Ariane Rivellis,1 Mafalda Megumi Yoshinaga Novaes,1 Dalton de Alencar Fisher Chamone,2 Israel Bendit1,21Laboratory of Tumor Biology, 2Department of Hematology, School of Medicine, University of São Paulo, São Paulo, BrazilBackground: Imatinib mesylate has been a breakthrough treatment for chronic myeloid leukemia. It has become the ideal tyrosine kinase inhibitor and the standard treatment for chronic-phase leukemia. Striking results have rec...

  10. Effect of Imatinib on the Oogenesis and Pituitary -Ovary Hormonal Axis in Female Wistar Rat

    Directory of Open Access Journals (Sweden)

    Parichehreh Yaghmaei

    2009-01-01

    Full Text Available Background: Imatinib mesylate, a small-molecular analog of adenosine triphosphate (ATPthat potently inhibits tyrosine kinase activities of Bcr–Abl, PDGFR-β, PDGFR-α, c-Fms, Argand c-kit, is one of the novel molecularly targeted drugs being introduced into cancer therapy.We tested the effect of imatinib on the ovarian histological structure and the concentration ofestrogen and progesterone, luteinizing hormone (LH and follicle stimulating hormone (FSHin the serum of female Wistar rats.Materials and Methods: Two groups of rats (180 ± 15 grams were gavaged with doses of 50and 100 mg/kg body weight imatinib dissolved in distilled water for 14 days. The control groupreceived sterile water. On day 7, after termination of the treatment, blood serum concentrationwas measured with the radioimmunoassay (RIA method. Also, sections (5 μm thick of ovariesstained with hematoxylin and eosin (H&E were investigated histologically.Results: Progesterone concentration in the experimental groups was increased (p<0.001,estrogen and FSH concentrations were decreased (p<0.01, and the LH concentration decreasedbut was not statistically different in comparison with the control group. The weight of ovaries andnumber of atretic follicles in the experimental groups was increased compared with the controlgroup (p<0.05. The diameter of corpus lutea were increased but the number of corpus luteadecreased in both experimental groups (p<0.01.Conclusion: These findings suggest that administration of imatinib may have profound effects onfemale fertility.

  11. Therapeutic options for chronic myeloid leukemia: focus on imatinib (Glivec®, Gleevec™

    Directory of Open Access Journals (Sweden)

    Martin Henkes

    2008-03-01

    Full Text Available 1Martin Henkes, 2Heiko van der Kuip, 1Walter E Aulitzky12nd Department of Internal Medicine, Oncology and Hematology, Robert Bosch Hospital, Auerbachstr. 110, Stuttgart, Germany; 2Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, Stuttgart, and University of Tuebingen, GermanyAbstract: Treatment options for chronic myeloid leukemia (CML have changed dramatically during the last decades. Interferon-α treatment and stem cell transplantation (SCT clearly improved survival over conventional chemotherapy and offered the possibility of complete and durable responses. With the advent of the small molecule inhibitor imatinib mesylate (Glivec®, GleevecTM targeting the causative Bcr-Abl oncoprotein, the era of molecular cancer therapy began with remarkable success especially in chronic phase patients. Today, imatinib is the first-line treatment for CML. However, imatinib does not appear to be capable to eliminate all leukemia cells in the patients and pre-existing as well as acquired resistance to the drug has been increasingly recognized. To overcome these problems, several strategies involving dose escalation, combinations with other agents, and novel Bcr-Abl inhibitors have been developed.Keywords: CML therapy, imatinib, SCT, novel kinase inhibitors

  12. Gamma dosimetry of high doses

    International Nuclear Information System (INIS)

    Martinez C, T.; Galvan G, A.; Canizal, G.

    1991-01-01

    The gamma dosimetry of high doses is problematic in almost all the classic dosemeters either based on the thermoluminescence, electric, chemical properties, etc., because they are saturated to very high dose and they are no longer useful. This work carries out an investigation in the interval of high doses. The solid system of heptahydrate ferrous sulfate, can be used as solid dosemeter of routine for high doses of radiation. The proposed method is simple, cheap and it doesn't require sophisticated spectrophotometers or spectrometers but expensive and not common in some laboratories

  13. Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma.

    Science.gov (United States)

    Reardon, D A; Dresemann, G; Taillibert, S; Campone, M; van den Bent, M; Clement, P; Blomquist, E; Gordower, L; Schultz, H; Raizer, J; Hau, P; Easaw, J; Gil, M; Tonn, J; Gijtenbeek, A; Schlegel, U; Bergstrom, P; Green, S; Weir, A; Nikolova, Z

    2009-12-15

    We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.

  14. 75 FR 76017 - Determination That GLEEVEC (Imatinib Mesylate) Capsules, 50 Milligrams and 100 Milligrams, Were...

    Science.gov (United States)

    2010-12-07

    ... initially approved on May 10, 2001. GLEEVEC is a protein-tyrosine kinase inhibitor used in the treatment of a variety of malignancies, including Ph+ chronic myeloid leukemia and acute lymphoblastic leukemia, myelodysplastic/myeloproliferative diseases, aggressive systemic mastocytosis, hypereosinophilic syndrome, chronic...

  15. Imatinib-induced fulminant liver failure in chronic myeloid leukemia: role of liver transplant and second-generation tyrosine kinase inhibitors: a case report.

    Science.gov (United States)

    Nacif, Lucas Souto; Waisberg, Daniel R; Pinheiro, Rafael Soares; Lima, Fabiana Roberto; Rocha-Santos, Vinicius; Andraus, Wellington; D'Albuquerque, Luiz Carneiro

    2018-03-10

    There is a worldwide problem of acute liver failure and mortality associated with remaining on the waiting for a liver transplant. In this study, we highlight results published in recent years by leading transplant centers in evaluating imatinib-induced acute liver failure in chronic myeloid leukemia and follow-up in liver transplantation. A 36-year-old brown-skinned woman (mixed Brazilian race) diagnosed 1 year earlier with chronic myeloid leukemia was started after delivery of a baby and continued for 6 months with imatinib mesylate (selective inhibitor of Bcr-Abl tyrosine kinase), which induced liver failure. We conducted a literature review using the PubMed database for articles published through September 2017, and we demonstrate a role of liver transplant in this situation for imatinib-induced liver failure. We report previously published results and a successful liver transplant after acute liver failure due to imatinib-induced in chronic myeloid leukemia treatment. We report a case of a successful liver transplant after acute liver failure resulting from imatinib-induced chronic myeloid leukemia treatment. The literature reveals the importance of prompt acute liver failure diagnosis and treatment with liver transplant in selected cases.

  16. Bioequivalence of a single 400-mg dose of imatinib 100-mg oral tablets and a 400-mg tablet in healthy adult Korean volunteers.

    Science.gov (United States)

    Lee, Hae Won; Seong, Sook Jin; Park, Sung Min; Lee, Joomi; Gwon, Mi-Ri; Kim, Hyun-Ju; Lim, Sung Mook; Lim, Mi-Sun; Kim, Woomi; Yang, Dong Heon; Yoon, Young-Ran

    2015-06-01

    Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. A new once-daily 400-mg film-coated tablet of imatinib has been developed by a pharmaceutical company in Korea. The present study was designed to assess and compare the PK parameters, bioavailability, and bioequivalence of the new imatinib 400-mg formulation (test) versus the conventional 100-mg formulation (reference) administered as a single 400-mg dose in healthy adult male volunteers. This randomized, open-label, single-dose, two-way crossover study was conducted in healthy Korean male volunteers. Eligible subjects were randomly assigned in a 1 : 1 ratio to receive 400 mg of the test (one 400-mg tablet) or reference (four 100-mg tablets) formulation, followed by a 2-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours after administration. Plasma imatinib concentrations were determined using liquid chromatography coupled with tandem mass spectrometry. The formulations were to be considered bioequivalent if the 90% confidence intervals (CIs) of the adjusted geometric mean ratios for Cmax, AUC(0-t), and AUC(0-∞)ž were within the predetermined range of 0.80 - 1.25. In total, 35 subjects completed the study. No serious adverse event was reported during the study. The 90% CIs of the adjusted geometric mean ratios of the test formulation to the reference formulation for C(max), AUC(0-t) and AUC(0-∞)ž of imatinib were all within the bioequivalence criteria range of 0.8 - 1.25. The test formulation of imatinib met the Korean regulatory requirements for bioequivalence. Both imatinib formulations were well-tolerated in all subjects.

  17. Imatinib treatment induces CD5+ B lymphocytes and IgM natural antibodies with anti-leukemic reactivity in patients with chronic myelogenous leukemia.

    Directory of Open Access Journals (Sweden)

    Silvia Catellani

    Full Text Available Imatinib mesylate is a first line treatment of Chronic Myelogenous Leukemia and of a rare form of gastrointestinal stromal cancer, where the response to the drug is also linked to the immune system activation with production of antineoplastic cytokines. In this study, forty patients in the chronic phase of disease, treated with imatinib mesylate, were analyzed. Bone marrow aspirates were drawn at diagnosis, after 3, 6, 12, 18 months for haematological, cytofluorimetric, cytogenetic, biomolecular evaluation and cytokine measurement. Responder and non responder patients were defined according to the European LeukemiaNet recommendations. In responder patients (n = 32, the percentage of bone marrow CD20(+CD5(+sIgM(+ lymphocytes, and the plasma levels of IgM, were significantly higher, at 3 months and up to 9 months, than in non responders. These IgM reacted with O-linked sugars expressed by leukemic cells and could induce tumor cell apoptosis. In responder patients the stromal-derived factor-1 and the B-lymphocyte-activating factor of the tumor necrosis factor family significantly raised in the bone marrow after imatinib administration, together with the bone morphogenetic proteins-2 and -7. All patients with high number of CD20(+CD5(+sIgM(+ cells and high stromal-derived factor-1 and B lymphocyte activating factor levels, underwent complete cytogenetic and/or molecular remission by 12 months. We propose that CD20(+CD5(+sIgM(+ lymphocytes producing anti-carbohydrate antibodies with anti-tumor activity, might contribute to the response to imatinib treatment. As in multivariate analysis bone marrow CD20(+CD5(+sIgM(+ cells and stromal-derived factor-1 and B-lymphocyte-activating factor levels were significantly related to cytogenetical and molecular changes, they might contribute to the definition of the pharmacological response.

  18. Quantification of imatinib in human serum: validation of a high-performance liquid chromatography-mass spectrometry method for therapeutic drug monitoring and pharmacokinetic assays.

    Science.gov (United States)

    Rezende, Vinicius Marcondes; Rivellis, Ariane; Novaes, Mafalda Megumi Yoshinaga; de Alencar Fisher Chamone, Dalton; Bendit, Israel

    2013-01-01

    Imatinib mesylate has been a breakthrough treatment for chronic myeloid leukemia. It has become the ideal tyrosine kinase inhibitor and the standard treatment for chronic-phase leukemia. Striking results have recently been reported, but intolerance to imatinib and noncompliance with treatment remain to be solved. Molecular monitoring by quantitative real-time polymerase chain reaction is the gold standard for monitoring patients, and imatinib blood levels have also become an important tool for monitoring. A fast and cheap method was developed and validated using high-performance liquid chromatography-mass spectrometry for quantification of imatinib in human serum and tamsulosin as the internal standard. Remarkable advantages of the method includes use of serum instead of plasma, less time spent on processing and analysis, simpler procedures, and requiring reduced amounts of biological material, solvents, and reagents. Stability of the analyte was also studied. This research also intended to drive the validation scheme in clinical centers. The method was validated according to the requirements of the US Food and Drug Administration and Brazilian National Health Surveillance Agency within the range of 0.500-10.0 μg/mL with a limit of detection of 0.155 μg/mL. Stability data for the analyte are also presented. Given that the validated method has proved to be linear, accurate, precise, and robust, it is suitable for pharmacokinetic assays, such as bioavailability and bioequivalence, and is being successfully applied in routine therapeutic drug monitoring in the hospital service.

  19. Cisplatin and doxorubicin induce distinct mechanisms of ovarian follicle loss; imatinib provides selective protection only against cisplatin.

    Directory of Open Access Journals (Sweden)

    Stephanie Morgan

    Full Text Available Chemotherapy treatment in premenopausal women has been linked to ovarian follicle loss and premature ovarian failure; the exact mechanism by which this occurs is uncertain. Here, two commonly used chemotherapeutic agents (cisplatin and doxorubicin were added to a mouse ovary culture system, to compare the sequence of events that leads to germ cell loss. The ability of imatinib mesylate to protect the ovary against cisplatin or doxorubicin-induced ovarian damage was also examined.Newborn mouse ovaries were cultured for a total of six days, exposed to a chemotherapeutic agent on the second day: this allowed for the examination of the earliest stages of follicle development. Cleaved PARP and TUNEL were used to assess apoptosis following drug treatment. Imatinib was added to cultures with cisplatin and doxorubicin to determine any protective effect.Histological analysis of ovaries treated with cisplatin showed oocyte-specific damage; in comparison doxorubicin preferentially caused damage to the granulosa cells. Cleaved PARP expression significantly increased for cisplatin (16 fold, p<0.001 and doxorubicin (3 fold, p<0.01. TUNEL staining gave little evidence of primordial follicle damage with either drug. Imatinib had a significant protective effect against cisplatin-induced follicle damage (p<0.01 but not against doxorubicin treatment.Cisplatin and doxorubicin both induced ovarian damage, but in a markedly different pattern, with imatinib protecting the ovary against damage by cisplatin but not doxorubicin. Any treatment designed to block the effects of chemotherapeutic agents on the ovary may need to be specific to the drug(s the patient is exposed to.

  20. Distinct Dasatinib-Induced Mechanisms of Apoptotic Response and Exosome Release in Imatinib-Resistant Human Chronic Myeloid Leukemia Cells

    Directory of Open Access Journals (Sweden)

    Juan Liu

    2016-04-01

    Full Text Available Although dasatinib is effective in most imatinib mesylate (IMT-resistant chronic myeloid leukemia (CML patients, the underlying mechanism of its effectiveness in eliminating imatinib-resistant cells is only partially understood. This study investigated the effects of dasatinib on signaling mechanisms driving-resistance in imatinib-resistant CML cell line K562 (K562RIMT. Compared with K562 control cells, exsomal release, the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt/ mammalian target of rapamycin (mTOR signaling and autophagic activity were increased significantly in K562RIMT cells and mTOR-independent beclin-1/Vps34 signaling was shown to be involved in exosomal release in these cells. We found that Notch1 activation-mediated reduction of phosphatase and tensin homolog (PTEN was responsible for the increased Akt/mTOR activities in K562RIMT cells and treatment with Notch1 γ-secretase inhibitor prevented activation of Akt/mTOR. In addition, suppression of mTOR activity by rapamycin decreased the level of activity of p70S6K, induced upregulation of p53 and caspase 3, and led to increase of apoptosis in K562RIMT cells. Inhibition of autophagy by spautin-1 or beclin-1 knockdown decreased exosomal release, but did not affect apoptosis in K562RIMT cells. In summary, in K562RIMT cells dasatinib promoted apoptosis through downregulation of Akt/mTOR activities, while preventing exosomal release and inhibiting autophagy by downregulating expression of beclin-1 and Vps34. Our findings reveal distinct dasatinib-induced mechanisms of apoptotic response and exosomal release in imatinib-resistant CML cells.

  1. Cost-utility analysis of dasatinib and nilotinib in patients with chronic myeloid leukemia refractory to first-line treatment with imatinib in Thailand.

    Science.gov (United States)

    Kulpeng, Wantanee; Sompitak, Sumalai; Jootar, Saengsuree; Chansung, Kanchana; Teerawattananon, Yot

    2014-04-01

    Recently, the second-generation tyrosine kinase inhibitors dasatinib and nilotinib have emerged as alternative treatments in patients with chronic myeloid leukemia (CML) who are resistant to or intolerant of imatinib. This article aimed to assess the cost utility and budget impact of using dasatinib or nilotinib, rather than high-dose (800-mg/d) imatinib, in patients with chronic phase (CP) CML who are resistant to standard-dose (400-mg/d) imatinib in Thailand. A Markov simulation model was developed and used to estimate the lifetime costs and outcomes of treating patients aged ≥38 years with CP-CML. The efficacy parameters were synthesized from a systematic review. Utilities using the European Quality of Life-5 Dimensions tool and costs were obtained from the Thai CML population. Costs and outcomes were compared and presented as the incremental cost-effectiveness ratio in 2011 Thai baht (THB) per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were performed to estimate parameter uncertainty. From a societal perspective, treatment with dasatinib was found to yield more QALYs (2.13) at a lower cost (THB 1,631,331) per person than high-dose imatinib. Nilotinib treatment was also found to be more cost-effective than high-dose imatinib, producing an incremental cost-effectiveness ratio of THB 83,328 per QALY gained. This treatment option also resulted in the highest number of QALYs gained of all of the treatment options. The costs of providing dasatinib, nilotinib, and high-dose imatinib were estimated at THB 5 billion, THB 6 billion, and THB 7 billion, respectively. Treatment with dasatinib or nilotinib is likely to be more cost-effective than treatment with high-dose imatinib in CP-CML patients who do not respond positively to standard-dose imatinib in the Thai context. Dasatinib was found to be more cost-effective than nilotinib. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

  2. Imatinib

    Science.gov (United States)

    ... types of leukemia (cancer that begins in the white blood cells) and other cancers and disorders of ... In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has ...

  3. Quantification of imatinib in human serum: validation of a high-performance liquid chromatography-mass spectrometry method for therapeutic drug monitoring and pharmacokinetic assays

    Directory of Open Access Journals (Sweden)

    Rezende VM

    2013-08-01

    Full Text Available Vinicius Marcondes Rezende,1 Ariane Rivellis,1 Mafalda Megumi Yoshinaga Novaes,1 Dalton de Alencar Fisher Chamone,2 Israel Bendit1,21Laboratory of Tumor Biology, 2Department of Hematology, School of Medicine, University of São Paulo, São Paulo, BrazilBackground: Imatinib mesylate has been a breakthrough treatment for chronic myeloid leukemia. It has become the ideal tyrosine kinase inhibitor and the standard treatment for chronic-phase leukemia. Striking results have recently been reported, but intolerance to imatinib and noncompliance with treatment remain to be solved. Molecular monitoring by quantitative real-time polymerase chain reaction is the gold standard for monitoring patients, and imatinib blood levels have also become an important tool for monitoring.Methods: A fast and cheap method was developed and validated using high-performance liquid chromatography-mass spectrometry for quantification of imatinib in human serum and tamsulosin as the internal standard. Remarkable advantages of the method includes use of serum instead of plasma, less time spent on processing and analysis, simpler procedures, and requiring reduced amounts of biological material, solvents, and reagents. Stability of the analyte was also studied. This research also intended to drive the validation scheme in clinical centers. The method was validated according to the requirements of the US Food and Drug Administration and Brazilian National Health Surveillance Agency within the range of 0.500–10.0 µg/mL with a limit of detection of 0.155 µg/mL. Stability data for the analyte are also presented.Conclusion: Given that the validated method has proved to be linear, accurate, precise, and robust, it is suitable for pharmacokinetic assays, such as bioavailability and bioequivalence, and is being successfully applied in routine therapeutic drug monitoring in the hospital service.Keywords: imatinib, high-performance liquid chromatography-mass spectrometry, therapeutic

  4. Low educational level but not low income impairs the achievement of cytogenetic remission in chronic myeloid leukemia patients treated with imatinib in Brazil

    Directory of Open Access Journals (Sweden)

    Monica Napoleão Fortes Rego

    2015-05-01

    Full Text Available OBJECTIVES: In Brazil, imatinib mesylate is supplied as the first-line therapy for chronic myeloid leukemia in the chronic phase through the public universal healthcare program, Sistema Único de Saúde (SUS. We studied the socio-demographic factors that influenced therapy success in a population in the northeast region of Brazil. METHODS: Patients with chronic myeloid leukemia from the state of Piauí were treated in only one reference center. Diagnosis was based on WHO 2008 criteria. Risk was assessed by Sokal, Hasford and EUTOS scores. Patients received 400 mg imatinib daily. We studied the influence of the following factors on the achievement of complete cytogenetic response within one year of treatment: age, clinical risk category, time interval between diagnosis and the start of imatinib treatment, geographic distance from the patient's home to the hospital, years of formal education and monthly income. RESULTS: Among 103 patients studied, the median age was 42 years; 65% of the patients had 2-9 years of formal education, and the median monthly income was approximately 100 US$. Imatinib was started in the first year after diagnosis (early chronic phase in 69 patients. After 12 months of treatment, 68 patients had a complete cytogenetic response. The Hasford score, delay to start imatinib and years of formal education influenced the attainment of a complete cytogenetic response, whereas income and the distance from the home to the healthcare facility did not. CONCLUSION: Patients require additional healthcare information to better understand the importance of long-term oral anticancer treatment and to improve their compliance with the treatment.

  5. Compound list: imatinib, methanesulfonate salt [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available imatinib, methanesulfonate salt IMA 00186 ftp://ftp.biosciencedbc.jp/archive/open-t...ggates/LATEST/Rat/in_vivo/Liver/Single/imatinib%2C_methanesulfonate_salt.Rat.in_vivo.Liver.Single.zip ...

  6. Evaluation of different substrates for inkjet printing of rasagiline mesylate

    DEFF Research Database (Denmark)

    Genina, Natalja; Janßen, Eva Maria; Breitenbach, Armin

    2013-01-01

    The main goal of the present study was to evaluate applicability of the different model substrates, namely orodispersible films (ODFs), porous copy paper sheets, and water impermeable transparency films (TFs) in preparation of the inkjet-printed drug-delivery systems. Rasagiline mesylate (RM...

  7. Profile of imatinib in pediatric leukemia

    Directory of Open Access Journals (Sweden)

    Burke MJ

    2014-02-01

    Full Text Available Michael J BurkeDepartment of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI, USAAbstract: Using targeted therapy for treatment of cancer has become the paradigm to which clinical trials aspire. Imatinib, the BCR-ABL1 tyrosine kinase inhibitor (TKI, was the first of its kind to specifically target and inhibit the underlying Philadelphia chromosome (Ph+ oncogene found to be driving chronic myeloid leukemia in adults, and has since become standard of care for the treatment of chronic myeloid leukemia in children. Imatinib, with its ability to target Ph+ leukemia, has been successfully incorporated into the treatment of not only pediatric chronic myeloid leukemia but also Ph+ acute lymphoblastic leukemia. With the incorporation of imatinib into combination chemotherapy for pediatric Ph+ acute lymphoblastic leukemia, current survival rates are far higher than at any other time for this once dreadful disease. With more children today receiving treatment with imatinib for either chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia, knowledge is accumulating surrounding the short-term and long-term toxicities observed in children, adolescents, and young adults treated with this TKI. In summary, the TKI imatinib has made a historic impact in the treatment of pediatric Ph+ leukemias, transforming what were once very high-risk diseases with considerable morbidity and mortality into ones that are now very treatable but with a new awareness surrounding the long-term toxicities that may come with this price for cure.Keywords: imatinib, leukemia, lymphoblastic leukemia, chronic myeloid leukemia, pediatric

  8. Safety pharmacology of sibutramine mesylate, an anti-obesity drug.

    Science.gov (United States)

    Kim, Eun-Joo; Park, Eun-Kyung; Suh, Kwee-Hyun

    2005-03-01

    Sibutramine mesylate is a new anti-obesity drug. It is a crystalline salt of sibutramine developed to improve the solubility of sibutramine hydrochloride. Methanesulfonic acid was used as a salt-forming acid instead of hydrochloric acid, resulting in a greatly improved solubility of 1000 mg/mL in water. Sibutramine mesylate was administered orally to ICR mice, Sprague-Dawley rats, and beagle dogs at dose levels of 1.15, 3.45, and 11.50 mg/kg to measure its effects on the central nervous system (CNS), general behaviour, cardiovascular-respiratory system and the other organ systems. Following administration of sibutramine mesylate, spontaneous locomotor activity was significantly increased from 120 min to 24 hours at 3.45 mg/kg and from 30 min to 24 hours at 11.50 mg/kg. Furthermore, there were a decrease in hexobarbital-induced sleep time, an increase in respiratory rate at 120 min, increases in intestinal transport capacity and gastric pH at 11.50 mg/kg, and decreases in gastric volume and total acidity at 3.45 and 11.50 mg/kg. However sibutramine mesylate caused no effects on general behaviour, motor coordination, body temperature, analgesia, convulsion, blood pressure, heart rate, electrocardiogram, cardiac functions of the isolated rat heart, isolated smooth muscles and renal function. Based on the above results, it was concluded that sibutramine mesylate caused effects on the spontaneous locomotor activity, hexobarbital-induced sleep time, respiration, gastrointestinal transport, and gastric secretion at a dose level of 3.45 mg/kg or greater but caused no effects on other general pharmacological reactions.

  9. Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib.

    Science.gov (United States)

    Swords, Ronan; Mahalingam, Devalingam; Padmanabhan, Swaminathan; Carew, Jennifer; Giles, Francis

    2009-09-21

    Chronic myeloid leukemia (CML) is the consequence of a single balanced translocation that produces the BCR-ABL fusion oncogene which is detectable in over 90% of patients at presentation. The BCR-ABL inhibitor imatinib mesylate (IM) has improved survival in all phases of CML and is the standard of care for newly diagnosed patients in chronic phase. Despite the very significant therapeutic benefits of IM, a small minority of patients with early stage disease do not benefit optimally while IM therapy in patients with advanced disease is of modest benefit in many. Diverse mechanisms may be responsible for IM failures, with point mutations within the Bcr-Abl kinase domain being amongst the most common resistance mechanisms described in patients with advanced CML. The development of novel agents designed to overcome IM resistance, while still primarily targeted on BCR-ABL, led to the creation of the high affinity aminopyrimidine inhibitor, nilotinib. Nilotinib is much more potent as a BCR-ABL inhibitor than IM and inhibits both wild type and IM-resistant BCR-ABL with significant clinical activity across the entire spectrum of BCR-ABL mutants with the exception of T315I. The selection of a second generation tyrosine kinase inhibitor to rescue patients with imatinib failure will be based on several factors including age, co-morbid medical problems and ABL kinase mutational profile. It should be noted that while the use of targeted BCR-ABL kinase inhibitors in CML represents a paradigm shift in CML management these agents are not likely to have activity against the quiescent CML stem cell pool. The purpose of this review is to summarize the pre-clinical and clinical data on nilotinib in patients with CML who have failed prior therapy with IM or dasatinib.

  10. Behandling af ideopatisk hypereosinofilt syndrom med imatinib

    DEFF Research Database (Denmark)

    Sørensen, Anne Louise; Larsen, Herdis

    2008-01-01

    We here report a case of idiopathic hypereosinophilic syndrome with prompt response to treatment with imatinib. The patient presented with chest pain, myalgias, fatigue and weakness. Blood tests and bone marrow examination revealed striking eosinophilia. Clonal or reactive disorders were excluded...

  11. Nilotinib: optimal therapy for patients with chronic myeloid leukemia and resistance or intolerance to imatinib

    Directory of Open Access Journals (Sweden)

    Ronan Swords

    2009-03-01

    Full Text Available Ronan Swords, Devalingam Mahalingam, Swaminathan Padmanabhan, Jennifer Carew, Francis GilesInstitute for Drug Development, Cancer Therapy and Research Centre, University of Texas Health Science Centre at San Antonio, USAAbstract: Chronic myeloid leukemia (CML is the consequence of a single balanced translocation that produces the BCR-ABL fusion oncogene which is detectable in over 90% of patients at presentation. The BCR-ABL inhibitor imatinib mesylate (IM has improved survival in all phases of CML and is the standard of care for newly diagnosed patients in chronic phase. Despite the very significant therapeutic benefits of IM, a small minority of patients with early stage disease do not benefit optimally while IM therapy in patients with advanced disease is of modest benefit in many. Diverse mechanisms may be responsible for IM failures, with point mutations within the Bcr-Abl kinase domain being amongst the most common resistance mechanisms described in patients with advanced CML. The development of novel agents designed to overcome IM resistance, while still primarily targeted on BCR-ABL, led to the creation of the high affinity aminopyrimidine inhibitor, nilotinib. Nilotinib is much more potent as a BCR-ABL inhibitor than IM and inhibits both wild type and IM-resistant BCR-ABL with significant clinical activity across the entire spectrum of BCR-ABL mutants with the exception of T315I. The selection of a second generation tyrosine kinase inhibitor to rescue patients with imatinib failure will be based on several factors including age, co-morbid medical problems and ABL kinase mutational profile. It should be noted that while the use of targeted BCR-ABL kinase inhibitors in CML represents a paradigm shift in CML management these agents are not likely to have activity against the quiescent CML stem cell pool. The purpose of this review is to summarize the pre-clinical and clinical data on nilotinib in patients with CML who have failed prior

  12. Effect of STI-571 (imatinib mesylate) in combination with retinoic acid and γ-irradiation on viability of neuroblastoma cells

    International Nuclear Information System (INIS)

    Roessler, Jochen; Zambrzycka, Izabella; Lagodny, Jeanette; Kontny, Udo; Niemeyer, Charlotte Marie

    2006-01-01

    Neuroblastoma (NB) expresses the tyrosine kinase receptors c-Kit, PDGFR-α and -β-targets for STI-571.We investigated a possible combination therapy of STI-571 with retinoic acid (RA) and γ-irradiation on NB cell viability in vitro. Expression of tyrosine kinase receptors and their ligands was examined in 6 NB cell lines by RT-PCR and FACS. The effect on cell viability was determined by MTT assay. Cell viability of all 6 NB cell lines was significantly inhibited after treatment with 20 μM STI-571 for 72 h, two cell lines responding already to 10 μM. Cell lines responded irrespective of their mRNA status or cell surface expression of c-Kit, PDGFR-α and -β. Co-incubation with 9-cis RA sensitized cells to the inhibitory effects of STI-571. However, pre-treatment with 9-cis RA resulted in resistance of NB cell lines to STI-571 and γ-irradiation. Treatment of NB with STI-571 in combination with 9-cis RA might be a therapeutic strategy for patients in consolidation therapy who have completed γ-irradiation therapy

  13. Imatinib Mesylate in Treating Patients With Progressive, Refractory, or Recurrent Stage II or Stage III Testicular or Ovarian Cancer

    Science.gov (United States)

    2013-01-15

    Ovarian Dysgerminoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Ovarian Germ Cell Tumor; Stage II Malignant Testicular Germ Cell Tumor; Stage II Ovarian Germ Cell Tumor; Stage III Malignant Testicular Germ Cell Tumor; Stage III Ovarian Germ Cell Tumor; Testicular Seminoma

  14. Concomitant chemoradiotherapy with high dose rate brachytherapy ...

    African Journals Online (AJOL)

    Concomitant chemoradiotherapy with high dose rate brachytherapy as a definitive treatment modality for locally advanced cervical cancer. T Refaat, A Elsaid, N Lotfy, K Kiel, W Small Jr, P Nickers, E Lartigau ...

  15. Fiber optics in high dose radiation fields

    International Nuclear Information System (INIS)

    Partin, J.K.

    1985-01-01

    A review of the behavior of state-of-the-art optical fiber waveguides in high dose (greater than or equal to 10 5 rad), steady state radiation fields is presented. The influence on radiation-induced transmission loss due to experimental parameters such as dose rate, total dose, irradiation history, temperature, wavelength, and light intensity, for future work in high dose environments are given

  16. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Saglio, Giuseppe; Kim, Dong-Wook; Issaragrisil, Surapol

    2010-01-01

    Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.......Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase....

  17. Progress in high-dose radiation dosimetry

    International Nuclear Information System (INIS)

    Ettinger, K.V.; Nam, J.W.; McLaughlin, W.L.; Chadwick, K.H.

    1981-01-01

    The last decade has witnessed a deluge of new high-dose dosimetry techniques and expanded applications of methods developed earlier. Many of the principal systems are calibrated by means of calorimetry, although production of heat is not always the final radiation effect of interest. Reference systems also include a number of chemical dose meters: ferrous sulphate, ferrous-cupric sulphate, and ceric sulphate acidic aqueous solutions. Requirements for stable and reliable transfer dose meters have led to further developments of several important high-dose systems: amino acids and saccharides analysed by ESR or lyoluminescence, thermoluminescent materials, radiochromic dyes and plastics, ceric-cerous solutions analysed by potentiometry, and ethanol-chlorobenzene solutions analysed by high-frequency oscillometry. A number of other prospective dose meters are also treated in this review. In addition, an IAEA programme of high-dose standardization and intercomparison for industrial radiation processing is described. (author)

  18. Pd-Catalyzed Cross-Coupling Reactions of Amides and Aryl Mesylates

    Science.gov (United States)

    Dooleweerdt, Karin; Fors, Brett P.; Buchwald, Stephen L.

    2010-01-01

    A catalyst, based on a biarylphosphine ligand, for the Pd-catalyzed cross-coupling reactions of amides and aryl mesylates is described. This system allows an array of aryl and heteroaryl mesylates to be transformed into the corresponding N-arylamides in moderate to excellent yields. PMID:20420379

  19. Intracranial meningiomas after high-dose irradiation

    International Nuclear Information System (INIS)

    Soffer, D.; Gomori, J.M.; Siegal, T.; Shalit, M.N.

    1989-01-01

    Three patients who presented with intracranial meningiomas 12, 15, and 20 years, respectively, after therapeutic high-dose irradiation of a primary brain tumor are described. Analysis of these cases and similar documented cases suggests that meningiomas after high-dose irradiation constitute a recognizable entity. Patients with such tumors received radiation therapy at a young age (mean age, 9.4 years). After a latent period of 2 to 47 years (mean, 19.8 years) they developed meningiomas at the site of irradiation, at a much younger age than patients with ''spontaneous'' meningiomas. Similar to the situation with meningiomas after low-dose irradiation, a relatively high proportion of meningiomas induced by high-dose irradiation tend to be malignant and biologically aggressive. A very young age at the time of irradiation seems to predispose to the induction of malignant meningiomas, rather than benign tumors. These unusual features provide indirect evidence that high-dose radiation may play a role in the pathogenesis of meningiomas.41 references

  20. Endorectal high dose rate brachytherapy quality assurance

    International Nuclear Information System (INIS)

    Devic, S.; Vuong, T.; Evans, M.; Podgorsak, E.

    2008-01-01

    We describe our quality assurance method for preoperative high dose rate (HDR) brachytherapy of endorectal tumours. Reproduction of the treatment planning dose distribution on a daily basis is crucial for treatment success. Due to the cylindrical symmetry, two types of adjustments are necessary: applicator rotation and dose distribution shift along the applicator axis. (author)

  1. Tirilazad mesylate protects stored erythrocytes against osmotic fragility.

    Science.gov (United States)

    Epps, D E; Knechtel, T J; Bacznskyj, O; Decker, D; Guido, D M; Buxser, S E; Mathews, W R; Buffenbarger, S L; Lutzke, B S; McCall, J M

    1994-12-01

    The hypoosmotic lysis curve of freshly collected human erythrocytes is consistent with a single Gaussian error function with a mean of 46.5 +/- 0.25 mM NaCl and a standard deviation of 5.0 +/- 0.4 mM NaCl. After extended storage of RBCs under standard blood bank conditions the lysis curve conforms to the sum of two error functions instead of a possible shift in the mean and a broadening of a single error function. Thus, two distinct sub-populations with different fragilities are present instead of a single, broadly distributed population. One population is identical to the freshly collected erythrocytes, whereas the other population consists of osmotically fragile cells. The rate of generation of the new, osmotically fragile, population of cells was used to probe the hypothesis that lipid peroxidation is responsible for the induction of membrane fragility. If it is so, then the antioxidant, tirilazad mesylate (U-74,006f), should protect against this degradation of stored erythrocytes. We found that tirilazad mesylate, at 17 microM (1.5 mol% with respect to membrane lecithin), retards significantly the formation of the osmotically fragile RBCs. Concomitantly, the concentration of free hemoglobin which accumulates during storage is markedly reduced by the drug. Since the presence of the drug also decreases the amount of F2-isoprostanes formed during the storage period, an antioxidant mechanism must be operative. These results demonstrate that tirilazad mesylate significantly decreases the number of fragile erythrocytes formed during storage in the blood bank.

  2. Dasatinib in the treatment of imatinib refractory chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Radhakrishnan Ramchandren

    2009-05-01

    Full Text Available Radhakrishnan Ramchandren, Charles A SchifferDivision of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USAAbstract: The development of imatinib for the treatment of chronic myeloid leukemia (CML has proven to be an example of medical success in the era of targeted therapy. However, imatinib resistance or intolerance occurs in a substantial number of patients. Additionally, patients who have progressed beyond the chronic phase of CML do relatively poorly with imatinib therapy. Mechanisms of imatinib resistance include BCR-ABL point mutations resulting in decreased imatinib binding, as well as mutation-independent causes of resistance such as SRC family kinase dysregulation, BCR-ABL gene amplification, drug influx/efflux mechanisms and other poorly understood processes. The options for therapy in these patients include stem cell transplantation, imatinib dose escalation as well as the use of second-generation tyrosine kinase inhibitors. Dasatinib is a second-generation multi-kinase inhibitor with several theoretical and mechanistic advantages over imatinib. Moreover, several studies have evaluated dasatinib in patients who have progressed on imatinib therapy with encouraging results. Other novel agents such as mTOR inhibitors, bosutinib and INNO 406 have also shown promise in this setting. Although treatment options have increased, the choice of second-line therapy in patients with CML is influenced by concerns surrounding the duration of response as well as toxicity. Consequently, there is no agreed upon optimal second-line agent. This paper reviews the current data and attempts to address these issues. Keywords: chronic myeloid leukemia (CML, dasatinib, imatinib, resistance (imatinib resistance, nilotinib, tyrosine kinase inhibitor

  3. High-dose irradiation of food

    International Nuclear Information System (INIS)

    Diehl, J.F.

    1999-01-01

    Studies performed on behalf of the International Project on Food Irradiation in the period from 1971 until 1980 resulted in the concluding statement that ''.the irradiation of any food commodity up to an overall average dose of 10 kGy presents no toxicological hazard; hence, toxicological testing of foods so treated is no longer required.'' Since then, licenses for food irradiation have been restricted to this maximum dose in any country applying this technology. Further testing programmes have been carried out investigating the wholesomeness or hazards of high-dose irradiation, but there has been little demand so far by the food industry for licensing of high-dose irradiation, as there is only a small range of products whose irradiation at higher doses offers advantages for given, intended use. These include eg. spices, dried herbs, meat products in flexible pouch packagings for astronauts, or patients with immune deficiencies. (orig./CB) [de

  4. High-dose erythropoietin for tissue protection

    DEFF Research Database (Denmark)

    Lund, Anton; Lundby, Carsten; Olsen, Niels Vidiendal

    2014-01-01

    BACKGROUND: The discovery of potential anti-apoptotic and cytoprotective effects of recombinant human erythropoietin (rHuEPO) has led to clinical trials investigating the use of high-dose, short-term rHuEPO therapy for tissue protection in conditions such as stroke and myocardial infarction....... Experimental studies have been favourable, but the clinical efficacy has yet to be validated. MATERIALS AND METHODS: We have reviewed clinical studies regarding the use of high-dose, short-term rHuEPO therapy for tissue protection in humans with the purpose to detail the safety and efficacy of r...... no effect of rHuEPO therapy on measures of tissue protection. Five trials including 1025 patients reported safety concerns in the form of increased mortality or adverse event rates. No studies reported reduced mortality. CONCLUSIONS: Evidence is sparse to support a tissue-protective benefit of r...

  5. Studies on the toxic effects of periodontal sustained release drug containing ornidazole and pefloxacin mesylate on early embryonic development of SD rat

    Directory of Open Access Journals (Sweden)

    Zheng-mou DONG

    2011-01-01

    Full Text Available Objective To evaluate the toxic effects of periodontal sustained release drug containing ornidazole and pefloxacin mesylate on early embryonic development of SD rats.Methods A total of 100female SD rats were randomly divided into negative control,low-,medium-,high-dose group and intervention group(20each.Rats in low-,medium-and high-dose group were fed daily with the sustained release drug at 1,4,and 8g/kg respectively;those in negative control group were fed daily with distilled water from the 14th day before mating to the 7th day of pregnancy continuously,and those in intervention group received cyclophosphamide(40mg/kgby intraperitoneal injection for 5successive days.During this period,the general status,mating,pregnancy,coefficient of ovary and uterus,the numbers of corpus luteum,nidation,live births,stillbirths,absorbed embryo,prenidatory and postnidatory mortality,serum testosterone(Tand estradiol(E2were determined respectively.Histopathologic examination of the ovary and uterus,immunohistochemical observation of ovaries for proliferating cell nuclear antigen(PCNAand Bcl-2associated X protein(Baxwere also performed respectively.Results The general status of those rats was good except one in the low-dose group and one in the intervention group died on the 14th day of administration,and one in negative control and one in high dose group died on the 5th day of pregnancy,respectively.The body weight of animals decreased significantly(P 0.05.The serum T level in medium-and high-dose group and the E2level in high-dose group declined compared to that in negative control group(P < 0.05.Conclusions Although the periodontal sustained release drug containing ornidazole and pefloxacin mesylate shows no toxicity to the early embryonic development of SD rats,the high dose drug has certain toxicity to ovary.Declined serum concentrations of T and E2,reduced expression of PCNA,and increased Bax may be the causes of the toxicity.

  6. Imatinib-induced pleural effusion: A case report

    Directory of Open Access Journals (Sweden)

    R Banka

    2017-01-01

    Full Text Available Imatinib is a tyrosine kinase inhibitor and has rarely been reported to cause pleural effusion. We report the case of an 88-year-old male, known case of gastrointestinal stromal tumor on treatment with imatinib, who presented with a 2-week history of cough and dyspnea. He was diagnosed to have a right-sided pleural effusion and thoracentesis of the fluid revealed an exudate with low adenosine deaminase and negative cytology. Withdrawal of the drug lead to resolution of symptoms. We report this case to highlight the side effect profile of imatinib and warn physicians regarding this potential adverse effect which may be mistaken for metastasis or infection.

  7. Imatinib-loaded polyelectrolyte microcapsules for sustained targeting of BCR-ABL+ leukemia stem cells.

    Science.gov (United States)

    Palamà, Ilaria E; Leporatti, Stefano; de Luca, Emanuela; Di Renzo, Nicola; Maffia, Michele; Gambacorti-Passerini, Carlo; Rinaldi, Ross; Gigli, Giuseppe; Cingolani, Roberto; Coluccia, Addolorata M L

    2010-04-01

    The lack of sensitivity of chronic myeloid leukemia (CML) stem cells to imatinib mesylate (IM) commonly leads to drug dose escalation or early disease relapses when therapy is stopped. Here, we report that packaging of IM into a biodegradable carrier based on polyelectrolyte microcapsules increases drug retention and antitumor activity in CML stem cells, also improving the ex vivo purging of malignant progenitors from patient autografts. Microparticles/capsules were obtained by layer-by-layer (LbL) self-assembly of oppositely charged polyelectrolyte multilayers on removable calcium carbonate (CaCO(3)) templates and loaded with or without IM. A leukemic cell line (KU812) and CD34(+) cells freshly isolated from healthy donors or CML patients were tested. Polyelectrolyte microcapsules (PMCs) with an average diameter of 3 microm, fluorescently labelled multilayers sensitive to the action of intracellular proteases and 95-99% encapsulation efficiency of IM, were prepared. Cell uptake efficiency of such biodegradable carriers was quantified in KU812, leukemic and normal CD34(+) stem cells (range: 70-85%), and empty PMCs did not impact cell viability. IM-loaded PMCs selectively targeted CML cells, by promoting apoptosis at doses that exert only cytostatic effects by IM alone. More importantly, residual CML cells from patient leukapheresis products were reduced or eliminated more efficiently by using IM-loaded PMCs compared with freely soluble IM, with a purging efficiency of several logs. No adverse effects on normal CD34(+) stem-cell survival and their clonogenic potential was noticed in long-term cultures of hematopoietic progenitors in vitro. This pilot study provides the proof-of-principle for the clinical application of biodegradable IM-loaded PMC as feasible, safe and effective ex vivo purging agents to target CML stem cells, in order to improve transplant outcome of resistant/relapsed patients or reduce IM dose escalation.

  8. High dose rate endobronchial brachytherapy - treatment technique

    International Nuclear Information System (INIS)

    Carvalho, Heloisa de Andrade; Aisen, Salim; Haddad, Cecilia Maria Kalil; Nadalin, Wladimir; Pedreira Junior, Wilson Leite; Chavantes, Maria Cristina

    1998-01-01

    High dose rate endobronchial brachytherapy is efficient in symptom relief due to obstructive endobronchial malignancies. However, it's role in survival improvement for patients with lung cancer is not yet established. The use of this treatment in increasing, specially in the developing countries. The purpose of this paper is to present the treatment technique used in the Radiotherapy Department of the Hospital da Clinicas, University of Sao Paulo, based on an experience of 60 cases treated with 180 procedures. Some practical suggestions and rules adopted in the Department are described. The severe complications rate is 6.7%, demonstrating an adequate patient selection associated with the technique utilized. (author)

  9. Neuroprotective potential of high-dose biotin.

    Science.gov (United States)

    McCarty, Mark F; DiNicolantonio, James J

    2017-11-01

    A recent controlled trial has established that high-dose biotin supplementation - 100 mg, three times daily - has a stabilizing effect on progression of multiple sclerosis (MS). Although this effect has been attributed to an optimization of biotin's essential cofactor role in the brain, a case can be made that direct stimulation of soluble guanylate cyclase (sGC) by pharmacological concentrations of biotin plays a key role in this regard. The utility of high-dose biotin in MS might reflect an anti-inflammatory effect of cGMP on the cerebral microvasculature, as well on oligodendrocyte differentiation and on Schwann cell production of neurotrophic factors thought to have potential for managing MS. But biotin's ability to boost cGMP synthesis in the brain may have broader neuroprotective potential. In many types of neurons and neural cells, cGMP exerts neurotrophic-mimetic effects - entailing activation of the PI3K-Akt and Ras-ERK pathways - that promote neuron survival and plasticity. Hippocampal long term potentiation requires nitric oxide synthesis, which in turn promotes an activating phosphorylation of CREB via a pathway involving cGMP and protein kinase G (PKG). In Alzheimer's disease (AD), amyloid beta suppresses this mechanism by inhibiting sGC activity; agents which exert a countervailing effect by boosting cGMP levels tend to restore effective long-term potentiation in rodent models of AD. Moreover, NO/cGMP suppresses amyloid beta production within the brain by inhibiting expression of amyloid precursor protein and BACE1. In conjunction with cGMP's ability to oppose neuron apoptosis, these effects suggest that high-dose biotin might have potential for the prevention and management of AD. cGMP also promotes neurogenesis, and may lessen stroke risk by impeding atherogenesis and hypertrophic remodeling in the cerebral vasculature. The neuroprotective potential of high-dose biotin likely could be boosted by concurrent administration of brain

  10. Imatinib en leucemia mieloide crónica Imatinib in chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Valia Pavón Morán

    2005-12-01

    Full Text Available La leucemia mieloide crónica (LMC fue la primera neoplasia en la que se pudo presentar un modelo de genotipo que sirviera de blanco a una terapia de acción molecular. La activación de múltiples vías de señales de transducción en las células con el gen BCR- ABL favorece el incremento de la proliferación celular, interfiere en la apoptosis y perturba la interacción con la matriz extracelular y el estroma. La introducción del Imatinib en el tratamiento de la LMC ha modificado la evolución y pronóstico de la enfermedad. Cuando se compara con los regímenes basados en interferón e hidroxiurea, el imatinib ha demostrado un alto nivel de eficacia asociado con un número menor de reacciones adversasChronic myeloid leukemia (CML was the first neoplasia in which it was possible to present a model of genotype that served as a target for a molecular action therapy. The activation of multiple ways of transduction signals in the cells with the BCR-ABL gene favors the increase of the cellular proliferation, interferes the apoptosis, and perturbs the interaction with the extracellular matrix and the stroma. The introduction of Imatinib in the treatment of CML has modified the evolution and prognosis of this disease. Imatinib has proved to have a high level of efficiency associated with a smaller number of adverse reactions on being compared with the regimens based on interferon and hydroxyurea

  11. Immune reactivity after high-dose irradiation

    International Nuclear Information System (INIS)

    Gassmann, W.; Wottge, H.U.; von Kolzynski, M.; Mueller-Ruchholtz, W.

    1986-01-01

    Immune reactivity after total-body irradiation was investigated in rats using skin graft rejection as the indicator system. After sublethal irradiation with 10.5 Gy (approximately 50% lethality/6 weeks) the rejection of major histocompatibility complex allogeneic skin grafts was delayed significantly compared with nonirradiated control animals (28 versus 6.5 days). In contrast, skin grafts were rejected after 7.5 days in sublethally irradiated animals and 7 days in lethally irradiated animals if additional skin donor type alloantigens--namely, irradiated bone marrow cells--were given i.v. either simultaneously or with a delay of not more than 24 hr after the above conditioning regimen. These reactions were alloantigen-specific. They were observed in six different strain combinations with varying donors and recipients. Starting on day 2 after irradiation, i.v. injection of bone marrow gradually lost its effectivity and skin grafts were no longer rejected with uniform rapidity; skin donor marrow given on days 4 or 8 did not accelerate skin graft rejection at all. These data show that for approximately 1-2 days after high-dose total-body irradiation rats are still capable of starting a vigorous immune reaction against i.v.-injected alloantigens. The phenomenon of impaired rejection of skin grafted immediately after high-dose irradiation appears to result from the poor accessibility of skin graft alloantigens during the early postirradiation phase when vascularization of the grafted skin is insufficient

  12. High-dose vitamin C and cancer

    Directory of Open Access Journals (Sweden)

    Ahmet Unlu, M.D.

    2016-01-01

    Full Text Available Vitamin C (ascorbic acid, ascorbate is a basic compound that is of great importance with its role in various enzymatic reactions including the synthesis of collagen, as well as with its redox functions. Vitamin C has become the center of interest in cancer studies, in consequence of the facts that connective tissue changes and vitamin C deficiency were first alleged to be associated with cancer in the 1950s; and that high doses of vitamin C was asserted to be cytotoxic for cancer cells, later on. The results of the first study carried out in the 1970s were promising; but afterwards, the studies were ascertained to be faulty. Despite the positive results achieved from some laboratory and animal experiments, randomized clinical trials did not verify those findings, and no clear benefit of vitamin C for cancer treatment could be demonstrated. As for studies, where its use in combination with other cancer treatment regimens was assessed, conflicting results were obtained. Although intake of high doses of vitamin C is alleged to be harmless, based on that it is in the group of water soluble vitamins and is not stored in the body, there are many side effects and drug interactions reported in the literature. For now, it is better to abstain from this treatment, until the benefit of the treatment (if any is clearly demonstrated, considering the potential side effects and interactions.

  13. Phentolamine mesylate: It′s role as a reversal agent for unwarranted prolonged local analgesia

    Directory of Open Access Journals (Sweden)

    Harpreet Singh Grover

    2015-01-01

    Full Text Available Administration of local anesthesia is an integral procedure prior to dental treatments to minimize the associated pain. It is learned that its effect stays more than the time required for the dental procedure to be completed. This prolonged soft tissue anesthesia (STA can be detrimental, inconvenient, and unnecessary. Phentolamine mesylate, a Food and Drug Administration-approved drug essentially serves the purpose of faster recovery from numbness at the site of local anesthesia. This article reviews the development of the drug phentolamine mesylate and its indication as a local anesthetic reversal agent. A literature search for phentolamine mesylate as a STA reversal agent was conducted in PubMed using the terms "dental local anesthesia reversal, phentolamine mesylate" up to March 2014. The search was limited to articles published in English. The search revealed 13 PubMed indexed articles stating the development and application of phentolamine mesylate. Phentolamine mesylate is an important step in the progress of developing patient care as well as an aid to the dental clinician.

  14. NIST high-dose calibration services

    International Nuclear Information System (INIS)

    Humphreys, J.C.

    1989-01-01

    There is a need for the standardization of high-dose measurements used in the radiation-processing industry in order to provide assured traceability to national standards. NIST provides dosimetry calibration services to this industry. One of these services involves administration of known absorbed doses of gamma rays to customer-supplied dosimeters. The dosimeters are packaged to provide electron equilibrium conditions and are irradiated in a standard 60 Co calibration facility; this provides a calibration of that batch of dosimeters. Another service consists of supplying to a customer calibrated transfer dosimeters for irradiation with the customer's radiation source. The irradiated transfer dosimeters are then returned to NIST for analysis; the results are reported to the customer, providing a calibration of the dose rate of the customer's source. (orig.)

  15. Onyx as radiation detector for high doses

    International Nuclear Information System (INIS)

    Teixeira, Maria Inês; Souza, Divanizia N.; Caldas, Linda V.E.

    2011-01-01

    A study of the thermoluminescent (TL) characteristics of white, black and stripped onyx samples is reported in this work. Onyx is a variety of chalcedony, a form of quartz. The onyx stone is considered nobler than marble. The irradiations were performed using a Gamma-Cell 220 system ( 60 Co). The TL emission curves presented two peaks around 150 °C and 210 °C for all samples. The dose–response curves showed a sublinear behavior between 0.5 Gy and 5 kGy, and the lower detection limit for the white onyx pellets was 1.5 mGy. The main dosimetric characteristics were studied, and the material showed good performance for high dose dosimetry.

  16. Nonlinear model of high-dose implantation

    International Nuclear Information System (INIS)

    Danilyuk, A.

    2001-01-01

    The models of high-dose implantation, using the distribution functions, are relatively simple. However, they must take into account the variation of the function of distribution of the implanted ions with increasing dose [1-4]. This variation takes place owing to the fact that the increase of the concentration of the implanted ions results in a change of the properties of the target. High-dose implantation is accompanied by sputtering, volume growth, diffusion, generation of defects, formation of new phases, etc. The variation of the distribution function is determined by many factors and is not known in advance. The variation within the framework of these models [1-4] is taken into account in advance by the introduction of intuitive assumptions on the basis of implicit considerations. Therefore, these attempts should be regarded as incorrect. The model prepared here makes it possible to take into account the sputtering of the target, volume growth and additional declaration on the implanted ions. Without any assumptions in relation to the variation of the distribution function with increasing dose. In our model it is assumed that the type of distribution function for small doses in a pure target substance is the same as in substances with implanted ions. A second assumption relates to the type of the distribution function valid for small doses in the given substances. These functions are determined as a result of a large number of theoretical and experimental investigations and are well-known at the present time. They include the symmetric and nonsymmetric Gauss distribution, the Pearson distribution, and others. We examine implantation with small doses of up to 10 14 - 10 15 cm -2 when the accurately known distribution is valid

  17. Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib: A novel strategy with potent efficacy in experimental liver fibrosis.

    Science.gov (United States)

    El-Mezayen, Nesrine S; El-Hadidy, Wessam F; El-Refaie, Wessam M; Shalaby, Th I; Khattab, Mahmoud M; El-Khatib, Aiman S

    2017-11-28

    Liver fibrosis is a global health problem without approved treatment. Imatinib inhibits two key profibrotic pathways; platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) and thus can be used to treat liver fibrosis. However, conventional imatinib therapy is hampered by low concentration at target tissue and increased toxicity to other tissues especially heart, lung and liver. Since hepatic stellate cells (HSCs) are the main contributors to liver fibrosis pathogenesis and sole hepatic vitamin A (V A ) storage cells, they can be actively targeted by coupling liposomes to V A . In this study, novel V A -coupled imatinib-loaded liposomes (ILC) were prepared and optimized regarding V A -coupling efficiency, imatinib entrapment efficiency, and particle size. Preferential accumulation of the selected formula in liver was proved by tracing intraperitoneally (i.p.)-injected V A -coupled liposomes loaded with Nile Red (LCNR) to rats with CCl 4 -induced liver fibrosis using live animal imaging. Co-localization of LCNR with immunofluorescently-labeled PDGFR-β in frozen liver tissue sections confirmed HSCs targeting. ILC bio-distribution, following single i.p. injection, revealed 13.5 folds higher hepatic accumulation than conventional imatinib in addition to limited bio-distribution to other organs including heart and lung reflecting diminished adverse effects. ILC therapy resulted in a potent inhibition of phosphorylated PDGFR-β expression when compared to conventional imatinib. Subsequently, there was a statistically significant improvement in liver function tests and reversal of hepatotoxicity along with liver fibrosis. Anti-fibrotic effect was evident from histopathologic Ishak score reduction as well as normalization of the level of profibrotic mediators (hydroxyproline, TGF-B and matrix metalloproteinase-2). Thus, HSC-targeted imatinib therapy shows outstanding anti-fibrotic effects with reduced cytotoxicity compared to conventional

  18. Sequential Use of Second-Generation Tyrosine Kinase Inhibitor Treatment and Intensive Chemotherapy Induced Long-Term Complete Molecular Response in Imatinib-Resistant CML Patient Presenting as a Myeloid Blast Crisis

    Directory of Open Access Journals (Sweden)

    Masaaki Tsuji

    2017-01-01

    Full Text Available Myeloid blast crisis of chronic myeloid leukemia (CML-MBC is rarely seen at presentation and has a poor prognosis. There is no standard therapy for CML-MBC. It is often difficult to distinguish CML-MBC from acute myeloid leukemia expressing the Philadelphia chromosome (Ph+ AML. We present a case in which CML-MBC was seen at the initial presentation in a 75-year-old male. He was treated with conventional AML-directed chemotherapy followed by imatinib mesylate monotherapy, which failed to induce response. However, he achieved long-term complete molecular response after combination therapy involving dasatinib, a second-generation tyrosine kinase inhibitor, and conventional chemotherapy.

  19. Ionization chamber for high dose measurements

    International Nuclear Information System (INIS)

    Rodrigues Junior, Ary de Araujo

    2005-01-01

    Industrial gamma irradiators facilities are designed for processing large amounts of products, which are exposed to large doses of gamma radiation. The irradiation, in industrial scale, is usually carried out in a dynamic form, where the products go through a 60 Co gamma source with activity of TBq to P Bq (k Ci to MCi). The dose is estimated as being directly proportional to the time that the products spend to go through the source. However, in some situations, mainly for research purposes or for validation of customer process following the ISO 11137 requirements, it is required to irradiate small samples in a static position with fractional deliver doses. The samples are put inside the irradiation room at a fixed distance from the source and the dose is usually determined using dosimeters. The dose is only known after the irradiation, by reading the dosimeter. Nevertheless, in the industrial irradiators, usually different kinds of products with different densities go through between the source and the static position samples. So, the dose rate varies in function of the product density. A suitable methodology would be to monitor the samples dose in real time, measuring the dose on line with a radiation detector, which would improve the dose accuracy and avoid the overdose. A cylindrical ionization chamber of 0.9 cm 3 has been developed for high-doses real-time monitoring, during the sample irradiation at a static position in a 60 Co gamma industrial plant. Nitrogen and argon gas at pressure of 10 exp 5 Pa (1 bar) was utilized to fill the ionization chamber, for which an appropriate configuration was determined to be used as a detector for high-dose measurements. To transmit the signal generated in the ionization chamber to the associated electronic and processing unit, a 20 m mineral insulated cable was welded to the ionization chamber. The signal to noise ratio produced by the detector was about 100. The dosimeter system was tested at a category I gamma

  20. Brachytherapy treatment with high dose rate

    International Nuclear Information System (INIS)

    Santana Rodriguez, Sergio Marcelino; Rodriguez Rodriguez, Lissi Lisbet; Ciscal Chiclana, Onelio Alberto

    2009-01-01

    Retrospectively analyze results and prognostic factors of cervical cancer patients treated with radio concomitant cisplatin-based chemotherapy, radiation therapy combined modality. Methods: From January 2003 to December 2007, 198 patients with invasive cervical cancer were treated at the Oncology Department of Hospital Robau Celestino Hernandez (brachytherapy performed at INOR). The most common age group was 31 to 40 years. The histology in squamous cell carcinoma accounted for 84.3% of cases. The treatment consisted of external pelvic irradiation and vaginal brachytherapy, high dose rate. Concomitant chemotherapy consisted of cisplatin 40 mg/m2 weekly with a maximum of 70 mg for 5 weeks. Results: 66.2% of patients completed 5 cycles of chemotherapy. The median overall survival was 39 months, overall survival, disease-free survival and survival free of locoregional recurrence at 5 years of 78%, 76% and 78.6% respectively .. We found that clinical stage, histological type (adenocarcinoma worst outcome) were statistically related to level of response. Conclusions: Treatment with external pelvic radiation, brachytherapy and concurrent weekly cisplatin in patients with stage IIIB cervical cancer is feasible in the Chilean public health system, well tolerated and results comparable to international literature. (Author)

  1. Effect of imatinib on growth of experimental endometriosis in rats.

    Science.gov (United States)

    Yildiz, Caglar; Kacan, Turgut; Akkar, Ozlem Bozoklu; Karakus, Savas; Seker, Metin; Kacan, Selen Baloglu; Ozer, Hatice; Cetin, Ali

    2016-02-01

    Currently, medical and surgical treatment options for endometriosis are limited due to suboptimal efficacy, and also safety and tolerance issues. Long-term use of gonadotrophin-releasing hormone analogs, androgenes, and the danazol, which are widely used drugs for endometriosis, is usually not possible due to their suboptimal safety and tolerance profile. The lack of an effective, tolerable and safe treatment option for endometriosis makes animal models of experimental endometriosis necessary to study candidate drugs. The aim of this study was to investigate the efficacy of imatinib on the experimental endometriosis in a rat model. Endometriosis was induced by autotransplantation of uterine tissue into the peritoneal cavity. Twenty-four rats, which had visually confirmed endometriotic implants on subsequent laparotomy, were randomized into three groups to receive imatinib (25mg/kg/day, p.o.), anastrozole (0.004 mg/day, p.o.), or normal saline (0.1 mL, i.p.) for 14 days. After removal of endometriotic tissue and H & E staining, endometriosis score was determined according to a semiquantitative histological classification. Also, immunostaining with primary antibodies including VEGF, CD117, and Bax were used for immunohistochemical (IHC) examination. Both anastrozole and imatinib suppressed the growth of endometriotic tissue and reduced the number of ovarian follicles. Although the difference was not statistically significant, imatinib was less effective than anastrozole for treatment of endometriosis. Imatinib effectively treats experimental endometriosis by its inhibitor effects on angiogenesis and cell proliferation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. New use of an old drug: inhibition of breast cancer stem cells by benztropine mesylate.

    Science.gov (United States)

    Cui, Jihong; Hollmén, Maija; Li, Lina; Chen, Yong; Proulx, Steven T; Reker, Daniel; Schneider, Gisbert; Detmar, Michael

    2017-01-03

    Cancer stem cells (CSCs) play major roles in cancer initiation, metastasis, recurrence and therapeutic resistance. Targeting CSCs represents a promising strategy for cancer treatment. The purpose of this study was to identify selective inhibitors of breast CSCs (BCSCs). We carried out a cell-based phenotypic screening with cell viability as a primary endpoint, using a collection of 2,546 FDA-approved drugs and drug-like molecules in spheres formed by malignant human breast gland-derived cells (HMLER-shEcad cells, representing BCSCs) and control immortalized non-tumorigenic human mammary cells (HMLE cells, representing normal stem cells). 19 compounds were identified from screening. The chemically related molecules benztropine mesylate and deptropine citrate were selected for further validation and both potently inhibited sphere formation and self-renewal of BCSCs in vitro. Benztropine mesylate treatment decreased cell subpopulations with high ALDH activity and with a CD44+/CD24- phenotype. In vivo, benztropine mesylate inhibited tumor-initiating potential in a 4T1 mouse model. Functional studies indicated that benztropine mesylate inhibits functions of CSCs via the acetylcholine receptors, dopamine transporters/receptors, and/or histamine receptors. In summary, our findings identify benztropine mesylate as an inhibitor of BCSCs in vitro and in vivo. This study also provides a screening platform for identification of additional anti-CSC agents.

  3. High dose rate brachytherapy for oral cancer

    International Nuclear Information System (INIS)

    Yamazaki, Hideya; Yoshida, Ken; Yoshioka, Yasuo; Shimizutani, Kimishige; Koizumi, Masahiko; Ogawa, Kazuhiko; Furukawa, Souhei

    2013-01-01

    Brachytherapy results in better dose distribution compared with other treatments because of steep dose reduction in the surrounding normal tissues. Excellent local control rates and acceptable side effects have been demonstrated with brachytherapy as a sole treatment modality, a postoperative method, and a method of reirradiation. Low-dose-rate (LDR) brachytherapy has been employed worldwide for its superior outcome. With the advent of technology, high-dose-rate (HDR) brachytherapy has enabled health care providers to avoid radiation exposure. This therapy has been used for treating many types of cancer such as gynecological cancer, breast cancer, and prostate cancer. However, LDR and pulsed-dose-rate interstitial brachytherapies have been mainstays for head and neck cancer. HDR brachytherapy has not become widely used in the radiotherapy community for treating head and neck cancer because of lack of experience and biological concerns. On the other hand, because HDR brachytherapy is less time-consuming, treatment can occasionally be administered on an outpatient basis. For the convenience and safety of patients and medical staff, HDR brachytherapy should be explored. To enhance the role of this therapy in treatment of head and neck lesions, we have reviewed its outcomes with oral cancer, including Phase I/II to Phase III studies, evaluating this technique in terms of safety and efficacy. In particular, our studies have shown that superficial tumors can be treated using a non-invasive mold technique on an outpatient basis without adverse reactions. The next generation of image-guided brachytherapy using HDR has been discussed. In conclusion, although concrete evidence is yet to be produced with a sophisticated study in a reproducible manner, HDR brachytherapy remains an important option for treatment of oral cancer. (author)

  4. High dose rate brachytherapy for oral cancer.

    Science.gov (United States)

    Yamazaki, Hideya; Yoshida, Ken; Yoshioka, Yasuo; Shimizutani, Kimishige; Furukawa, Souhei; Koizumi, Masahiko; Ogawa, Kazuhiko

    2013-01-01

    Brachytherapy results in better dose distribution compared with other treatments because of steep dose reduction in the surrounding normal tissues. Excellent local control rates and acceptable side effects have been demonstrated with brachytherapy as a sole treatment modality, a postoperative method, and a method of reirradiation. Low-dose-rate (LDR) brachytherapy has been employed worldwide for its superior outcome. With the advent of technology, high-dose-rate (HDR) brachytherapy has enabled health care providers to avoid radiation exposure. This therapy has been used for treating many types of cancer such as gynecological cancer, breast cancer, and prostate cancer. However, LDR and pulsed-dose-rate interstitial brachytherapies have been mainstays for head and neck cancer. HDR brachytherapy has not become widely used in the radiotherapy community for treating head and neck cancer because of lack of experience and biological concerns. On the other hand, because HDR brachytherapy is less time-consuming, treatment can occasionally be administered on an outpatient basis. For the convenience and safety of patients and medical staff, HDR brachytherapy should be explored. To enhance the role of this therapy in treatment of head and neck lesions, we have reviewed its outcomes with oral cancer, including Phase I/II to Phase III studies, evaluating this technique in terms of safety and efficacy. In particular, our studies have shown that superficial tumors can be treated using a non-invasive mold technique on an outpatient basis without adverse reactions. The next generation of image-guided brachytherapy using HDR has been discussed. In conclusion, although concrete evidence is yet to be produced with a sophisticated study in a reproducible manner, HDR brachytherapy remains an important option for treatment of oral cancer.

  5. High dose gamma-ray standard

    International Nuclear Information System (INIS)

    Macrin, R.; Moraru, R.

    1999-01-01

    The high gamma-ray doses produced in a gamma irradiator are used, mainly, for radiation processing, i.e. sterilization of medical products, processing of food, modifications of polymers, irradiation of electronic devices, a.s.o. The used absorbed doses depend on the application and cover the range 10 Gy to 100 MGy. The regulations in our country require that the response of the dosimetry systems, used for the irradiation of food and medical products, be calibrated and traceable to the national standards. In order to be sure that the products receive the desired absorbed dose, appropriate dosimetric measurements must be performed, including the calibration of the dosemeters and their traceability to the national standards. The high dose gamma-ray measurements are predominantly based on the use of reference radiochemical dosemeters. Among them the ferrous sulfate can be used as reference dosemeter for low doses (up to 400 Gy) but due to its characteristics it deserves to be considered a standard dosemeter and to be used for transferring the conventional absorbed dose to other chemical dosemeters used for absorbed doses up to 100 MGy. The study of the ferrous sulfate dosemeter consisted in preparing many batches of solution by different operators in quality assurance conditions and in determining for all batches the linearity, the relative intrinsic error, the repeatability and the reproducibility. The principal results are the following: the linear regression coefficient: 0.999, the relative intrinsic error: max.6 %, the repeatability (for P* = 95 %): max.3 %, the reproducibility (P* = 95%): max.5 %. (authors)

  6. Downregulated microRNA-148b in circulating PBMCs in chronic myeloid leukemia patients with undetectable minimal residual disease: a possible biomarker to discontinue imatinib safely

    Directory of Open Access Journals (Sweden)

    Ohyashiki JH

    2014-08-01

    Full Text Available Junko H Ohyashiki,1 Kazushige Ohtsuki,1 Izuru Mizoguchi,2 Takayuki Yoshimoto,2 Seiichiro Katagiri,3 Tomohiro Umezu,1,4 Kazuma Ohyashiki3,4 1Department of Molecular Oncology, Institute of Medical Science, 2Department of Immunoregulation, Institute of Medical Science, 3Department of Hematology, 4Department of Molecular Science, Tokyo Medical University, Tokyo, Japan Background: A subset of patients with chronic myeloid leukemia (CML can sustain a complete molecular response after discontinuing imatinib mesylate (IM. We focused on microRNAs (miRNAs, with the aim of finding a molecular biomarker to discriminate which patients can safely and successfully discontinue IM use. Methods: To identify miRNAs that showed altered expression in patients who had discontinued IM (STOP-IM group, we first screened miRNA expression of peripheral blood mononuclear cells by using a TaqMan miRNA array on samples from five unselected patients from the STOP-IM group, seven CML patients receiving IM (IM group, and five healthy volunteers. We then performed miRNA quantification in 49 CML patients with deep molecular response. Mann–Whitney U and chi-square tests were used to determine statistical significance for comparisons between the control (healthy volunteers and test groups (STOP-IM and IM groups. Multiple groups were compared by one-way analysis of variance. Results: Downregulation of miR-148b was noted in patients in the STOP-IM group and in a subset of the IM group. We then subdivided the IM patients into two groups: one with downregulated miR-148b expression (IM-1; less than the cut-off value and the other without downregulated miR-148b expression (IM-2; greater than the cut-off value. The number of patients who had a sustained stable molecular response was significantly lower in IM-2 group. This group also had a significantly lower percentage of natural killer cells. Conclusion: Downregulated miR-148 may contribute to immune surveillance in STOP-IM patients

  7. A novel dic (17;18 (p13.1;q11.2 with loss of TP53 and BCR/ABL rearrangement in an Imatinib resistant chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Al-achkar Walid

    2012-08-01

    Full Text Available Abstract Background The so-called Philadelphia (Ph chromosome is present in more than 90% of chronic myeloid leukemia (CML cases. It results in juxtaposition of the 5′ part of the BCR gene on chromosome 22 to the 3′ part of the ABL gene on chromosome 9. Since the majority of CML cases are currently treated with Imatinib, variant rearrangements in general have no specific prognostic significance, although the mechanisms involved in resistance to therapy have yet to be investigated. The T315I mutation within the abl-gene is the most frequent one associated with resistance to tyrosine kinase inhibitors. Results This study evaluated a Ph chromosome positive CML case resistant to imatinib mesylate. A dic(17;18, loss of TP53 gene, co-expression of b2a2 and b3a2 fusions transcript and a T315I mutation were found. Conclusions We reported here a novel case of a Ph chromosome positive CML with a secondary abnormality [dic(17;18], resulting to Glivec resistance but good response to nilotinib. The dic(17;18 might be a marker for poor prognosis in CML. Our finding indicated for an aggressive progression of the disease. The patient died under the treatment due to unknown reasons.

  8. Solution-mediated phase transformation of haloperidol mesylate in the presence of sodium lauryl sulfate.

    Science.gov (United States)

    Greco, Kristyn; Bogner, Robin

    2011-09-01

    Forming a salt is a common way to increase the solubility of a poorly soluble compound. However, the solubility enhancement gained by salt formation may be lost due to solution-mediated phase transformation (SMPT) during dissolution. The SMPT of a salt can occur due to a supersaturated solution near the dissolving surface caused by pH or other solution conditions. In addition to changes in pH, surfactants are also known to affect SMPT. In this study, SMPT of a highly soluble salt, haloperidol mesylate, at pH 7 in the presence of a commonly used surfactant, sodium lauryl sulfate (SLS), was investigated. Dissolution experiments were performed using a flow-through dissolution apparatus with solutions containing various concentrations of SLS. Compacts of haloperidol mesylate were observed during dissolution in the flow-through apparatus using a stereomicroscope. Raman microscopy was used to characterize solids. The dissolution of haloperidol mesylate was significantly influenced by the addition of sodium lauryl sulfate. In conditions where SMPT was expected, the addition of SLS at low concentrations (0.1-0.2 mM) reduced the dissolution of haloperidol mesylate. In solutions containing concentrations of SLS above the critical micelle concentration (CMC) (10-15 mM), the dissolution of haloperidol mesylate increased compared to below the CMC. The solids recovered from solubility experiments of haloperidol mesylate indicated that haloperidol free base precipitated at all concentrations of SLS. Above 5 mM of SLS, Raman microscopy suggested a new form, perhaps the estolate salt. The addition of surfactant in solids that undergo solution-mediated phase transformation can add complexity to the dissolution profiles and conversion.

  9. Exploiting mitochondrial dysfunction for effective elimination of imatinib-resistant leukemic cells.

    Directory of Open Access Journals (Sweden)

    Jérome Kluza

    Full Text Available Challenges today concern chronic myeloid leukemia (CML patients resistant to imatinib. There is growing evidence that imatinib-resistant leukemic cells present abnormal glucose metabolism but the impact on mitochondria has been neglected. Our work aimed to better understand and exploit the metabolic alterations of imatinib-resistant leukemic cells. Imatinib-resistant cells presented high glycolysis as compared to sensitive cells. Consistently, expression of key glycolytic enzymes, at least partly mediated by HIF-1α, was modified in imatinib-resistant cells suggesting that imatinib-resistant cells uncouple glycolytic flux from pyruvate oxidation. Interestingly, mitochondria of imatinib-resistant cells exhibited accumulation of TCA cycle intermediates, increased NADH and low oxygen consumption. These mitochondrial alterations due to the partial failure of ETC were further confirmed in leukemic cells isolated from some imatinib-resistant CML patients. As a consequence, mitochondria generated more ROS than those of imatinib-sensitive cells. This, in turn, resulted in increased death of imatinib-resistant leukemic cells following in vitro or in vivo treatment with the pro-oxidants, PEITC and Trisenox, in a syngeneic mouse tumor model. Conversely, inhibition of glycolysis caused derepression of respiration leading to lower cellular ROS. In conclusion, these findings indicate that imatinib-resistant leukemic cells have an unexpected mitochondrial dysfunction that could be exploited for selective therapeutic intervention.

  10. Validated UV-Spectrophotometric Methods for Determination of Gemifloxacin Mesylate in Pharmaceutical Tablet Dosage Forms

    Directory of Open Access Journals (Sweden)

    R. Rote Ambadas

    2010-01-01

    Full Text Available Two simple, economic and accurate UV spectrophotometric methods have been developed for determination of gemifloxacin mesylate in pharmaceutical tablet formulation. The first UV-spectrophotometric method depends upon the measurement of absorption at the wavelength 263.8 nm. In second area under curve method the wavelength range for detection was selected from 268.5-258.5 nm. Beer’s law was obeyed in the range of 2 to 12 μgmL-1 for both the methods. The proposed methods was validated statistically and applied successfully to determination of gemifloxacin mesylate in pharmaceutical formulation.

  11. Performance of thermoluminescent materials for high dose dosimetry

    International Nuclear Information System (INIS)

    Texeira, Maria I.; Cecatti, Sonia G.P.; Caldas, Linda V.E.

    2008-01-01

    Cases involving high-doses of ionizing radiation are becoming increasingly common.The objective of this work was to characterize thermoluminescent materials for the dosimetry of workers exposed to high doses. Samples of TLD-200, TLD-400 and TLD-800 pellets from Thermo Electron Corporation were studied in gamma high-doses. Dose-response curves were obtained for doses between 100 mGy and 100 Gy. The reproducibility, the lower detection limits and dose-response curves were obtained for all three materials. The different kinds of detectors show usefulness for dosimetry of workers exposed accidentally to high doses. (author)

  12. SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Onkar Singh

    Full Text Available OBJECTIVE: This study aimed to explore the influence of SLC22A1, PXR, ABCG2, ABCB1 and CYP3A5 3 genetic polymorphisms on imatinib mesylate (IM pharmacokinetics in Asian patients with chronic myeloid leukemia (CML. PATIENTS AND METHODS: Healthy subjects belonging to three Asian populations (Chinese, Malay, Indian; n = 70 each and CML patients (n = 38 were enrolled in a prospective pharmacogenetics study. Imatinib trough (C(0h and clearance (CL were determined in the patients at steady state. Haplowalk method was applied to infer the haplotypes and generalized linear model (GLM to estimate haplotypic effects on IM pharmacokinetics. Association of haplotype copy numbers with IM pharmacokinetics was defined by Mann-Whitney U test. RESULTS: Global haplotype score statistics revealed a SLC22A1 sub-haplotypic region encompassing three polymorphisms (rs3798168, rs628031 and IVS7+850C>T, to be significantly associated with IM clearance (p = 0.013. Haplotype-specific GLM estimated that the haplotypes AGT and CGC were both associated with 22% decrease in clearance compared to CAC [CL (10(-2 L/hr/mg: CAC vs AGT: 4.03 vs 3.16, p = 0.017; CAC vs CGC: 4.03 vs 3.15, p = 0.017]. Patients harboring 2 copies of AGT or CGC haplotypes had 33.4% lower clearance and 50% higher C(0h than patients carrying 0 or 1 copy [CL (10(-2 L/hr/mg: 2.19 vs 3.29, p = 0.026; C(0h (10(-6 1/ml: 4.76 vs 3.17, p = 0.013, respectively]. Further subgroup analysis revealed SLC22A1 and ABCB1 haplotypic combinations to be significantly associated with clearance and C(0h (p = 0.002 and 0.009, respectively. CONCLUSION: This exploratory study suggests that SLC22A1-ABCB1 haplotypes may influence IM pharmacokinetics in Asian CML patients.

  13. Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines.

    Science.gov (United States)

    Deguchi, Yasuyuki; Kimura, Shinya; Ashihara, Eishi; Niwa, Tomoko; Hodohara, Keiko; Fujiyama, Yoshihide; Maekawa, Taira

    2008-06-01

    We compared the growth-inhibitory effects and inhibition profile of the SRC family kinases (SFKs) of imatinib, dasatinib, nilotinib and INNO-406. Dasatinib exhibited the strongest potency against BCR-ABL with little selectivity over SFKs. Nilotinib exhibited a weaker affinity than the other inhibitors, but was highly specific for ABL and may be useful for the treatment of P-glycoprotein overexpressing leukemic cells. INNO-406 had an intermediate affinity for BCR-ABL between that of dasatinib and nilotinib, and inhibited only SFKs LCK and LYN among SFKs. Both nilotinib and INNO-406 were potent inhibitors of the dasatinib-resistant T315A, F317L and F317V BCR-ABL mutations.

  14. Women Administered Standard Dose Imatinib for Chronic Myeloid Leukemia Have Higher Dose-Adjusted Plasma Imatinib and Norimatinib Concentrations Than Men.

    Science.gov (United States)

    Belsey, Sarah L; Ireland, Robin; Lang, Kathryn; Kizilors, Aytug; Ho, Aloysius; Mufti, Ghulam J; Bisquera, Alessandra; De Lavallade, Hugues; Flanagan, Robert J

    2017-10-01

    The standard dose of imatinib for the treatment of chronic-phase chronic myeloid leukemia (CML) is 400 mg·d. A predose plasma imatinib concentration of >1 mg·L is associated with improved clinical response. This study aimed to assess the plasma imatinib and norimatinib concentrations attained in patients with chronic myeloid leukemia administered standard doses of imatinib adjusted for dose, age, sex, body weight, and response. We evaluated data from a cohort of patients treated between 2008 and 2014 with respect to dose, age, sex, body weight, and response. The study comprised 438 samples from 93 patients (54 male, 39 female). The median imatinib dose was 400 mg·d in men and in women. The plasma imatinib concentration ranged 0.1-5.0 mg·L and was below 1 mg·L in 20% and 16% of samples from men and women, respectively. The mean dose normalized plasma imatinib and norimatinib concentrations were significantly higher in women in comparison with men. This was partially related to body weight. Mixed effects ordinal logistic regression showed no evidence of an association between sex and plasma imatinib (P = 0.13). However, there was evidence of an association between sex and plasma norimatinib, with higher norimatinib concentrations more likely in women than in men (P = 0.02). Imatinib therapeutic drug monitoring only provides information on dosage adequacy and on short-term adherence; longer-term adherence cannot be assessed. However, this analysis revealed that approximately 1 in 5 samples had a plasma imatinib concentration <1 mg·L, which was suggestive of inadequate dosage and/or poor adherence and posed a risk of treatment failure. Higher imatinib exposure in women may be a factor in the increased rate of long-term, stable, deep molecular response (undetectable breakpoint cluster-Abelson (BCR-ABL) transcript levels with a PCR sensitivity of 4.5 log, MR4.5) reported in women.

  15. Acute renal failure in high dose carboplatin chemotherapy

    NARCIS (Netherlands)

    Frenkel, J.; Kool, G.; de Kraker, J.

    1995-01-01

    Carboplatin has been reported to cause acute renal failure when administered in high doses to adult patients. We report a 4 1/2-year-old girl who was treated with high-dose carboplatin for metastatic parameningeal embryonal rhabdomyosarcoma. Acute renal failure developed followed by a slow partial

  16. Pharmacogenetics and Pharmacokinetics in high-dose alkylating chemotherapy

    NARCIS (Netherlands)

    Ekhart, G.C. (Corine)

    2008-01-01

    High-dose chemotherapy in combination with peripheral blood progenitor cell transplantation has been developed as a possible curative treatment modality in several solid tumours. A frequently used high-dose regimen in the Netherlands is the CTC regimen, which is a 4-day course of cyclophosphamide,

  17. Physico-chemical stability of eribulin mesylate containing concentrate and ready-to-administer solutions.

    Science.gov (United States)

    Spindeldreier, Kirsten; Thiesen, Judith; Lipp, Hans-Peter; Krämer, Irene

    2014-06-01

    The aim of this study was to determine the stability of commercially available eribulin mesylate containing injection solution as well as diluted ready-to-administer solutions stored under refrigeration or at room temperature. Stability was studied by a novel developed stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) assay with ultraviolet detection (detection wavelength 200 nm). Triplicate test solutions of eribulin mesylate containing injection concentrate (0.5 mg/mL) and with 0.9% sodium chloride solution diluted ready-to-administer preparations (0.205 mg/mL eribulin mesylate in polypropylene (PP) syringes, 0.020 mg/mL eribulin mesylate in polypropylene/polyethylene (PE) bags) were stored protected from light either at room temperature (25) or under refrigeration (2-8). Samples were withdrawn on day 0 (initial), 1, 3, 5, 7, 14, 21 and 28 of storage and assayed. Physical stability was determined by measuring the pH value once a week and checking for visible precipitations or colour changes. The stability tests revealed that concentrations of eribulin mesylate remained unchanged over a period of 28 days irrespective of concentration, container material or storage temperature. Neither colour changes nor visible particles have been observed. The pH value varied slightly over time but remained in the stability favourable range of 5-9. Eribulin mesylate injection (0.5 mg/mL) is physico-chemically stable over a period of 28 days after first puncture of the vial. After dilution with 0.9% NaCl vehicle solution, ready-to-administer eribulin mesylate injection solutions (0.205 mg/mL in PP syringe) and infusion solutions (0.02 mg/mL in prefilled PP/PE bags) are physico-chemically stable for a period of at least four weeks either refrigerated or stored at room temperature. For microbiological reasons storage under refrigeration is recommended.

  18. The Culture Repopulation Ability (CRA) Assay and Incubation in Low Oxygen to Test Antileukemic Drugs on Imatinib-Resistant CML Stem-Like Cells.

    Science.gov (United States)

    Cheloni, Giulia; Tanturli, Michele

    2016-01-01

    Chronic myeloid leukemia (CML) is a stem cell-driven disorder caused by the BCR/Abl oncoprotein, a constitutively active tyrosine kinase (TK). Chronic-phase CML patients are treated with impressive efficacy with TK inhibitors (TKi) such as imatinib mesylate (IM). However, rather than definitively curing CML, TKi induces a state of minimal residual disease, due to the persistence of leukemia stem cells (LSC) which are insensitive to this class of drugs. LSC persistence may be due to different reasons, including the suppression of BCR/Abl oncoprotein. It has been shown that this suppression follows incubation in low oxygen under appropriate culture conditions and incubation times.Here we describe the culture repopulation ability (CRA) assay, a non-clonogenic assay capable - together with incubation in low oxygen - to reveal in vitro stem cells endowed with marrow repopulation ability (MRA) in vivo. The CRA assay can be used, before moving to animal tests, as a simple and reliable method for the prescreening of drugs potentially active on CML and other leukemias with respect to their activity on the more immature leukemia cell subsets.

  19. Impact of CYP2C8*3 polymorphism on in vitro metabolism of imatinib to N-desmethyl imatinib.

    Science.gov (United States)

    Khan, Muhammad Suleman; Barratt, Daniel T; Somogyi, Andrew A

    2016-01-01

    1. Imatinib is metabolized to N-desmethyl imatinib by CYPs 3A4 and 2C8. The effect of CYP2C8*3 genotype on N-desmethyl imatinib formation was unknown. 2. We examined imatinib N-demethylation in human liver microsomes (HLMs) genotyped for CYP2C8*3, in CYP2C8*3/*3 pooled HLMs and in recombinant CYP2C8 and CYP3A4 enzymes. Effects of CYP-selective inhibitors on N-demethylation were also determined. 3. A single-enzyme Michaelis-Menten model with autoinhibition best fitted CYP2C8*1/*1 HLM (n = 5) and recombinant CYP2C8 kinetic data (median ± SD Ki = 139 ± 61 µM and 149 µM, respectively). Recombinant CYP3A4 showed two-site enzyme kinetics with no autoinhibition. Three of four CYP2C8*1/*3 HLMs showed single-enzyme kinetics with no autoinhibition. Binding affinity was higher in CYP2C8*1/*3 than CYP2C8*1/*1 HLM (median ± SD Km = 6 ± 2 versus 11 ± 2 µM, P=0.04). CYP2C8*3/*3 (pooled HLM) also showed high binding affinity (Km = 4 µM) and single-enzyme weak autoinhibition (Ki = 449 µM) kinetics. CYP2C8 inhibitors reduced HLM N-demethylation by 47-75%, compared to 0-30% for CYP3A4 inhibitors. 4. In conclusion, CYP2C8*3 is a gain-of-function polymorphism for imatinib N-demethylation, which appears to be mainly mediated by CYP2C8 and not CYP3A4 in vitro in HLM.

  20. Non-Hodgkin's lymphoma in a chronic myelocytic leukemia patient treated with imatinib

    Directory of Open Access Journals (Sweden)

    Semra Paydaş

    2011-09-01

    Full Text Available Imatinib is an important example of tyrosine kinase inhibitors (TKIs used in clinical practice. Imatinib blocks the ATP binding site of the Bcr-Abl fusion protein and selectively inhibits Bcr-Abl tyrosine kinase (TK activity. Treatment of chronic myelocytic leukemia (CML with imatinib is encouraging and it has an acceptable toxicity profile, and as such has changed the management of CML during the last decade. As with all drugs used in clinical practice, side effects of imatinib have been reported in studies with extended follow-up periods. In addition, some neoplastic disorders have been reported to occur during imatinib therapy. Herein we present a CML case that developed non-Hodgkin’s lymphoma (NHL while receiving imatinib treatment.

  1. Accelerated Irradiations for High Dose Microstructures in Fast Reactor Alloys

    Energy Technology Data Exchange (ETDEWEB)

    Jiao, Zhijie [Univ. of Michigan, Ann Arbor, MI (United States)

    2017-03-31

    The objective of this project is to determine the extent to which high dose rate, self-ion irradiation can be used as an accelerated irradiation tool to understand microstructure evolution at high doses and temperatures relevant to advanced fast reactors. We will accomplish the goal by evaluating phase stability and swelling of F-M alloys relevant to SFR systems at very high dose by combining experiment and modeling in an effort to obtain a quantitative description of the processes at high and low damage rates.

  2. Combinations of Novel Histone Deacetylase and Bcr-Abl Inhibitors in the Therapy of Imatinib Mesylate-Sensitive and -Refractory Bcr-Abl Expressing Leukemia

    Science.gov (United States)

    2008-12-01

    Balasis,1Purva Bali,1Veronica Estrella ,1Sandhya Kumaraswamy,1 Rekha Rao,1Kathy Rocha,1Bryan Herger,1Francis Lee,2 Victoria Richon,3 and Kapil Bhalla1...Balasis M, Bali P, Estrella V, Kumaraswamy S, et al. Histone deacetylase inhibitors deplete EZH2 and associated Polycomb Repressive Complex 2 proteins

  3. Relative safety profiles of high dose statin regimens

    Directory of Open Access Journals (Sweden)

    Carlos Escobar

    2008-06-01

    Full Text Available Carlos Escobar, Rocio Echarri, Vivencio BarriosDepartment of Cardiology, Hospital Ramón y Cajal, Madrid, SpainAbstract: Recent clinical trials recommend achieving a low-density lipoprotein cholesterol level of <100 mg/dl in high-risk and <70 mg/dl in very high risk patients. To attain these goals, however, many patients will need statins at high doses. The most frequent side effects related to the use of statins, myopathy, rhabdomyolysis, and increased levels of transaminases, are unusual. Although low and moderate doses show a favourable profile, there is concern about the tolerability of higher doses. During recent years, numerous trials to analyze the efficacy and tolerability of high doses of statins have been published. This paper updates the published data on the safety of statins at high doses.Keywords: statins, high doses, tolerability, liver, muscle

  4. Treatment of the prostate cancer with high dose rate brachytherapy

    International Nuclear Information System (INIS)

    Martinez, Alvaro; Torres Silva, Felipe

    2002-01-01

    The prostate cancer treatment in early stages is controversial. The high dose rate brachytherapy has been used like monotherapy or boost with external beam radiotherapy in advanced disease. This paper describes the technique and the advantages over other modalities

  5. High-dose dosimetry using natural silicate minerals

    International Nuclear Information System (INIS)

    Carmo, Lucas S. do; Mendes, Leticia; Watanabe, Shigueo; Rao, Gundu; Lucas, Natasha; Sato, Karina; Barbosa, Renata F.

    2015-01-01

    In the present study, certain natural silicate minerals such as aquamarine (AB), morganite (PB), goshenite (WB), white jadeite (JW), green jadeite (JG), pink tourmaline (PT) and two varieties of jadeite-like quartz, denoted here by JQ1 and JQ2, were investigated using the thermoluminescence technique to evaluate their potential for use as very-high- and high-dose dosimeters. These minerals respond to high doses of γ-rays of up to 1000 kGy and often to very high doses of up to 3000 kGy. The TL response of these minerals may be considered to be satisfactory for applications in high-dose dosimetry. Investigations of electron paramagnetic resonance and optically stimulated luminescence dosimetry are in progress. (author)

  6. High-dose dosimetry using natural silicate minerals

    Energy Technology Data Exchange (ETDEWEB)

    Carmo, Lucas S. do; Mendes, Leticia, E-mail: isatiro@usp.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Watanabe, Shigueo; Rao, Gundu; Lucas, Natasha; Sato, Karina, E-mail: lacifid@if.usp.br [Universidade de Sao Paulo (USP), Sao Paulo, SP (Brazil). Instituto de Fisica. Departamento de Fisica Nuclear; Barbosa, Renata F., E-mail: profcelta@hotmail.com [Universidade Federal de Sao Paulo (UNIFESP), Santos, SP (Brazil). Departamento de Ciencias do Mar

    2015-07-01

    In the present study, certain natural silicate minerals such as aquamarine (AB), morganite (PB), goshenite (WB), white jadeite (JW), green jadeite (JG), pink tourmaline (PT) and two varieties of jadeite-like quartz, denoted here by JQ1 and JQ2, were investigated using the thermoluminescence technique to evaluate their potential for use as very-high- and high-dose dosimeters. These minerals respond to high doses of γ-rays of up to 1000 kGy and often to very high doses of up to 3000 kGy. The TL response of these minerals may be considered to be satisfactory for applications in high-dose dosimetry. Investigations of electron paramagnetic resonance and optically stimulated luminescence dosimetry are in progress. (author)

  7. Improved oral absorption of cilostazol via sulfonate salt formation with mesylate and besylate

    Directory of Open Access Journals (Sweden)

    Seo JH

    2015-07-01

    Full Text Available Jae Hong Seo, Jung Bae Park, Woong-Kee Choi, Sunhwa Park, Yun Jin Sung, Euichaul Oh, Soo Kyung Bae College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea Objective: Cilostazol is a Biopharmaceutical Classification System class II drug with low solubility and high permeability, so its oral absorption is variable and incomplete. The aim of this study was to prepare two sulfonate salts of cilostazol to increase the dissolution and hence the oral bioavailability of cilostazol.Methods: Cilostazol mesylate and cilostazol besylate were synthesized from cilostazol by acid addition reaction with methane sulfonic acid and benzene sulfonic acid, respectively. The salt preparations were characterized by nuclear magnetic resonance spectroscopy. The water contents, hygroscopicity, stress stability, and photostability of the two cilostazol salts were also determined. The dissolution profiles in various pH conditions and pharmacokinetic studies in rats were compared with those of cilostazol-free base.Results: The two cilostazol salts exhibited good physicochemical properties, such as nonhygroscopicity, stress stability, and photostability, which make it suitable for the preparation of pharmaceutical formulations. Both cilostazol mesylate and cilostazol besylate showed significantly improved dissolution rate and extent of drug release in the pH range 1.2–6.8 compared to the cilostazol-free base. In addition, after oral administration to rats, cilostazol mesylate and cilostazol besylate showed increases in Cmax and AUCt of approximately 3.65- and 2.87-fold and 3.88- and 2.94-fold, respectively, compared to cilostazol-free base.Conclusion: This study showed that two novel salts of cilostazol, such as cilostazol mesylate and cilostazol besylate, could be used to enhance its oral absorption. The findings warrant further preclinical and clinical studies on cilostazol mesylate and

  8. Response of Complex Undefined Hypereosinophilic Syndrome to Treatment with Imatinib.

    Science.gov (United States)

    Yılmaz, İnsu; Kaynar, Leylagül; Tutar, Nuri; Pala, Çiğdem; Canöz, Özlem; Yıldırım, Afra; Büyükoğlan, Hakan; Gülmez, İnci

    2016-07-01

    Hypereosinophilic syndomes (HESs) include potentially lethal multisystem disorders characterized by eosinophilic infiltration of a variable spectrum of target organs, predominantly the skin, heart, lungs, gastrointestinal tract, and nervous system. Based on recent advances in molecular and genetic diagnostic techniques and increasing experience with differences in clinical features and prognosis, subtypes have been defined, including "myeloproliferative-HES ", "lymphocytic-HES", "familial eosinophilia", "overlap HES", "undefined HES" ("complex undefined HES", "simple undefined HES", "episodic undefined HES") and "eosinophil associated diseases" (such as Churg-Strauss syndrome). HES should be kept in mind in the differential diagnosis of eosinophilic lung diseases especially in patients with peripheral eosinophilia and pulmonary infiltrates. Corticosteroids represent an effective firstline approach to decreasing eosinophil counts in the majority of cases. Imatinib might be used for corticosteroid nonresponders. We herein report a patient with "complex undefined HES" who had disease resistant to corticosteroids, but who had a significant response after treatment with imatinib.

  9. Homologous recombination induced by doxazosin mesylate and saw palmetto in the Drosophila wing-spot test.

    Science.gov (United States)

    Gabriel, Katiane Cella; Dihl, Rafael Rodrigues; Lehmann, Mauricio; Reguly, Maria Luiza; Richter, Marc François; Andrade, Heloisa Helena Rodrigues de

    2013-03-01

    Benign prostatic hyperplasia (BPH) is the most common tumor in men over 40 years of age. Acute urinary retention (AUR) is regarded as the most serious hazard of untreated BPH. α-Blockers, such as doxazosin mesylate, and 5-α reductase inhibitors, such as finasteride, are frequently used because they decrease both AUR and the need for BPH-related surgery. An extract of the fruit from American saw palmetto plant has also been used as an alternative treatment for BPH. The paucity of information available concerning the genotoxic action of these compounds led us to assess their activity as inducers of different types of DNA lesions using the somatic mutation and recombination test in Drosophila melanogaster. Finasteride did not induce gene mutation, chromosomal mutation or mitotic recombination, which means it was nongenotoxic in our experimental conditions. On the other hand, doxazosin mesylate and saw palmetto induced significant increases in spot frequencies in trans-heterozygous flies. In order to establish the actual role played by mitotic recombination and by mutation in the genotoxicity observed, the balancer-heterozygous flies were also analyzed, showing no increment in the total spot frequencies in relation to the negative control, for both drugs. Doxazosin mesylate and saw palmetto were classified as specific inducers of homologous recombination in Drosophila proliferative cells, an event linked to the loss of heterozygosity. Copyright © 2011 John Wiley & Sons, Ltd.

  10. Imatinib prevents beta cell death in vitro but does not improve islet transplantation outcome.

    Science.gov (United States)

    King, Aileen J F; Griffiths, Lisa A; Persaud, Shanta J; Jones, Peter M; Howell, Simon L; Welsh, Nils

    2016-05-01

    Introduction Improving islet transplantation outcome could not only bring benefits to individual patients but also widen the patient pool to which this life-changing treatment is available. Imatinib has previously been shown to protect beta cells from apoptosis in a variety of in vitro and in vivo models. The aim of this study was to investigate whether imatinib could be used to improve islet transplantation outcome. Methods Islets were isolated from C57Bl/6 mice and pre-cultured with imatinib prior to exposure to streptozotocin and cytokines in vitro. Cell viability and glucose-induced insulin secretion were measured. For transplantation experiments, islets were pre-cultured with imatinib for either 72 h or 24 h prior to transplantation into streptozotocin-diabetic C57Bl/6 mice. In one experimental series mice were also administered imatinib after islet transplantation. Results Imatinib partially protected islets from beta cell death in vitro. However, pre-culturing islets in imatinib or administering the drug to the mice in the days following islet transplantation did not improve blood glucose concentrations more than control-cultured islets. Conclusion Although imatinib protected against beta cell death from cytokines and streptozotocin in vitro, it did not significantly improve syngeneic islet transplantation outcome.

  11. Implementation of high-dose chemical dosimetry for industrial facilities

    International Nuclear Information System (INIS)

    Conceicao, Cirilo Cezar Sant'Anna da

    2006-01-01

    The purpose of this work is the implementation of methodology for high dose measurements using chemical dosimeters in liquid phase, traceable to the international metrology system, and make available in the country, the standard of high-dose to industrial irradiation facilities and research irradiators, trough the quality program with comparative measurements and direct use of the standard dosimeters in routine. The use of these low cost dosimetry systems in industrial irradiation facilities, assists to the certification requirements and it can reduce the costs with dosimetry for approximately 20% of the total dosimetry costs, using these systems in routine measurements and validation process, largely substituting the imported PMMA dosimeters, among others. (author)

  12. Statistical behavior of high doses in medical radiodiagnosis

    International Nuclear Information System (INIS)

    Barboza, Adriana Elisa

    2014-01-01

    This work has as main purpose statistically estimating occupational exposure in medical diagnostic radiology in cases of high doses recorded in 2011 at national level. For statistical survey of this study, doses of 372 IOE's diagnostic radiology in different Brazilian states were evaluated. Data were extracted from the work of monograph (Research Methodology Of High Doses In Medical Radiodiagnostic) that contains the database's information Sector Management doses of IRD/CNEN-RJ, Brazil. The identification of these states allows the Sanitary Surveillance (VISA) responsible, becomes aware of events and work with programs to reduce these events. (author)

  13. Study of teflon pads as high doses dosemeters

    International Nuclear Information System (INIS)

    Teixeira, Maria Ines; Caldas, Linda V.E.

    2013-01-01

    The aim of this work is to study the Teflon, which is used as a binder in the manufacture of dosimetric tablets, for the feasibility of this material as high dose dosemeter. In this paper we used the technique of thermally stimulated luminescence (OSL) to characterize the dosimetric properties of Teflon. Teflon samples were exposed to different doses of radiation, using a source of gamma radiation ( 60 Co). It was obtained dose-response curve between 100 Gy to 50 kGy and reproducibility of OSL response. The preliminary results show that Teflon is a useful material to high dose dosimetry

  14. Chronic myeloid leukemia patients sensitive and resistant to imatinib treatment show different metabolic responses.

    Directory of Open Access Journals (Sweden)

    Jiye A

    Full Text Available The BCR-ABL tyrosine kinase inhibitor imatinib is highly effective for chronic myeloid leukemia (CML. However, some patients gradually develop resistance to imatinib, resulting in therapeutic failure. Metabonomic and genomic profiling of patients' responses to drug interventions can provide novel information about the in vivo metabolism of low-molecular-weight compounds and extend our insight into the mechanism of drug resistance. Based on a multi-platform of high-throughput metabonomics, SNP array analysis, karyotype and mutation, the metabolic phenotypes and genomic polymorphisms of CML patients and their diverse responses to imatinib were characterized. The untreated CML patients (UCML showed different metabolic patterns from those of healthy controls, and the discriminatory metabolites suggested the perturbed metabolism of the urea cycle, tricarboxylic acid cycle, lipid metabolism, and amino acid turnover in UCML. After imatinib treatment, patients sensitive to imatinib (SCML and patients resistant to imatinib (RCML had similar metabolic phenotypes to those of healthy controls and UCML, respectively. SCML showed a significant metabolic response to imatinib, with marked restoration of the perturbed metabolism. Most of the metabolites characterizing CML were adjusted to normal levels, including the intermediates of the urea cycle and tricarboxylic acid cycle (TCA. In contrast, neither cytogenetic nor metabonomic analysis indicated any positive response to imatinib in RCML. We report for the first time the associated genetic and metabonomic responses of CML patients to imatinib and show that the perturbed in vivo metabolism of UCML is independent of imatinib treatment in resistant patients. Thus, metabonomics can potentially characterize patients' sensitivity or resistance to drug intervention.

  15. Use of glasses as radiation detectors for high doses

    International Nuclear Information System (INIS)

    Caldas, L.

    1989-08-01

    Glass samples were tested in relation to the possibility of use in high dose dosimetry in medical and industrial areas. The main characteristics were determined: detection threshold, reproducibility, response to gamma radiation of 137 Cs and 6 Co and thermal decay at ambient temperature, with the use of optical absorption and thermoluminesce techniques. (author) [pt

  16. Oval pulsed high-dose dexamethasone for myositis

    NARCIS (Netherlands)

    Hoogendijk, JE; Wokke, JHJ; de Visser, M

    To study the short-term effect of oral pulsed high-dose dexamethasone for myositis we treated eight newly diagnosed patients with three 28-day cycles of oral dexamethasone. Primary outcome measures were muscle strength, pain, and serum creatine kinase activity. Sis patients responded. Side effects

  17. Oral pulsed high-dose dexamethasone for myositis

    NARCIS (Netherlands)

    van der Meulen, M. F.; Hoogendijk, J. E.; Wokke, J. H.; de Visser, M.

    2000-01-01

    To study the short-term effect of oral pulsed high-dose dexamethasone for myositis we treated eight newly diagnosed patients with three 28-day cycles of oral dexamethasone. Primary outcome measures were muscle strength, pain, and serum creatine kinase activity. Six patients responded. Side effects

  18. Safety and tolerability of high doses of glucocorticoides

    Directory of Open Access Journals (Sweden)

    Rakić Branislava D.

    2016-01-01

    Full Text Available Introduction: Treatment of acute lymphoblastic leukemia includes the use of high doses of glucocorticoides (prednisone and dexamethasone, which significantly increase the success of therapy due to lymphocytolitic effect. The aim: The aim of the study was to determine tolerability of high doses of prednisone and dexamethasone in children with acute lymphoblastic leukemia and the structure and the intensity of adverse effects, occurred after application of these medicines. Subjects and methods: In a prospective study, we analyzed adverse effects of high doses of glucocorticoides in children suffering acute lymphoblastic leukemia treated in the Institute for Child and Youth Health Care of Vojvodina, since December 2010. until October 2014, were analyzed. This study included 18 patients, aged from 2 to 15 years. Results: Hyperglycemia appeared in 89% of patients treated with prednisone and in 61% of patients treated with dexamethasone. In order to control the high blood glucose level (above 10 mmol /L, in 11% of patients insulin was used. Hypertension appeared in 28% patients treated with prednisone and dexamethasone. Antihypertensives were needed for regulation in 17% patients. Hypopotassemia and hypocalcaemia were significantly more expressed after the use of prednisone in comparison to dexamethasone. In 11% of patients, the treatment with dexamethasone caused depressive behavior, followed by agitation. Conclusion: Adverse effects of dexamethasone and prednisone, administered in high doses in children with ALL were known, expected and reversible. Adverse reactions usually disappeared spontaneously or after short-term symptomatic therapy.

  19. Relevance of high-dose chemotherapy in solid tumours

    NARCIS (Netherlands)

    Nieboer, P; de Vries, EGE; Mulder, NH; van der Graaf, WTA

    Drug resistance is a major problem in the treatment of solid tumours. Based on a steep dose-response relationship for especially alkylating agents on tumour cell survival, high-dose chemotherapy was considered of interest for the treatment of solid tumours. Results of phase 1 and 2 studies with

  20. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma

    NARCIS (Netherlands)

    P.G. Richardson (Paul Gerard); P. Sonneveld (Pieter); M.W. Schuster (Michael); D. Irwin (David); E.A. Stadtmauer (Edward); T. Facon (Thierry); J-L. Harousseau (Jean-Luc); D. Ben-Yehuda (Dina); S. Lonial (Sagar); H. Goldschmidt (Hartmut); D. Reece (Donna); J.F. San Miguel (Jesús Fernando); J. Bladé (Joan); M. Boccadoro (Mario); J. Cavenagh (Jamie); W. Dalton (William); A.L. Boral (Anthony); D.-L. Esseltine (Dixie-Lee); J.B. Porter (Jane); D. Schenkein (David); K.C. Anderson (Kenneth)

    2005-01-01

    textabstractBACKGROUND: This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies. METHODS: We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3

  1. Unusual complication and successful high-dose chemotherapy ...

    African Journals Online (AJOL)

    ... treated with high-dose chemotherapy in our institution, complicated by unusual bilateral renal vein tumour thrombi and tumour lysis syndrome. We believe this unique case highlights the need for early recognition of current and potential complications on staging computed tomography imaging, as well as successful use of ...

  2. Gemfibrozil impairs imatinib absorption and inhibits the CYP2C8-mediated formation of its main metabolite.

    Science.gov (United States)

    Filppula, A M; Tornio, A; Niemi, M; Neuvonen, P J; Backman, J T

    2013-09-01

    Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, gemfibrozil reduced the peak plasma concentration (Cmax) of imatinib by 35% (P Gemfibrozil also reduced the Cmax and area under the plasma concentration-time curve (AUC0-∞) of N-desmethylimatinib by 56 and 48% (P gemfibrozil reduced the Cmax/plasma concentration at 24 h (C24 h) ratios of imatinib and N-desmethylimatinib by 44 and 17% (P gemfibrozil. Our findings indicate significant participation of CYP2C8 in the metabolism of imatinib in humans, and support involvement of an intestinal influx transporter in imatinib absorption.

  3. The synthesis of [[sup 2]H],[[sup 3]H], and [[sup 14]C]-labeled 8[beta]-[(methylthio)methyl]-6-propylergoline mesylate (pergolide mesylate), a potent, long-acting dopamine agonist

    Energy Technology Data Exchange (ETDEWEB)

    Wheeler, W.J.; Kau, D.L.K.; Bach, N.J. (Lilly (Eli) and Co., Indianapolis, IN (United States). Lilly Research Labs.)

    1990-03-01

    The [[sup 3]H]- and two[[sup 14]C]-isopomers of 8[beta]-[(methylthio)methyl]-6-propylergoline mesylate (pergolide mesylate) have been synthesized. The [[sup 3]H]-derivative was synthesized by the palladium catalyzed tritiation of the corresponding 6-allyl derivative. Reaction of 8[beta]-[(methylthio)methyl]-ergoline with 1-[[sup 14]C]-1-propyl bromide yielded pergolide labeled in the 6-propyl group. Alternatively, reaction of 8[beta]-mesyloxy-6-propylergoline with [[sup 14]C]-sodium cyanide, followed by base hydrolysis, yielded 8 [beta]-carboxy-6-propylergoline-[[sup 14]C], which was subsequently converted to pergolide mesylate radiolabeled in the 17-position via a four step sequence. (Author).

  4. OUTCOME OF FRONTLINE TREATMENT WITH “GENERIC” IMATINIB IN ADULT PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN ALGERIAN POPULATION: A MULTICENTER STUDY

    Directory of Open Access Journals (Sweden)

    Mohamed Amine BEKADJA

    2017-10-01

    Full Text Available Introduction: In a developing country like Algeria, such expensive therapy is not available. Alternative approaches are needed to help these adult. In Algeria ‘imatib’ (CIPLA-India was introduced in 2006; but no study has been published yet in the North Africa region regarding response and outcome of this copy in CML patients. The goal of this multicenter study is to characterize newly adult CML in the western region of Algeria and to assess the effectiveness and safety of imatib (IM, copy as frontline therapy for patients with CML. Patients and Methods: The study was carried out in 7 hematology centers in the western Algeria. Patients, who were diagnosed to be suffering from CML between January 1st, 2007 and  December 31st, 2014 were selected for data analysis. All patients received a copy preparation, consisting of the alpha crystal form of imatinib, (IM, copy at a oral dose of 400 mg daily and monitored for tolerance and side effects while on therapy. Results: Between January 2007 and December 2014, 355 patients with CML were treated with imatib (Copy. The median follow- up of the study was 46 months (range: 13–107 months. Complete hematological response (CHR was seen in 83% of patients within 3 months. According to the Sokal score, 72% patients with low, 78% with intermediate and 69% with high risk disease achieved a CHR in 3 months (p=0.26 and according to the EUTOS score, 81% of patients with low and 70% with high risk disease achieved a CHR in 3 months (p=0.08. The major molecular response (MMR at six months (M6, M9, M12, M18 and M24 was 21%, 38%, 35%, 51% and 67% respectively and 34% of patients achieved a complete molecular response (CMR. The projected 5-year overall survival (OS rate was 83%. Side effects of imatib (copy in this study were similar to those reported previously for the entire imatinib mesylate treatment study and only 8% of patients were intolerant to imatib (copy and treated with a second generation of BCR

  5. CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients.

    Science.gov (United States)

    Barratt, Daniel T; Cox, Hannah K; Menelaou, Andrew; Yeung, David T; White, Deborah L; Hughes, Timothy P; Somogyi, Andrew A

    2017-08-01

    The aims of this study were to determine the effects of the CYP2C8*3 and *4 polymorphisms on imatinib metabolism and plasma imatinib concentrations in chronic myeloid leukaemia (CML) patients. We genotyped 210 CML patients from the TIDELII trial receiving imatinib 400-800 mg/day for CYP2C8*3 (rs11572080, rs10509681) and *4 (rs1058930). Steady-state trough total plasma N-desmethyl imatinib (major metabolite):imatinib concentration ratios (metabolic ratios) and trough total plasma imatinib concentrations were compared between genotypes (one-way ANOVA with Tukey post hoc). CYP2C8*3 (n = 34) and *4 (n = 15) carriers had significantly higher (P  50% higher for CYP2C8*1/*4 than for CYP2C8*1/*1 and CYP2C8*3 carriers (2.18 ± 0.66 vs. 1.45 ± 0.74 [P < 0.05] and 1.36 ± 0.98 μg/mL [P < 0.05], respectively). CYP2C8 genotype significantly alters imatinib metabolism in patients through gain- and loss-of-function mechanisms.

  6. High-dose secondary calibration laboratory accreditation program

    Energy Technology Data Exchange (ETDEWEB)

    Humphreys, J.C. [National Institute of Standards and Technology, Gaithersburg, MD (United States)

    1993-12-31

    There is a need for high-dose secondary calibration laboratories to serve the multi-billion dollar radiation processing industry. This need is driven by the desires of industry for less costly calibrations and faster calibration-cycle response time. Services needed include calibration irradiations of routine processing dosimeters and the supply of reference standard transfer dosimeters for irradiation in the production processing facility. In order to provide measurement quality assurance and to demonstrate consistency with national standards, the high-dose secondary laboratories would be accredited by means of an expansion of an existing National Voluntary Laboratory Accreditation Program. A laboratory performance criteria document is under development to implement the new program.

  7. High-dose secondary calibration laboratory accreditation program

    International Nuclear Information System (INIS)

    Humphreys, J.C.

    1993-01-01

    There is a need for high-dose secondary calibration laboratories to serve the multi-billion dollar radiation processing industry. This need is driven by the desires of industry for less costly calibrations and faster calibration-cycle response time. Services needed include calibration irradiations of routine processing dosimeters and the supply of reference standard transfer dosimeters for irradiation in the production processing facility. In order to provide measurement quality assurance and to demonstrate consistency with national standards, the high-dose secondary laboratories would be accredited by means of an expansion of an existing National Voluntary Laboratory Accreditation Program. A laboratory performance criteria document is under development to implement the new program

  8. Anticoagulation and high dose liver radiation. A preliminary report

    International Nuclear Information System (INIS)

    Lightdale, C.J.; Wasser, J.; Coleman, M.; Brower, M.; Tefft, M.; Pasmantier, M.

    1979-01-01

    Two groups of patients were observed for evidence of acute radiation hepatitis during high dose radiation to the liver. The first group of 18 patients with metastatic liver disease received an average of 4,050 rad to the whole liver. Half received anticoagulation with warfarin. One patient on anticoagulation developed evidence of acute radiation hepatitis while 2 patients did so without anticoagulation. Eleven patients with Hodgkin's disease received 4,000 rad to the left lobe of the liver during extended field radiation. Four of these 11 patients were anticoagulated to therapeutic range. Only one of the fully anticoagulated patients showed changes on liver scan consistent with radiation hepatitis whereas three did so without anticoagulation. No serious sequelae from anticoagulation occurred in either group. These preliminary data suggest that anticoagulation may be safely administered with high dose hepatic radiation and that further trials with anticoagulation are warranted

  9. Radiotherapy and high-dose chemotherapy in advanced Ewing's tumors

    International Nuclear Information System (INIS)

    Pape, H.; Glag, M.; Gripp, S.; Wittkamp, M.; Schmitt, G.; Laws, H.J.; Kaik, B. van; Goebel, U.; Burdach, S.; Juergens, H.

    1999-01-01

    Background: Ewing's tumors are sensitive to radio- and chemotherapy. Patients with multifocal disease suffer a poor prognosis. Patients presenting primary bone marrow involvement or bone metastases at diagnosis herald a 3-year disease-free survival below 15%. The European Intergroup Cooperative Ewing's Sarcoma Study (EICESS) has established the following indications for high-dose therapy in advanced Ewing's tumors: Patients with primary multifocal bone disease, patients with early ( [de

  10. Effects of Tyrosine Kinase inhibitor Imatinib (Glivec) on PDGFR-positive primary and metastatic melanoma cells

    International Nuclear Information System (INIS)

    Straface, E.; Gambardella, L.; Vona, R.

    2009-01-01

    In summary these preliminary results indicate that Imatinib is able to induce apoptosis in metastatic cells and to sensitize these cells to pro-apoptotic agents commonly used in melanoma therapy, e.g. radiation or Cisplatin. Conversely, primary melanoma cells seem to be intrinsically resistant either to Imatinib given alone or in combination with Cisplatin or radiation. By contrast, these cells underwent autophagy and replicative senescence boostering their survival. Interestingly, the use of Imatinib in combination with anti-CD95/Fas antibodies sensitizes primary melanoma cells to apoptosis

  11. High-dose buprenorphine: perioperative precautions and management strategies.

    Science.gov (United States)

    Roberts, D M; Meyer-Witting, M

    2005-02-01

    Buprenorphine has been in clinical use in anaesthesia for several decades. Recently, the high-dose sublingual formulation (Subutex, Reckitt Benckiser, Slough, U.K.) has been increasingly used as maintenance therapy in opioid dependence, as an alternative to methadone and other pharmacological therapies. Buprenorphine has unique pharmacological properties making it well suited for use as a maintenance therapy in opioid dependence. However, these same properties may cause difficulty in the perioperative management of pain. Buprenorphine is a partial opioid agonist, attenuating the effects of supplemental illicit or therapeutic opioid agonists. As a result of its high receptor affinity, supplemental opioids do not readily displace buprenorphine from the opioid receptor in standard doses. High-dose buprenorphine has an extended duration of action that prolongs both of these effects. The perioperative management of patients stabilized on high-dose buprenorphine and undergoing surgery requires consideration of the likely analgesic requirements. Where possible the buprenorphine should be continued. Pain management should focus on maximizing non-opioid analgesia, local anaesthesia and non-pharmacological techniques. Where pain may not be adequately relieved by these methods, the addition of a full opioid agonist such as fentanyl or morphine at appropriate doses should be considered, accompanied by close monitoring in a high dependency unit. In situations where this regimen is unlikely to be effective, preoperative conversion to morphine or methadone may be an option. Where available, liaison with a hospital-based alcohol and drug service should always be considered.

  12. A novel theory of radiation damage at high doses

    International Nuclear Information System (INIS)

    Seeger, A.; Stuttgart Univ.

    1989-01-01

    Deviations of radiation damage (in the case of metals usually monitored by the residual electrical resistivity) from proportionality with the irradiation dose have so far been analysed almost exclusively in terms of extensions of models originally developed for small doses. The present theory considers the opposite limit i.e. the quasi-saturated state. It is argued that at high doses the Lueck-Sizmann effect may result in a self-organization of clusters of vacancies and self-interstitials, forming a heterogeneous froth. Possible structures of this froth and its effect on the electrical resistivity of metals are discussed. The model is shown to account for the dependence of the ''saturation resistivity'' on the nature of the irradiation as well as for several other hitherto poorly explained observations. Among them are the electrical-resistivity variation induced by high-dose irradiation with heavy ions, the amorphization of certain alloys by high-dose electron irradiation, and the occurrence of ordered arrays of stacking-fault tetrahedra after in-situ irradiations in high-voltage electron microscopes. (author)

  13. Radiophotoluminescence light scope for high-dose dosimetry

    International Nuclear Information System (INIS)

    Sato, Fuminobu; Zushi, Naoki; Sakiyama, Tomoki; Kato, Yushi; Murata, Isao; Shimizu, Kikuo; Yamamoto, Takayoshi; Iida, Toshiyuki

    2015-01-01

    A radiophotoluminescence (RPL) light scope is a remote-sensing technique for measuring in situ the radiation dose in an RPL detector placed at a distance. The RPL light scope is mainly composed of an ultraviolet (UV) pulse laser, telescopic lenses, a photomultiplier tube, and camera modules. In a performance test, some RPL detectors were placed at distances up to 30 m and were illuminated with a pulsed UV laser beam. The photoluminescence responses of the RPL detectors were analyzed using this scope. Their radiation doses were determined from the amplitude of the given component of the photoluminescence responses. The RPL readout could be repeated without fading, and its amplitude exhibited good linearity at a dose ranging from 0.1 to 60 Gy. Furthermore, a two-dimensional distribution of radiation dose was obtained by laser scanning on an RPL detector. It was confirmed that the RPL light scope was a useful remote-sensing tool for high-dose dosimetry. - Highlights: • A radiophotoluminescence (RPL) light scope was developed for high-dose dosimetry. • The RPL light scope has high sensitivity and accuracy in high-dose dosimetry. • Two-dimensional radiation dose distribution was obtained by the RPL light scope.

  14. Precision, high dose radiotherapy: helium ion treatment of uveal melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Saunders, W.M.; Char, D.H.; Quivey, J.M.; Castro, J.R.; Chen, G.T.Y.; Collier, J.M.; Cartigny, A.; Blakely, E.A.; Lyman, J.T.; Zink, S.R.

    1985-02-01

    The authors report on 75 patients with uveal melanoma who were treated by placing the Bragg peak of a helium ion beam over the tumor volume. The technique localizes the high dose region very tightly around the tumor volume. This allows critical structures, such as the optic disc and the macula, to be excluded from the high dose region as long as they are 3 to 4 mm away from the edge of the tumor. Careful attention to tumor localization, treatment planning, patient immobilization and treatment verification is required. With a mean follow-up of 22 months (3 to 60 months) the authors have had only five patients with a local recurrence, all of whom were salvaged with another treatment. Pretreatment visual acuity has generally been preserved as long as the tumor edge is at least 4 mm away from the macula and optic disc. The only serious complication to date has been an 18% incidence of neovascular glaucoma in the patients treated at our highest dose level. Clinical results and details of the technique are presented to illustrate potential clinical precision in administering high dose radiotherapy with charged particles such as helium ions or protons.

  15. Precision, high dose radiotherapy: helium ion treatment of uveal melanoma

    International Nuclear Information System (INIS)

    Saunders, W.M.; Char, D.H.; Quivey, J.M.

    1985-01-01

    The authors report on 75 patients with uveal melanoma who were treated by placing the Bragg peak of a helium ion beam over the tumor volume. The technique localizes the high dose region very tightly around the tumor volume. This allows critical structures, such as the optic disc and the macula, to be excluded from the high dose region as long as they are 3 to 4 mm away from the edge of the tumor. Careful attention to tumor localization, treatment planning, patient immobilization and treatment verification is required. With a mean follow-up of 22 months (3 to 60 months) the authors have had only five patients with a local recurrence, all of whom were salvaged with another treatment. Pretreatment visual acuity has generally been preserved as long as the tumor edge is at least 4 mm away from the macula and optic disc. The only serious complication to date has been an 18% incidence of neovascular glaucoma in the patients treated at our highest dose level. Clinical results and details of the technique are presented to illustrate potential clinical precision in administering high dose radiotherapy with charged particles such as helium ions or protons

  16. The clinical effect of deferoxamine mesylate on edema after intracerebral hemorrhage.

    Science.gov (United States)

    Yu, Yao; Zhao, Wei; Zhu, Chunpeng; Kong, Zhiping; Xu, Yan; Liu, Guangzhi; Gao, Xuguang

    2015-01-01

    It has been shown that 3 days of 62 mg/kg/day deferoxamine infusion (maximum dose not to exceed 6000 mg/day) is safe and tolerated by intracerebral hemorrhage (ICH) patients. The aim of this study was to investigate the efficacy of deferoxamine mesylate for edema resolution and hematoma absorption after ICH. From February 2013 to May 2014, spontaneous ICH patients diagnosed by computed tomography (CT) within 18 hours of onset were evaluated. Patients were randomly divided into two groups: an experimental group and a control group. The treatment of the two groups was similar except that the experimental group received deferoxamine mesylate. Patients were evaluated by CT and neurology scale at the time of admission, and on the fourth, eighth, and fifteenth day (or at discharge) after admission. Patients were followed up for the first 30 days and clinical data of the two groups were compared. Forty-two patients completed 30 days of follow-up by May 2014; 21 cases in the experimental group and 21 cases in the control group. The control group's relative edema volume on the fifteenth day (or discharge) was 10.26 ± 17.54, which was higher than the experimental group (1.91 ± 1.94; P edema volume on the fourth, eighth, and fifteenth day (or discharge) was higher than the experimental group (P edema after ICH, although further investigation is required to form definitive conclusions. Chinese Clinical Trial Registry ChiCTR-TRC-14004979.

  17. High dose vitamin K3 infusion in advanced hepatocellular carcinoma.

    Science.gov (United States)

    Sarin, Shiv K; Kumar, Manoj; Garg, Sanjay; Hissar, Syed; Pandey, Chandana; Sharma, Barjesh C

    2006-09-01

    The survival of patients with unresectable advanced hepatocellular carcinoma (HCC) with portal vein thrombosis is dismal. Current therapeutic options have limited efficacy. Vitamin K has been shown to have antitumor effect on HCC cells both in cell lines and patients with advanced HCC. The aim of this study was to assess the clinical efficacy of high dose vitamin K3 in the treatment of advanced HCC with portal vein thrombosis. Forty-two consecutive patients with advanced HCC (Stage C according to BCLC staging system) with portal vein thrombosis were randomized into two groups: (i) high dose vitamin K3 (n = 23); and (ii) placebo (n = 19). The vitamin K3 was administered by i.v. infusion of 50 mg/day with daily increase of dose by 50 mg for 6 days, followed by 20 mg i.m. twice daily for 2 weeks. Of the 23 patients treated with vitamin K, one (4.3%) achieved complete response and three (13%) partial response, for a total of four (17.4%) objective responders overall. The overall mean survival was 8.9 +/- 8.8 months (median: 6; range 1-37 months) in the vitamin K group and 6.8 +/- 5.3 months (median: 5; range 1.5-21 months) in the placebo group (P = 0.552). The mean duration of survival was longer in patients in the vitamin K group who achieved objective response (22.5 +/- 12.2; median: 21; range 11-37 months) as compared to patients not achieving objective response (6.1 +/- 4.6; median: 5; range 1-16 months) (P = 0.0.002). Portal vein thrombosis resolved with complete patency in one (4.35%) patient. Treatment with high dose vitamin K produces objective response in 17% patients with improved survival in patients achieving objective response; however, it does not affect the overall survival.

  18. Cooperative binding mitigates the high-dose hook effect.

    Science.gov (United States)

    Roy, Ranjita Dutta; Rosenmund, Christian; Stefan, Melanie I

    2017-08-14

    The high-dose hook effect (also called prozone effect) refers to the observation that if a multivalent protein acts as a linker between two parts of a protein complex, then increasing the amount of linker protein in the mixture does not always increase the amount of fully formed complex. On the contrary, at a high enough concentration range the amount of fully formed complex actually decreases. It has been observed that allosterically regulated proteins seem less susceptible to this effect. The aim of this study was two-fold: First, to investigate the mathematical basis of how allostery mitigates the prozone effect. And second, to explore the consequences of allostery and the high-dose hook effect using the example of calmodulin, a calcium-sensing protein that regulates the switch between long-term potentiation and long-term depression in neurons. We use a combinatorial model of a "perfect linker protein" (with infinite binding affinity) to mathematically describe the hook effect and its behaviour under allosteric conditions. We show that allosteric regulation does indeed mitigate the high-dose hook effect. We then turn to calmodulin as a real-life example of an allosteric protein. Using kinetic simulations, we show that calmodulin is indeed subject to a hook effect. We also show that this effect is stronger in the presence of the allosteric activator Ca 2+ /calmodulin-dependent kinase II (CaMKII), because it reduces the overall cooperativity of the calcium-calmodulin system. It follows that, surprisingly, there are conditions where increased amounts of allosteric activator actually decrease the activity of a protein. We show that cooperative binding can indeed act as a protective mechanism against the hook effect. This will have implications in vivo where the extent of cooperativity of a protein can be modulated, for instance, by allosteric activators or inhibitors. This can result in counterintuitive effects of decreased activity with increased concentrations of

  19. Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Michio [Minamata City Hospital and Medical Center, Minamata City, Kumamoto 867 (Japan); Kortylewicz, Zbigniew P.; Enke, Charles A.; Mack, Elizabeth; Baranowska-Kortylewicz, Janina, E-mail: jbaranow@unmc.edu [Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, Omaha, NE 68198 (United States)

    2011-05-25

    Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment-and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy.

  20. Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer

    International Nuclear Information System (INIS)

    Abe, Michio; Kortylewicz, Zbigniew P.; Enke, Charles A.; Mack, Elizabeth; Baranowska-Kortylewicz, Janina

    2011-01-01

    Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment-and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy

  1. Radiation processing and high-dose dosimetry at ANSTO

    International Nuclear Information System (INIS)

    Gant, G.J.; Saunders, M.; Banos, C.; Mo, L.; Davies, J.; Evans, O.

    2001-01-01

    The Radiation Technology group at ANSTO is part of the Physics Division and provides services and advice in the areas of gamma irradiation and high-dose dosimetry. ANSTO's irradiation facilities are designed for maximum dose uniformity and provide a precision irradiation service unique in Australia. Radiation Technology makes and sells reference and transfer standard dosimeters which are purchased by users and suppliers of commercial irradiation services in Australia and the Asia-Pacific region. A calibration service is also provided for dosimeters purchased from other suppliers

  2. An evaluation of high-dose jobs for ALARA improvement

    International Nuclear Information System (INIS)

    Mun, J. H.; Kim, H. S.

    1997-01-01

    It is well known that about 70 percent of occupational dose have incurred from maintenance jobs at outage period. To reduce occupational dose, first, the high-dose jobs at the outage period should be identified and evaluated. For this, the database program is used, which contains the ORE data of reference plants, Kori Units 3 and 4. As a result, it is found that the jobs related to steam generator are the highest dose jobs in terms of collective ORE dose. From the analysis of the job procedures of those jobs, the ALARA improvements are also derived

  3. Australian high-dose-rate brachytherapy protocols for gynaecological malignancy

    International Nuclear Information System (INIS)

    MacLeod, C.; Dally, M.; Stevens, M.; Thornton, D.; Carruthers, S.; Jeal, P.

    2001-01-01

    There is no consensus over the optimal dose fractionation schedules for high-dose-rate (HDR) brachytherapy used for gynaecological malignancy. In Australian public hospital departments of radiation oncology, HDR brachytherapy for gynaecological cancer is being more commonly used. A survey of public departments that are using this technology, or that plan to introduce this technology, was performed. Their current protocols are presented. In general, protocols are similar biologically; however, the practical aspects such as the number of fractions given do vary and may reflect resource restrictions or, alternatively, differences in interpretations of the literature and of the best protocols by clinicians. Copyright (2001) Blackwell Science Pty Ltd

  4. Prehospital high-dose sublingual nitroglycerin rarely causes hypotension.

    Science.gov (United States)

    Clemency, Brian M; Thompson, Jeffrey J; Tundo, Gina N; Lindstrom, Heather A

    2013-10-01

    High-dose intravenous nitroglycerin is a common in-hospital treatment for respiratory distress due to congestive heart failure (CHF) with hypertension. Intravenous (IV) nitroglycerin administration is impractical in the prehospital setting. In 2011, a new regional Emergency Medical Services (EMS) protocol was introduced allowing advanced providers to treat CHF with high-dose oral nitroglycerin. The protocol calls for patients to be treated with two sublingual tabs (0.8 mg) when systolic blood pressure (SBP) was >160 mm Hg, or three sublingual tabs (1.2 mg) when SBP was >200 mm Hg, every five minutes as needed. Hypothesis/Problem To assess the protocol's safety, the incidence of hypotension following prehospital administration of multiple simultaneous nitroglycerin (MSN) tabs by EMS providers was studied. This study was a retrospective cohort study of patients from a single commercial EMS agency over a 6-month period. Records from patients with at least one administration of MSN were reviewed. For each administration, the first documented vital signs pre- and post-administration were compared. Administrations were excluded if pre- or post-administration vital signs were missing. One hundred case-patients had at least one MSN administration by an advanced provider during the study period. Twenty-five case-patients were excluded due to incomplete vital signs. Seventy-five case-patients with 95 individual MSN administrations were included for analysis. There were 65 administrations of two tabs, 29 administrations of three tabs, and one administration of four tabs. The mean change in SBP following MSN was -14.7 mm Hg (SD = 30.7; range, +59 to -132). Three administrations had documented systolic hypotension in the post-administration vital signs (97/71, 78/50 and 66/47). All three patients were over 65 years old, were administered two tabs, had documented improved respiratory status, and had repeat SBP of at least 100. The incidence of hypotension following MSN

  5. High-dose irradiated food: Current progress, applications, and prospects

    Science.gov (United States)

    Feliciano, Chitho P.

    2018-03-01

    Food irradiation as an established and mature technology has gained more attention in the food industry for ensuring food safety and quality. Primarily used for phytosanitary applications, its use has been expanded for developing various food products for varied purposes (e.g. ready-to-eat & ready-to-cook foods, hospital diets, etc.). This paper summarized and analyzed the recent progress and application of high-dose irradiation and discussed its prospects in the field of food product development, its safety and quality.

  6. Establishment of a dosimetric system for high doses using glasses

    International Nuclear Information System (INIS)

    Correa Quezada, Valeria de la Asuncion

    1997-01-01

    A routine dosimetric system was developed using commercial glass samples. The dosimetric characteristics of national and imported samples were studied: batch uniformity, response repeatability, reutilization, absorbed dose response, detection range, response stability as a function of absorbed dose, storage temperature and thermal treatments pre- and post-irradiation, using the optical absorption technique. As an application, the dosimetric system was tested in a flower irradiation process at IPEN. All the obtained results show the usefulness of the proposed system for high dose dosimetry. (author)

  7. Effects of co-dergocrine mesylate (Hydergine) in multi-infarct dementia as evaluated by positron emission tomography

    International Nuclear Information System (INIS)

    Nagasawa, Haruo; Kogure, Kyuya; Kawashima, Koichiro; Ido, Tatsuo; Itoh, Masatoshi; Hatazawa, Jun.

    1990-01-01

    Three female patients aged from 74 to 79 with multi-infarct dementia were studied using positron emission tomography (PET) to assess the effect of co-dergocrine mesylate (Hydergine) on cerebral glucose metabolism. The cerebral glucose utilization (CMRGlc) of each patient was evaluated by PET scan using 2-deoxy-[ 18 F]-2-fluoro-D-glucose (FDG). Following the first PET study, 0.04 mg/kg of co-dergocrine mesylate was injected intravenously with 250 ml saline solution, and then the second PET study was performed. The CMRGlc was determined from the images of the PET scan and the radioactivity of 18 F in the plasma. After the administration of co-dergocrine mesylate, the value of CMRGlc increased significantly in the cerebral cortex (p<0.01 and p<0.05) and basal ganglia (p<0.05) compared with values before the administration, but no significant increase was found in the centrum semiovale. These results suggest that co-dergocrine mesylate stimulates glucose metabolism of neurons in the human brain. (author)

  8. A radioprotective effect of imatinib (Gleevec registered) in human squamous carcinoma cells

    International Nuclear Information System (INIS)

    Bartkowiak, D.; Hipp, P.R.; Roettinger, E.M.; Mendonca, M.S.

    2007-01-01

    Purpose: To study the radiation response-modifying effect of imatinib (Gleevec registered ) in a squamous cell carcinoma line, PECA. Patients and Methods: Cytotoxicity was determined by colony forming and multiplying capacity. Drug stability was shown by HPLC. Multidrug resistance phenotype was studied by rhodamine-123 efflux. Cell-cycle responses were measured by flow cytometry. Homologous recombination repair was determined by Rad51 immunohistochemistry. Results: Inactivating 50% of the PECA cells required approximately 7 μM imatinib. The drug did not decay nor was it degraded during test periods. Drug efflux occurred only to a minor extent. Multiplying capacity but not survival fractions revealed a radioprotective effect of imatinib. There were only minor cell-cycle alterations in the presence of imatinib but the rate of Rad51-positive repair foci was significantly increased. Conclusion: PECA cells apparently lack a highly specific target for imatinib. In cells surviving at high drug concentrations, imatinib may exert a radioprotective effect on multiplying capacity by inducing DNA repair. Under prolonged exposure, drug-resistant cells may show an accelerated recovery from acute or delayed radiation damage. (orig.)

  9. Could imatinib replace surgery in esophageal gastrointestinal stromal tumor

    International Nuclear Information System (INIS)

    Al-Salam, Suhail N.; El-Teraifi, Hassan A.; Taha, Mazen S.

    2006-01-01

    Gastrointestinal stromal tumors (GISTs) are cellular spindle, or epithelioid tumors that occur in the stomach, intestine and rarely in the esophagus. A 61-years-old man was complaining of resistant dry cough with dysphagia for one month duration. Upper gastrointestinal tract endoscopic examination showed a polypoid mass 30 cm from the incisors obstructing 50% of the lumen, where multiple biopsies were taken. Magnetic resonance imaging (MRI) showed a mass in the wall of the esophagus extending into the thoracic cavity. Histologically, the stained sections with routine hematoxylin and eosin as well as the immunohistochemical stainsfor CD117, CD34, S100, vimentin and smooth muscle actin confirmed the diagnosis of esophageal GIST. The patient was treated with imatinib 400mg/day. There was a dramatic reduction in the size of the tumor with successful improvement of his symptoms after 2 months of treatment, which was confirmed by reapeated upper GIT endoscopy, and MRI. (author)

  10. Leucemia Mielóide Crônica: causas de falha do tratamento com mesilato de imatinibe Chronic Myeloid Leukemia: causes of treatment failure with imatinib

    Directory of Open Access Journals (Sweden)

    Katia B. B. Pagnano

    2008-04-01

    Full Text Available O mesilato de imatinibe (MI é atualmente o tratamento de escolha da Leucemoa Mielóide Crônica (LMC, mas, apesar dos excelentes resultados, não é capaz de erradicar completamente a doença, podendo ocorrer resistência ao tratamento. O mecanismo mais conhecido de resistência é o desenvolvimento de mutações do BCR-ABL, que impedem a ação ligação adequada do imatinibe à quinase, além de amplificação gênica e evolução clonal. No entanto, há uma série de outros mecanismos envolvidos e ainda pouco estudados, como alterações na absorção, efluxo e influxo de droga para o interior das células. Devem-se também considerar outros fatores, como aderência ao tratamento e uso de medicamentos concomitantes que podem interferir com imatinibe, diminuindo sua ação. O entendimento desses mecanismos poderá contribuir no desenvolvimento de novas estratégias para o tratamento dos casos resistentes.Imatinib is currently the treatment of choice of CML, but despite of the excellent results, it is not able to completely eradicate the disease and resistance may occur. The most studied mechanism is the presence of ABL kinase mutations that interfere with imatinib binding and action, gene amplification and clonal evolution. However, there are other mechanisms involved and less studied such as drug absorption and influx and efflux of imatinib. Besides the true causes of resistance, compliance is always a concern and also drug interaction should be checked. An understanding of these mechanisms will certainly contribute to develop new strategies for the treatment of resistant cases.

  11. Molecular response to imatinib & its correlation with mRNA expression levels of imatinib influx & efflux transporters in patients with chronic myeloid leukaemia in chronic phase

    Directory of Open Access Journals (Sweden)

    Hemant Malhotra

    2015-01-01

    Full Text Available Background & objectives: Imatinib is the standard first-line treatment for chronic myeloid leukaemia (CML patients. About 20 to 30 per cent patients develop resistance to imatinib and fail imatinib treatment. One of the mechanisms proposed is varying expression levels of the drug transporters. This study was aimed to determine the expression levels of imatinib transporter genes (OCT1, ABCB1, ABCG2 in CML patients and to correlate these levels with molecular response. Methods: Sixty three CML chronic phase patients who were on 400 mg/day imatinib for more than two years were considered for gene expression analysis study for OCT1, ABCB1 and ABCG2 genes. These were divided into responders and non-responders. The relative transcript expression levels of the three genes were compared between these two categories. The association between the expression values of these three genes was also determined. Results: No significant difference in the expression levels of OCT1, ABCB1 and ABCG2 was found between the two categories. The median transcript expression levels of OCT1, ABCB1 and ABCG2 genes in responders were 26.54, 10.78 and 0.64 versus 33.48, 7.09 and 0.53 in non-responders, respectively. A positive association was observed between the expression of the ABCB1 and ABCG2 transporter genes (r=0.407, P<0.05 while no association was observed between the expression of either of the ABC transporter genes with the OCT1 gene. Interpretation & conclusions: Our findings demonstrated that the mRNA expression levels of imatinib transporter genes were not correlated with molecular response in CML patients. Further studies need to be done on a large sample of CML patients to confirm these findings.

  12. The influence of high doses of radiation in citrine stones

    International Nuclear Information System (INIS)

    Teixeira, M. I.; Caldas, L. V. E.

    2014-08-01

    The possibility of using samples of Brazilian stones as quartz, amethyst, topaz, jasper, etc. for high-dose dosimetry has been studied in recent years at IPEN, using the techniques of optical absorption (Oa), thermoluminescent (Tl), optically stimulated luminescence (OSL) and resonance paramagnetic electron (EPR). In this work, the Tl properties of citrine samples were studied. They were exposed to different doses of gamma radiation ( 60 Co). The natural citrine stone was extracted from a mine in Minas Gerais state, Brazil; it is a tecto silicate ranked as one of three-dimensional structure, showing clear yellow to golden brown color. The natural citrine stone is classified as quartz (SiO 2 ), and it has a lower symmetry and more compact reticulum. The Tl emission curve showed two peaks at 160 grades C and 220 grades C. To remove the Tl peak (160 grades C) of the sintered citrine pellet glow curves, different thermal treatments were tested during several time intervals. The Tl dose-response curve between 50 Gy and 100 kGy, the reproducibility of Tl response and the lower detection dose were obtained. The results show that citrine may be useful as high-dose detectors. (Author)

  13. High-dose contrast-enhanced MRI in multiple sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Koudriavtseva, T. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Pozzilli, C. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Di Biasi, C. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy); Iannilli, M. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy); Trasimeni, G. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy); Gasperini, C. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Argentino, C. [Department of Neurosciences, University of Rome ``La Sapienza`` Rome (Italy); Gualdi, G.F. [MR Unit, Clinica Medica 1, University of Rome ``La Sapienza``, Rome (Italy)

    1996-05-01

    Contrast-enhanced MRI is effective for assessing disease activity in multiple sclerosis (MS) and may provide an outcome measure for testing the efficacy of treatment in clinical trials. To compare the sensitivity of high-dose gadolinium-HP-DO3A with that of a standard dose of gadolinium-DTPA, we studied 16 patients with relapsing-remitting MS in the acute phase of the disease. Each underwent two MRI examinations within at most 48 h. The initial MRI study was with a standard dose of gadolinium-DTPA (0.1 mmol/kg), and the second one an experimental dose of gadolinium-HP-DO3A (0.3 mmol/kg). No adverse effects were attributed to the contrast media. The high-dose study revealed more enhancing lesions than the standard-dose study (56 vs 38). This difference was found to be more relevant for infratentorial and small lesions. Furthermore, with the higher dose, there was a marked qualitative improvement in the visibility and delineation of the lesions. (orig.). With 4 figs., 2 tabs.

  14. TL response of citrine samples for high-dose dosimetry

    International Nuclear Information System (INIS)

    Teixeira, Maria Ines; Caldas, Linda V.E.

    2011-01-01

    The possibility of using samples of Brazilian stones as quartz, amethyst, topaz, etc. for high-dose dosimetry has been studied in recent years at IPEN, using the thermoluminescence technique (TL). In this work, the TL properties of citrine samples were studied. They were exposed to different doses of gamma radiation ( 60 Co). The natural citrine stone was extracted from a mine in Minas Gerais state, Brazil; it is a tectosilicate ranked as one of three-dimensional structure, showing clear yellow to golden brown color. The natural citrine stone is classified as quartz (SiO 2 ), and it has a lower symmetry and more compact reticulum. The citrine stone samples were powdered, and the selected grains were mixed with Teflon in the proportion 2 (Teflon):1 (Citrine). The mixture was pressed and sintered for production of Citrine -Teflon pellets of 50 mg. The TL emission curve showed two peaks at 160 deg C and 220 deg C. To remove the TL peak (160 deg C) of the sintered citrine pellet glow curves, different thermal treatments were tested during several time intervals. The TL dose-response curve between 50 Gy and 100 kGy, the reproducibility of TL response and the lower detection dose were obtained. The preliminary results show that citrine may be useful for high-dose dosimetry. (author)

  15. Spectroscopic gamma camera for use in high dose environments

    Energy Technology Data Exchange (ETDEWEB)

    Ueno, Yuichiro, E-mail: yuichiro.ueno.bv@hitachi.com [Research and Development Group, Hitachi, Ltd., Hitachi-shi, Ibaraki-ken 319-1221 (Japan); Takahashi, Isao; Ishitsu, Takafumi; Tadokoro, Takahiro; Okada, Koichi; Nagumo, Yasushi [Research and Development Group, Hitachi, Ltd., Hitachi-shi, Ibaraki-ken 319-1221 (Japan); Fujishima, Yasutake; Kometani, Yutaka [Hitachi Works, Hitachi-GE Nuclear Energy, Ltd., Hitachi-shi, Ibaraki-ken (Japan); Suzuki, Yasuhiko [Measuring Systems Engineering Dept., Hitachi Aloka Medical, Ltd., Ome-shi, Tokyo (Japan); Umegaki, Kikuo [Faculty of Engineering, Hokkaido University, Sapporo-shi, Hokkaido (Japan)

    2016-06-21

    We developed a pinhole gamma camera to measure distributions of radioactive material contaminants and to identify radionuclides in extraordinarily high dose regions (1000 mSv/h). The developed gamma camera is characterized by: (1) tolerance for high dose rate environments; (2) high spatial and spectral resolution for identifying unknown contaminating sources; and (3) good usability for being carried on a robot and remotely controlled. These are achieved by using a compact pixelated detector module with CdTe semiconductors, efficient shielding, and a fine resolution pinhole collimator. The gamma camera weighs less than 100 kg, and its field of view is an 8 m square in the case of a distance of 10 m and its image is divided into 256 (16×16) pixels. From the laboratory test, we found the energy resolution at the 662 keV photopeak was 2.3% FWHM, which is enough to identify the radionuclides. We found that the count rate per background dose rate was 220 cps h/mSv and the maximum count rate was 300 kcps, so the maximum dose rate of the environment where the gamma camera can be operated was calculated as 1400 mSv/h. We investigated the reactor building of Unit 1 at the Fukushima Dai-ichi Nuclear Power Plant using the gamma camera and could identify the unknown contaminating source in the dose rate environment that was as high as 659 mSv/h.

  16. High-dose contrast-enhanced MRI in multiple sclerosis

    International Nuclear Information System (INIS)

    Koudriavtseva, T.; Pozzilli, C.; Di Biasi, C.; Iannilli, M.; Trasimeni, G.; Gasperini, C.; Argentino, C.; Gualdi, G.F.

    1996-01-01

    Contrast-enhanced MRI is effective for assessing disease activity in multiple sclerosis (MS) and may provide an outcome measure for testing the efficacy of treatment in clinical trials. To compare the sensitivity of high-dose gadolinium-HP-DO3A with that of a standard dose of gadolinium-DTPA, we studied 16 patients with relapsing-remitting MS in the acute phase of the disease. Each underwent two MRI examinations within at most 48 h. The initial MRI study was with a standard dose of gadolinium-DTPA (0.1 mmol/kg), and the second one an experimental dose of gadolinium-HP-DO3A (0.3 mmol/kg). No adverse effects were attributed to the contrast media. The high-dose study revealed more enhancing lesions than the standard-dose study (56 vs 38). This difference was found to be more relevant for infratentorial and small lesions. Furthermore, with the higher dose, there was a marked qualitative improvement in the visibility and delineation of the lesions. (orig.). With 4 figs., 2 tabs

  17. Radiation safety program in a high dose rate brachytherapy facility

    International Nuclear Information System (INIS)

    Rodriguez, L.V.; Hermoso, T.M.; Solis, R.C.

    2001-01-01

    The use of remote afterloading equipment has been developed to improve radiation safety in the delivery of treatment in brachytherapy. Several accidents, however, have been reported involving high dose-rate brachytherapy system. These events, together with the desire to address the concerns of radiation workers, and the anticipated adoption of the International Basic Safety Standards for Protection Against Ionizing Radiation (IAEA, 1996), led to the development of the radiation safety program at the Department of Radiotherapy, Jose R. Reyes Memorial Medical Center and at the Division of Radiation Oncology, St. Luke's Medical Center. The radiation safety program covers five major aspects: quality control/quality assurance, radiation monitoring, preventive maintenance, administrative measures and quality audit. Measures for evaluation of effectiveness of the program include decreased unnecessary exposures of patients and staff, improved accuracy in treatment delivery and increased department efficiency due to the development of staff vigilance and decreased anxiety. The success in the implementation required the participation and cooperation of all the personnel involved in the procedures and strong management support. This paper will discuss the radiation safety program for a high dose rate brachytherapy facility developed at these two institutes which may serve as a guideline for other hospitals intending to install a similar facility. (author)

  18. ELDRS Characterization for a Very High Dose Mission

    Science.gov (United States)

    Harris, Richard D.; McClure, Steven S.; Rax, Bernard G.; Kenna, Aaron J.; Thorbourn, Dennis O.; Clark, Karla B.; Yan, Tsun-Yee

    2010-01-01

    Evaluation of bipolar linear parts which may have Enhanced Low Dose Rate Sensitivity (ELDRS) is problematic for missions that have very high dose radiation requirements. The accepted standards for evaluating parts that display ELDRS require testing at a very low dose rate which could be prohibitively long for very high dose missions. In this work, a methodology for ELDRS characterization of bipolar parts for mission doses up to 1 Mrad(Si) is evaluated. The procedure employs an initial dose rate of 0.01 rad(Si)/s to a total dose of 50 krad(Si) and then changes to 0.04 rad(Si)/s to a total dose of 1 Mrad(Si). This procedure appears to work well. No change in rate of degradation with dose has been observed when the dose rate is changed from 0.01 to 0.04 rad(Si)/s. This is taken as an indication that the degradation due to the higher dose rate is equivalent to that at the lower dose rate at the higher dose levels, at least for the parts studied to date. In several cases, significant parameter degradation or functional failure not observed at HDR was observed at fairly high total doses (50 to 250 krad(Si)) at LDR. This behavior calls into question the use of dose rate trend data and enhancement factors to predict LDR performance.

  19. Methodology of high dose research in medical radiodiagnostic

    International Nuclear Information System (INIS)

    Barboza, Adriana E.; Martins, Cintia P. de S.

    2013-01-01

    This work has as main purpose to study occupational exposure in diagnostic radiology in medical cases of high doses recorded in 2011 at the national level . These doses were recorded by monitoring individual of the occupationally exposed individuals (OEI's). This monitoring of the doses received by ionizing radiation has as main objective to ensure that the principle of dose limitation is respected. In this study it were evaluated doses of 372 OEI's radiology in different Brazilian states. Doses were extracted from the database of Sector Management Doses of the Institute for Radioprotection and Dosimetry - IRD/CNEN-RJ, Brazil. The information from the database provide reports of doses from several states, which allows to quantify statistically, showing those with the highest doses in four areas: dose greater than or equal to 20 mSv apron and chest and dose greater than or equal to 100 mSv apron and chest. The identification of these states allows the respective Sanitary Surveillance (VISA), be aware of the events and make plans to reduce them. This study clarified the required procedures when there is a record of high dose emphasizing the importance of using protective radiological equipment, dosimeter and provide a safety environment work by maintaining work equipment. Proposes the ongoing training of professionals, emphasizing the relevance of the concepts of radiation protection and the use of the questionnaire with their investigative systematic sequence, which will allow quickly and efficiently the success the investigations

  20. Dosimetric properties of commercial glasses and sand for high doses

    International Nuclear Information System (INIS)

    Teixeira, Maria Ines

    2004-01-01

    Commercial glasses (transparent and colored) produced by Cebrace, Brazil, Sao Paulo, and sand samples of different Brazilian beaches were studied, due to their low cost and easy handling, to verify the possibility of their use in high dose dosimetry. The main dosimetric characteristics were determined using a densitometer, a spectrophotometer, a thermoluminescent (TL) reader and an electronic paramagnetic resonance system. The gamma irradiations were carried out using a Gamma-Cell 220 and a panoramic source ( 60 Co) of IPEN. An optical absorption band was observed at 420 nm in the glass samples. The TL glow curves presented peaks at 205 deg C, 135 deg C, 150 deg C and 145 deg C for the transparent, bronze, brown and green glass samples, respectively. All EPR spectra of the glasses showed Fe 3+ characteristic signals at g = 4.27 and 2.01. The gamma irradiated sand samples presented two peaks at 110 deg C and 170 deg C and an EPR signal at g= 1.999. However, these materials present a pronounced thermal fading at room temperature after irradiation. With the objective to minimize this thermal fading, both glass and sand samples were submitted to different pre- and post-irradiation thermal treatments. The glass and sand samples showed the possibility of utilization for high dose dosimetry and as Yes/No irradiation detectors. (author)

  1. Multifocal Electroretinography after High Dose Chloroquine Therapy for Malaria

    Directory of Open Access Journals (Sweden)

    Aline Correa de Carvalho

    2013-01-01

    Full Text Available Purpose: To investigate changes in multifocal electroretinography (mfERG parameters associated with high dose chloroquine therapy for treatment of malaria in the Amazonia region of Brazil. Methods: Forty-eight subjects who had received chloroquine treatment for single or multiple malaria infections with a cumulative dose ranging from 1,050 to 27,000mg were included. The control group consisted of 37 healthy aged-matched subjects. Data was collected on amplitude and implicit time of the N1, P1 and N2 waves in the central macular hexagon (R1 and in five concentric rings at different retinal eccentricities (R2-R6. Results: No significant difference was observed in any mfERG parameter between chloroquine treated patients and control subjects. A comparison with previous data obtained from patients with rheumatologic disorders in the same region of Brazil who had received larger cumulative doses of chloroquine and had displayed mfERG changes, indicated that retinal toxicity seems to be dependent on cumulative dose. Conclusion: Lack of mfERG changes in the current study suggests that intensive high dose chloroquine therapy for treatment of malaria is not associated with retinal toxicity.

  2. The influence of high doses of radiation in citrine stones

    Energy Technology Data Exchange (ETDEWEB)

    Teixeira, M. I. [Universidade Nove de Julho - UNINOVE, Rua Vergueiro 235/249, 01504-001 Sao Paulo (Brazil); Caldas, L. V. E., E-mail: miteixeira@ipen.br [Instituto de Pesquisas Energeticas e Nucleares / CNEN, Av. Lineu Prestes 2242, Cidade Universitaria, 05508-000 Sao Paulo (Brazil)

    2014-08-15

    The possibility of using samples of Brazilian stones as quartz, amethyst, topaz, jasper, etc. for high-dose dosimetry has been studied in recent years at IPEN, using the techniques of optical absorption (Oa), thermoluminescent (Tl), optically stimulated luminescence (OSL) and resonance paramagnetic electron (EPR). In this work, the Tl properties of citrine samples were studied. They were exposed to different doses of gamma radiation ({sup 60}Co). The natural citrine stone was extracted from a mine in Minas Gerais state, Brazil; it is a tecto silicate ranked as one of three-dimensional structure, showing clear yellow to golden brown color. The natural citrine stone is classified as quartz (SiO{sub 2}), and it has a lower symmetry and more compact reticulum. The Tl emission curve showed two peaks at 160 grades C and 220 grades C. To remove the Tl peak (160 grades C) of the sintered citrine pellet glow curves, different thermal treatments were tested during several time intervals. The Tl dose-response curve between 50 Gy and 100 kGy, the reproducibility of Tl response and the lower detection dose were obtained. The results show that citrine may be useful as high-dose detectors. (Author)

  3. Audits in high dose rate brachytherapy in Brazil

    International Nuclear Information System (INIS)

    Marechal, M.H.; Rosa, L.A.; Velasco, A.; Paiva, E. de; Goncalves, M.; Castelo, L.C.

    2002-01-01

    The lack of well established dosimetry protocols for HDR sources is a point of great concern regarding the uniformity of procedures within a particular country. The main objective of this paper is to report the results of an implementation of the audit program in dosimetry of high dose rate brachytherapy sources used by the radiation therapy centers in Brazil. In Brazil, among 169 radiotherapy centers, 35 have HDR brachytherapy systems. This program started in August 2001 and until now eight radiotherapy services were audited. The audit program consists of the visit in loco to each center and the evaluation of the intensity of the source with a well type chamber specially design for HDR 192 Ir sources. The measurements was carried out with a HDR1000PLUS Brachytherapy Well Type Chamber and a MAX 4000 Electrometer, both manufactured by Standard Imaging Inc. The chamber was calibrated in air kerma strength by the Accredited Dosimetry Calibration Laboratory, Department of Medical Physics, University of Wisconsin in the USA. The same chamber was calibrated in Brazil using a 192 lr high dose rate source whose intensity was determined by 60 Co gamma rays and 250 kV x rays interpolation methodology. The Nk of 60 Co and 250 kV x rays were provided by the Brazilian National Standard Laboratory for Ionizing Radiation (LMNRI)

  4. Lack of inhibitory effects of the anti-fibrotic drug imatinib on endothelial cell functions in vitro and in vivo.

    Science.gov (United States)

    Venalis, Paulius; Maurer, Britta; Akhmetshina, Alfiya; Busch, Nicole; Dees, Clara; Stürzl, Michael; Zwerina, Jochen; Jüngel, Astrid; Gay, Steffen; Schett, Georg; Distler, Oliver; Distler, Jörg H W

    2009-10-01

    Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by microangiopathy with progressive loss of capillaries and tissue fibrosis. Imatinib exerts potent anti-fibrotic effects and is currently evaluated in clinical trials. The aim of the present study was to exclude that the anti-fibrotic effects of imatinib are complicated by inhibitory effects on endothelial cell functions, which might augment vascular disease in SSc. Endothelial cells and mice were treated with pharmacologically relevant concentrations of imatinib. The expression of markers of vascular activation was assessed with real-time PCR. Proliferation was analysed with the cell counting experiments and the MTT assay. Apoptosis was quantified with caspase 3 assays, annexin V in vitro and with TUNEL staining in vivo. Migration was studied with scratch and transwell assays. Tube forming was investigated with the matrigel assay. Imatinib did not alter the expression of markers of vascular activation. Imatinib did not increase the percentage of annexin V positive cells or the activity of caspase 3. No reduction in proliferation or metabolic activity of endothelial cells was observed. Imatinib did not affect migration of endothelial cells and did not reduce the formation of capillary tubes. Consistent with the in vitro data, no difference in the number of apoptotic endothelial cells was observed in vivo in mice treated with imatinib. Imatinib does not inhibit activation, viability, proliferation, migration or tube forming of endothelial cells in vitro and in vivo. Thus, treatment with imatinib might not augment further endothelial cell damage in SSc.

  5. Stock selection of high-dose-irradiation-resistant materials for filter press under high-dose irradiation operation

    International Nuclear Information System (INIS)

    Ishiyama, Shintaro; Minami, Mamoru; Hara, Kouji; Yamashita, Manabu

    2015-01-01

    In a volume reduction process for the decontamination of contained soil, the performance degradation of a filter press is expected owing to material deterioration under high-dose irradiation. Eleven-stock selection of candidate materials including polymers, fibers and rubbers for the filter press was conducted to achieve a high performance of volume reduction of contaminated soil and the following results were derived. Crude rubber and nylon were selected as prime candidates for packing, diaphragm and filter plate materials. Polyethylene was also selected as a prime candidate for the filter cloth material. (author)

  6. High Doses Gamma Radiolysis of PVC: Mechanisms of Degradation

    International Nuclear Information System (INIS)

    Colombani, J.

    2006-01-01

    PVC radiolysis leads to the formation of various degradation products: radicals, gas, oxidized products or polyenes. In order to predict the formation of the degradation products with regard to irradiation and ageing parameters, it is important to improve the understanding of the radiolysis mechanisms of PVC. Thus, we used several analytical techniques (Electron Spin Resonance, Fourier Transform Infrared spectroscopy, Nuclear Magnetic Resonance, Size Exclusion Chromatography) to get information on PVC samples irradiated at high doses (up to 4MGy) under different conditions. Gamma irradiation induces the formation of various radicals into PVC. Older studies were generally focused on the effect of low dose and/or low temperature irradiations on PVC. We present here ESR signals of PVC irradiated at high doses and at room temperature. We show that peroxyl radicals are producted by radiolysis under aerobe conditions and that polyenyl radicals are formed under anaerobe conditions. PVC radiolysis induces gas production and especially hydrogen chloride. Production of hydrogen chloride is well known until 1 MGy. We have studied by FTIR, the evolution of the quantity of HCl produced until 4 MGy. We show that higher irradiation dose leads to the lower radiolytic yield of HCl (G(HCl)). Moreover, G(HCl) obtained in aerobe conditions is about fourfold as great as G(HCl) observed in anaerobe radiolysis. Propagation and termination reactions induce degradation products: polyene sequences and crosslinking reactions are observed under anaerobe conditions; oxidized products with addition of chain scissions are formed under aerobe conditions. Although the literature about PVC radiolysis is rich, the main reacting pathways are not well established. Moreover the high doses studies are almost non-existent. We show by FTIR that aerobe radiolysis induces formation of ketons and acids. NMR experiments confirme these results but also focuse on small acids formed (with 2, 3 or 4 carbons). The

  7. High-dose radioiodine therapy of Graves disease

    International Nuclear Information System (INIS)

    Solodky, V.; Fomin, D.; Pestritskaya, E.

    2015-01-01

    Full text of publication follows. Objectives: to estimate the effectiveness and safety of the disease treatment under different modes of applying RIT. Materials and methods: 67 patients with the thyrotoxicosis condition associated with Graves disease were researched. The patients were divided into 2 groups: a control group with 25 people (18 women and 7 men), who underwent a low-dose therapy of 150-500 MBq; and a main group of 42 people (32 women and 10 men), who underwent a high-dose therapy of 550 and 800 MBq. The volume of thyroid prior to the treatment made up 23.8 ± 20 ml in the main group and 30.2 ± 23 ml in the control one. The average age in the high-dose group was 44.6 ±23 years old and in the low-dose -47.2 ± 24 years old. In terms of the hormone level before the RIT, 52% of the main group patients experienced euthyroidism, while 48% - thyrotoxicosis. The corresponding indices in the control group were 42% and 58% respectively. The cessation of the thyreostatic therapy came on 5. to 21. day prior to the treatment, with the average of 14 ±7 days in both groups. The diagnosis of the disease was based on ultrasonography, planar scintigraphy, the hormone level and antibody titer. The performance was assessed through the attainment of hypo-thyrosis and the transition to a substitutive hormonal therapy with L-thyroxine in 6 months or more. The attainment of euthyroidism was seen as a partial effect due to a possibility of relapse. Results: in 6 months a positive result in the form of hypo-thyrosis was achieved for 39 patients in the main group, which accounted for 93%, and 3 patients (7%) experienced euthyroidism. No symptomatic thyrotoxicosis relapses were revealed. In the control group, hypo-thyrosis was achieved by 18 patients, which accounted for 72%; euthyroidism came up to 12%; 4 patients needed a refresher course of RIT, which made up 16% of the group. 93% of the main group patients tolerated the treatment favourably. 3 patients complained of the

  8. Routine quality control of high dose rate brachytherapy equipment

    International Nuclear Information System (INIS)

    Guzman Calcina, Carmen S.; Almeida, Adelaide de; Rocha, Jose R. Oliveira

    2001-01-01

    A Quality Assurance program should be installed also for High Dose Rate brachytherapy, in the order to achieve a correct dose administration to the patient and for the safety to those involved directly with the treatment. The work presented here has the following purposes: Analyze the types of equipment tests presented by the official protocols (TG40, TG56 e ARCAL XXX), evaluate the brachytherapy routine tests of protocols from various national and international radiotherapy services and compare the latter with those presented in the official protocols. As a result, we conclude the following: TG56 presents a higher number of tests when compared to the other official protocols and most of the tests presented by the analyzed services are present in TG56. A suggestion for a basic protocol is presented, emphasizing the periodicity and tolerance level of each of the tests. (author)

  9. Surface sputtering in high-dose Fe ion implanted Si

    International Nuclear Information System (INIS)

    Ishimaru, Manabu

    2007-01-01

    Microstructures and elemental distributions in high-dose Fe ion implanted Si were characterized by means of transmission electron microscopy and Rutherford backscattering spectroscopy. Single crystalline Si(0 0 1) substrates were implanted at 350 deg. C with 120 keV Fe ions to fluences ranging from 0.1 x 10 17 to 4.0 x 10 17 /cm 2 . Extensive damage induced by ion implantation was observed inside the substrate below 1.0 x 10 17 /cm 2 , while a continuous iron silicide layer was formed at 4.0 x 10 17 /cm 2 . It was found that the spatial distribution of Fe projectiles drastically changes at the fluence between 1.0 x 10 17 and 4.0 x 10 17 /cm 2 due to surface sputtering during implantation

  10. measurement of high dose radiation using yellow perspex dosimeter

    International Nuclear Information System (INIS)

    Thamrin, M Thoyib; Sofyan, Hasnel

    1996-01-01

    Measurement of high dose radiation using yellow perspex dosemeter has been carried out. Dose range used was between 0.1 to 3.0 kGy. Measurement of dose rate against Fricke dosemeter as a standard dose meter From the irradiation of Fricke dosemeter with time variation of 3,6,9,12,15 and 18 minute, it was obtained average dose rate of 955.57 Gy/hour, linear equation of dose was Y= 2.333+15.776 X with its correlation factor r = 0.9999. Measurement result using yellow perspex show that correlation between net optical density and radiation dose was not linear with its equation was ODc exp. [Bo + In(dose).Bi] Value of Bo = -0.215 and Bi=0.5020. From the experiment it was suggested that routine dosimeter (yellow perspex) should be calibrated formerly against standard dosemeters

  11. High Fidelity Ion Beam Simulation of High Dose Neutron Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Was, Gary; Wirth, Brian; Motta, Athur; Morgan, Dane; Kaoumi, Djamel; Hosemann, Peter; Odette, Robert

    2018-04-30

    Project Objective: The objective of this proposal is to demonstrate the capability to predict the evolution of microstructure and properties of structural materials in-reactor and at high doses, using ion irradiation as a surrogate for reactor irradiations. “Properties” includes both physical properties (irradiated microstructure) and the mechanical properties of the material. Demonstration of the capability to predict properties has two components. One is ion irradiation of a set of alloys to yield an irradiated microstructure and corresponding mechanical behavior that are substantially the same as results from neutron exposure in the appropriate reactor environment. Second is the capability to predict the irradiated microstructure and corresponding mechanical behavior on the basis of improved models, validated against both ion and reactor irradiations and verified against ion irradiations. Taken together, achievement of these objectives will yield an enhanced capability for simulating the behavior of materials in reactor irradiations

  12. High-dose erythropoietin in patients with progressive multiple sclerosis

    DEFF Research Database (Denmark)

    Schreiber, Karen; Magyari, Melinda; Sellebjerg, Finn

    2017-01-01

    BACKGROUND: Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS). OBJECTIVE: To evaluate a treatment effect of EPO on progressive MS. METHODS: This was a single-center, randomized......, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6......: This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS....

  13. Safety handling manual for high dose rate remote afterloading system

    International Nuclear Information System (INIS)

    1999-01-01

    This manual is mainly for safety handling of 192 Ir-RALS (remote afterloading system) of high dose rate and followings were presented: Procedure and document format for the RALS therapy and for handling of its radiation source with the purpose of prevention of human errors and unexpected accidents, Procedure for preventing errors occurring in the treatment schedule and operation, and Procedure and format necessary for newly introducing the system into a facility. Consistency was intended in the description with the quality assurance guideline for therapy with small sealed radiation sources made by JASTRO (Japan Society for Therapeutic Radiology and Oncology). Use of the old type 60 Co-RALS was pointed out to be a serious problem remained and its safety handling procedure was also presented. (K.H.)

  14. Pharmacokinetics of high-dose intravenous melatonin in humans

    DEFF Research Database (Denmark)

    Andersen, Lars P H; Werner, Mads U; Rosenkilde, Mette Marie

    2016-01-01

    This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60......, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments...... of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221...

  15. Calibration of {sup 192}Ir high dose rate brachytherapy sources

    Energy Technology Data Exchange (ETDEWEB)

    Marechal, M H [Instituto de Radioprotecao e Dozimetria, Rio de Jainero (Brazil); Almeida, C.E. de [Laboratorio de Ciencias Radiologicas, UERL, Rio de Janeiro (Brazil); Sibata, C H [Roswell Park Cancer Inst., Buffalo, NY (United States)

    1996-08-01

    A method for calibration of high dose rate sources used in afterloading brachytherapy systems is described. The calibration for {sup 192}Ir is determined by interpolating {sup 60}Co gamma-rays and 250 kV x-rays calibration factors. All measurements were done using the same build up caps as described by Goetsch et al and recommended by AAPM. The attenuation correction factors were determined to be 0.9903, 0.9928 and 0.9993 for {sup 192}Ir, {sup 60}Co and 250 kV x-ray, respectively. A wall + cap thickness of 0.421 g.cm{sup -2} is recommended for all measurements to ensure electronic equilibrium for {sup 60}Co and {sup 192}Ir gamma-ray beams. A mathematical formalism is described for determination of (N{sub x}){sub Ir}. (author). 5 refs, 1 fig.

  16. Assessments for high dose radionuclide therapy treatment planning

    International Nuclear Information System (INIS)

    Fisher, D.R.

    2003-01-01

    Advances in the biotechnology of cell specific targeting of cancer and the increased number of clinical trials involving treatment of cancer patients with radiolabelled antibodies, peptides, and similar delivery vehicles have led to an increase in the number of high dose radionuclide therapy procedures. Optimised radionuclide therapy for cancer treatment is based on the concept of absorbed dose to the dose limiting normal organ or tissue. The limiting normal tissue is often the red marrow, but it may sometimes be the lungs, liver, intestinal tract, or kidneys. Appropriate treatment planning requires assessment of radiation dose to several internal organs and tissues, and usually involves biodistribution studies in the patient using a tracer amount of radionuclide bound to the targeting agent and imaged at sequential timepoints using a planar gamma camera. Time-activity curves are developed from the imaging data for the major organ tissues of concern, for the whole body and sometimes for selected tumours. Patient specific factors often require that dose estimates be customised for each patient. In the United States, the Food and Drug Administration regulates the experimental use of investigational new drugs and requires 'reasonable calculation of radiation absorbed dose to the whole body and to critical organs' using the methods prescribed by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine. Review of high dose studies shows that some are conducted with minimal dosimetry, that the marrow dose is difficult to establish and is subject to large uncertainties. Despite the general availability of software, internal dosimetry methods often seem to be inconsistent from one clinical centre to another. (author)

  17. Identification of cysteine-644 as the covalent site of attachment of dexamethasone 21-mesylate to murine glucocorticoid receptors in WEHI-7 cells

    International Nuclear Information System (INIS)

    Smith, L.I.; Bodwell, J.E.; Mendel, D.B.; Ciardelli, T.; North, W.G.; Munck, A.

    1988-01-01

    Dexamethasone 21-mesylate is a highly specific synthetic glucocorticoid derivative that binds covalently to glucocorticoid receptors via sulfhydryl groups. The authors have identified the amino acid that reacts with the dexamethasone 21-mesylate by using enzymatic digestion and microsequencing for radiolabel. Nonactivated glucocorticoid receptors obtained from labeling intact WEHI-7 mouse thymoma cells with [ 3 H]dexamethasone 21-mesylate were immunopurified and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Trypsin digestion followed by reversed-phase high-performance liquid chromatography (reversed-phase HPLC) produced a single [ 3 H]dexamethasone 21-mesylate labeled peptide. Automated Edman degradation of this peptide revealed that the [ 3 H]dexamethasone 21-mesylate was located at position 5 from the amino terminus. Dual-isotope labeling studies with [ 3 H]dexamethasone 21-mesylate and [ 35 S]methionine demonstrated that this peptide contained methionine. Staphylococcus aureus V8 protease digestion of [ 3 H]dexamethasone 21-mesylate labeled steroid-binding subunits generated a different radiolabeled peptide containing label at position 7 from the amino terminus. On the basis of the published amino acid sequence of the murine glucocorticoid receptor, their data clearly identify cysteine-644 as the single residue in the steroid-binding domain that covalently binds dexamethasone 21-mesylate. They have confirmed this finding by demonstrating that a synthetic peptide representing the amino acid sequence 640-650 of the murine glucocorticoid receptor behaves in an identical manner on reversed-phase HPLC as the trypsin-generated peptide from intact cells

  18. Synthesis of chitosan-PEO hydrogels via mesylation and regioselective Cu(I)-catalyzed cycloaddition.

    Science.gov (United States)

    Tirino, Pasquale; Laurino, Rosaria; Maglio, Giovanni; Malinconico, Mario; d'Ayala, Giovanna Gomez; Laurienzo, Paola

    2014-11-04

    In this work, a well-defined hydrogel was developed by coupling chitosan with PEO through "click chemistry". Azide functionalities were introduced onto chitosan, through mesylation of C-6 hydroxyl groups, and reacted with a di-alkyne PEO by a regioselective Cu(I)-catalyzed cycloaddition. This synthetic approach allowed us to obtain a hydrogel with a controlled crosslinking degree. In fact, the extent of coupling is strictly dependent on the amount of azido groups on chitosan, which in turn can be easily modulated. The obtained hydrogel, with a crosslinking degree of around 90%, showed interesting swelling properties. With respect to chitosan hydrogels reported in literature, a considerably higher equilibrium uptake was reached (940%). The possibility to control the crosslinking degree of hydrogel and its capability to rapidly absorb high amounts of water make this material suitable for several applications, such as controlled drug release and wound healing. Copyright © 2014. Published by Elsevier Ltd.

  19. Effects of pergolide mesylate on transduction efficiency of PEP-1-catalase protein

    International Nuclear Information System (INIS)

    Sohn, Eun Jeong; Kim, Dae Won; Kim, Young Nam; Kim, So Mi; Lim, Soon Sung; Kang, Tae-Cheon; Kwon, Hyeok Yil; Kim, Duk-Soo; Cho, Sung-Woo; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Hwang, Hyun Sook; Choi, Soo Young

    2011-01-01

    Research highlights: → We studied effects of pergolide mesylate (PM) on in vitro and in vivo transduction of PEP-1-catalase. → PEP-1-catatase inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation. → PM enhanced the transduction of PEP-1-catalase into HaCaT cells and skin tissue. → PM increased anti-inflammatory activity of PEP-1-catalase. → PM stimulated therapeutic action of anti-oxidant enzyme catalase in oxidative-related diseases. -- Abstract: The low transduction efficiency of various proteins is an obstacle to their therapeutic application. However, protein transduction domains (PTDs) are well-known for a highly effective tool for exogenous protein delivery to cells. We examined the effects of pergolide mesylate (PM) on the transduction of PEP-1-catalase into HaCaT human keratinocytes and mice skin and on the anti-inflammatory activity of PEP-1-catatase against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation using Western blot and histological analysis. PM enhanced the time- and dose-dependent transduction of PEP-1-catalase into HaCaT cells without affecting the cellular toxicity. In a mouse edema model, PEP-1-catalase inhibited the increased expressions of inflammatory mediators and cytokines such as cyclooxygenase-2, inducible nitric oxide synthase, interleukin-6 and -1β, and tumor necrosis factor-α induced by TPA. On the other hand, PM alone failed to exert any significant anti-inflammatory effects. However, the anti-inflammatory effect of co-treatment with PEP-1-catalase and PM was more potent than that of PEP-1-catalase alone. Our results indicate that PM may enhance the delivery of PTDs fusion therapeutic proteins to target cells and tissues and has potential to increase their therapeutic effects of such drugs against various diseases.

  20. Effects of pergolide mesylate on transduction efficiency of PEP-1-catalase protein

    Energy Technology Data Exchange (ETDEWEB)

    Sohn, Eun Jeong; Kim, Dae Won; Kim, Young Nam; Kim, So Mi [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Lim, Soon Sung [Department of Food Science and Nutrition and RIC Center, Hallym University, Chunchon 200-702 (Korea, Republic of); Kang, Tae-Cheon [Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of); Kwon, Hyeok Yil [Department of Physiology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of); Kim, Duk-Soo [Department of Anatomy, College of Medicine, Soonchunhyang University, Cheonan-Si 330-090 (Korea, Republic of); Cho, Sung-Woo [Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of); Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Hwang, Hyun Sook, E-mail: wazzup@hallym.ac.kr [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Choi, Soo Young, E-mail: sychoi@hallym.ac.kr [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of)

    2011-03-18

    Research highlights: {yields} We studied effects of pergolide mesylate (PM) on in vitro and in vivo transduction of PEP-1-catalase. {yields} PEP-1-catatase inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation. {yields} PM enhanced the transduction of PEP-1-catalase into HaCaT cells and skin tissue. {yields} PM increased anti-inflammatory activity of PEP-1-catalase. {yields} PM stimulated therapeutic action of anti-oxidant enzyme catalase in oxidative-related diseases. -- Abstract: The low transduction efficiency of various proteins is an obstacle to their therapeutic application. However, protein transduction domains (PTDs) are well-known for a highly effective tool for exogenous protein delivery to cells. We examined the effects of pergolide mesylate (PM) on the transduction of PEP-1-catalase into HaCaT human keratinocytes and mice skin and on the anti-inflammatory activity of PEP-1-catatase against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation using Western blot and histological analysis. PM enhanced the time- and dose-dependent transduction of PEP-1-catalase into HaCaT cells without affecting the cellular toxicity. In a mouse edema model, PEP-1-catalase inhibited the increased expressions of inflammatory mediators and cytokines such as cyclooxygenase-2, inducible nitric oxide synthase, interleukin-6 and -1{beta}, and tumor necrosis factor-{alpha} induced by TPA. On the other hand, PM alone failed to exert any significant anti-inflammatory effects. However, the anti-inflammatory effect of co-treatment with PEP-1-catalase and PM was more potent than that of PEP-1-catalase alone. Our results indicate that PM may enhance the delivery of PTDs fusion therapeutic proteins to target cells and tissues and has potential to increase their therapeutic effects of such drugs against various diseases.

  1. High-dose MeV electron irradiation of Si-SiO2 structures implanted with high doses Si+

    Science.gov (United States)

    Kaschieva, S.; Angelov, Ch; Dmitriev, S. N.

    2018-03-01

    The influence was studied of 22-MeV electron irradiation on Si-SiO2 structures implanted with high-fluence Si+ ions. Our earlier works demonstrated that Si redistribution is observed in Si+-ion-implanted Si-SiO2 structures (after MeV electron irradiation) only in the case when ion implantation is carried out with a higher fluence (1016 cm-2). We focused our attention on the interaction of high-dose MeV electron irradiation (6.0×1016 cm-2) with n-Si-SiO2 structures implanted with Si+ ions (fluence 5.4×1016 cm-2 of the same order magnitude). The redistribution of both oxygen and silicon atoms in the implanted Si-SiO2 samples after MeV electron irradiation was studied by Rutherford back-scattering (RBS) spectroscopy in combination with a channeling technique (RBS/C). Our results demonstrated that the redistribution of oxygen and silicon atoms in the implanted samples reaches saturation after these high doses of MeV electron irradiation. The transformation of amorphous SiO2 surface into crystalline Si nanostructures (after MeV electron irradiation) was evidenced by atomic force microscopy (AFM). Silicon nanocrystals are formed on the SiO2 surface after MeV electron irradiation. The shape and number of the Si nanocrystals on the SiO2 surface depend on the MeV electron irradiation, while their size increases with the dose. The mean Si nanocrystals height is 16-20 nm after irradiation with MeV electrons at the dose of 6.0×1016 cm-2.

  2. Protonation effects on the UV/Vis absorption spectra of imatinib: a theoretical and experimental study.

    Science.gov (United States)

    Grante, Ilze; Actins, Andris; Orola, Liana

    2014-08-14

    An experimental and theoretical investigation of protonation effects on the UV/Vis absorption spectra of imatinib showed systematic changes of absorption depending on the pH, and a new absorption band appeared below pH 2. These changes in the UV/Vis absorption spectra were interpreted using quantum chemical calculations. The geometry of various imatinib cations in the gas phase and in ethanol solution was optimized with the DFT/B3LYP method. The resultant geometries were compared to the experimentally determined crystal structures of imatinib salts. The semi-empirical ZINDO-CI method was employed to calculate the absorption lines and electronic transitions. Our study suggests that the formation of the extra near-UV absorption band resulted from an increase of imatinib trication concentration in the solution, while the rapid increase of the first absorption maximum could be attributed to both the formation of imatinib trication and tetracation. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Imatinib Intolerance Is Associated With Blastic Phase Development in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia.

    Science.gov (United States)

    Ángeles-Velázquez, Jorge Luis; Hurtado-Monroy, Rafael; Vargas-Viveros, Pablo; Carrillo-Muñoz, Silvia; Candelaria-Hernández, Myrna

    2016-08-01

    Over the past years, the survival of patients with Philadelphia-positive chronic myeloid leukemia (CML Ph(+)) has increased as a result of therapy with tyrosin kinase inhibitors (TKIs). Intolerance to TKIs has been described in approximately 20% of patients receiving treatment. We studied the incidence of imatinib intolerance in patients with CML Ph(+) and their outcome in our CML reference site, as there is no information about the evolution of patients intolerant to TKIs. A group of 86 patients with CML Ph(+) receiving imatinib monotherapy who abandoned treatment were the basis for this study. We present the trends of their disease evolution. The median of age at diagnosis was 42 years. Within a year, 19 (22%) of 86 patients developed imatinib intolerance, all of them with grade III or IV disease that required imatinib dose reduction or discontinuation. Of these patients, 16 (84%) of 19 developed transformation to blastic phase. The cumulative incidences of blastic phase development were 47% in the nonintolerant group and 84% in the intolerant group. There was a relative risk for those with imatinib intolerance to develop blastic phase of 1.78 (95% confidence interval, 1.28 to 2.42) (P treatment is available. Future research should to determine whether the origin of this evolution is really due to the intolerance itself or whether it is due to a more aggressive form of the disease, perhaps related to genetic transformation. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. High dose rate brachytherapy for superficial cancer of the esophagus

    International Nuclear Information System (INIS)

    Maingon, Philippe; D'Hombres, Anne; Truc, Gilles; Barillot, Isabelle; Michiels, Christophe; Bedenne, Laurent; Horiot, Jean Claude

    2000-01-01

    Purpose: We analyzed our experience with external radiotherapy, combined modality treatment, or HDR brachytherapy alone to limited esophageal cancers. Methods and Materials: From 1991 to 1996, 25 patients with limited superficial esophagus carcinomas were treated by high dose rate brachytherapy. The mean age was 63 years (43-86 years). Five patients showed superficial local recurrence after external radiotherapy. Eleven patients without invasion of the basal membrane were staged as Tis. Fourteen patients with tumors involving the submucosa without spreading to the muscle were staged as T1. Treatment consisted of HDR brachytherapy alone in 13 patients, external radiotherapy and brachytherapy in 8 cases, and concomitant chemo- and radiotherapy in 4 cases. External beam radiation was administered to a total dose of 50 Gy using 2 Gy daily fractions in 5 weeks. In cases of HDR brachytherapy alone (13 patients), 6 applications were performed once a week. Results: The mean follow-up is 31 months (range 24-96 months). Twelve patients received 2 applications and 13 patients received 6 applications. Twelve patients experienced a failure (48%), 11/12 located in the esophagus, all of them in the treated volume. One patient presented an isolated distant metastasis. In the patients treated for superficial recurrence, 4/5 were locally controlled (80%) by brachytherapy alone. After brachytherapy alone, 8/13 patients were controlled (61%). The mean disease-free survival is 14 months (1-36 months). Overall survival is 76% at 1 year, 37% at 2 years, and 14% at 3 years. Overall survival for Tis patients is 24% vs. 20% for T1 (p 0.83). Overall survival for patients treated by HDR brachytherapy alone is 43%. One patient presented with a fistula with local failure after external radiotherapy and brachytherapy. Four stenosis were registered, two were diagnosed on barium swallowing without symptoms, and two required dilatations. Conclusion: High dose rate brachytherapy permits the treating

  5. High dose implantations of antimony for buried layer applications

    International Nuclear Information System (INIS)

    Gailliard, J.P.; Dupuy, M.; Garcia, M.; Roussin, J.C.

    1978-01-01

    Electrical and physical properties of high dose implantations of antimony in silicon have been studied for use in buried layer applications. The results have been obtained both on and oriented silicon wafers. Following implantations which lead to amorphization we perform an annealing at 600 0 C for 10 mn in order to recrystallize the layer. The observed electrical properties (μ, R) show that the concentration of electrically active antimony ions is greater than that predicted from the solubility of antimony in silicon. Further annealing (in the range 1050 0 - 1200 0 ) induces: firstly a precipitation of the Sb and secondly a diffusion and dissolution of the precipitates. There is a different evolution of the defects in the and silicon slices. T.E.M. reveals no defects in the wafers after one hour annealing at 1200 0 C, whereas defects and twins remain in wafers. Having obtained the evolution of R with time and temperature it is then determined the implantation and annealing conditions which lead to the low resistivity (R = 10) needed for buried layer applications. Results with very many industrially made devices are discussed

  6. Optimized dose distribution of a high dose rate vaginal cylinder

    International Nuclear Information System (INIS)

    Li Zuofeng; Liu, Chihray; Palta, Jatinder R.

    1998-01-01

    Purpose: To present a comparison of optimized dose distributions for a set of high-dose-rate (HDR) vaginal cylinders calculated by a commercial treatment-planning system with benchmark calculations using Monte-Carlo-calculated dosimetry data. Methods and Materials: Optimized dose distributions using both an isotropic and an anisotropic dose calculation model were obtained for a set of HDR vaginal cylinders. Mathematical optimization techniques available in the computer treatment-planning system were used to calculate dwell times and positions. These dose distributions were compared with benchmark calculations with TG43 formalism and using Monte-Carlo-calculated data. The same dwell times and positions were used for a quantitative comparison of dose calculated with three dose models. Results: The isotropic dose calculation model can result in discrepancies as high as 50%. The anisotropic dose calculation model compared better with benchmark calculations. The differences were more significant at the apex of the vaginal cylinder, which is typically used as the prescription point. Conclusion: Dose calculation models available in a computer treatment-planning system must be evaluated carefully to ensure their correct application. It should also be noted that when optimized dose distribution at a distance from the cylinder surface is calculated using an accurate dose calculation model, the vaginal mucosa dose becomes significantly higher, and therefore should be carefully monitored

  7. Shelf-stable food through high dose irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Placek, V. E-mail: pla@ujv.cz; Svobodova, V.; Bartonicek, B.; Rosmus, J.; Camra, M

    2004-10-01

    Irradiation of food with high doses (radappertization) is a way, how to prepare shelf-stable ready-to-eat food. The radappertization process requires that the food be heated at first to an internal temperature of at least 75 deg. C to inactivate autolytic enzyme, which could cause the spoilage during storage without refrigeration. In order to prevent radiation induced changes in sensory properties (off flavors, odors, undesirable color change, etc.) the food was vacuum packed and irradiated in frozen state at -30 deg. C or less to a minimum dose of 35 kGy. Such products have characteristics of fresh food prepared for eating even if they are stored for long time under tropical conditions. The wholesomeness (safety for consumption) has been confirmed during 40 years of testing. Within the NRI Rez 10 kinds of shelf-stable meat products have been prepared. The meat was cooked, vacuum packed in SiO{sub x}-containing pouch, freezed in liquid nitrogen and irradiated with electron beam accelerator. The microbial, chemical, and organoleptic properties have been tested.

  8. High-dose processing and application to Korean space foods

    Energy Technology Data Exchange (ETDEWEB)

    Song, Beom-Seok; Park, Jin-Gyu; Park, Jae-Nam; Han, In-Jun; Choi, Jong-il [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Kim, Jae-Hun [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Korea Astronaut Project Division, Korea Aerospace Research Institute, Daejeon 305-333 (Korea, Republic of); Byun, Myung-Woo [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of); Kang, Sang-Wook; Choi, Gi-Hyuk [Korea Astronaut Project Division, Korea Aerospace Research Institute, Daejeon 305-333 (Korea, Republic of); Lee, Ju-Woon [Team for Radiation Food Science and Biotechnology, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185 (Korea, Republic of)], E-mail: sjwlee@kaeri.re.kr

    2009-07-15

    Nutrition bar, Ramen (ready-to-cook noodle), and two Korean traditional foods (Kimchi, fermented vegetable; Sujeonggwa, cinnamon beverage) have been developed as space foods using high-dose gamma irradiation. Addition of calcium lactate and vitamin C, a mild heating, deep-freezing, and gamma irradiation at 25 kGy were conducted to prepare Kimchi as a ready-to-eat space food. Sterilization of Space Kimchi (SK) was confirmed by a microbiological test. The hardness of the Space Kimchi was lower than the untreated Kimchi (CON), but higher than the irradiated only Kimchi. Sensory attributes of the SK were similar to CON, and maintained during preservation at 35 {sup o}C for 30 days. The optimal doses for eliminating the contaminated microbes and maintaining the qualities of the Nutrition bars, Ramen, and Sujeonggwa were determined at 15, 10 and 6 kGy, respectively. All the Korean space food were certificated for use in space flight conditions of 30 days by the Russian Institute for Biomedical Problems.

  9. Characterization of Thymol blue Radiochromic dosimeters for high dose applications

    Directory of Open Access Journals (Sweden)

    Feras M. Aldweri

    2018-03-01

    Full Text Available Thymol blue (TB solutions and Thymol blue Polyvinyl Alcohol (TB-PVA films have been introduced as Radiochromic dosimeter for high dose applications. The dosimeters were irradiated with gamma ray (60Co source from 5 to 30 kGy for film, and from 0.150 kGy to 4 kGy for solution. The optical density of unirradiated and irradiated TB solution as well as TB-PVA film dosimeters were studied in terms of absorbance at 434 nm using UV/VIS spectrophotometer. The effects of scan temperature, light pre-gamma irradiation, dose rate, relative humidity and stability of the absorbance of solutions and films after irradiation were investigated. We found the dose sensitivity of TB solution and TB-PVA film dosimeters increases significantly with increases of the absorbed dose as well as with the increases of TB dye concentrations. The useful dose range of developed TB solutions and TB-PVA films dosimeters is in the range 0.125–1 kGy and of 5–20 kGy, respectively. Keywords: Dose sensitivity, Radio-chromic dosimeter, Thymol blue, Absorbance, Concentrations

  10. Shelf-stable food through high dose irradiation

    International Nuclear Information System (INIS)

    Placek, V.; Svobodova, V.; Bartonicek, B.; Rosmus, J.; Camra, M.

    2004-01-01

    Irradiation of food with high doses (radappertization) is a way, how to prepare shelf-stable ready-to-eat food. The radappertization process requires that the food be heated at first to an internal temperature of at least 75 deg. C to inactivate autolytic enzyme, which could cause the spoilage during storage without refrigeration. In order to prevent radiation induced changes in sensory properties (off flavors, odors, undesirable color change, etc.) the food was vacuum packed and irradiated in frozen state at -30 deg. C or less to a minimum dose of 35 kGy. Such products have characteristics of fresh food prepared for eating even if they are stored for long time under tropical conditions. The wholesomeness (safety for consumption) has been confirmed during 40 years of testing. Within the NRI Rez 10 kinds of shelf-stable meat products have been prepared. The meat was cooked, vacuum packed in SiO x -containing pouch, freezed in liquid nitrogen and irradiated with electron beam accelerator. The microbial, chemical, and organoleptic properties have been tested

  11. Ion exchange resins as high-dose radiation dosimeters

    International Nuclear Information System (INIS)

    Alian, A.; Dessouki, A.; El-Assay, N.B.

    1984-01-01

    This paper reports on the possibility of using various types of ion exchange resins as high-dose radiation dosimeters, by analysis of the decrease in exchange capacity with absorbed dose. The resins studied are Sojuzchim-export-Moscow Cation Exchanger KU-2 and Anion Exchanger AV-17 and Merck Cation Exchanger I, and Merck Anion Exchangers II and III. Over the dose range 1 to 100 kGy, the systems show linearity between log absorbed dose and decrease in resin ion exchange capacity. The slope of this response function differs for the different resins, depending on their ionic form and degree of cross-linking. The radiation sensitivity increases in the order KU-2; Exchanger I; AV-17; Exchanger II; Exchanger III. Merck resins with moisture content of 21% showed considerably higher radiation sensitivity than those with 2 to 3% moisture content. The mechanism of radiation-induced denaturing of the ion exchanger resins involves cleavage and decomposition of functional substituents, with crosslinking playing a stabilizing role, with water and its radiolytic products serving to inhibit radical recombination and interfering with the protection cage effect of crosslinking. (author)

  12. High dose rate brachytherapy for the palliation of malignant dysphagia

    International Nuclear Information System (INIS)

    Homs, Marjolein Y.V.; Eijkenboom, Wilhelmina M.H.; Coen, Veronique L.M.A.; Haringsma, Jelle; Blankenstein, Mark van; Kuipers, Ernst J.; Siersema, Peter D.

    2003-01-01

    Background and purpose: High dose rate (HDR) brachytherapy is a commonly used palliative treatment for esophageal carcinoma. We evaluated the outcome of HDR brachytherapy in patients with malignant dysphagia. Material and methods: A retrospective analysis over a 10-year period was performed of 149 patients treated with HDR brachytherapy, administered in one or two sessions, at a median dose of 15 Gy. Patients were evaluated for functional outcome, complications, recurrent dysphagia, and survival. Results: At 6 weeks after HDR brachytherapy, dysphagia scores had improved from a median of 3 to 2 (n=104; P<0.001), however, dysphagia had not improved in 51 (49%) patients. Procedure-related complications occurred in seven (5%) patients. Late complications, including fistula formation or bleeding, occurred in 11 (7%) patients. Twelve (8%) patients experienced minor retrosternal pain. Median survival of the patients was 160 days with a 1-year survival rate of 15%. Procedure-related mortality was 2%. At follow-up, 55 (37%) patients experienced recurrent dysphagia. In 34 (23%) patients a metal stent was placed to relieve persistent or recurrent dysphagia. Conclusion: HDR brachytherapy is a moderately effective treatment for the palliation of malignant dysphagia. The incidence of early major complications is low, however, persistent and recurrent dysphagia occur frequently, and require often additional treatment

  13. High dose tetrabromobisphenol A impairs hippocampal neurogenesis and memory retention.

    Science.gov (United States)

    Kim, Ah Hyun; Chun, Hye Jeong; Lee, Seulah; Kim, Hyung Sik; Lee, Jaewon

    2017-08-01

    Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that is commonly used in commercial and household products, such as, computers, televisions, mobile phones, and electronic boards. TBBPA can accumulate in human body fluids, and it has been reported that TBBPA possesses endocrine disruptive activity. However, the neurotoxic effect of TBBPA on hippocampal neurogenesis has not yet been investigated. Accordingly, the present study was undertaken to evaluate the effect of TBBPA on adult hippocampal neurogenesis and cognitive function. Male C57BL/6 mice were orally administrated vehicle or TBBPA (20 mg/kg, 100 mg/kg, or 500 mg/kg daily) for two weeks. TBBPA was observed to significantly and dose-dependently reduce the survival of newly generated cells in the hippocampus but not to affect the proliferation of newly generated cells. Numbers of hippocampal BrdU and NeuN positive cells were dose-dependently reduced by TBBPA, indicating impaired neurogenesis in the hippocampus. Interestingly, glial activation without neuronal death was observed in hippocampi exposed to TBBPA. Furthermore, memory retention was found to be adversely affected by TBBPA exposure by a mechanism involving suppression of the BDNF-CREB signaling pathway. The study suggests high dose TBBPA disrupts hippocampal neurogenesis and induces associated memory deficits. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Dimethyl sulfoxyde diethyl fumarate solution for high dose dosimetry

    International Nuclear Information System (INIS)

    Al-Kassiri, H.; Kattan, M.; Daher, Y.

    2007-06-01

    Dosimetric characterization of diethyl fumarate DEF in dimethyl sulfoxyde DMSO solution has been studied spectrophotometrically for possible application at high dose radiation dosimetry in the range (0-225 kGy). The absorption spectra of irradiated solution showed broad absorption bands between (325-400 nm) with a shoulder at 332 nm. The absorption increases as the dose is increased. Absorbance at 332 nm were measured and plotted against absorbed dose. Linear relationship and good response were found between absorbed dose and absorbance of 20% DEF concentration in the range (0-225 kGy) at the wave length, and linearity up to 250 kGy of absorbance at 332 nm .Good dose rate independence was observed in the range (14-33 kGy/h). The effect of post irradiation storage in darkness and indirect daylight conditions were not found to influence the absorption up to 700 h after irradiation. The effect of irradiation temperature within the range (0 to 60 centigrade degree) on the dosimetry performance was discussed.(author)

  15. Radiation Parameters of High Dose Rate Iridium -192 Sources

    Science.gov (United States)

    Podgorsak, Matthew B.

    A lack of physical data for high dose rate (HDR) Ir-192 sources has necessitated the use of basic radiation parameters measured with low dose rate (LDR) Ir-192 seeds and ribbons in HDR dosimetry calculations. A rigorous examination of the radiation parameters of several HDR Ir-192 sources has shown that this extension of physical data from LDR to HDR Ir-192 may be inaccurate. Uncertainty in any of the basic radiation parameters used in dosimetry calculations compromises the accuracy of the calculated dose distribution and the subsequent dose delivery. Dose errors of up to 0.3%, 6%, and 2% can result from the use of currently accepted values for the half-life, exposure rate constant, and dose buildup effect, respectively. Since an accuracy of 5% in the delivered dose is essential to prevent severe complications or tumor regrowth, the use of basic physical constants with uncertainties approaching 6% is unacceptable. A systematic evaluation of the pertinent radiation parameters contributes to a reduction in the overall uncertainty in HDR Ir-192 dose delivery. Moreover, the results of the studies described in this thesis contribute significantly to the establishment of standardized numerical values to be used in HDR Ir-192 dosimetry calculations.

  16. High-dose processing and application to Korean space foods

    Science.gov (United States)

    Song, Beom-Seok; Park, Jin-Gyu; Park, Jae-Nam; Han, In-Jun; Choi, Jong-il; Kim, Jae-Hun; Byun, Myung-Woo; Kang, Sang-Wook; Choi, Gi-Hyuk; Lee, Ju-Woon

    2009-07-01

    Nutrition bar, Ramen (ready-to-cook noodle), and two Korean traditional foods ( Kimchi, fermented vegetable; Sujeonggwa, cinnamon beverage) have been developed as space foods using high-dose gamma irradiation. Addition of calcium lactate and vitamin C, a mild heating, deep-freezing, and gamma irradiation at 25 kGy were conducted to prepare Kimchi as a ready-to-eat space food. Sterilization of Space Kimchi (SK) was confirmed by a microbiological test. The hardness of the Space Kimchi was lower than the untreated Kimchi (CON), but higher than the irradiated only Kimchi. Sensory attributes of the SK were similar to CON, and maintained during preservation at 35 °C for 30 days. The optimal doses for eliminating the contaminated microbes and maintaining the qualities of the Nutrition bars, Ramen, and Sujeonggwa were determined at 15, 10 and 6 kGy, respectively. All the Korean space food were certificated for use in space flight conditions of 30 days by the Russian Institute for Biomedical Problems.

  17. Colon mucosal cells after high-dose fractional irradiation

    International Nuclear Information System (INIS)

    Zorc-Pleskovic, R.; Vraspir-Porenta, O.; Petrovic, D.; Zorc, M.; Pleskovic, L.

    2000-01-01

    The aim of this study was to investigate histological and stereological changes in cryptal enterocytes, mucosal lymphocytes and mast cells 10 days after irradiation. For experimental model, 24 Beagle dogs 1-2 years old were used. Twelve dogs were irradiated 20 days with 32 Gy over the whole pelvis and tail. Another 12 dogs represented a control group. For the detection of apoptosis, the TUNEL technique was used. Histological and stereological analyses were performed using a Wild sampling microscope M 1000. In the irradiated group, volume density (P < 0.01), numerical density (P < 0.05) and average volume of lymphocytes (P < 0.001) were significantly lower than in the nonirradiated group. Numerical areal density of mast cells in the irradiated group was also significantly lower (P < 0.05). Volume density (P < 0.001) and average volume of mast cells (P < 0.001) were significantly higher in the irradiated group. The results of our experiments show that irradiation causes injury and loss of lymphocytes and mast cells in the colon mucosa. Apoptosis was detected in enterocytes and lymphocytes in the irradiated group and in nonirradiated group in equal numbers (2.5 ± 0.3 vs. 2.3 ± 0.3; ns.), suggesting that 10 days after high-dose irradiation, the cell loss is not due to apoptosis. (author)

  18. Tungsten and carbon surface change under high dose plasma exposure

    International Nuclear Information System (INIS)

    Martynenko, Y.V.; Khripunov, B.I.; Petrov, V.B.

    2009-01-01

    Study of surface composition dynamics has been made on the LENTA linear plasma simulator. Experiments have been made on tungsten and carbon materials subjected to steady-state plasma exposure. The achieved ion doses on the surface were 10 21 ion cm -2 . WL 10 tungsten containing 1% of La2O3 oxide and titanium-doped graphite RG-T were studied. The following experimental conditions were varied in these experiments: energy of ions, surface temperature, working gas. Irradiations of tungsten WL 10 were executed in deuterium plasma at low ion energies (about 20 eV) and at 200 eV for temperatures below 340 K. Graphite RG-T was exposed at 1300 K. Elevated surface temperature (about 1050K) was also characteristic of experiments on tungsten sample under nitrogen plasma impact (simulated inter-ELMs condition). Surface microstructure modification has been observed and surface composition changes were found on the materials showing influence of high dose plasma irradiations on element redistribution in the near surface layers. (author)

  19. High dose progesterone effects the growth of early chick embryo

    International Nuclear Information System (INIS)

    Iqbal, I.; Qamar, K.

    2014-01-01

    Objective: To find out the effect of high dose progesterone on the development of early chick embryo. Study Design: Lab based randomized controlled trial. Place and Duration of study: This study was carried out in Army Medical College and Post Graduate Institute of Poultry Sciences, Rawalpindi from June 2010 - December 2010. Material and Methods: Forty five specific pathogen free, fertile, eggs of Fyoumi species of chick were selected at zero hour of incubation. They were incubated at 37.5oC and 75% relative humidity for 26 hrs until the embryos reached stage 8 of the development. Then on stage 8 the eggs were divided into three groups consisting of 15 eggs per group. The first group (GI) was incubated without any operation. The second (G2) and third groups (G3) were injected with two and twenty times more than physiologic does of progesterone respectively. After 48 hours of incvbation, all embryos were examined for their development under light microscopy. Results: All the embryos of G1 and G2 showed normal development according to their stage of development, while 4 out of 11 embryos of G3 were under developed and their survival rate was also less. Conclusion: Exogenous progesterone at levels twenty times above its physiologic range effects the development of chick embryos. Further studies are needed to explain the mechanisms of this effect. (author)

  20. Calibration of high-dose radiation facilities (Handbook)

    International Nuclear Information System (INIS)

    Gupta, B.L.; Bhat, R.M.

    1986-01-01

    In India at present several high intensity radiation sources are used. There are 135 teletheraphy machines and 65 high intensity cobalt-60 sources in the form of gamma chambers (2.5 Ci) and PANBIT (50 Ci). Several food irradiation facilities and a medical sterilization plant ISOMED are also in operation. The application of these high intensity sources involve a wide variation of dose from 10 Gy to 100 kGy. Accurate and reproducible radiation dosimetry is essential in the use of these sources. This handbook is especially compiled for calibration of high-dose radiation facilities. The first few chapters discuss such topics as interaction of radiation with matter, radiation chemistry, radiation processing, commonly used high intensity radiation sources and their special features, radiation units and dosimetry principles. In the chapters which follow, chemical dosimeters are discussed in detail. This discussion covers Fricke dosimeter, FBX dosimeter, ceric sulphate dosimeter, free radical dosimetry, coloured indicators for irrdiation verification. A final chapter is devoted to practical hints to be followed in calibration work. (author)

  1. High-dose processing and application to Korean space foods

    International Nuclear Information System (INIS)

    Song, Beom-Seok; Park, Jin-Gyu; Park, Jae-Nam; Han, In-Jun; Choi, Jong-il; Kim, Jae-Hun; Byun, Myung-Woo; Kang, Sang-Wook; Choi, Gi-Hyuk; Lee, Ju-Woon

    2009-01-01

    Nutrition bar, Ramen (ready-to-cook noodle), and two Korean traditional foods (Kimchi, fermented vegetable; Sujeonggwa, cinnamon beverage) have been developed as space foods using high-dose gamma irradiation. Addition of calcium lactate and vitamin C, a mild heating, deep-freezing, and gamma irradiation at 25 kGy were conducted to prepare Kimchi as a ready-to-eat space food. Sterilization of Space Kimchi (SK) was confirmed by a microbiological test. The hardness of the Space Kimchi was lower than the untreated Kimchi (CON), but higher than the irradiated only Kimchi. Sensory attributes of the SK were similar to CON, and maintained during preservation at 35 o C for 30 days. The optimal doses for eliminating the contaminated microbes and maintaining the qualities of the Nutrition bars, Ramen, and Sujeonggwa were determined at 15, 10 and 6 kGy, respectively. All the Korean space food were certificated for use in space flight conditions of 30 days by the Russian Institute for Biomedical Problems.

  2. Imatinib Increases Serum Creatinine by Inhibiting Its Tubular Secretion in a Reversible Fashion in Chronic Myeloid Leukemia.

    Science.gov (United States)

    Vidal-Petiot, Emmanuelle; Rea, Delphine; Serrano, Fidéline; Stehlé, Thomas; Gardin, Claude; Rousselot, Philippe; Peraldi, Marie-Noëlle; Flamant, Martin

    2016-03-01

    Monitoring renal function is important in imatinib-treated patients with chronic myeloid leukemia because serum creatinine may increase during the course of therapy. The mechanism of this increase and its reversibility on treatment cessation have never been investigated. We retrospectively analyzed data from imatinib-treated patients explored in our renal physiology unit with measurement of glomerular filtration rate (urinary clearance of (51)CrEDTA) and of urinary clearance and tubular secretion of creatinine. Results were compared with those of controls matched for measured glomerular filtration rate, age, gender, and ethnicity. We also analyzed variations of serum creatinine before and during imatinib cessation and after imatinib resumption in patients enrolled in imatinib discontinuation studies. In 4 imatinib-treated patients who underwent thorough renal exploration, the part of creatinine clearance due to tubular secretion was negligible (2.4, 3.1, -1.3, and 2.8 mL/min) and significantly lower than that measured in their respective controls (17.7 ± 5.6, 43.0 ± 18.0, 23.1 ± 6.7, and 18.6 ± 5.6 mL/min, P creatinine tubular secretion (20.3 vs. 17.9 ± 5.2 mL/min in the control population, P = .2). In 15 patients of imatinib discontinuation studies, a median decrease in serum creatinine of 17.9% was observed after imatinib cessation. Resumption of treatment in 6 patients led to a median increase in serum creatinine of 18.8%. Imatinib completely blunts tubular secretion of creatinine, a previously unreported pharmacologic property. This inhibition increases serum creatinine independently of any glomerular dysfunction and is fully reversible on imatinib cessation. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Randomized assessment of imatinib in patients with acute ischaemic stroke treated with intravenous thrombolysis.

    Science.gov (United States)

    Wahlgren, N; Thorén, M; Höjeberg, B; Käll, T-B; Laska, A-C; Sjöstrand, C; Höijer, J; Almqvist, H; Holmin, S; Lilja, A; Fredriksson, L; Lawrence, D; Eriksson, U; Ahmed, N

    2017-03-01

    Imatinib, a tyrosine kinase inhibitor, has been shown to restore blood-brain barrier integrity and reduce infarct size, haemorrhagic transformation and cerebral oedema in stroke models treated with tissue plasminogen activator. We evaluated the safety of imatinib, based on clinical and neuroradiological data, and its potential influence on neurological and functional outcomes. A phase II randomized trial was performed in patients with acute ischaemic stroke treated with intravenous thrombolysis. A total of 60 patients were randomly assigned to four groups [3 (active): 1 (control)]; the active treatment groups received oral imatinib for 6 days at three dose levels (400, 600 and 800 mg). Primary outcome was any adverse event; secondary outcomes were haemorrhagic transformation, cerebral oedema, neurological severity on the National Institutes of Health Stroke Scale (NIHSS) at 7 days and at 3 months and functional outcomes on the modified Rankin scale (mRS). Four serious adverse events were reported, which resulted in three deaths (one in the control group and two in the 400-mg dose group; one patient in the latter group did not receive active treatment and the other received two doses). Nonserious adverse events were mostly mild, resulting in full recovery. Imatinib ameliorated neurological outcomes with an improvement of 0.6 NIHSS points per 100 mg imatinib (P = 0.02). For the 800-mg group, the mean unadjusted and adjusted NIHSS improvements were 4 (P = 0.037) and 5 points (P = 0.012), respectively, versus controls. Functional independence (mRS 0-2) increased by 18% versus controls (61 vs. 79; P = 0.296). This phase II study showed that imatinib is safe and tolerable and may reduce neurological disability in patients treated with intravenous thrombolysis after ischaemic stroke. A confirmatory randomized trial is currently underway. © 2016 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The

  4. The treatment of pediatric chronic myelogenous leukemia in the imatinib era

    Directory of Open Access Journals (Sweden)

    Jae Wook Lee

    2011-03-01

    Full Text Available Childhood chronic myelogenous leukemia (CML is a rare hematologic disease, with limited literature on the methods of treatment. Previously, allogeneic hematopoietic stem cell transplantation (HSCT was considered the only curative treatment for this disease. Treatment with imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase (TKI, has resulted in prolonged molecular response with limited drug toxicity. Imatinib is now implemented in the primary treatment regimen for children, but the paucity of evidence on its ability to result in permanent cure and the potential complications that may arise from long-term treatment with TKIs have prevented imatinib from superseding HSCT as the primary means of curative treatment in children. The results of allogeneic HSCT in children with CML are similar to those observed in adults; HSCT-related complications such as transplant-related mortality and graft-versus-host disease remain significant challenges. An overall consensus has been formed with regards to the need for HSCT in patients with imatinib resistance or those with advanced-phase disease. However, issues such as when to undertake HSCT in chronic-phase CML patients or how best to treat patients who have relapsed after HSCT are still controversial. The imatinib era calls for a reevaluation of the role of HSCT in the treatment of CML. Specific guidelines for the treatment of pediatric CML have not yet been formulated, underscoring the importance of prospective studies on issues such as duration of imatinib treatment, optimal timing of HSCT and the type of conditioning utilized, possible treatment preand post-HSCT, and the role of second-generation TKIs.

  5. Physics and quality assurance for high dose rate brachytherapy

    International Nuclear Information System (INIS)

    Anderson, Lowell L.

    1995-01-01

    Purpose: To review the physical aspects of high dose rate (HDR) brachytherapy, including commissioning and quality assurance, source calibration and dose distribution measurements, and treatment planning methods. Following the introduction of afterloading in brachytherapy, development efforts to make it 'remote' culminated in 1964 with the near-simultaneous appearance of remote afterloaders in five major medical centers. Four of these machines were 'high dose rate', three employing 60Co and one (the GammaMed) using a single, cable-mounted 192Ir source. Stepping-motor source control was added to the GammaMed in 1974, making it the precursor of modern remote afterloaders, which are now suitable for interstitial as well as intracavitary brachytherapy by virtue of small source-diameter and indexer-accessed multiple channels. Because the 192Ir sources currently used in HDR remote afterloaders are supplied at a nominal air-kerma strength of 11.4 cGy cm2 s-1 (10 Ci), are not collimated in clinical use, and emit a significant fraction (15%) of photons at energies greater than 600 keV, shielding and facility design must be undertaken as carefully and thoroughly as for external beam installations. Licensing requirements of regulatory agencies must be met with respect both to maximum permissible dose limits and to the existence and functionality of safety devices (door interlocks, radiation monitors, etc.). Commissioning and quality assurance procedures that must be documented for HDR remote afterloading relate to (1) machine, applicator, guide-tube, and facility functionality checks, (2) source calibration, (3) emergency response readiness, (4) planning software evaluation, and (5) independent checks of clinical dose calculations. Source calibration checks must be performed locally, either by in-air measurement of air kerma strength or with a well ionization chamber calibrated (by an accredited standards laboratory) against an in-air measurement of air kerma strength for the

  6. Investigation of polymer composite for high dose dosimetry

    International Nuclear Information System (INIS)

    Pereira, E.L.M.; Batista, A.S.M.; Ribeiro, F.A.S.; Santos, A.P.; Faria, L.O.; Oliveira, A.H.

    2017-01-01

    Introduction: This paper presents the efficacy evaluation of PVDF and nanocomposites of the PVDF films for high gamma dosimetry. Our scope in this first part of our studies is the selection of the most promising film for future dosimetry trials, where the proportionality of response of the selected material will be investigated over a large range of doses and dose rates. Methods: Was prepared nanocomposites made by mixing Poly(vinylidene fluoride) (PVDF), zirconium oxide (ZrO 2 ) and multi-walled carbon nanotubes (MWCNTs) aiming to find dosimetric properties for applications in high dose dosimetry. The samples were irradiated with a Co-60 source at constant dose rate (16.7 kGy/h), with doses ranging from 100 to 2750 kGy. The UV-Vis and FTIR spectrophotometry have been used to monitor the appearing of C=C conjugated bonds and radio-oxidation of carbon (C=O). Results: FTIR spectrometry has that the absorbance intensities at 1715 cm -1 and 1730 cm -1 can be used for high dosimetry purposes for gamma doses ranging from 400 to 2750 kGy. In this range, it is possible to observe a linear relationship between Abs & Dose. Fading of signal was evaluated for one month and reproducibility in 2000 kGy dose. Conclusion: FTIR spectroscopic data revealed two optical absorption bands at 1715 cm -1 and 1730 cm -1 whose intensities are unambiguously related to gamma delivered dose ranging from 400 kGy to 2750 kGy. (author)

  7. Investigation of polymer composite for high dose dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Pereira, E.L.M.; Batista, A.S.M., E-mail: adriananuclear@yahoo.com.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil); Ribeiro, F.A.S.; Santos, A.P.; Faria, L.O.; Oliveira, A.H. [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil)

    2017-07-01

    Introduction: This paper presents the efficacy evaluation of PVDF and nanocomposites of the PVDF films for high gamma dosimetry. Our scope in this first part of our studies is the selection of the most promising film for future dosimetry trials, where the proportionality of response of the selected material will be investigated over a large range of doses and dose rates. Methods: Was prepared nanocomposites made by mixing Poly(vinylidene fluoride) (PVDF), zirconium oxide (ZrO{sub 2}) and multi-walled carbon nanotubes (MWCNTs) aiming to find dosimetric properties for applications in high dose dosimetry. The samples were irradiated with a Co-60 source at constant dose rate (16.7 kGy/h), with doses ranging from 100 to 2750 kGy. The UV-Vis and FTIR spectrophotometry have been used to monitor the appearing of C=C conjugated bonds and radio-oxidation of carbon (C=O). Results: FTIR spectrometry has that the absorbance intensities at 1715 cm{sup -1} and 1730 cm{sup -1} can be used for high dosimetry purposes for gamma doses ranging from 400 to 2750 kGy. In this range, it is possible to observe a linear relationship between Abs & Dose. Fading of signal was evaluated for one month and reproducibility in 2000 kGy dose. Conclusion: FTIR spectroscopic data revealed two optical absorption bands at 1715 cm{sup -1} and 1730 cm{sup -1} whose intensities are unambiguously related to gamma delivered dose ranging from 400 kGy to 2750 kGy. (author)

  8. Urethral stricture following high dose rate brachytherapy for prostate cancer

    International Nuclear Information System (INIS)

    Sullivan, Lisa; Williams, Scott G.; Tai, Keen Hun; Foroudi, Farshad; Cleeve, L.; Duchesne, Gillian M.

    2009-01-01

    Purpose: To evaluate the incidence, timing, nature and outcome of urethral strictures following high dose rate brachytherapy (HDRB) for prostate carcinoma. Methods and materials: Data from 474 patients with clinically localised prostate cancer treated with HDRB were analysed. Ninety percent received HDRB as a boost to external beam radiotherapy (HDRBB) and the remainder as monotherapy (HDRBM). Urethral strictures were graded according to the Common Terminology Criteria for Adverse Events v3.0. Results: At a median follow-up of 41 months, 38 patients (8%) were diagnosed with a urethral stricture (6-year actuarial risk 12%). Stricture location was bulbo-membranous (BM) urethra in 92.1%. The overall actuarial rate of grade 2 or more BM urethral stricture was estimated at 10.8% (95% CI 7.0-14.9%), with a median time to diagnosis of 22 months (range 10-68 months). All strictures were initially managed with either dilatation (n = 15) or optical urethrotomy (n = 20). Second line therapy was required in 17 cases (49%), third line in three cases (9%) and 1 patient open urethroplasty (grade 3 toxicity). Predictive factors on multivariate analysis were prior trans-urethral resection of prostate (hazard ratio (HR) 2.81, 95% CI 1.15-6.85, p = 0.023); hypertension (HR 2.83, 95% CI 1.37-5.85, p = 0.005); and dose per fraction used in HDR (HR for 1 Gy increase per fraction 1.33, 95% CI 1.08-1.64, p = 0.008). Conclusions: BM urethral strictures are the most common late grade 2 or more urinary toxicity following HDR brachytherapy for prostate cancer. Most are manageable with minimally invasive procedures. Both clinical and dosimetric factors appear to influence the risk of stricture formation.

  9. Tolerance of the Brachial Plexus to High-Dose Reirradiation

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Allen M., E-mail: achen5@kumc.edu; Yoshizaki, Taeko; Velez, Maria A.; Mikaeilian, Argin G.; Hsu, Sophia; Cao, Minsong

    2017-05-01

    Purpose: To study the tolerance of the brachial plexus to high doses of radiation exceeding historically accepted limits by analyzing human subjects treated with reirradiation for recurrent tumors of the head and neck. Methods and Materials: Data from 43 patients who were confirmed to have received overlapping dose to the brachial plexus after review of radiation treatment plans from the initial and reirradiation courses were used to model the tolerance of this normal tissue structure. A standardized instrument for symptoms of neuropathy believed to be related to brachial plexus injury was utilized to screen for toxicity. Cumulative dose was calculated by fusing the initial dose distributions onto the reirradiation plan, thereby creating a composite plan via deformable image registration. The median elapsed time from the initial course of radiation therapy to reirradiation was 24 months (range, 3-144 months). Results: The dominant complaints among patients with symptoms were ipsilateral pain (54%), numbness/tingling (31%), and motor weakness and/or difficulty with manual dexterity (15%). The cumulative maximum dose (Dmax) received by the brachial plexus ranged from 60.5 Gy to 150.1 Gy (median, 95.0 Gy). The cumulative mean (Dmean) dose ranged from 20.2 Gy to 111.5 Gy (median, 63.8 Gy). The 1-year freedom from brachial plexus–related neuropathy was 67% and 86% for subjects with a cumulative Dmax greater than and less than 95.0 Gy, respectively (P=.05). The 1-year complication-free rate was 66% and 87%, for those reirradiated within and after 2 years from the initial course, respectively (P=.06). Conclusion: The development of brachial plexus–related symptoms was less than expected owing to repair kinetics and to the relatively short survival of the subject population. Time-dose factors were demonstrated to be predictive of complications.

  10. "Time sequential high dose of Cytarabine in acute myelocytic leukemia "

    Directory of Open Access Journals (Sweden)

    Ghavamzadeh A

    2003-05-01

    Full Text Available Given preliminary evidence of timed, sequential chemotherapy of high dose cytosine arabinoside the current study was initiated to assess the side effects and efficacy of this regimen in patients with newly acute myelocytic leukemia (AML. Nineteen adults who referred to Hematology-Oncology and Bone Marrow Transplantation (BMT research center of Tehran University of Medical Sciences were enrolled in a trial from Aug 1999 to Nov 2000. All patients had a Karnofski classification above 60%. At this time induction therapy consisted of daunorubicin or idarubicin given at a dose of 60 mg/m² and 12 mg/m² IV respectively on days 1-3, and cytarabine (Ara-C 100 mg/m² intravenously by continuous infusion on days 1-7, followed by Ara-C 1000 mg/m² given on day 8-10 every 12 hours by IV infusion. Consolidation therapy started after 35th day. Of 19 fully evaluable patients, 10 patients achieved a complete remission, whereas 36.6% patients succumbed to death due to regeneration failure. The clinical data show that the overall survival rate from diagnosis 55.5% (95% CI, 30.8-78.5 at 6 months for the entire cohort of the patients. Disease free survival is also 50% (95% CI, 26-74. Mean duration of death due to treatment was 20 days (range 17-29 after beginning the regimen. Presenting WBC counts, French-American-British (FAB classification, sex and age were not useful prognostic variables. Fever, diarrhea, nausea and vomiting and GI hemorrhage were seen in 19, 6, 4, 7 patients respectively. It seems the 3+7+3 regimen is a promising approach for the AML patients regarding to high complete remission rate, but more supportive care should be considered. Furthermore any, benefit in long-term outcome can’t be determined regardless to the choice of post remission therapy (e.g., GCSF, appropriate antibiotics and etc.

  11. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit

    2011-01-01

    Biologic and clinical observations suggest that combining imatinib with IFN-a may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission......%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-a2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-a2b arm (82%) compared...... with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-a2b treatment ( 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-a2b to imatinib markedly increased the MMR rate at 12 months...

  12. HIGH-DOSE RATE BRACHYTHERAPY IN CARCINOMA CERVIX STAGE IIIB

    Directory of Open Access Journals (Sweden)

    Sathya Maruthavanan

    2016-07-01

    Full Text Available INTRODUCTION Radiotherapy is the standard treatment in locally advanced (IIB-IVA and early inoperable cases. The current standard of practice with curable intent is concurrent chemoradiation in which intracavitary brachytherapy is an integral component of radiotherapy. This study aims at assessing the efficacy of HDR ICBT (High-dose rate intracavitary brachytherapy in terms local response, normal tissue reactions, and feasibility. METHODS AND MATERIALS A total of 20 patients of stage IIIB cancer of the uterine cervix were enrolled in the study and were planned to receive concurrent chemotherapy weekly along with EBRT (external beam radiotherapy to a dose of 50 Gy/25 Fr. Suitability for ICBT was assessed at 40 Gy/20 Fr. 6/20 patients were suitable at 40 Gy and received HDR ICBT with a dose of 5.5 Gy to point A in 4 sessions (5.5 Gy/4 Fr. The remaining 14/20 patients completed 50 Gy and received HDR ICBT with a dose of 6 Gy to point A in 3 sessions (6 Gy/3 Fr. RESULTS A total of 66 intracavitary applications were done and only one application required dose modification due to high bladder dose, the pelvic control rate was 85% (17/20. 10% (2/20 had stable disease and 5% (1/20 had progressive disease at one year of follow up. When toxicity was considered only 15% developed grade I and grade II rectal complications. Patient compliance and acceptability was 100%. Patients were very comfortable with the short treatment time as compared with patients on LDR ICBT (low-dose rate intracavitary brachytherapy treatment interviewed during the same period. CONCLUSION This study proves that HDR brachytherapy is efficacious and feasible in carcinoma of cervix stage IIIB. It also proves that good dose distribution can be achieved with HDR intracavitary facility by the use of dose optimization. The short treatment time in HDR ICBT makes it possible to maintain this optimised dose distribution throughout the treatment providing a gain in the therapeutic ratio and

  13. Downregulation of miR-451 in Tunisian chronic myeloid leukemia patients: potential implication in imatinib resistance.

    Science.gov (United States)

    Soltani, Ismael; Douzi, Kais; Gharbi, Hanen; Benhassine, Islem; Teber, Mouheb; Amouri, Hassiba; Ben Hadj Othman, Hind; Farrah, Ahlem; Ben Lakhel, Raihane; Abbes, Salem; Menif, Samia

    2017-05-01

    Resistance to imatinib has been recognized as a major challenge for the treatment of chronic myeloid leukemia (CML). Aberrant expression of miR-451 has been reported to participate in anticancer drug resistance. However, the role of miR-451 in imatinib resistance has not been investigated. The present study was undertaken to determine the expression of miR-451 in order to find a possible association between the expression of this miRNA and imatinib resistance in Tunisian CML patients. First, real-time RT-PCR was performed to identify the expression of miR-451 in peripheral leukocytes of 59 CML patients treated with imatinib. Then, bioinformatics analysis was carried out to understand the regulatory roles of miR-451 in imatinib-resistant process. Downregulated miR-451 was observed in imatinib-resistant CML cases. In silico analysis identified MYC as a potential target of miR-451. We further revealed the existence of an MYC-binding site in MiR-451 promoter region. On the other hand, increased level of MYC was detected in imatinib-resistant CML cases which may explain the causative role of MYC in CML cases and the downregulation of miR-451. Taken together, our findings suggest that miR-451 and MYC form together a regulatory loop which may act as a potential therapeutic target, and disruption of suggested regulatory loop could help to improve CML therapy.

  14. Phase I study of imatinib, cisplatin and 5-fluoruracil or capecitabine in advanced esophageal and gastric adenocarcinoma

    International Nuclear Information System (INIS)

    Mayr, Martina; Becker, Karen; Schulte, Nadine; Belle, Sebastian; Hofheinz, Ralf; Krause, Annekatrin; Schmid, Roland M; Röcken, Christoph; Ebert, Matthias P

    2012-01-01

    Despite all benefit provided by established therapies prognosis of gastric cancer remains poor. Targeted inhibition of platelet derived growth factor receptor (PDGFR) by imatinib may influence tumor growth and amplify chemotherapeutic effects. This phase I study evaluated dose limiting toxicity (DLT) of imatinib combinated with chemotherapy according to a 3-patient cohort dose-escalating design. Thirty-five patients received cisplatin (60 mg/m 2 d1 q 3w)/ capecitabine (1250 mg/m 2 bid d1-14 q 21) or cisplatin (50 mg/m 2 d1 q 2w)/ 5-fluoruracil (2 g/m 2 d1, q 1w). Imatinib was started d - 4 with dose escalation from 300 to 700 mg QD in 100 mg steps. At imatinib dose level 1 (300mg) one DLT was observed, three more patients were enrolled without further DLT. At dose level 5 (700 mg) two gastric perforations occurred, so 600 mg imatinib emerged as the maximum tolerated dose. Major grade 3/4 toxicities were nausea (6%), anemia (6%) and fatigue (3%). Response evaluation revealed partial response in 27% and stable disease in 43% of the assessable patients. Combination of imatinib and chemotherapy is well tolerated. Response rates were not superior to those of standard therapy. Further investigations of a larger group of patients are required to confirm the amplification of chemotherapy effects by imatinib. European Clinical Trials Database: Eudra-CT2006-005792-17 and Clinical Trials Database: NCT00601510

  15. Imatinib and gastrointestinal stromal tumor (GIST: a selective targeted therapy Imatinib y tumor del estroma gastrointestinal (GIST: un tratamiento selectivo frente a una diana molecular

    Directory of Open Access Journals (Sweden)

    A. Fernández

    2004-10-01

    Full Text Available Gastrointestinal stromal tumors are the most frequent mesenchymal tumors in the gastrointestinal tract. They originate from the interstitial cells of Cajal and are characterized by an anomalous receptor for a growth factor with tyrosine-kinase activity (c-kit. This anomaly causes a permanent activation of the receptor and uncontrolled cell growth. These tumors show a poor response to traditional chemotherapy drugs, and are thus associated with low survival in cases of advanced disease. Imatinib, a tyrosine kinase inhibitor, is an example of selective targeted oncologic therapy that induces improved survival in these patients. We discuss two cases of metastatic gastrointestinal stromal tumors with a good response to imatinib, and also review the pathophysiology and treatment-related outcome of this type of tumors. We include results from clinical phase-III studies.Los tumores del estroma gastrointestinal son los tumores mesenquimales más frecuentes del tracto digestivo y se originan de las células intersticiales de Cajal. Se caracterizan por presentar un receptor para el factor de crecimiento con actividad tirosin kinasa (c-kit anómalo que condiciona su activación permanente y un crecimiento celular incontrolado. Tienen una baja supervivencia en casos de enfermedad avanzada, con escasa respuesta a los agentes quimioterápicos tradicionales. El imatinib es un fármaco inhibidor de la tirosín kinasa y un ejemplo de terapia oncológica selectiva que condiciona un importante aumento en la supervivencia de estos pacientes. Se presentan 2 casos de enfermedad metastásica con buena respuesta a imatinib, así como una revisión sobre la fisiopatología y evolución en el tratamiento de este tipo de tumores, incluyendo resultados de estudios en fase III.

  16. Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled trial

    DEFF Research Database (Denmark)

    Grunberg, Steven M; Rolski, Janusz; Strausz, Janos

    2009-01-01

    in the control group. The most common serious adverse events were neutropenia (n=5 [3%] in the control group, n=3 [1%] in the single-dose oral casopitant mesylate group, and n=11 [4%] in the 3-day intravenous plus oral casopitant mesylate group), febrile neutropenia (n=1 [

  17. An expeditious synthesis of imatinib and analogues utilising flow chemistry methods.

    Science.gov (United States)

    Hopkin, Mark D; Baxendale, Ian R; Ley, Steven V

    2013-03-21

    A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a number of analogues which were screened for biological activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor solubility of many of the reaction components.

  18. Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

    NARCIS (Netherlands)

    Deenik, Wendy; Janssen, Jeroen J. W. M.; van der Holt, Bronno; Verhoef, Gregor E. G.; Smit, Willem M.; Kersten, Marie José; Daenen, Simon M. G. J.; Verdonck, Leo F.; Ferrant, Augustin; Schattenberg, Anton V. M. B.; Sonneveld, Pieter; van Marwijk Kooy, Marinus; Wittebol, Shulamit; Willemze, Roelof; Wijermans, Pierre W.; Beverloo, H. Berna; Löwenberg, Bob; Valk, Peter J. M.; Ossenkoppele, Gert J.; Cornelissen, Jan J.

    2010-01-01

    In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. Having reported feasibility previously, we hereby

  19. Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

    NARCIS (Netherlands)

    Deenik, W.; Janssen, J.J.W.M.; van der Holt, B.; Verhoef, G.E.G.; Smit, W.M.; Kersten, M.J.; Daenen, S.M.G.J.; Verdouck, L.F.; Ferrant, A.; Schattenberg, A.V.M.B.; Sonneveld, P.; Kooy, M.V.M.; Wittebol, S.; Willemze, R.; Wijermans, P.W.; Beverloo, H.B.; Lowenberg, B.; Valk, P.J.M.; Ossenkoppele, G.J.; Cornelissen, J.J.

    2010-01-01

    Background In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. Design and Methods Having reported

  20. Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

    NARCIS (Netherlands)

    Deenik, Wendy; Janssen, Jeroen J. W. M.; van der Holt, Bronno; Verhoef, Gregor E. G.; Smit, Willem M.; Kersten, Marie Jose; Daenen, Simon M. G. J.; Verdouck, Leo F.; Ferrant, Augustin; Schattenberg, Anton V. M. B.; Sonneveld, Pieter; Kooy, Marinus van Marwijk; Wittebol, Shulamit; Willemze, Roelof; Wijermans, Pierre W.; Beverloo, H. Berna; Lowenberg, Bob; Valk, Peter J. M.; Ossenkoppele, Gert J.; Cornelissen, Jan J.

    Background In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. Design and Methods Having reported

  1. Spectrophotometric Determination of Gemifloxacin Mesylate in Pharmaceutical Formulations Through Ion-Pair Complex Formation

    Directory of Open Access Journals (Sweden)

    Marothu Vamsi Krishna

    2008-01-01

    Full Text Available Four simple and sensitive ion-pairing spectrophotometric methods have been described for the assay of gemifloxacin mesylate (GFX either in pure form or in pharmaceutical formulations. The developed methods involve formation of colored chloroform extractable ion-pair complexes of the drug with safranin O (SFN O and methylene blue (MB in basic medium; Napthol blue 12BR (NB 12BR and azocaramine G (AG in acidic medium. The extracted complexes showed absorbance maxima at 525, 650, 620 and 540 nm for SFN O, MB, NB 12BR and AG, respectively.Beer's law is obeyed in the concentration ranges 3-15, 4-20, 2-10 and 2-10 μg/mL with molar absorptivity of 2.81 × 104, 2.20 x 104, 4.02 × 104 and 4.15 × 104 L mole−1 cm−1 and relative standard deviation of 0.077, 0.104, 0.080 and 0.103% for SFN O, MB, NB 12BR and AG, respectively. These methods have been successfully applied for the assay of drug in pharmaceutical formulations. No interference was observed from common pharmaceutical adjuvants. Results of analysis were validated statistically and through recovery studies.

  2. Spectrophotometric Determination of Gemifloxacin Mesylate, Moxifloxacin Hydrochloride, and Enrofloxacin in Pharmaceutical Formulations Using Acid Dyes

    Directory of Open Access Journals (Sweden)

    Ayman A. Gouda

    2014-01-01

    Full Text Available Simple, rapid, and extractive spectrophotometric methods were developed for the determination of some fluoroquinolones antibiotics: gemifloxacin mesylate (GMF, moxifloxacin hydrochloride (MXF, and enrofloxacin (ENF in pure forms and pharmaceutical formulations. These methods are based on the formation of ion-pair complexes between the basic drugs and acid dyes, namely, bromocresol green (BCG, bromocresol purple (BCP, bromophenol blue (BPB, bromothymol blue (BTB, and methyl orange (MO in acidic buffer solutions. The formed complexes were extracted with chloroform and measured at 420, 408, 416, 415, and 422 nm for BCG, BCP, BPB, BTB, and MO, respectively, for GMF; at 410, 415, 416, and 420 nm for BCP, BTB, BPB, and MO, respectively, for MXF; and at 419 and 414 nm for BCG and BTB, respectively, in case of ENF. The analytical parameters and their effects are investigated. Beer’s law was obeyed in the ranges 1.0–30, 1.0–20, and 2.0–24 μg mL−1 for GMF, MXF, and ENF, respectively. The proposed methods have been applied successfully for the analysis of the studied drugs in pure forms and pharmaceutical formulations. Statistical comparison of the results with the reference methods showed excellent agreement and indicated no significant difference in accuracy and precision.

  3. Effect of gamma-irradiation on biodegradable microspheres loaded with rasagiline mesylate

    International Nuclear Information System (INIS)

    Fernandez, Marcos; Barcia, Emilia; Negro, Sofia

    2016-01-01

    In the present study, the influence of gamma-irradiation was evaluated on the physicochemical characteristics and in vitro release of rasagiline mesylate (RM), a selective MAO-B inhibitor used in Parkinson's disease, from poly(D,L-lactide-co-glycolide) (PLGA) microspheres. Microspheres were prepared using PLGA 50:50 by the solvent evaporation technique (O/W emulsion). Microspheres were sterilized by gamma-irradiation and their influence was assessed by scanning electron microscopy (SEM), laser light diffraction, differential scanning calorimetry (DSC), X-ray diffraction (XRD), gel permeation chromatography (GPC), encapsulation efficiency (EE) and in vitro drug release. Gamma-irradiation of RM-loaded microspheres did not affect EE, DSC and XRD patterns. After gamma-irradiation, changes on the surface were observed by SEM, but no significant difference in mean particle size was observed. GPC measurements showed a decrease in molecular weight of the polymer after five days of in vitro release. The similarity factor value between irradiated and non-irradiates microspheres was <50, indicating the non-similarity of the release profiles. The sterilization technique had an effect on the integrity of polymeric system, significantly affecting in vitro release of RM from PLGA microspheres. Therefore, from our results we conclude that gamma-irradiation is not a suitable sterilization procedure for this formulation

  4. Quantitative determination of pefloxacin mesylate by residual-base neutralisation method

    Directory of Open Access Journals (Sweden)

    HULIKALCHANDRA SHEKAR PRAMEELA

    2004-05-01

    Full Text Available This work describes two procedures based on residual base determination for the quantification of pefloxacin mesylate (PFM in bulk drug and in pharmaceutical products. In the first method involving titrimetry, the drug solution is treated with a measured excess of sodium hydroxide followed by back titration of the residual base with hydrochloric acid using a phenol red-bromothymol blue mixed indicator. The second spectrophotometrie method involves treatment of a fixed amount of sodium hydroxide – phenol red mixture with varying amounts of the drug, and measuring the decrease in the absorbance of the dye at 560 nm. In the titrimetric method, a reaction stoichiometry of 1:1 was found in the quantification range of 4–20 mg of drug. The spectrophotometric method allows the determination of PFM in the 5–40 mg ml-1 range. The molar absorptivity is 5.91¤103 l mol-1 cm-1 and the Sandell sensitivity is 56.37 ng cm-2. The methods were applied successfully to the determination of PFM in pharmaceutical preparations.

  5. Enhanced Silver Nanoparticle Chemiluminescence Method for the Determination of Gemifloxacin Mesylate using Sequential Injection Analysis

    International Nuclear Information System (INIS)

    Alarfaj, N.A.; Aly, F.A.; Tamimi, A.A.

    2013-01-01

    A sequential injection analysis (SIA) with chemiluminescence detection has been proposed for the determination of the antibiotic gemifloxacin mesylate (GFX). The developed method is based on the enhancement effect of silver nanoparticles (Ag NPs) on the chemiluminescence (CL) signal of luminol-potassium ferricyanide reaction in alkaline medium. The introduction of gemifloxacin in this system produced a significant decrease in the CL intensity in presence of (Ag NPs). The optimum conditions for CL emission were investigated. Linear relationship between the decrease in CL intensity and concentration was obtained in the range 0.01-1000 ng mL-1, (r = 0.9997) with detection limit of 2.0 pg mL-1 and quantification limit of 0.01 pg mL-1. The relative standard deviation was 1.3 %. The proposed method was employed for the determination of gemifloxacin in bulk drug, in its pharmaceutical dosage forms and biological fluids such as human serum and urine. The interference of some common additive compounds such as glucose, lactose, starch, talc and magnesium stearate was investigated, and no interference was found from these excipients. The obtained SIA results were statistically compared with those obtained from a reported method and did not show any significant difference at confidence level 95%. (author)

  6. High dose rate 192Ir calibration: Indonesia experiences

    International Nuclear Information System (INIS)

    Nasukha; Tjiptanto, D.; Darmasyah, R.; Kurniawan, B.

    2002-01-01

    Indonesia with a population of more than 200 Million people which spread on about 5000 islands, up to now only has 23 radiotherapy centers and some not active anymore. As mention by Parkin et al that Cervix/Utery and breast cancer are the most estimated numbers of new cases of cancers in women for developing countries, stomach and lung cancers in men. Indonesia as a developing country is likely similar to other developing countries on numbers of new cases of cancers in women. But quite different in men, in Indonesia the most common cancers are nasopharynx and thyroid cancers. The use of lr-192 sources in high dose-rate (HDR) remotely afterloaded brachytherapy treatments have greatly increased in recent years and variety of such sources are commercially available. Nine radiotherapy centers in Indonesia installed Nucletron microSelectron HDR remote afterloader. Based on the data of CiptoMangunkusurno Hospital, Jakarta that the most common cancers are the cervix, breast, nasopharynx and thyroid cancers which of percentage are about 31%, 25 %, 13%, and 6 % respectively. It means that the use of HDR 192 Ir brachytherapy has to be an effective tool in the treatments. Two methods have been studied and applied to calibrate HDR 192 Ir brachytherapy in Indonesia, especially for Nucletron microSelectron HDR 192 lr remote afterloader brachytherapy. Calibration of HDR 192 Ir brachytherapy source has been done by Cavity lonization Chamber and with Well Type lonization Chamber. First, 0.6 cc of NE Farmer type dosimeter that was calibrated to 60 Co and 250 kV of x-rays in air kerma was used in this experiment. Position of measurement (detector and source) at the center of the room and about 1 meter from the floor. Eight variation of distances from 10 cm to 40 cms have been carried out measurement as recommended by IAEA-TECDOC-1079. Correction have been given for scatters, non-uniformity, and attenuation. To solve the problem of scatter correction factor was used Matlab programming

  7. High-dose-rate brachytherapy in uterine cervical carcinoma

    International Nuclear Information System (INIS)

    Patel, Firuza D.; Rai, Bhavana; Mallick, Indranil; Sharma, Suresh C.

    2005-01-01

    Purpose: High-dose-rate (HDR) brachytherapy is in wide use for curative treatment of cervical cancer. The American Brachytherapy Society has recommended that the individual fraction size be <7.5 Gy and the range of fractions should be four to eight; however, many fractionation schedules, varying from institution to institution, are in use. We use 9 Gy/fraction of HDR in two to five fractions in patients with carcinoma of the uterine cervix. We found that our results and toxicity were comparable to those reported in the literature and hereby present our experience with this fractionation schedule. Methods and Materials: A total of 121 patients with Stage I-III carcinoma of the uterine cervix were treated with HDR brachytherapy between 1996 and 2000. The total number of patients analyzed was 113. The median patient age was 53 years, and the histopathologic type was squamous cell carcinoma in 93% of patients. The patients were subdivided into Groups 1 and 2. In Group 1, 18 patients with Stage Ib-IIb disease, tumor size <4 cm, and preserved cervical anatomy underwent simultaneous external beam radiotherapy to the pelvis to a dose of 40 Gy in 20 fractions within 4 weeks with central shielding and HDR brachytherapy of 9 Gy/fraction, given weekly, and interdigitated with external beam radiotherapy. The 95 patients in Group 2, who had Stage IIb-IIIb disease underwent external beam radiotherapy to the pelvis to a dose of 46 Gy in 23 fractions within 4.5 weeks followed by two sessions of HDR intracavitary brachytherapy of 9 Gy each given 1 week apart. The follow-up range was 3-7 years (median, 36.4 months). Late toxicity was graded according to the Radiation Therapy Oncology Group criteria. Results: The 5-year actuarial local control and disease-free survival rate was 74.5% and 62.0%, respectively. The actuarial local control rate at 5 years was 100% for Stage I, 80% for Stage II, and 67.2% for Stage III patients. The 5-year actuarial disease-free survival rate was 88.8% for

  8. Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib

    Science.gov (United States)

    Hochhaus, Andreas; le Coutre, Philipp D.; Rosti, Gianantonio; Pinilla-Ibarz, Javier; Jabbour, Elias; Gillis, Kathryn; Woodman, Richard C.; Blakesley, Rick E.; Giles, Francis J.; Kantarjian, Hagop M.; Baccarani, Michele

    2011-01-01

    Nilotinib has significant efficacy in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) and in patients with CML-CP or CML in accelerated phase (CML-AP) after imatinib failure. We investigated the occurrence of cross-intolerance to nilotinib in imatinib-intolerant patients with CML. Only 1/75 (1%) patients with nonhematologic imatinib intolerance experienced a similar grade 3/4 adverse event (AE), and 3/75 (4%) experienced a similar persistent grade 2 nonhematologic AE on nilotinib. Only 7/40 (18%) patients with hematologic imatinib intolerance discontinued nilotinib, all because of grade 3/4 thrombocytopenia. Ninety percent of imatinib-intolerant patients with CML-CP who did not have complete hematologic response (CHR) at baseline (n = 52) achieved CHR on nilotinib. Nilotinib induced a major cytogenetic response in 66% and 41% of patients with imatinib-intolerant CML-CP and CML-AP (complete cytogenetic response in 51% and 30%), respectively. Minimal cross-intolerance was confirmed in patients with imatinib-intolerant CML. The favorable tolerability of nilotinib in patients with imatinib intolerance leads to alleviation of AE-related symptoms and significant and durable responses. In addition to its established clinical benefit in patients with newly diagnosed CML and those resistant to imatinib, nilotinib is effective and well-tolerated for long-term use in patients with imatinib intolerance. This study is registered at http://www.clinicaltrials.gov as NCT00471497 PMID:21467546

  9. The Role of High Dose Interleukin-2 in the Era of Targeted Therapy.

    Science.gov (United States)

    Gills, Jessie; Parker, William P; Pate, Scott; Niu, Sida; Van Veldhuizen, Peter; Mirza, Moben; Holzbeierlein, Jeffery M; Lee, Eugene K

    2017-09-01

    We assessed survival outcomes following high dose interleukin-2 in a contemporary cohort of patients during the era of targeted agents. We retrospectively reviewed the records of patients with metastatic renal cell carcinoma treated with high dose interleukin-2 between July 2007 and September 2014. Clinicopathological data were abstracted and patient response to therapy was based on RECIST (Response Evaluation Criteria In Solid Tumors), version 1.1 criteria. The Kaplan-Meier method was used to estimate progression-free and overall survival in the entire cohort, the response to high dose interleukin-2 in regard to previous targeted agent therapy and the response to the targeted agent in relation to the response to high dose interleukin-2. We identified 92 patients, of whom 87 had documentation of a response to high dose interleukin-2. Median overall survival was 34.4 months from the initiation of high dose interleukin-2 therapy in the entire cohort. Patients who received targeted therapy before high dose interleukin-2 had overall survival (median 34.4 and 30.0 months, p = 0.88) and progression-free survival (median 1.5 and 1.7 months, p = 0.8) similar to those in patients who received no prior therapy, respectively. Additionally, patients with a complete or partial response to high dose interleukin-2 had similar outcomes for subsequent targeted agents compared to patients whose best response was stable or progressive disease (median overall survival 30.1 vs 25.4 months, p = 0.4). Our data demonstrate that patient responses to high dose interleukin-2 and to targeted agents before and after receiving high dose interleukin-2 are independent. As such, carefully selected patients should be offered high dose interleukin-2 for the possibility of a complete and durable response without the fear of limiting the treatment benefit of targeted agents. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  10. ON012380: A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant CMLs

    National Research Council Canada - National Science Library

    Reddy, E. P

    2007-01-01

    Because it is now apparent that a significant proportion of patients chronically treated with imatinib develop resistance due to the acquisition of mutations in the kinase domain of BCR-ABL our aim...

  11. WT1 expression in peripheral leukocytes of patients with chronic myeloid leukemia serves for the prediction of Imatinib resistance

    Czech Academy of Sciences Publication Activity Database

    Otahalová, E.; Ullmannová-Benson, Veronika; Klamová, H.; Haškovec, C.

    2009-01-01

    Roč. 56, č. 5 (2009), s. 393-397 ISSN 0028-2685 Institutional research plan: CEZ:AV0Z50200510 Keywords : Imatinib * drug resistance * cml Subject RIV: EC - Immunology Impact factor: 1.192, year: 2009

  12. Bosutinib, dasatinib, imatinib, nilotinib, and ponatinib differentially affect the vascular molecular pathways and functionality of human endothelial cells.

    Science.gov (United States)

    Gover-Proaktor, Ayala; Granot, Galit; Pasmanik-Chor, Metsada; Pasvolsky, Oren; Shapira, Saar; Raz, Oshrat; Raanani, Pia; Leader, Avi

    2018-05-09

    The tyrosine kinase inhibitors (TKIs), nilotinib, ponatinib, and dasatinib (but not bosutinib or imatinib), are associated with vascular adverse events (VAEs) in chronic myeloid leukemia (CML). Though the mechanism is inadequately understood, an effect on vascular cells has been suggested. We investigated the effect of imatinib, nilotinib, dasatinib, bosutinib, and ponatinib on tube formation, cell viability, and gene expression of human vascular endothelial cells (HUVECs). We found a distinct genetic profile in HUVECs treated with dasatinib, ponatinib, and nilotinib compared to bosutinib and imatinib, who resembled untreated samples. However, unique gene expression and molecular pathway alterations were detected between dasatinib, ponatinib, and nilotinib. Angiogenesis/blood vessel-related pathways and HUVEC function (tube formation/viability) were adversely affected by dasatinib, ponatinib, and nilotinib but not by imatinib or bosutinib. These results correspond to the differences in VAE profiles of these TKIs, support a direct effect on vascular cells, and provide direction for future research.

  13. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial.

    Science.gov (United States)

    Lipton, Jeffrey H; Chuah, Charles; Guerci-Bresler, Agnès; Rosti, Gianantonio; Simpson, David; Assouline, Sarit; Etienne, Gabriel; Nicolini, Franck E; le Coutre, Philipp; Clark, Richard E; Stenke, Leif; Andorsky, David; Oehler, Vivian; Lustgarten, Stephanie; Rivera, Victor M; Clackson, Timothy; Haluska, Frank G; Baccarani, Michele; Cortes, Jorge E; Guilhot, François; Hochhaus, Andreas; Hughes, Timothy; Kantarjian, Hagop M; Shah, Neil P; Talpaz, Moshe; Deininger, Michael W

    2016-05-01

    Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia. The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0-2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805. Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the

  14. The clinical pharmacology of alkylating agents in high-dose chemotherapy

    NARCIS (Netherlands)

    Huitema, A. D.; Smits, K. D.; Mathôt, R. A.; Schellens, J. H.; Rodenhuis, S.; Beijnen, J. H.

    2000-01-01

    Alkylating agents are widely used in high-dose chemotherapy regimens in combination with hematological support. Knowledge about the pharmacokinetics and pharmacodynamics of these agents administered in high doses is critical for the safe and efficient use of these regimens. The aim of this review is

  15. Risks Associated with High-Dose Lactobacillus rhamnosus in an Escherichia coli Model of Piglet Diarrhoea

    DEFF Research Database (Denmark)

    Li, Xiao-Qiong; Zhu, Yao-Hong; Zhang, Hong-Fu

    2012-01-01

    might be more effective than a high dose at ameliorating diarrhoea. There is a risk that high-dose L. rhamnosus pretreatment may negate the preventative effects, thus decreasing the prophylactic benefits against potential enteric pathogens. Our data suggest a safe threshold for preventative use...

  16. Split high-dose oral levothyroxine treatment as a successful therapy option in myxedema coma.

    Science.gov (United States)

    Charoensri, Suranut; Sriphrapradang, Chutintorn; Nimitphong, Hataikarn

    2017-10-01

    High-dose intravenous thyroxine (T4) is the preferable treatment for myxedema coma. We describe the clinical course of a 69-year-old man who presented with myxedema coma and received oral levothyroxine (LT4) therapy (1 mg) in a split dose. This suggests split high-dose oral LT4 as a therapeutic option in myxedema coma.

  17. Successful combination treatment of a patient with progressive juvenile localized scleroderma (morphea) using imatinib, corticosteroids, and methotrexate.

    Science.gov (United States)

    Inamo, Yasuji; Ochiai, Toyoko

    2013-01-01

    We report a case of progressive juvenile localized scleroderma (JLS or morphea) treated with a combination of imatinib, corticosteroids, and methotrexate. This therapy halted the progressive skin thickening and the hand and finger joint deformity in the early stages of the disease. We conclude that imatinib used in addition to standard treatment with systemic corticosteroids and methotrexate may be of therapeutic benefit for individuals with JLS. © 2012 Wiley Periodicals, Inc.

  18. Reversal of soft-tissue local anesthesia with phentolamine mesylate in adolescents and adults.

    Science.gov (United States)

    Hersh, Elliot V; Moore, Paul A; Papas, Athena S; Goodson, J Max; Navalta, Laura A; Rogy, Siegfried; Rutherford, Bruce; Yagiela, John A

    2008-08-01

    The authors conducted two multicenter, randomized, double-blinded, controlled Phase III clinical trials to study the efficacy and safety of phentolamine mesylate (PM) in shortening the duration and burden of soft-tissue anesthesia. The study involved 484 subjects who received one of four commercially available local anesthetic solutions containing vasoconstrictors for restorative or scaling procedures. On completion of the dental procedure, subjects randomly received a PM or a sham injection (an injection in which a needle does not penetrate the soft tissue) in the same site as the local anesthetic injection. The investigators measured the duration of soft-tissue anesthesia by using standardized lip- and tongue-tapping procedures every five minutes for five hours. They also evaluated functional measures and subject-perceived altered function, sensation, appearance and safety. Median recovery times in the lower lip and tongue for subjects in the PM group were 70 minutes and 60 minutes, respectively. Median recovery times in the lower lip and tongue for subjects in the sham group were 155 minutes and 125 minutes, respectively. Upper lip median recovery times were 50 minutes for subjects in the PM group and 133 minutes for subjects in the sham group. These differences were significant (P < .0001). Recovery from actual functional deficits and subject-perceived altered function, sensation and appearance also showed significant differences between the PM and the sham groups. PM was efficacious and safe in reducing the duration of local anesthetic- induced soft-tissue numbness and its associated functional deficits. Clinicians can use PM to accelerate reversal of soft-tissue anesthesia and the associated functional deficits.

  19. Dihydroergotamine mesylate-loaded dissolving microneedle patch made of polyvinylpyrrolidone for management of acute migraine therapy.

    Science.gov (United States)

    Tas, Cetin; Joyce, Jessica C; Nguyen, Hiep X; Eangoor, Padmanabhan; Knaack, Jennifer S; Banga, Ajay K; Prausnitz, Mark R

    2017-12-28

    Migraine is a widespread neurological disease with negative effects on quality of life and productivity. Moderate to severe acute migraine attacks can be treated with dihydroergotamine mesylate (DHE), an ergot derivative that is especially effective in non-responders to triptan derivatives. To overcome limitations of current DHE formulations in subcutaneous injection and nasal spray such as pain, adverse side effects and poor bioavailability, a new approach is needed for DHE delivery enabling painless self-administration, quick onset of action, and high bioavailability. In this study, we developed a dissolving microneedle patch (MNP) made of polyvinylpyrrolidone, due to its high aqueous solubility and solubility enhancement properties, using a MNP design previously shown to be painless and simple to administer. DHE-loaded MNPs were shown to have a content uniformity of 108±9% with sufficient mechanical strength for insertion to pig skin ex vivo and dissolution within 2min. In vivo pharmacokinetic studies were carried out on hairless rats, and DHE plasma levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under curve (AUC) value after DHE delivery by MNP (1259±917ng/mL min) was not significantly different (p>0.05) as compared to subcutaneous injection, with a relative bioavailability of 97%. Also, appreciable plasma levels of DHE were seen within 5min for both delivery methods and t max value of MNPs (38±23min) showed no significant difference (p>0.05) compared to subcutaneous injection (24±13min). These results suggest that DHE-loaded MNPs have promise as an alternative DHE delivery method that can be painlessly self-administered with rapid onset and high bioavailability. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Surgery and imatinib therapy for liver oligometastasis of GIST: a study of Japanese Study Group on GIST.

    Science.gov (United States)

    Kanda, Tatsuo; Masuzawa, Toru; Hirai, Toshihiro; Ikawa, Osamu; Takagane, Akinori; Hata, Yasuhiro; Ojima, Hitoshi; Sodeyama, Harutsugu; Mochizuki, Izumi; Ishikawa, Takashi; Kagimura, Tatsuo; Nishida, Toshirou

    2017-04-01

    We conducted a multicenter prospective study to clarify the efficacy and safety of surgery and imatinib for liver oligometastasis of gastrointestinal stromal tumors. Eligible gastrointestinal stromal tumor patients were enrolled in the surgery trial or the imatinib trial. Primary endpoints were recurrence-free survival and progression-free survival, respectively. The trials were prematurely terminated due to amendment of guidelines for adjuvant imatinib therapy and low patient accrual. In the surgery trial, all the six patients showed hepatic recurrence: median recurrence-free survival was 145 days (range: 62-1366 days). Of the five patients receiving salvage imatinib therapy, two showed progressive disease although no death was observed. Of the five patients enrolled in the imatinib trial, one died of pneumonia after progressive disease, and four had not shown progressive disease as of last visit. The results suggest that liver oligometastasis of gastrointestinal stromal tumor may not be controllable by surgery alone and require concomitant imatinib therapy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein.

    LENUS (Irish Health Repository)

    Elzinga, Baukje M

    2013-06-01

    Chronic Myeloid Leukemia (CML) is a disease of hematopoietic stem cells which harbor the chimeric gene Bcr-Abl. Expression levels of this constitutively active tyrosine kinase are critical for response to tyrosine kinase inhibitor treatment and also disease progression, yet the regulation of protein stability is poorly understood. We have previously demonstrated that imatinib can induce autophagy in Bcr-Abl expressing cells. Autophagy has been associated with the clearance of large macromolecular signaling complexes and abnormal proteins, however, the contribution of autophagy to the turnover of Bcr-Abl protein in imatinib treated cells is unknown. In this study, we show that following imatinib treatment, Bcr-Abl is sequestered into vesicular structures that co-localize with the autophagy marker LC3 or GABARAP. This association is inhibited by siRNA mediated knockdown of autophagy regulators (Beclin 1\\/ATG7). Pharmacological inhibition of autophagy also reduced Bcr-Abl\\/LC3 co-localization in both K562 and CML patient cells. Bcr-Abl protein expression was reduced with imatinib treatment. Inhibition of both autophagy and proteasome activity in imatinib treated cells was required to restore Bcr-Abl protein levels to those of untreated cells. This ability to down-regulate Bcr-Abl protein levels through the induction of autophagy may be an additional and important feature of the activity of imatinib.

  2. Cumulative clinical experience from a decade of use: imatinib as first-line treatment of chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Baran Y

    2012-11-01

    Full Text Available Yusuf Baran,1 Guray Saydam21Department of Molecular Biology and Genetics, Izmir Institute of Technology, Izmir, Turkey; 2Department of Hematology, School of Medicine, Ege University, Izmir, TurkeyAbstract: Chronic myeloid leukemia (CML is a malignant disease that originates in the bone marrow and is designated by the presence of the Philadelphia (Ph+ chromosome, a translocation between chromosomes 9 and 22. Targeted therapy against CML commenced with the development of small-molecule tyrosine kinase inhibitors (TKIs exerting their effect against the oncogenic breakpoint cluster region (BCR-ABL fusion protein. Imatinib emerged as the first successful example of a TKI used for the treatment of chronic-phase CML patients and resulted in significant improvements in response rate and overall survival compared with previous treatments. However, a significant portion of patients failed to respond to the therapy and developed resistance against imatinib. Second-generation TKIs nilotinib and dasatinib were to have higher efficiency in clinical trials in imatinib- resistant or intolerant CML patients compared with imatinib. Identification of novel strategies such as dose escalation, drug combination therapy, and use of novel BCR-ABL inhibitors may eventually overcome resistance against BCR-ABL TKIs. This article reviews the history of CML, including the treatment strategies used prediscovery of TKIs and the preclinical and clinical data obtained after the use of imatinib, and the second-generation TKIs developed for the treatment of CML.Keywords: drug resistance, tyrosine kinase inhibitors, chronic myeloid leukemia, imatinib, BCR/ABL

  3. Imatinib treatment causes substantial transcriptional changes in adult Schistosoma mansoni in vitro exhibiting pleiotropic effects.

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    Christin Buro

    2014-06-01

    Full Text Available Schistosome parasites cause schistosomiasis, one of the most important infectious diseases worldwide. For decades Praziquantel (PZQ is the only drug widely used for controlling schistosomiasis. The absence of a vaccine and fear of PZQ resistance have motivated the search for alternatives. Studies on protein kinases (PKs demonstrated their importance for diverse physiological processes in schistosomes. Among others two Abl tyrosine kinases, SmAbl1 and SmAbl2, were identified in Schistosoma mansoni and shown to be transcribed in the gonads and the gastrodermis. SmAbl1 activity was blocked by Imatinib, a known Abl-TK inhibitor used in human cancer therapy (Gleevec/Glivec. Imatinib exhibited dramatic effects on the morphology and physiology of adult schistosomes in vitro causing the death of the parasites.Here we show modeling data supporting the targeting of SmAbl1/2 by Imatinib. A biochemical assay confirmed that SmAbl2 activity is also inhibited by Imatinib. Microarray analyses and qRT-PCR experiments were done to unravel transcriptional processes influenced by Imatinib in adult schistosomes in vitro demonstrating a wide influence on worm physiology. Surface-, muscle-, gut and gonad-associated processes were affected as evidenced by the differential transcription of e.g. the gynecophoral canal protein gene GCP, paramyosin, titin, hemoglobinase, and cathepsins. Furthermore, transcript levels of VAL-7 and egg formation-associated genes such as tyrosinase 1, p14, and fs800-like were affected as well as those of signaling genes including a ribosomal protein S6 kinase and a glutamate receptor. Finally, a comparative in silico analysis of the obtained microarray data sets and previous data analyzing the effect of a TGFβR1 inhibitor on transcription provided first evidence for an association of TGFβ and Abl kinase signaling. Among others GCP and egg formation-associated genes were identified as common targets.The data affirm broad negative effects of

  4. Sensitive detection of pre-existing BCR-ABL kinase domain mutations in CD34+ cells of newly diagnosed chronic-phase chronic myeloid leukemia patients is associated with imatinib resistance: implications in the post-imatinib era.

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    Zafar Iqbal

    Full Text Available BACKGROUND: BCR-ABL kinase domain mutations are infrequently detected in newly diagnosed chronic-phase chronic myeloid leukemia (CML patients. Recent studies indicate the presence of pre-existing BCR-ABL mutations in a higher percentage of CML patients when CD34+ stem/progenitor cells are investigated using sensitive techniques, and these mutations are associated with imatinib resistance and disease progression. However, such studies were limited to smaller number of patients. METHODS: We investigated BCR-ABL kinase domain mutations in CD34+ cells from 100 chronic-phase CML patients by multiplex allele-specific PCR and sequencing at diagnosis. Mutations were re-investigated upon manifestation of imatinib resistance using allele-specific PCR and direct sequencing of BCR-ABL kinase domain. RESULTS: Pre-existing BCR-ABL mutations were detected in 32/100 patients and included F311L, M351T, and T315I. After a median follow-up of 30 months (range 8-48, all patients with pre-existing BCR-ABL mutations exhibited imatinib resistance. Of the 68 patients without pre-existing BCR-ABL mutations, 24 developed imatinib resistance; allele-specific PCR and BCR-ABL kinase domain sequencing detected mutations in 22 of these patients. All 32 patients with pre-existing BCR-ABL mutations had the same mutations after manifestation of imatinib-resistance. In imatinib-resistant patients without pre-existing BCR-ABL mutations, we detected F311L, M351T, Y253F, and T315I mutations. All imatinib-resistant patients except T315I and Y253F mutations responded to imatinib dose escalation. CONCLUSION: Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid

  5. Efficacy and tolerability of high-dose phenobarbital in children with focal seizures.

    Science.gov (United States)

    Okumura, Akihisa; Nakahara, Eri; Ikeno, Mitsuru; Abe, Shinpei; Igarashi, Ayuko; Nakazawa, Mika; Takasu, Michihiko; Shimizu, Toshiaki

    2016-04-01

    We retrospectively reviewed the outcomes of children with focal epilepsy treated with oral high-dose phenobarbital. We reviewed data on children (agedphenobarbital (>5 mg/kg/day to maintain a target serum level >40 μg/mL) for at least 6 months. Seizure frequency was evaluated after phenobarbital titration, and 1 and 2 years after high-dose phenobarbital treatment commenced. Treatment was judged effective when seizure frequencies fell by ⩾75%. Seven boys and eight girls were treated. The median age at commencement of high-dose phenobarbital therapy was 30 months. The maximal serum phenobarbital level ranged from 36.5 to 62.9 μg/mL. High-dose PB was effective in seven. In two patients, treatment was transiently effective, but seizure frequency later returned to the baseline. High-dose PB was ineffective in six. No significant association between effectiveness and any clinical variable was evident. Drowsiness was recorded in nine patients, but no patient developed a behavioral problem or hypersensitivity. Oral high-dose phenobarbital was effective in 7 of 15 patients with focal epilepsy and well tolerated. High-dose PB may be useful when surgical treatment is difficult. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  6. Erythemal and therapeutic response of psoriasis to PUVA using high-dose UVA

    International Nuclear Information System (INIS)

    Speight, E.L.; Farr, P.M.

    1994-01-01

    In PUVA treatment of psoriasis, clinical observation suggests that uninvolved skin is more susceptible to PUVA erythema than lesions of psoriasis. If this is the case, then the efficacy of PUVA treatment might be increased by using localized high-dose UVA restricted to lesional skin. We have therefore studied the erythemal and therapeutic response of psoriasis to PUVA using high-dose UVA and, for comparison, the erythemal response to UVB. This study demonstrates that psoriasis may clear rapidly, without burning, using high-dose UVA. Availability of a suitable irradiation apparatus would allow rapid and effective PUVA treatment to be used for localized, resistant disease. (author)

  7. Cumulative high doses of inhaled formoterol have less systemic effects in asthmatic children 6-11 years-old than cumulative high doses of inhaled terbutaline

    DEFF Research Database (Denmark)

    Kaae, Rikke; Agertoft, Lone; Pedersen, Sören

    2004-01-01

    OBJECTIVES: To evaluate high dose tolerability and relative systemic dose potency between inhaled clinically equipotent dose increments of formoterol and terbutaline in children. METHODS: Twenty boys and girls (6-11 years-old) with asthma and normal ECGs were studied. Ten doses of formoterol (Oxi...

  8. Imatinib preserves blood-brain barrier integrity following experimental subarachnoid hemorrhage in rats.

    Science.gov (United States)

    Zhan, Yan; Krafft, Paul R; Lekic, Tim; Ma, Qingyi; Souvenir, Rhonda; Zhang, John H; Tang, Jiping

    2015-01-01

    Blood-brain barrier (BBB) disruption and consequent edema formation contribute to the development of early brain injury following subarachnoid hemorrhage (SAH). Various cerebrovascular insults result in increased platelet-derived growth factor receptor (PDGFR)-α stimulation, which has been linked to BBB breakdown and edema formation. This study examines whether imatinib, a PDGFR inhibitor, can preserve BBB integrity in a rat endovascular perforation SAH model. Imatinib (40 or 120 mg/kg) or a vehicle was administered intraperitoneally at 1 hr after SAH induction. BBB leakage, brain edema, and neurological deficits were evaluated. Total and phosphorylated protein expressions of PDGFR-α, c-Src, c-Jun N-terminal kinase (JNK), and c-Jun were measured, and enzymatic activities of matrix metalloproteinase (MMP)-2 and MMP-9 were determined in the injured brain. Imatinib treatment significantly ameliorated BBB leakage and edema formation 24 hr after SAH, which was paralleled by improved neurological functions. Decreased brain expressions of phosphorylated PDGFR-α, c-Src, JNK, and c-Jun as well as reduced MMP-9 activities were found in treated animals. PDGFR-α inhibition preserved BBB integrity following experimental SAH; however, the protective mechanisms remain to be elucidated. Targeting PDGFR-α signaling might be advantageous to ameliorate early brain injury following SAH. © 2014 Wiley Periodicals, Inc.

  9. Phase I study of imatinib, cisplatin and 5-fluoruracil or capecitabine in advanced esophageal and gastric adenocarcinoma

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    Mayr Martina

    2012-12-01

    Full Text Available Abstract Background Despite all benefit provided by established therapies prognosis of gastric cancer remains poor. Targeted inhibition of platelet derived growth factor receptor (PDGFR by imatinib may influence tumor growth and amplify chemotherapeutic effects. Methods This phase I study evaluated dose limiting toxicity (DLT of imatinib combinated with chemotherapy according to a 3-patient cohort dose-escalating design. Thirty-five patients received cisplatin (60 mg/m2 d1 q 3w/ capecitabine (1250 mg/m2 bid d1-14 q 21 or cisplatin (50 mg/m2 d1 q 2w/ 5-fluoruracil (2 g/m2 d1, q 1w. Imatinib was started d - 4 with dose escalation from 300 to 700 mg QD in 100 mg steps. Results At imatinib dose level 1 (300mg one DLT was observed, three more patients were enrolled without further DLT. At dose level 5 (700 mg two gastric perforations occurred, so 600 mg imatinib emerged as the maximum tolerated dose. Major grade 3/4 toxicities were nausea (6%, anemia (6% and fatigue (3%. Response evaluation revealed partial response in 27% and stable disease in 43% of the assessable patients. Conclusions Combination of imatinib and chemotherapy is well tolerated. Response rates were not superior to those of standard therapy. Further investigations of a larger group of patients are required to confirm the amplification of chemotherapy effects by imatinib. Trial registration European Clinical Trials Database: Eudra-CT2006-005792-17 and Clinical Trials Database: NCT00601510

  10. High-dose zolpidem dependence - Psychostimulant effects? A case report and literature review

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    Abhijna Chandan Chattopadhyay

    2016-01-01

    Full Text Available Zolpidem, an imidazoline nonbenzodiazepine sedative drug, is used widely. Initial reports showed minimal abuse potential. However, multiple reports have appeared of dose escalation and abuse. Subjective effects of high-dose zolpidem are not known. In light of accumulating evidence of abuse potential, we hereby report a case of high-dose dependence and a review of relevant literature. A 33-year-old male presented with 5 years of daily use of 600–1700 mg of zolpidem tartrate. He reported subjective effects of euphoria, intense craving, and inability to stop use. Loss of receptor specificity, pharmacokinetic factors, and different receptor distributions can explain paradoxical stimulatory effects of high-dose zolpidem. Further studies are required to characterize subjective effects of high-dose zolpidem.

  11. Acute effects of high-dose furosemide on residual renal function in CAPD patients

    NARCIS (Netherlands)

    van Olden, Rudolf W.; Guchelaar, Henk-Jan; Struijk, Dirk G.; Krediet, Raymond T.; Arisz, Lambertus

    2003-01-01

    BACKGROUND: High doses of furosemide can increase urine volume in chronic peritoneal dialysis (CAPD) patients. However, no information is available about effects on urinary solute excretion in relation to residual glomerular filtration rate (GFR), urinary furosemide excretion, and peritoneal solute

  12. Methamphetamine treatment during development attenuates the dopaminergic deficits caused by subsequent high-dose methamphetamine administration

    OpenAIRE

    McFadden, Lisa M; Hoonakker, Amanda J; Vieira-Brock, Paula L; Stout, Kristen A; Sawada, Nicole M; Ellis, Jonathan D; Allen, Scott C; Walters, Elliot T; Nielsen, Shannon M; Gibb, James W; Alburges, Mario E; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

    2011-01-01

    Administration of high doses of methamphetamine (METH) causes persistent dopaminergic deficits in both nonhuman preclinical models and METH-dependent persons. Noteworthy, adolescent (i.e., postnatal day (PND) 40) rats are less susceptible to this damage than young adult (PND90) rats. In addition, biweekly treatment with METH, beginning at PND40 and continuing throughout development, prevents the persistent dopaminergic deficits caused by a “challenge” high-dose METH regimen when administered ...

  13. Safety aspects of preoperative high-dose glucocorticoid in primary total knee replacement

    DEFF Research Database (Denmark)

    Jørgensen, C C; Pitter, F T; Kehlet, H

    2017-01-01

    Background: Preoperative single high-dose glucocorticoid may have early outcome benefits in total hip arthroplasty (THA) and knee arthroplasty (TKA), but long-term safety aspects have not been evaluated. Methods: From October 2013, the departments reporting to the prospective Lundbeck Foundation....... Conclusions: In this detailed prospective cohort study, preoperative high-dose glucocorticoid administration was not associated with LOS >4 days, readmissions or infectious complications in TKA patients without contraindications....

  14. Evaluation of functioning of high dose rate brachytherapy at the Instituto Nacional do Cancer

    International Nuclear Information System (INIS)

    Guedes, Laura M.A.; Barreto, Rodrigo V.; Silva, Penha M.; Macedo, Afranio A.; Borges, Solange C.; Martinez, Valeria P.O.

    2001-01-01

    Quality control tests are very useful tools to assure the quality of patient's treatment. A daily control of the high dose rate micro selectron was performed based on the security parameters of the equipment and on the quickness of performance. The purpose of this report is to evaluate and to discuss the errors found during the first three years with the high dose rate brachytherapy, at the Instituto Nacional de Cancer. (author)

  15. High-dose Sulbactam Treatment for Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant

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    In Beom Jeong

    2016-11-01

    Full Text Available Background Several antibiotics can be used to treat ventilator-associated pneumonia caused by carbapenem-resistant A. baumannii (CRAB-VAP including high-dose sulbactam. However, the effectiveness of high-dose sulbactam therapy is not well known. We report our experience with high-dose sulbactam for treatment of CRAB-VAP. Methods Medical records of patients with CRAB-VAP who were given high-dose sulbactam between May 2013 and June 2015 were reviewed. Results Fifty-eight patients with CRAB-VAP were treated with high-dose sulbactam. The mean age was 72.0 ± 15.2 years, and the acute physiology and chronic health evaluation II (APACHE II score was 15.1 ± 5.10 at the time of CRAB-VAP diagnosis. Early clinical improvement was observed in 65.5% of patients, and 30-day mortality was 29.3%. Early clinical failure (odds ratio [OR]: 8.720, confidence interval [CI]: 1.346-56.484; p = 0.023 and APACHE II score ≥ 14 at CRAB-VAP diagnosis (OR: 10.934, CI: 1.047-114.148; p = 0.046 were associated with 30-day mortality. Conclusions High-dose sulbactam therapy may be effective for the treatment of CRAB-VAP. However, early clinical failure was observed in 35% of patients and was associated with poor outcome.

  16. Transperineal high-dose-rate interstitial radiation therapy in the management of gynecologic malignancies

    Energy Technology Data Exchange (ETDEWEB)

    Itami, Jun; Hara, Ryuseke; Kozuka, Takuyou; Yamashita, Hideomi; Nakajima, Kaori; Shibata, Kouji; Abe, Yoshihisa; Fuse, Masashi; Ito, Masashi [International Medical Center of Japan, Tokyo (Japan). Dept. of Radiation Therapy and Oncology

    2003-11-01

    Background: High-dose-rate interstitial radiation therapy is a newly introduced modality, and its role in the management of gynecologic malignancies remains to be studied. Clinical experience in high-dose-rate interstitial radiation therapy was retrospectively investigated. Patients and Methods: Eight patients with primary and nine with recurrent gynecologic malignancies underwent high-dose-rate interstitial radiation therapy with/without external-beam irradiation. Fractional dose of the high-dose-rate interstitial radiation therapy ranged between 4 and 6 Gy with total doses of 15-54 Gy. Interstitial irradiation was performed twice daily with an interval of > 6 h. Results: 2-year local control rate was 75% for primary treatment and 47% for treatment of recurrence (p = 0.46). Maximum tumor size had a statistically significant impact on local control (p < 0.002). Grade 2 and 4 late complications were seen in five patients, and the incidence was significantly higher in patients with a larger volume enclosed by the prescribed fractional dose of high-dose-rate interstitial radiation therapy. The incidence of grade 2 and 4 complications at 18 months was 78% and 0% with a volume > 100 cm{sup 3} and {<=} 100 cm{sup 3}, respectively (p < 0.04). Conclusion: Although high-dose-rate interstitial radiation therapy is a promising modality, it must be applied cautiously to patients with bulky tumors because of the high incidence of serious complications. (orig.)

  17. Increased financial burden among patients with chronic myelogenous leukaemia receiving imatinib in Japan: a retrospective survey

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    Kodama Yuko

    2012-04-01

    Full Text Available Abstract Background The financial burden of medical expenses has been increasing for cancer patients. We investigated the relationship between household income and financial burden among patients with chronic myelogenous leukaemia (CML who have been treated with imatinib. Methods A questionnaire was distributed to 1200 patients between May and August 2009. We retrospectively surveyed their household incomes, out-of-pocket medical expenses, final co-payments after refunds, and the perceived financial burden of their medical expenses in 2000, 2005 and 2008. Results A total of 577 patients completed the questionnaire. Their median age was 61 years (range, 15–94. A financial burden was felt by 41.2 % (28 of 68 of the patients treated with imatinib in 2000, 70.8 % (201 of 284 in 2005, and 75.8 % (400 of 528 in 2008. Overall, 182 patients (31.7 % considered its discontinuation because of the financial burden and 15 (2.6 % temporarily stopped their imatinib prescription. In 2000, 2005 and 2008, the patients’ median annual household incomes were 49,615 US Dollars (USD, 38,510 USD and 36,731 USD, respectively, with an average currency exchange rate of 104 Yen/USD in 2008. Their median annual out-of-pocket expenses were 11,548, 12,067 and 11,538 USD and their median final annual co-payments were 4,375, 4,327 and 3,558 USD, respectively. Older patients (OR = 0.96, 95 % CI: 0.95–0.98, p ≪ 0.0001 for 1-year increments, and patients with higher household incomes (OR = 0.92, 95 % CI: 0.85–0.99, p = 0.03 for 10,000 USD-increments were less likely to have considered discontinuing their imatinib treatment. Conversely, patients with higher annual final co-payments (OR = 2.21, 95 % CI: 1.28–4.28, p = 0.004 for 10,000 USD-increments were more likely to have considered discontinuing their imatinib treatment. Conclusions The proportion of CML patients who sensed a financial burden increased between 2000 and 2008

  18. Activity and side effects of imatinib in patients with gastrointestinal stromal tumors: data from a german multicenter trial

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    Schlemmer M

    2011-05-01

    Full Text Available Abstract Gastrointestinal stromal tumors (GIST are mesenchymal tumors that in the past were classified as leiomyosarcomas or leiomyomas not responding to standard sarcoma chemotherapy. In several phase I and II trials the efficacy and safety of imatinib was shown before the largest trial ever performed in a single sarcoma entity revealed response rates (CR/PR of 52%. This multicenter phase II trial presented here was performed to open access to imatinib for patients with unresectable or metastastatic GIST when the EORTC 62005 trial had been closed before imatinib was approved in Germany. It was designed to follow the best clinical response and to assess the efficacy, safety and tolerability of imatinib 400 mg/d in patients with unresectable or metastatic gastrointestinal stromal tumor. 95 patients were treated in this trial with Imatinib 400 mg/d. Four patients (4.6% attained a complete response and 26 patients (29.9% a partial response to imatinib treatment. Forty-one patients (47.1% revealed a stable disease and 16 patients (18.4% had a progressive disease. Of the progressive patients 22% showed a partial response and 67% showed stable disease after escalating the dose to 800 mg. According to SWOG tumor response classification, 66 patients (70% were free of progression within the first year of treatment. Seventy-one patients (74.7% experienced adverse events or severe adverse events with a suspected relationship to the study drug. Among these, the most common were nausea (n = 27 patients, 28.4%, eyelid edema and peripheral edema in 23 patients each (24.2%, diarrhea in 20 patients (21.1%, muscle cramps in 15 patients (15.8% and fatigue in 13 patients (13.7%. Imatinib 400 mg/d led to disease stabilisation in 81,6% of patients with unresectable or metastatic malignant GIST. Thirty-four percent of patients attained a tumor remission (partial or complete response. The safety profile of imatinib based on adverse event assessment is favorable

  19. Phase I Pharmacokinetic Study of the VEGFR Tyrosine Kinase Inhibitor Vatalanib (PTK787) plus Imatinib and Hydroxyurea for Malignant Glioma

    Science.gov (United States)

    Reardon, David A.; Egorin, Merrill J.; Desjardins, Annick; Vredenburgh, James J.; Beumer, Jan H.; Lagattuta, Theodore F.; Gururangan, Sridharan; Herndon, James E.; Salvado, August J.; Friedman, Henry S.

    2009-01-01

    Background We determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients. Methods All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme-inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice-a-day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed. Results Thirty-seven recurrent patients, including 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice-a-day. DLTs were hematologic, gastrointestinal, renal and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures. Conclusion Vatalanib doses up to 1000 mg twice-a-day combined with imatinib and hydroxyurea are well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and PDGFR, respectively, are safe among recurrent malignant glioma patients and may enhance anti-angiogenesis activity. PMID:19248046

  20. The use of imatinib in the treatment of inoperable dermatofibrosarcoma protuberans in the area of the shoulder joint

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    Joanna Huszno

    2014-06-01

    Full Text Available Introduction. Dermatofibrosarcoma protuberans (DFSP is a rare sarcoma of the skin and subcutaneous tissue. The most common clinical problem is its local recurrence. The therapeutic procedure of choice is radical surgery. In the case of inoperable disease, targeted therapy with imatinib, a tyrosine kinase inhibitor, may cause significant reduction of tumor volume and even enable radical surgery. Objective. We present the effectiveness of imatinib for the treatment of unresectable DFSP localized in the area of the shoulder joint of a 62-year-old woman. Case report. The patient met the criteria for inclusion in treatment with imatinib. After 3 cycles of treatment, partial regression of the lesions (above 50% was observed. Therapy was complicated by hepatological side effects during the sixth cycle. Treatment was continued with a reduced dose when transaminase levels normalized. In a physical examination and imaging studies, further regression was observed. The patient has regained considerable mobility of the shoulder joint. A decision to continue the treatment has been made. Conclusions. The use of imatinib allowed a clinical benefit to be gained in the form of significant regression of lesions. A very good treatment response and significant improvement in quality of life of the patient were achieved. The patient has been treated with imatinib for 30 months.

  1. Impact of imatinib interruption and duration of prior hydroxyurea on the treatment outcome in patients with chronic myeloid leukemia: Single institution experience.

    Science.gov (United States)

    Edesa, Wael Abdelgawad; Abdel-malek, Raafat Ragaey

    2015-06-01

    Optimal response requires that patients should be maintained on the drug continuously. To evaluate the influence of imatinib interruption and prior hydroxyurea use on the outcome of patients with chronic myeloid leukemia. Between January 2010 and November 2013, patients with chronic phase who received imatinib at the Kasr Al-ainy Center of Clinical Oncology were included. Sixty patients were included in this study, thirty three patients (55%) received imatinib upfront, while 27 (45%) received imatinib post hydroxyurea. Imatinib was not given regularly in 50% of patients. In terms of response, only major molecular response and complete molecular response were statistically significant in favor of patients who were receiving imatinib regularly compared to those who had interruption (phydroxyurea. The median progression free survival was 30.3 months (95% CI 24.3-36.3). Among the group of patients who received imatinib regularly, progression free survival was longer (p=0.049), there was no difference between those who received prior hydroxyurea versus those who did not (p=0.67). Duration of prior hydroxyurea had no impact on response or progression free survival, while patients regular on imatinib had statistically significant difference with respect to major molecular response, complete molecular response and progression free survival compared to those who had periods of drug interruption, thus we need more governmental support to supply the drug without interruption to improve the outcome of therapy. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  2. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Gedde-Dahl, Tobias; Markevärn, Berit

    2011-01-01

    Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remissio...

  3. Combined derivatization and high-performance liquid chromatography with fluorescence and ultraviolet detection for simultaneous analysis of octreotide and gabexate mesylate metabolite in human pancreatic juice samples.

    Science.gov (United States)

    Carlucci, Giuseppe; Selvaggi, Federico; Sulpizio, Sara; Bassi, Claudio; Carlucci, Maura; Cotellese, Roberto; Ferrone, Vincenzo; Innocenti, Paolo; Locatelli, Marcello

    2015-06-01

    A simple and sensitive method based on the combination of derivatization and high-performance liquid chromatography with ultraviolet and fluorimetric detection was developed for the simultaneous determination of octreotide and gabexate mesylate metabolite in human pancreatic juice samples. Parameters of the derivatization procedure affecting extraction efficiency were optimized. The developed method was validated according to the International Conference on Harmonization guidelines. The calibration curves were linear over a range of 0.1-15 µg/mL for octreotide and 0.20-15 µg/mL for gabexate mesylate metabolite. Derivatized products of octreotide and gabexate mesylate metabolite were separated on a Luna C18 column (4.6 × 250 mm; 5 µm particle size) using a gradient with a run time of 36 min, without further purification. The limits of detection were 0.025 and 0.05, respectively, for octreotide and gabexate mesylate metabolite. This paper reports the validation of a quantitative high performance liquid chromatography-photodiode array-fluorescence (HPLC-PDA-FL) method for the simultaneous analysis of octreotide and gabexate mesylate metabolite in pancreatic juice by protein precipitation using zinc sulfate-methanol-acetonitrile containing the derivatizing reagent, 4-fluoro-7-nitro-[2,1,3]-benzoxadiazole (NBD-F). Derivatized products of octreotide and gabexate mesylate metabolite were separated on a Luna C18 column (4.6 × 250 mm; 5 µm particle size) using a gradient with a run time of 36 min, without further purification. The method was validated over the concentration ranges 0.1-15 and 0.2-15 µg/mL for octreotide and gabexate mesylate metabolite, respectively, in human pancreatic juice. Biphalin and methyl-p-hydroxybenzoate were used as the internal standards. This method was successfully utilized to support clinical studies in humans. The results from assay validations show that the method is selective, sensitive and robust. The limit

  4. High dose vitamin D may improve lower urinary tract symptoms in postmenopausal women.

    Science.gov (United States)

    Oberg, Johanna; Verelst, Margareta; Jorde, Rolf; Cashman, Kevin; Grimnes, Guri

    2017-10-01

    Lower urinary tract symptoms (LUTS) are common in postmenopausal women, and have been reported inversely associated with vitamin D intake and serum 25-hydroxyvitamin D (25(OH)D) levels. The aim of this study was to investigate if high dose vitamin D supplementation would affect LUTS in comparison to standard dose. In a randomized controlled study including 297 postmenopausal women with low bone mineral density, the participants were allocated to receive capsules of 20 000IU of vitamin D 3 twice a week (high dose group) or similar looking placebo (standard dose group). In addition, all the participants received 1g of calcium and 800IU of vitamin D daily. A validated questionnaire regarding LUTS was filled in at baseline and after 12 months. At baseline, 76 women in the high dose group and 82 in the standard dose group reported any LUTS. Levels of serum 25(OH)D increased significantly more in the high dose group (from 64.7 to 164.1nmol/l compared to from 64.1 to 81.8nmol/l, p<0.01). No differences between the groups were seen regarding change in LUTS except for a statistically significant reduction in the reported severity of urine incontinence in the high dose group as compared to the standard dose group after one year (p<0.05). The results need confirmation in a study specifically designed for this purpose. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. High-dose gadolinium-enhanced MRI for diagnosis of meningeal metastases

    International Nuclear Information System (INIS)

    Kallmes, D.F.; Gray, L.; Glass, J.P.

    1998-01-01

    We compared high-dose (0.3 mmol/kg) and standard-dose (0.1 mmol/kg) gadolinium-enhanced MRI for diagnosis of meningeal metastases in 12 patients with suspected meningeal metastases. They were imaged with both standard-dose and high-dose gadolinium. All patients with abnormal meningeal enhancement underwent at least one lumbar puncture for cerebrospinal fluid (CSF) cytology, while patients with normal meningeal enhancement were followed clinically. All patients with negative CSF cytology also were followed clinically. A single observer reviewed all the images, with specific attention to the enhancement pattern of the meninges. Abnormal leptomeningeal enhancement was present in three cases, and abnormal pachymeningeal enhancement in three other patients. All of these patients had abnormal CSF analyses. In two of the three cases of abnormal leptomeningeal enhancement the disease was more evident on high-dose than on standard-dose imaging; in one case the abnormal enhancement was visible only on high-dose imaging. In one of the three cases with abnormal pachymeningeal enhancement, the disease was evident prospectively only with high-dose imaging. (orig.)

  6. p53 Gene (NY-CO-13 Levels in Patients with Chronic Myeloid Leukemia: The Role of Imatinib and Nilotinib

    Directory of Open Access Journals (Sweden)

    Hayder M. Al-kuraishy

    2018-01-01

    Full Text Available The p53 gene is also known as tumor suppressor p53. The main functions of the p53 gene are an anticancer effect and cellular genomic stability via various pathways including activation of DNA repair, induction of apoptosis, and arresting of cell growth at the G1/S phase. Normally, the p53 gene is inactivated by mouse double minute 2 proteins (mdm2, but it is activated in chronic myeloid leukemia (CML. Tyrosine kinase inhibitors are effective chemotherapeutic agents in the management of CML. The purpose of the present study was to evaluate the differential effect of imatinib and nilotinib on p53 gene serum levels in patients with CML. A total number of 60 patients with chronic myeloid leukemia with ages ranging from 47 to 59 years were recruited from the Iraqi Hematology Center. They started with tyrosine kinase inhibitors as first-line chemotherapy. They were divided into two groups—Group A, 29 patients treated with imatinib and Group B, 31 patients treated with nilotinib—and compared with 28 healthy subjects for evaluation p53 serum levels regarding the selective effect of either imatinib or nilotinib. There were significantly (p < 0.01 high p53 gene serum levels in patients with CML (2.135 ± 1.44 ng/mL compared to the control (0.142 ± 0.11 ng/mL. Patients with CML that were treated with either imatinib or nilotinib showed insignificant differences in most of the hematological profile (p > 0.05 whereas, p53 serum levels were high (3.22 ± 1.99 ng/mL in nilotinib-treated patients and relatively low (1.18 ± 0.19 ng/mL in imatinib-treated patients (p = 0.0001. Conclusions: Nilotinib is more effective than imatinib in raising p53 serum levels in patients with chronic myeloid leukemia.

  7. GSTT1 copy number gain and ZNF overexpression are predictors of poor response to imatinib in gastrointestinal stromal tumors.

    Directory of Open Access Journals (Sweden)

    Eui Jin Lee

    Full Text Available Oncogenic mutations in gastrointestinal stromal tumors (GISTs predict prognosis and therapeutic responses to imatinib. In wild-type GISTs, the tumor-initiating events are still unknown, and wild-type GISTs are resistant to imatinib therapy. We performed an association study between copy number alterations (CNAs identified from array CGH and gene expression analyses results for four wild-type GISTs and an imatinib-resistant PDGFRA D842V mutant GIST, and compared the results to those obtained from 27 GISTs with KIT mutations. All wild-type GISTs had multiple CNAs, and CNAs in 1p and 22q that harbor the SDHB and GSTT1 genes, respectively, correlated well with expression levels of these genes. mRNA expression levels of all SDH gene subunits were significantly lower (P≤0.041, whereas mRNA expression levels of VEGF (P=0.025, IGF1R (P=0.026, and ZNFs (P<0.05 were significantly higher in GISTs with wild-type/PDGFRA D842V mutations than GISTs with KIT mutations. qRT-PCR validation of the GSTT1 results in this cohort and 11 additional malignant GISTs showed a significant increase in the frequency of GSTT1 CN gain and increased mRNA expression of GSTT1 in wild-type/PDGFRA D842V GISTs than KIT-mutant GISTs (P=0.033. Surprisingly, all four malignant GISTs with KIT exon 11 deletion mutations with primary resistance to imatinib had an increased GSTT1 CN and mRNA expression level of GSTT1. Increased mRNA expression of GSTT1 and ZNF could be predictors of a poor response to imatinib. Our integrative approach reveals that for patients with wild-type (or imatinib-resistant GISTs, attempts to target VEGFRs and IGF1R may be reasonable options.

  8. Results in patients treated with high-dose-rate interstitial brachytherapy for oral tongue cancer

    International Nuclear Information System (INIS)

    Yamamoto, Michinori; Shirane, Makoto; Ueda, Tsutomu; Miyahara, Nobuyuki

    2006-01-01

    Eight patients were treated with high-dose-rate interstitial brachytherapy for oral tongue cancer between September 2000 and August 2004. The patient distribution was 1 T1, 5 T2, 1 T3, and 1 T4a. Patients received 50-60 Gy in 10 fractions over seven days with high-dose-rate brachytherapy. Six of the eight patients were treated with a combination of external beam radiotherapy (20-30 Gy) and interstitial brachytherapy. The two-year primary local control rate was 83% for initial case. High-dose-rate brachytherapy was performed safely even for an aged person, and was a useful treatment modality for oral tongue cancer. (author)

  9. High dose therapy with autologous stem cell support in malignant disorders

    International Nuclear Information System (INIS)

    Holte, H.; Kvaloey, S.O.; Engan, T.

    1996-01-01

    New biomedical knowledge may improve the diagnostic procedures and treatment provided by the Health Services, but at additional cost. In a social democratic health care system, the hospital budgets have no room for expensive, new procedures or treatments, unless these are funded through extra allocation from the central authorities. High dose therapy with autologous stem cell support in malignant disorders is an example of a new and promising, but rather expensive treatment, but its role in cancer therapy has yet to be established. The indications for testing high dose therapy with autologous stem cell support in various malignancies are discussed, with emphasis on the principles for deciding which categories of disease should have priority. The authors suggest some malignant disorder for which high dose therapy with stem cell support should be explored versus conventional treatment in randomized prospective trials. 8 refs., 1 tab

  10. Plasma Doping - Enabling Technology for High Dose Logic and Memory Applications

    International Nuclear Information System (INIS)

    Miller, T.; Godet, L.; Papasouliotis, G. D.; Singh, V.

    2008-01-01

    As logic and memory device dimensions shrink with each generation, there are more high dose implants at lower energies. Examples include dual poly gate (also referred to as counter-doped poly), elevated source drain and contact plug implants. Plasma Doping technology throughput and dopant profile benefits at these ultra high dose and lower energy conditions have been well established [1,2,3]. For the first time a production-worthy plasma doping implanter, the VIISta PLAD tool, has been developed with unique architecture suited for precise and repeatable dopant placement. Critical elements of the architecture include pulsed DC wafer bias, closed-loop dosimetry and a uniform low energy, high density plasma source. In this paper key performance metrics such as dose uniformity, dose repeatability and dopant profile control will be presented that demonstrate the production-worthiness of the VIISta PLAD tool for several high dose applications.

  11. Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial.

    Science.gov (United States)

    Strain, E C; Bigelow, G E; Liebson, I A; Stitzer, M L

    1999-03-17

    Methadone hydrochloride treatment is the most common pharmacological intervention for opioid dependence, and recent interest has focused on expanding methadone treatment availability beyond traditional specially licensed clinics. However, despite recommendations regarding effective dosing of methadone, controlled clinical trials of higher-dose methadone have not been conducted. To compare the relative clinical efficacy of moderate- vs high-dose methadone in the treatment of opioid dependence. A 40-week randomized, double-blind clinical trial starting in June 1992 and ending in October 1995. Outpatient substance abuse treatment research clinic at the Johns Hopkins University Bayview Campus, Baltimore, Md. One hundred ninety-two eligible clinic patients. Daily oral methadone hydrochloride in the dose range of 40 to 50 mg (n = 97) or 80 to 100 mg (n = 95), with concurrent substance abuse counseling. Opioid-positive urinalysis results and retention in treatment. By intent-to-treat analysis through week 30 patients in the high-dose group had significantly lower rates of opioid-positive urine samples compared with patients in the moderate-dose group (53.0% [95% confidence interval [CI], 46.9%-59.2%] vs 61.9% [95% CI, 55.9%-68.0%]; P = .047. These differences persisted during withdrawal from methadone. Through day 210 no significant difference was evident between dose groups in treatment retention (high-dose group mean retention, 159 days; moderate-dose group mean retention, 157 days). Nineteen (33%) of 57 patients in the high-dose group and 11 (20%) of 54 patients in the moderate-dose group completed detoxification. Both moderate- and high-dose methadone treatment resulted in decreased illicit opioid use during methadone maintenance and detoxification. The high-dose group had significantly greater decreases in illicit opioid use.

  12. A decrease in ubiquitination and resulting prolonged life-span of KIT underlies the KIT overexpression-mediated imatinib resistance of KIT mutation-driven canine mast cell tumor cells.

    Science.gov (United States)

    Kobayashi, Masato; Kuroki, Shiori; Kurita, Sena; Miyamoto, Ryo; Tani, Hiroyuki; Tamura, Kyoichi; Bonkobara, Makoto

    2017-10-01

    Overexpression of KIT is one of the mechanisms that contributes to imatinib resistance in KIT mutation-driven tumors. Here, the mechanism underlying this overexpression of KIT was investigated using an imatinib-sensitive canine mast cell tumor (MCT) line CoMS, which has an activating mutation in KIT exon 11. A KIT-overexpressing imatinib-resistant subline, rCoMS1, was generated from CoMS cells by their continuous exposure to increasing concentrations of imatinib. Neither a secondary mutation nor upregulated transcription of KIT was detected in rCoMS1 cells. A decrease in KIT ubiquitination, a prolonged KIT life-span, and KIT overexpression were found in rCoMS1 cells. These events were suppressed by withdrawal of imatinib and were re-induced by re‑treatment with imatinib. These findings suggest that imatinib elicited overexpression of KIT via suppression of its ubiquitination. These results also indicated that imatinib-induced overexpression of KIT in rCoMS1 cells was not a permanently acquired feature but was a reversible response of the cells. Moreover, the pan deubiquitinating enzyme inhibitor PR619 prevented imatinib induction of KIT overexpression, suggesting that the imatinib-induced decrease in KIT ubiquitination could be mediated by upregulation and/or activation of deubiquitinating enzyme(s). It may be possible that a similar mechanism of KIT overexpression underlies the acquisition of imatinib resistance in some human tumors that are driven by KIT mutation.

  13. ON012380: A Non-ATP Competitive Inhibitor of BCR-ABL for the Therapy of Imatinib-Resistant CMLs

    Science.gov (United States)

    2010-05-01

    imatinib resistance with a novel ABL kinase inhibitor. Science. 2004; 305(5682):399-401 3. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob... Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid...araldehyde (5) (10 mmol), glacial acetic acid (5 mL), and a catalytic amount (100 lL ) of benzyl amine was re- fluxed for 5–8 h. After completion of

  14. Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis

    OpenAIRE

    Shaker, Mohamed E.; Zalata, Khaled R.; Mehal, Wajahat Z.; Shiha, Gamal E.; Ibrahim, Tarek M.

    2011-01-01

    Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl4) rat model. Male Wistar rats received intraperitoneal injections of CCl4 twice weekly for 8 weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20 mg/kg), nilotinib (10 and 20 mg/kg) and silymarin (100 mg/kg) durin...

  15. Intravitreal Bevacizumab and Triamcinolone for Treatment of Cystoid Macular Oedema Associated with Chronic Myeloid Leukaemia and Imatinib Therapy

    Directory of Open Access Journals (Sweden)

    Eric K. Newcott

    2015-01-01

    Full Text Available Purpose. To evaluate the efficacy of intravitreal bevacizumab and triamcinolone in the treatment of cystoid macular oedema in a case with chronic myeloid leukaemia on imatinib treatment. Methods. We treated a 78-year-old man with bilateral cystoid macular oedema with intravitreal triamcinolone and subsequent bevacizumab in one eye and intravitreal bevacizumab, alone, in the fellow eye. Results. Serial intravitreal bevacizumab with and without triamcinolone treated cystoid macular oedema in both eyes and improved the vision. Conclusion. Intravitreal bevacizumab and triamcinolone could be viable options to treat cystoid macular oedema due to chronic myeloid leukaemia and imatinib therapy.

  16. Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages.

    Science.gov (United States)

    Bellora, Francesca; Dondero, Alessandra; Corrias, Maria Valeria; Casu, Beatrice; Regis, Stefano; Caliendo, Fabio; Moretta, Alessandro; Cazzola, Mario; Elena, Chiara; Vinti, Luciana; Locatelli, Franco; Bottino, Cristina; Castriconi, Roberta

    2017-08-15

    Tyrosine kinase inhibitors (TKIs) are used in the clinical management of hematological neoplasms. Moreover, in solid tumors such as stage 4 neuroblastomas (NB), imatinib showed benefits that might depend on both on-target and immunological off-target effects. We investigated the effects of imatinib and nilotinib on human NK cells, monocytes, and macrophages. High numbers of monocytes died upon exposure to TKI concentrations similar to those achieved in patients. Conversely, NK cells were highly resistant to the TKI cytotoxic effect, were properly activated by immunostimulatory cytokines, and degranulated in the presence of NB cells. In NB, neither drug reduced the expression of ligands for activating NK receptors or upregulated that of HLA class I, B7-H3, PD-L1, and PD-L2, molecules that might limit NK cell function. Interestingly, TKIs modulated the chemokine receptor repertoire of immune cells. Acting at the transcriptional level, they increased the surface expression of CXCR4, an effect observed also in NK cells and monocytes of patients receiving imatinib for chronic myeloid leukemia. Moreover, TKIs reduced the expression of CXCR3 (in NK cells) and CCR1 (in monocytes). Monocytes also decreased the expression of M-CSFR, and low numbers of cells underwent differentiation toward macrophages. M0 and M2 macrophages were highly resistant to TKIs and maintained their phenotypic and functional characteristics. Importantly, also in the presence of TKIs, the M2 immunosuppressive polarization was reverted by TLR engagement, and M1-oriented macrophages fully activated autologous NK cells. Our results contribute to better interpreting the off-target efficacy of TKIs in tumors and to envisaging strategies aimed at facilitating antitumor immune responses. Copyright © 2017 by The American Association of Immunologists, Inc.

  17. Experimental research on fresh mussel meat irradiated by high-dose electron beam

    International Nuclear Information System (INIS)

    Xiao Lin; Lu Ruifeng; Hu Huachao; Wang Chaoqi; Liu Yanna

    2011-01-01

    The sterilization storage of fresh mussel irradiated high-dose electron beam was studied. From the subjective assessment by the weighted average of the test and other determined parameters, it can be concluded that the flavor of fresh mussel meat sealed canned food irradiated by high-dose electron beam has not been significant affected, and various micro-organisms can be killed effectively, which means that the irradiated fresh mussel meat can be preserved for long-term at room temperature. Therefore the method might resolve the problems induced by traditional frozen preservation methods. (authors)

  18. Statistical behavior of high doses in medical radiodiagnosis; Comportamento estatistico das altas doses em radiodiagnostico medico

    Energy Technology Data Exchange (ETDEWEB)

    Barboza, Adriana Elisa, E-mail: adrianaebarboza@gmail.com, E-mail: elisa@bolsista.ird.gov.br [Instituto de Radioprotecao e Dosimetria, (IRD/CNEN-RJ), Rio de Janeiro, RJ (Brazil)

    2014-07-01

    This work has as main purpose statistically estimating occupational exposure in medical diagnostic radiology in cases of high doses recorded in 2011 at national level. For statistical survey of this study, doses of 372 IOE's diagnostic radiology in different Brazilian states were evaluated. Data were extracted from the work of monograph (Research Methodology Of High Doses In Medical Radiodiagnostic) that contains the database's information Sector Management doses of IRD/CNEN-RJ, Brazil. The identification of these states allows the Sanitary Surveillance (VISA) responsible, becomes aware of events and work with programs to reduce these events. (author)

  19. [High-dosed gestagen therapy of the metastatic mammary carcinoma (author's transl)].

    Science.gov (United States)

    Firusian, N; Becher, R

    1981-12-01

    Thirty patients with histologically proven metastatic mammary carcinoma were treated, after exhaustion of hormonal and cytostatic therapeutic means, with high-dosed medroxyprogesterone acetate (MPA) during a ten-day induction phase with 1000 mg MPAi.m. per day and then with 600 mg oral MPA per day. In eleven patients a complete or partial remission was achieved. The median period of remission comprised ten months. A positive relationship was found between the response to high-dosed MPA therapy and the length of free intervals. Side effects were tolerable.

  20. Analysis of volatile organic compounds and sensory characteristics of pork loin samples irradiated to high doses

    International Nuclear Information System (INIS)

    Hou Zhengchi; Sun Dakuan; Qin Zongying; Jin Jiang; Zhu Liandi; Yao Side; Sheng Kanglong

    2005-01-01

    Fresh pork loin samples, protein enzyme inactivated at (72 ± 3) degree C and vacuum packaged, were irradiated to up to 45 kGy at -20 degree C by 60 Co γ-rays. The irradiated samples were examined by various kinds of method to study high dose irradiation effects of sensory changes (meat color and off-odor), transverse shearing strength, weight loss in steam cooking, volatile organic compounds, and lipid oxidation. The results showed that the high dose irradiation produced no serious effects to the pork loin samples, and volunteer responses showed fine acceptability to the irradiated meat. (authors)

  1. Evaluation of glasses containing cadmium for high dose dosimetry by the thermoluminescence technique

    International Nuclear Information System (INIS)

    Carvalho, Gabriel Soares Marchiori de; Ferreira, Pamela Zati; Cunha, Diego Merigue da; Dantas, Noelio Oliveira; Silva, Anielle C.A.; Perini, Ana Paula; Neves, Lucio Pereira; Carrera, Betzabel Noemi Silva; Watanabe, Shigueo

    2016-01-01

    New glass matrices were evaluated for high dose dosimetry by the thermoluminescence technique. Their nominal composition are 20Li_2CO_3.10Al_2O_3.15CdO.55B_2O_3 and 20Li_2CO_3.10Al_2O_3.20CdO.50B_2O_3 (mol%). The glass matrices were irradiated with different doses: 50, 100, 200, 500, 700 and 900 Gy, and the thermoluminescence emission curves were obtained for each of these values. The results show a great potential of using these matrices in high dose dosimetry. (author)

  2. Salvage high-dose-rate brachytherapy for local prostate cancer recurrence after radical radiotherapy

    Directory of Open Access Journals (Sweden)

    V. A. Solodkiy

    2016-01-01

    Full Text Available Studies salvage interstitial radiation therapy for recurrent prostate cancer, launched at the end of the XX century. In recent years, more and more attention is paid to high-dose-rate brachytherapy (HDR-BT as a method of treating local recurrence.The purpose of research – preliminary clinical results of salvage high-dose-rate brachytherapy applied in cases of suspected local recurrence or of residual tumour after radiotherapy.Preliminary findings indicate the possibility of using HDR-BT, achieving local tumor control with low genitourinary toxicity.

  3. Identifying and validating a combined mRNA and microRNA signature in response to imatinib treatment in a chronic myeloid leukemia cell line.

    Directory of Open Access Journals (Sweden)

    Steven Bhutra

    Full Text Available Imatinib, a targeted tyrosine kinase inhibitor, is the gold standard for managing chronic myeloid leukemia (CML. Despite its wide application, imatinib resistance occurs in 20-30% of individuals with CML. Multiple potential biomarkers have been identified to predict imatinib response; however, the majority of them remain externally uncorroborated. In this study, we set out to systematically identify gene/microRNA (miRNA whose expression changes are related to imatinib response. Through a Gene Expression Omnibus search, we identified two genome-wide expression datasets that contain expression changes in response to imatinib treatment in a CML cell line (K562: one for mRNA and the other for miRNA. Significantly differentially expressed transcripts/miRNAs post imatinib treatment were identified from both datasets. Three additional filtering criteria were applied 1 miRbase/miRanda predictive algorithm; 2 opposite direction of imatinib effect for genes and miRNAs; and 3 literature support. These criteria narrowed our candidate gene-miRNA to a single pair: IL8 and miR-493-5p. Using PCR we confirmed the significant up-regulation and down-regulation of miR-493-5p and IL8 by imatinib treatment, respectively in K562 cells. In addition, IL8 expression was significantly down-regulated in K562 cells 24 hours after miR-493-5p mimic transfection (p = 0.002. Furthermore, we demonstrated significant cellular growth inhibition after IL8 inhibition through either gene silencing or by over-expression of miR-493-5p (p = 0.0005 and p = 0.001 respectively. The IL8 inhibition also further sensitized K562 cells to imatinib cytotoxicity (p < 0.0001. Our study combined expression changes in transcriptome and miRNA after imatinib exposure to identify a potential gene-miRNA pair that is a critical target in imatinib response. Experimental validation supports the relationships between IL8 and miR-493-5p and between this gene-miRNA pair and imatinib sensitivity in a CML cell

  4. BCR-ABL V280G Mutation, Potential Role in Imatinib Resistance: First Case Report

    OpenAIRE

    Azevedo, Ana P; Reichert, Alice; Afonso, Celina; Alberca, Maria D; Tavares, Purifica??o; Lima, Fernando

    2017-01-01

    Export Date: 28 December 2017 Correspondence Address: Azevedo, A.P.; Department of Clinical Pathology, Hospital São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Estrada do Forte do Alto do Duque, Portugal; email: Chemicals/CAS: glycine, 56-40-6, 6000-43-7, 6000-44-8; hydroxyurea, 127-07-1; imatinib, 152459-95-5, 220127-57-1; nilotinib, 641571-10-0; valine, 7004-03-7, 72-18-4 References: Radich, J.P., Shah, N.P., Mauro, M.J., Integrating current treatment options ...

  5. Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer

    NARCIS (Netherlands)

    Rodenhuis, S.; Bontenbal, M.; Hoesel, Q.G.C.M. van; Smit, W.M.; Nooij, M.A.; Voest, E.E.; Wall, E. van der; Hupperets, P.; Tinteren, H. van; Peterse, J.L.; Vijver, M.J. van de; Vries, E.G.E. de

    2006-01-01

    Background: High-dose chemotherapy in the adjuvant treatment of breast cancer has been abandoned by many. Patients and methods: 885 patients with stage III primary breast cancer and four or more axillary lymph node metastases were randomised to receive either five courses of FEC (fluorouracil,

  6. Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer

    NARCIS (Netherlands)

    Rodenhuis, S; Bontenbal, M; van Hoesel, QGCM; Smit, WM; Nooij, MA; Voest, EE; van der Wall, E; Hupperets, P; van Tinteren, H; Peterse, JL; van de Vijver, MJ; de Vries, EGE

    Background: High-dose chemotherapy in the adjuvant treatment of breast cancer has been abandoned by many. Patients and methods: 885 patients with stage III primary breast cancer and four or more axillary lymph node metastases were randomised to receive either five courses of FEC (fluorouracil,

  7. Daily high doses of fluoxetine for weight loss and improvement in lifestyle before bariatric surgery

    NARCIS (Netherlands)

    Dolfing, JG; Wolffenbuttel, BHR; Oei, HI; ten Hoor-Aukerna, NM; Schweitzer, DH

    Background: The number of gastric restrictive bariatric operations is increasing each year, but about one-fifth of patients will become disappointed due to unsatisfactory weight reduction or annoying complications. We questioned whether weight reduction by taking high doses of fluoxetine improves

  8. Fertility of Tall Girls Treated with High-Dose Estrogen, a Dose-Response Relationship

    NARCIS (Netherlands)

    Hendriks, A. E. J.; Drop, S. L. S.; Laven, J. S. E.; Boot, A. M.

    Context: High-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life. Objective: The aim was to study the effect of estrogen dose on fertility outcome of these women. Design/Setting: We conducted a retrospective cohort study of university

  9. Differential sensitivity of long-sleep and short-sleep mice to high doses of cocaine.

    Science.gov (United States)

    de Fiebre, C M; Ruth, J A; Collins, A C

    1989-12-01

    The cocaine sensitivity of male and female long-sleep (LS) and short-sleep (SS) mice, which have been selectively bred for differential ethanol-induced "sleep-time," was examined in a battery of behavioral and physiological tests. Differences between these two mouse lines were subtle and were seen primarily at high doses. At high doses, SS mice were more sensitive than LS mice, particularly to cocaine-induced hypothermia; however, significant hypothermia was not seen except at doses which were very near to the seizure threshold. During a 60-min test of locomotor activity, LS mice showed greater stimulation of Y-maze activity by 20 mg/kg cocaine than SS mice. Consistent with the finding of subtle differences in sensitivity to low doses of cocaine. LS and SS mice did not differ in sensitivity to cocaine inhibition of synaptosomal uptake of [3H]-dopamine, [3H]-norepinephrine or [3H]-5-hydroxytryptamine. However, consistent with the finding of differential sensitivity to high doses of cocaine, SS mice were more sensitive to the seizure-producing effects of the cocaine and lidocaine, a local anesthetic. It is hypothesized that the differential sensitivity of these mouse lines to high doses of cocaine is due to differential sensitivity to cocaine's actions on systems that regulate local anesthetic effects. Selective breeding for differential duration of alcohol-induced "sleep-time" may have resulted in differential ion channel structure or function in these mice.

  10. Perennial soybean seeds coated with high doses of boron and zinc ...

    African Journals Online (AJOL)

    The objective of this work was to study combinations of high doses of boron (B) and zinc (Zn) in the recoating of perennial soybean seeds, in order to provide these nutrients to the future plants. The physical, physiological and nutritional characteristics of the coated seeds and initial development of plants in a greenhouse ...

  11. Early Angiographic Resolution of Cerebral Vasospasm with High Dose Intravenous Milrinone Therapy

    Directory of Open Access Journals (Sweden)

    F. A. Zeiler

    2015-01-01

    Full Text Available Background. Treatment of symptomatic delayed cerebral ischemia (DCI after subarachnoid hemorrhage (SAH is difficult. Recent studies suggest intravenous (IV high dose milrinone as a potential therapy. The timing to angiographic response with this is unclear. Methods. We reviewed the chart of one patient admitted for SAH who developed symptomatic DCI and was treated with high dose IV milrinone. Results. A 66-year-old female was admitted with a Hunt and Hess clinical grade 4, World Federation of Neurological Surgeons (WFNS clinical grade 4, and SAH secondary to a left anterior choroidal artery aneurysm which was clipped. After bleed day 6, the patient developed symptomatic DCI. We planned for angioplasty of the proximal segments. We administered high dose IV milrinone bolus followed by continuous infusion which led to clinical improvement prior to angiography. The angiogram performed 1.5 hours after milrinone administration displayed resolution of the CT angiogram and MRI based cerebral vasospasm such that further intra-arterial therapy was aborted. She completed 6 days of continuous IV milrinone therapy, was transferred to the ward, and subsequently rehabilitated. Conclusions. High dose IV milrinone therapy for symptomatic DCI after SAH can lead to rapid neurological improvement with dramatic early angiographic improvement of cerebral vasospasm.

  12. Quantitative MR changes in Gd-DTPA enhancement after high dose intravenous methylprednisolone in multiple sclerosis

    International Nuclear Information System (INIS)

    Barkhof, F.; Valk, J.; Hommes, O.R.; Scheltens, P.

    1991-01-01

    The purpose of this study was to investigate the effect of high dose intravenous methylprednisolone (MP) on gadolinium-DTPA enhancement in MS-lesions. By means of this the influence of MP on the permeability of the blood-brain barrier can be studied. (author). 19 refs.; 1 fig

  13. Irreversible neurological worsening following high-dose corticosteroids in advanced progressive multiple sclerosis

    NARCIS (Netherlands)

    Koch, M; De Keyser, J

    2006-01-01

    Background: A course of high-dose corticosteroids has been shown to hasten recovery from a relapse of multiple sclerosis (MS). Some patients with progressive MS ask for a course with corticosteroids outside a relapse, hoping to gain some functional improvement. Objective: To describe 4 patients with

  14. Cytoprotective responses in HaCaT keratinocytes exposed to high doses of curcumin

    NARCIS (Netherlands)

    Lundvig, D.M.S.; Pennings, S.W.C.; Brouwer, K.M.; Mtaya-Mlangwa, M.; Mugonzibwa, E.; Kuijpers-Jagtman, A.M.; Wagener, F.A.D.T.G.; Hoff, J.W. Von den

    2015-01-01

    Wound healing is a complex process that involves the well-coordinated interactions of different cell types. Topical application of high doses of curcumin, a plant-derived polyphenol, enhances both normal and diabetic cutaneous wound healing in rodents. For optimal tissue repair interactions between

  15. Absorption of high-dose enteral vitamin A in lowbirth- weight neonates

    African Journals Online (AJOL)

    A randomised, double-blind placebo-controlled trial was designed to detennine whether high-dose (25 000 IU) enteral vitamin A. to correct deficiency, would be absorbed and well tolerated in low-birth-weight (LBW) neonates. Thirty-five LBW infants (950 - 1 700 g; gestational age 27 - 36 weeks) were allocated to receive ...

  16. Severe encephalopathy after high-dose chemotherapy with autologous stem cell support for brain tumours

    NARCIS (Netherlands)

    van den Berkmortel, F.; Gidding, C.; de Kanter, M.; Punt, C. J. A.

    2006-01-01

    Recurrent medulloblastoma carries a poor prognosis. Long-term survival has been obtained with high-dose chemotherapy with autologous stem cell transplantation and secondary irradiation. A 21-year-old woman with recurrent medulloblastoma after previous chemotherapy and radiotherapy is presented. The

  17. Surface damage of 316 stainless steel irradiated with 4He+ to high doses

    International Nuclear Information System (INIS)

    Kaminsky, M.; Das, S.K.

    1978-01-01

    Surface blistering of niobium by implantation with helium ions in the 9 to 15 keV range was investigated. The apparent disappearance of blisters at sufficiently high doses was believed to be an equilibrium effect. To determine whether high temperature annealing causes the equilibrium condition, stainless steel-316 samples were irradiated at a constant 450 0 C. Results are presented

  18. Clinical approaches involving thrombopoietin to shorten the period of thrombocytopenia after high-dose chemotherapy

    NARCIS (Netherlands)

    Tijssen, Marloes R.; van der Schoot, C. Ellen; Voermans, Carlijn; Zwaginga, Jaap Jan

    2006-01-01

    High-dose chemotherapy followed by a peripheral blood stem cell transplant is successfully used for a wide variety of malignancies. A major drawback, however, is the delay in platelet recovery. Several clinical strategies using thrombopoietin (Tpo) have been developed in an attempt to speed up

  19. High-dose chemotherapy : studies on supportive care, quality of life and late effects of treatment

    NARCIS (Netherlands)

    Nieboer, Peter

    2008-01-01

    Drug resistance is a major problem in the treatment of malignancies. Based on steep dose-response relationship for certain chemotherapeutic drugs in vitro on tumor cell survival, high-dose chemotherapy was considered of interest for the treatment of malignancies. Introduction of autologous

  20. Hemolytic uremic syndrome after high dose chemotherapy with autologous stem cell support

    NARCIS (Netherlands)

    van der Lelie, H.; Baars, J. W.; Rodenhuis, S.; Van Dijk, M. A.; de Glas-Vos, C. W.; Thomas, B. L.; van Oers, R. H.; von dem Borne, A. E.

    1995-01-01

    BACKGROUND: Chemotherapy intensification may lead to new forms of toxicity such as hemolytic uremic syndrome. METHODS: Three patients are described who developed this complication 4 to 6 months after high dose chemotherapy followed by autologous stem cell support. The literature on this subject is

  1. Perioperative Interstitial High-Dose-Rate Brachytherapy for the Treatment of Recurrent Keloids

    DEFF Research Database (Denmark)

    Jiang, Ping; Baumann, René; Dunst, Jürgen

    2016-01-01

    PURPOSE: To prospectively evaluate high-dose-rate brachytherapy in the treatment of therapy-resistant keloids and report first results, with emphasis on feasibility and early treatment outcome. METHODS AND MATERIALS: From 2009 to 2014, 24 patients with 32 recurrent keloids were treated with immed...

  2. Influence of high doses of manganese, copper, zinc and boron on some legumes

    Energy Technology Data Exchange (ETDEWEB)

    Vogel, G

    1973-01-01

    Macroscopic and microscopic examinations showed the following symptoms of an excess in trace elements: (1) High doses of manganese (50-150 ppm) cause dark patches (chloroplast accumulation) in young leaves, and necrosis of the leaf margin (MnO/sub 2/ accumulation) in older leaves. The roots become brown and die off. Roots newly formed in compensation are strikingly light-colored. (2) High doses of copper (5-40 ppm) cause iron deficiency chlorosis. A large number of side roots develop in quick succession as a result of damage to the root apex, so that a thick tangle of roots is formed. (3) High doses of zinc (50-150 ppm) bring about dark green, very brittle young leaves with very high ZnO content. The older leaves become red and then yellow. The roots remain stunted because of inhibited growth in length. (4) High doses of boron (30-90 ppm) cause a leaf necrosis which proceeds in the sequence tip, margin, lamina. The roots are not affected in any characteristic way. They become brown and die off.

  3. Determination of air kerma standard of high dose rate 192Ir brachytherapy source

    International Nuclear Information System (INIS)

    Pires, E.J.; Alves, C.F.E.; Leite, S.P.; Magalhaes, L.A.G.; David, M.G.; Almeida, C.E. de

    2015-01-01

    This paper presents the methodology developed by the Laboratorio de Ciencias Radiologicas and presently in use for determining of the air kerma standard of 192 Ir high dose rate sources to calibrate well-type chambers. Uncertainty analysis involving the measurements procedure are presented. (author)

  4. Hemolytic anemia following high dose intravenous immunoglobulin in patients with chronic neurological disorders

    DEFF Research Database (Denmark)

    Markvardsen, Lars Høj; Christiansen, I; Harbo, Thomas

    2014-01-01

    High dose intravenous immunoglobulin (IVIG) is an established treatment for various neuromuscular disorders. Recently, cases of hemolytic anemia following IVIG have been observed. The objective of this study was to determine the extent of anemia and hemolysis after IVIG and its relationship...

  5. High-dose therapy followed by bone marrow transplantation for relapsed follicular non-Hodgkin's lymphoma

    NARCIS (Netherlands)

    Schouten, IC; Raemaekers, JJM; Kluin-Nelemans, HC; vanKamp, H; Mellink, WAM; vantVeer, MB

    1996-01-01

    Purpose: To analyze whether, in addition to survival, and disease-free survival progression-free interval after transplantation would be longer than the last progression-free interval before transplantation, supporting the argument that high-dose therapy may change the biologic behavior of the

  6. Maternal high-dose folic acid during pregnancy and asthma medication in the offspring

    NARCIS (Netherlands)

    Zetstra-van der Woude, Priscilla A.; De Walle, Hermien E. K.; Hoek, Annemieke; Bos, H. Jens; Boezen, H. Marike; Koppelman, Gerhard H.; de Jong-van den Berg, Lolkje T. W.; Scholtens, Salome

    2014-01-01

    Purpose Low-dose folic acid supplementation (0.5 mg) taken during pregnancy has been associated with an increased risk for childhood asthma. The effect of high-dose folic acid (5 mg) advised to women at risk for having a child with neural tube defect has not been assessed so far. Our aim was to

  7. Occlusion-amblyopia following high dose oral levodopa combined with part time patching

    OpenAIRE

    Mihir Kothari

    2014-01-01

    Part time occlusion therapy is not reported to cause occlusion (reverse) amblyopia. However, when combined with high dose oral levodopa, an increase in the plasticity of the visual cortex can lead to occlusion amblyopia. In this case report, we describe a six year old child who developed occlusion amblyopia following part time patching combined with oral levodopa.

  8. Occlusion-amblyopia following high dose oral levodopa combined with part time patching.

    Science.gov (United States)

    Kothari, Mihir

    2014-12-01

    Part time occlusion therapy is not reported to cause occlusion (reverse) amblyopia. However, when combined with high dose oral levodopa, an increase in the plasticity of the visual cortex can lead to occlusion amblyopia. In this case report, we describe a six year old child who developed occlusion amblyopia following part time patching combined with oral levodopa.

  9. Occlusion-amblyopia following high dose oral levodopa combined with part time patching

    Directory of Open Access Journals (Sweden)

    Mihir Kothari

    2014-01-01

    Full Text Available Part time occlusion therapy is not reported to cause occlusion (reverse amblyopia. However, when combined with high dose oral levodopa, an increase in the plasticity of the visual cortex can lead to occlusion amblyopia. In this case report, we describe a six year old child who developed occlusion amblyopia following part time patching combined with oral levodopa.

  10. High Dose Ascorbate Causes Both Genotoxic and Metabolic Stress in Glioma Cells

    Science.gov (United States)

    Castro, Maria Leticia; Carson, Georgia M.; McConnell, Melanie J.; Herst, Patries M.

    2017-01-01

    We have previously shown that exposure to high dose ascorbate causes double stranded breaks (DSBs) and a build-up in S-phase in glioblastoma (GBM) cell lines. Here we investigated whether or not this was due to genotoxic stress as well as metabolic stress generated by exposure to high dose ascorbate, radiation, ascorbate plus radiation and H2O2 in established and primary GBM cell lines. Genotoxic stress was measured as phosphorylation of the variant histone protein, H2AX, 8-oxo-7,8-dihydroguanine (8OH-dG) positive cells and cells with comet tails. Metabolic stress was measured as a decrease in NADH flux, mitochondrial membrane potential (by CMXRos), ATP levels (by ATP luminescence) and mitochondrial superoxide production (by mitoSOX). High dose ascorbate, ascorbate plus radiation, and H2O2 treatments induced both genotoxic and metabolic stress. Exposure to high dose ascorbate blocked DNA synthesis in both DNA damaged and undamaged cell of ascorbate sensitive GBM cell lines. H2O2 treatment blocked DNA synthesis in all cell lines with and without DNA damage. DNA synthesis arrest in cells with damaged DNA is likely due to both genotoxic and metabolic stress. However, arrest in DNA synthesis in cells with undamaged DNA is likely due to oxidative damage to components of the mitochondrial energy metabolism pathway. PMID:28737676

  11. Diagnosis of cerebral metastases by means of standard doses of Gadobutrol versus a high-dose protocol. Intraindividual evaluation of a phase-II high-dose study

    International Nuclear Information System (INIS)

    Vogl, T.J.; Friebe, C.E.; Balzer, T.; Mack, M.G.; Steiner, S.; Schedel, H.; Pegios, W.; Lanksch, W.; Banzer, D.; Felix, R.

    1995-01-01

    In a clinical phase-II study 20 patients who had been diagnosed as having brain metastases with CT or MRT were studied prospectively with Gadobutrol, a new nonionic, low osmolality contrast agent. Each patient received an initial injection of 0.1 mmol/kg body weight and an additional dose of 0.2 mmol/kg Gadobutrol 10 min later. Spinecho images were obtained before and after the two applications of Gadobutrol. Dynamic scanning (Turbo-FLASH) was performed for 3 min after each injection of the contrast agent. Both quantitative and qualitative data were intraindividually evaluated. The primary tumor was a bronchial carcinoma in 11 cases; in 9 other cases there were different primary tumors. Forty-eight hours after the use of Gadobutrol there were no adverse signs in the clinical examination, vital signs or blood and urine chemistry. Statistical analysis (Friedman test and Wilcoxon test) of the C/N ratios between tumor and white matter, percentage enhancement, and visual assessment rating revealed statistically significant superiority of high-dose Gadobutrol injection in comparison to the standard dose. The percentage enhancement increased on average from 104% after 0.1 mmol/kg to 162% after 0.3 mmol/kg Gadobutrol. Qualitative delineation and contrast of the lesions increased significantly. The use of high-dose Gadobutrol improved the detection of 36 additional lesions in 6 patients. (orig./VHE) [de

  12. Hypertonic saline solution and high-dose furosemide infusion in cardiorenal syndrome: our experience

    Directory of Open Access Journals (Sweden)

    Francesco Ventrella

    2013-03-01

    Full Text Available Introduction Heart failure is frequently complicated by renal failure, and this association is a negative prognostic factor. These patients sometimes present oligo-/anuria and resistance to high-dose furosemide, a condition referred to as the cardiorenal syndrome (CRS. Acute or chronic reductions in left ventricular function result in decreased blood flow, with reduction of renal perfusion and activation of several neurohormonal systems, which cause resistance to diuretic therapy. This condition often requires ultrafiltration, which is an effective, but invasive and expensive procedure. Infusions of hypertonic saline solution (HSS and high-dose furosemide can be an effective alternative. Materials and methods From November 2009 through May 2010, our team treated 20 patients with CRS and resistance to iv boluses of high-dose furosemide. These patients were treated with small-volume (150-250 mL infusions of HSS (NaCl 1.57 – 4.5%, depending on serum Na values and high-dose furosemide twice a day. The aim of this treatment is to modify renal hemodynamics and the water-saline balance in the kidney by counteracting the extracellular fluid accumulation and eliminating symptoms of congestion. Results In 18 patients (90%, urine output was restored and renal function improved during the first hours of treatment. Clinical improvement was evident from the first day of therapy, and there were no adverse events. Two patients (10% did not respond to the treatment: one (who had been in critical condition since admission died; the other required regular sessions of ultrafiltration. Conclusions HSS combined with high-dose furosemide is a safe, effective, low-cost approach to the treatment of CRS that is resistant to diuretic therapy.

  13. Review of high-dose intravenous vitamin C as an anticancer agent.

    Science.gov (United States)

    Wilson, Michelle K; Baguley, Bruce C; Wall, Clare; Jameson, Michael B; Findlay, Michael P

    2014-03-01

    In the 1970s, Pauling and Cameron reported increased survival of patients with advanced cancer treated with high-dose intravenous (IV) vitamin C (L-ascorbate, ascorbic acid). These studies were criticized for their retrospective nature and lack of standardization of key prognostic factors including performance status. Subsequently, several well-designed randomized controlled trials failed to demonstrate a significant survival benefit, although these trials used high-dose oral vitamin C. Marked differences are now recognized in the pharmacokinetics of vitamin C with oral and IV administration, opening the issue of therapeutic efficacy to question. In vitro evidence suggests that vitamin C functions at low concentrations as an antioxidant but may have pro-oxidant activity at high concentrations. The mechanism of its pro-oxidant action is not fully understood, and both intra- and extracellular mechanisms that generate hydrogen peroxide have been proposed. It remains to be proven whether vitamin C-induced reactive oxygen species occur in vivo and, if so, whether this will translate to a clinical benefit. Current clinical evidence for a therapeutic effect of high-dose IV vitamin C is ambiguous, being based on case series. The interpretation and validation of these studies is hindered by limited correlation of plasma vitamin C concentrations with response. The methodology exists to determine if there is a role for high-dose IV vitamin C in the treatment of cancer, but the limited understanding of its pharmacodynamic properties makes this challenging. Currently, the use of high-dose IV vitamin C cannot be recommended outside of a clinical trial. © 2014 Wiley Publishing Asia Pty Ltd.

  14. High Dose Oral Calcium Treatment in Patients with Vitamin D-dependent Rickets Type II

    Directory of Open Access Journals (Sweden)

    R Vakili

    2017-02-01

    Full Text Available BACKGROUND AND OBJECTIVE: Vitamin D-dependent rickets type II (VDDR2 is a rare genetic disorder caused by mutations in vitamin D receptor (VDR and leads to resistance to biological effects of calcitriol. Based on the type of mutation, this disease is resistant to calcitriol even at high doses of calcitriol and successful treatment of these patients requires hypocalcemic modification through administration of high doses of calcium and bypassing the intestinal defect in VDR signaling. In addition to the need for frequent hospitalization and high costs, intravenous administration of calcium is associated with complications and problems such as arrhythmia and sepsis, venous catheter infection and hypercalciuria. This study aims to report the positive treatment effects of high doses of oral calcium in 4 patients with vitamin D-dependent rickets type II. CASE REPORT: In this study, 4 patients with vitamin D-dependent rickets type II, diagnosed based on clinical and biochemical symptoms of rickets with alopecia, underwent therapy using high doses of oral calcium (300 mg/kg/day in pediatric endocrinology and metabolism center of Imam Reza hospital. After a short period, increased growth rate in height, strength and elasticity of muscles was observed in addition to biochemical improvements without serious side effects and even one patient started walking independently within the first week of therapy for the first time. Patients were regularly followed up in terms of height and weight, growth rate and biochemical factors including calcium, phosphorus and alkaline phosphatase every 3 months for one year. CONCLUSION: Regardless of the type of mutation in vitamin D receptor, it is suggested that a 3-6 months trial of high dose oral calcium be started in each patient with vitamin D-dependent rickets type II, particularly for patients whose disease was diagnosed at lower ages.

  15. Treatment of carcinoma of uterine cervix with high-dose-rate intracavitary irradiation using Ralstron

    International Nuclear Information System (INIS)

    Suh, C.O.; Kim, G.E.; Loh, J.J.K.

    1988-01-01

    From May 1979 through December 1981, a total of 530 patients with carcinoma of the uterine cervix were treated with radiation therapy with curative intent. Of the 530 patients, 365 were treated with a high-dose-rate remote-controlled afterloading system (RALS) using a cobalt source, and 165 patients received a low dose rate using a radium source. External pelvic irradiation with a total of 40-50 Gy to the whole pelvis followed by intracavitary radiation (ICR) with a total dose of 30-39 Gy in ten to 13 fractions to point A was the treatment protocol. ICR was given three times a week with a dose of 3 Gy per fraction. Five-year actuarial survival rate with high-dose-rate ICR by stage was as follows: stage I:82.7% (N = 19) stage II:69.6% (N = 184), and stage III:52.2% (N = 156). The above results were comparable with those with conventional low-dose-rate ICR treatment, and late complications were far less. The application of high-dose-rate ICR was technically simple and easily performed on an outpatient basis without anesthesia, and the patients tolerated it very well. Radiation exposure to personnel was virtually none as compared with that of low-dose-rate ICR. Within a given period of time, more patients can be treated with high-dose-rate ICR because of the short treatment time. The authors therefore conclude that high-dose-rate ICR is suitable for a cancer center where a large number of patients are to be treated

  16. High-dose anti-histamine use and risk factors in children with urticaria.

    Science.gov (United States)

    Uysal, Pınar; Avcil, Sibelnur; Erge, Duygu

    2016-12-01

    The drugs of choice in the treatment of urticaria in children are H1-antihistamines. The aim of the study was to evaluate children with urticaria and define risk factors for requirement of high-dose H1-antihistamines in children with urticaria. The medical data of children who were diagnosed as having urticaria admitted to our outpatient clinic between January 2014 and January 2016 were searched. The medical histories, concomitant atopic diseases, parental atopy histories, medications, treatment responses, blood eosinophil and basophil counts, and serum total IgE levels were recorded. In addition, the urticaria activity score for seven days, autoimmune antibody tests, and skin prick test results were evaluated in children with chronic urticaria. The numbers of the children with acute and chronic urticaria were 138 and 92, respectively. The age of the children with chronic urticaria was higher than that of those with acute urticaria (p0.05). There was a negative correlation between blood eosinophil count and the UAS7 score in children with chronic urticaria (r=-0.276, p=0.011). Chronic urticaria and requirement of high dose H1-antihistamines were significant in children aged ≥10 years (p<0.001, p=0.015). High UAS7 score (OR: 1.09; CI 95%: [1.03-1.15]) and basopenia (OR: 6.77; CI 95%: [2.01-22.75]) were associated with the requirement of high-dose H1-AH in children with chronic urticaria. The requirement of high-dose H1-antihistamines was higher with children's increasing age. Disease severity and basopenia were risk factors for the requirement of high-dose H1-antihistamines.

  17. Braquiterapia de alta taxa de dose no Brasil High-dose rate brachytherapy in Brazil

    Directory of Open Access Journals (Sweden)

    Sérgio Carlos Barros Esteves

    2004-10-01

    Full Text Available A braquiterapia de alta taxa de dose foi introduzida em nosso meio em janeiro de 1991. Desde então, houve uma mudança significativa na abordagem das neoplasias malignas em relação às vantagens do novo método, e também resolução da demanda reprimida de braquiterapia para as neoplasias ginecológicas. Nos primeiros dez anos de atividade, o Brasil tratou, em 31 serviços, 26.436 pacientes com braquiterapia, sendo mais de 50% das pacientes portadoras de neoplasias do colo uterino. Este estudo mostra o número e o perfil de pacientes tratados com esse método e a sua distribuição no território nacional, deixando explícito o benefício da braquiterapia de alta taxa de dose para o Brasil.High-dose rate brachytherapy was first introduced in Brazil in January 1991. Significant changes in the management of malignant neoplasms were observed since utilization of high-dose rate brachytherapy. The high number of gynecological patients awaiting for brachytherapy also decreased during this period. In the first ten years 26,436 patients were treated with high-dose rate brachytherapy. More than 50% of these patients presented neoplasms of the uterine cervix. In this study we present the number and profile of the patients treated with high-dose rate brachytherapy as well as the distribution of these patients in the Brazilian territory, proving the benefit of the use of high-dose rate brachytherapy in Brazil.

  18. Impact of therapeutic and high doses of florfenicol on kidney and liver functional indicators in goat

    Directory of Open Access Journals (Sweden)

    Jan Muhammad Shah

    2016-10-01

    Full Text Available Aim: The aim of this study was to evaluate the impact of therapeutic and high doses of florfenicol on kidney and liver functional indicators in goat species. Materials and Methods: Six mature, healthy goats (combine breed and sex with average weight 25 kg were selected for this study. The therapeutic (20 mg/kg b.w. and high doses (40 and 60 mg of florfenicol were administered for 3 days with 24 h interval. Blood samples were collected at 0, 24, 48, 72, 96, and 120 h following the each administered dose. Results: The results showed that the therapeutic dose of florfenicol produced nonsignificant effect on serum urea, creatinine, total protein (TP, alkaline phosphatase (ALP, gamma-glutamyl transferase (GGT and bilirubin on all timings, and increased (p<0.05 the serum glutamic oxaloacetic transaminase (SGOT and serum glutamate-pyruvate transaminase (SGPT levels for 48 h. Whereas the high doses of florfenicol (40 and 60 mg significantly altered the kidney and liver functional indicators in the blood. In contrast with control, the serum urea level was (p<0.01 increased at all timing points. Creatinine values were altered (p<0.01, <0.05 in increasing manner from 24 to 96 h. The high dose of 40 mg decreased the TP (p<0.05 for 72 h and 60 mg persisted same effect (p<0.01 up to 120 h. The indices of ALP, GGT, SGOT, and SGPT were raised (p<0.01, <0.05 at all timings. The bilirubin indexes also (p<0.05 elevated from 48 to 72. Conclusion: It was concluded that the high doses of florfenicol produced reversible dose-dependent effects on functional indicators of kidney and liver such as urea, creatinine, TP, ALP, SGOT, SGPT, GGT, and bilirubin.

  19. Effects of imatinib and nilotinib on the whole transcriptome of cultured murine osteoblasts.

    Science.gov (United States)

    Kirschner, Gyöngyi; Balla, Bernadett; Horváth, Péter; Kövesdi, Andrea; Lakatos, Gergely; Takács, István; Nagy, Zsolt; Tóbiás, Bálint; Árvai, Kristóf; Kósa, János Pál; Lakatos, Péter

    2016-09-01

    Numerous clinical observations have confirmed that breakpoint cluster region-abelson fusion oncoprotein tyrosine kinase inhibitors used in leukemia treatment alter bone physiology in a complex manner. The aim of the present study was to analyze the whole transcriptome of cultured murine osteoblasts and determine the changes following treatment with imatinib and nilotinib using Sequencing by Oligonucleotide Ligation and Detection next generation RNA sequencing. This study also aimed to identify candidate signaling pathways and network regulators by multivariate Ingenuity Pathway Analysis. Based on the right-tailed Fisher's exact test, significantly altered pathways including upstream regulators were defined for each drug. The correlation between these pathways and bone metabolism was also examined. The preliminary results suggest the two drugs have different mechanisms of action on osteoblasts, and imatinib was shown to have a greater effect on gene expression. Data also indicated the potential role of a number of genes and signaling cascades that may contribute to identifying novel targets for the treatment of metabolic bone diseases.

  20. Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation.

    Science.gov (United States)

    Wilson, J; Connock, M; Song, F; Yao, G; Fry-Smith, A; Raftery, J; Peake, D

    2005-07-01

    To assess the clinical and cost-effectiveness of imatinib in the treatment of unresectable and/or metastatic, KIT-positive, gastrointestinal stromal tumours (GISTs), relative to current standard treatments. Electronic databases. As there were no randomised trials that have directly compared imatinib with the current standard treatment in patients with advanced GIST, this review included non-randomised controlled studies, cohort studies, and case series that reported effectiveness results of treatment with imatinib and/or other interventions in patients with advanced GIST. The effectiveness assessment was based on the comparison of results from imatinib trials and results from studies of historical control patients. Economic evaluation was mainly based on an assessment and modification (when judged necessary) of a model submitted by Novartis. Evidence from published uncontrolled trials involving 187 patients, and from abstracts reporting similar uncontrolled trials involving 1700 patients, indicates that approximately 50% of imatinib-treated individuals with advanced GIST experience a dramatic clinical response in terms of at least a 50% reduction in tumour mass. At present, although useful data are accumulating, it is not possible to predict which patients may respond in this way. Fifteen studies where possible GIST patients had been treated with therapies other than imatinib or best supportive care were also identified. All imatinib-treated patients experienced adverse effects, although they were relatively mild. Overall, imatinib was reported to be well tolerated. The most common serious events included unspecified haemorrhage and neutropenia. Skin rash, oedema and periorbital oedema were the common adverse events observed. Patients on the highest dose regimen (1000 mg per day in one trial) may experience dose-limiting drug toxicity. A structured assessment was carried out of the Novartis economic evaluation of imatinib for unresectable and/or metastatic GIST

  1. Lack of Association of Multidrug Resistance Gene-1 Polymorphisms with Treatment Outcome in Chronic Myeloid Leukemia Patients Treated with Imatinib

    Directory of Open Access Journals (Sweden)

    Yaya Kassogue

    2015-10-01

    Full Text Available Background: Despite the impressive results obtained with imatinib, inadequate response or resistance are observed in certain patients. It is known that imatinib is a substrate of a multidrug resistance gene (MDR1. Thus, interindividual genetic differences linked to single nucleotide polymorphisms in MDR1 may influence the metabolism of imatinib. The present study has aimed to examine the impact of MDR1 polymorphisms on the hematologic and cytogenetic responses in 70 chronic myeloid leukemia patients who received imatinib. Methods: We used a polymerase chain reaction followed by restriction fragment length polymorphism to identify different profiles of 1236C>T, 2677G>T and 3435C>T in MDR1. Results: The distribution of the three SNPs in responders and poor responders did not show any particular trend (P>0.05. The T allele was slightly higher in responders, but not significantly regardless of the type of SNP (40.3% vs. 33.8% for 1236C>T; 25% vs. 14.7% for 2677G>T and 33.3% vs. 22% for 3435C>T. The dominant model showed a similar trend (P>0.05. Diplotypes composed by the T allele in different exons were frequent in responders. Haplotype analysis showed that 1236C-2677G-3435C was slightly higher in poor responders (60.02% compared to responders (50.42%. However, 1236T-2677T-3435T was frequent in responders (16.98% compared to poor responders (13.1%. Overall, none of the haplotypes were associated with IM response in our cohort (global haplotype association test, P=0.39. Conclusion: The identification of 1236C>T, 2677G>T and 3435C>T polymorphisms may not be advantageous to predict imatinib response for our chronic myeloid leukemia patients.

  2. PTCH1 is a reliable marker for predicting imatinib response in chronic myeloid leukemia patients in chronic phase.

    Directory of Open Access Journals (Sweden)

    Juan M Alonso-Dominguez

    Full Text Available Patched homolog 1 gene (PTCH1 expression and the ratio of PTCH1 to Smoothened (SMO expression have been proposed as prognostic markers of the response of chronic myeloid leukemia (CML patients to imatinib. We compared these measurements in a realistic cohort of 101 patients with CML in chronic phase (CP using a simplified qPCR method, and confirmed the prognostic power of each in a competing risk analysis. Gene expression levels were measured in peripheral blood samples at diagnosis. The PTCH1/SMO ratio did not improve PTCH1 prognostic power (area under the receiver operating characteristic curve 0.71 vs. 0.72. In order to reduce the number of genes to be analyzed, PTCH1 was the selected measurement. High and low PTCH1 expression groups had significantly different cumulative incidences of imatinib failure (IF, which was defined as discontinuation of imatinib due to lack of efficacy (5% vs. 25% at 4 years, P = 0.013, probabilities of achieving a major molecular response (81% vs. 53% at first year, P = 0.02, and proportions of early molecular failure (14% vs. 43%, P = 0.015. Every progression to an advanced phase (n = 3 and CML-related death (n = 2 occurred in the low PTCH1 group (P<0.001 for both comparisons. PTCH1 was an independent prognostic factor for the prediction of IF. We also validated previously published thresholds for PTCH1 expression. Therefore, we confirmed that PTCH1 expression can predict the imatinib response in CML patients in CP by applying a more rigorous statistical analysis. Thus, PTCH1 expression is a promising molecular marker for predicting the imatinib response in CML patients in CP.

  3. Dramatic response to high-dose icotinib in a lung adenocarcinoma patient after erlotinib failure.

    Science.gov (United States)

    Guan, Yin; Zhao, Hong; Meng, Jing; Yan, Xiang; Jiao, ShunChang

    2014-02-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) retreatment is rarely administered for non-small cell lung cancer (NSCLC) patients who did not respond to previous TKI treatment. A high dose of TKI may overcome resistance to the standard dose of TKI and have different effectiveness toward cancer compared with the standard dose of TKI. This manuscript describes a dramatic and durable response to high-dose icotinib in a NSCLC patient who did not respond to a previous standard dose of erlotinib. The treatment extended the life of the patient for one additional year. A higher dose of icotinib deserves further study not only for patients whose therapy failed with the standard dose of TKI but also for newly diagnosed NSCLC patients with a sensitive mutation. Serial mutation testing during disease development is necessary for analysis and evaluation of EGFR TKI treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. Heavy ion time-of-flight ERDA of high dose metal implanted germanium

    Energy Technology Data Exchange (ETDEWEB)

    Dytlewski, N.; Evans, P.J.; Noorman, J.T. [Australian Nuclear Science and Technology Organisation, Lucas Heights, NSW (Australia); Wielunski, L.S. [Commonwealth Scientific and Industrial Research Organisation (CSIRO), Lindfield, NSW (Australia). Div. of Applied Physics; Bunder, J. [New South Wales Univ., Wollongong, NSW (Australia). Wollongong Univ. Coll

    1996-12-31

    With the thick Ge substrates used in ion implantation, RBS can have difficulty in resolving the mass-depth ambiguities when analysing materials composed of mixtures of elements with nearly equal masses. Additional, and complimentary techniques are thus required. This paper reports the use of heavy ion time-of-flight elastic recoil detection analysis (ToF- ERDA), and conventional RBS in the analysis of Ge(100) implanted with high dose Ti and Cu ions from a MEWA ion source . Heavy ion ToF ERDA has been used to resolve, and profile the implanted transition metal species, and also to study any oxygen incorporation into the sample resulting from the implantation, or subsequential reactions with air or moisture. This work is part of a study on high dose metal ion implantation of medium atomic weight semiconductor materials. 13 refs., 6 figs.

  5. Heavy ion time-of-flight ERDA of high dose metal implanted germanium

    Energy Technology Data Exchange (ETDEWEB)

    Dytlewski, N; Evans, P J; Noorman, J T [Australian Nuclear Science and Technology Organisation, Lucas Heights, NSW (Australia); Wielunski, L S [Commonwealth Scientific and Industrial Research Organisation (CSIRO), Lindfield, NSW (Australia). Div. of Applied Physics; Bunder, J [New South Wales Univ., Wollongong, NSW (Australia). Wollongong Univ. Coll

    1997-12-31

    With the thick Ge substrates used in ion implantation, RBS can have difficulty in resolving the mass-depth ambiguities when analysing materials composed of mixtures of elements with nearly equal masses. Additional, and complimentary techniques are thus required. This paper reports the use of heavy ion time-of-flight elastic recoil detection analysis (ToF- ERDA), and conventional RBS in the analysis of Ge(100) implanted with high dose Ti and Cu ions from a MEWA ion source . Heavy ion ToF ERDA has been used to resolve, and profile the implanted transition metal species, and also to study any oxygen incorporation into the sample resulting from the implantation, or subsequential reactions with air or moisture. This work is part of a study on high dose metal ion implantation of medium atomic weight semiconductor materials. 13 refs., 6 figs.

  6. High dose rate intracavitary afterloading irradiation in malignant inoperable obturation of bile ducts

    Energy Technology Data Exchange (ETDEWEB)

    Itami, J.; Saegusa, K.; Mamiya, T.; Miyoshi, T.; Arimizu, N.; Tsuchiya, Y.; Ohto, M.

    1986-02-01

    After decompression of the bile duct with PTCD, seven patients with carcinomas of the bile ducts were submitted to an intracavitary Ir-afterloading irradiation performed according to the high-dose-rate method with a Buchler device. Most of the patients were irradiated with 30 Gy in two fractions. Five patients were also exposed to percutaneous radiation with 40 to 50 Gy. Local control was achieved in six patients. One patient developed a locoregional recurrence which was possibly due to a so-called 'geographic miss'. In one patient a benign fibrotic stenosis of the bile duct was found at the site of most intensive irradiation. Intracavitary irradiation is very important in the treatment of malignant of bile ducts. However, there is an urgent need of research with regard to the combined method with percutaneous irradiation and to the optimum fractionation of intracavitary high dose rate irradiation.

  7. Evaluation of glasses containing cadmium for high dose dosimetry by the thermoluminescence technique

    Energy Technology Data Exchange (ETDEWEB)

    Carvalho, Gabriel Soares Marchiori de; Ferreira, Pamela Zati; Cunha, Diego Merigue da; Dantas, Noelio Oliveira; Silva, Anielle C.A.; Perini, Ana Paula; Neves, Lucio Pereira, E-mail: lucio.neves@ufu.br [Universidade Federal de Uberlandia (INFIS/UFU), MG (Brazil). Instituto de Fisica; Caldas, Linda V.E. [Instituto de Pesquisas Energeticas e Nucleares (IPEN-CNEN/SP), Sao Paulo, SP (Brazil); Carrera, Betzabel Noemi Silva; Watanabe, Shigueo [Universidade de Sao Paulo (IF/USP), SP (Brazil). Instituto de Fisica

    2016-07-01

    New glass matrices were evaluated for high dose dosimetry by the thermoluminescence technique. Their nominal composition are 20Li{sub 2}CO{sub 3}.10Al{sub 2}O{sub 3}.15CdO.55B{sub 2}O{sub 3} and 20Li{sub 2}CO{sub 3}.10Al{sub 2}O{sub 3}.20CdO.50B{sub 2}O{sub 3} (mol%). The glass matrices were irradiated with different doses: 50, 100, 200, 500, 700 and 900 Gy, and the thermoluminescence emission curves were obtained for each of these values. The results show a great potential of using these matrices in high dose dosimetry. (author)

  8. Study of a new glass matrix by thermoluminescent technique for high-dose dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Ferreira, Pamela Z.; Carvalho, Gabriel S. Marchiori de; Cunha, Diego M. da; Dantas, Noelio O.; Silva, Anielle C.A.; Neves, Lucio P.; Perini, Ana P., E-mail: anapaula.perini@ufu.br [Universidade Federal de Uberlandia (UFU), MG (Brazil). Instituto de Fisica; Linda, V.E. Caldas [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil); Carrera, Betzabel N.S.; Watanabe, Shigueo [Universidade de Sao Paulo (IF/USP), Sao Paulo, SP (Brazil). Instituto de Fisica

    2016-07-01

    The thermoluminescence technique is widely used for both personal and for high-dose dosimetry. In this work, the thermoluminescence technique was utilized to study a new glass matrix, with nominal composition of 20Li{sub 2}CO{sub 3}.10Al{sub 2}O{sub 3}.30BaO.40B{sub 2}O{sub 3} (mol%), irradiated with different doses in a {sup 60}Co source. The glow curves and the dose-response curve were obtained for radiation doses of 10, 50, 100, 200 e 700 Gy. The results showed that this new glass matrix has potential use in high-dose dosimetry. (author)

  9. Practice for characterization and performance of a high-dose radiation dosimetry calibration laboratory

    International Nuclear Information System (INIS)

    2003-01-01

    This practice addresses the specific requirements for laboratories engaged in dosimetry calibrations involving ionizing radiation, namely, gamma-radiation, electron beams or X-radiation (bremsstrahlung) beams. It specifically describes the requirements for the characterization and performance criteria to be met by a high-dose radiation dosimetry calibration laboratory. The absorbed-dose range is typically between 10 and 10 5 Gy. This practice addresses criteria for laboratories seeking accreditation for performing high-dose dosimetry calibrations, and is a supplement to the general requirements described in ISO/IEC 17025. By meeting these criteria and those in ISO/IEC 17025, the laboratory may be accredited by a recognized accreditation organization. Adherence to these criteria will help to ensure high standards of performance and instill confidence regarding the competency of the accredited laboratory with respect to the services it offers

  10. Synergies Between ' and Cavity Formation in HT-9 Following High Dose Neutron Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Field, Kevin G. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Parish, Chad M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Saleh, Tarik A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Eftink, Benjamin P. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2017-06-01

    Candidate cladding materials for advanced nuclear power reactors including fast reactor designs require materials capable of withstanding high dose neutron irradiation at elevated temperatures. One candidate material, HT-9, through various research programs have demonstrated the ability to withstand significant swelling and other radiation-induced degradation mechanisms in the high dose regime (>50 displacements per atom, dpa) at elevated temperatures (>300 C). Here, high efficiency multi-dimensional scanning transmission electron microscopy (STEM) acquisition with the aid of a three-dimensional (3D) reconstruction and modeling technique is used to probe the microstructural features that contribute to the exceptional swelling resistance of HT-9. In particular, the synergies between ' and fine-scale and moderate-scale cavity formation is investigated.

  11. CT of multiple sclerosis: reassessment of delayed scanning with high doses of contrast material

    International Nuclear Information System (INIS)

    Spiegel, S.M.; Vinuela, F.; Fox, A.J.; Pelz, D.M.

    1985-01-01

    A prospective study involving 87 patients was carried out to evaluate the necessity for a high dose of contrast material in addition to delayed computed tomographic (CT) scanning for optimal detection of the lesions of multiple sclerosis in the brain. In patients with either clinically definite multiple sclerosis or laboratory-supported definite multiple sclerosis, CT scans were obtained with a uniform protocol. Lesions consistent with multiple sclerosis were demonstrated on the second scan in 54 patients. In 36 of these 54 patients, the high-dose delayed scan added information. These results are quite similar to those of a previous study from this institution using different patients, in whom the second scan was obtained immediately after the bolus injection of contrast material containing 40 g of organically bound iodine. The lack of real difference in the results of the two studies indicate that the increased dose, not just the delay in scanning, is necessary for a proper study

  12. Gene expression profiles following high-dose exposure to gamma radiation in salmonella enterica serovar typhimurium

    International Nuclear Information System (INIS)

    Lim, Sang Yong; Jung, Sun Wook; Joe, Min Ho; Kim, Dong Ho

    2008-01-01

    Microarrays can measure the expression of thousands of genes to identify the changes in expression between different biological states. To survey the change of whole Salmonella genes after a relatively high dose of gamma radiation (1 kGy), transcriptome dynamics were examined in the cells by using DNA microarrays. At least 75 genes were induced and 89 genes were reduced two-fold or more after irradiation. Several genes located in pSLT plasmid, cyo operon, and Gifsy prophage were induced along with many genes encoding uncharacterized proteins.While, the expression of genes involved in the virulence of Salmonella as well as metabolic functions were decreased. Although the radiation response as a whole could not be illustrated by using DNA microarrays, the data suggest that the response to high dose of irradiation might be more complex than the SOS response

  13. No seasonal accumulation of resistant P. falciparum when high-dose chloroquine is used

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia

    2009-01-01

    increase of pfcrt 76T if the high doses of CQ commonly used are effective. METHODS AND FINDINGS: P. falciparum parasite density, age, sex, the proportion of chloroquine resistance associated haplotypes pfcrt 76T and P. falciparum multidrug resistance gene 1 86Y were assessed in 988 samples collected from...... to become the dominant P.falciparum type in Guinea-Bissau. This is most likely due to the efficacy of high-dose chloroquine as used in Guinea-Bissau, combined with a loss of fitness associated with pfcrt 76T.......BACKGROUND: Potentially chloroquine resistant P. falciparum, identified by the 76T haplotype in the chloroquine resistance transporter (pfcrt 76T), are highly prevalent throughout Africa. In Guinea-Bissau, normal and double dose chloroquine have respective efficacies of 34% and 78% against P...

  14. The radiosensitizing effect of doranidazole on human colorectal cancer cells exposed to high doses of irradiation

    International Nuclear Information System (INIS)

    Zhang, Li; Gong, Aimin; Ji, Jun; Wu, Yuanyuan; Zhu, Xiaoyu; Lv, Suqing; Lv, Hongzhu; Sun, Xizhuo

    2007-01-01

    This paper investigates the effects of a new radiosensitizer, doranidazole, and enhancing irradiation on colorectal cancer cells. The radiosensitizing effect of doranidazole was determined using colony formation and propidium iodide (PI) assays to measure cell growth inhibition and the cell killing effect of human colorectal cancer cell lines exposed to high doses of γ-ray irradiation under hypoxic conditions in vitro. Fluorescence staining and cell migration assays were also used to assess the radiosensitizing effect. Cell proliferation evaluated by clonogenic survival curves was significantly inhibited by 5 mmol/L doranidazole, particularly at doses ranging from 10 to 30 Gy of irradiation. The radiosensitizing effect of doranidazole on colorectal cancer cells occurs in a time- and dose-dependent manner. Doranidazole also inhibited the mobility of cell invasion and migration. Doranidazole can enhance the killing effect and the cell growth inhibition of colorectal cancer after high-dose irradiation in a time and dose-dependent manner

  15. Gene expression profiles following high-dose exposure to gamma radiation in salmonella enterica serovar typhimurium

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Sang Yong; Jung, Sun Wook; Joe, Min Ho; Kim, Dong Ho [Radiation Research Division for Biotechnology, Korea Atomic Energy Research Institute, Jeongeup (Korea, Republic of)

    2008-08-15

    Microarrays can measure the expression of thousands of genes to identify the changes in expression between different biological states. To survey the change of whole Salmonella genes after a relatively high dose of gamma radiation (1 kGy), transcriptome dynamics were examined in the cells by using DNA microarrays. At least 75 genes were induced and 89 genes were reduced two-fold or more after irradiation. Several genes located in pSLT plasmid, cyo operon, and Gifsy prophage were induced along with many genes encoding uncharacterized proteins.While, the expression of genes involved in the virulence of Salmonella as well as metabolic functions were decreased. Although the radiation response as a whole could not be illustrated by using DNA microarrays, the data suggest that the response to high dose of irradiation might be more complex than the SOS response.

  16. High-dose therapy improved the bone remodelling compartment canopy and bone formation in multiple myeloma

    DEFF Research Database (Denmark)

    Hinge, Maja; Delaissé, Jean-Marie; Plesner, Torben

    2015-01-01

    transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed......Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling....... Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high-dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first-line treatment with high-dose melphalan followed by autologous stem cell...

  17. A photocurrent compensation method of bipolar transistors under high dose rate radiation and its experimental research

    International Nuclear Information System (INIS)

    Yin Xuesong; Liu Zhongli; Li Chunji; Yu Fang

    2005-01-01

    Experiment using discrete bipolar transistors has been performed to verify the effect of the photocurrent compensation method. The theory of the dose rate effects of bipolar transistors and the photocurrent compensation method are introduced. The comparison between the response of hardened and unhardened circuits under high dose rate radiation is discussed. The experimental results show instructiveness to the hardness of bipolar integrated circuits under transient radiation. (authors)

  18. High dose radiation damage in nuclear energy structural materials investigated by heavy ion irradiation simulation

    International Nuclear Information System (INIS)

    Zheng Yongnan; Xu Yongjun; Yuan Daqing

    2014-01-01

    Structural materials in ITER, ADS and fast reactor suffer high dose irradiations of neutrons and/or protons, that leads to severe displacement damage up to lOO dpa per year. Investigation of radiation damage induced by such a high dose irradiation has attracted great attention along with the development of nuclear energy facilities of new generation. However, it is deeply hampered for the lacking of high dose neutron and proton sources. Irradiation simulation of heavy ions produced by accelerators opens up an effective way for laboratory investigation of high dose irradiation induced radiation damage encountered in the ITER, ADS, etc. Radiation damage is caused mainly by atomic displacement in materials. The displacement rate of heavy ions is about lO 3 ∼10 7 orders higher than those of neutrons and protons. High displacement rate of heavy ions significantly reduces the irradiation time. The heavy ion irradiation simulation technique (HIIS) technique has been developed at China Institute of Atomic Energy and a series of the HIIS experiments have been performed to investigate radiation damage in stainless steels, tungsten and tantalum at irradiation temperatures from room temperature to 800 ℃ and in the irradiation dose region up to 100 dpa. The experimental results show that he radiation swelling peak for the modified stainless steel appears in the temperature region around 580 ℃ and the radiation damage is more sensitive to the temperature, the size of the radiation induced vacancy cluster or void increase with the increasing of the irradiation dose, and among the three materials the home-made modified stainless steel has the best radiation resistant property. (authors)

  19. Persistent DNA damage after high dose in vivo gamma exposure of minipig skin.

    Directory of Open Access Journals (Sweden)

    Emad A Ahmed

    Full Text Available Exposure to high doses of ionizing radiation (IR can lead to localized radiation injury of the skin and exposed cells suffer dsDNA breaks that may elicit cell death or stochastic changes. Little is known about the DNA damage response after high-dose exposure of the skin. Here, we investigate the cellular and DNA damage response in acutely irradiated minipig skin.IR-induced DNA damage, repair and cellular survival were studied in 15 cm(2 of minipig skin exposed in vivo to ~50 Co-60 γ rays. Skin biopsies of control and 4 h up to 96 days post exposure were investigated for radiation-induced foci (RIF formation using γ-H2AX, 53BP1, and active ATM-p immunofluorescence. High-dose IR induced massive γ-H2AX phosphorylation and high 53BP1 RIF numbers 4 h, 20 h after IR. As time progressed RIF numbers dropped to a low of 3-fold elevated at all subsequent time points. Replicating basal cells (Ki67+ were reduced 3 days post IR followed by increased proliferation and recovery of epidermal cellularity after 28 days.Acute high dose irradiation of minipig epidermis impaired stem cell replication and induced elevated apoptosis from 3 days onward. DNA repair cleared the high numbers of DBSs in skin cells, while RIFs that persisted in <1% cells marked complex and potentially lethal DNA damage up to several weeks after exposure. An elevated frequency of keratinocytes with persistent RIFs may thus serve as indicator of previous acute radiation exposure, which may be useful in the follow up of nuclear or radiological accident scenarios.

  20. High-Dose Mannose-Binding Lectin Therapy for Ebola Virus Infection

    Science.gov (United States)

    2010-06-01

    host defense against a wide range of viral and other pathogens. MBL is a C-type lectin that recognizes hexose sugars including man- nose, glucose...should be evaluatedmore broadly as an immunotherapeutic agent for a wide spectrum of glycosylated pathogens. MATERIALS AND METHODS Production and... coagulation mod- ulators, antisense technologies, therapeutic antibodies and Table 1. Pharmacokinetic Parameters of Low- vs High-Dose Recombinant Human

  1. Biological dose estimation for accidental supra-high dose gamma-ray exposure

    International Nuclear Information System (INIS)

    Chen, Y.; Yan, X.K.; Du, J.; Wang, Z.D.; Zhang, X.Q.; Zeng, F.G.; Zhou, P.K.

    2011-01-01

    To correctly estimate the biological dose of victims accidentally exposed to a very high dose of 60 Co gamma-ray, a new dose-effect curve of chromosomal dicentrics/multicentrics and rings in the supra-high dose range was established. Peripheral blood from two healthy men was irradiated in vitro with doses of 60 Co gamma-rays ranging from 6 to 22 Gy at a dose rate of 2.0 Gy/min. Lymphocytes were concentrated, cultured and harvested at 52 h, 68 h and 72 h. The numbers of dic + r were counted. The dose-effect curves were established and validated using comparisons with doses from the Tokai-mura accident and were then applied to two victims of supra-high dose exposure accident. The results indicated that there were no significant differences in chromosome aberration frequency among the different culture times from 52 h to 72 h. The 6-22 Gy dose-effect curve was fitted to a linear quadratic model Y = -2.269 + 0.776D - 7.868 x l0 -3 D 2 . Using this mathematic model, the dose estimates were similar to data from Tokai-mura which were estimated by PCC ring. Whole body average doses of 9.7 Gy and 18.1 Gy for two victims in the Jining accident were satisfactorily given. We established and successfully applied a new dose-effect curve of chromosomal dicentrics plus ring (dic + r) after 6-22 Gy γ-irradiation from a supra-high dose 60 Co gamma-ray accident.

  2. Quality control of 192Ir high dose rate after loading brachytherapy dose veracity

    International Nuclear Information System (INIS)

    Feng Zhongsu; Xu Xiao; Liu Fen

    2008-01-01

    Recently, 192 Ir high dose rate (HDR) afterloading are widely used in brachytherapy. The advantage of using HDR systems over low dose rate systems are shorter treatment time and higher fraction dose. To guarantee the veracity of the delivery dose, several quality control methods are deseribed in this work. With these we can improve the position precision, time precision and dose precision of the brachytherapy. (authors)

  3. Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy.

    Science.gov (United States)

    Leung, Loh-Shan B; Neal, Joel W; Wakelee, Heather A; Sequist, Lecia V; Marmor, Michael F

    2015-10-01

    To report rapid onset of retinal toxicity in a series of patients followed on high-dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with erlotinib for non-small cell lung cancer. Retrospective observational case series. Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high-dose (1000 mg daily) hydroxychloroquine for advanced non-small cell lung cancer. The US Food & Drug Administration-recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing, and multifocal electroretinography (mfERG). Out of the 7 patients having exposure of at least 6 months, 2 developed retinal toxicity (at 11 and 17 months of exposure). Damage was identified by OCT imaging, mfERG testing, and, in 1 case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss. These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1-2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high-dose hydroxychloroquine to improve safety monitoring and preservation of vision. Published by Elsevier Inc.

  4. Controversies in external beam and high dose rate brachytherapy of oesophageal cancer

    International Nuclear Information System (INIS)

    Sur, R.K.; Levin, V.C.; Malas, Simon; Donde, Bernard

    1994-01-01

    Various controversies in the treatment of oesophageal carcinoma with external beam radiotherapy and high dose rate intracavitary irradiation have been reviewed. Conflicting results from different parts of the world has made it difficult to optimize the radiation dose that may give the best results. More studies and longer follow-up are needed before a definite conclusion can be made on the optimization of dose. (author). 18 refs., 2 tabs

  5. Non-linear failure analysis of HCPB blanket for DEMO taking into account high dose irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Aktaa, J., E-mail: jarir.aktaa@kit.edu [Karlsruhe Institute of Technology (KIT), Institute for Applied Materials, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen (Germany); Kecskés, S.; Pereslavtsev, P.; Fischer, U.; Boccaccini, L.V. [Karlsruhe Institute of Technology (KIT), Institute for Neutron Physics and Reactor Technology, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen (Germany)

    2014-10-15

    Highlights: • First non-linear structural analysis for the European Helium Cooled Pebble Bed Blanket Module taking into account high dose irradiation. • Most critical areas were identified and analyzed with regard to the effect of irradiation on predicted damage at these areas. • Despite the extensive computing time 100 cycles were simulated by using the sub-modelling technique investigating damage at most critical area. • The results show a positive effect of irradiation on calculated damage which is mainly attributed to the irradiation induced hardening. - Abstract: For the European helium cooled pebble bed (HCPB) blanket of DEMO the reduced activation ferritic martensitic steel EUROFER has been selected as structural material. During operation the HCPB blanket will be subjected to complex thermo-mechanical loadings and high irradiation doses. Taking into account the material and structural behaviour under these conditions is a precondition for a reliable blanket design. For considering high dose irradiation in structural analysis of the DEMO blanket, the coupled deformation damage model, extended recently taking into account the influence of high dose irradiation on the material behaviour of EUROFER and implemented in the finite element code ABAQUS, has been used. Non-linear finite element (FE) simulations of the DEMO HCPB blanket have been performed considering the design of the HCPB Test Blanket Module (TBM) as reference and the thermal and mechanical boundary conditions of previous analyses. The irradiation dose rate required at each position in the structure as an additional loading parameter is estimated by extrapolating the results available for the TBM in ITER scaling the value calculated in neutronics and activation analysis for ITER boundary conditions to the DEMO boundary conditions. The results of the FE simulations are evaluated considering damage at most critical highly loaded areas of the structure and discussed with regard to the impact of

  6. Charge collection efficiency in ionization chambers exposed to electron beams with high dose per pulse

    Energy Technology Data Exchange (ETDEWEB)

    Laitano, R F [Istituto Nazionale di Metrologia delle Radiazioni Ionizzanti, ENEA Centro Ricerche Casaccia, c.p. 2400 Rome (Italy); Guerra, A S [Istituto Nazionale di Metrologia delle Radiazioni Ionizzanti, ENEA Centro Ricerche Casaccia, c.p. 2400 Rome (Italy); Pimpinella, M [Istituto Nazionale di Metrologia delle Radiazioni Ionizzanti, ENEA Centro Ricerche Casaccia, c.p. 2400 Rome (Italy); Caporali, C [Istituto Nazionale di Metrologia delle Radiazioni Ionizzanti, ENEA Centro Ricerche Casaccia, c.p. 2400 Rome (Italy); Petrucci, A [A.C.O. S. Filippo Neri, U.O. Fisica Sanitaria, Rome (Italy)

    2006-12-21

    The correction for charge recombination was determined for different plane-parallel ionization chambers exposed to clinical electron beams with low and high dose per pulse, respectively. The electron energy was nearly the same (about 7 and 9 MeV) for any of the beams used. Boag's two-voltage analysis (TVA) was used to determine the correction for ion losses, k{sub s}, relevant to each chamber considered. The presence of free electrons in the air of the chamber cavity was accounted for in determining k{sub s} by TVA. The determination of k{sub s} was made on the basis of the models for ion recombination proposed in past years by Boag, Hochhaeuser and Balk to account for the presence of free electrons. The absorbed dose measurements in both low-dose-per-pulse (less than 0.3 mGy per pulse) and high-dose-per-pulse (20-120 mGy per pulse range) electron beams were compared with ferrous sulphate chemical dosimetry, a method independent of the dose per pulse. The results of the comparison support the conclusion that one of the models is more adequate to correct for ion recombination, even in high-dose-per-pulse conditions, provided that the fraction of free electrons is properly assessed. In this respect the drift velocity and the time constant for attachment of electrons in the air of the chamber cavity are rather critical parameters because of their dependence on chamber dimensions and operational conditions. Finally, a determination of the factor k{sub s} was also made by zero extrapolation of the 1/Q versus 1/V saturation curves, leading to the conclusion that this method does not provide consistent results in high-dose-per-pulse beams.

  7. Radiation proctitis after the high dose rate brachytherapy for prostate cancer

    International Nuclear Information System (INIS)

    Kitano, Masashi; Katsumata, Tomoe; Satoh, Takefumi

    2006-01-01

    We reviewed the medical records of 12 patients treated for rectal bleeding after high-dose rate brachytherapy for prostate cancer. All patients developed grade 2 proctitis according to the Common Terminology Criteria for Adverse Events (CTCAC) and no patients needed blood transfusion. The patients were treated with argon plasma coagulation (APC) and/or steroid suppositories. The bleeding stopped or improved in 11 patients. Although re-bleeding was noticed in 7 patients the same treatment was effective in 5 patients. (author)

  8. Non-linear failure analysis of HCPB blanket for DEMO taking into account high dose irradiation

    International Nuclear Information System (INIS)

    Aktaa, J.; Kecskés, S.; Pereslavtsev, P.; Fischer, U.; Boccaccini, L.V.

    2014-01-01

    Highlights: • First non-linear structural analysis for the European Helium Cooled Pebble Bed Blanket Module taking into account high dose irradiation. • Most critical areas were identified and analyzed with regard to the effect of irradiation on predicted damage at these areas. • Despite the extensive computing time 100 cycles were simulated by using the sub-modelling technique investigating damage at most critical area. • The results show a positive effect of irradiation on calculated damage which is mainly attributed to the irradiation induced hardening. - Abstract: For the European helium cooled pebble bed (HCPB) blanket of DEMO the reduced activation ferritic martensitic steel EUROFER has been selected as structural material. During operation the HCPB blanket will be subjected to complex thermo-mechanical loadings and high irradiation doses. Taking into account the material and structural behaviour under these conditions is a precondition for a reliable blanket design. For considering high dose irradiation in structural analysis of the DEMO blanket, the coupled deformation damage model, extended recently taking into account the influence of high dose irradiation on the material behaviour of EUROFER and implemented in the finite element code ABAQUS, has been used. Non-linear finite element (FE) simulations of the DEMO HCPB blanket have been performed considering the design of the HCPB Test Blanket Module (TBM) as reference and the thermal and mechanical boundary conditions of previous analyses. The irradiation dose rate required at each position in the structure as an additional loading parameter is estimated by extrapolating the results available for the TBM in ITER scaling the value calculated in neutronics and activation analysis for ITER boundary conditions to the DEMO boundary conditions. The results of the FE simulations are evaluated considering damage at most critical highly loaded areas of the structure and discussed with regard to the impact of

  9. Influence of high dose irradiation on core structural and fuel materials in advanced reactors

    International Nuclear Information System (INIS)

    1998-08-01

    The IAEA International Working Group on Fast Reactors (IWGFR) periodically organizes meeting to discuss and review important aspects of fast reactor technology. The fifth meeting held in Obninsk, Russian Federation, 16-19 June 1997, was devoted to the influence of high dose irradiation on the mechanical properties of reactor core structural and fuel materials. The proceedings includes the papers submitted at this meeting each with a separate abstract

  10. Salvage high-dose-rate interstitial brachytherapy for locally recurrent rectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Pellizzon, Antonio Cassio Assis, E-mail: acapellizzon@hcancer.org.br [A.C. Camargo Cancer Center, Sao Paulo, SP (Brazil). Departamento de Radioterapia

    2016-05-15

    For tumors of the lower third of the rectum, the only safe surgical procedure is abdominal-perineal resection. High-dose-rate interstitial brachytherapy is a promising treatment for local recurrence of previously irradiated lower rectal cancer, due to the extremely high concentrated dose delivered to the tumor and the sparing of normal tissue, when compared with a course of external beam radiation therapy. (author)

  11. Management of hilar bile duct carcinoma with high-dose radiotherapy and expandable metallic stent placement

    International Nuclear Information System (INIS)

    Saito, Hiroya; Takamura, Akio

    2000-01-01

    This article describes our experience with high-dose radiotherapy in combination with the placement of expandable metallic stents (EMS) in the management of hilar bile duct carcinoma. Between 1988 and 1999, 107 consecutive patients with hilar bile duct carcinoma were treated with EMS placement either alone or in combination with high-dose radiotherapy. External beam radiotherapy (EBRT) was indicated in 101 patients, and in 86 this was combined with intraluminal 192 Ir irradiation (ILRT, 59-98 Gy) EMS were placed after the completion of radiotherapy. The 1-, 2-, 3-, and 5-year actuarial survival rates for the radiotherapy group were 66.4%, 23.4%, 15.6%, 7.8%, respectively, and the 1- and 2-year actuarial survival rates for the nonradiotherapy group were 66.4% and 0%, respectively. The placement of EMS was useful for the early establishment of an internal bile passage in radically irradiated patients and the 1-, 2-, 3-, and 5-year actuarial patency rates for the radiotherapy group were 56.3%, 45.3%, 35.2%, and 23.4%, respectively, and the 1- and 2-year actuarial patency rates for the non radiotherapy group were 50.0% and 0% respectively. High-dose radiotherapy, consisting of ILRT and EBRT, appears to be feasible in the management of hilar bile duct carcinoma, and it offers a survival advantage for patients no suited for surgical resection. The placement of EMS assists the internal bile flow and lengthens survival after high-dose radiotherapy. (author)

  12. Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes.

    Science.gov (United States)

    Xu, Yuhui; Wu, Jianan; Liao, Sha; Sun, Zhaogang

    2017-10-03

    Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts' body weight, metabolic processing of the drug, malabsorption and/or drug-drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen's physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs.

  13. Epithelial regeneration of transposed intestine after high doses of X irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Both, N.J. de; Vermey, M [Erasmus Universiteit, Rotterdam (Netherlands)

    1976-01-01

    The regeneration capacities of normal and transposed small bowel epithelium were compared in rats after applying high doses of x irradiation. It has been shown that the potency of the mucosa to regenerate was much higher than assumed and that the mucosa could regenerate after single doses varying from 2000 to 5000 R. Even in the villus epithelium and in flat epithelium covering infiltrates of the lamina propria cells survived, which were still able to resume proliferative activity several days after irradiation.

  14. Polybutadiene and Styrene-Butadiene rubbers for high-dose dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, Lucas N. [Instituto Federal de Educacao, Ciencia e Tecnologia de Goias-IFG,Campus Goiania, Goiania -GO (Brazil); Instituto de Pesquisas Energeticas e Nucleares -IPEN, Sao Paulo-SP (Brazil); Vieira, Silvio L. [Instituto de Fisica, Universidade Federal de Goias-UFG, Campus Samambaia, Goiania-GO (Brazil); Schimidt, Fernando [Instituto Federal de Educacao, Ciencia e Tecnologia de Goias-IFG,Campus Inhumas, Inhumas-GO (Brazil); Antonio, Patricia L.; Caldas, Linda V.E. [Instituto de Pesquisas Energeticas e Nucleares -IPEN, Sao Paulo-SP (Brazil)

    2015-07-01

    Polybutadiene and Styrene-Butadiene are synthetical rubbers used widely for pneumatic tires manufacturing. In this research, the dosimeter characteristics of those rubbers were studied for application in high-dose dosimetry. The rubber samples were irradiated with doses of 10 Gy up to 10 kGy, using a {sup 60}Co Gamma Cell-220 system (dose rate of 1.089 kGy/h) and their readings were taken on a Fourier Transform Infrared Spectroscopy-FTIR system (model Frontier/Perkin Elmer). The ratios of two absorbance peaks were taken for each kind of rubber spectrum, Polybutadiene (1306/1130 cm{sup -1}) and Styrene-Butadiene (1449/1306 cm{sup -1}). The ratio calculated was used as the response to the irradiation, and is not uniform across the sample. From the results, it can be concluded for both rubbers: a) the dose-response curves may be useful for high-dose dosimetry (greater than 250 Gy); b) their response for reproducibility presented standard deviations lower than 2.5%; c) the relative sensitivity was higher for Styrene-Butadiene (1.86 kGy{sup -1}) than for Polybutadiene (1.81 kGy{sup -1}), d) for doses of 10 kGy to 200 kGy, there was no variation in the dosimetric response. Both types of rubber samples showed usefulness as high-dose dosimeters. (authors)

  15. Cosmetic results in early stage breast cancer patients with high-dose brachytherapy after conservative surgery

    International Nuclear Information System (INIS)

    Torres, Felipe; Pineda, Beatriz E

    2004-01-01

    Purpose: to reveal cosmetic results in patients at early stages of low risk breast cancer treated with partial accelerated radiotherapy using high dose rate brachytherapy. Methods and materials: from March 2001 to July 2003,14 stages l and ll breast cancer patients were treated at the Colombian national cancer institute in Bogota with conservative surgery and radiotherapy upon the tumor bed (partial accelerated radiotherapy), using interstitial implants with iridium 192 (high dose rate brachytherapy) with a dose of 32 Gys, over 4 days, at 8 fractions twice a day. Results: with an average follow up of 17.7 months, good cosmetic results were found among 71.4 % of patients and excellent results among 14.3% of patients, furthermore none of the patients neither local nor regional or distant relapses. Conclusion: among patients who suffer from breast cancer at early stages, it showed is possible to apply partial accelerated radiotherapy upon the tumor bed with high doses over 4 days with good to excellent cosmetic results

  16. Development of computerized dose planning system and applicator for high dose rate remote afterloading irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Choi, T. J. [Keimyung Univ., Taegu (Korea); Kim, S. W. [Fatima Hospital, Taegu (Korea); Kim, O. B.; Lee, H. J.; Won, C. H. [Keimyung Univ., Taegu (Korea); Yoon, S. M. [Dong-a Univ., Pusan (Korea)

    2000-04-01

    To design and fabricate of the high dose rate source and applicators which are tandem, ovoids and colpostat for OB/Gyn brachytherapy includes the computerized dose planning system. Designed the high dose rate Ir-192 source with nuclide atomic power irradiation and investigated the dose characteristics of fabricated brachysource. We performed the effect of self-absorption and determining the gamma constant and output factor and determined the apparent activity of designed source. he automated computer planning system provided the 2D distribution and 3D includes analysis programs. Created the high dose rate source Ir-192, 10 Ci(370GBq). The effective attenuation factor from the self-absorption and source wall was examined to 0.55 of the activity of bare source and this factor is useful for determination of the apparent activity and gamma constant 4.69 Rcm{sup 2}/mCi-hr. Fabricated the colpostat was investigated the dose distributions of frontal, axial and sagittal plane in intra-cavitary radiation therapy for cervical cancer. The reduce dose at bladder and rectum area was found about 20 % of original dose. The computerized brachytherapy planning system provides the 2-dimensional isodose and 3-D include the dose-volume histogram(DVH) with graphic-user-interface mode. emoted afterloading device was built for experiment of created Ir-192 source with film dosimetry within {+-}1 mm discrepancy. 34 refs., 25 figs., 11 tabs. (Author)

  17. High-dose calcium stimulation test in a case of insulinoma masquerading as hysteria.

    Science.gov (United States)

    Nakamura, Yoshio; Doi, Ryuichiro; Kohno, Yasuhiro; Shimono, Dai; Kuwamura, Naomitsu; Inoue, Koichi; Koshiyama, Hiroyuki; Imamura, Masayuki

    2002-11-01

    It is reported that some cases with insulinoma present with neuropsychiatric symptoms and are often misdiagnosed as psychosis. Here we report a case of insulinoma masquerading as hysteria, whose final diagnosis could be made using high-dose calcium stimulation test. A 28-yr-old woman was referred presenting with substupor, mutism, mannerism, restlessness, and incoherence. Laboratory examinations revealed hypoglycemia (33 mg/dL) and detectable insulin levels (9.7 microU/mL), suggesting the diagnosis of insulinoma. However, neither imaging studies nor selective arterial calcium injection (SACI) test with a conventional dose of calcium (0.025 mEq/kg) indicated the tumor. High-dose calcium injection (0.05 mEq/kg) evoked insulin secretion when injected into superior mesenteric artery. A solitary tumor in the head of the pancreas was resected, and her plasma glucose returned to normal. Postoperatively, iv injection of secretin resulted in a normal response of insulin, which was not found preoperatively. This case suggests the usefulness of the SACI test with high-dose of calcium in the case of insulinoma when the standard dose fails to detect such a tumor.

  18. Base of skull and cervical spine chordomas in children treated by high-dose irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Benk, Veronique; Liebsch, Norbert J; Munzenrider, John E; Efird, John; McManus, Patricia; Suit, Herman

    1995-02-01

    Purpose: To evaluate the outcome of children with base of skull or cervical spine chordomas treated by high dose irradiation. Methods and Materials: Eighteen children, 4 to 18 years of age, with base of skull or cervical spine chordomas, received fractionated high-dose postoperative radiation using mixed photon and 160 MeV proton beams. The median tumor dose was 69 Cobalt Gray-equivalent (CGE) with a 1.8 CGE daily fraction. Results: The median follow-up was 72 months. The 5-year actuarial survival was 68% and the 5-year disease-free survival (DFS) was 63%. The only significant prognostic factor was the location: patients with cervical spine chordomas had a worse survival than those with base of skull lesions (p = 0.008). The incidence of treatment-related morbidity was acceptable: two patients developed a growth hormone deficit corrected by hormone replacement, one temporal lobe necrosis, and one fibrosis of the temporalis muscle, improved by surgery. Conclusion: Chordomas in children behave similarly to those in adults: children can receive the same high-dose irradiation as adults with acceptable morbidity.

  19. The effect of high-dose dronabinol (oral THC) maintenance on cannabis self-administration.

    Science.gov (United States)

    Schlienz, Nicolas J; Lee, Dustin C; Stitzer, Maxine L; Vandrey, Ryan

    2018-06-01

    There is a clear need for advancing the treatment of cannabis use disorders. Prior research has demonstrated that dronabinol (oral THC) can dose-dependently suppress cannabis withdrawal and reduce the acute effects of smoked cannabis. The present study was conducted to evaluate whether high-dose dronabinol could reduce cannabis self-administration among daily users. Non-treatment seeking daily cannabis users (N = 13) completed a residential within-subjects crossover study and were administered placebo, low-dose dronabinol (120 mg/day; 40 mg tid), or high-dose dronabinol (180-240 mg/day; 60-80 mg tid) for 12 consecutive days (order counterbalanced). During each 12-day dronabinol maintenance phase, participants were allowed to self-administer smoked cannabis containing <1% THC (placebo) or 5.7% THC (active) under forced-choice (drug vs. money) or progressive ratio conditions. Participants self-administered significantly more active cannabis compared with placebo in all conditions. When active cannabis was available, self-administration was significantly reduced during periods of dronabinol maintenance compared with placebo maintenance. There was no difference in self-administration between the low- and high-dose dronabinol conditions. Chronic dronabinol dosing can reduce cannabis self-administration in daily cannabis users and suppress withdrawal symptoms. Cannabinoid agonist medications should continue to be explored for therapeutic utility in the treatment of cannabis use disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine.

    Science.gov (United States)

    Babaei-Jadidi, Roya; Karachalias, Nikolaos; Ahmed, Naila; Battah, Sinan; Thornalley, Paul J

    2003-08-01

    Accumulation of triosephosphates arising from high cytosolic glucose concentrations in hyperglycemia is the trigger for biochemical dysfunction leading to the development of diabetic nephropathy-a common complication of diabetes associated with a high risk of cardiovascular disease and mortality. Here we report that stimulation of the reductive pentosephosphate pathway by high-dose therapy with thiamine and the thiamine monophosphate derivative benfotiamine countered the accumulation of triosephosphates in experimental diabetes and inhibited the development of incipient nephropathy. High-dose thiamine and benfotiamine therapy increased transketolase expression in renal glomeruli, increased the conversion of triosephosphates to ribose-5-phosphate, and strongly inhibited the development of microalbuminuria. This was associated with decreased activation of protein kinase C and decreased protein glycation and oxidative stress-three major pathways of biochemical dysfunction in hyperglycemia. Benfotiamine also inhibited diabetes-induced hyperfiltration. This was achieved without change in elevated plasma glucose concentration and glycated hemoglobin in the diabetic state. High-dose thiamine and benfotiamine therapy is a potential novel strategy for the prevention of clinical diabetic nephropathy.

  1. Does High-Dose Antimicrobial Chemotherapy Prevent the Evolution of Resistance?

    Science.gov (United States)

    Day, Troy; Read, Andrew F.

    2016-01-01

    High-dose chemotherapy has long been advocated as a means of controlling drug resistance in infectious diseases but recent empirical studies have begun to challenge this view. We develop a very general framework for modeling and understanding resistance emergence based on principles from evolutionary biology. We use this framework to show how high-dose chemotherapy engenders opposing evolutionary processes involving the mutational input of resistant strains and their release from ecological competition. Whether such therapy provides the best approach for controlling resistance therefore depends on the relative strengths of these processes. These opposing processes typically lead to a unimodal relationship between drug pressure and resistance emergence. As a result, the optimal drug dose lies at either end of the therapeutic window of clinically acceptable concentrations. We illustrate our findings with a simple model that shows how a seemingly minor change in parameter values can alter the outcome from one where high-dose chemotherapy is optimal to one where using the smallest clinically effective dose is best. A review of the available empirical evidence provides broad support for these general conclusions. Our analysis opens up treatment options not currently considered as resistance management strategies, and it also simplifies the experiments required to determine the drug doses which best retard resistance emergence in patients. PMID:26820986

  2. Rectal dose assessment in patients submitted to high-dose-rate brachytherapy for uterine cervix cancer

    International Nuclear Information System (INIS)

    Oliveira, Jetro Pereira de; Batista, Delano Valdivino Santos; Bardella, Lucia Helena; Carvalho, Arnaldo Rangel

    2009-01-01

    Objective: The present study was aimed at developing a thermoluminescent dosimetric system capable of assessing the doses delivered to the rectum of patients submitted to high-dose-rate brachytherapy for uterine cervix cancer. Materials and methods: LiF:Mg,Ti,Na powder was the thermoluminescent material utilized for evaluating the rectal dose. The powder was divided into small portions (34 mg) which were accommodated in a capillary tube. This tube was placed into a rectal probe that was introduced into the patient's rectum. Results: The doses delivered to the rectum of six patients submitted to high-dose-rate brachytherapy for uterine cervix cancer evaluated by means of thermoluminescent dosimeters presented a good agreement with the planned values based on two orthogonal (anteroposterior and lateral) radiographic images of the patients. Conclusion: The thermoluminescent dosimetric system developed in the present study is simple and easy to be utilized as compared to other rectal dosimetry methods. The system has shown to be effective in the evaluation of rectal doses in patients submitted to high-dose-rate brachytherapy for uterine cervix cancer. (author)

  3. False-positive buprenorphine EIA urine toxicology results due to high dose morphine: a case report.

    Science.gov (United States)

    Tenore, Peter L

    2012-01-01

    In monitoring a patient with chronic pain who was taking high-dose morphine and oxycodone with weekly urine enzymatic immunoassay (EIA) toxicology testing, the authors noted consistent positives for buprenorphine. The patient was not taking buprenorphine, and gas chromatography/mass spectroscopy (GCMS) testing on multiple samples revealed no buprenorphine, indicating a case of false-positive buprenorphine EIAs in a high-dose opiate case. The authors discontinued oxycodone for a period of time and then discontinued morphine. Urine monitoring with EIAs and GCMS revealed false-positive buprenorphine EIAs, which remained only when the patient was taking morphine. When taking only oxycodone and no morphine, urine samples became buprenorphine negative. When morphine was reintroduced, false-positive buprenorphine results resumed. Medical practitioners should be aware that high-dose morphine (with morphine urine levels turning positive within the 15,000 to 28,000 mg/mL range) may produce false-positive buprenorphine EIAs with standard urine EIA toxicology testing.

  4. Extra-high doses detected in the enamel of human teeth in the Techa riverside region

    Energy Technology Data Exchange (ETDEWEB)

    Shishkina, E.A., E-mail: ElenaA.Shishkina@gmail.com [Urals Research Center for Radiation Medicine, 68A, Vorovsky Str., 454076 Chelyabinsk (Russian Federation); Degteva, M.O.; Tolstykh, E.I.; Volchkova, A. [Urals Research Center for Radiation Medicine, 68A, Vorovsky Str., 454076 Chelyabinsk (Russian Federation); Ivanov, D.V. [Institute of Metal Physics, Russian Academy of Sciences, 18 S. Kovalevsky Str, 620041 Yekaterinburg (Russian Federation); Wieser, A. [Helmholtz Zentrum Muenchen, German Research Centre for Environmental Health, D-85764 Neuherberg (Germany); Della Monaca, S. [Istituto Superiore di Sanita, 00161 Rome (Italy); Istituto Regina Elena, 00144 Rome (Italy); Fattibene, P. [Istituto Superiore di Sanita, 00161 Rome (Italy); Istituto Nazionale di Fisica Nucleare, 00161 Rome (Italy)

    2011-09-15

    During the long-term study of tooth enamel by EPR dosimetry for population exposed to radiation due to contamination of the Techa River, it was found out that for some of the tooth donors the dose accumulated in tooth enamel could be as high as several tens of Gy. Such doses were absorbed only in tooth enamel and they should not be associated with exposures to other organs or the whole body. The nature of such doses was discussed in a number of previous papers where it was shown that the source of such doses is {sup 90}Sr incorporated in the calcified dental tissues. However, among specialists in radiation dosimetry who were not involved in the biokinetic studies, the nature and dosimetric significance of extra-high doses in tooth enamel are still raising questions. The aim of the current paper is to summarize the accumulated information on extra-high doses in the teeth of the Techa riverside residents, describe the dose levels observed, explain the nature of extra-high doses in the enamel and discuss their informative value. The paper includes an overview of already published findings and an analysis of information collected in the data bank of the Urals Research Center for Radiation Medicine (URCRM), Chelyabinsk, Russia, which has not been published before.

  5. Base of skull and cervical spine chordomas in children treated by high-dose irradiation

    International Nuclear Information System (INIS)

    Benk, Veronique; Liebsch, Norbert J.; Munzenrider, John E.; Efird, John; McManus, Patricia; Suit, Herman

    1995-01-01

    Purpose: To evaluate the outcome of children with base of skull or cervical spine chordomas treated by high dose irradiation. Methods and Materials: Eighteen children, 4 to 18 years of age, with base of skull or cervical spine chordomas, received fractionated high-dose postoperative radiation using mixed photon and 160 MeV proton beams. The median tumor dose was 69 Cobalt Gray-equivalent (CGE) with a 1.8 CGE daily fraction. Results: The median follow-up was 72 months. The 5-year actuarial survival was 68% and the 5-year disease-free survival (DFS) was 63%. The only significant prognostic factor was the location: patients with cervical spine chordomas had a worse survival than those with base of skull lesions (p = 0.008). The incidence of treatment-related morbidity was acceptable: two patients developed a growth hormone deficit corrected by hormone replacement, one temporal lobe necrosis, and one fibrosis of the temporalis muscle, improved by surgery. Conclusion: Chordomas in children behave similarly to those in adults: children can receive the same high-dose irradiation as adults with acceptable morbidity

  6. High dose per fraction dosimetry of small fields with Gafchromic EBT2 film

    International Nuclear Information System (INIS)

    Hardcastle, Nicholas; Basavatia, Amar; Bayliss, Adam; Tome, Wolfgang A.

    2011-01-01

    Purpose: Small field dosimetry is prone to uncertainties due to the lack of electronic equilibrium and the use of the correct detector size relative to the field size measured. It also exhibits higher sensitivity to setup errors as well as large variation in output with field size and shape. Radiochromic film is an attractive method for reference dosimetry in small fields due to its ability to provide 2D dose measurements while having minimal impact on the dose distribution. Gafchromic EBT2 has a dose range of up to 40 Gy; therefore, it could potentially be useful for high dose reference dosimetry with high spatial resolution. This is a requirement in stereotactic radiosurgery deliveries, which deliver high doses per fraction to small targets. Methods: Targets of 4 mm and 12 mm diameters were treated to a minimum peripheral dose of 21 Gy prescribed to 80% of the maximum dose in one fraction. Target doses were measured with EBT2 film (both targets) and an ion chamber (12 mm target only). Measured doses were compared with planned dose distributions using profiles through the target and minimum peripheral dose coverage. Results: The measured target doses and isodose coverage agreed with the planned dose within ±1 standard deviation of three measurements, which were 2.13% and 2.5% for the 4 mm and 12 mm targets, respectively. Conclusions: EBT2 film is a feasible dosimeter for high dose per fraction reference 2D dosimetry.

  7. High-dose ascorbic acid decreases cholesterolemic factors of an atherogenic diet in guinea pigs.

    Science.gov (United States)

    Filis, Konstantinos; Anastassopoulou, Aikaterini; Sigala, Fragiska; Theodorou, Dimitrios; Manouras, Andreas; Leandros, Emanouel; Sigalas, Panagiotis; Hepp, Wolfgang; Bramis, John

    2007-03-01

    The study evaluates the effect of a high supplemental dose of ascorbic acid (AA) on plasma concentrations of total cholesterol (TC), triglycerides (TG), total lipids (TL), and lipoprotein fractions high-density, very-low-density-, and low-density lipoprotein (HDL, VLDL, LDL) in guinea pigs fed with atherogenic diet. Group I consisted of 5 normally fed guinea pigs plus a low dose of AA (1 mg/100 g/day), group II consisted of 7 guinea pigs fed with food enriched with 2% cholesterol plus a low dose of AA (1 mg/100 g/day), and group III consisted of 7 guinea pigs fed with food enriched with 2% cholesterol plus a high dose of AA (30 mg/100 g/day). Cholesterolemic factors concentrations were determined after nine weeks. Concentrations of TC, TG, TL, LDL, and VLDL were increased in group II compared to group I (p < 0.01 for all differences). Supplementation with a high dose of AA resulted in decreased concentrations of TC (p < 0.01), TG (p < 0.01), TL (p < 0.01), and LDL (p < 0.01) in group III compared to group II. Additionally, concentration of HDL was increased in group III compared to group II (p < 0.01). High-dose AA supplementation to an atherogenic diet decreases concentrations of TC, TG, TL, and LDL and increases concentration of HDL compared to low-dose AA.

  8. Image-Guided Stereotactic Radiosurgery Using a Specially Designed High-Dose-Rate Linac

    International Nuclear Information System (INIS)

    Bayouth, John E.; Kaiser, Heather S.; Smith, Mark C.; Pennington, Edward C.; Anderson, Kathleen M. C.; Ryken, Timothy C.; Buatti, John M.

    2007-01-01

    Stereotactic radiosurgery and image-guided radiotherapy (IGRT) place enhanced demands on treatment delivery machines. In this study, we describe a high-dose-rate output accelerator as a part of our stereotactic IGRT delivery system. The linac is a Siemens Oncor without a flattening filter, and enables dose rates to reach 1000 monitor units (MUs) per minute. Even at this high-dose-rate, the linac dosimetry system remains robust; constancy, linearity, and beam energy remain within 1% for 3 to 1000 MU. Dose profiles for larger field sizes are not flat, but they are radially symmetric and, as such, able to be modeled by a treatment planning system. Target localization is performed via optical guidance utilizing a 3-dimensional (3D) ultrasound probe coupled to an array of 4 infrared light-emitting diodes. These diodes are identified by a fixed infrared camera system that determines diode position and, by extension, all objects imaged in the room coordinate system. This system provides sub-millimeter localization accuracy for cranial applications and better than 1.5 mm for extracranial applications. Because stereotactic IGRT can require significantly longer times for treatment delivery, the advantages of the high-dose-rate design and its direct impact on IGRT are discussed

  9. Myocardial protection induced by fentanyl in pigs exposed to high-dose adrenaline.

    Science.gov (United States)

    da Luz, Vinicius Fernando; Otsuki, Denise Aya; Gonzalez, Maria Margarita Castro; Negri, Elnara Marcia; Caldini, Elia Garcia; Damaceno-Rodrigues, Nilsa Regina; Malbouisson, Luiz Marcelo Sá; Viana, Bruno Gonçalves; Vane, Matheus Fachini; Carmona, Maria Jose Carvalho

    2015-10-01

    The use of high doses of adrenaline is common in critical patients, especially during cardiac arrest. During these situations, myocardial dysfunction can be a result of multiple factors, including adrenaline use. In addition, opioids have been shown to have anti-arrhythmic and anti-ischemic mechanisms that may confer cardiac protection. This study aimed to evaluate the effects of fentanyl on myocardial function in pigs exposed to high-dose adrenaline. After institutional ethics committee approval, 26 pigs were randomly allocated to receive either 20 μg/kg fentanyl (n = 10; fentanyl group) administered 5 min before five doses of adrenaline (20 μg/kg), equivalent-volume saline (n = 10; saline group) using the same adrenaline dosing protocol, or neither fentanyl nor adrenaline (n = 6; sham group). The fentanyl group showed lower levels of troponin at the end of the sixth hour compared with the saline group (1.91 ± 1.47 vs 5.44 ± 5.35 ng/mL, P = 0.019). Transmission electron microscopy and immunohistochemistry also showed less myocardial injury in the fentanyl group. The conclusion was reached that fentanyl attenuates myocardial injury caused by high-dose adrenaline without blunting the hemodynamic effect of adrenaline. © 2015 Wiley Publishing Asia Pty Ltd.

  10. Evaluating complications of local anesthesia administration and reversal with phentolamine mesylate in a portable pediatric dental clinic.

    Science.gov (United States)

    Boynes, Sean G; Riley, Amah E; Milbee, Sarah; Bastin, Meghan R; Price, Maylyn E; Ladson, Andrea

    2013-08-01

    This study sought to identify and quantify complications with local anesthetic administration and reversal on consecutive patients seen for comprehensive dental care in a school-based, portable dental clinic, and includes data on the patients seen by the participating portable dental providers. In 923 dental visits where local anesthetic was administered, a standardized form was used to gain further information and identify any complications; this was accompanied by a questionnaire for the student's teacher, in order to quantify the student's distraction and disruption ratings following the dental visit. After statistical analysis of the 923 consecutive cases, the overall complication rate was 5.3%. All of the complications were considered to be mild or moderate, and there were no severe event reports. The complications encountered most frequently (n = 49) were associated with self-inflicted soft tissue injury. The results of this study indicate that comprehensive care with local anesthesia delivered by a school-based portable dental clinic has a low risk of complications. Whereas safe administration of dental care is achievable with or without phentolamine mesylate as a local anesthetic reversal agent, its use was determined to improve safety outcomes. Three factors appeared to directly increase the incidence of complications: the administration of an inferior alveolar nerve block, attention deficit disorder, and obesity. Teacher evaluations demonstrated that children receiving care by a portable dental team were able to reorient back to classwork and were not disruptive to classmates.

  11. Thermodynamic solution properties of pefloxacin mesylate and its interactions with organized assemblies of anionic surfactant, sodium dodecyl sulphate

    International Nuclear Information System (INIS)

    Usman, Muhammad; Rashid, Muhammad Abid; Mansha, Asim; Siddiq, Mohammad

    2013-01-01

    Graphical abstract: - Highlights: • Free energy of adsorption is more negative than free energy of micellization. • Micellization becomes more spontaneous at high temperature. • There is strong interaction between PFM and SDS. - Abstract: This manuscript reports the physicochemical behavior of antibiotic amphiphilic drug pefloxacin mesylate (PFM) and its interaction with anionic surfactant, sodium dodecyl sulfate (SDS). The data of surface tension and electrical conductivity are helpful to detect the CMC as well as to calculate surface parameters, i.e. surface pressure, π, surface excess concentration, Γ, area per molecule of drug and standard Gibbs free energy of adsorption, ΔG ads and thermodynamic parameters like standard free energy of micellization, ΔG m , standard enthalpy of micellization, ΔH m and standard entropy of micellization, ΔS m . The interaction of this drug with anionic surfactant, sodium dodecyl sulfate (SDS) was studied by electrical conductivity and UV/visible spectroscopy. This enabled us to compute the values of partition coefficient (K x ), free energy of partition, ΔG p , binding constant, K b , free energy of binding, ΔG b , number of drug molecules per micelle, n, and thermodynamic parameters of drug–surfactant interaction

  12. Measurement and prediction of dabigatran etexilate mesylate Form II solubility in mono-solvents and mixed solvents

    International Nuclear Information System (INIS)

    Xiao, Yan; Wang, Jingkang; Wang, Ting; Ouyang, Jinbo; Huang, Xin; Hao, Hongxun; Bao, Ying; Fang, Wen; Yin, Qiuxiang

    2016-01-01

    Highlights: • Solubility of DEM Form II in mono-solvents and binary solvent mixtures was measured. • Regressed UNIFAC model was used to predict the solubility in solvent mixtures. • The experimental solubility data were correlated by different models. - Abstract: UV spectrometer method was used to measure the solubility data of dabigatran etexilate mesylate (DEM) Form II in five mono-solvents (methanol, ethanol, ethane-1,2-diol, DMF, DMAC) and binary solvent mixtures of methanol and ethanol in the temperature range from 287.37 K to 323.39 K. The experimental solubility data in mono-solvents were correlated with modified Apelblat equation, van’t Hoff equation and λh equation. GSM model and Modified Jouyban-Acree model were employed to correlate the solubility data in mixed solvent systems. And Regressed UNIFAC model was used to predict the solubility of DEM Form II in the binary solvent mixtures. Results showed that the predicted data were consistent with the experimental data.

  13. Spectrofluorimetric determination of gemifloxacin mesylate and linezolid in pharmaceutical formulations: Application of quinone-based fluorophores and enhanced native fluorescence

    Directory of Open Access Journals (Sweden)

    Moussa Bahia Abbas

    2014-03-01

    Full Text Available Quinone-based fluorophores and enhanced native fluorescence techniques were applied for a fast quantitative analysis of gemifloxacin mesylate (GEM and linezolid (LIN in pharmaceutical formulations. For this purpose, three sensitive, accurate and precise spectrofluorimetric methods were developed. GEM, as an n-electron donor, reacts with 7,7,8,8-tetracyanoquinodimethane (method A and 2,5-dichloro-3,6-dihydroxy-p-benzoquinone (method B as п-electron acceptors, forming charge transfer complexes that exhibit high fluorescence intensity at 441 and 390 nm upon excitation at 260 and 339 nm, respectively. Method C depends on measurement of enhanced native fluorescence of LIN in phosphate buffer (pH 5 at 380 nm upon excitation at 260 nm. Experimental factors affecting fluorescence intensity were optimized. Linearity was obtained over concentration ranges 50-500, 10-60 and 20-400 ng mL-1 for methods A, B and C, respectively. The developed methods were validated and successfully applied for determination of the cited drugs in tablets.

  14. Electroanalytical Determination of Gemifloxacin Mesylate in Bulk, Tablets and Human Urine Using Gold Nanoparticles Modified Carbon Paste Electrode

    Directory of Open Access Journals (Sweden)

    Ali Attia

    2014-12-01

    Full Text Available A simple, precise, inexpensive and sensitive voltammetric method has been developed for the determination of gemifloxacin mesylate (GEM in the presence of tween 80 in the bulk, farmaceutical dosage forms and human urine at gold nanoparticles modified carbon paste electrode (GNCPE. The electrochemical behavior of GEM has been investigated by using cyclic voltammetry (CV and differential pulse voltammetry (DPV techniques. The electrochemical oxidation of GEM was an irreversible process which exhibited adsorption-diffusion controlled process behavior in Britton-Robinson (BR buffer over the entire pH range of values from 2 to 9. The adsorptive stripping response was evaluated as a function of some variables such as pH, type of surfactant, scan rate and accumulation time. The anodic peak current varied linearly over the range from 8.0 × 10-7 to 2.8 × 10-5 M. The limits of detection and quantification were 7.32 × 10-8 M and 2.44 × 10-7 M, respectively. The relative standard deviations and the percentage recoveries were found in the following ranges: 0.58-1.35% and 99.37-101.76%, respectively.

  15. Slow desensitization of imatinib-induced nonimmediate reactions and dynamic changes of drug-specific CD4+CD25+CD134+ lymphocytes.

    Science.gov (United States)

    Klaewsongkram, Jettanong; Thantiworasit, Pattarawat; Sodsai, Pimpayao; Buranapraditkun, Supranee; Mongkolpathumrat, Pungjai

    2016-11-01

    Imatinib is a tyrosine kinase inhibitor indicated for the treatment of gastrointestinal stromal tumors (GISTs) and certain neoplastic diseases; however, nonimmediate adverse reactions are common. To describe the process of imatinib slow desensitization in patients who experienced nonimmediate reactions to imatinib and the dynamic change in drug-specific CD4 + CD25 + CD134 + T-lymphocyte percentages. Five patients diagnosed as having GISTs and with a recent history of imatinib-induced nonimmediate reactions (maculopapular exanthema with eosinophilia, exfoliative dermatitis, palmar-plantar erythrodysesthesia, and drug rash with eosinophilia and systemic symptoms) were desensitized using a slow desensitization protocol. The reintroduced imatinib dosage was stepped up every week starting from 10 mg/d and increasing to 25, 50, 75, 100, 150, 200, and 300 mg/d until the target dose of 400 mg/d was achieved. Prednisolone of up to 30 mg/d was allowed if allergic reactions recurred. The percentages of CD4 + CD25 + CD134 + T cells present after incubating peripheral blood mononuclear cells with imatinib, at baseline and after successful desensitization, were analyzed using flow cytometric analysis. By using a slow desensitization technique, all patients were able to receive 400 mg/d of imatinib, and prednisolone was gradually tapered off. The percentages of imatinib-induced CD4 + CD25 + CD134 + T cells decreased from a mean (SD) of 11.3% (6.5%) and 13.4% (7.3%) at baseline to 3.2% (0.7%) and 3.0% (1.1%) after successful desensitization, when stimulating peripheral blood mononuclear cells with 1 and 2 μM of imatinib, respectively. Slow desensitization is a helpful procedure in treating patients with imatinib-induced nonimmediate reactions other than simple maculopapular exanthema. The reduced percentages of imatinib-induced CD4 + CD25 + CD134 + T cells in these patients may be associated with immune tolerance. Copyright © 2016 American College of Allergy, Asthma & Immunology

  16. Impact of imatinib interruption and duration of prior hydroxyurea on the treatment outcome in patients with chronic myeloid leukemia: Single institution experience

    International Nuclear Information System (INIS)

    Edesa, W.A.; Abdel-malek, R.R.

    2015-01-01

    Background: Optimal response requires that patients should be maintained on the drug continuously. Objectives: To evaluate the influence of imatinib interruption and prior hydroxyurea use on the outcome of patients with chronic myeloid leukemia. Materials and methods: Between January 2010 and November 2013, patients with chronic phase who received imatinib at the Kasr Al-ainy Center of Clinical Oncology were included. Results: Sixty patients were included in this study, thirty three patients (55%) received imatinib upfront, while 27 (45%) received imatinib post hydroxyurea. Imatinib was not given regularly in 50% of patients. In terms of response, only major molecular response and complete molecular response were statistically significant in favor of patients who were receiving imatinib regularly compared to those who had interruption (ρ < 0.001, ρ < 0.001, respectively) , while there was no difference in patients stratified according to prior hydroxyurea. The median progression free survival was 30.3 months (95% CI 24.3–36.3). Among the group of patients who received imatinib regularly, progression free survival was longer (ρ = 0.049), there was no difference between those who received prior hydroxyurea versus those who did not (ρ = 0.67). Conclusion: Duration of prior hydroxyurea had no impact on response or progression free survival, while patients regular on imatinib had statistically significant difference with respect to major molecular response, complete molecular response and progression free survival compared to those who had periods of drug interruption, thus we need more governmental support to supply the drug without interruption to improve the outcome of therapy

  17. Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase After Generic Entry of Imatinib in the United States.

    Science.gov (United States)

    Padula, William V; Larson, Richard A; Dusetzina, Stacie B; Apperley, Jane F; Hehlmann, Rudiger; Baccarani, Michele; Eigendorff, Ekkehard; Guilhot, Joelle; Guilhot, Francois; Hehlmann, Rudiger; Mahon, Francois-Xavier; Martinelli, Giovanni; Mayer, Jiri; Müller, Martin C; Niederwieser, Dietger; Saussele, Susanne; Schiffer, Charles A; Silver, Richard T; Simonsson, Bengt; Conti, Rena M

    2016-07-01

    We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib's price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness ("imatinib-first") would be cost-effective compared with the current standard of care: "physicians' choice" of initiating treatment with any one of the three TKIs. We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician's choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models' clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven's MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study's conduct. Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician's choice ($365 744, 3.97 QALYs). The imatinib-first incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses. When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP. © The Author 2016. Published by Oxford University Press.

  18. Imatinib as the first and only treatment in Europe for adult patients at significant risk of relapse following gastrointestinal stromal tumor removal

    Science.gov (United States)

    Duffaud, F; Salas, S; Huyn, T; Deville, JL

    2010-01-01

    Mutations of the KIT gene are the molecular hallmark of most gastrointestinal stromal tumors (GISTs). GIST has become a model for targeted treatment of solid tumors, imatinib becoming the standard first-line treatment of these tumors in the advanced/metastatic phase. Because of the efficacy of imatinib treatment in the advanced setting, its role following resection of a primary non-metastatic GIST was investigated. The recently published phase III, double-blind, placebo-controlled, multicenter ACOSOG Z9001 study showed that adjuvant therapy is safe, and significantly improves recurrence-free survival compared to placebo when given after resection. To what extent imatinib will improve overall survival has yet to be answered. What is clear is that high-risk GIST patients definitely need adjuvant therapy, and that 1 year of imatinib is not enough for the patients who do need it. The questions of optimal duration of imatinib treatment in the adjuvant setting, adequate selection of risk patients and effect of imatinib on overall survival are currently being studied. PMID:21694845

  19. BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase.

    Science.gov (United States)

    Hughes, T P; Saglio, G; Quintás-Cardama, A; Mauro, M J; Kim, D-W; Lipton, J H; Bradley-Garelik, M B; Ukropec, J; Hochhaus, A

    2015-09-01

    BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use because of higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib (n=259) or imatinib (n=260) in DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML-CP), with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response (cCCyR) and no major molecular response (MMR) within 12 months; fivefold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n=17; imatinib, n=18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate-binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients) and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247.

  20. High-dose Extended-Field Irradiation and High-Dose-Rate Brachytherapy With Concurrent Chemotherapy for Cervical Cancer With Positive Para-Aortic Lymph Nodes

    International Nuclear Information System (INIS)

    Kim, Young Seok; Kim, Jong Hoon; Ahn, Seung Do; Lee, Sang-wook; Shin, Seong Soo; Nam, Joo-Hyun; Kim, Young-Tak; Kim, Yong-Man; Kim, Jong-Hyeok; Choi, Eun Kyung

    2009-01-01

    Purpose: To determine the efficacy and toxicity of extended-field radiotherapy (RT) with concurrent platinum-based chemotherapy in patients with uterine cervical carcinoma and positive para-aortic nodes. Methods and Materials: We retrospectively reviewed the results for 33 women with Stage IB-IVB cervical cancer. Each patient had received 59.4 Gy, including a three-dimensional conformal boost to the para-aortic lymph nodes and 41.4-50.4 Gy of external beam radiotherapy to the pelvis. Each patient also underwent six or seven applications of high-dose-rate brachytherapy (median, 5 Gy to point A at each session). Results: The median follow-up period of surviving patients was 39 months. The most common acute toxicity was hematologic, observed in 23 women. Severe acute and late gastrointestinal toxicity was observed in 3 and 4 patients, respectively. More than three-quarters of patients showed a complete response, encompassing the primary mass, metastatic pelvic, and para-aortic lymph nodes. Of the 33 women, 15 had no evidence of disease, 6 had persistent disease, 4 developed in-field failures, and 6 developed distant failures. The 5-year overall and disease-free survival rate was 47% and 42%, respectively. Conclusion: Concurrent chemoradiotherapy with extended-field radiotherapy is feasible in women with uterine cervical carcinoma and positive para-aortic lymph nodes, with acceptable late morbidity and a high survival rate, although it was accompanied by substantial acute toxicity.

  1. Reduced-intensity allogeneic hematopoietic stem cell transplantation combined with imatinib has comparable event-free survival and overall survival to long-term imatinib treatment in young patients with chronic myeloid leukemia.

    Science.gov (United States)

    Zhao, Yanmin; Wang, Jiasheng; Luo, Yi; Shi, Jimin; Zheng, Weiyan; Tan, Yamin; Cai, Zhen; Huang, He

    2017-08-01

    The relative merits of reduced intensity hematopoietic stem cell transplantation (RIST) for chronic myeloid leukemia (CML) in the first chronic phase (CP) in imatinib era have not been evaluated. The study was designed to compare the outcomes of combination therapy of RIST plus imatinib (RIST + IM) vs. imatinib (IM) alone for young patients with early CP (ECP) and late CP (LCP). Of the patients, 130 were non-randomly assigned to treatment with IM alone (n = 88) or RIST + IM (n = 42). The 10-year overall survival (OS) and event-free survival (EFS) were comparable between RIST + IM and IM groups. LCP, high Sokal score, and no complete cytogenetic response at 3 months were adverse prognostic factors for survival, but only the time from diagnosis to IM was an independent predictor after multivariate analysis. For ECP, IM was similar to RIST + IM, with 10-year EFS rates of 77.2 vs. 81.6% (p = 0.876) and OS rates of 93.8 vs. 87.9% (p = 0.102), respectively. For LCP, both treatments resulted in similar survival, but more patients in the imatinib group experienced events (10-year EFS 40.8 vs. 66.7%, p = 0.047). The patients with higher EBMT risk scores had an inferior survival than those with lower scores (69.2 vs. 92.9%, p = 0.04). We concluded that RIST + IM was comparable to IM in terms of OS and EFS. However, RIST + IM was more affordable than IM alone in a 10-year scale. Thus, RIST + IM could be considered as an alternative treatment option, especially when the patients have low EBMT risk scores and demand a definite cure for CML.

  2. Calibration procedure for thermoluminescent dosemeters in water absorbed doses for Iridium-192 high dose rate sources

    International Nuclear Information System (INIS)

    Reyes Cac, Franky Eduardo

    2004-10-01

    Thermoluminescent dosimeters are used in brachytherapy services quality assurance programs, with the aim of guaranteeing the correct radiation dose supplied to cancer patients, as well as with the purpose of evaluating new clinical procedures. This work describes a methodology for thermoluminescent dosimeters calibration in terms of absorbed dose to water for 192 Ir high dose rate sources. The reference dose used is measured with an ionization chamber previously calibrated for 192 Ir energy quality, applying the methodology proposed by Toelli. This methodology aims to standardizing the procedure, in a similar form to that used for external radiotherapy. The work evolves the adaptation of the TRS-277 Code of the International Atomic Energy Agency, for small and big cavities, through the introduction for non-uniform experimental factor, for the absorbed dose in the neighborhood of small brachytherapy sources. In order to simulate a water medium around the source during the experimental work, an acrylic phantom was used. It guarantees the reproducibility of the ionization chamber and the thermoluminescent dosimeter's location in relation to the radiation source. The values obtained with the ionization chamber and the thermoluminescent dosimeters, exposed to a 192 Ir high dose rate source, were compared and correction factors for different source-detector distances were determined for the thermoluminescent dosimeters. A numeric function was generated relating the correction factors and the source-detector distance. These correction factors are in fact the thermoluminescent dosimeter calibration factors for the 192 Ir source considered. As a possible application of this calibration methodology for thermoluminescent dosimeters, a practical range of source-detector distances is proposed for quality control of 192 Ir high dose rate sources. (author)

  3. Development of radiation fusion technology with food technology by the application of high dose irradiation

    International Nuclear Information System (INIS)

    Lee, Juwoon; Kim, Jaehun; Choi, Jongil

    2012-04-01

    This study was performed to achieve stable food supply and food safety with radiation fusion technology as a preparation for food weaponization. Results at current stage are following: First, for the development of radiation and food engineering fusion technology using high dose irradiation, the effects of high dose irradiation on food components were evaluated. The combination treatment of irradiation with food engineering was developed. Irradiation condition to destroy radiation resistant foodborne bacteria were determined. Second, for the development of E-beam irradiation technology, the effects of radiation sources on food compounds, processing conditions, and food quality of final products were compared. Food processing conditions for agricultural/aquatic products with different radiation sources was developed and the domination of E-beam irradiation foods were determined. The physical marker for E-beam irradiated foods or not was developed. Third, for the fundamental researches to develop purposed foods to extreme environmental, ready-to-eat foods were developed using high dose irradiation. Food processing for export strategy foods such as process ginseng were developed. Food processing with irradiation to destroy mycotoxin and to inhibit production of mycotoxin was developed. Mathematical models to predict necessary irradiation doses and radiation sources were developed and validated. Through the fundamental researches, the legislation for irradiation approval on meat products, sea foods and dried sea foods, and use of E-beam was introduced. Results from this research project, the followings are expected. Improvement of customer acceptance and activation of irradiation technology by the use of various irradiation rays. Increase of indirect food productivity, and decrease of SOC and improvement of public health by prevention of foodborne outbreaks. Build of SPS/TBT system against imported products and acceleration of domestic product export. Systemized

  4. Development of Radiation Fusion Technology with Food Technology by the Application of High Dose Irradiation

    International Nuclear Information System (INIS)

    Kim, Ju Won; Kim, Jae Hun; Choi, Jong Il

    2010-04-01

    This study was studied to achieve stable food supply and food safety with radiation fusion technology as a preparation for food weaponization. Results at current stage are following: First, for the development of radiation and food engineering fusion technology using high dose irradiation, the effects of high dose irradiation on food components were evaluated. The combination treatment of irradiation with food engineering were developed. Irradiation condition to destroy radiation resistant food borne bacteria were determined. Second, for the development of E-beam irradiation technology, the effects of radiation sources on food compounds, processing conditions, and food quality of final products were compared. Food processing conditions for agricultural/aquatic products with different radiation sources were developed and the domination of E-beam irradiation foods were determined. The physical marker for E-beam irradiated foods or not were developed. Third, for the fundamental researches to develop purposed foods to extreme environmental, ready-to-eat foods were developed using high dose irradiation. Food processing for export strategy foods such as process ginseng were developed. Food processing with irradiation to destroy mycotoxin and to inhibit production of mycotoxin were developed. Mathematical models to predict necessary irradiation doses and radiation sources were developed and validated. Through the fundamental researches, the legislation for irradiation approval on meat products, sea foods and dried sea foods, and use of E-beam were introduced. Results from this research project, the followings are expected. (1) Improvement of customer acceptance and activation of irradiation technology by the use of various irradiation rays. (2) Increase of indirect food productivity, and decrease of SOC and improvement of public health by prevention of food borne outbreaks. (3) Build of SPS/TBT system against imported products and acceleration of domestic product export

  5. Does perioperative high-dose prednisolone have clinical benefits for generalized myasthenia gravis?

    Science.gov (United States)

    Sekine, Yasuo; Kawaguchi, Naoki; Hamada, Chikuma; Sekiguchi, Hiromi; Yasufuku, Kazuhiro; Iyoda, Akira; Shibuya, Kiyoshi; Fujisawa, Takehiko

    2006-06-01

    The purpose of this study was to clarify the clinical benefits of perioperative administration of high-dose prednisolone (PSL) combined with extended thymectomy on the long-term outcomes of 116 consecutive patients with generalized myasthenia gravis (MG). A retrospective review was conducted on 116 patients diagnosed with generalized MG who received alternate-day oral administration of high-dose PSL (100 mg/alternate days) and had undergone transsternal extended thymectomy. Incidences of postoperative myasthenic crisis, adverse effects of steroid, long-term outcomes, such as complete stable remission (CSR), pharmacologic remission (PR) or improvement (Imp), and disease recurrence after CSR were evaluated. Six patients (5.2%) experienced post-thymectomy myasthenic crisis. Crude cumulative CSR and PR + CSR rates were 44.8 and 62.7%, respectively. Life table analysis showed that 41.8, 52.8 and 63.4% of the patients were in CSR at 3, 5 and 10 years, respectively. Multivariate analysis revealed that age and pretreatment classification according to the Myasthenia Gravis Foundation of America (MGFA) criteria tended to be independent predictors of CSR. There were 6.9% with compressive vertebral fracture, 13.8% with cataract, and 5.2% with steroid-induced diabetes. Life table analysis revealed that recurrence rates after CSR were 36.8 and 46.0% at 3 and 5 years, respectively. Patients with thymoma had a significantly higher rate of recurrence than those without thymoma (p = 0.001). Alternate-day administration of high-dose prednisolone reduced the risk of post-thymectomy myasthenic crisis. Presence of thymoma was a risk factor for MG recurrence after CSR.

  6. Development of Radiation Fusion Technology with Food Technology by the Application of High Dose Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ju Won; Kim, Jae Hun; Choi, Jong Il

    2010-04-15

    This study was studied to achieve stable food supply and food safety with radiation fusion technology as a preparation for food weaponization. Results at current stage are following: First, for the development of radiation and food engineering fusion technology using high dose irradiation, the effects of high dose irradiation on food components were evaluated. The combination treatment of irradiation with food engineering were developed. Irradiation condition to destroy radiation resistant food borne bacteria were determined. Second, for the development of E-beam irradiation technology, the effects of radiation sources on food compounds, processing conditions, and food quality of final products were compared. Food processing conditions for agricultural/aquatic products with different radiation sources were developed and the domination of E-beam irradiation foods were determined. The physical marker for E-beam irradiated foods or not were developed. Third, for the fundamental researches to develop purposed foods to extreme environmental, ready-to-eat foods were developed using high dose irradiation. Food processing for export strategy foods such as process ginseng were developed. Food processing with irradiation to destroy mycotoxin and to inhibit production of mycotoxin were developed. Mathematical models to predict necessary irradiation doses and radiation sources were developed and validated. Through the fundamental researches, the legislation for irradiation approval on meat products, sea foods and dried sea foods, and use of E-beam were introduced. Results from this research project, the followings are expected. (1) Improvement of customer acceptance and activation of irradiation technology by the use of various irradiation rays. (2) Increase of indirect food productivity, and decrease of SOC and improvement of public health by prevention of food borne outbreaks. (3) Build of SPS/TBT system against imported products and acceleration of domestic product export

  7. Development of radiation fusion technology with food technology by the application of high dose irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Juwoon; Kim, Jaehun; Choi, Jongil; and others

    2012-04-15

    This study was performed to achieve stable food supply and food safety with radiation fusion technology as a preparation for food weaponization. Results at current stage are following: First, for the development of radiation and food engineering fusion technology using high dose irradiation, the effects of high dose irradiation on food components were evaluated. The combination treatment of irradiation with food engineering was developed. Irradiation condition to destroy radiation resistant foodborne bacteria were determined. Second, for the development of E-beam irradiation technology, the effects of radiation sources on food compounds, processing conditions, and food quality of final products were compared. Food processing conditions for agricultural/aquatic products with different radiation sources was developed and the domination of E-beam irradiation foods were determined. The physical marker for E-beam irradiated foods or not was developed. Third, for the fundamental researches to develop purposed foods to extreme environmental, ready-to-eat foods were developed using high dose irradiation. Food processing for export strategy foods such as process ginseng were developed. Food processing with irradiation to destroy mycotoxin and to inhibit production of mycotoxin was developed. Mathematical models to predict necessary irradiation doses and radiation sources were developed and validated. Through the fundamental researches, the legislation for irradiation approval on meat products, sea foods and dried sea foods, and use of E-beam was introduced. Results from this research project, the followings are expected. Improvement of customer acceptance and activation of irradiation technology by the use of various irradiation rays. Increase of indirect food productivity, and decrease of SOC and improvement of public health by prevention of foodborne outbreaks. Build of SPS/TBT system against imported products and acceleration of domestic product export. Systemized

  8. The biochemical changes of bone collagen after high-dose irradiation

    International Nuclear Information System (INIS)

    Tajiri, Ken

    1980-01-01

    In our clinic, patients with malignant bone tumors have been treated by high-dose irradiation therapy, 10,000-20,000 rads, for primary lesions. In order to study the biochemical changes of normal bone around tumor tissue, especially bone collagen, after high-dose irradiation, the author performed the following experiments. The right knee joint of rabbits was irradiated with either 6,000, 10,000, or 15,000 rads by 60 Co-γ ray. The cortical bone of the right tibial metaphysis was used for analyses and compared with the left tibia of the same rabbit. These studies were followed for one year after the final irradiation. The calcium, phosphorous and collagen contents of irradiated bone were remarkably changed. These data indicate that collagen biosynthesis of irradiated bone was decreased and the calcification was disturbed. An increase in the amount of total soluble collagen and a decrease in the amount of hydroxylysine bound sugar were observed. The ratio of β to α chains of the collagen molecule was also changed by the irradiation. The amount of reducible cross-links per hydroxyproline residue was strikingly increased three months after the final irradiation. These changes were remarkable especially in the 10,000 and 15,000 rads irradiated group and found to be recovered approximately six months to one year after the final irradiation. These findings indicate that high-dose irradiation reduces the stability of bone collagen both with the destruction of sugar bonds of hydroxylysine residues and the replacement of matured collagen matrix to immatured one which contain mostly labile reducible cross-links. (author)

  9. Successfully Managing Impending Skin Necrosis following Hyaluronic Acid Filler Injection, using High-Dose Pulsed Hyaluronidase

    Directory of Open Access Journals (Sweden)

    Kwok Thye David Loh, MBBS

    2018-02-01

    Full Text Available Summary:. Facial fillers are becoming increasingly popular as aesthetic procedures to temporarily reduce the depth of wrinkles or to contour faces. However, even in the hands of very experienced injectors, there is always a small possibility of vascular complications like intra-arterial injection of filler substance. We present a case report of a patient who developed features of vascular obstruction in right infraorbital artery and tell-tale signs of impending skin necrosis, after hyaluronic acid filler injection by an experienced injector. The diagnosis of a vascular complication was made quickly with the help of clinical features like blanching, livedo reticularis, and poor capillary refill. Patient was treated promptly with “high-dose pulsed hyaluronidase protocol” comprising three 1,000-unit pulses of hyaluronidase, administered hourly. There was no further increase in size of the involved area after the first dose of hyaluronidase. All of the involved area, along with 1 cm overlapping in uninvolved skin area, was injected during each injection pulse, using a combination of cannula and needle. Complete reperfusion and good capillary filling were achieved after completion of 3 pulses, and these were taken as the end-point of high-dose pulsed hyaluronidase treatment. Immediate skin changes after filler injections, as well as after hyaluronidase injections and during the 3-week recovery period, were documented with photographs and clinical notes. Involved skin was found to have been fully recovered from this vascular episode, thus indicating that complete recovery of the ischemic skin changes secondary to possible intra-arterial injection could be achieved using high-dose pulsed hyaluronidase protocol.

  10. Effects of high dose coffee intake on aerobic power in dragon female athletes

    Directory of Open Access Journals (Sweden)

    Shabani Ramin

    2016-08-01

    Full Text Available Background : There are few studies that consider the effect of high doses of caffeine on aerobic power (VO2max. Also, to date, no study examined the effect of coffee intake on dragon boat paddler specifically on women. The purpose of this study was to investigate the effect of espresso coffee on improvement of aerobic power of dragon boat paddler. Material : Twenty women athletes of Guilan dragon bout team members of Malavan club of port city of Anzali (mean ±SD age, 23.60± 3.49 years; BMI,23.77±1.88kg/m2; body fat, 30.32±4.65% were recruited to this study, after they completed a primary test without consuming any coffee, they consumed 6mg/kg of coffee (espresso or decaffeinated and following that they completed two experimental trials. A randomized, double-blind, repeated-measures, design was employed whereby paddlers complete a 2000m paddling dragon boat ergo-meter. Results : Coffee could improve VO2max (Without coffee =74.40± QUOTE 4.99, Espresso coffee =90.10± QUOTE 6.19, Decaffeinated coffee =91.00± QUOTE 5.67, P≤ QUOTE 0.05. VO2max amount after exercise were significantly higher for both espresso coffee and decaffeinated coffee, when compared with without coffee condition. No significant differences were observed between espresso coffee and decaffeinated coffee (P≤ QUOTE 0.05. Conclusion : The present study shows that both high doses of caffeine (espresso coffee and decaffeinated coffee can enhance VO2max during aerobic exercise including 2000m dragon boat paddling. It seems that some compounds except caffeine in decaffeinated coffee can act improve VO2max. Further studies needed for considering the effect of high doses of coffee on endurance exercises. Also in other age ranges of women athletes and other sport athletes.

  11. Pre-installation empirical testing of room shielding for high dose rate remote afterloaders

    International Nuclear Information System (INIS)

    Klein, E.E.; Grigsby, P.W.; Williamson, J.F.; Meigooni, A.S.

    1993-01-01

    PURPOSE: Many facilities are acquiring high dose rate remote afterloading units. It is economical that these units be placed in existing shielded teletherapy rooms. Scatter-radiation barriers marginally protect uncontrolled areas from a high dose rate source especially in a room that houses a non-dynamic Cobalt-60 unit. In addition the exact thickness and material composition of the barriers are unknown and therefore, a calculation technique may give misleading results. Also, it would be impossible to evaluate an entire wall barrier by taking isolated core samples in order to assist in the calculations. A quick and inexpensive measurement of dose equivalent using a rented high activity 192Ir source evaluates the barriers and locates shielding deficiencies. METHODS AND MATERIALS: We performed transmission calculations for primary and scattered radiation based on National Council on Radiation Protection and Measurements Reports 49 and 51, respectively. We then rented a high activity 21.7 Ci (8.03 x 10(11) Bq) Ir-192 source to assess our existing teletherapy room shielding for adequacy and voids. This source was placed at the proposed location for clinical high dose rate treatment and measurements were performed. RESULTS: No deficiencies were found in controlled areas surrounding the room, but large differences were found between the calculated and measured values. Our survey located a region in the uncontrolled area above the room requiring augmented shielding which was not predicted by the calculations. A canopy shield was designed to potentially augment the shielding in the ceiling direction. CONCLUSION: Pre-installation testing by measurement is an invaluable method for locating shielding deficiencies and avoiding unnecessary enhancement of shielding particularly when there is lack of information of the inherent shielding

  12. Efficacy and Tolerability of High-Dose Escitalopram in Posttraumatic Stress Disorder.

    Science.gov (United States)

    Qi, Wei; Gevonden, Martin; Shalev, Arieh

    2017-02-01

    Open-label trials suggest that escitalopram (up to 20 mg/d) is an effective treatment for some, but not all posttraumatic stress disorder (PTSD) patients. Higher doses of escitalopram effectively reduced major depression symptoms in patients who had not responded to regular doses. The current study examines the efficacy, tolerability, and adherence to high-dose escitalopram in PTSD. Forty-five PTSD patients received 12 weeks of gradually increasing doses of escitalopram reaching 40 mg daily at 4 weeks. Among those, 12 participants received regular doses of antidepressants at study onset including escitalopram (n = 7). The Clinician-Administered PTSD Scale (CAPS) evaluated PTSD symptoms severity before treatment, at 3 months (upon treatment termination), and at 6 months (maintenance effect). A 20% reduction in CAPS scores was deemed clinically significant. Adverse events and medication adherence were monitored at each clinical session. Linear mixed-models analysis showed a significant reduction of mean CAPS scores (11.5 ± 18.1 points) at 3 months and maintenance of gains by 6 months (F2,34.56 = 8.15, P = 0.001). Eleven participants (34.3%) showed clinically significant improvement at 3 months. Only 9 participants (20%) left the study. There were no serious adverse events and few mild ones with only 2 adverse events (diarrhea, 11.1%; drowsiness, 11.1%) reported by more than 10% of participants. High doses of escitalopram are tolerable and well adhered to in PTSD. Their beneficial effect at a group level is due to a particularly good response in a subset of patients.Variability in prior pharmacological treatment precludes a definite attribution of the results to high doses of escitalopram.

  13. High-Dose Citalopram and Escitalopram and the Risk of Out-of-Hospital Death.

    Science.gov (United States)

    Ray, Wayne A; Chung, Cecilia P; Murray, Katherine T; Hall, Kathi; Stein, C Michael

    2017-02-01

    Studies demonstrating that higher doses of citalopram (> 40 mg) and escitalopram (> 20 mg) prolong the corrected QT interval prompted regulatory agency warnings, which are controversial, given the absence of confirmatory clinical outcome studies. We compared the risk of potential arrhythmia-related deaths for high doses of these selective serotonin reuptake inhibitors (SSRIs) to that for equivalent doses of fluoxetine, paroxetine, and sertraline. The Tennessee Medicaid retrospective cohort study included 54,220 persons 30-74 years of age without cancer or other life-threatening illness who were prescribed high-dose SSRIs from 1998 through 2011. The mean age was 47 years, and 76% were female. Demographic characteristics and comorbidity for individual SSRIs were comparable. Because arrhythmia-related deaths are typically sudden and occur outside the hospital, we analyzed out-of-hospital sudden unexpected death as well as sudden cardiac deaths, a more specific indicator of proarrhythmic effects. The adjusted risk of sudden unexpected death for citalopram did not differ significantly from that for the other SSRIs. The respective hazard ratios (HRs) for citalopram versus escitalopram, fluoxetine, paroxetine, and sertraline were 0.84 (95% CI, 0.40-1.75), 1.24 (95% CI, 0.75-2.05), 0.75 (95% CI, 0.45-1.24), and 1.53 (95% CI, 0.91-2.55). There were no significant differences for sudden cardiac death or all study deaths, nor were there significant differences among high-risk patients (≥ 60 years of age, upper quartile baseline cardiovascular risk). Escitalopram users had no significantly increased risk for any study end point. We found no evidence that risk of sudden unexpected death, sudden cardiac death, or total mortality for high-dose citalopram and escitalopram differed significantly from that for comparable doses of fluoxetine, paroxetine, and sertraline. © Copyright 2016 Physicians Postgraduate Press, Inc.

  14. Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer.

    Science.gov (United States)

    Martinez, Alvaro A; Gustafson, Gary; Gonzalez, José; Armour, Elwood; Mitchell, Chris; Edmundson, Gregory; Spencer, William; Stromberg, Jannifer; Huang, Raywin; Vicini, Frank

    2002-06-01

    To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level >or=10.0 ng/mL, Gleason score >or=7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose 93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause-specific survival with higher doses. These results, coupled with the low risk of complications, the advantage of not being radioactive after implantation, and the real-time interactive planning, define a new standard for treatment.

  15. High-dose alcohol intoxication differentially modulates cognitive subprocesses involved in response inhibition.

    Science.gov (United States)

    Stock, Ann-Kathrin; Schulz, Tom; Lenhardt, Martin; Blaszkewicz, Meinolf; Beste, Christian

    2016-01-01

    Aside from well-known physiological effects, high-dose alcohol intoxication (a.k.a. binge drinking) can lead to aversive social and legal consequences because response inhibition is usually compromised under the influence of alcohol. Although the behavioral aspects of this phenomenon were reported on extensively, the underlying neurophysiological mechanisms mediating this disinhibition are unclear. To close this gap, we used both behavioral and neurophysiological measures (event-related potentials, ERPs) to investigate which subprocesses of response inhibition are altered under the influence of high-dose alcohol intoxication. Using a within-subject design, we asked young healthy participants (n = 27) to complete a GO/NOGO task once sober and once intoxicated (approximately 1.2‰). During intoxication, high-dose alcohol effects were highest in a condition where the participants could not rely on automated stimulus-response mapping processes during response inhibition. In this context, the NOGO-P3 (ERP), that likely depends on dopaminergic signaling within mesocorticolimbic pathways and is thought to reflect motor inhibition and/or the evaluation of inhibitory processes, was altered in the intoxicated state. In contrast to this, the N2 component, which largely depends on nigrostriatal dopamine pathways and is thought to reflect inhibition on a pre-motor level, was not altered. Based on these results, we demonstrate that alcohol-induced changes of dopaminergic neurotransmission do not exert a global effect on response inhibition. Instead, changes are highly subprocess-specific and seem to mainly target mesocorticolimbic pathways that contribute to motor inhibition and the evaluation of such. © 2014 Society for the Study of Addiction.

  16. Acute cognitive effects of high doses of dextromethorphan relative to triazolam in humans

    Science.gov (United States)

    Carter, Lawrence P.; Reissig, Chad J.; Johnson, Matthew W.; Klinedinst, Margaret A.; Griffiths, Roland R.

    2012-01-01

    BACKGROUND Although concerns surrounding high-dose dextromethorphan (DXM) abuse have recently increased, few studies have examined the acute cognitive effects of high doses of DXM. The aim of this study was to compare the cognitive effects of DXM with those of triazolam and placebo. METHODS Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg /70 kg), and placebo were administered p.o. to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Effects on cognitive performance were examined at baseline and after drug administration for up to 6 hours. RESULTS Both triazolam and DXM produced acute impairments in attention, working memory, episodic memory, and metacognition. Impairments observed following doses of 100-300 mg/70 kg DXM were generally smaller in magnitude than those observed after 0.5 mg/70 kg triazolam. Doses of DXM that impaired performance to the same extent as triazolam were in excess of 10-30 times the therapeutic dose of DXM. CONCLUSION The magnitude of the doses required for these effects and the absence of effects on some tasks within the 100-300 mg/70 kg dose range of DXM, speak to the relatively broad therapeutic window of over-the-counter DXM preparations when used appropriately. However, the administration of supratherapeutic doses of DXM resulted in acute cognitive impairments on all tasks that were examined. These findings are likely relevant to cases of high-dose DXM abuse. PMID:22989498

  17. High doses of biotin in chronic progressive multiple sclerosis: a pilot study.

    Science.gov (United States)

    Sedel, Frédéric; Papeix, Caroline; Bellanger, Agnès; Touitou, Valérie; Lebrun-Frenay, Christine; Galanaud, Damien; Gout, Olivier; Lyon-Caen, Olivier; Tourbah, Ayman

    2015-03-01

    No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. Uncontrolled, non-blinded proof of concept study 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset. These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  18. Surface applicators for high dose rate brachytherapy in AIDS-related kaposi's sarcoma

    International Nuclear Information System (INIS)

    Evans, Michael D.C.; Yassa, Mariam; Podgorsak, Ervin B.; Roman, Ted N.; Schreiner, L. John; Souhami, Luis

    1997-01-01

    Purpose: The development of commercially available surface applicators using high dose rate remote afterloading devices has enabled radiotherapy centers to treat selected superficial lesions using a remote afterloading brachytherapy unit. The dosimetric parameters of these applicators, the clinical implementation of this technique, and a review of the initial patient treatment regimes are presented. Methods and Materials: A set of six fixed-diameter (1, 2, and 3 cm), tungsten/steel surface applicators is available for use with a single stepping-source (Ir-192, 370 GBq) high dose rate afterloader. The source can be positioned either in a parallel or perpendicular orientation to the treatment plane at the center of a conical aperture that sits at an SSD of approximately 15 mm and is used with a 1-mm thick removable plastic cap. The surface dose rates, percent depth dose, and off-axis ratios were measured. A custom-built, ceiling-mounted immobilization device secures the applicator on the surface of the patient's lesion during treatment. Results: Between November 1994, and September 1996, 16 AIDS-related Kaposi's sarcoma patients having a total of 120 lesions have been treated with palliative intent. Treatment sites were distributed between the head and neck, extremity, and torso. Doses ranged from 8 to 20 Gy, with a median dose of 10 Gy delivered in a single fraction. Treatments were well tolerated with minimal skin reaction, except for patients with lesions treated to 20 Gy who developed moderate/severe desquamation. Conclusion: Radiotherapy centers equipped with a high dose rate remote afterloading unit may treat small selected surface lesions with commercially available surface applicators. These surface applicators must be used with a protective cap to eliminate electron contamination. The optimal surface dose appears to be either 10 or 15 Gy depending upon the height of the lesion

  19. Induction of regulatory T cells by high-dose gp96 suppresses murine liver immune hyperactivation.

    Directory of Open Access Journals (Sweden)

    Xinghui Li

    Full Text Available Immunization with high-dose heat shock protein gp96, an endoplasmic reticulum counterpart of the Hsp90 family, significantly enhances regulatory T cell (Treg frequency and suppressive function. Here, we examined the potential role and mechanism of gp96 in regulating immune-mediated hepatic injury in mice. High-dose gp96 immunization elicited rapid and long-lasting protection of mice against concanavalin A (Con A-and anti-CD137-induced liver injury, as evidenced by decreased alanine aminotransaminase (ALT levels, hepatic necrosis, serum pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6, and number of IFN-γ (+ CD4(+ and IFN-γ (+ CD8(+ T cells in the spleen and liver. In contrast, CD4(+CD25(+Foxp3(+ Treg frequency and suppressive function were both increased, and the protective effect of gp96 could be generated by adoptive transfer of Treg cells from gp96-immunized mice. In vitro co-culture experiments demonstrated that gp96 stimulation enhanced Treg proliferation and suppressive function, and up-regulation of Foxp3, IL-10, and TGF-β1 induced by gp96 was dependent on TLR2- and TLR4-mediated NF-κB activation. Our work shows that activation of Tregs by high-dose gp96 immunization protects against Con A- and anti-CD137-induced T cell-hepatitis and provides therapeutic potential for the development of a gp96-based anti-immune hyperactivation vaccine against immune-mediated liver destruction.

  20. The Effect of High Dose Radioiodine Therapy on Formation of Radiation Retinopathy During Thyroid Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Tülay Kaçar Güvel

    2014-10-01

    Full Text Available Objective: Non-thyroidal complication of high-dose radioiodine therapy for thyroid carcinoma might cause salivary and lacrimal gland dysfunction, which may be transient or permanent in a dose-dependent manner. However, radiation retinopathy complicating 131I therapy, has not been previously well characterized. The aim of this study was to evaluate the extent of retinal damage among patients who had received high doses of radioiodine treatment. Methods: Forty eyes of 20 patients (3 male, 17 female who received 250-1000 mCi during 131I therapy and on ophthalmological follow up for a year after the last treatment were included in the study. Mean age of the study group was 50 years (range 25-70 years. In ophthalmologic examination, visual acuity was measured in order to determine visual loss. Intraocular pressure was measured in all the patients. Then lens examination was carried out with slit lamp biomicroscopy in order to investigate cataract or partial lens opacities. Fundus observation was carried out through the dilated pupil with slit lamp biomicroscopy using 90 D noncontact lens. Result: The best corrected visual aquity with Snellen chart was found as 1.0 in 36 eyes (90% and between 0.6 and 0.9 (10% in 4 eyes (10%. At the biomicroscopic fundus examination, retinal hemorrhage consistent with radiation retinopathy, microaneurysm, microinfarction, edema or exudation, vitreus hemorrhage, partial or total optical disc pallor indicating papillopathy in the optic disc were not observed in any of the eyes. Conclusion: This result indicates that there is not any significant correlation between repeated high-dose radioiodine therapy and radiation retinopathy in differentiated thyroid carcinomas. Even though there is not a significant restriction in use of higher doses of radioiodine therapy in differentiated thyroid carcinoma, more extensive studies are needed in order to obtain more accurate data on possible occurrence of retinopathy.

  1. Verification of the calculation program for brachytherapy planning system of high dose rate (PLATO)

    International Nuclear Information System (INIS)

    Almansa, J.; Alaman, C.; Perez-Alija, J.; Herrero, C.; Real, R. del; Ososrio, J. L.

    2011-01-01

    In our treatments are performed brachytherapy high dose rate since 2007. The procedures performed include gynecological intracavitary treatment and interstitial. The treatments are performed with a source of Ir-192 activity between 5 and 10 Ci such that small variations in treatment times can cause damage to the patient. In addition the Royal Decree 1566/1998 on Quality Criteria in radiotherapy establishes the need to verify the monitor units or treatment time in radiotherapy and brachytherapy. All this justifies the existence of a redundant system for brachytherapy dose calculation that can reveal any abnormality is present.

  2. Advantages of high-dose rate (HDR) brachytherapy in treatment of prostate cancer

    Science.gov (United States)

    Molokov, A. A.; Vanina, E. A.; Tseluyko, S. S.

    2017-09-01

    One of the modern methods of preserving organs radiation treatment is brachytherapy. This article analyzes the results of prostate brachytherapy. These studies of the advantages of high dose brachytherapy lead to the conclusion that this method of radiation treatment for prostate cancer has a favorable advantage in comparison with remote sensing methods, and is competitive, preserving organs in comparison to surgical methods of treatment. The use of the method of polyfocal transperineal biopsy during the brachytherapy session provides information on the volumetric spread of prostate cancer and adjust the dosimetry plan taking into account the obtained data.

  3. Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer

    International Nuclear Information System (INIS)

    Martinez, Alvaro A.; Gustafson, Gary; Gonzalez, Jose; Armour, Elwood; Mitchell, Chris; Edmundson, Gregory; Spencer, William; Stromberg, Jannifer; Huang, Raywin; Vicini, Frank

    2002-01-01

    Purpose: To overcome radioresistance for patients with unfavorable prostate cancer, a prospective trial of pelvic external beam irradiation (EBRT) interdigitated with dose-escalating conformal high-dose-rate (HDR) prostate brachytherapy was performed. Methods and Materials: Between November 1991 and August 2000, 207 patients were treated with 46 Gy pelvic EBRT and increasing HDR brachytherapy boost doses (5.50-11.5 Gy/fraction) during 5 weeks. The eligibility criteria were pretreatment prostate-specific antigen level ≥10.0 ng/mL, Gleason score ≥7, or clinical Stage T2b or higher. Patients were divided into 2 dose levels, low-dose biologically effective dose 93 Gy (149 patients). No patient received hormones. We used the American Society for Therapeutic Radiology and Oncology definition for biochemical failure. Results: The median age was 69 years. The mean follow-up for the group was 4.4 years, and for the low and high-dose levels, it was 7.0 and 3.4 years, respectively. The actuarial 5-year biochemical control rate was 74%, and the overall, cause-specific, and disease-free survival rate was 92%, 98%, and 68%, respectively. The 5-year biochemical control rate for the low-dose group was 52%; the rate for the high-dose group was 87% (p<0.001). Improvement occurred in the cause-specific survival in favor of the brachytherapy high-dose level (p=0.014). On multivariate analysis, a low-dose level, higher Gleason score, and higher nadir value were associated with increased biochemical failure. The Radiation Therapy Oncology Group Grade 3 gastrointestinal/genitourinary complications ranged from 0.5% to 9%. The actuarial 5-year impotency rate was 51%. Conclusion: Pelvic EBRT interdigitated with transrectal ultrasound-guided real-time conformal HDR prostate brachytherapy boost is both a precise dose delivery system and a very effective treatment for unfavorable prostate cancer. We demonstrated an incremental beneficial effect on biochemical control and cause

  4. Effect of high dose irradiation on the red cell span in rabbits

    International Nuclear Information System (INIS)

    Kang, T.W.; Koh, J.W.; Woo, K.S.; Lee, O.H.; Youn, C.S.

    1982-01-01

    As a part of studies on acute effects of high dose irradiation in vivo, the present report was carried out to evaluate the changes of the red cell life span in the white rabbits by a single whole body exposure to gamma rays from 60 Co teletherapy unit. The exposure was done in dose levels of 100, 600 and 900 rads to each experimental group of 10 rabbits. The life span apparent half survival time of red cells, and that the red cell volume in the circulting blood were measured by ICSH Reference method using 51 Cr. (Author)

  5. A double-blind, placebo controlled trial of high-dose lecithin in Alzheimer's disease.

    OpenAIRE

    Little, A; Levy, R; Chuaqui-Kidd, P; Hand, D

    1985-01-01

    The first long-term double-blind placebo controlled trial of high dose lecithin in senile dementia of the Alzheimer type is reported. Fifty one subjects were given 20-25 g/day of purified soya lecithin (containing 90% phosphatidyl plus lysophosphatidyl choline) for six months and followed up for at least a further six months. Plasma choline levels were monitored throughout the treatment period. There were no differences between the placebo group and the lecithin group but there was an improve...

  6. MRI dosimetry using an echo-quotient technique for high dose rate brachytherapy

    International Nuclear Information System (INIS)

    Ansbacher, W.

    1996-01-01

    MRI gel dosimetry is a relatively new technique that has many advantages over conventional methods, and is particularly suited to High Dose Rate (HDR) Brachytherapy. The dosimeter has high spatial resolution and a water-equivalent response over a wide range of photon energies. Because it is an integrating dosimeter, it allows for efficient mapping of the dynamically-produced distributions from an HDR source. As an example of this technique, the dose response, which is calibrated in terms of the change in spin-spin relaxation time, has been used to investigate the anisotropy of an HDR source. (author). 1 fig

  7. Effect of high-dose intravenous vitamin C on inflammation in cancer patients

    Directory of Open Access Journals (Sweden)

    Mikirova Nina

    2012-09-01

    Full Text Available Abstract Background An inflammatory component is present in the microenvironment of most neoplastic tissues. Inflammation and elevated C-reactive protein (CRP are associated with poor prognosis and decreased survival in many types of cancer. Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels. Since in vitro studies demonstrated inhibition of pro-inflammatory pathways by millimolar concentrations of vitamin C, we decided to analyze the effects of high dose IVC therapy in suppression of inflammation in cancer patients. Methods 45 patients with prostate cancer, breast cancer, bladder cancer, pancreatic cancer, lung cancer, thyroid cancer, skin cancer and B-cell lymphoma were treated at the Riordan Clinic by high doses of vitamin C (7.5 g -50 g after standard treatments by conventional methods. CRP and tumor markers were measured in serum or heparin-plasma as a routine analysis. In addition, serum samples were collected before and after the IVCs for the cytokine kit tests. Results According to our data positive response to treatment, which was demonstrated by measurements of C- reactive protein, was found in 75% of patients and progression of the inflammation in 25% of patients. IVC treatments on all aggressive stage cancer patients showed the poor response of treatment. There was correlation between tumor markers (PSA, CEA, CA27.29 and CA15-3 and changes in the levels of C-reactive protein. Our test of the effect of IVC on pro-inflammatory cytokines demonstrated that inflammation cytokines IL-1α, IL-2, IL-8, TNF-α, chemokine eotaxin and CRP were reduced significantly after treatments. Conclusions The high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases

  8. High dose-rate brachytherapy source position quality assurance using radiochromic film

    International Nuclear Information System (INIS)

    Evans, M.D.C.; Devic, S.; Podgorsak, E.B.

    2007-01-01

    Traditionally, radiographic film has been used to verify high-dose-rate brachytherapy source position accuracy by co-registering autoradiographic and diagnostic images of the associated applicator. Filmless PACS-based clinics that do not have access to radiographic film and wet developers may have trouble performing this quality assurance test in a simple and practical manner. We describe an alternative method for quality assurance using radiochromic-type film. In addition to being easy and practical to use, radiochromic film has some advantages in comparison with traditional radiographic film when used for HDR brachytherapy quality assurance

  9. Peripheral arterial disease in a female using high-dose combined oral contraceptive pills.

    Science.gov (United States)

    Pallavee, P; Samal, Sunita; Samal, Rupal

    2013-01-01

    The association between oral contraceptive (OC) pills and vascular diseases is well-known, although, the present generation of pills is considered to be relatively safer in this regard. Hormonal treatment for severe abnormal uterine bleeding is usually considered after ruling out malignancy, when such bleeding is resistant to all other forms of treatment. We report a case of severe peripheral arterial disease in a female, who had been on high-dose OC pills for an extended period of time for severe uterine bleeding.

  10. On the use of multi-dimensional scaling and electromagnetic tracking in high dose rate brachytherapy

    Science.gov (United States)

    Götz, Th I.; Ermer, M.; Salas-González, D.; Kellermeier, M.; Strnad, V.; Bert, Ch; Hensel, B.; Tomé, A. M.; Lang, E. W.

    2017-10-01

    High dose rate brachytherapy affords a frequent reassurance of the precise dwell positions of the radiation source. The current investigation proposes a multi-dimensional scaling transformation of both data sets to estimate dwell positions without any external reference. Furthermore, the related distributions of dwell positions are characterized by uni—or bi—modal heavy—tailed distributions. The latter are well represented by α—stable distributions. The newly proposed data analysis provides dwell position deviations with high accuracy, and, furthermore, offers a convenient visualization of the actual shapes of the catheters which guide the radiation source during the treatment.

  11. A high dose dosimeter based polyvinyl chloride dyed with malachite green

    International Nuclear Information System (INIS)

    Kattan, M.; Daher, Y.; Alkassiri, H.

    2007-01-01

    Polyvinyl chloride film (PVC) dyed with malachite green has been studied for high dose radiation dosimetry using visible spectrophotometry. A linear relationship between the relative absorbance and the absorbed dose at the wavelength 628 nm in the range of 0-125 kGy was found. The effect of dose rate, irradiation temperature, film thickness and dye intensity were found not to influence the response. The effects of shelf-life and the post-irradiation storage in darkness and indirect daylight conditions on dosimetry performance were discussed. (author)

  12. In phantom calibration of a high dose rate remote afterloading device

    International Nuclear Information System (INIS)

    Alfonso, R.; Tolede, P.; Pich, V.

    1995-01-01

    The high dose-rate (HDR) brachytherapy in Cuba is based on soviet made devices type AGAT-V. In order to calibration one of these for clinical use a method based of the different measurement of absorbed dose at the reference point B in a paraffin phantom was developed. The results of the calibration are shown. From these results an analysis was made of the effective doses to prescription point a considering the Lineal-Quadratic model. The clinical results by using the AGAT-V device are displayed in a comparative way

  13. High-dose treatment with autologous stem cell transplantation versus sequential chemotherapy: the GELA experience.

    Science.gov (United States)

    Bosly, A; Haioun, C; Gisselbrecht, C; Reyes, F; Coiffier, B

    2001-07-01

    Autologous stem-cell transplantation (ASCT) has permitted to deliver high-dose therapy (HDT). In aggressive lymphomas, the GELA group conducted prospective and retrospective studies comparing HDT + ASCT to conventional sequential chemotherapy. In relapsing patients and in partial remission, retrospective studies showed a survival advantage for HDT + ASCT over sequential chemotherapy. In complete response, advantage for HDT + ASCT was demonstrated in a prospective trial only for patients with high intermediate or high risk in the IPI score. The attainment of a maximal reduction of the tumoral mass before going HDT is very important either in first line or in relapsing patients.

  14. Total skin high-dose-rate electron therapy dosimetry using TG-51

    International Nuclear Information System (INIS)

    Gossman, Michael S.; Sharma, Subhash C.

    2004-01-01

    An approach to dosimetry for total skin electron therapy (TSET) is discussed using the currently accepted TG-51 high-energy calibration protocol. The methodology incorporates water phantom data for absolute calibration and plastic phantom data for efficient reference dosimetry. The scheme is simplified to include the high-dose-rate mode conversion and provides support for its use, as it becomes more available on newer linear accelerators. Using a 6-field, modified Stanford technique, one may follow the process for accurate determination of absorbed dose

  15. Applichation of the sulphate ceric dosimetric in the high doses range

    International Nuclear Information System (INIS)

    Prieto Miranda, F.

    1991-01-01

    The ceric-cerous dosimetric system is one of the system more employed in the high dose dosimetry. The spectrophotometric procedure to measure the ceric-concentration is an usual analityc method to determine the absorbed dose. On the other hand, due at increase employ of the irradiation process control. In this paper is realized the ceric-cerous dosimetric calibration in the dose range of 0,6 - 5 kGy and the application in the irradiation process control to differents absorbed dose values

  16. Intravenous high-dose immunotherapy: practical recommendations for use in the treatment of neurological disimmune diseases

    Directory of Open Access Journals (Sweden)

    N. A. Suponeva

    2015-01-01

    Full Text Available Current publication summarizes main indications and benefits of intravenous high-dose immunotherapy (IHI in the treatment of various autoimmune diseases of the peripheral nervous system. Available products of intravenous immunoglobulin (IVIG on the Russian market are reviewed. Tactics for choosing optimal medication for IHI based on its effectiveness and safety are analyzed. Dosage calculation and way of administration of IVIG are described, beeing of a high practical value in neurologist’s daily work.

  17. Application of RADPOS in Vivo Dosimetry for QA of High Dose Rate Brachytherapy

    DEFF Research Database (Denmark)

    Cherpak, A.; Kertzscher Schwencke, Gustavo Adolfo Vladimir; Cygler, J.

    2012-01-01

    cancer, where high dose gradients and movement of the prostate gland can present unique in vivo dosimetry challenges. Financial and technical support has been received from Best Medical Canada and Ascension Technology Corporation. © 2012 American Association of Physicists in Medicine......Purpose: The RADPOS in vivo dosimetry system combines an electromagnetic positioning sensor with MOSFET dosimetry, allowing for simultaneous online measurements of dose and spatial position. In this work, we assess the potential use of RADPOS for measurements of motion and dose during prostate HDR...

  18. Radiation shielding and dose rate distribution for the building of the high dose rate accelerator

    International Nuclear Information System (INIS)

    Matsuda, Koji; Takagaki, Torao; Nakase, Yoshiaki; Nakai, Yohta.

    1984-03-01

    A high dose rate electron accelerator was established at Osaka Laboratory for Radiation Chemistry, Takasaki Establishment, JAERI in the fiscal year of 1975. This report shows the fundamental concept for the radiation shielding of the accelerator building and the results of their calculations which were evaluated through the model experiments. After the construction of the building, the leak radiation was measured in order to evaluate the calculating method of radiation shielding. Dose rate distribution of X-rays was also measured in the whole area of the irradiation room as a data base. (author)

  19. Calibration in a manikin of a high dose rate equipment by remote charge

    International Nuclear Information System (INIS)

    Alfonso La Guardia, Rodolfo; Toledo Jimenez, Pablo; Pich Leon, Victor

    1996-01-01

    The aim of this study was to know the immediate results obtained with laparoscopic cholecystectomy in The use of High Dose Rate brachytherapy in Cuba has been limited to AGAT-V Soviet installations. In order to calibrate one of these installations for its clinical use, it was developed a procedure based on the direct measurement of the dose absorbed in referral point B of a paraffin manikin. Results obtained as a result of calibration are shown. According to these results, it was carried out an evaluation of the effective doses administered on prescription point A by using the linear quadratic model

  20. Collection of radiation resistant characteristics reports for instruments and materials in high dose rate environment

    International Nuclear Information System (INIS)

    Kusano, Joichi

    2008-03-01

    This document presents the collected official reports of radiation irradiation study for the candidate materials to be used in high dose rate environment as J-PARC facility. The effect of radiation damage by loss-beam or secondary particle beam of the accelerators influences the performance and the reliability of various instruments. The knowledge on the radiation resistivity of the materials is important to estimate the life of the equipments, the maintenance interval and dose evaluation for the personnel at the maintenance period. The radiation damage consists with mechanical property, electrical property and gas-evolution property. (author)

  1. Metabolic effects of feeding high doses of propanol and propylacetate to lactating Holstein cows

    DEFF Research Database (Denmark)

    Raun, Birgitte Marie Løvendahl; Kristensen, Niels Bastian

    2012-01-01

    Three lactating Holstein cows implanted with ruminal cannulas and permanent indwelling catheters in major splanchnic blood vessels were used to investigate alcohol metabolism and metabolic effects of feeding high doses of propanol and propylacetate. Cows were fed three diets control (basal ration......; C), propanol (C plus 50 g propanol/kg DM; P), and propylacetate (C plus 50 g propanol/kg DM and 15 g propylacetate/kg DM; PPA) in a 3 × 3 Latin square design with 14 d period. Daily rations were fed in three equally sized portions at 8 hour intervals and 8 hourly sets of ruminal fluid, arterial...

  2. High dose stainless steel swelling data on interior and peripheral oxide fuel pins

    International Nuclear Information System (INIS)

    Boltax, A.; Foster, J.P.; Nayak, U.P.

    1983-01-01

    High dose (2 x 10 23 n/cm 2 , E > 0.1 Mev) swelling data obtained on 20% cold-worked AISI 316 stainless steel (N-lot) cladding from mixed-oxide fuel pins show large differences in swelling incubation dose due to pre-incubation dose temperature changes. Circumferential swelling variations of 1.5 to 4 times were found in peripheral fuel pin cladding which experienced 30 to 60 deg C temperature changes due to movement in a temperature gradient. Consideration is given to the implications of these results to low swelling materials development and core design. (author)

  3. Epithelial regeneration of transposed intestine after high doses of X-irradiation

    International Nuclear Information System (INIS)

    Both, N.J. de; Vermey, M.

    1976-01-01

    The regeneration capacities of normal and transposed small bowel epithelium were compared in rats after applying high doses of X-irradiation. It has been shown that the potency of the mucosa to regenerate was much higher than assumed and that the mucosa could regenerate after single doses varying from 2000 to 5000 R. Even in the villus epithelium and in flat epithelium covering infiltrates of the lamina propria cells survived, which were still able to resume proliferative activity several days after irradiation. (author)

  4. High-dose radiation-induced meningioma following prophylactic cranial irradiation for acute lymphoblastic leukaemia

    International Nuclear Information System (INIS)

    Matsuda, Ryosuke; Nikaido, Yuji; Yamada, Tomonori; Mishima, Hideaki; Tamaki, Ryo

    2005-01-01

    A 12 year-old girl was treated with prophylactic cranial irradiation for acute lymphoblastic leukaemia (ALL). At the age of 39, she was admitted to our hospital for status epilepticus. Computed tomography demonstrated two, enhancing bilateral sided intracranial tumors. After surgery, this patient presented meningiomas which histologically, were of the meningothelial type. The high cure rate in childhood ALL, attributable to aggressive chemotherapy and prophylactic cranial irradiation, is capable of inducing secondary brain tumor. Twelve cases of high-dose radiation-induced meningioma following ALL are also reviewed. (author)

  5. High-dose radiation-induced meningioma following prophylactic cranial irradiation for acute lymphoblastic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, Ryosuke; Nikaido, Yuji; Yamada, Tomonori; Mishima, Hideaki; Tamaki, Ryo [National Hospital Organization Osaka Minami Medical Center, Kawachinagano (Japan)

    2005-03-01

    A 12 year-old girl was treated with prophylactic cranial irradiation for acute lymphoblastic leukaemia (ALL). At the age of 39, she was admitted to our hospital for status epilepticus. Computed tomography demonstrated two, enhancing bilateral sided intracranial tumors. After surgery, this patient presented meningiomas which histologically, were of the meningothelial type. The high cure rate in childhood ALL, attributable to aggressive chemotherapy and prophylactic cranial irradiation, is capable of inducing secondary brain tumor. Twelve cases of high-dose radiation-induced meningioma following ALL are also reviewed. (author)

  6. Expression of c-kit receptor in human cholangiocarcinoma and in vivo treatment with imatinib mesilate in chimeric mice

    Science.gov (United States)

    Kamenz, Thomas; Caca, Karel; Blüthner, Thilo; Tannapfel, Andrea; Mössner, Joachim; Wiedmann, Marcus

    2006-01-01

    AIM: To investigate the c-kit expression in biliary tract cancer cell lines and histological sections from patients with extrahepatic cholangiocarcinoma (CC) and to evaluate the efficacy of in vitro and in vitro treatment with imatinib mesilate. METHODS: The protein expression of c-kit in the human biliary tract cancer cell lines Mz-ChA-2 and EGI-1 and histological sections from 19 patients with extrahepatic CC was assessed by immunoblotting, immunocytochemistry, and immunohistochemistry. The anti-proliferative effect of imatinib mesilate on biliary tract cancer cell lines Mz-ChA-2 and EGI-1 was studied in vitro by automated cell counting. In addition, immunodeficient NMRI mice (TaconicTM) were subcutaneously injected with 5 x 106 cells of cell lines MzChA-2 and EGI-1. After having reached a tumour volume of 200 mm3, daily treatment was started intraperitoneally with imatinib mesilate at a dose of 50 mg/kg or normal saline (NS). Tumor volume was calculated with a Vernier caliper. After 14 d, mice were sacrificed with tumors excised and tumor mass determined. RESULTS: Immunoblotting revealed presence of c-kit in Mz-ChA-2 and absence in EGI-1 cells. Immunocytochemistry with c-kit antibodies displayed a cytoplasmatic and membraneous localization of receptor protein in Mz-ChA-2 cells and absence of c-kit in EGI-1 cells. c-kit was expressed in 7 of 19 (37%) extrahepatic human CC tissue samples, 2 showed a moderate and 5 a rather weak immunostaining. Imatinib mesilate at a low concentration of 5 µmol/L caused a significant growth inhibition in the c-kit positive cell line Mz-ChA-2 (31%), but not in the c-kit negative cell line EGI-1 (0%) (P < 0.05). Imatinib mesilate at an intermediate concentration of 10 µmol/L inhibited cellular growth of both cell lines (51% vs 57%). Imatinib mesilate at a higher concentration of 20 µmol/L seemed to have a general toxic effect on both cell lines. The IC50 values were 9.7 µmol/L and 11 µmol/L, respectively. After 14 d of in vitro

  7. Preparation of 14C-labeled 8,9-didehydro-6,8-dimethyl-2-methylthioergoline mesylate, a dopamine antagonist potentially useful in the treatment of schizophrenia

    International Nuclear Information System (INIS)

    Wheeler, W.J.

    1988-01-01

    We have prepared 14 C-labeled 8,9-didehydro-6,8-dimethyl-2-methyl-thioergoline mesylate (LY 170542), a dopamine antagonist potentially useful as an anti-psychotic. The 14 C-label was introduced via a novel application of the Wittig reaction on 1-(4'-toluene-sulfonyl)-8,9-didehydro-6-methyl-ergolin-8-one and subsequent reduction of 1-(4'-toluenesulfonyl)-17-[ 14 C]-lysergene by lithium/ammonia at -33 0 C. The 17-[ 14 C]-agroclavine thus prepared was converted into 17-[ 14 C]-LY 170542 by reaction with methanesulfenyl chloride/methanesulfonic acid. (author)

  8. Characterization and response of newly developed high-grade glioma cultures to the tyrosine kinase inhibitors, erlotinib, gefitinib and imatinib

    International Nuclear Information System (INIS)

    Kinsella, Paula; Howley, Rachel; Doolan, Padraig; Clarke, Colin; Madden, Stephen F.; Clynes, Martin; Farrell, Michael; Amberger-Murphy, Verena

    2012-01-01

    High-grade gliomas (HGG), are the most common aggressive brain tumours in adults. Inhibitors targeting growth factor signalling pathways in glioma have shown a low clinical response rate. To accurately evaluate response to targeted therapies further in vitro studies are necessary. Growth factor pathway expression using epidermal growth factor receptor (EGFR), mutant EGFR (EGFRvIII), platelet derived growth factor receptor (PDGFR), C-Kit and C-Abl together with phosphatase and tensin homolog (PTEN) expression and downstream activation of AKT and phosphorylated ribosomal protein S6 (P70S6K) was analysed in 26 primary glioma cultures treated with the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and imatinib. Response to TKIs was assessed using 50% inhibitory concentrations (IC 50 ). Response for each culture was compared with the EGFR/PDGFR immunocytochemical pathway profile using hierarchical cluster analysis (HCA) and principal component analysis (PCA). Erlotinib response was not strongly associated with high expression of the growth factor pathway components. PTEN expression did not correlate with response to any of the three TKIs. Increased EGFR expression was associated with gefitinib response; increased PDGFR-α expression was associated with imatinib response. The results of this in vitro study suggest gefitinib and imatinib may have therapeutic potential in HGG tumours with a corresponding growth factor receptor expression profile. -- Highlights: ► Non-responders had low EGFR expression, high PDGFR-β, and a low proliferation rate. ► PTEN is not indicative of response to a TKI. ► Erlotinib response was not associated with expression of the proteins examined. ► Imatinib-response correlated with expression of PDGFR-α. ► Gefitinib response correlated with increased expression of EGFR.

  9. Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis.

    Science.gov (United States)

    Shaker, Mohamed E; Zalata, Khaled R; Mehal, Wajahat Z; Shiha, Gamal E; Ibrahim, Tarek M

    2011-04-15

    Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl(4)) rat model. Male Wistar rats received intraperitoneal injections of CCl(4) twice weekly for 8weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20mg/kg), nilotinib (10 and 20mg/kg) and silymarin (100mg/kg) during the last 4weeks of CCl(4)-intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stress parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4-hydroxyproline contents. Nilotinib (20mg/kg) was the most effective treatment to counteract CCl(4)-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10mg/kg), nilotinib (20mg/kg) and silymarin (100mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl(4)-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl(4)-induced fibrosis was ameliorated significantly by nilotinib (20mg/kg) and imatinib (20mg/kg). Unlike nilotinib, imatinib (20mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylin-eosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Subcellular distribution of [3H]-dexamethasone mesylate binding sites in Leydig cells using electron microscope radioautography

    International Nuclear Information System (INIS)

    Stalker, A.; Hermo, L.; Antakly, T.

    1991-01-01

    The present view is that glucocorticoid hormones bind to their cytoplasmic receptors before reaching their nuclear target sites, which include specific DNA sequences. Although it is believed that cytoplasmic sequestration of steroid receptors and other transcription factors (such as NFKB) may regulate the overall activity of these factors, there is little information on the exact subcellular sites of steroid receptors or even of any other transcription factors. Tritiated (3H)-dexamethasone 21-mesylate (DM) is an affinity label that binds covalently to the glucocorticoid receptor (GR), thereby allowing morphological localization of the receptor at the light and electron microscope levels as well as for quantitative radioautographic (RAG) analysis. After injection of 3H-DM into the testis, a specific radioautographic signal was observed in Leydig cells, which correlated with a high level of immunocytochemically demonstrable GR in these cells at the light-microscope level. To localize the 3H-DM binding sites at the electron microscope (EM) level, the testes of 5 experimental and 3 control adrenalectomized rats were injected directly with 20 microCi 3H-DM; control rats received simultaneously a 25-fold excess of unlabeled dexamethasone; 15 min later, rats were fixed with glutaraldehyde and the tissue was processed for EM RAG analysis combined with quantitative morphometry. The radioautographs showed that the cytosol, nucleus, smooth endoplasmic reticulum (sER), and mitochondria were labeled. Since the cytosol was always adjacent to tubules of the sER, the term sER-rich cytosol was used to represent label over sER networks, which may also represent cytosol labeling due to the limited resolution of the radioautographic technique. Labeling was highest in sER-rich cytosol and mitochondria, at 53% and 31% of the total, respectively

  11. Characterization and response of newly developed high-grade glioma cultures to the tyrosine kinase inhibitors, erlotinib, gefitinib and imatinib.

    LENUS (Irish Health Repository)

    Kinsella, Paula

    2012-03-10

    High-grade gliomas (HGG), are the most common aggressive brain tumours in adults. Inhibitors targeting growth factor signalling pathways in glioma have shown a low clinical response rate. To accurately evaluate response to targeted therapies further in vitro studies are necessary. Growth factor pathway expression using epidermal growth factor receptor (EGFR), mutant EGFR (EGFRvIII), platelet derived growth factor receptor (PDGFR), C-Kit and C-Abl together with phosphatase and tensin homolog (PTEN) expression and downstream activation of AKT and phosphorylated ribosomal protein S6 (P70S6K) was analysed in 26 primary glioma cultures treated with the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and imatinib. Response to TKIs was assessed using 50% inhibitory concentrations (IC(50)). Response for each culture was compared with the EGFR\\/PDGFR immunocytochemical pathway profile using hierarchical cluster analysis (HCA) and principal component analysis (PCA). Erlotinib response was not strongly associated with high expression of the growth factor pathway components. PTEN expression did not correlate with response to any of the three TKIs. Increased EGFR expression was associated with gefitinib response; increased PDGFR-α expression was associated with imatinib response. The results of this in vitro study suggest gefitinib and imatinib may have therapeutic potential in HGG tumours with a corresponding growth factor receptor expression profile.

  12. 'Real-life' study of imatinib therapy in chronic phase-chronic myeloid leukemia: A novel retrospective observational longitudinal analysis.

    Science.gov (United States)

    Merante, Serena; Ferretti, Virginia; Elena, Chiara; Calvello, Celeste; Rocca, Barbara; Zappatore, Rita; Cavigliano, Paola; Orlandi, Ester

    2017-01-01

    Imatinib is a cornerstone of treatment of chronic myeloid leukemia. It remains unclear whether transient treatment discontinuation or dose changes affect outcome and this approach has not yet been approved for use outside clinical trials. We conducted a retrospective single-institution observational study to evaluate factors affecting response in 'real-life' clinical practice in 138 chronic myeloid leukemia patients in chronic phase treated with imatinib. We used a novel longitudinal data analytical model, with a generalized estimating equation model, to study BCR-ABL variation according to continuous standard dose, change in dose or discontinuation; BCR-ABL transcript levels were recorded. Treatment history was subdivided into time periods for which treatment was given at constant dosage (total 483 time periods). Molecular and cytogenetic complete response was observed after 154 (32%) and 358 (74%) time periods, respectively. After adjusting for length of time period, no association between dose and cytogenetic complete response rate was observed. There was a significantly lower molecular complete response rate after time periods at a high imatinib dosage. This statistical approach can identify individual patient variation in longitudinal data collected over time and suggests that changes in dose or discontinuation of therapy could be considered in patients with appropriate biological characteristics.

  13. Fluid retention associated with imatinib treatment in patients with gastroenterol stromal: Quantitative radiologic assessment and implications for management

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung Won; Shinagare, Atul B.; Krajewski, Katherine M.; Tirumani, Sree Harsha; Jagannathan, Jyothi P.; Ramaiya, Nikihil H. [Dept. of Imaging, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Harvard Medical School, Boston (United States); Pyo, Jun Hee [The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston (United States)

    2015-04-15

    We aimed to describe radiologic signs and time-course of imatinib-associated fluid retention (FR) in patients with gastrointestinal stromal tumor (GIST), and its implications for management. In this Institutional Review Board-approved, retrospective study of 403 patients with GIST treated with imatinib, 15 patients with imaging findings of FR were identified by screening radiology reports, followed by manual confirmation. Subcutaneous edema, ascites, pleural effusion, and pericardial effusion were graded on a four-point scale on CT scans; total score was the sum of these four scores. The most common radiologic sign of FR was subcutaneous edema (15/15, 100%), followed by ascites (12/15, 80%), pleural effusion (11/15, 73%), and pericardial effusion (6/15, 40%) at the time of maximum FR. Two distinct types of FR were observed: 1) acute/progressive FR, characterized by acute aggravation of FR and rapid improvement after management, 2) intermittent/steady FR, characterized by occasional or persistent mild FR. Acute/progressive FR always occurred early after drug initiation/dose escalation (median 1.9 month, range 0.3-4.0 months), while intermittent/steady FR occurred at any time. Compared to intermittent/steady FR, acute/progressive FR was severe (median score, 5 vs. 2.5, p = 0.002), and often required drug-cessation/dose-reduction. Two distinct types (acute/progressive and intermittent/steady FR) of imatinib-associated FR are observed and each type requires different management.

  14. Techniques for high dose dosimetry in industry, agriculture and medicine. Proceedings of a symposium

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1999-03-01

    In radiation processing, it is important that the irradiated products are reliable and safe. For processes that impact directly on public health, dosimetry provides a formal means of regulation. For other applications, measurements are indispensable for process control to improve quality and the measurements have to be standardized. Thus, dosimetry is an essential part of quality standards for radiation processes. In the developing world, establishment of such quality standards is only in the embryonic stage, and the IAEA should and does play a role in the development and implementation of these standards. The IAEA initiated a programme of high dose dosimetry in 1977 to accomplish dose standardization on an industrial scale, to promote dosimetry as a quality control measure in radiation processing, and to help develop new dosimetry techniques. Since dosimetry has such a key role in these processes, the IAEA organized this international symposium to provide a forum for presentation and discussion of up-to-date developments in this field. Since the International Symposium on High Dose Dosimetry for Radiation Processing held in 1990 the field of dosimetry has deepened and broadened. There is a definite shift towards quality assurance, which calls for dependable dosimetry systems with well established traceability to national or international standards. Also, many new applications of radiation have been developed and for these new and innovative dosimetry methods are needed. This symposium has provided a forum for the discussion of many of these developments and consideration of the outstanding issues in these vital areas Refs, figs, tabs

  15. Techniques for high dose dosimetry in industry, agriculture and medicine. Proceedings of a symposium

    International Nuclear Information System (INIS)

    1999-03-01

    In radiation processing, it is important that the irradiated products are reliable and safe. For processes that impact directly on public health, dosimetry provides a formal means of regulation. For other applications, measurements are indispensable for process control to improve quality and the measurements have to be standardized. Thus, dosimetry is an essential part of quality standards for radiation processes. In the developing world, establishment of such quality standards is only in the embryonic stage, and the IAEA should and does play a role in the development and implementation of these standards. The IAEA initiated a programme of high dose dosimetry in 1977 to accomplish dose standardization on an industrial scale, to promote dosimetry as a quality control measure in radiation processing, and to help develop new dosimetry techniques. Since dosimetry has such a key role in these processes, the IAEA organized this international symposium to provide a forum for presentation and discussion of up-to-date developments in this field. Since the International Symposium on High Dose Dosimetry for Radiation Processing held in 1990 the field of dosimetry has deepened and broadened. There is a definite shift towards quality assurance, which calls for dependable dosimetry systems with well established traceability to national or international standards. Also, many new applications of radiation have been developed and for these new and innovative dosimetry methods are needed. This symposium has provided a forum for the discussion of many of these developments and consideration of the outstanding issues in these vital areas

  16. High-dose proton beam therapy for sinonasal mucosal malignant melanoma

    International Nuclear Information System (INIS)

    Fuji, Hiroshi; Yoshikawa, Shusuke; Kasami, Masako; Murayama, Shigeyuki; Onitsuka, Tetsuro; Kashiwagi, Hiroya; Kiyohara, Yoshio

    2014-01-01

    The significance of definitive radiotherapy for sinonasal mucosal melanoma (SMM) is sill controvertial. This study was to evaluate the role of high-dose proton beam therapy (PBT) in patients with SMM. The cases of 20 patients with SMM localized to the primary site who were treated by PBT between 2006 and 2012 were retrospectively analyzed. The patterns of overall survival and morbidity were assessed. The median follow-up time was 35 months (range, 6–77 months). The 5-year overall and disease-free survival rates were 51% and 38%, respectively. Four patients showed local failure, 2 showed regrowth of the primary tumor, and 2 showed new sinonasal tumors beyond the primary site. The 5-year local control rate after PBT was 62%. Nodal and distant failure was seen in 7 patients. Three grade 4 late toxicities were observed in tumor-involved optic nerve. Our findings suggested that high-dose PBT is an effective local treatment that is less invasive than surgery but with comparable outcomes

  17. The use of caffeine to assess high dose exposures to ionising radiation by dicentric analysis

    International Nuclear Information System (INIS)

    Pujol, M.; Puig, R.; Caballin, M. R.; Barrios, L.; Barquinero, J. F.

    2012-01-01

    Dicentric analysis is considered as a 'gold standard' method for biological dosimetry. However, due to the radiation-induced mitotic delay or inability to reach mitosis of heavily damaged cells, the analysis of dicentrics is restricted to doses up to 4-5 Gy. For higher doses, the analysis by premature chromosome condensation technique has been proposed. Here, it is presented a preliminary study is presented in which an alternative method to analyse dicentrics after high dose exposures to ionising radiation (IR) is evaluated. The method is based on the effect of caffeine in preventing the G2/M checkpoint allowing damaged cells to reach mitosis. The results obtained indicate that the co-treatment with Colcemide and caffeine increases significantly increases the mitotic index, and hence allows a more feasible analysis of dicentrics. Moreover in the dose range analysed, from 0 to 15 Gy, the dicentric cell distribution followed the Poisson distribution, and a simulated partial-body exposure has been clearly detected. Overall, the results presented here suggest that caffeine has a great potential to be used for dose-assessment after high dose exposure to IR. (authors)

  18. High-dose steroid therapy for idiopathic optic perineuritis: a case series

    Directory of Open Access Journals (Sweden)

    Mimura Tatsuya

    2010-12-01

    Full Text Available Abstract Introduction It has been reported that the prognosis of optic perineuritis may be poor when initiation of treatment is delayed. Here we report the successful treatment of three patients with idiopathic optic perineuritis, including two in whom initiation of therapy was delayed. Case presentation Three Japanese patients (two women aged 73 and 66 years, and one man aged 27 years presented with loss of vision (for five months, several months, and two months respectively and pain on eye movement in the third case only, and were diagnosed as having idiopathic optic perineuritis. Fat-suppressed T2-weighted magnetic resonance images showed high signal intensity areas around the affected optic nerves, suggesting the presence of optic perineuritis. Two patients received steroid pulse therapy and the third was given high-dose steroid therapy. The visual acuity improved in all three cases. Conclusion High-dose steroid therapy may be effective for idiopathic perineuritis in patients without optic nerve atrophy, even if initial treatment (including moderate-dose steroids has failed.

  19. Effects of high dose rate gamma radiation on survival and reproduction of Biomphalaria glabrata

    International Nuclear Information System (INIS)

    Cantinha, Rebeca S.; Nakano, Eliana; Silva, Luanna R.S.

    2009-01-01

    Ionizing radiations are known as mutagenic agents, causing lethality and infertility. This characteristic has motivated its application on animal biological control. In this context, the freshwater snail Biomphalaria glabrata can be considered an excellent experimental model to study effects of ionizing radiations on lethality and reproduction. This work was designed to evaluate effects of 60 Co gamma radiation at high dose rate (10.04 kGy/h) on B. glabrata. For this purpose, adult snails were selected and exposed to doses ranging from 20 to 100 Gy, with 10 Gy intervals; one group was kept as control. There was not effect of dose rate in the lethality of gamma radiation; the value of 64,3 Gy of LD 50 obtained in our study was similar to that obtained by other authors with low dose rates. Nevertheless, our data suggest that there was a dose rate effect in the reproduction. On all dose levels, radiation improved the production of embryos for all exposed individuals. However, viability indexes were below 6% and, even 65 days after irradiation, fertility was not recovered. These results are not in agreement with other studies using low dose rates. Lethality was obtained in all groups irradiated, and the highest doses presented percentiles of dead animals above 50%. The results demonstrated that doses of 20 and 30 Gy were ideal for population control of B. glabrata. Further studies are needed; nevertheless, this research evidenced great potential of high dose rate gamma radiation on B. glabrata reproductive control. (author)

  20. Early and late effects of local high dose radiotherapy of the brain on memory and attention

    International Nuclear Information System (INIS)

    Duchstein, S.; Gademann, G.; Peters, B.

    2003-01-01

    Early and Late Effects of Local High Dose Radiotherapy of the Brain on Memory and Attention Background: Stereotactic radiotherapy of benign tumors of the base of skull shows excellent tumor control and long survival. Aim is to study the impact of high dose radiation therapy on functions of memory and attention over time. Patients and Methods: 21 patients (age 42 ± 11 years) with tumors of the base of skull (meningiomas, pituitary gland adenomas) were treated by fractionated stereotactic radiotherapy (mean total dose 56,6 Gy/1,8 Gy). Comprehensive neuropsychological tests and MRI brain scans were performed before, 3, 9 and 21 months after therapy. 14 healthy volunteers were tested in parallel at baseline. In the follow-ups patients were their own controls. Results: In pretreatment tests there were significantly worse test results in comparison to the control group in ten of 32 tests. In postradiation tests only few changes were found in the early-delayed period and not much difference was seen in comparison to the baseline tests. In MRI scans tumor recurrences or radiation induced changes were not found. Conclusion: Radiation with high local doses in target volume extremely close to sensitive brain structures like temporal lobes did not induce significant decline of cognitive functions. (orig.) [de

  1. Mechanical Performance of Ferritic Martensitic Steels for High Dose Applications in Advanced Nuclear Reactors

    Science.gov (United States)

    Anderoglu, Osman; Byun, Thak Sang; Toloczko, Mychailo; Maloy, Stuart A.

    2013-01-01

    Ferritic/martensitic (F/M) steels are considered for core applications and pressure vessels in Generation IV reactors as well as first walls and blankets for fusion reactors. There are significant scientific data on testing and industrial experience in making this class of alloys worldwide. This experience makes F/M steels an attractive candidate. In this article, tensile behavior, fracture toughness and impact property, and creep behavior of the F/M steels under neutron irradiations to high doses with a focus on high Cr content (8 to 12) are reviewed. Tensile properties are very sensitive to irradiation temperature. Increase in yield and tensile strength (hardening) is accompanied with a loss of ductility and starts at very low doses under irradiation. The degradation of mechanical properties is most pronounced at martensitic steels exhibit a high fracture toughness after irradiation at all temperatures even below 673 K (400 °C), except when tested at room temperature after irradiations below 673 K (400 °C), which shows a significant reduction in fracture toughness. Creep studies showed that for the range of expected stresses in a reactor environment, the stress exponent is expected to be approximately one and the steady state creep rate in the absence of swelling is usually better than austenitic stainless steels both in terms of the creep rate and the temperature sensitivity of creep. In short, F/M steels show excellent promise for high dose applications in nuclear reactors.

  2. On-Line High Dose-rate Gamma Irradiation Test of the Profibus/DP module

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Jai Wan; Choi, Young Soo; Kim, Chang Hoi; Koo, In Soo; Hong, Seok Boong [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2009-05-15

    The field bus data communication is considered for application in nuclear environments. The nuclear facilities, including nuclear power plants, high radioactivity waste disposals, reprocessing plants and thermonuclear fusion installations can benefit from the unique advantages of the field bus communication network for the smart field instruments and controls. A major problem which arises when dealing with one in these nuclear environments, in special circumstances such as the RCS (reactor coolant system) area, is the presence of high gamma-ray irradiation fields. Radioactive constraints for the DBA(design basis accident) qualification of the RTD transmitter installed in the inside of the RCS pump are typically on the order of 4kGy/h with total doses up to 10kGy. In order to use an industrial field bus communication network as an ad-hoc sensor data link in the vicinity of the RCS area of the nuclear power plant, the robust survivability of these system in such intense gamma-radiation fields therefore needs to be verified. We have conducted high dose-rate (up to 4kGy) gamma irradiation experiments on a profibus/DP communication module. In this paper we describe the evolution of its basic characteristics with high dose-rate gamma irradiation and shortly explain the observed phenomena.

  3. Methamphetamine treatment during development attenuates the dopaminergic deficits caused by subsequent high-dose methamphetamine administration.

    Science.gov (United States)

    McFadden, Lisa M; Hoonakker, Amanda J; Vieira-Brock, Paula L; Stout, Kristen A; Sawada, Nicole M; Ellis, Jonathan D; Allen, Scott C; Walters, Elliot T; Nielsen, Shannon M; Gibb, James W; Alburges, Mario E; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

    2011-08-01

    Administration of high doses of methamphetamine (METH) causes persistent dopaminergic deficits in both nonhuman preclinical models and METH-dependent persons. Noteworthy, adolescent [i.e., postnatal day (PND) 40] rats are less susceptible to this damage than young adult (PND90) rats. In addition, biweekly treatment with METH, beginning at PND40 and continuing throughout development, prevents the persistent dopaminergic deficits caused by a "challenge" high-dose METH regimen when administered at PND90. Mechanisms underlying this "resistance" were thus investigated. Results revealed that biweekly METH treatment throughout development attenuated both the acute and persistent deficits in VMAT2 function, as well as the acute hyperthermia, caused by a challenge METH treatment. Pharmacokinetic alterations did not appear to contribute to the protection afforded by the biweekly treatment. Maintenance of METH-induced hyperthermia abolished the protection against both the acute and persistent VMAT2-associated deficits suggesting that alterations in thermoregulation were caused by exposure of rats to METH during development. These findings suggest METH during development prevents METH-induced hyperthermia and the consequent METH-related neurotoxicity. Copyright © 2011 Wiley-Liss, Inc.

  4. Quality of life in a cohort of high-dose benzodiazepine dependent patients.

    Science.gov (United States)

    Lugoboni, Fabio; Mirijello, Antonio; Faccini, Marco; Casari, Rebecca; Cossari, Anthony; Musi, Gessica; Bissoli, Giorgia; Quaglio, Gianluca; Addolorato, Giovanni

    2014-09-01

    Benzodiazepines (BZD) are among the most widely prescribed drugs in developed countries. Since BZD can produce tolerance and dependence even in a short time, their use is recommended for a very limited time. However, these recommendations have been largely disregarded. The chronic use of BZD causes a number of serious side effects, i.e., cognitive impairment, falls, traffic accidents, dependence and tolerance. The aim of the present study was to evaluate quality of life (QoL) in a cohort of 62 consecutive high-dose BZD-dependent patients seeking a BZD detoxification. Patients seeking BZD detoxification were evaluated using the General Health Questionnaire (GHQ-12) and the short form-36 questionnaire (SF-36). Patients showed a significant reduction of QoL as measured by either SF-36 or GHQ-12. In particular, the greater impairment was observed in the items exploring physical and emotional status. Physical functioning was the item more influenced by the length of BZD abuse. Female patients showed a greater reduction of QoL compared to male, at least in some of the explored items. Social functioning scores were greatly reduced. The present study shows for the first time that high-doses BZD dependent patients have a reduced QoL and a reduced social functioning, along with high levels of psychological distress. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  5. Dosimetric properties of bio minerals applied to high-dose dosimetry using the TSEE technique

    International Nuclear Information System (INIS)

    Vila, G. B.; Caldas, L. V. E.

    2014-08-01

    The study of the dosimetric properties such as reproducibility, the residual signal, lower detection dose, dose-response curve and fading of the thermally stimulated emission exo electronic (TSEE) signal of Brazilian bio minerals has shown that these materials present a potential use as radiation dosimeters. The reproducibility within ± 10% for oyster shell, mother-of-pearl and coral reef samples showed that the signal dispersion is small when compared with the mean value of the measurements. The study showed that the residual signal can be eliminated with a thermal treatment at 300 grades C/1 h. The lower detection dose of 9.8 Gy determined for the oyster shell samples when exposed to beta radiation and 1.6 Gy for oyster shell and mother-of-pearl samples when exposed to gamma radiation can be considered good, taking into account the high doses of this study. The materials presented linearity at the dose response curves in some ranges, but the lack of linearity in other cases presents no problem since a good mathematical description is possible. The fading study showed that the loss of TSEE signal can be minimized if the samples are protected from interferences such as light, heat and humidity. Taking into account the useful linearity range as the main dosimetric characteristic, the tiger shell and oyster shell samples are the most suitable for high-dose dosimetry using the TSEE technique. (Author)

  6. Effects of high dose rate gamma radiation on survival and reproduction of Biomphalaria glabrata

    Energy Technology Data Exchange (ETDEWEB)

    Cantinha, Rebeca S.; Nakano, Eliana [Instituto Butantan, Sao Paulo, SP (Brazil). Lab. de Parasitologia], e-mail: rebecanuclear@gmail.com, e-mail: eliananakano@butantan.gov.br; Borrely, Sueli I. [Instituto de Pesquisas Energeticas e Nucleares (IPEN-CNEN/SP), Sao Paulo, SP (Brazil). Centro de Tecnologia das Radiacoes], e-mail: sborrely@ipen.br; Amaral, Ademir; Melo, Ana M.M.A. [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Energia Nuclear. Grupo de Estudos em Radioprotecao e Radioecologia (GERAR)], e-mail: amaral@ufpe.br; Silva, Luanna R.S. [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Biofisica e Radiobiologia. Lab. de Radiobiologia], e-mail: amdemelo@hotmail.com, e-mail: luannaribeiro_lua@hotmail.com

    2009-07-01

    Ionizing radiations are known as mutagenic agents, causing lethality and infertility. This characteristic has motivated its application on animal biological control. In this context, the freshwater snail Biomphalaria glabrata can be considered an excellent experimental model to study effects of ionizing radiations on lethality and reproduction. This work was designed to evaluate effects of {sup 60}Co gamma radiation at high dose rate (10.04 kGy/h) on B. glabrata. For this purpose, adult snails were selected and exposed to doses ranging from 20 to 100 Gy, with 10 Gy intervals; one group was kept as control. There was not effect of dose rate in the lethality of gamma radiation; the value of 64,3 Gy of LD{sub 50} obtained in our study was similar to that obtained by other authors with low dose rates. Nevertheless, our data suggest that there was a dose rate effect in the reproduction. On all dose levels, radiation improved the production of embryos for all exposed individuals. However, viability indexes were below 6% and, even 65 days after irradiation, fertility was not recovered. These results are not in agreement with other studies using low dose rates. Lethality was obtained in all groups irradiated, and the highest doses presented percentiles of dead animals above 50%. The results demonstrated that doses of 20 and 30 Gy were ideal for population control of B. glabrata. Further studies are needed; nevertheless, this research evidenced great potential of high dose rate gamma radiation on B. glabrata reproductive control. (author)

  7. Prognosis of emergency room stabilization of decompensated congestive heart failure with high dose lasix

    Directory of Open Access Journals (Sweden)

    Mahboob Pouraghaei

    2015-06-01

    Full Text Available Objective: Congestive heart failure (CHF has become one of the most important health care problems in western countries. This article focuses on the outpatient diagnosis and management of heart failure. We want to compare the outcome of patients who were treated with high dose diuretics in the emergency department (ED without admission with patients who were admitted to hospital for standard treatment. Methods: This was a randomized prospective clinical trial study. The patients who came to the ED from March 20, 2008 up to August 20, 2008 were divided into two groups randomly. The length of ED stay in the experimental group was documented. Also, readmission and mortality in 6 months and satisfaction in both groups were taken into consideration. All data were analyzed using SPSS 15.0. Results: In experimental group, the rate of recurrent admission, expiration, discharge, clinic visit, and clinic admission was 8%, 4%, 29%, 18%, and 0% respectively. On the other hand, in control group it was 16%, 40%, 18%, 22%, and 2% respectively. Additionally, there was a significant difference between these groups (P = 0.00. Conclusion: This study is the first regional prospective trial to comprehensively examine the therapeutic management in patients with CHF. This study, comparing the high dose diuretic efficacy in the decreasing of hospital stay and readmission; and decreasing mortality rate with routine therapy, showed that there was a significant difference between these two strategies in the mortality rate, readmission, and length of hospital stay (P = 0.00.

  8. Radiation safety program in high dose rate brachytherapy facility at INHS Asvini

    Directory of Open Access Journals (Sweden)

    Kirti Tyagi

    2014-01-01

    Full Text Available Brachytherapy concerns primarily the use of radioactive sealed sources which are inserted into catheters or applicators and placed directly into tissue either inside or very close to the target volume. The use of radiation in treatment of patients involves both benefits and risks. It has been reported that early radiation workers had developed radiation induced cancers. These incidents lead to continuous work for the improvement of radiation safety of patients and personnel The use of remote afterloading equipment has been developed to improve radiation safety in the delivery of treatment in brachytherapy. The widespread adoption of high dose rate brachytherapy needs appropriate quality assurance measures to minimize the risks to both patients and medical staff. The radiation safety program covers five major aspects: quality control, quality assurance, radiation monitoring, preventive maintenance, administrative measures and quality audit. This paper will discuss the radiation safety program developedfor a high dose rate brachytherapy facility at our centre which may serve as a guideline for other centres intending to install a similar facility.

  9. Low- and high-dose laser irradiation effects on cell migration and destruction

    Science.gov (United States)

    Layton, Elivia; Gallagher, Kyra A.; Zukerman, Sara; Stevens, Brianna; Zhou, Feifan; Liu, Hong; Chen, Wei R.

    2018-02-01

    Metastases are the cause of more than 90 percent of cancer-related deaths. Current treatment methods, including chemotherapy, radiation, and surgery, fail to target the metastases effectively. One potential treatment for metastatic cancer is laser immunotherapy (LIT). LIT combines the use of a photothermal laser with an immunoadjuvant, Glycated Chitosan (GC). GC combined with single-walled carbon nanotubes (SWNTs) has proven to be a viable alternative to traditional cancer treatment methods, when under irradiation of laser with appropriate wavelength. In this study, the effects of low dose and high dose laser irradiation on metastatic pancreatic cancer cell migration were observed. It was found that low dose irradiation increased the migration rate, but the high dose irradiation significantly decreased the migration rate of the cancer cells. When using LIT, the goal is to kill tumor cells and to prompt the correct immune response. If the tumor were irradiated with a low dose, it would promote metastasis. If the dose of irradiation were too high, it would destroy the entire tumor and the immune response would not recognize the tumor. Therefore, the laser dose plays an important role in LIT, particularly when using SWNT as light absorbing agent. Our results from this study will delineate the optimal laser irradiation dose for destroying tumor cells and at the same time preserve and release tumor antigens as a precursor of antitumor immune response.

  10. Dose-reduction techniques for high-dose worker groups in nuclear power plants

    International Nuclear Information System (INIS)

    Khan, T.A.; Baum, J.W.; Dionne, B.J.

    1991-03-01

    This report summarizes the main findings of a study of the extent of radiation dose received by special work groups in the nuclear power industry. Work groups which chronically get large doses were investigated, using information provided by the industry. The tasks that give high doses to these work groups were examined and techniques described that were found to be particularly successful