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Sample records for mesylates

  1. Imatinib mesylate in chordoma.

    Science.gov (United States)

    Casali, Paolo G; Messina, Antonella; Stacchiotti, Silvia; Tamborini, Elena; Crippa, Flavio; Gronchi, Alessandro; Orlandi, Rosaria; Ripamonti, Carla; Spreafico, Carlo; Bertieri, Raffaello; Bertulli, Rossella; Colecchia, Maurizio; Fumagalli, Elena; Greco, Angela; Grosso, Federica; Olmi, Patrizia; Pierotti, Marco A; Pilotti, Silvana

    2004-11-01

    To the authors' knowledge, no effective medical therapy currently is available for advanced chordoma. Imatinib mesylate is a tyrosine kinase inhibitor targeting platelet-derived growth factor receptor-beta (PDGFRB), BCR-ABL, and KIT. Six patients with advanced chordoma were treated with imatinib mesylate at a dose of 800 mg daily. In all patients, the tumor was found to be positive for PDGFRB, and in four patients PDGFRB was shown to be phosphorylated/expressed. After a treatment period of > or = 1 year, overt tumor liquefaction was evident on computed tomography (CT) scan in the first patient. In previous months, a decrease in contrast enhancement on magnetic resonance imaging (MRI) and a decrease in glucose uptake on positron emission tomography (PET) were detected. Similar signs on MRI and PET were observed in subsequent patients, who had a shorter treatment period. One of these patients initially was removed from therapy and then was readmitted to therapy because of difficulties with regard to tumor response assessment; 1 month after the reinitiation of therapy, an overt decrease in tumor density was visible on CT scan in this patient. In four of five symptomatic patients, a subjective improvement was observed early in the course of treatment. The first patient died after 17 months, with a sizeable, mostly liquefied mass. Another patient died early, apparently of unrelated causes. The remaining patients were on therapy at the time of last follow-up. Imatinib mesylate has been found to have antitumor activity in patients with chordoma. This activity might be mediated by inactivation of PDGFRB. Tumor response manifests through patterns that are similar to those observed in patients with gastrointestinal stromal tumors who respond to molecular-targeted therapy, but evolves more slowly. The benefit to the patient entailed by this pattern of tumor response in chordoma needs to be elucidated, but may be limited in the presence of significant local disease.

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

    Science.gov (United States)

    2015-10-01

    AD______________ AWARD NUMBER: W81XWH-14-1-0132 TITLE: LAM Pilot Study with Imatinib Mesylate (LAMP-1) PRINCIPAL INVESTIGATOR: Charlie...AND SUBTITLE LAM Pilot Study with Imatinib Mesylate (LAMP-1) 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0132 5c. PROGRAM ELEMENT...designed to generate short-term safety and efficacy data regarding imatinib mesylate ( imatinib ) in the treatment of Lymphangioleiomyomatosis (LAM

  3. IMATINIB MESYLATE INHIBITS FIBROGENESIS IN ASBESTOS-INDUCED INTERSTITIAL PNEUMONIA

    Science.gov (United States)

    Vuorinen, Kirsi; Gao, Fei; Oury, Tim D.; Kinnula, Vuokko L.; Myllärniemi, Marjukka

    2009-01-01

    Profibrogeneic cytokines contribute to the accumulation of myofibroblasts in the lung interstitium in idiopathic pulmonary fibrosis (IPF). Imatinib mesylate, a tyrosine kinase inhibitor specific for Abl, platelet-derived growth factor receptor (PDGFR) and c-Kit tyrosine kinases, has been shown to inhibit fibrosis and profibrotic signaling in mouse models of inflammation-mediated lung reactions. The authors tested imatinib mesylate in vivo in a mouse model of crocidolite asbestos-induced progressive fibrosis. The ability of imatinib mesylate to inhibit profibrogeneic cytokine-induced human pulmonary fibroblast migration was tested in vitro and the expression of its target protein tyrosine kinases was assessed with immunofluorescence. In vivo, 10 mg/kg/day imatinib mesylate inhibited histological parenchymal fibrosis and led to a decrease in collagen deposition, but had no significant effect on asbestos-induced neutrophilia. However, 50 mg/kg/day imatinib mesylate did not inhibit collagen deposition. In vitro, IPF fibroblasts expressed Abl, PDGFR-α, PDGF-β, but not c-Kit, and 1 μM imatinib mesylate inhibited profibrogeneic cytokine-induced IPF fibroblast migration. These results suggest that imatinib mesylate is a potential and specific inhibitor of fibroblast accumulation in asbestos-induced pulmonary fibrosis. PMID:17849262

  4. Combined treatment of 3-hydroxyflavone and imatinib mesylate increases apoptotic cell death of imatinib mesylate-resistant leukemia cells.

    Science.gov (United States)

    Kim, Jung-Hyun; Song, Minjung; Kang, Geun-Ho; Lee, Eung-Ryoung; Choi, Hye-Yeon; Lee, Chung; Kim, Jin-Hoi; Kim, Youngsoo; Koo, Bon-Nyeo; Cho, Ssang-Goo

    2012-09-01

    Imatinib mesylate, a Bcr/Abl tyrosine kinase inhibitor, is widely used in treating chronic myeloid leukemia. However, drug-resistance of leukemia cells becomes an emergent problem. Herein, various flavonoids were screened for applicability in leukemia treatment, and 3-hydroxyflavone (3-HF) was found to be most effective in reducing cancer cell viability. The combination of 3-HF and imatinib mesylate resulted in significant apoptotic cell death in imatinib mesylate-resistant leukemia cells. Combined treatment resulted in apparent activation of caspases and decrease of the oncoprotein phosphor-Bcr/Abl in leukemia cells. Our results suggest that this combined treatment is beneficial in imatinib mesylate-resistant chronic myelogenous leukemia. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Imatinib mesylate-induced lichenoid drug eruption.

    Science.gov (United States)

    Penn, Erin H; Chung, Hye Jin; Keller, Matthew

    2017-03-01

    Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor initially approved by the US Food and Drug Administration in 2001 for chronic myeloid leukemia (CML). Since then, the number of indicated uses for imatinib has substantially increased. It is increasingly important that dermatologists recognize adverse cutaneous manifestations of imatinib and are aware of their management and outcomes to avoid unnecessarily discontinuing a potentially lifesaving medication. Adverse cutaneous manifestations in response to imat-inib are not infrequent and can include dry skin, alopecia, facial edema, and photosensitivity rash. Other less common manifestations include exfoliative dermatitis, nail disorders, psoriasis, folliculitis, hypotrichosis, urticaria, petechiae, Stevens-Johnson syndrome, erythema multiforme, Sweet syndrome, and leukocytoclastic vasculitis. We report a case of imatinib-induced lichenoid drug eruption (LDE), a rare cutaneous manifestation, along with a review of the literature.

  6. Imatinib mesylate (Gleevec) induced unilateral optic disc edema.

    Science.gov (United States)

    DeLuca, Crystal; Shenouda-Awad, Nancy; Haskes, Charles; Wrzesinski, Stephen

    2012-10-01

    Imatinib mesylate (Gleevec) is a chemotherapy medication developed to treat chronic myelogenous leukemia as well as gastrointestinal stromal tumors (Savage, N Engl J Med 2002;346:683-93). Ocular side effects are commonly reported with the use of imatinib mesylate, such as periorbital edema and epiphora. More serious ocular side effects, such as optic disc edema, are rarely reported. This case is of a patient who presented with monocular painless loss of vision in the left eye from a previously documented 20/20 to 20/70 shortly after starting treatment with imatinib mesylate. Every aspect of the ocular presentation and clinical history were addressed to unveil the cause of the disc edema. After ruling out all other causes, the patient was later diagnosed with unilateral optic disc edema as a related side effect of the toxicity from imatinib mesylate. The properties of imatinib mesylate and the possible etiology of secondary optic disc edema are discussed. This study aims to highlight the importance of systemic medications review for possible etiology of ocular disease as well as the multidisciplinary approach to managing oncology patients with ocular side effects.

  7. Eribulin Mesylate: A New Therapeutic Option for Metastatic Breast ...

    African Journals Online (AJOL)

    Eribulin Mesylate: A New Therapeutic Option for Metastatic Breast Cancer. Suruchi Aditya. Department of Pharmacology, Dr. Harvansh Singh Judge Institute of Dental Sciences, Panjab University, Chandigarh, India. ABSTRACT. More than a million women are diagnosed with breast cancer annually worldwide. Death from ...

  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. Sab mediates mitochondrial dysfunction involved in imatinib mesylate-induced cardiotoxicity.

    Science.gov (United States)

    Chambers, Tara P; Santiesteban, Luis; Gomez, David; Chambers, Jeremy W

    2017-05-01

    Imatinib mesylate is an effective treatment for chronic myelogenous leukemia and gastrointestinal stromal tumors. Although imatinib mesylate is highly tolerable, it has been implicated in severe congestive heart failure in mouse models and patients. A hallmark of imatinib mesylate-induced cardiotoxicity is mitochondrial dysfunction. The mitochondrial scaffold Sab has been implicated in facilitating signaling responsible for mitochondrial dysfunction in a c-Jun N-terminal Kinase (JNK)-dependent manner. We examined the impact of Sab-mediated signaling on imatinib mesylate cardiotoxicity in H9c2 rat cardiomyocyte-like cells. Silencing Sab increased the LD 50 of imatinib mesylate 4-fold in H9c2 cells. Disrupting Sab-mediated signaling prevented imatinib mesylate-induced apoptosis as well. Knockdown of Sab or inhibition with a small peptide prevented oxidative stress, which was indicated by decreased reactive oxygen species production, lipid peroxidation, and protein carbonylation. Further, inhibition of Sab-related signaling partially rescued deficits in mitochondrial respiration, ATP production, and membrane potential in imatinib mesylate-treated H9c2 cells. Conversely, over-expression of Sab in H9c2 cells increased the cardiotoxicity of imatinib mesylate in vitro decreasing the LD 50 over 4-fold. Sab expression was induced in H9c2 cells following cardiovascular-like stress in an AP-1 dependent manner. These data demonstrate that imatinib mesylate influences mitochondrial signaling leading to mitochondrial dysfunction and cardiotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Drug repurposing identifies a synergistic combination therapy with imatinib mesylate for gastrointestinal stromal tumor.

    Science.gov (United States)

    Pessetto, Ziyan Y; Ma, Yan; Hirst, Jeff J; von Mehren, Margaret; Weir, Scott J; Godwin, Andrew K

    2014-10-01

    Gastrointestinal stromal tumor (GIST) is a rare and therefore often neglected disease. Introduction of the kinase inhibitor imatinib mesylate radically improved the clinical response of patients with GIST; however, its effects are often short-lived, with GISTs demonstrating a median time-to-progression of approximately two years. Although many investigational drugs, approved first for other cancers, have been subsequently evaluated for the management of GIST, few have greatly affected the overall survival of patients with advanced disease. We employed a novel, focused, drug-repurposing effort for GIST, including imatinib mesylate-resistant GIST, evaluating a large library of FDA-approved drugs regardless of current indication. As a result of the drug-repurposing screen, we identified eight FDA-approved drugs, including fludarabine phosphate (F-AMP), that showed synergy with and/or overcame resistance to imatinib mesylate. F-AMP induces DNA damage, Annexin V, and caspase-3/7 activities as the cytotoxic effects on GIST cells, including imatinib mesylate-resistant GIST cells. F-AMP and imatinib mesylate combination treatment showed greater inhibition of GIST cell proliferation when compared with imatinib mesylate and F-AMP alone. Successful in vivo experiments confirmed the combination of imatinib mesylate with F-AMP enhanced the antitumor effects compared with imatinib mesylate alone. Our results identified F-AMP as a promising, repurposed drug therapy for the treatment of GISTs, with potential to be administered in combination with imatinib mesylate or for treatment of imatinib mesylate-refractory tumors. ©2014 American Association for Cancer Research.

  11. Imatinib mesylate-induced pseudoporphyria in two children.

    Science.gov (United States)

    Mahon, Caroline; Purvis, Diana; Laughton, Stephen; Bradbeer, Peter; Teague, Lochie

    2014-01-01

    Imatinib mesylate was the first of several tyrosine kinase inhibitors approved for use in the treatment of a number of human cancers. Adverse cutaneous reactions to imatinib are common. Pseudoporphyria has been infrequently reported in adults undergoing imatinib therapy for chronic myeloid leukemia. We present two children with pseudoporphyria induced by imatinib therapy for hematologic malignancies. In view of the burgeoning use of imatinib in children, physicians should be aware that pseudoporphyria may develop as a consequence of imatinib therapy. © 2014 Wiley Periodicals, Inc.

  12. Newly diagnosed breast cancer in a patient receiving imatinib mesylate.

    Science.gov (United States)

    Kaygusuz-Atagunduz, Isik; Toptas, Tayfur; Yumuk, Fulden; Firatli-Tuglular, Tulin; Bayik, Mahmut

    2014-01-01

    Imatinib mesylate is the standard treatment of chronic myeloid leukemia (CML). Despite imatinib is being used in the treatment of other malignancies as well, its potential role on de novo tumor growth is not known. Secondary malignancies are rarely seen in patients with CML and particularly in those receiving imatinib. Here, we present a CML patient taking imatinib therapy that was diagnosed to have breast cancer and received adjuvant chemo-and radiotherapy with imatinib. We tried to explain co-occurrence of these rare events by probable pathogenetic mechanisms.

  13. In vitro effect of imatinib mesylate loaded on polybutylcyanoacrylate nanoparticles on leukemia cell line K562.

    Science.gov (United States)

    Hasandoost, Leyla; Akbarzadeh, Azim; Attar, Hossein; Heydarinasab, Amir

    2017-05-01

    The study aimed to prepare imatinib mesylate-loaded polybutylcyanoacrylate (PBCA) nanoparticles and evaluate their efficacy on leukemia cell line K562. The formulation was prepared by miniemulsion polymerization technique. Nanoparticles were characterized by dynamic light scattering (DLS), spectrophotometry, Fourier transform infrared spectroscopy (FTIR), dialysis membrane, and 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) techniques. Nanoscale particles with high encapsulation efficiency (86%) and physical entrapment of drug were observed. In addition, nanoparticles showed suitable drug retention capability and potentiate the cytotoxicity effects of imatinib mesylate. Findings of study suggested PBCA nanoparticles are promising carrier for imatinib mesylate delivery to leukemia cell line K562.

  14. The teratogenic effects of imatinib mesylate on rat fetuses

    Directory of Open Access Journals (Sweden)

    M.M. El Gendy

    2015-01-01

    Full Text Available Imatinib mesylate, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukemia and gastrointestinal stromal tumors. The aim of the present study is to investigate the effects of imatinib mesylate on the pregnant rats and their fetuses. Pregnant rats were divided into three groups; the first group served as a control group. The second and third groups were orally administered imatinib at doses of 36 mg/kg body weight or 54 mg/kg b.wt. on gestation days (SDs 6 through 13 or SDs 13 through 19, respectively. All animals were sacrificed on the 20th day of gestation. Treatment with imatinib caused a reduction of maternal body weight gain, uterine and placental weights, increased rate of abortion and fetal resorptions. High dose of imatinib caused fetal congenital deformities represented in harelip, contraction of the fore limbs, and paralysis of the hind limbs, exencephaly, encephalocoele and distended abdominal wall, besides occurrence of wavy ribs and absence of other ribs in addition to skeletal growth retardation and lack of ossification of the most skeletal elements. The present work concluded that imatinib is teratogenic when given orally to pregnant rats at 54 mg/kg b.wt. and causes direct maternal or developmental toxicity.

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

    OpenAIRE

    Liu, HeLi; Liao, GuoQing; Yan, ZhongShu

    2011-01-01

    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 lesi...

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

    Directory of Open Access Journals (Sweden)

    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

  17. 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......) was used as a low-dose active pharmaceutical ingredient (API). Flexible doses of the drug in a single unit were obtained by printing several subsequent layers on top of the already printed ones, using an off-the-shelf consumer thermal inkjet (TIJ) printer. The produced drug-delivery systems were subjected...... to microscopic and chemical analysis together with solid-state characterization and content uniformity studies. The results revealed that RM recrystallized on the surface of ODFs and TFs, and the printed crystals were arranged in lines. No drug crystals were detected after printing on the surface of the copy...

  18. Ageing is a risk factor in imatinib mesylate cardiotoxicity.

    Science.gov (United States)

    Maharsy, Wael; Aries, Anne; Mansour, Omar; Komati, Hiba; Nemer, Mona

    2014-04-01

    Chemotherapy-induced heart failure is increasingly recognized as a major clinical challenge. Cardiotoxicity of imatinib mesylate, a highly selective and effective anticancer drug belonging to the new class of tyrosine kinase inhibitors, is being reported in patients, some progressing to congestive heart failure. This represents an unanticipated challenge that could limit effective drug use. Understanding the mechanisms and risk factors of imatinib mesylate cardiotoxicity is crucial for prevention of cardiovascular complications in cancer patients. We used genetically engineered mice and primary rat neonatal cardiomyocytes to analyse the action of imatinib on the heart. We found that treatment with imatinib (200 mg/kg/day for 5 weeks) leads to mitochondrial-dependent myocyte loss and cardiac dysfunction, as confirmed by electron microscopy, RNA analysis, and echocardiography. Imatinib cardiotoxicity was more severe in older mice, in part due to an age-dependent increase in oxidative stress. Mechanistically, depletion of the transcription factor GATA4 resulting in decreased levels of its prosurvival targets Bcl-2 and Bcl-XL was an underlying cause of imatinib toxicity. Consistent with this, GATA4 haploinsufficient mice were more susceptible to imatinib, and myocyte-specific up-regulation of GATA4 or Bcl-2 protected against drug-induced cardiotoxicity. The results indicate that imatinib action on the heart targets cardiomyocytes and involves mitochondrial impairment and cell death that can be further aggravated by oxidative stress. This in turn offers a possible explanation for the current conflicting data regarding imatinib cardiotoxicity in cancer patients and suggests that cardiac monitoring of older patients receiving imatinib therapy may be especially warranted. © 2014 The Authors. European Journal of Heart Failure

  19. Mechanisms of resistance to imatinib mesylate in KIT-positive metastatic uveal melanoma.

    Science.gov (United States)

    Calipel, Armelle; Landreville, Solange; De La Fouchardière, Arnaud; Mascarelli, Frédéric; Rivoire, Michel; Penel, Nicolas; Mouriaux, Frédéric

    2014-06-01

    Imatinib mesylate is used in targeted therapy of cancer to inhibit type III tyrosine kinase receptors, such as KIT and platelet-derived growth factor receptors (PDGFRs). Expression of KIT in uveal melanoma (UM) suggests that this receptor may be the target of imatinib mesylate therapy. However, phase II multicenter clinical studies have shown no effect of imatinib mesylate in patients with unresectable liver metastases of UM. We therefore investigated which molecular mechanisms promote imatinib mesylate-resistance in metastatic UM. Expression of KIT, stem cell factor (SCF), PDGFRα and PDGFRβ, was analyzed by RT-PCR, immunostaining, and Western blot in twenty-four samples of UM liver metastases, as well as UM primary tumor and metastatic cell lines. Soluble SCF was quantified in UM cell lines using enzyme-linked immunosorbent assay. Cell viability of UM cell lines treated with imatinib mesylate and grown in SCF-supplemented medium or in microvascular endothelial cells-conditioned medium was studied by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assays. UM liver metastases and cell lines expressed KIT and SCF, but not the PDGFRs. Ninety-five percent of liver metastases expressed KIT at the protein level, but PDGFRs were not detected in these samples. Imatinib mesylate reduced the viability of UM metastatic cell lines in a concentration-dependent manner, but an increased resistance to this drug was observed when cells were incubated in SCF-supplemented or microvascular endothelial cells-conditioned medium. This study provides evidence that tumor microenvironment cytokines such as SCF may promote resistance to imatinib mesylate in metastatic UM.

  20. Pilot Study of Gleevec/Imatinib Mesylate (STI 571, NSC 716051) in Neurofibromatosis (NF1) Patients with Plexiform Neurofibromas

    Science.gov (United States)

    2016-03-01

    AWARD NUMBER: W81XWH-09-1-0120 TITLE: Pilot Study of Gleevec/Imatinib Mesylate ( STI -571, NSC 716051) in Neurofibromatosis (NF1) Patients with...19b. TELEPHONE NUMBER (include area code) Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 Pilot Study of Gleevec/Imatinib Mesylate ( STI

  1. Delivery as nanoparticles reduces imatinib mesylate-induced cardiotoxicity and improves anticancer activity.

    Science.gov (United States)

    Marslin, Gregory; Revina, Ann Mary; Khandelwal, Vinoth Kumar Megraj; Balakumar, Krishnamoorthy; Prakash, Jose; Franklin, Gregory; Sheeba, Caroline J

    2015-01-01

    Clinical effectiveness of imatinib mesylate in cancer treatment is compromised by its off-target cardiotoxicity. In the present study, we have developed physically stable imatinib mesylate-loaded poly(lactide-co-glycolide) nanoparticles (INPs) that could sustainably release the drug, and studied its efficacy by in vitro anticancer and in vivo cardiotoxicity assays. MTT (methylthiazolyldiphenyl-tetrazolium bromide) assay revealed that INPs are more cytotoxic to MCF-7 breast cancer cells compared to the equivalent concentration of free imatinib mesylate. Wistar rats orally administered with 50 mg/kg INPs for 28 days showed no significant cardiotoxicity or associated changes. Whereas, increased alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels, and reduced white blood cell, red blood cell, and hemoglobin content were observed in the animals administered with free drug. While the histological sections from hearts of animals that received INPs did not show any significant cardiotoxic symptoms, loss of normal architecture and increased cytoplasmic vacuolization were observed in the heart sections of animals administered with free imatinib mesylate. Based on these results, we conclude that nano-encapsulation of imatinib mesylate increases its efficacy against cancer cells, with almost no cardiotoxicity.

  2. Expression study of the target receptor tyrosine kinase of Imatinib mesylate in skull base chordomas.

    Science.gov (United States)

    Orzan, Francesca; Terreni, Maria Rosa; Longoni, Mauro; Boari, Nicola; Mortini, Pietro; Doglioni, Claudio; Riva, Paola

    2007-07-01

    Chordomas are rare neoplasms arising along the axial skeleton. Up to now, the most suitable therapeutic approach is based on a combination of surgical excision and radiotherapy. Chemotherapy in not applied due to its reported low efficacy. Recently, evidence on the efficacy of Imatinib mesylate in two patients has been reported. We analyzed 14 chordoma samples for the expression of the Imatinib mesylate targets by means of RT-PCR and immunohistochemistry and found that PDGFR alpha and PDGFR beta are in some cases expressed in neoplastic cells, while the stromal counterpart of the same tumor shows the above receptors. Findings on the PDGFA/PDGFB expression suggest a receptor-activated status. Our study provides new insights into the specific localization of Imatinib mesylate targets in skull base chordomas that could be taken into account for the setting up of a pharmacological treatment for this tumor.

  3. Soft tissue calcification secondary to imatinib mesylate in a patient with gastrointestinal stromal tumor.

    Science.gov (United States)

    Enck, Robert E; Abushahin, Fadi; Bossaer, John B

    2014-04-01

    Imatinib mesylate has been associated with the changes in bone turnover. We report a case of the development of tissue calcification in a patient on long-term therapy with this drug. A 48-year-old male patient with gastrointestinal stromal tumor and liver metastasis complained of abdominal pain. His treatment included hepatic artery chemoembolization and partial hepatectomy in addition to chronic imatinib mesylate for 4 years. On physical examination, he had a peritoneal mass just beneath the laparotomy incision scar that, after resection, was found to be dystrophic bone formation. Based on the previous studies suggesting bone changes due to chronic therapy with imatinib mesylate, we believe that the patient's new bone formation was causally related to the use of this drug. To our knowledge, there are no similar reported cases in the literature.

  4. Effects of imatinib mesylate on the spontaneous activity generated by the guinea-pig prostate.

    Science.gov (United States)

    Lam, Michelle; Dey, Anupa; Lang, Richard J; Exintaris, Betty

    2013-08-01

    What's known on the subject? and what does the study add?: Several studies have examined the functional role of tyrosine kinase receptors in the generation of spontaneous activity in various segments of the gastrointestinal and urogenital tracts through the application of its inhibitor, imatinib mesylate (Glivec®), but results are fairly inconsistent. This is the first study detailing the effects of imatinib mesylate on the spontaneous activity in the young and ageing prostate gland. As spontaneous electrical activity underlies the spontaneous rhythmic prostatic contractions that occur at rest, elucidating the mechanisms involved in the regulation of the spontaneous electrical activity and the resultant phasic contractions could conceivably lead to the identification of better targets and the development of more specific therapeutic agents to treat prostate conditions. To investigate the effect of imatinib mesylate, a tyrosine kinase receptor inhibitor, in the generation of spontaneous electrical and contractile activity in the young and ageing guinea-pig prostate. Standard tension and intracellular recording were used to measure spontaneous contractions and slow waves, respectively from the guinea-pig prostate at varying concentrations of imatinib mesylate (1-50 μm). Imatinib mesylate (1-10 μm), did not significantly affect slow waves recorded in the prostate of both age groups but at 50 μm, the amplitude of slow waves from the ageing guinea-pig prostate was significantly reduced (P imatinib mesylate attenuated the amplitude and slowed the frequency of contractions in ageing guinea-pigs to 5.15% and 3.3% at 1 μm (n = 6); 21.1% and 20.8% at 5 μm (n = 8); 58.4% and 8.8% at 10 μm (n = 11); 72.7% and 60% at 50 μm (n = 5). A significant reduction in contractions but persistence of slow waves suggests imatinib mesylate may affect the smooth muscle contractile mechanism. Imatinib mesylate also significantly reduced contractions in the prostates of younger guinea

  5. Effectiveness of Imatinib Mesylate Treatment in a Patient with Dermatofibrosarcoma Protuberans with Pulmonary and Pancreatic Metastases.

    Science.gov (United States)

    Tatai, Toshiharu; Gomi, Daisuke; Fukushima, Toshirou; Kobayashi, Takashi; Sekiguchi, Nodoka; Sakamoto, Akiyuki; Sasaki, Shigeru; Koizumi, Tomonobu; Sano, Kenji

    2016-01-01

    We herein encountered a case of abdominal wall dermatofibrosarcoma protuberans (DFSP) that developed pulmonary and pancreatic metastases 5 years after complete resection. Because specific rearrangements of the platelet-derived growth factor beta (PDGFB) locus by a novel fluorescence in situ hybridization method was detected, the patient was treated with imatinib mesylate at 400 mg/day. A partial response was achieved by imatinib without any specific toxicity. Although metastatic DFSP is an extremely rare disease, an evaluation of PDGFB fusion is essential and imatinib mesylate should be considered as an optimal therapeutic choice in patients with metastatic or locally advanced DFSP.

  6. Wnt5a enhances the response of CML cells to Imatinib Mesylate through JNK activation and γ-catenin inhibition.

    Science.gov (United States)

    Niu, Chang-Chun; Zhao, Chen; Zhang, Xiao-Li; Pan, Jing; Zhao, Chen; Wu, Wei-Ru; Li, Zhi-Qiang; Liu, Tao; Yang, Zhong; Si, Wei-Ke

    2013-11-01

    Imatinib Mesylate is widely used for the treatment of chronic myelogenous leukaemia (CML), and its effects on CML cells are influenced by several signalling proteins. The research is aimed at determining whether Wnt5a affects the effects of Imatinib Mesylate against BCR-ABL positive CML cells (K562 cells and KU812 cells) and which signalling proteins are involved in. The results showed that Wnt5a augmented the effects of Imatinib Mesylate on inhibiting CML cells proliferation and inducing apoptosis in vitro; Wnt5a enhanced the inhibition effect of Imatinib Mesylate on the growth of K562 cells xenograft tumour in an animal model. Furthermore, Wnt5a inhibited β-catenin and its target gene Survivin, increased the activity of JNK and suppressed γ-catenin expression. When inhibiting the activity of JNK, the influence of Wnt5a on the effects of Imatinib Mesylate was attenuated. Moreover, JNK suppressed β-catenin and its target gene Survivin, and enhanced the effects of Imatinib Mesylate. These results suggest that Wnt5a can enhance the efficacy of Imatinib Mesylate through JNK/β-catenin/Survivin and γ-catenin/β-catenin/Survivin pathways. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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

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

    Science.gov (United States)

    Gobin, Bérengère; Moriceau, Gatien; Ory, Benjamin; Charrier, Céline; Brion, Régis; Blanchard, Frederic; Redini, Françoise; Heymann, Dominique

    2014-01-01

    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 status of patients.

  9. Nonaqueous capillary electrophoresis of imatinib mesylate and related substances.

    Science.gov (United States)

    Ye, Lei; Huang, Yifei; Li, Jian; Xiang, Guangya; Xu, Li

    2012-08-01

    In the present study, nonaqueous capillary electrophoretic separation of imatinib mesylate (IM) and related substances, N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (PYA), N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((piperazin-1-yl)methyl) benzamide (NDI) and 4-chloromethyl-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (CPB) was developed. The influential factors affecting separation, including type and concentration of the electrolyte, applied voltage, and buffer modifier were investigated. Baseline separation of the studied analytes was obtained using a buffer of 50 mM Tris and 50 mM methanesulfonic acid in methanol at a apparent pH (pH*) of 1.65. To enhance the sensitivity, large-volume sample stacking was employed for online concentration. The strongest analytical signal with a suitable separation was achieved when the injection time was 100 s. The linearity ranges of PYA and NDI were 0.100-2.50 μg mL(-1), and that of CPB was 0.125-2.50 μg mL(-1), with good coefficients (r(2) > 0.9948). The relative standard deviations of intra- and interday were satisfactory. Under the optimized conditions, seven batches of the synthesized samples were analyzed and CPB was detected in two batches. Owing to its simplicity, effectiveness, and low price, the developed method is promising for quality control of IM. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Preoperative imatinib mesylate (IM) for huge gastrointestinal stromal tumors (GIST).

    Science.gov (United States)

    Tang, Sumin; Yin, Yuan; Shen, Chaoyong; Chen, Jiaju; Yin, Xiaonan; Zhang, Bo; Yao, Yuqin; Yang, Jinliang; Chen, Zhixin

    2017-04-11

    Preoperative imatinib mesylate (IM) treatment has not yet been standardized. Here, we aim to further explore such therapy on patients with gastrointestinal stromal tumors (GIST) retrospectively. Patients experiencing preoperative IM were identified from January 2009 to February 2015. A total of 28 GIST patients were identified. The patients received preoperative IM treatment for a median length of 13.5 months, ranging from 5 to 37 months. PR and SD were observed in 24 (85.7%) and 4 (15.3%) patients, respectively. The tumor shrinkage occurred predominantly within 6 to 12 months, and slight tumor shrinkage could be observed after 12 months in certain patients. Nineteen patients (67.9%) received surgery, and R0 resection was acquired in 18 (94.7%) patients. The initial mean maximum diameter was 10.5 (5.2 to 19.0) cm and decreased to 5.9 (2.7 to 19.0) cm after preoperative treatment with a median length of 12 (ranging from 5 to 36) months (P < 0.001) in patients receiving operations. Three in 7 cases of rectum GIST underwent abdominoperineal resection, and four others adopted sphincter-sparing resection. Partial gastrectomy was performed in four patients. IM prior to surgery can effectively prevent tumor rupture and facilitate surgery with low surgical morbidity for GIST patients. Tumor shrinkage following IM occurred predominantly within 6 to 12 months, and slight tumor shrinkage could be observed after 12 months in certain patients. In selected patients, prolonged exposure to IM is seemingly advisable under close radiological surveillance.

  11. [Pathological complete response in a large gastric GIST that became resectable after neoadjuvant chemotherapy with imatinib mesylate].

    Science.gov (United States)

    Otsubo, Dai; Sawa, Hidehiro; Fukuoka, Eiji; Murata, Kouichi; Mii, Yasuhiko; Oka, Shigeteru; Iwatani, Yoshiteru; Kuroda, Daisuke

    2014-11-01

    We report a case of a large gastric gastrointestinal stromal tumor (GIST), which became resectable and achieved pathological complete response after neoadjuvant chemotherapy with imatinib mesylate. A 59-year-old man presented with left hypochondrial pain. Abdominal computed tomography (CT) revealed gastric GIST invading the spleen and the diaphragm. Administration of imatinib mesylate was initiated as neoadjuvant chemotherapy. Six months after neoadjuvant chemotherapy with imatinib mesylate, abdominal CT revealed a reduction in tumor size. We judged the tumor resectable and performed partial gastrectomy and splenectomy. Histologically, number of myofibroblasts increased, but no viable tumor cells were observed. Pathological complete response was obtained.

  12. New pharmacological therapies for vasomotor symptom management: focus on bazedoxifene/conjugated estrogens and paroxetine mesylate.

    Science.gov (United States)

    Carris, Nicholas; Kutner, Sara; Reilly-Rogers, Shane

    2014-10-01

    To review 2 recently approved therapies for vasomotor symptoms (VMSs) of menopause. PubMed searches (June 2003 to May 2014) were conducted using the keywords paroxetine vasomotor and bazedoxifene vasomotor. References from relevant articles were reviewed for pertinent citations that were not identified in the PubMed search. Phase 3 clinical trials of recently approved hormonal and nonhormonal therapies for the treatment of VMSs of menopause were selected. Studies that evaluated the use of paroxetine mesylate or bazedoxifene (BZA)/conjugated estrogens (CEs) for VMSs were included. Four studies for BZA/CEs were identified. One published report of low-dose paroxetine mesylate was identified that was a combined analysis of 2 phase 3 studies. Both agents significantly decrease the incidence of hot flushes compared with placebo and are approved for the treatment of moderate to severe VMSs associated with menopause. BZA/CEs is only approved for women with an intact uterus. In all circumstances, the use of BZA/CEs should be limited to the shortest duration possible. Paroxetine mesylate was not studied head-to-head against hormone therapy, but the magnitude of its effect on VMSs is less than expected with hormone therapy. BZA/CEs is an effective hormonal therapy for treating VMSs in women with an intact uterus. Paroxetine mesylate is the first nonhormonal therapy that the FDA has approved for VMSs, making both viable options for the treatment of VMSs of menopause. © The Author(s) 2014.

  13. Imatinib mesylate in the treatment of systemic mastocytosis - A phase II trial

    NARCIS (Netherlands)

    Droogendijk, H.J.; Kluin-Nelemans, Hanneke; van Doormaal, Jaap J.; Oranje, A.P.; Van De Loosdrecht, A.A.; Van Daele, P.L.

    2006-01-01

    BACKGROUND. Mastocytosis is characterized by the abnormal proliferation of mast cells in I or more organs. In most patients, a mutation is present in the gene for C-KIT resulting in deregulation of the c-kit receptor. Imatinib mesylate is a potent inhibitor of c-kit receptor tyrosine kinase

  14. Imaging of Gastrointestinal Stromal Tumors before and after Imatinib Mesylate Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Shankar, S.; Dundamadappa, S.K.; Karam, A.R. (Radiology Dept., Univ. of Massachusetts Medical Center, Worcester, MA (United States)); Stay, R.M. (Radiology Dept., Univ. of Virginia, Charlottesville, VA (United States)); Sonnenberg, E. van (Radiology Dept., Dana Farber Cancer Inst., Boston, MA (United States))

    2009-10-15

    Gastrointestinal stromal tumors (GISTs) account for the majority of gastrointestinal mesenchymal tumors. Recent advances in treatment using the molecular targeting agent imatinib mesylate have shown startling response rates and variegated imaging findings. We present the various imaging appearances of GIST on computed tomography (CT) and magnetic resonance imaging (MRI), both before and after treatment.

  15. Possible Role of Interleukin-31/33 Axis in Imatinib Mesylate-Associated Skin Toxicity.

    Science.gov (United States)

    Musolino, Caterina; Allegra, Alessandro; Mannucci, Carmen; Russo, Sabina; Alonci, Andrea; Maisano, Valerio; Calapai, Gioacchino; Gangemi, Sebastiano

    2015-06-01

    Imatinib mesylate is a small-molecule tyrosine kinase inhibitor (TKi) designed to target c-ABL and BCR-ABL, approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Adverse cutaneous reactions induced by imatinib are frequent, generally moderate, and dose-dependent. The aim of this work was to investigate the possible contribution of interleukin (IL)-33 and IL-31, cytokines involved in disorders associated with itching, in the pathogenesis of pruritus in a patient undergoing imatinib mesylate treatment. His IL-31 and IL-33 serum levels were significantly higher than in the control group (respectively 96.6 pg/mL vs. 7.623±7.681 pg/mL and 27.566 pg/mL vs. 6.170±7.060 pg/mL). In light of these findings, imatinib mesylate-related symptoms of dermatologic toxicities might be related to the release of IL-31 and IL-33. In particular, it is supposable that TKi usage could cause keratinocyte injury, the release of IL-33, and the consequent interaction with its receptor on mast cells that induces the secretion of several factors capable of causing skin manifestations, including IL-31, a known pruritus-inducing cytokine. This report, to the best of our knowledge, is the first work describing the possible involvement of the IL-31/IL-33 axis in the pathogenesis of skin side effects related to imatinib mesylate treatment.

  16. Stability-Indicating HPTLC Determination of Imatinib Mesylate in Bulk Drug and Pharmaceutical Dosage

    Science.gov (United States)

    Musmade, P.; Vadera, N.; Subramanian, G.

    A simple, selective, precise and stability-indicating high-performance thin-layer chromatographic method of analysis of imatinib mesylate both as a bulk drug and in formulations was developed and validated. The method employed HPTLC aluminum plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of chloroform:methanol (6:4, v/v). The system was found to give compact spot for imatinib mesylate (R f value of 0.53 ± 0.02). Densitometric analysis of imatinib mesylate was carried out in the absorbance mode at 276 nm. The linear regression analysis data for the calibration plots showed good linear relationship with r 2 = 0.9966 ± 0.0013 with respect to peak area in the concentration range 100-1,000 ng per spot. The mean value ± SD of slope and intercept were 164.85 ± 0.72 and 1168.3 ± 8.26, respectively, with respect to peak area. The method was validated for precision, recovery, and robustness. The limits of detection and quantitation were 10 and 30 ng per spot, respectively. Imatinib mesylate was subjected to acid and alkali hydrolysis, and oxidation and thermal degradation. The drug undergoes degradation under acidic, basic, oxidation, and heat conditions. This indicates that the drug is susceptible to acid, base hydrolysis, oxidation, and heat. Statistical analysis proves that the method is repeatable, selective, and accurate for the estimation of the said drug. The proposed developed HPTLC method can be applied for identification and quantitative determination of imatinib mesylate in bulk drug and dosage forms.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. Inhibition of human chronic myelogenous leukemia K562 cell growth following combination treatment with resveratrol and imatinib mesylate.

    Science.gov (United States)

    Wang, X J; Li, Y H

    2015-06-11

    To investigate the effect of treatment with resveratrol combined with imatinib mesylate on human chronic myelogenous leukemia K562 cell growth inhibition and apoptosis, in vitro cultured human chronic myelogenous leukemia K562 cells were incubated with different concentrations of resveratrol and imatinib mesylate when the cells were in the logarithmic phase. Next, the cell growth inhibition was evaluated using the MTT assay and cellular morphology observation. Apoptosis was determined using Annexin V fluorescein isothiocyanate/propidium iodide double staining. The results demonstrated that treatment with resveratrol (concentration-dependent) and imatinib mesylate showed significantly greater inhibition of K562 cell growth and a higher apoptosis rate of K562 cells than imatinib mesylate medication alone and the control group (P imatinib mesylate medication alone group showed significant inhibition of K562 cell growth and apoptosis rate of K562 cells compared to the control group (P imatinib mesylate and resveratrol are potent drug treatments for human chronic myelogenous leukemia, offering a promising means of inhibiting cell growth and apoptosis.

  19. [Secondary mutation of c-kit/PDGFRα genotypes after imatinib mesylate therapy and its relationship with efficacy of sunitinib].

    Science.gov (United States)

    Hong, Jin-ling; Li, Jian; Li, Jie; Shen, Lin

    2012-06-01

    To investigate the relationship between secondary mutations of c-kit/PDGFRα resistance to imatinib mesylate and the efficacy of sunitinib in patients with gastrointestinal stromal tumor (GIST). Five pairs specimens were collected before and after imatinib mesylate resistance. DNA for molecular genetic investigation was extracted from formalin-fixed, paraffin-embedded tissues. Mutational analysis was performed by using PCR and direct sequencing. Five pairs of specimens were collected before and after imatinib mesylate resistance from 5 GIST patients. C-kit exon 11 mutations were detected in 3 patients, which were all acquired mutations, including c-kit exon 13 V654A, c-kit exon 13 V654E and c-kit exon 17 N822K, after imatinib mesylate resistance. Furthermore, after sunitinib treatment, 3 patients had stable disease and progression free survival (PFS) were 3.5 months, 4.4 months and 3.8 months, respectively. C-kit exon 9 mutations were detected in 2 patients with no acquired mutations after imatinib mesylate resistance. And the both had partial response from sunitinib, following with 13.1 months and 12.0 months PFS respectively. The c-kit/PDGFRα genotypes after imatinib mesylate resistance may both relate to primary mutations and efficacy of sunitinib treatment.

  20. 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

  1. Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial.

    Science.gov (United States)

    Robertson, Kent A; Nalepa, Grzegorz; Yang, Feng-Chun; Bowers, Daniel C; Ho, Chang Y; Hutchins, Gary D; Croop, James M; Vik, Terry A; Denne, Scott C; Parada, Luis F; Hingtgen, Cynthia M; Walsh, Laurence E; Yu, Menggang; Pradhan, Kamnesh R; Edwards-Brown, Mary K; Cohen, Mervyn D; Fletcher, James W; Travers, Jeffrey B; Staser, Karl W; Lee, Melissa W; Sherman, Marcie R; Davis, Cynthia J; Miller, Lucy C; Ingram, David A; Clapp, D Wade

    2012-12-01

    Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. Eligible patients had to be aged 3-65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m(2) twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. Six of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results. Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for

  2. Determination of Alkyl Methanesulfonates in Doxazosin Mesylate by Gas Chromatography-mass Spectrometer.

    Science.gov (United States)

    Sitaram, C; Rupakula, R B; Reddy, B N; Sastry, C S P

    2011-01-01

    High sensitive rapid gas chromatography-mass spectrometry method for the determination of four carcinogenic alkyl methanesulfonates viz. methyl methanesulfonate, ethyl methanesulfonate, isopropyl methanesulfonate and n-butyl methanesulfonate in doxazosin mesylate has been presented by using selective ion monitoring mode. The optimum separation was achieved between methyl methanesulfonate, ethyl methanesulfonate, isopropyl methanesulfonate and n-butyl methanesulfonate on a DB-5 (30 m×0.32 mm×1.0 μm) capillary column under programming temperature. Acetonitrile, water and ammonia (90:9:1 v/v/v) mixture was used as diluent. Various factors involved in the gas chromatography-mass spectrometry method development are also presented. This method was validated as per International Conference on Harmonization guidelines. The limit of quantitation of methyl methanesulfonate, ethyl methanesulfonate, isopropyl methanesulfonate and n-butyl methanesulfonate is 6 ppm with respect to 30 mg/ml of doxazosin mesylate.

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

    Science.gov (United States)

    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.

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

    OpenAIRE

    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; Kang, Yoon-Koo

    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 prescribe...

  5. Determination of Alkyl Methanesulfonates in Doxazosin Mesylate by Gas Chromatography-mass Spectrometer

    OpenAIRE

    Sitaram, C.; Rupakula, R. B.; Reddy, B. N.; Sastry, C. S. P

    2011-01-01

    High sensitive rapid gas chromatography-mass spectrometry method for the determination of four carcinogenic alkyl methanesulfonates viz. methyl methanesulfonate, ethyl methanesulfonate, isopropyl methanesulfonate and n-butyl methanesulfonate in doxazosin mesylate has been presented by using selective ion monitoring mode. The optimum separation was achieved between methyl methanesulfonate, ethyl methanesulfonate, isopropyl methanesulfonate and n-butyl methanesulfonate on a DB-5 (30 m×0.32 mm×1...

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Imatinib mesylate treatment of recurrent meningiomas in preselected patients: a retrospective analysis.

    Science.gov (United States)

    Horak, Peter; Wöhrer, Adelheid; Hassler, Marco; Hainfellner, Johannes; Preusser, Matthias; Marosi, Christine

    2012-09-01

    Some unresectable and symptomatic meningiomas recur after conventional radiation therapy or stereotactic radiosurgery and are a therapeutic challenge. Evidence-based data from medical therapy for patients with recurrent meningioma can be deemed insufficient. Because of the prevalent expression of PDGF receptors in meningiomas, the tyrosine kinase imatinib mesylate has attracted interest as a treatment option for this patient group. In this retrospective study we analyzed 18 patients with recurrent meningiomas who were treated at our institution between 1996 and 2008. Nine patients with positive immunohistochemical staining of at least one of the PDGF receptors were given a daily oral dose of 400 mg imatinib mesylate as first, second, or third-line systemic therapy. Immunohistochemical staining was performed on formalin-fixed and paraffin-embedded tumor tissue with antibodies against PDGFR-α and β, c-Kit, Arg, and c-Abl. Imatinib mesylate at a dose of 400-800 mg/day was well tolerated. Of nine patients treated with imatinib, seven had stable disease and two had progressed at the first scan after three months. We observed no complete or partial responses, although prolonged disease stabilization with progression-free survival of 66.7 % at six months was observed. Overall median progression-free survival was 16 months. We conclude that single-agent imatinib mesylate might be a well-tolerated therapeutic option with high achievement of disease stabilization for preselected patients with recurrent meningiomas. Because of the small cohort, non-randomized design, and highly diverse patient population, we propose future prospective studies to validate our results.

  8. Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor.

    Science.gov (United States)

    Zook, Phillip; Pathak, Harsh B; Belinsky, Martin G; Gersz, Lawrence; Devarajan, Karthik; Zhou, Yan; Godwin, Andrew K; von Mehren, Margaret; Rink, Lori

    2017-01-01

    Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet-derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3K/AKT pathway in the survival of imatinib mesylate-resistant GIST cell lines and tumors. Here, we performed in vitro and in vivo studies evaluating the novel combination of imatinib mesylate with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST. This drug combination demonstrated significant synergistic effects in a panel of imatinib mesylate-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in imatinib mesylate-sensitive GIST xenografts as compared with treatment with imatinib mesylate or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 and neuronal pentraxin I, whose expression was significantly upregulated in combination-treated tumors compared with tumors treated with the two monotherapies. These studies provide strong preclinical justification for combining imatinib mesylate with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect. Clin Cancer Res; 23(1); 171-80. ©2016 AACR. ©2016 American Association for Cancer Research.

  9. Comparison of oral and transdermal administration of rasagiline mesylate on human melanoma tumor growth in vivo.

    Science.gov (United States)

    Meier-Davis, Susan R; Dines, Kevin; Arjmand, Fatima M; Hamlin, Richard; Huang, Betsy; Wen, Jainye; Christianson, Chad; Shudo, Jutaro; Nagata, Tetsuto

    2012-12-01

    Transdermal patch administration results in a locally high concentration of drug that induce local toxicity, including tumorogenicity. As a worst-case scenario for consequences of repeated application on neoplastic growth, the melanin-binding drug, rasagiline, was used in a transdermal formulation applied directly to a human-derived melanoma to determine the effects on tumor growth. Rasagiline mesylate was administered either orally or transdermally to athymic mice implanted with human melanoma (SKMEL28) to determine the effects on tumor growth and survival. Over a 21-day period, animals were administered daily oral gavage (15 mg/kg) or one or two rasagiline mesylate transdermal patches every 3 days. After the last dose administration, blood samples were collected to confirm drug exposure. All animals from the untreated, vehicle and rasagiline groups survived to the end of the study; however, 7 out of the 10 cisplatin-treated animals died before the end of the study. Rasagiline mesylate dosed either via the oral or transdermal routes had comparable plasma exposure and, unexpectedly, significantly reduced absolute tumor volumes and tumor growth rates in the nude mouse SKMEL28 xenograft model. Transdermal delivery of melanin-binding rasagiline does not increase melanoma growth in the xenograft model. Because rasagiline decreases melanoma growth, it may be candidate for combination therapy for melanoma.

  10. Neoodjuvant imatinib mesylate for advanced primary and metastactic/recurrent gastro-intestinal stromal tumour (GIST).

    Science.gov (United States)

    Das, Diptimay; Ganguly, Subir; Deb, Asit Ranjan; Aich, Ranen Kanti

    2013-01-01

    Therapy of gastro-intestinal stromal tumour (GIST) has changed significantly with the use of imatinib mesylate. Disease progression remains a complicated clinical issue, suggesting the need for multimodality management. This is a prospective clinical study evaluating the neoadjuvant use of Imatinib mesylate in primary GIST. There is pre-operative use of imatinib in 10 patients with operable advanced and metastatic GIST. The follow-up continued postoperatively for maximum period of two years and postoperative imatinib was given for two years. Ten patients were accrued in the study. Following imatinib mesylate therapy, the median reduction of tumour volume was 45% (range 20-60%). Six of the ten patients underwent complete resection of the tumour following neoadjuvant imatinib for a median period of three months, and are disease-free for a median follow-up of eleven months (range 6-24 months). Three patients in whom the tumours were deemed to be operable after downsizing and who refused surgery are also continuing imatinib. Imatinib did not produce serious toxicity in any patient.

  11. Early onset imatinib mesylate-induced hepatotoxicity in a patient with gastrointestinal stromal tumors.

    Science.gov (United States)

    Yachoui, Ralph

    2014-01-01

    Imatinib mesylate is used for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia and gastrointestinal stromal tumors (GISTs). It has been associated with severe hepatotoxicity, which may lead to liver failure and death. Few cases of imatinib mesylate-induced liver failure have been reported; most of them were observed in patients treated for chronic myeloid leukemia. To date, 2 cases were reported in patients treated for GISTs. Elevation of liver function tests is usually observed during the first 2-3 months after the initiation of therapy. We report a 46-year-old woman with advanced GISTs who developed hepatotoxicity 11 days after the initiation of imatinib therapy. Before therapy with imatinib, her liver function tests were normal. She had no known risk factors for viral or alcoholic liver disease. Imatinib was her only regular medication, and she had not used acetaminophen or over-the-counter medications. Her serologic studies for hepatitis were all negative. One week after imatinib discontinuation, liver function tests improved significantly. The present report confirms the possibility of early onset imatinib mesylate-induced liver failure in patients treated for GISTs. Surveillance of liver function tests should start early after the initiation of treatment and during all the duration of therapy.

  12. Development and Validation of a Spectrophotometric method for estimation of Rasagiline Mesylate in bulk and tablet dosage Form

    OpenAIRE

    Patel Pinal R; Mulgund Sugandha V

    2013-01-01

    Rasagiline mesylate is a new molecule which acts as irreversible monoamine oxidase inhibitor used for the treatment of idiopathic parkinson’s disease. The aim of present work was to develop a simple, accurate, reproducible and cost effective spectrophotomeric method for determination of Rasagiline mesylate in a pharmaceutical dosage form using phosphate buffer pH 6.8 as a solvent. The drug in solution form showed absorption maxima at 265 nm and obeys Beer’s Lambert’s law in concentration rang...

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

    Directory of Open Access Journals (Sweden)

    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.

  14. [Clinical experience of imatinib mesylate for metastatic or recurrent gastrointestinal stromal tumor].

    Science.gov (United States)

    Toyokawa, Takahiro; Yamashita, Yoshito; Yamamoto, Atsushi; Shimizu, Sadatoshi; Inoue, Tohru; Kanazawa, Akisige; Tsukamoto, Tadashi; Ikehara, Teruyuki; Nishiguchi, Yukio

    2014-01-01

    We examined the clinical results of 15 patients treated with imatinib mesylate for metastatic or recurrent gastrointestinal stromal tumors(GIST)at the Osaka City General Hospital. Treatment with imatinib was initiated at 400 mg daily; however, in case of severe adverse events, the dose was gradually reduced to 300 mg or 200 mg to reach a tolerable dose so that administration could be continued for as long as possible. Assessments were performed according to the Response Evaluation Criteria in Solid Tumors(RECIST)and Choi criteria. According to the assessment by the RECIST criteria, clinical response(CR)was observed in 1 patient; partial response(PR), in 5 patients; stable disease(SD), in 6 patients; and progressive disease(PD), in 3 patients; the response rate was 40%. However, as per the Choi criteria, CR was observed in 1 patient; PR, in 11 patients; SD, in 1 patient; and PD, in 2 patients; the response rate was 80%. The median period of progression-free survival was 2,031 days and the 5-year survival rate was 80.0%. Grade 3 or higher adverse reactions observed included leukopenia(1 case), neutropenia( 2 cases), and anemia(1 case). In 6 patients(40%), the dose of imatinib was reduced to 300 mg or less; however, no significant difference in progression-free survival was observed between the 200/300mg group and 400/800mg group. Choi criteria are useful in assessing the response of advanced GIST to imatinib mesylate, and reducing the dose of imatinib mesylate to 200/300mg daily might be sufficient for treating patients who experience severe adverse reactions.

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

    Directory of Open Access Journals (Sweden)

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

    OpenAIRE

    Olga Meltem Akay; Fezan Mutlu; Zafer Gülbaş

    2016-01-01

    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 ...

  17. Synthesis of adinazolam mesylate multiply labeled with carbon-13 and deuterium

    International Nuclear Information System (INIS)

    Hsi, R.S.P.; Stelzer, L.S.

    1989-01-01

    Adinazolam mesylate an anxiolytic and antidepressant, labelled with stable isotopes was synthesized for conducting bioavailability studies. Adinazolam labelled uniformly with carbon-13, > 99% enrichment, in the unsubstituted phenyl ring was prepared for administration as drug. In addition, adinazolam was also dual-labelled with carbon-13, as in the drug, and with deuterium, six atoms per molecule, in the N-methyl groups. The double-labelled material was prepared for use as an internal standard in the mass spectral assay procedure to be employed in the study. (author)

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

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

    2015-01-01

    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. In conclusion

  20. Imatinib mesylate inhibits cell growth of malignant peripheral nerve sheath tumors in vitro and in vivo through suppression of PDGFR-β.

    Science.gov (United States)

    Ohishi, Jun; Aoki, Mikiko; Nabeshima, Kazuki; Suzumiya, Junji; Takeuchi, Tamotsu; Ogose, Akira; Hakozaki, Michiyuki; Yamashita, Yuichi; Iwasaki, Hiroshi

    2013-05-04

    Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and associated with poor prognosis. Basic research to develop new treatment regimens is critically needed. The effects of imatinib mesylate on MPNSTs were examined in six human MPNST cell lines and in a xenograft mouse model. The results showed expression of platelet-derived growth factor receptor-β and suppression of its phosphorylation by imatinib mesylate in all six cell lines. Imatinib mesylate effectively suppressed MPNST cell growth in vitro at concentrations similar to those used clinically (1.46 - 4.6 μM) in three of six cell lines. Knockdown of PDGFR-β by transfection with a specific siRNA also caused significant reduction in cell proliferation in the sensitive cell lines, but not in the resistant cell lines. Furthermore, imatinib mesylate also significantly suppressed colony formation within soft agar and tumor growth in xenograft models using two of the three sensitive MPNST cell lines. There was excellent agreement between in vitro and in vivo sensitivity to imatinib mesylate, suggesting possible selection of imatinib-sensitive tumors by in vitro analysis. The results suggest that imatinib mesylate may be useful in the treatment of MPNST patients and in vitro studies may help select cells that are sensitive to imatinib mesylate in vivo.

  1. Malignant stromal tumor of the stomach with giant cystic liver metastases prior to treatment with imatinib mesylate.

    Science.gov (United States)

    Colović, Radoje; Micev, Marjan; Matić, Slavko; Colović, Natasa; Grubor, Nikica; Atkinson, Henry Dushan

    2013-02-01

    Gastrointestinal stromal tumors (GISTs) are rare and account for 0.1%-3% of all gastrointestinal neoplasms. GISTs are most commonly located in the stomach (60%) and 20%-25% are malignant, with metastases involving the peritoneum or the liver. Cystic liver metastases are extremely rare. Only two previous cases of patients with cystic liver metastases, prior to treatment with imatinib mesylate, have been described so far. We reported a 52-year-old woman presented with a history of abdominal fullness and discomfort. Clinical examination revealed two palpable masses, first in the right upper abdomen and second left to the umbilicus. Examinations revealed 4 cystic metastases in the liver, 3 in the right lobe (including a huge one measuring 20.5 x 16 cm), and 1 in the left lobe, together with a primary tumor on the greater curvature of the stomach. Gastric tumor was removed with a Billroth II gastrectomy. Partial excision of the largest liver metastasis was performed for histopathology. Immunohistochemistry confirmed the diagnosis of a GIST in both tissue samples. After an uneventful recovery the patient was commenced on imatinib mesylate therapy. The patient remainsed symptom-free at 24 months follow-up. This was the third reported case of gastric GIST with giant cystic liver metastases present prior to treatment with imatinib mesylate. Although extremely rare, GISTs may present with cystic liver metastases prior to treatment with imatinib mesylate, and should be considered in the differential diagnoses of patients with liver cysts of uncertain aetiology.

  2. Nonhematologic toxicity of imatinib mesylate in pediatric patients with chronic myelogenous leukemia: a predominance of musculoskeletal pain.

    Science.gov (United States)

    Heym, Kenneth M; Gressett Ussery, Sarah M; Trinkman, Heidi; Philpot, Lindsey M

    2015-03-01

    Therapy with the tyrosine kinase inhibitor imatinib mesylate has become standard initial treatment for adult and pediatric patients with chronic myelogenous leukemia. Long-term follow-up data are now available in the adult population, and the toxicity profile of imatinib mesylate among adults has been extensively studied and reported. Despite its increasing use in the pediatric population, there are limited data regarding adverse event profiles of imatinib mesylate in children, and few reports exist in the literature focusing on nonhematologic toxicity in this population. We reviewed our institutional experience with imatinib therapy for chronic myelogenous leukemia over an 8-year period of time. Nine pediatric patients began therapy with imatinib mesylate and were included in this review. We reviewed the occurrence of nonhematologic toxicity in this cohort and the impact of that toxicity on continuation of therapy. Eight patients experienced nonhematologic toxicity, including nausea/vomiting (44.4%) and musculoskeletal pain (88.9%). Three patients (33.3%) required discontinuation of imatinib therapy due to grade 3/4 musculoskeletal pain, a rate that is significantly higher than that seen in the adult population. As imatinib therapy becomes increasingly widespread in the treatment of pediatric malignancies, there may be different patterns of clinically significant nonhematologic toxicity, including higher grade musculoskeletal pain.

  3. A Case of Brain Metastases from Breast Cancer Treated with Whole-Brain Radiotherapy and Eribulin Mesylate

    Directory of Open Access Journals (Sweden)

    Carsten Nieder

    2012-01-01

    Full Text Available Patients with triple receptor-negative breast cancer often develop aggressive metastatic disease, which also might involve the brain. In many cases, systemic and local treatment is needed. It is important to consider the toxicity of chemo- and radiotherapy, especially when newly approved drugs become available. Randomised studies leading to drug approval often exclude patients with newly diagnosed brain metastases. Here we report our initial experience with eribulin mesylate and whole-brain radiotherapy (WBRT in a heavily pretreated patient with multiple brain, lung, and bone metastases from triple receptor-negative breast cancer. Eribulin mesylate was given after 4 previous lines for metastatic disease. Two weeks after the initial dose, that is, during the first cycle, the patient was diagnosed with 5 brain metastases with a maximum size of approximately 4.5 cm. She continued chemotherapy and received concomitant WBRT with 10 fractions of 3 Gy. After 3 cycles of eribulin mesylate, treatment was discontinued because of newly diagnosed liver metastases and progression in the lungs. No unexpected acute toxicity was observed. The only relevant adverse reactions were haematological events after the third cycle (haemoglobin 9.5 g/dL, leukocytes 3.1×109/L. The patient died from respiratory failure 18.5 months from diagnosis of metastatic disease, and 2.7 months from diagnosis of brain metastases. To the best of our knowledge, this is the first report on combined WBRT and eribulin mesylate.

  4. Successful treatment of gemcitabine-induced acute interstitial pneumonia with imatinib mesylate: a case report.

    Science.gov (United States)

    Fenocchio, Elisabetta; Depetris, Ilaria; Campanella, Delia; Garetto, Lucia; Schianca, Fabrizio Carnevale; Galizia, Danilo; Grignani, Giovanni; Aglietta, Massimo; Leone, Francesco

    2016-10-12

    Gemcitabine is currently the standard chemotherapy for the adjuvant treatment of pancreatic cancer. This chemotherapeutic agent is generally well-tolerated, myelosuppression and gastrointestinal toxicity being common side effects. Nevertheless, gemcitabine-induced pulmonary toxicity has been rarely reported. Despite its low incidence, the spectrum of pulmonary injury is wide, including potentially fatal conditions. We report a case of acute interstitial pneumonia related to gemcitabine, completely solved with Imatinib Mesylate (IM). The patient was a 69-year-old man, who developed a hypoxemic respiratory distress during adjuvant treatment with gemcitabine for stage IIA pancreatic cancer. The nonspecific diffuse alveolar involvement found on computed tomography (CT), together with the negative tests for infectious aetiology and the continuing severe respiratory failure despite a long course of broad-spectrum therapy, suggested gemcitabine-induced acute pneumonia as the most likely diagnosis. Thus, after the failure of steroids and all other conventional therapies, the patient was treated with imatinib mesylate on the basis of its activity in the management of graft-versus-host-induced lung fibrosis. A follow-up CT scan of chest one month later showed complete resolution of pneumonia. Despite the low frequency of serious pulmonary toxicity, gemcitabine widespread use warns clinicians to consider this life-threatening toxicity. The favourable clinical outcome with IM treatment was remarkable, warranting additional study of IM in the treatment of lung fibrosis.

  5. Effectiveness of imatinib mesylate over etoposide in the treatment of sensitive and resistant chronic myeloid leukaemia cellsin vitro.

    Science.gov (United States)

    Husaini, Roslina; Ahmad, Munirah; Zakaria, Zubaidah

    2017-06-01

    Chronic myeloid leukaemia (CML) is a form of leukaemia derived from the myeloid cell lineage. Imatinib mesylate, the breakpoint cluster region-abelson murine leukeamia kinase inhibitor, is a specific reagent used in the clinical treatment of CML. The DNA topoisomerase II inhibitor, etoposide, is also employed as a therapeutic, though it is used to a lesser extent. The present study aims to evaluate the effects of CML-targeted therapy, utilising imatinib mesylate and etoposide in the in vitro treatment of parental sensitive and adriamycin-resistant CML in the K562 and K562/ADM cell lines, respectively. Preliminary work involved the screening of multidrug resistant (MDR) gene expression, including MDR1, MRP1 and B-cell lymphoma 2 (BCL-2) at the mRNA levels. The sensitive and resistant CML cell lines expressed the MRP1 gene, though the sensitive K562 cells expressed low, almost undetectable levels of MDR1 and BCL-2 genes relative to the K562/ADM cells. Following treatment with imatinib mesylate or etoposide, the IC50 for imatinib mesylate did not differ between the sensitive and resistant cell lines (0.492±0.024 and 0.378±0.029, respectively), indicating that imatinib mesylate is effective in the treatment of CML regardless of cell chemosensitivity. However, the IC50 for etoposide in sensitive K562 cells was markedly lower than that of K562/ADM cells (50.6±16.5 and 194±8.46 µM, respectively), suggesting that the higher expression levels of MDR1 and/or BCL-2 mRNA in resistant cells may be partially responsible for this effect. This is supported by terminal deoxynucleotidyl transferase dUTP nick-end labeling data, whereby a higher percentage of apoptotic cells were found in the sensitive and resistant K562 cells treated with imatinib mesylate (29.3±0.2 and 31.9±16.7%, respectively), whereas etoposide caused significant apoptosis of sensitive K562 cells (18.3±8.35%) relative to K562/ADM cells (5.17±3.3%). In addition, the MDR genes in K562/ADM cells were knocked

  6. [Induction of hospital indebtedness due to medicine purchases under monopoly conditions: the case of imatinib mesylate].

    Science.gov (United States)

    Scopel, Carolinne Thays; Chaves, Gabriela Costa

    2015-03-01

    Medicine expenditures consume a large share of the health budget, so knowledge on the use of these funds is essential for decision-making in public health and improvement of pharmaceutical care. This study analyzed the indebtedness of a high-complexity university hospital due to increased spending on imatinib mesylate. The descriptive study was based on analysis of documents and records in the Hospital Information System (SIH) from 2002 to 2010. Starting with inclusion of the medicine in the budget, the study mapped strategies by the pharmaceutical industry and government, as well as government responses to reduce the product's price. The systematization and publication of information stored in files and electronic databases can help monitor the results of programs funded by the Brazilian Ministry of Health.

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

    Science.gov (United States)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Ohtomo, Tadashi [Department of Biochemistry, Tokyo Medical University, Tokyo (Japan); Miyazawa, Keisuke, E-mail: miyazawa@tokyo-med.ac.jp [Department of Biochemistry, Tokyo Medical University, Tokyo (Japan); Naito, Munekazu [Department of Anatomy, Tokyo Medical University, Tokyo (Japan); Moriya, Shota [Department of Biochemistry, Tokyo Medical University, Tokyo (Japan); Kuroda, Masahiko [Department of Molecular Pathology, Tokyo Medical University, Tokyo (Japan); Itoh, Masahiro [Department of Anatomy, Tokyo Medical University, Tokyo (Japan); Tomoda, Akio [Department of Biochemistry, Tokyo Medical University, Tokyo (Japan)

    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{sup -/-} 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.

  9. Gastric Antral Vascular Ectasia during the Treatment of Chronic Myelogenous Leukemia with Imatinib Mesylate.

    Science.gov (United States)

    Narukawa, Kensuke; Kakihana, Kazuhiko; Fujiwara, Takashi; Kobayashi, Takeshi; Doki, Noriko; Sakamaki, Hisashi; Ohashi, Kazuteru

    2016-01-01

    This report describes three patients with chronic myelogenous leukemia who developed gastric antral vascular ectasia (GAVE) during treatment with imatinib mesylate (IM). Cessation and/or switching from IM to nilotinib resulted in the alleviation of gastrointestinal (GI) bleeding and ectatic lesions. Furthermore, GI bleeding recurred after the re-administration of IM in one patient. Thus, we consider that the occurrence of GAVE in our patients was induced by IM. Although the precise mechanism of IM-GAVE is not understood, all patients took at least 400 mg/day of IM at the onset of GAVE. Thus, higher doses of IM (≥400 mg/day) may be a risk factor for IM-GAVE.

  10. 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.

  11. 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.

  12. Study of polymorphism in imatinib mesylate: A quantum chemical approach using electronic and vibrational spectra

    Science.gov (United States)

    Srivastava, Anubha; Joshi, B. D.; Tandon, Poonam; Ayala, A. P.; Bansal, A. K.; Grillo, Damián

    2013-02-01

    Imatinib mesylate, 4-(4-methyl-piperazin-1-ylmethyl)-N-u[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2-ylamino)phenyl]benzamide methanesulfonate is a therapeutic drug that is approved for the treatment of chronic myelogeneous leukemia (CML) and gastrointestinal stromal tumors (GIST). It is known that imatinib mesylate exists in two polymorphic forms α and β. However, β-form is more stable than the α-form. In this work, we present a detailed vibrational spectroscopic investigation of β-form by using FT-IR and FT-Raman spectra. These data are supported by quantum mechanical calculations using DFT employing 6-311G(d,p) basis set, which allow us to characterize completely the vibrational spectra of this compound. The FT-IR spectrum of α-form has also been discussed. The importance of hydrogen-bond formation in the molecular packing arrangements of both forms has been examined with the vibrational shifts observed due to polymorphic changes. The red shift of the NH stretching bands in the infrared spectrum from the computed wavenumber indicates the weakening of the NH bond. The UV-vis spectroscopic studies along with the HOMO-LUMO analysis of both polymorphs (α and β) were performed and their chemical activity has been discussed. The TD-DFT method was used to calculate the electronic absorption spectra in the gas phase as well as in the solvent environment using IEF-PCM model and 6-31G basis set. Finally, the results obtained complements to the experimental findings.

  13. 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.

  14. 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.

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

    International Nuclear Information System (INIS)

    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

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

    Science.gov (United States)

    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

  17. Two Validated Spectrofluorometric Methods for Determination of Gemifloxacin Mesylate in Tablets and Human Plasma

    Directory of Open Access Journals (Sweden)

    Noha N. Atia

    2013-01-01

    Full Text Available Two new, sensitive, and selective spectrofluorometric methods were developed for the determination of gemifloxacin mesylate (GFX in tablets and spiked human plasma. Method A was based on measurement of the enhanced fluorescence spectral behaviour of GFX in a sodium dodecyl sulphate (SDS micellar system. In aqueous solution of acetate buffer pH 5.5, the fluorescence intensity of GFX was greatly enhanced about tenfold in the presence of SDS. The fluorescence intensity was measured at 402 nm after excitation at 274 nm. Method B was based on Hantzsch condensation reaction between the primary amino group of GFX with acetylacetone and formaldehyde in acetate buffer of pH 3.5 yielding a highly yellow fluorescent derivative. The reaction of GFX with acetylacetone-formaldehyde system solution resulted in bathochromic shift of both emission (476 nm and excitation (420 nm wavelengths. The fluorescence intensity was directly proportional to the concentration over the range 10–1000 ng/ml and 100–2000 ng/ml for method A and B, respectively. The proposed methods were applied successfully for determination of GFX in its tablets and spiked plasma. Therefore, these methods can be considered of real interest for reliable and practical quality control analysis of GFX.

  18. 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

  19. 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)

  20. Management of HIV infection in Nigeria with zalcitabine in combination with saquinavir mesylate: preliminary findings.

    Science.gov (United States)

    Akinsete, I; Njoku, O S; Okanny, C C; Chukwuani, C M; Akanmu, A S

    2000-01-01

    The efficacy and safety of a combination therapy with two anti-retroviral drugs, zalcitabine (ddC) and saquinavir mesylate was evaluated in 24 adult Nigerian patients with HIV infection. The result of an interim analysis after a 6-month course of therapy is presented herein. Patients were given zalcitabine 2.25 mg and saquinavir 1800 mg per day. Efficacy was evaluated by improvement in the CD4 cell count and disappearance and/or resolution of clinical signs and symptoms from the patient baseline condition. Tolerability and safety were assessed by the occurrence of adverse event and monitoring of biochemical parameters such as alanine transaminase, alkaline phosphatase and total bilirubin. The haemogram profile of patients was also monitored. There was clinical improvement in 79.2% of the patients, a minimal increase in the CD4 cell count was observed and the incidence of adverse event was 40%. The haematological and biochemical profile of the patients were not significantly affected by treatment (p > 0.05). We therefore conclude that the drug cocktail comprising zalcitabine and saquinavir does posses good potentials for effective management of Nigerian patients with HIV infection. However, it is imperative and important to continue treatment with the drugs for a longer time in order to demonstrate sustained response.

  1. Optimal Duration of Imatinib Mesylate Therapy in Metastatic Gastrointestinal Stromal Tumours

    Directory of Open Access Journals (Sweden)

    Ruth Gauden

    2011-04-01

    Full Text Available While current literature provides evidence that imatinib mesylate has significant activity in patients with advanced and metastatic gastrointestinal stromal tumour (GIST, and highlights the potential for the development of anticancer drugs based on specific molecular abnormalities present in cancers, specific recommendations concerning the optimal duration of therapy remain controversial. This case presents the favourable outcome of a patient who originally presented almost 9 years ago with widespread, bulky, metastatic GIST involving the abdomen and pelvis. A sustained, complete response was achieved with imatinib and prompted an interruption in treatment 7 years after initial presentation. The disease reoccurred extensively within 9 months of treatment interruption, but once again rapidly completely responded to the recommencement of imatinib, with that response being now maintained for over 9 months. This report suggests that dramatic and durable responses to imatinib can be achieved in individual cases despite the lack of specific guidelines in the literature with respect to defining how long treatment with imatinib should be continued in the absence of evidence of tumour progression.

  2. Interactions with polynucleotides and antitumor activity of amidino and imidazolinyl substituted 2-phenylbenzothiazole mesylates.

    Science.gov (United States)

    Racané, Livio; Stojković, Ranko; Tralić-Kulenović, Vesna; Cerić, Helena; Đaković, Marijana; Ester, Katja; Krpan, Ana Mišir; Stojković, Marijana Radić

    2014-10-30

    Based on previously reported antiproliferative activity screening, four most promising disubstituted 2-phenylbenzothiazole hydrochlorides were chosen for detailed study. Water solubility, as well as liphophilicity/hydrophilicity balance of organic core were modified by conversion to mesylate salts. For purpose of structure/activity studies their structures were determined by X-ray structure analysis. Detailed analysis of interactions of new compounds with double stranded (ds-) DNA/RNA by UV/Vis and CD titrations, thermal melting and viscometry experiments revealed that most of studied compounds intercalate into ds-RNA but bind into minor groove of AT-DNA, and agglomerate along GC-DNA. Furthermore, compounds also interact with ss-RNA, but only amino-imidazolinyl 2-phenylbenzothiazole, 4b displayed well defined orientation and dominant binding mode (by induced CD signals) with poly A and poly G. Besides, in vitro investigations revealed moderate to high antiproliferative activity of benzothiazoles against seven human cancer cell lines, while in some cases (HTC 116, SW620, MIA PaCa-2) high correlation between the type of the amidino group and cytotoxic activity was observed. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  3. 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.

  4. Correlation between computed tomography and pathological findings of gstrointestinalstromal tumors treated with imatinib mesylate

    Energy Technology Data Exchange (ETDEWEB)

    Sim, Ki Choon; Park, Beom Jin; Han, Na Yeon; Sung, Deuk Jae; Kim Min Ju; Cho, Sung Bum [Dept. of Radiology, Anam Hospital, College of Medicine, Korea University, Seoul (Korea, Republic of); Ha, Hyun Kwon [Dept. of Radiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul (Korea, Republic of); Kim, Hyoung Rae [Dept. of Imaging Medicine, College of Medicine, Kangwon National University, Chuncheon (Korea, Republic of)

    2014-11-15

    To evaluate the correlation between pathological and computed tomography (CT) findings of gastrointestinal stromal tumors (GISTs) after imatinib mesylate (imatinib) treatment. Twenty-six patients with GIST (17 men, 9 women; mean age, 56 years) who underwent treatment with imatinib and who were registered at our institution were included. Eight patients had primary and 18 had metastatic tumors. The correlation between CT and pathological findings was evaluated for all 26 tumors, which were resected after imatinib treatment. The mean size change in the tumors after imatinib treatment was -1.4 cm (range, -7.8-2.5 cm). A reduction in tumor CT attenuation value was observed after imatinib treatment (mean, 29.1 Hounsfield units) in 20 of 26 tumors. Reduced attenuation was associated with non-tumorous pathological findings, including cystic degeneration (6/20), hemorrhagic necrosis (6/20), hyaline degeneration (6/20), and combined pathology without a viable portion (2/20). Of six tumors showing increased attenuation values after treatment, four (66.7%) showed an abundant viable portion. The increase in tumor size was not associated with the presence of a viable portion in any tumor. CT attenuation changes in GISTs may adequately reflect the pathological findings in GISTs after imatinib treatment.

  5. The DREAM complex in antitumor activity of imatinib mesylate in gastrointestinal stromal tumors.

    Science.gov (United States)

    DeCaprio, James A; Duensing, Anette

    2014-07-01

    Although most gastrointestinal stromal tumors respond well to treatment with the small molecule kinase inhibitor imatinib mesylate (Gleevec), complete remissions are rare and the majority of patients achieve disease stabilization. Furthermore, discontinuation of treatment in the presence of residual tumor mass almost inevitably leads to tumor progression. These observations suggest that a subset of tumor cells not only persists under imatinib treatment, but remains viable. The current article reviews the molecular basis for these findings and explores strategies to exploit them therapeutically. Although imatinib induces apoptosis in a subset of gastrointestinal stromal tumor cells, it leads to a reversible exit from the cell division cycle and entry into G0, a cell cycle state called quiescence, in the remaining cells. Mechanistically, this process involves the DREAM complex (DP, p130/RBL2, E2F4 and MuvB), a newly identified key regulator of quiescence. Interfering with DREAM complex formation either by siRNA-mediated knockdown or by pharmacological inhibition of the regulatory kinase dual-specificity tyrosine phosphorylation-regulated kinase 1A was shown to enhance imatinib-induced gastrointestinal stromal tumor cell death. Targeting the DREAM complex and imatinib-induced quiescence could provide opportunities for future therapeutic interventions toward more efficient imatinib responses.

  6. Effects of imatinib mesylate in mouse models of multiple sclerosis and in vitro determinants.

    Science.gov (United States)

    Azizi, Gholamreza; Haidari, Mohsen Reza; Khorramizadeh, Mohammadreza; Naddafi, Fatemeh; Sadria, Reza; Javanbakht, Mohammad Hassan; Sedaghat, Reza; Tofighi Zavareh, Farzaneh; Mirshafiey, Abbas

    2014-06-01

    Experimental autoimmune encephalomyelitis (EAE) is a mouse model for multiple sclerosis (MS), This autoimmune disease is mainly mediated by adaptive and innate immune responses that lead to an inflammatory demyelination and axonal damage. Imatinib mesylate is a selective protein tyrosine kinase inhibitor with immunomodulatory properties that abrogates multiple signal transduction pathways in immune cells. In the present research, our aim was to test the therapeutic efficacy of imatinib in experimental model of MS. We performed EAE induction in 23 female C57 mice by myelin oligodendrocyte glycoprotein-35-55 (MOG35-55) in Complete Freund's Adjuvant (CFA) emulsion and used imatinib for treatment of EAE. The clinical evaluation and histopathology were assessed. Also for in vitro analysis, we used U-87 MG, C6 and WEHI-164 cell lines to evaluate the inhibitory effects of imatinib in cell proliferation, as well as pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and matrix metalloproteinase (MMP) secretion. Our findings demonstrated that this drug had beneficial effects on EAE by attenuation in the severity and a delay in the onset of disease. In vitro, imatinib inhibited cell proliferation, MMP-2 expression and activity and also attenuated the production of proinflammatory cytokines. Imatinib with its potential therapeutic effects and immunomodulatory properties may be considered, after additional necessary tests and trials, for treatment of MS.

  7. Hyaluronan coated liposomes as the intravenous platform for delivery of imatinib mesylate in MDR colon cancer.

    Science.gov (United States)

    Negi, Lalit Mohan; Jaggi, Manu; Joshi, Vidushi; Ronodip, Kar; Talegaonkar, Sushama

    2015-02-01

    Imatinib mesylate has been evaluated for possible potential in treatment of colon cancer in recent times. However, due to significant reporting of P-gp expression in colon cancer, it can come across set back due to MDR. Therefore, in present work the liposomal formulation containing imatinib-bile salt conjugate was developed and investigated for its comparative performance in MDR colon cancer cells and surface modified with hyaluronic acid for achieving low hemotoxicity with stealth characteristics. Imatinib was successfully conjugated with sodium-deoxycholate by charged conjugation and evaluated through FTIR, DSC and PXRD. The developed conjugate (IM-SD) was encapsulated in liposomes and the conditions were optimized by Box-Behnken statistical design to achieve a size of 56.56±1.23 nm along with 99.11±0.89% entrapment efficiency (LIPO). The liposomes were surface modified with hyaluronic acid and the size was enhanced to 159.14±3.2 nm (HA-LIPO). Flow cytometric studies demonstrated the enhanced uptake of P-gp substrate rhodamine dye in P-gp positive colo 320 colon cancer cells. In addition, an enhanced cellular internalization of HA-LIPO in CD-44 positive HT-29 and colo 320 cells indicates the targeting attributes of the hyaluronan coated liposomes. Finally, the hyaluronan coated liposomes were also found to have low opsonization activity. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Appropriate modulation of autophagy sensitizes malignant peripheral nerve sheath tumor cells to treatment with imatinib mesylate.

    Science.gov (United States)

    Okano, Munehiro; Sakata, Naoki; Ueda, Satoshi; Takemura, Tsukasa

    2014-04-01

    Malignant peripheral nerve sheath tumor (MPNST), very rare in childhood, is a highly aggressive soft-tissue tumor. We experienced a case of a 7-year-old boy with MPNST who was treated with imatinib mesylate (imatinib) after the identification of platelet-derived growth factor receptor expression in his tumor. We were unable to observe clinical benefits of imatinib in this patient. Therefore, cellular reactions of imatinib were investigated in vitro using 3 MPNST cell lines. Imatinib induced cytotoxicity in vitro with variable IC50 values (11.7 to >30 μM). Induction of apoptosis was not a pivotal mechanism in the inhibitory effects. We found that the treatment of MPNST cell lines with imatinib induced autophagy. Suppression of the initiation of autophagy by 3-methyladenine or small interfering RNA (siRNA) against beclin-1 attenuated the imatinib-mediated cytotoxicity. In contrast, blocking the formation of autophagosomes or the development of autolysosomes using siRNA against microtubule-associated protein light chain 3B, bafilomycin A1, chloroquine, or an MEK1/2 inhibitor (U0126) enhanced the imatinib-induced cytotoxicity in MPNST cells. Our data showed that the imatinib-mediated autophagy can function as a cytotoxic mechanism and that appropriate modulation of autophagy may sensitize MPNST cells to imatinib, which in turn may be a novel therapeutic strategy for MPNST.

  9. A safety evaluation of imatinib mesylate in the treatment of gastrointestinal stromal tumor.

    Science.gov (United States)

    Ben Ami, Eytan; Demetri, George D

    2016-01-01

    For the last 15 years, imatinib mesylate has been the first line treatment of choice for advanced (metastatic) GIST. This review describes key efficacy data on imatinib for the treatment of GIST, and focuses on safety and tolerability of imatinib, with emphasis on common adverse events management and long term toxicity profile. Imatinib has been the standard of care for metastatic GIST and probably will continue to be so for the next few years. Still, despite dramatic responses initially, imatinib drug resistance continues to be the major factor for treatment discontinuation. The toxicity profile of imatinib has been well characterized, and although the majority of patients experience an adverse event during treatment with imatinib, these side effects are usually mild and manageable, with the majority of patients continuing treatment uninterruptedly. Early concerns regarding imatinib related cardiotoxicity in GIST have not been confirmed in large prospective randomized trials, with reports indicating a low incidence of approximately 0.2%-0.4%. Future strategies for treatment of imatinib resistant GIST will probably include novel tyrosine kinase inhibitors, combination therapies or immunotherapy.

  10. Imatinib mesylate lacks efficacy in relapsed/refractory peripheral T cell lymphoma.

    Science.gov (United States)

    Jacobsen, Eric; Pozdnyakova, Olga; Redd, Robert; Fisher, David C; Dorfman, David M; Dal Cin, Paola; LaCasce, Ann; Armand, Philippe; Hochberg, Ephraim; Cote, Gregory; Shahsafaei, Ali; Neuberg, Donna; Brown, Jennifer R; Freedman, Arnold S

    2015-04-01

    Platelet derived growth factor-α (PDGFR-α) is expressed in peripheral T cell lymphoma, not otherwise specified (PTCL, NOS). Imatinib mesylate demonstrated in vitro cytotoxicity against primary PTCL, NOS cells. We initiated a trial of imatinib in 12 patients with relapsed or refractory T-cell non-Hodgkin lymphoma (T-NHL). PDGFR-α expression by immunohistochemistry and fluorescence in situ hybridization (FISH) to assess for FIP1L1-PDGFR-α fusion and/or PDGFR-α amplification were not required for study entry. We documented no objective responses. The median progression-free survival was 21.0 days (90% confidence interval [CI] 15.0, 28.0) and median overall survival was 154 days (90% CI 35, 242). Four patients had tissue available for analysis of PDGFR-α by immunohistochemistry and three of these patients' tumors expressed PDGFR-α. Imatinib was not effective for the treatment of peripheral T cell lymphoma in an unselected group of patients in which PDGFR-α expression was not required for study entry.

  11. Concurrent male gynecomastia and testicular hydrocele after imatinib mesylate treatment of a gastrointestinal stromal tumor.

    Science.gov (United States)

    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; Kang, Yoon-Koo

    2005-06-01

    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 noncommunicative 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.

  12. A long-term follow-up of the imatinib mesylate treatment for the patients with recurrent gastrointestinal stromal tumor (GIST): the liver metastasis and the outcome

    International Nuclear Information System (INIS)

    Zhu, Jiang; Yang, Yu; Zhou, Lin; Jiang, Ming; Hou, Mei

    2010-01-01

    About 80% of patients with GIST would experience tumor recurrence or metastasis after radical resection. The most common site of the metastasis is the liver. Imatinib mesylate has been proved effective for advanced GIST. The present study was designed to further observe the effectiveness of the imatinib mesylate treatment on the recurrent GIST and the correlation between the liver metastasis and the outcome. Forty-two patients who had recurrent GIST after the first radical resection were enrolled. According to the recurrent sites, the patients were divided into 3 groups: group LG (recurrent liver GISTs), group AG (recurrent abdominal GISTs) and group ALG (recurrent abdominal and liver GISTs). All the patients were given imatinib mesylate at an initial dose of 400 mg per day. Their clinical data was prospectively collected. A follow-up over 3 years was conducted. Tumor response, time to progression and survival were evaluated. The long-term Imatinib mesylate treatment was safe and well tolerated. At a median follow-up time for 39.5 months, the 3-year survival rate was 66.7%. Median TTP and OS were 37 months (95% CI: 28.2~45.8 months) and 48 months (95% CI: 37.0~58.9 months), respectively. There was no statistical difference in tumor response among the 3 groups. The similar TTP (P = 0.291) and OS (P = 0.160) were observed in the 3 groups. The imatinib mesylate treatment could prolong the survival of the patients who have recurrent GIST after the radical surgery in spite of an existence of the liver metastasis. Survival was not significantly affected by liver metastasis when imatinib mesylate was warranted

  13. A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted olid tumours

    OpenAIRE

    Adenis, A; Ray-Coquard, I; Italiano, A; Chauzit, E; Bui-Nguyen, B; Blay, J-Y; Tresch-Bruneel, E; Fournier, C; Clisant, S; Amela, E Y; Cassier, P A; Molimard, M; Penel, N

    2013-01-01

    Background: Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells. Methods: We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) an...

  14. 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.

  15. Pharmacokinetics and pharmacodynamics of fenoldopam mesylate for blood pressure control in pediatric patients

    Directory of Open Access Journals (Sweden)

    Yaster Myron

    2008-10-01

    Full Text Available Abstract Background Fenoldopam mesylate, a selective dopamine1-receptor agonist, is used by intravenous infusion to treat hypertension in adults. Fenoldopam is not approved by the FDA for use in children; reports describing its use in pediatrics are limited. In a multi-institutional, placebo controlled, double-blind, multi-dose trial we determined the pharmacokinetic (PK and pharmacodynamic (PD characteristics and side-effect profile of fenoldopam in children. Methods Seventy seven (77 children from 3 weeks to 12 years of age scheduled for surgery in which deliberate hypotension would be induced were enrolled. Patients were randomly assigned to one of five, blinded treatment groups (placebo or fenoldopam 0.05, 0.2, 0.8, or 3.2 mcg/kg/min iv for a 30-minute interval after stabilization of anesthesia and placement of vascular catheters. Following the 30-minute blinded interval, investigators adjusted the fenoldopam dose to achieve a target mean arterial pressure in the open-label period until deliberate hypotension was no longer indicated (e.g., muscle-layer closure. Mean arterial pressure and heart rate were continuously monitored and were the primary endpoints. Results Seventy-six children completed the trial. Fenoldopam at doses of 0.8 and 3.2 mcg/kg/min significantly reduced blood pressure (p Conclusion Fenoldopam is a rapid-acting, effective agent for intravenous control of blood pressure in children. The effective dose range is significantly higher in children undergoing anesthesia and surgery (0.8–1.2 mcg/kg/min than as labeled for adults (0.05–0.3 mcg/kg/min. The PK and side-effect profiles for children and adults are similar.

  16. 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.

  17. Synergy between proteasome inhibitors and imatinib mesylate in chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Zheng Hu

    Full Text Available BACKGROUND: Resistance developed by leukemic cells, unsatisfactory efficacy on patients with chronic myeloid leukemia (CML at accelerated and blastic phases, and potential cardiotoxity, have been limitations for imatinib mesylate (IM in treating CML. Whether low dose IM in combination with agents of distinct but related mechanisms could be one of the strategies to overcome these concerns warrants careful investigation. METHODS AND FINDINGS: We tested the therapeutic efficacies as well as adverse effects of low dose IM in combination with proteasome inhibitor, Bortezomib (BOR or proteasome inhibitor I (PSI, in two CML murine models, and investigated possible mechanisms of action on CML cells. Our results demonstrated that low dose IM in combination with BOR exerted satisfactory efficacy in prolongation of life span and inhibition of tumor growth in mice, and did not cause cardiotoxicity or body weight loss. Consistently, BOR and PSI enhanced IM-induced inhibition of long-term clonogenic activity and short-term cell growth of CML stem/progenitor cells, and potentiated IM-caused inhibition of proliferation and induction of apoptosis of BCR-ABL+ cells. IM/BOR and IM/PSI inhibited Bcl-2, increased cytoplasmic cytochrome C, and activated caspases. While exerting suppressive effects on BCR-ABL, E2F1, and beta-catenin, IM/BOR and IM/PSI inhibited proteasomal degradation of protein phosphatase 2A (PP2A, leading to a re-activation of this important negative regulator of BCR-ABL. In addition, both combination therapties inhibited Bruton's tyrosine kinase via suppression of NFkappaB. CONCLUSION: These data suggest that combined use of tyrosine kinase inhibitor and proteasome inhibitor might be helpful for optimizing CML treatment.

  18. Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines

    Science.gov (United States)

    2012-01-01

    Background Imatinib mesylate is currently the drug of choice to treat chronic myeloid leukemia. However, patient resistance and cytotoxicity make secondary lines of treatment, such as omacetaxine mepesuccinate, a necessity. Given that drug cytotoxicity represents a major problem during treatment, it is essential to understand the biological pathways affected to better predict poor drug response and prioritize a treatment regime. Methods We conducted cell viability and gene expression assays to determine heritability and gene expression changes associated with imatinib and omacetaxine treatment of 55 non-cancerous lymphoblastoid cell lines, derived from 17 pedigrees. In total, 48,803 transcripts derived from Illumina Human WG-6 BeadChips were analyzed for each sample using SOLAR, whilst correcting for kinship structure. Results Cytotoxicity within cell lines was highly heritable following imatinib treatment (h2 = 0.60-0.73), but not omacetaxine treatment. Cell lines treated with an IC20 dose of imatinib or omacetaxine showed differential gene expression for 956 (1.96%) and 3,892 transcripts (7.97%), respectively; 395 of these (0.8%) were significantly influenced by both imatinib and omacetaxine treatment. k-means clustering and DAVID functional annotation showed expression changes in genes related to kinase binding and vacuole-related functions following imatinib treatment, whilst expression changes in genes related to cell division and apoptosis were evident following treatment with omacetaxine. The enrichment scores for these ontologies were very high (mostly >10). Conclusions Induction of gene expression changes related to different pathways following imatinib and omacetaxine treatment suggests that the cytotoxicity of such drugs may be differentially tolerated by individuals based on their genetic background. PMID:22917222

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

    Science.gov (United States)

    Soares, P.B.; Jeremias, T.S.; Alvarez-Silva, M.; Licínio, M.A.; Santos-Silva, M.C.; Vituri, C.L.

    2012-01-01

    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. PMID:23011404

  20. Imatinib Mesylate Causes Genome-wide Transcriptional Changes in Systemic Sclerosis Fibroblasts in vitro

    Science.gov (United States)

    Hinchcliff, Monique; Huang, Chiang-Ching; Ishida, Wataru; Fang, Feng; Lee, Jungwha; Jafari, Nadereh; Wilkes, Mark; Bhattacharyya, Swati; Leof, Edward; Varga, John

    2013-01-01

    Objective Systemic sclerosis (SSc) is a heterogeneous multifactorial disease dominated by progressive skin and internal organ fibrosis that is driven in part by Transforming Growth Factor-beta (TGF-β). An important downstream target of TGF-β is the Abelson (c-Abl) tyrosine kinase, and its inhibition by imatinib mesylate (Gleevec)attenuates fibrosis in mice. Here we examined the effect of c-Abl activation and blockade in explanted healthy control and SSc fibroblasts. Methods Skin biopsies and explanted fibroblasts from healthy subjects and patients with SSc were studied. Changes in genome-wide expression patterns in imatinib-treated control and SSc fibroblasts were analyzed by DNA microarray. Results Treatment of control fibroblasts with TGF-β resulted in activation of c-Abl and stimulation of fibrotic gene expression that was prevented by imatinib. Moreover, imatinib reduced basal collagen gene expression in SSc but not control fibroblasts. No significant differences in tissue levels of c-Abl and phospho-c-Abl were detected between SSc and control skin biopsies. In vitroimatinib induced dramatic changes in the expression of genes involved in fibrosis, cardiovascular disease, inflammation, and lipid and cholesterol metabolism. Remarkably, of the 587-imatinib-responsive genes, 91% showed significant change in SSc fibroblasts, but only 12% in control fibroblasts. Conclusion c-Abl plays a key role in fibrotic responses. Imatinib treatment results in dramatic changes in gene expression in SSc fibroblasts but has only modest effects in control fibroblasts. These data provide novel insights into the mechanisms underlying the antifibrotic effect of imatinib in SSc. PMID:22691216

  1. Development and Validation of a Stability-Indicating HPTLC Method for Analysis of Rasagiline Mesylate in the Bulk Drug and Tablet Dosage Form

    Directory of Open Access Journals (Sweden)

    Singaram Kathirvel

    2012-01-01

    Full Text Available A simple and sensitive thin-layer chromatographic method has been established for analysis of rasagiline mesylate in pharmaceutical dosage form. Chromatography on silica gel 60 F254 plates with 6 : 1 : 2(v/v/v butanol-methanol water as mobile phase furnished compact spots at Rf  0.76±0.01. Densitometric analysis was performed at 254 nm. To show the specificity of the method, rasagiline mesylate was subjected to acid, base, neutral hydrolysis, oxidation, photolysis, and thermal decomposition, and the peaks of degradation products were well resolved from that of the pure drug. Linear regression analysis revealed a good linear relationship between peak area and amount of rasagiline mesylate in the range of 100–350 ng/band. The minimum amount of rasagiline mesylate that could be authentically detected and quantified was 11.12 and 37.21 ng/band, respectively. The method was validated, in accordance with ICH guidelines for precision, accuracy, and robustness. Since the method could effectively separate the drug from its degradation products, it can be regarded as stability indicating.

  2. [A case of rectal gastrointestinal stromal tumor in an elderly patient who was successfully treated with imatinib mesylate with no significant adverse events].

    Science.gov (United States)

    Gomi, Kuniyuki; Mihara, Motohiro; Abe, Mitsutoshi; Ikeda, Yoshiaki; Shimada, Kou; Maruyama, Kiyotomi; Kajikawa, Shoji; Shirota, Hiroshi

    2014-01-01

    An 89-year-old male patient was found to have a mass with a diameter of 54 mm in the pelvic cavity, connected to the rectum, and was diagnosed with a gastrointestinal stromal tumor (GIST)of the rectum by transrectal biopsy. The patient was treated continuously with 400mg/day of imatinib mesylate with no significant adverse events, and the tumor gradually reduced in size. The tumor reduced in size to a diameter of 24 mm at 57 months post-treatment, and a partial response has been maintained for 60 months. Colorectal GIST is rare, comprising 5% of all GIST cases, and surgical resection is the first choice of treatment. In this case, due to a lack of consent, we chose imatinib mesylate as the treatment. However, imatinib mesylate has been reported to induce adverse events more frequently in older patients, and thus we took care to reduce the treatment dosage. We report this case to highlight that a normal quantity of imatinib mesylate can be administered, with no significant adverse events.

  3. "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

    of skin fibrosis and increase in joint mobility evaluated by the modified Rodnan skin score and a goniometer. Results In two patients, the imatinib mesylate dose was reduced to 200 mg⁄ day and in one patient to 100 mg⁄ day. Two patients were treated for 24 weeks, one patient for 16 weeks and one patient...

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

    Directory of Open Access Journals (Sweden)

    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.

  5. ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate for operable malignant gastrointestinal stromal tumor: monitoring with 18F-FDG PET and correlation with genotype and GLUT4 expression.

    Science.gov (United States)

    Van den Abbeele, Annick D; Gatsonis, Constantine; de Vries, Daniel J; Melenevsky, Yulia; Szot-Barnes, Agnieszka; Yap, Jeffrey T; Godwin, Andrew K; Rink, Lori; Huang, Min; Blevins, Meridith; Sicks, Jorean; Eisenberg, Burton; Siegel, Barry A

    2012-04-01

    We investigated the correlation between metabolic response by (18)F-FDG PET and objective response, glucose transporter type 4 (GLUT4) expression, and KIT/PDGFRA mutation status in patients with gastrointestinal stromal tumor undergoing neoadjuvant imatinib mesylate therapy. (18)F-FDG PET was performed at baseline, 1-7 d, and 4 or 8 wk after imatinib mesylate initiation. Best objective response was defined by version 1.0 of the Response Evaluation Criteria in Solid Tumors (RECIST). Mutational analysis and tumor GLUT4 expression by immunohistochemistry were done on tissue obtained at baseline or surgery. (18)F-FDG PET showed high baseline tumor glycolytic activity (mean SUV(max), 14.2; range, 1.3-53.2), decreasing after 1 wk of imatinib mesylate (mean, 5.5; range, -0.5-47.7, P imatinib mesylate initiation, metabolic response by (18)F-FDG PET was documented earlier (1-7 d) and was of much greater magnitude (36/44) than that documented by RECIST (2/39). Immunohistochemistry data suggest that GLUT4 may play a role in (18)F-FDG uptake in gastrointestinal stromal tumor, GLUT4 levels decrease after imatinib mesylate therapy in most patients with PMR, and the biologic action of imatinib mesylate interacts with glycolysis and GLUT4 expression. A greater than 85% metabolic response was observed as early as days 1-7 in patients with exon 11 mutations.

  6. Formulation and statistical optimization of self-microemulsifying drug delivery system of eprosartan mesylate for improvement of oral bioavailability.

    Science.gov (United States)

    Dangre, Pankaj; Gilhotra, Ritu; Dhole, Shashikant

    2016-10-01

    The present investigation is aimed to design a statistically optimized self-microemulsifying drug delivery system (SMEDDS) of eprosartan mesylate (EM). Preliminary screening was carried out to find a suitable combination of various excipients for the formulation. A 3(2) full factorial design was employed to determine the effect of various independent variables on dependent (response) variables. The independent variables studied in the present work were concentration of oil (X 1) and the ratio of S mix (X 2), whereas the dependent variables were emulsification time (s), globule size (nm), polydispersity index (pdi), and zeta potential (mV), and the multiple linear regression analysis (MLRA) was employed to understand the influence of independent variables on dependent variables. Furthermore, a numerical optimization technique using the desirability function was used to develop a new optimized formulation with desired values of dependent variables. The optimized SMEDDS formulation of eprosartan mesylate (EMF-O) by the above method exhibited emulsification time, 118.45 ± 1.64 s; globule size, 196.81 ± 1.29 nm; zeta potential, -9.34 ± 1.2 mV, and polydispersity index, 0.354 ± 0.02. For the in vitro dissolution study, the optimized formulation (EMF-O) and pure drug were separately entrapped in the dialysis bag, and the study indicated higher release of the drug from EMF-O. In vivo pharmacokinetic studies in Wistar rats using PK solver software revealed 2.1-fold increment in oral bioavailability of EM from EMF-O, when compared with plain suspension of pure drug.

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

    Science.gov (United States)

    Elmholdt, T R; Buus, N H; Ramsing, M; Olesen, A B

    2013-06-01

    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. To investigate if the tyrosine kinase inhibitor, imatinib mesylate was effective in patients with moderate to severe nephrogenic systemic fibrosis. Among 25 patients with nephrogenic systemic fibrosis evaluated for the study from 1 October 2009 to 1 December 2010, four were included. They were treated with oral imatinib mesylate at a start dose of 400 mg/day. Reduction of skin fibrosis and increase in joint mobility evaluated by the modified Rodnan skin score and a goniometer. In two patients, the imatinib mesylate dose was reduced to 200 mg/day and in one patient to 100 mg/day. Two patients were treated for 24 weeks, one patient for 16 weeks and one patient for 4 weeks. Three patients experienced tethering of their skin which lessened with reduction in modified Rodnan skin score from 24 to 20, 24 to 17 and 21 to 14 but with very limited changes in joint mobility. The fourth patient discontinued the treatment due to a complicating infection. 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 and conclusions of the results. © 2011 The Authors. Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology.

  8. PLK1 inhibitors synergistically potentiate HDAC inhibitor lethality in imatinib mesylate-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo.

    Science.gov (United States)

    Dasmahapatra, Girija; Patel, Hiral; Nguyen, Tri; Attkisson, Elisa; Grant, Steven

    2013-01-15

    To determine whether Polo-like kinase 1 (PLK1) inhibitors (e.g., BI2536) and histone deacetylase (HDAC) inhibitors (e.g., vorinostat) interact synergistically in the BCR/ABL(+) leukemia cells sensitive or resistant to imatinib mesylate (IM) in vitro and in vivo. K562 and LAMA84 cells sensitive or resistant to imatinib mesylate and primary CML cells were exposed to BI2536 and vorinostat. Effects on cell viability and signaling pathways were determined using flow cytometry, Western blotting, and gene transfection. K562 and BV173/E255K animal models were used to test in vivo efficacy. Cotreatment with BI2536 and vorinostat synergistically induced cell death in parental or imatinib mesylate-resistant BCR/ABL(+) cells and primary CD34(+) bone marrow cells but was minimally toxic to normal cells. BI2536/vorinostat cotreatment triggered pronounced mitochondrial dysfunction, inhibition of p-BCR/ABL, caspase activation, PARP cleavage, reactive oxygen species (ROS) generation, and DNA damage (manifest by increased expression of γH2A.X, p-ATM, p-ATR), events attenuated by the antioxidant TBAP. PLK1 short hairpin RNA (shRNA) knockdown significantly increased HDACI lethality, whereas HDAC1-3 shRNA knockdown reciprocally increased BI2536-induced apoptosis. Genetic interruption of the DNA damage linker H1.2 partially but significantly reduced PLK1/HDAC inhibitor-mediated cell death, suggesting a functional role for DNA damage in lethality. Finally, BI2536/vorinostat cotreatment dramatically reduced tumor growth in both subcutaneous and systemic BCR/ABL(+) leukemia xenograft models and significantly enhanced animal survival. These findings suggest that concomitant PLK1 and HDAC inhibition is active against imatinib mesylate-sensitive or refractory CML and ALL cells both in vitro and in vivo and that this strategy warrants further evaluation in the setting of BCR/ABL(+) leukemias. ©2012 AACR.

  9. Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma.

    Science.gov (United States)

    Tsao, Anne S; Harun, Nusrat; Lee, J Jack; Heymach, John; Pisters, Katherine; Hong, Waun Ki; Fujimoto, Junya; Wistuba, Ignacio

    2014-05-01

    We conducted a phase I trial of cisplatin/pemetrexed/imatinib mesylate, an oral platelet-derived growth factor receptor (PDGFR) inhibitor, in chemonaive patients with malignant pleural mesothelioma (MPM). A standard 3 + 3 dose-escalating trial was used with the end points of maximum tolerated dose (MTD), response rate, survival, safety/toxicity, and tumor PDGFR levels. Seventeen patients with MPM were enrolled. The most common (any grade) side effects were nausea, fatigue, hypomagnesemia, and anemia. The MTD was established at dose level 3 (imatinib 600 mg) with a dose-limiting toxicity (DLT) of nausea and vomiting. The median progression-free survival (PFS) was 7.9 months and the median overall survival (OS) was 8.8 months. Patients with a sarcomatoid subtype had worse PFS (P = .01) and OS (P = .009), whereas they had a better Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 predicted for improved OS (P = .001) and PFS (P = .013). The 6 patients who completed all 6 treatment cycles had better OS (P = .006); the median PFS was 9.6 months and the OS was 22.4 months. In the translational studies, 14 patients had adequate tumor tissue that could be assessed for immunohistochemical (IHC) analysis and fluorescence in situ hybridization (FISH). Patients with higher than median p-PDGFRα IHC expression had a better OS (P = .013). When assessed as a continuous variable, higher p-PDGFRα in tumor cells correlated with an improved OS (P = .045). None of the other 4 IHC biomarkers were predictive or prognostic for survival. Twelve patients had successful PDGFRB FISH results, but none met the criteria of ≥ 4 copies of the PDGFRB gene; thus a correlation with clinical outcomes could not be done. The cisplatin/pemetrexed/imatinib mesylate combination had clinical benefit in some patients with MPM but was not well tolerated. Further investigation into alternative antiangiogenic agents, including PDGFRα inhibitors, is warranted. Copyright © 2014 Elsevier

  10. ERK2, but not ERK1, mediates acquired and "de novo" resistance to imatinib mesylate: implication for CML therapy.

    Directory of Open Access Journals (Sweden)

    Clara I Aceves-Luquero

    Full Text Available Resistance to Imatinib Mesylate (IM is a major problem in Chronic Myelogenous Leukaemia management. Most of the studies about resistance have focused on point mutations on BCR/ABL. However, other types of resistance that do not imply mutations in BCR/ABL have been also described. In the present report we aim to study the role of several MAPK in IM resistance not associate to BCR/ABL mutations. Therefore we used an experimental system of resistant cell lines generated by co-culturing with IM (K562, Lama 84 as well as primary material from resistant and responder patient without BCR/ABL mutations. Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype. However, Erk2, but not Erk1, is critical for the acquired resistance to IM. In fact, Bcr/Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c-Abl part of the chimeric protein. Finally, we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM. In summary our data support the use of therapeutic approaches based on Erk2 inhibition, which could be added to the therapeutic armamentarium to fight CML, especially when IM resistance develops secondary to Erk2 activation.

  11. 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.

  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. Comparison of tirilazad mesylate (U-74006F) and methylprednisolone sodium succinate treatments in experimental allergic encephalomyelitis in the guinea pig.

    Science.gov (United States)

    Karlik, S J; Stavraky, R T; Hall, E D

    1996-02-01

    The effects of the non-glucocorticoid 21-aminosteroid, tirilazad mesylate (U-74006F), on MRI and clinical findings in guinea pigs with experimental allergic encephalomyelitis were compared to treatment with methylprednisolone sodium succinate (MPSS). A dose response experiment for U-74006F was performed 1, 3 and 10 mg/kg/day i.p. on day 0-12 after immunization. Additionally, the 3 mg/kg/day i.p. dose was extended to 24 and 35 days. MPSS was given in three different protocols at doses ranging from 0.8 to 3.2 mg/kg/day. Abnormalities in T2-weighted images were assessed as measures of edema and inflammation and gadolinium-DTPA enhanced T1-weighted images were used to determine blood-brain barrier integrity. U-74006F improved the clinical status at doses of 3 and 10 mg/kg. For example, maximum clinical score was halved at 10 mg/ kg/day (P 24 days of dosing. MPSS treatment considerably worsened the clinical outcome of EAE. Mean clinical scores for vehicle and the highest MPSS dose were 0.94 +/- 0.66 versus 2.64 +/- 1.49 (P < 0.05). The combination of decreased T2-weighted abnormalities, clinical signs and gadolinium-DTPA permeation in the U-74006F treated animals suggested protection of the blood-brain barrier without the severe glucocorticoid effects associated with steroid therapy.

  14. 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

  15. A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted olid tumours

    Science.gov (United States)

    Adenis, A; Ray-Coquard, I; Italiano, A; Chauzit, E; Bui-Nguyen, B; Blay, J-Y; Tresch-Bruneel, E; Fournier, C; Clisant, S; Amela, E Y; Cassier, P A; Molimard, M; Penel, N

    2013-01-01

    Background: Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells. Methods: We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC. Results: No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug–drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2–18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1–6.6). Conclusion: This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients. PMID:24149182

  16. A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted solid tumours.

    Science.gov (United States)

    Adenis, A; Ray-Coquard, I; Italiano, A; Chauzit, E; Bui-Nguyen, B; Blay, J-Y; Tresch-Bruneel, E; Fournier, C; Clisant, S; Amela, E Y; Cassier, P A; Molimard, M; Penel, N

    2013-11-12

    Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells. We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC. No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug-drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2-18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1-6.6). This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients.

  17. Long-Term Outcomes after Imatinib Mesylate Discontinuation in Chronic Myeloid Leukemia Patients with Undetectable Minimal Residual Disease.

    Science.gov (United States)

    Yhim, Ho-Young; Lee, Na-Ri; Song, Eun-Kee; Yim, Chang-Yeol; Jeon, So Yeon; Lee, Bohee; Kim, Jeong-A; Kim, Hee Sun; Cho, Eun Hae; Kwak, Jae-Yong

    2016-01-01

    Imatinib mesylate (IM) discontinuation is under active investigation in chronic myeloid leukemia-chronic phase (CML-CP) patients with undetectable minimal residual disease (UMRD). However, limited data exist on the long-term outcomes following IM discontinuation in patients treated with frontline IM therapy. We consecutively enrolled patients with CML-CP who discontinued IM after achieving UMRD for ≥12 months between June 2009 and January 2013. Nineteen patients (8 male, 11 female) were included. After IM discontinuation, 14 patients (74%) lost UMRD after a median of 4.0 months. Of the 14 patients with molecular relapses, 12 (86%) relapsed within the first 9 months after IM discontinuation and 2 (14%) relapsed at 20.5 and 22.8 months, respectively. No molecular relapse was observed after 2 years of IM discontinuation. With a median follow-up of 58.1 months (range 23.0-66.5), the estimated UMRD persistence rate at 5 years was 23.7%. IM was readministered in all patients with molecular relapse, and 12 patients (86%) reachieved UMRD at a median of 5.3 months. A high-risk Sokal score, delayed UMRD achievement and short-term IM therapy were significantly associated with molecular relapse. These findings suggest that IM discontinuation in patients who achieved UMRD after frontline IM therapy resulted in favorable long-term outcomes in terms of safety and feasibility. © 2015 S. Karger AG, Basel.

  18. [A patient with acute Philadelphia-chromosome-positive mixed phenotype leukemia developing ecthyma gangrenosum while undergoing combined imatinib mesylate chemotherapy].

    Science.gov (United States)

    Suzuki, Kei; Sekine, Takao

    2014-05-01

    A 67-year-old woman with acute Philadelphia-chromosome-positive mixed phenotype leukemia developed bilateral periorbital ecthyma gangrenousum (EG) subsequent to periorbital edema while undergoing combined imatinib mesylate (imatinib) chemotherapy. Although initial periorbital edema was considered an imatinib side effect, the lesion deteriorated rapidly with high fever in the neutropenic phase, and the woman died of septic shock. Cultures from blood and exudative fluid grew Pseudomonas aeruginosa, after which EG was diagnosed. EG is a well-recognized emergent cutaneous infection most commonly associated with Pseudomonas aeruginosa bactremia. Because some patients present with EG a few days prior to developing life-threatening septicemia, it is important that EG be diagnosed correctly. Imatinib side effects such as edema are usually tolerable, and imatinib is widely used to treat Philadelphia-chromosome-positive leukemia, particularly in those with acute lymphoblastic leukemia, and neutropenic patients undergoing imatinib therapy are expected to increase in number. Delay in initiating appropriate therapy is correlated with poor outcome, so drug side effects and EG must be carefully differentiated when skin edema with surrounding erythema is noted in neutropenic patients undergoing imatinib therapy.

  19. Vitamin D Analogs Potentiate the Antitumor Effect of Imatinib Mesylate in a Human A549 Lung Tumor Model

    Science.gov (United States)

    Maj, Ewa; Filip-Psurska, Beata; Świtalska, Marta; Kutner, Andrzej; Wietrzyk, Joanna

    2015-01-01

    In previous papers, we presented data on studies on the anticancer activity of the vitamin D3 analogs, named PRI-2191 and PRI-2205, in different cancer models. In this study, we showed the improved antiproliferative activity of a combination of imatinib mesylate (Gleevec, GV) and cytostatic agents in in vitro studies, when used with a third compound, namely PRI-2191, in an A549 human lung cancer model. Furthermore, we analyzed the influence of both PRI-2191, as well as PRI-2205 on the anticancer activity of GV in mice bearing A549 tumors. The route of PRI-2191 analog administration showed a significant impact on the outcome of GV treatment: subcutaneous injection was more efficient and less toxic than oral gavage. Moreover, both vitamin D compounds increased the anticancer activity of GV; however, they might also potentiate some adverse effects. We also evaluated in tumor tissue the expression of VEGF, PDGF-BB, vitamin D receptor, CYP27B1, CYP24, p53 and Bcl-2, as well as PDGF receptors: α and β. We observed the upregulation of p53 expression and the downregulation of Bcl-2, as well as VEGF in A549 tumors as a result of the tested treatment. However, vitamin D analogs did not significantly influence the expression of these proteins. PMID:26580599

  20. Long-Term Exposure to Imatinib Mesylate Downregulates Hippo Pathway and Activates YAP in a Model of Chronic Myelogenous Leukemia.

    Science.gov (United States)

    Chorzalska, Anna; Kim, Javier Flores; Roder, Karim; Tepper, Alexander; Ahsan, Nagib; Rao, R Shyama Prasad; Olszewski, Adam J; Yu, Xiaoqing; Terentyev, Dmitry; Morgan, John; Treaba, Diana O; Zhao, Ting C; Liang, Olin; Gruppuso, Philip A; Dubielecka, Patrycja M

    2017-05-01

    Despite the success of tyrosine kinase inhibitor (TKI) therapy in chronic myelogenous leukemia (CML), leukemic stem/progenitor cells remain detectable even in the state of deep molecular remission. Mechanisms that allow them to persist despite continued kinase inhibition remain unclear. We have previously shown that prolonged exposure to imatinib mesylate (IM) results in dysregulation of Akt/Erk 1/2 signaling, upregulation of miR-181a, enhanced adhesiveness, and resistance to high IM. To characterize the molecular basis and reversibility of those effects, we applied gene and protein expression analysis, quantitative phosphoproteomics, and direct miR-181a inhibition to our cellular model of CML cells subjected to prolonged exposure to IM. Those cells demonstrated upregulation of pluripotency markers (SOX2, SALL4) and adhesion receptors (CD44, VLA-4, CXCR4), as well as downregulation of Hippo signaling and upregulation of transcription coactivator YAP. Furthermore, inhibition of miR-181a using a microRNA sponge inhibitor resulted in decreased transcription of SOX2 and SALL4, decreased activation of YAP, and increased sensitivity to IM. Our findings indicate that long-term exposure to IM results in dysregulation of stem cell renewal-regulatory Hippo/YAP signaling, acquisition of expression of stem cell markers and that experimental interference with YAP activity may help to restore chemosensitivity to TKI.

  1. [Treatment efficacy of imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in chronic phase].

    Science.gov (United States)

    Gao, Guan-lun; Xu, Na; Zhou, Xuan; Xiao, Ya-juan; Ding, Li; Lu, Qi-si; Wei, Yong-qiang; Zhang, Yu; Xu, Dan; Sun, Jing; Liu, Qi-fa; Liu, Xiao-li

    2013-10-15

    To compare the treatment efficacy of imatinib mesylate versus allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with chronic myeloid leukemia in chronic phase. The efficacy, overall survival, progression-free survival and adverse events were evaluated in 198 patients on these two therapies from February 2002 to December 2012 at our hospital. One hundred and fifteen cases in imatinib group (n = 115) received imatinib at an initial daily dose of 400 mg and then dose was adjusted according to blood routine test and therapy response. All patients were evaluated for hematologic, cytogenetic and molecular responses every 1-3 months. The allo-HSCT group (n = 83) received myeloablative preconditioning regimen and methotrexate (MTX) and cyclosporine A (CsA) were used for graft-versus-host disease (GVHD) partially plus mycophenolate mofetil (MMF) and antihuman thymocyte globulin (ATG). The engraftment evidence and evolution of cytogenetic and molecular response was conventionally detected after allo-HSCT. In imatinib group, 59 of 86 (68.6%) cases achieved complete cytogenetic response (CCyR) in the 12 months after therapy, while 67 of 70 (95.7%) cases achieved CCyR in allo-HSCT group. The relapse rates of two groups were 14.8% (17/115) , 12.3% (10/81) respectively. The adverse reaction of imatinib in imatinib group was obviously much more tolerable for patients compared with frequently occurred GVHD and infection in allo-HSCT group. The 10-year cumulative overall survival (OS) rate was 93.9% in imatinib group and 77.1% in allo-HSCT group (P = 0.015). And the 10-year cumulative progression-free survival (PFS) rate was 86.1% in imatinib group versus 88.0% in allo-HSCT group (P = 0.508) . For Sokal rating stratified analysis, the cumulative OS rates of two groups were 96.4% and 68.0% (P = 0.049) for intermediate-risk patients, 92.6% and 57.1% (P = 0.017) for high-risk patients while the cumulative PFS rates of two groups were 89.3% and 88.0% for

  2. Genetic Polymorphisms Contribute to the Individual Variations of Imatinib Mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients

    Directory of Open Access Journals (Sweden)

    Jing Liu

    2017-03-01

    Full Text Available Imatinib mesylate (IM has dramatically improved the outcomes of gastrointestinal stromal tumor (GIST patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme (CYP3A4, transporters (ABCB1, ABCG2, and nuclear receptor (Pregnane X Receptor (PXR, encoded by NR1I2 on IM plasma levels and related adverse reactions in Chinese GIST patients. A total of 68 Chinese GIST patients who have received IM 300–600 mg/day were genotyped for six single nucleotide polymorphisms (SNPs (CYP3A4 rs2242480; ABCB1 rs1045642; ABCG2 rs2231137; NRI12 rs3814055, rs6785049, rs2276706, and the steady-state IM trough plasma concentrations were measured by a validated HPLC method. There were statistically significant variances in the steady-state IM trough plasma concentrations (from 272.22 to 4365.96 ng/mL. Subjects of GG in rs2242480, T allele carriers in rs1045642 and CC in rs3814055 had significantly higher steady-state IM dose-adjusted trough plasma concentrations. Subjects of CC in rs3814055 had significantly higher incidence rate of edema. The genetic polymorphisms of rs2242480, rs1045642, rs3814055 were significantly associated with IM plasma levels, and the genetic variations of rs3814055 were significantly associated with the incidence rate of edema in Chinese GIST patients. The current results may serve as valuable fundamental knowledge for IM therapy in Chinese GIST patients.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Stability-Indicating UPLC and TLC-Densitometric Methods for Determination of Benztropine Mesylate and Its Carcinogenic Degradation Product.

    Science.gov (United States)

    Fares, Michel Y; Abdelwahab, Nada S; Abdelrahman, Maha M; Abdel-Rahman, Hamdy M

    2017-10-01

    Two accurate, precise and highly selective stability-indicating methods were adopted for simultaneous determination of benztropine mesylate (BNZ) in presence of its hepatotoxic and carcinogenic degradation product, benzophenone (BPH) either in pure form or in the pharmaceutical formulation without any preliminary separation steps. The first method is a thin layer chromatography (TLC)-densitometric method that depended on separation of BNZ from its degradate on TLC aluminum plates precoated with silica gel 60 F254 as the stationary phase using a developing system consisted of hexane:methylene chloride:triethylamine (5:5:0.6, by volume) and scanning the separated bands at 235 nm. Linear regression analysis data for the calibration plots of BNZ and BPH showed perfect linear relationships over the concentration range of 1.5-10 and 1-10 μg band-1, respectively. The second method is (UPLC) method, at which the mixture was separated on a reversed phase C8 analytical column (1.9 μm ps, 50 mm × 2.1 i.d.) using a mobile phase of acetonitrile: aqueous sodium dodecyl sulfate (50:50, v/v) Adjusted to pH = 3 with phosphoric acid, at a flow rate of 0.5 mL min-1. Quantification was achieved at 210 nm based on peak area and linear calibration curves over the concentration ranges of (20-200 μg mL-1) and (5-50 μg mL-1) for BNZ and BPH, respectively, were obtained. The investigated methods were successfully applied to available dosage form and method validation has been carried out. The results obtained by applying the proposed methods were statistically analyzed and compared with those obtained by reported one and no significant differences were obtained regarding both accuracy and precision. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. 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.

  6. Anti-fibrotic Activity and Enhanced Interleukin-6 Production by Hepatic Stellate cells in Response to Imatinib Mesylate

    Science.gov (United States)

    Kim, Youngchul; Fiel, Maria Isabel; Albanis, Efsevia; Chou, Hsin I; Zhang, Weijia; Khitrov, Gregory; Friedman, Scott L.

    2012-01-01

    Objective To examine imatinib mesylate’s effects on stellate cell responses in vivo and in vitro. The hepatic stellate cell (HSC) is a key target of anti-fibrotic therapies. Imatinib mesylate is a small molecule receptor tyrosine kinase (RTK) inhibitors indicated for treatment of chronic myelogenous leukemia and GI stromal tumors. Design Because imatinib inhibits β-PDGFR signaling, which stimulates HSC proliferation, we assessed its activity in culture and in vivo, and examined downstream targets of its activity in a human stellate cell line (LX-2) using cDNA microarray. Methods and Results Imatinib inhibited proliferation of LX-2 cells (0.5 mM – 10 mM) but not primary human stellate cells, with no effect on viability, associated with attenuated β-PDGFR phosphorylation. Mitochondrial activity and superoxide anion production were decreased in response to imatinib. cDNA microarray uncovered up-regulation of 29 genes in response to imatinib, including interleukin-6 (IL-6) mRNA, which was correlated with progressive IL-6 secretion. Imatinib also decreased gene expression of collagen α1(I), alpha SMA, β-PDGFR, TGF β1 receptor type 1, matrix metalloproteinase 2 (MMP2) and tissue inhibitor of metalloproteinase 2 (TIMP2). In vivo, imatinib administered to rats beginning 4 weeks after starting thioacetamide led to reduced collagen content, with significant reductions in portal pressure and down-regulation of fibrogenic genes in whole liver. Importantly, hepatic IL-6 mRNA levels were significantly increased in TAA-treated animals receiving imatinib. Conclusions: These findings reinforce the anti-fibrotic activity of imatinib and uncover an unexpected link between inhibition of HSC activation by imatinib and enhanced secretion of IL-6, a regenerative cytokine. PMID:22507133

  7. Genetic Polymorphisms Contribute to the Individual Variations of Imatinib Mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients.

    Science.gov (United States)

    Liu, Jing; Chen, Zhiyu; Chen, Hanmei; Hou, Yingyong; Lu, Weiqi; He, Junyi; Tong, Hanxing; Zhou, Yuhong; Cai, Weimin

    2017-03-13

    Imatinib mesylate (IM) has dramatically improved the outcomes of gastrointestinal stromal tumor (GIST) patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme (CYP3A4), transporters (ABCB1, ABCG2), and nuclear receptor (Pregnane X Receptor (PXR, encoded by NR1I2 )) on IM plasma levels and related adverse reactions in Chinese GIST patients. A total of 68 Chinese GIST patients who have received IM 300-600 mg/day were genotyped for six single nucleotide polymorphisms (SNPs) ( CYP3A4 rs2242480 ; ABCB1 rs1045642 ; ABCG2 rs2231137 ; NRI12 rs3814055 , rs6785049 , rs2276706 ), and the steady-state IM trough plasma concentrations were measured by a validated HPLC method. There were statistically significant variances in the steady-state IM trough plasma concentrations (from 272.22 to 4365.96 ng/mL). Subjects of GG in rs2242480 , T allele carriers in rs1045642 and CC in rs3814055 had significantly higher steady-state IM dose-adjusted trough plasma concentrations. Subjects of CC in rs3814055 had significantly higher incidence rate of edema. The genetic polymorphisms of rs2242480 , rs1045642 , rs3814055 were significantly associated with IM plasma levels, and the genetic variations of rs3814055 were significantly associated with the incidence rate of edema in Chinese GIST patients. The current results may serve as valuable fundamental knowledge for IM therapy in Chinese GIST patients.

  8. Imatinib mesylate for the treatment of steroid-refractory sclerotic-type cutaneous chronic graft-versus-host disease.

    Science.gov (United States)

    Baird, Kristin; Comis, Leora E; Joe, Galen O; Steinberg, Seth M; Hakim, Fran T; Rose, Jeremy J; Mitchell, Sandra A; Pavletic, Steven Z; Figg, William D; Yao, Lawrence; Flanders, Kathleen C; Takebe, Naoko; Sarantopoulos, Stefanie; Booher, Susan; Cowen, Edward W

    2015-06-01

    Sclerotic skin manifestations of chronic graft-versus-host disease (ScGVHD) lead to significant morbidity, including functional disability from joint range of motion (ROM) restriction. No superior second-line therapy has been established for steroid-refractory disease. Imatinib mesylate is a multikinase inhibitor of several signaling pathways implicated in skin fibrosis with in vitro antifibrotic activity. We performed an open-label pilot phase II trial of imatinib in children and adults with corticosteroid-refractory ScGVHD. Twenty patients were enrolled in a 6-month trial. Eight received a standard dose (adult, 400 mg daily; children, 260 mg/m(2) daily). Because of poor tolerability, 12 additional patients underwent a dose escalation regimen (adult, 100 mg daily initial dose up to 200 mg daily maximum; children, initial dose 65 mg/m(2) daily up to 130 mg/m(2) daily). Fourteen patients were assessable for primary response, improvement in joint ROM deficit, at 6 months. Primary outcome criteria for partial response was met in 5 of 14 (36%), stable disease in 7 of 14 (50%), and progressive disease in 2 of 14 (14%) patients. Eleven patients (79%), including 5 with partial response and 6 with stable disease, demonstrated a positive gain in ROM (range of 3% to 94% improvement in deficit). Of 13 patients with measurable changes at 6 months, the average improvement in ROM deficit was 24.2% (interquartile range, 15.5% to 30.5%; P = .011). This trial is registered at http://clinicaltrials.gov as NCT007020689. Published by Elsevier Inc.

  9. Layer-by-layer polymer coated gold nanoparticles for topical delivery of imatinib mesylate to treat melanoma.

    Science.gov (United States)

    Labala, Suman; Mandapalli, Praveen Kumar; Kurumaddali, Abhinav; Venuganti, Venkata Vamsi Krishna

    2015-03-02

    The aim of this study was to investigate the feasibility of using layer-by-layer polymer coated gold nanoparticles (AuNP) as a carrier for topical iontophoretic delivery of imatinib mesylate (IM). AuNP were prepared by the Turkevich method and were stabilized and functionalized using polyvinylpyrrolidone and polyethylene imine. The functionalized AuNP were then sequentially coated with anionic poly(styrenesulfonate) and cationic polyethylene imine and loaded with IM. The layer-by-layer polymer coated AuNP (LbL-AuNP) showed average particle size and zeta-potential of 98.5 ± 4.3 nm and 32.3 ± 1.3 mV respectively. After LbL coating of AuNP, the surface plasmon resonance wavelength shifted from 518 to 530 nm. The loading efficiency of IM in LbL-AuNP was found to be 28.3 ± 2.3%, which was greatest for any small molecule loaded in AuNP. In vitro skin penetration studies in excised porcine ear skin showed that iontophoresis (0.47 mA/cm(2)) application enhanced the skin penetration of IM loaded AuNP by 6.2-fold compared to passive application. Tape stripping studies showed that iontophoresis of IM loaded LbL-AuNP retained 7.8- and 4.9-fold greater IM in stratum corneum and viable skin respectively compared with iontophoresis of free IM. LbL-AuNP were taken up rapidly (15 min) by B16F10 murine melanoma cells. Furthermore, IM loaded LbL-AuNP significantly (p < 0.001) decreased B16F10 cell viability compared to free IM. We have shown for the first time that IM can be delivered by topical application using LbL coated gold nanoparticles to treat melanoma.

  10. 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

    intravenous plus oral casopitant mesylate (90 mg intravenous on day 1 plus 50 mg oral on days 2 and 3, n=270). Randomisation was done using a central telephone system at the study level, because some centres were expected to recruit only a few patients during the study period. The primary endpoint...

  11. 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.

  12. Ingestion of the anti-bacterial agent, gemifloxacin mesylate, leads to increased gst activity and peroxidation products in hemolymph of Galleria mellonella l. (lepidoptera: pyralidae).

    Science.gov (United States)

    Erdem, Meltem; Küçük, Ceyhun; Büyükgüzel, Ender; Büyükgüzel, Kemal

    2016-12-01

    Gemifloxacin mesylate (GEM) is a synthetic, fourth-generation fluoroquinolone antibacterial antibiotic that has a broad spectrum of activity against bacteria. GEM inhibits DNA synthesis by inhibiting DNA gyrase and topoisomerase IV activities. Recent research into insect nutrition and mass-rearing programs, in which antibiotics are incorporated into the culture media to maintain diet quality, raised a question of whether clinical antibiotics influence the health or biological performance of the insects that ingest these compounds. Because some antibiotics are pro-oxidant compounds, we addressed the question with experiments designed to assess the effects of GEM (mesylate salt) on oxidative stress indicators, using Galleria mellonella larvae. The insects were reared from first-instar larvae to adulthood on artificial diets amended with GEM at 0.001, 0.01, 0.1, or 1.0%. Feeding on the 1% diets led to significantly increased hemolymph contents of the lipid peroxidation product, malondialdehyde and protein oxidation products, protein carbonyl. All GEM concentrations led to increased hemolymph glutathione S-transferase activity. We inferred that although it was not directly lethal to G. mellonella larvae, dietary exposure to GEM exerts measurable oxidative damage, possibly on insects generally. Long-term, multigenerational effects remain unknown. © 2016 Wiley Periodicals, Inc.

  13. Marked response to imatinib mesylate in a patient with platelet-derived growth factor receptor beta-associated acute myeloid leukemia.

    Science.gov (United States)

    Shimomura, Yoshimitsu; Maruoka, Hayato; Ishikawa, Takayuki

    2017-05-01

    Abnormal platelet-derived growth factor receptor (PDGFR)-mediated signaling may cause hematologic neoplasm. The PDGFR beta (PDGFRB) gene, located at chromosome band 5q31-33, forms a fusion gene as a result of chromosome translocation. Although patients with PDGFRB rearrangement mostly present with myeloproliferative neoplasm and eosinophilia, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) have also been reported in this population. Treatment with imatinib mesylate alone has been shown to have excellent long-term efficacy against myeloproliferative neoplasms; however, its long-term effects on ALL and AML have not been elucidated. A 75-year-old man was diagnosed with acute myeloid leukemia having the PDGFRB and cGMP-dependent protein kinase 2 fusion gene with additional genetic abnormalities. Continuous therapy with single-agent imatinib mesylate resulted in cytogenetic remission and decreased molecular burden for 9 months; however, the leukemia subsequently recurred, and the patient died 1 year after initiation of treatment. This case report supports the importance of cytogenetic analysis during patient screening.

  14. Effects of Imatinib Mesylate (Gleevec) on Human Islet NF-kappaB Activation and Chemokine Production In Vitro

    Science.gov (United States)

    Mokhtari, Dariush; Li, Tingting; Lu, Tao; Welsh, Nils

    2011-01-01

    Purpose Imatinib Mesylate (Gleevec) is a drug that potently counteracts diabetes both in humans and in animal models for human diabetes. We have previously reported that this compound in human pancreatic islets stimulates NF-κB signaling and islet cell survival. The aim of this study was to investigate control of NF-κB post-translational modifications exerted by Imatinib and whether any such effects are associated with altered islet gene expression and chemokine production in vitro. Procedures Human islets were either left untreated or treated with Imatinib for different timepoints. IκB-α and NF-κB p65 phosphorylation and methylation were assessed by immunoblot analysis. Islet gene expression was assessed using a commercial Pathway Finder microarray kit and RT-PCR. Islet chemokine production was determined by flow cytometric bead array analysis. Findings Human islet IκB-α and Ser276-p65 phosphorylation were increased by a 20 minute Imatinib exposure. Methylation of p65 at position Lys221 was increased after 60 min of Imatinib exposure and persisted for 3 hours. Microarray analysis of islets exposed to Imatinib for 4 hours revealed increased expression of the inflammatory genes IL-4R, TCF5, DR5, I-TRAF, I-CAM, HSP27 and IL-8. The islet release of IL-8 was augmented in islets cultured over night in the presence of Imatinib. Following 30 hours of Imatinib exposure, the cytokine-induced IκB-α and STAT1 phosphorylation was abolished and diminished, respectively. The cytokine-induced release of the chemokines MIG and IP10 was lower in islets exposed to Imatinib for 30 hours. Conclusion Imatinib by itself promotes a modest activation of NF-κB. However, a prolonged exposure of human islets to Imatinib is associated with a dampened response to cytokines. It is possible that Imatinib induces NF-κB preconditioning of islet cells leading to lowered cytokine sensitivity and a mitigated islet inflammation. PMID:21935477

  15. Bromocriptine mesylate: Food and Drug Administration approved new approach in therapy of non-insulin dependant diabetes mellitus with poor glycemic control

    Directory of Open Access Journals (Sweden)

    Yogendra Keche

    2010-01-01

    Full Text Available Food and Drug Administration (FDA approved bromocriptine mesylate, a quick release formulation, 0.8 mg tablets, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Bromocriptine products were previously approved by the FDA for the treatment of pituitary tumors and Parkinson′s disease. Bromocriptine is thought to act on circadian neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in insulin-resistant patients. Adverse events most commonly reported in clinical trials of bromocriptine included nausea, fatigue, vomiting, headache, and dizziness. These events lasted a median of 14 days and were more likely to occur during initial titration of the drug. Due to novel mechanism of action, single daily dose, and lower incidence of stroke, myocardial infarction and vascular events, bromocriptine may act as landmark in treatment of type 2 diabetes.

  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. Single-dose, randomized crossover comparisons of different-strength imatinib mesylate formulations in healthy Korean male subjects.

    Science.gov (United States)

    Kim, Kyoung-Ah; Park, Shin Jung; Kim, Chin; Park, Ji-Young

    2013-10-01

    Imatinib mesylate is used to treat chronic myeloid leukemia and advanced gastrointestinal stromal tumors. The purpose of this study was to compare the pharmacokinetics of 2 different strengths of the imatinib formulation containing 100 mg (reference) and 400 mg (test) to satisfy the regulatory requirement for marketing. A single-center, randomized, single-dose, open-label, 2-period, 2-sequence, comparative crossover study with a 14-day washout period was conducted in 30 healthy male volunteers. Plasma samples for the drug analysis were collected up to 72 hours after drug treatment. Participants received either the reference (4 tablets of 100-mg imatinib) or the test (1 tablet of 400-mg imatinib) formulation during the first period and the alternative formulation during the second period. The safety profiles and tolerability of the 2 formulations were also assessed based on physical examinations, laboratory tests, a 12-lead ECG, and vital signs. Thirty participants were initially enrolled; their mean (SD) age, height, weight, and body mass index were 24.9 (2.0) years (range, 23-30 years), 174 (5) cm (range, 164-185 cm), 69.9 (2.0) kg (range, 54.1-87.4 kg), and 23.0 (2.0) kg/m(2) (range, 18.5-26.9 kg/m(2)); 28 healthy participants completed both treatment periods. Two subjects did not complete the study because they withdrew consent for personal reasons. The observed mean (SD) Cmax, AUC0-last, and AUC0-∞ values for the reference formulation were 1792 (357) ng/mL, 28,485 (6274) ng · h/mL, and 29,079 (6371) ng · h/mL, respectively. Corresponding values for the test formulation were 1710 (312) ng/mL, 27,222 (4624) ng · h/mL , and 27,872 (4751) ng · h/mL. The geometric mean ratios (90% CIs) between the 2 formulations at the 400-mg dose of imatinib were 0.9579 (0.9054-1.0136) for Cmax, 0.9652 (0.9174-1.0155) for AUC0-last, and 0.9679 (0.9203-1.0179) for AUC0-∞, respectively. During the study period, 6 adverse events (3 for the reference and 3 for the test

  18. 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.)

  19. A study to explore the correlation of ABCB1, ABCG2, OCT1 genetic polymorphisms and trough level concentration with imatinib mesylate-induced thrombocytopenia in chronic myeloid leukemia patients.

    Science.gov (United States)

    Francis, Jose; Dubashi, Biswajit; Sundaram, Rajan; Pradhan, Suresh Chandra; Chandrasekaran, Adithan

    2015-12-01

    Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). Therapeutic drug monitoring (TDM) and pharmacogenetic screening is warranted for better management of imatinib therapy. The present study was framed to explore the influence of common drug transporter gene polymorphisms of ABCB1, ABCG2, OCT1 and trough level concentration on commonly occurring adverse events in CML patients treated with imatinib mesylate. A total number of 111 patients in chronic phase (Philadelphia chromosome +ve) were included in the study. The plasma drug concentration of imatinib was estimated using LC-MS/MS method. The mean ± SD trough level concentration of imatinib mesylate was found to be 1430.7 ± 438.7 ng/ml. The trough level concentration at steady state (Cmin.ss) was significantly higher in patients with grade 2-4 thrombocytopenia compared with patients without the adverse event (P value 0.033). The drug level of imatinib in plasma correlates with the severity of thrombocytopenia, which adds to the utility of TDM in the management of CML patients.

  20. 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.

  1. Quality-by-design based development of a self-microemulsifying drug delivery system to reduce the effect of food on Nelfinavir mesylate.

    Science.gov (United States)

    Kamboj, Sunil; Rana, Vikas

    2016-03-30

    Poor aqueous solubility and moderate permeability of Nelfinavir mesylate (NFM) leads to high variability in absorption after oral administration. To improve the solubility and bioavailability of NFM, the self microemulsifying drug delivery system (SMEDDS) was developed. For this purpose, Quality by design (QbD) approach employing D-optimal mixture design was used to prepare SMEDDS of NFM. Further, the software generated numerically optimized SMEDDS were developed by utilizing desirability function. Maisine 35-1, Tween 80, and Transcutol HP were identified as oil, surfactant, and co-surfactant that had best solubility for NFM. Ternary phase diagrams were plotted to identify the self-emulsification region. Dissolution of putative NFM in simulated fasted or fed small intestinal conditions, respectively, predicted that there is a positive food effect. However, NFM loaded SMEDDS showed absence of food effect with no significant difference in dissolution performance either in Fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) biorelevent dissolution media. The prepared SMEDDS were thermodynamically stable with droplet size (121 nm), poly dispersity index (PDI) (0.198) and emulsification time (food effect on pure NFM suspension. However, absence of food effect and 3.5-3.6 fold enhancement in the oral bioavailability was observed when NFM was formulated into SMEDDS. Thus, it could be envisaged that development of SMEDDS formulation of NFM could be one of the best alternative to enhance oral bioavailability of NFM. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Multi criteria decision making to select the best method for the preparation of solid lipid nanoparticles of rasagiline mesylate using analytic hierarchy process

    Directory of Open Access Journals (Sweden)

    Viveksarathi Kunasekaran

    2014-01-01

    Full Text Available The objective of this study was to select best method for the development of rasagiline mesylate (RM loaded nanoscale solid lipid particles using analytic hierarchy process (AHP. Improper method selection may lead to waste of time, loss of material and financial resources. One of the possibilities to overcome these difficulties, AHP was employed to find the suitable method. In the AHP, a decision of hierarchy was constructed with a goal, criteria, sub-criteria, and alternatives. After constructing the AHP, the expert choice software was used to compute the overall priority of criteria, sub-criteria and alternatives. The best alternative selected was based on the highest priority. Nanoscale solid lipid particles of RM was formulated by the selected microemulsion method (M4 and it shows the particle size, polydispersity index and zeta potential were within acceptable limits. Drug content and entrapment efficiency of the RM-solid lipid nanoparticles were 97.26% and 86.57%, respectively. This study concludes that the AHP was viable and effective tool for selecting a most suitable method for the fabrication of RM loaded nanoscale solid lipid particles.

  3. Quality by design: a systematic and rapid liquid chromatography and mass spectrometry method for eprosartan mesylate and its related impurities using a superficially porous particle column.

    Science.gov (United States)

    Kalariya, Pradipbhai D; Kumar Talluri, Murali V N; Gaitonde, Vinay D; Devrukhakar, Prashant S; Srinivas, Ragampeta

    2014-08-01

    The present work describes the systematic development of a robust, precise, and rapid reversed-phase liquid chromatography method for the simultaneous determination of eprosartan mesylate and its six impurities using quality-by-design principles. The method was developed in two phases, screening and optimization. During the screening phase, the most suitable stationary phase, organic modifier, and pH were identified. The optimization was performed for secondary influential parameters--column temperature, gradient time, and flow rate using eight experiments--to examine multifactorial effects of parameters on the critical resolution and generated design space representing the robust region. A verification experiment was performed within the working design space and the model was found to be accurate. This study also describes other operating features of the column packed with superficially porous particles that allow very fast separations at pressures available in most liquid chromatography instruments. Successful chromatographic separation was achieved in less than 7 min using a fused-core C18 (100 mm × 2.1 mm, 2.6 μm) column with linear gradient elution of 10 mM ammonium formate (pH 3.0) and acetonitrile as the mobile phase. The method was validated for specificity, linearity, accuracy, precision, and robustness in compliance with the International Conference on Harmonization Q2 (R1) guidelines. The impurities were identified by liquid chromatography with mass spectrometry. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Selective and effective targeting of chronic myeloid leukemia stem cells by topoisomerase II inhibitor etoposide in combination with imatinib mesylate in vitro.

    Science.gov (United States)

    Liu, Man-Yu; Wang, Wei-Zhang; Liao, Fen-Fang; Wu, Qing-Qing; Lin, Xiang-Hua; Chen, Yong-Hen; Cheng, Lin; Jin, Xiao-Bao; Zhu, Jia-Yong

    2017-01-01

    Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (TKIs) have improved chronic myeloid leukemia (CML) patient survival markedly but fail to eradicate quiescent CML leukemia stem cells (LSCs). Thus, strategies targeting LSCs are required to induce long-term remission and achieve cure. Here, we investigated the ability of topoisomerase II (Top II) inhibitor etoposide (Eto) to target CML LSCs. Treatment with Eto combined with IM markedly induced apoptosis in primitive CML CD34 + CD38 - stem cells resistant to eradication by IM alone, but not in normal hematopoietic stem cells, CML and normal mature CD34 - cells, and other leukemia and lymphoma cell lines. The interaction of IM and Eto significantly inhibited phosphorylation of PDK1, AKT, GSK3, S6, and ERK proteins; increased the expression of pro-apoptotic gene Bax; and decreased the expression of anti-apoptotic gene c-Myc in CML CD34 + cells. Top II inhibitors treatment represents an attractive approach for targeting LSCs in CML patients undergoing TKIs monotherapy. © 2016 International Federation for Cell Biology.

  5. Stability-indicating UPLC method for determination of Imatinib Mesylate and their degradation products in active pharmaceutical ingredient and pharmaceutical dosage forms.

    Science.gov (United States)

    Nageswari, A; Reddy, K V S R Krishna; Mukkanti, K

    2012-07-01

    A simple, precise, accurate stability-indicating gradient reverse phase ultra-performance liquid chromatographic (RP-UPLC) method was developed for quantitative determination of purity of Imatinib Mesylate (IMM) drug substance and drug products in the presence of its process related impurities, and degradation products. The proposed RP-UPLC method utilizes Acquity UPLC BEH 50-mm, 2.1mm and 1.7 μm C-18 column at 30 °C, with a gradient program of 9.0 min at a flow rate of 0.3 mL/min. The compounds of interest were monitored at 237 nm. Resolution for Imatinib and eight related components was found to be greater than 1.5 for any pair of components. The correlation coefficients (r(2)>0.9990) obtained indicate clear correlations between the concentrations and their peak areas for the investigated compounds. RSD obtained for the repeatability and intermediate precision experiments, was less than 5.0%. Accuracy of the method was further ascertained by performing recovery studies through spiking experiments. The drug substance was subjected to hydrolytic, oxidative, photolytic and thermal stress conditions as per ICH. The developed method was validated according to the current ICH guidelines for specificity, limit of detection, limit of quantitation, linearity, accuracy, precision, ruggedness and robustness. The method is also suitable for the assay determination of IMM in pharmaceutical dosage forms. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. A prospective comparison of thromboembolic stockings, external sequential pneumatic compression stockings and heparin sodium/dihydroergotamine mesylate for the prevention of thromboembolic complications in urological surgery

    Energy Technology Data Exchange (ETDEWEB)

    Hansberry, K.L.; Thompson, I.M. Jr.; Bauman, J.; Deppe, S.; Rodriguez, F.R. (Brooke Army Medical Center, Fort Sam Houston, TX (USA))

    1991-06-01

    Deep venous thrombosis and pulmonary emboli are reported to occur in up to 66% of the patients undergoing a major urological operation. Thromboembolic stockings, external sequential pneumatic compression stockings and anticoagulant agents, such as heparin sodium plus dihydroergotamine mesylate, have been suggested to decrease the risk of deep venous thrombosis and pulmonary emboli. A total of 74 evaluable patients undergoing a major urological operation was randomized to receive either thromboembolic stockings, external sequential pneumatic compression stockings, or heparin plus dihydroergotamine as prophylaxis against deep venous thrombosis and pulmonary emboli. {sup 111}Indium-labeled platelet scans, performed preoperatively and on days 1, 3 and 6 postoperatively, were used to diagnose deep venous thrombosis and pulmonary emboli. Mean patient age was 63 years and all but 1 operation was performed for neoplastic disease. Deep venous thrombosis was detected in 5 of 25 patients (20%) with thromboembolic stockings, 3 of 24 (12.5%) with external sequential pneumatic compression stockings and 2 of 25 (8%) with heparin plus dihydroergotamine. There was no difference in blood loss or complications among the groups. Although statistical significance among the treatment groups was not reached in this study, the trend to a decrease in deep venous thrombosis and pulmonary emboli with external sequential pneumatic compression stockings and heparin plus dihydroergotamine, and an absence of an increase in morbidity in these groups supports the use of these modalities to decrease the morbidity and mortality of deep venous thrombosis and pulmonary emboli.

  7. Novel t(5;11)(q32;q13.4) with NUMA1-PDGFRB fusion in a myeloid neoplasm with eosinophilia with response to imatinib mesylate.

    Science.gov (United States)

    Zou, Ying S; Hoppman, Nicole L; Singh, Zeba N; Sawhney, Sameer; Kotiah, Sandy D; Baer, Maria R

    2017-04-01

    We report a NUMA1-PDGFRB fusion in a myeloproliferative neoplasm with eosinophilia in a 61-year old man, with response to imatinib mesylate therapy. A t(5;11) chromosome translocation involving bands 5q32 and 11q13.4 was identified by metaphase chromosome analysis, and rearrangement of the platelet-derived growth factor receptor beta (PDGFRB) gene on 5q32 was demonstrated by FISH using a PDGFRB break-apart probe set. Bacterial artificial chromosome (BAC) FISH mapping of the PDGFRB fusion partner gene narrowed the breakpoint at 11q13.4 to a 150 kb genomic region containing three genes, including NUMA1. Mate pair sequencing analysis demonstrated NUMA1-PDGFRB fusion. The fusion protein includes coiled-coil domains of nuclear mitotic apparatus protein 1 (NuMA1, involved in protein homodimerization and heteroassociation) and tyrosine kinase domains of PDGFRB. Diverse rearrangements involving the PDGFRB gene have been identified in myeloid and lymphoid neoplasms with eosinophilia, but rearrangement of the nuclear mitotic apparatus protein 1 (NUMA1) gene has previously been reported in a human malignancy in only one instance, a NUMA1-RARA fusion caused by a t(11;17) translocation in a patient with acute promyelocytic leukemia. The NUMA1-PDGFRB fusion is the second instance of rearrangement of NUMA1, encoding an element of the mitotic apparatus, in human cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Studying the Impact of Presence of Alpha Acid Glycoprotein and Protein Glycoprotein in Chronic Myeloid Leukemia Patients Treated with Imatinib Mesylate in the State of Qatar

    Directory of Open Access Journals (Sweden)

    Nader I. Ai-Dewik

    2015-01-01

    Full Text Available Despite the efficacy of imatinib mesylate (IM in treating chronic myeloid leukemia (CML, there is a high degree of resistance. Alpha-1-acid glycoprotein may reduce drug efficacy through its ability to interact with IM and blocks it from reaching its target, while protein glycoprotein (PGP may reduce the intracellular concentration of the drug via an active pump mechanism. We thus investigated the correlation between AGP and PGP levels and the resistance/response to treatment. A total of 26 CML patients were investigated for AGP and PGP levels at diagnosis and during treatment. There was no significant difference or correlation between AGP levels and the different groups of patients. There was also no significant difference in the fluorescence intensities of PGP levels among the different patient groups. The resistance observed in our CML patient population could not be correlated with AGP and PGP levels. There was no significant pattern of AGP and PGP expression, irrespective of the response or resistance to treatment.

  9. 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.

  10. Treating Philadelphia chromosome/BCR-ABL1 positive patients with Glivec (Imatinib mesylate): 10 years' experience at Patan Hospital, Nepal.

    Science.gov (United States)

    Kayastha, Gyan K; Ranjitkar, Nora; Gurung, Radha; Kc, Raj K; Karki, Sanjit; Shrestha, Roshan; Thapa, Raj K; Rajbhandari, Piyush; Poudyal, Buddhi; Acharya, Paras; Roberts, David J; Hayes, Bruce; Zimmerman, Mark; Basnyat, Buddha; Mansfield, Aaron

    2017-06-01

    The Glivec International Patient Assistance Programme makes Glivec (Imatinib mesylate) available to Philadelphia chromosome/BCR-ABL1 positive patients with chronic myeloid leukaemia (CML) in Lower and Middle Income Countries (LMIC). We have established a large cohort of 211 CML patients who are eligible for Imatinib, in Kathmandu, Nepal. Thirty-one patients were lost to follow-up. We report on 180 CML patients with a median age of 38 years (range 9-81). Of these 180 patients, 162 underwent cytogenetic testing and 110 were investigated by reverse transcription polymerase chain reaction. One hundred and thirty-nine of the 180 patients (77·2%) had at least one optimal response. Taken together, our cohort has a 95% overall survival rate and 78% of the patients were still taking Glivec at a median time of 48·8 months (range 3-140 months). The number of patients who actually failed therapy, as defined by the LeukaemiaNet 2013 criteria, was 39 (21·7%). While our cohort has some differences with those in North America or Europe, we have shown Glivec is effective in inducing an optimal response in our patients in Nepal and that it is possible to deliver a clinical service for CML patients using tyrosine kinase inhibitors in resource-poor settings. © 2017 John Wiley & Sons Ltd.

  11. 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.

  12. Imatinib mesylate inhibits STAT5 phosphorylation in response to IL-7 and promotes T cell lymphopenia in chronic myelogenous leukemia patients.

    Science.gov (United States)

    Thiant, S; Moutuou, M M; Laflamme, P; Sidi Boumedine, R; Leboeuf, D M; Busque, L; Roy, J; Guimond, M

    2017-04-07

    Imatinib mesylate (IM) therapy has been shown to induce lower T cell counts in chronic myelogenous leukemia (CML) patients and an interference of IM with T cell receptor (TCR) signaling has been invoked to explain this observation. However, IL-7 and TCR signaling are both essential for lymphocyte survival. This study was undertaken to determine whether IM interferes with IL-7 or TCR signaling to explain lower T cell counts in patients. At diagnosis, CML patients have typically lower CD4 + counts in their blood, yet CD8 + counts are normal or even increased in some. Following the initiation of IM treatment, CD4 + counts were further diminished and CD8 + T lymphocytes were dramatically decreased. In vitro studies confirmed IM interference with TCR signaling through the inhibition of ERK phosphorylation and we showed a similar effect on IL-7 signaling and STAT5 phosphorylation (STAT5-p). Importantly however, using an in vivo mouse model, we demonstrated that IM impaired T cell survival through the inhibition of IL-7 and STAT5-p but not TCR signaling which remained unaffected during IM therapy. Thus, off-target inhibitory effects of IM on IL-7 and STAT5-p explain how T cell lymphopenia occurs in patients treated with IM.

  13. A comparative proteomic study identified LRPPRC and MCM7 as putative actors in imatinib mesylate cross-resistance in Lucena cell line

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    Corrêa Stephany

    2012-03-01

    Full Text Available Abstract Background Although chronic myeloid leukemia (CML treatment has improved since the introduction of imatinib mesylate (IM, cases of resistance have been reported. This resistance has been associated with the emergence of multidrug resistance (MDR phenotype, as a BCR-ABL independent mechanism. The classic pathway studied in MDR promotion is ATP-binding cassette (ABC family transporters expression, but other mechanisms that drive drug resistance are largely unknown. To better understand IM therapy relapse due to the rise of MDR, we compared the proteomic profiles of K562 and Lucena (K562/VCR cells. Results The use of 2-DE coupled with a MS approach resulted in the identification of 36 differentially expressed proteins. Differential mRNA levels of leucine-rich PPR motif-containing (LRPPRC protein, minichromosome maintenance complex component 7 (MCM7 and ATP-binding cassette sub-family B (MDR/TAP member 1 (ABCB1 were capable of defining samples from CML patients as responsive or resistant to therapy. Conclusions Through the data presented in this work, we show the relevance of MDR to IM therapy. In addition, our proteomic approach identified candidate actors involved in resistance, which could lead to additional information on BCR-ABL-independent molecular mechanisms.

  14. Effect of HM30181 mesylate salt-loaded microcapsules on the oral absorption of paclitaxel as a novel P-glycoprotein inhibitor.

    Science.gov (United States)

    Kim, Jin Cheul; Kim, Kyeong Soo; Kim, Dong Shik; Jin, Sung Giu; Kim, Dong Wuk; Kim, Yong Il; Park, Jae-Hyun; Kim, Jong Oh; Yong, Chul Soon; Youn, Yu Seok; Woo, Jong Soo; Choi, Han-Gon

    2016-06-15

    The purpose of this study was to develop HM30181 mesylate salt (HM30181M)-loaded microcapsules as a novel P-glycoprotein inhibitor for enhancing the oral absorption of paclitaxel. The effect of various carriers including hydrophilic polymers and solvents on the solubility of HM30181M were evaluated. Among the hydrophilic polymers and solvents tested, HPMC and methylene chloride (and ethanol) provided the highest HM30181M solubility. Numerous HM30181M-loaded microcapsules were prepared with HPMC, silicon dioxide and acidifying agents using a spray-drying technique, and their solubility, dissolution and physicochemical properties were evaluated. Furthermore, a pharmacokinetic study was performed after oral administration of paclitaxel alone, simultaneously with HM30181M powder or HM30181M-loaded microcapsules to rats. Among the acidifying agents investigated, phosphoric acid provided the best improvement in the solubility and dissolution of HM30181M. Moreover, the microcapsule composed of HM30181M, HPMC, silicon dioxide and phosphoric acid at a weight ratio of 3:6:3:2 remarkably enhanced the solubility and dissolution of HM30181M compared with the HM30181M powder alone. The microcapsules were spherical in shape, had a reduced particle size of about 7μm, and contained HM30181M in an amorphous state. Furthermore, this microcapsule significantly enhanced HM30181M absorption, making it about 1.7-fold faster and 1.6-fold greater after simultaneous administration, leading to about 70- and 2-fold improved oral bioavailability of paclitaxel compared with paclitaxel alone and the simultaneous administration with HM30181M powder, respectively. Thus, this novel microcapsule could be a potential candidate for effective P-glycoprotein inhibition during oral administration of paclitaxel. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Kinetic Spectrophotometric Determination of Gemifloxacin Mesylate and Moxifloxacin Hydrochloride in Pharmaceutical Preparations Using 4-Chloro-7-nitrobenzo-2-oxa-1,3-diazole

    Directory of Open Access Journals (Sweden)

    Mohammed G. Abdel Wahed

    2014-01-01

    Full Text Available Simple, sensitive, and accurate kinetic spectrophotometric method was proposed for the determination of gemifloxacin mesylate (GMF and moxifloxacin hydrochloride (MOX in pure forms and pharmaceutical preparations (tablets. The method is based on coupling the studied drugs with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl in the presence of alkaline borate buffer. Spectrophotometric measurement was achieved by recording the absorbance at 466 and 464 nm for GMF and MOX, respectively, after a fixed time of 20 and 15 min on a water bath adjusted at 70 ± 5°C for both drugs. The different experimental parameters affecting the development and stability of the color were carefully studied and optimized. The absorbance-concentration plots were linear over the ranges 0.5–8.0 and 2.0–12 μg mL−1 for GMF and MOX, respectively. The limit of detection of the kinetic method was about 0.12 (2.47 × 10−7 M and 0.36 (8.22 × 10−7 M μg mL−1 for GMF and MOX, respectively. The proposed methods have been applied and validated successfully with percentage relative standard deviation (RSD% ≤ 0.52 as precision and percentage relative error (RE% ≤ 1.33 as accuracy. The robustness of the proposed method was examined with recovery values that were 97.5–100.5 ± 1.3–1.9%. Statistical comparison of the results with the reference spectrophotometric methods shows excellent agreement and indicates no significant difference in accuracy or precision.

  16. A Retrospective Study of Clinical Profile and Long Term Outcome to Imatinib Mesylate Alone in Childhood Chronic Myeloid Leukemia in Chronic Phase.

    Science.gov (United States)

    2017-01-01

    Chronic myeloid leukemia (CML) is relatively rare malignancy in childhood. There are limited studies of use of Imatinib Mesylate (IM) alone in management of CML in this age group. We retrospectively analyzed the outcome of 30 consecutive children with CML chronic phase treated with IM alone. The median age at the time of diagnosis was 11 years with male preponderance. Asthenia and abdominal discomfort due to splenomegaly were the most common presenting features and splenomegaly a dominant sign. At time of starting IM, 19 children were in early CP while 11 were in late CP. Complete hematological remission was achieved in 90% with a median time to achieve CHR was 60 days. Among evaluable children, 83.3% achieved cytogenetic response (CyGR). Those who achieved complete CyGR were in major molecular remission at the time of last follow up. At 3 years, progression-free survival was 81.5% and overall survival was 100%. At 10 years, 12 (40%) children failed on IM therapy of which 3(10%) children developed primary IM resistance while 9 (30%) developed secondary IM resistance. IM was well tolerated and severe (grade III-IV) events were infrequent. Non-haematological toxicities were uncommon except hypopigmentation of skin which was seen in 60% of the cohort. Presenting features of CML-CP in children is comparable to other Indian and international studies. IM is very effective and safe drug for the first line treatment of CML-CP in children. It is very effective in inducing CHR. Adherence to treatment is very important for achieving CyGR and long term survival. This data will be useful for financially deprived children in developing countries where allogeneic stem cell transplant (SCT) or second line tyrosine kinase inhibitors (TKIs) is not an affordable option.

  17. Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone.

    Science.gov (United States)

    Zhou, Yan; Crowley, Rachel Saylor; Ben, Konrad; Prisinzano, Thomas E; Kreek, Mary Jeanne

    2017-05-01

    Mesyl Salvinorin B (MSB) is a potent selective kappa opioid receptor (KOP-r) agonist that has potential for development as an anti-psychostimulant agent with fewer side-effects (e.g., sedation, depression and dysphoria) than classic KOP-r agonists. However, no such study has been done on alcohol. We investigated whether MSB alone or in combination with naltrexone (mu-opioid receptor antagonist) altered voluntary alcohol drinking in both male and female mice. Mice, subjected to 3weeks of chronic escalation drinking (CED) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference. We found that single, acute administration of MSB dose-dependently reduced alcohol intake and preference in mice after 3-week CED. The effect was specific to alcohol, as shown by the lack of any effect of MSB on sucrose or saccharin intake. We also used the drinking-in-the-dark (DID) model with limited access (4h/day) to evaluate the pharmacological effect of MSB after 3weeks of DID. However, MSB had no effect on alcohol drinking after 3-week DID. Upon investigation of potential synergistic effects between naltrexone and MSB, we found that acute administration of a combination of MSB and naltrexone reduced alcohol intake profoundly after 3-week CED at doses lower than those individual effective doses. Repeated administrations of this combination showed less tolerance development than repeated MSB alone. Our study suggests that the novel KOP-r agonist MSB both alone and in combination with naltrexone shows potential in alcoholism treatment models. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Activating mutations in c-KIT and PDGFRalpha are exclusively found in gastrointestinal stromal tumors and not in other tumors overexpressing these imatinib mesylate target genes.

    Science.gov (United States)

    Burger, Herman; den Bakker, Michael A; Kros, Johan M; van Tol, Hans; de Bruin, Alex M; Oosterhuis, Wolter; van den Ingh, Harry F G M; van der Harst, Erwin; de Schipper, Hans P; Wiemer, Erik A C; Nooter, Kees

    2005-11-01

    Previous studies have shown that Imatinib mesylate (Gleevec), a selective tyrosine kinase inhibitor of c-KIT and platelet-derived growth factor receptors (PDGFR), is highly effective in c-KIT/CD117-positive gastrointestinal stromal tumors (GIST), especially in those having activating mutations in c-kit exon 11. In addition, gain-of-function mutations in the juxtamembrane domain (exon 12) and the kinase activation loop (exon 18) of PDGFRalpha were found in GISTs. Importantly, the presence and type of these mutually exclusive c-KIT or PDGFRalpha mutations were found to be associated with the response to imatinib. Here, we examined the prevalence of c-kit exon 11 and PDGFRalpha exons 12 and 18 mutations in other tumor types known to express these tyrosine kinase receptors in order to explore which other cancer types may potentially benefit from imatinib treatment. We determined the mutational status of these commonly mutated exons by direct sequencing in 11 different tumor types (in total: 215 unrelated cases), including GIST, chordoma, and various distinct tumors of lung, brain and its coverings, and skin cancer. Of the 579 exons examined (211 c-kit exon 11, 192 PDGFRalpha exon 12, 142 PDGFRalpha exon18, 17 PDGFRbeta exon 12 and 17 PDGFRbeta exon 18), only 12 (all GIST) harbored mutations (10 c-kit exon 11 and 2 PDGFRalpha exon18). From these data we conclude that activating c-KIT and PDGFR mutations are sporadic in human cancers known to overexpress these tyrosine kinase receptor genes and suggest that, except in GIST, this overexpression is not correlated with activating mutations. The latter may imply that these wild-type c-KIT and PDGFR tumor types will probably not benefit from imatinib treatment.

  19. Korean Red Ginseng Extract Enhances the Anticancer Effects of Imatinib Mesylate Through Abrogation p38 and STAT5 Activation in KBM-5 Cells.

    Science.gov (United States)

    Jung, Sang Yoon; Kim, Chulwon; Kim, Wan-Seok; Lee, Seok-Geun; Lee, Jun-Hee; Shim, Bum Sang; Kim, Sung-Hoon; Ahn, Kyoo Seok; Ahn, Kwang Seok

    2015-07-01

    Although imatinib mesylate (IM) in the treatment of chronic myelogenous leukemia (CML) remains the best example of successful targeted therapy, majority of patients with CML suffer its toxicity profile and develop chemoresistance to existing therapeutic agents. Thus, there is a need to develop novel alternative therapies for the treatment of CML. Here, we investigated whether Korean red ginseng extract (KRGE) could suppress the proliferation and induce chemosensitization in human CML cells. Also, we used a human phospho-antibody array containing 46 antibodies against signaling molecules to examine a subset of phosphorylation events after treatment. Korean red ginseng extract broadly suppressed the proliferation of five different cell lines, but KRGE was found to be the most potent inducer of apoptosis against KBM-5 cells. It also abrogated the expression of Bcl-2 (B-cell lymphoma 2), Bcl-xL (B-cell lymphoma-extra large), survivin, inhibitors of apoptosis protein 1/2, COX-2 (Cyclooxygenase-2), cyclin D1, matrix metalloproteinase-9, and VEGF (Vascular endothelial growth factor), as well as upregulated the expression of pro-apoptotic gene products. Interestingly, KRGE also enhanced the cytotoxic and apoptotic effect of IM in KBM-5 cells. The combination treatment of KRGE and IM caused pronounced suppression of p38 and signal transducer and activator of transcription 5 phosphorylation and induced phosphorylation of p53 compared with the individual treatment. Our results demonstrate that KRGE can enhance the anticancer activity of IM and may have a substantial potential in the treatment of CML. Copyright © 2015 John Wiley & Sons, Ltd.

  20. 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

    Background: 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. Methods: 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. Results: With increasing drug concentration, cellular viability decreased significantly (pimatinib concentrations had no significant effect on SCF level. Increasing the duration of treatment from 2 to 6 days had no obvious effect on cellular viability, PDGF and SCF levels. Conclusion: 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. PMID:27141462

  1. Initial application of transanal endoscopic microsurgery for high-risk lower rectal gastrointestinal stromal tumor after imatinib mesylate neoadjuvant chemotherapy: A case report.

    Science.gov (United States)

    Liu, Qiaofei; Zhong, Guangxi; Zhou, Weixun; Lin, Guole

    2017-07-01

    The lower rectal gastrointestinal stromal tumor (GIST) is a rare entity and warrants special attentions because of the considerations of preserving of anal and urinal functions. Neoadjuvant therapy with imatinib mesylate (IM) has achieved great success in GIST, which potentially extends the applications of function-preserving minimally invasive surgical procedures. Transanal endoscopic microsurgery (TEM) is a well-developed minimally invasive technique for benign tumors in lower rectum. Herein, we reported the initial application of TEM for high risk GIST after IM treatment. A 52-year-old woman suffered mild lower abdominal pain and perianal discomfort. Physical examination found a soft mass 4 cm far away from anal verge. Rectal MRI and transrectal ultrasound (TRUS) showed that there was a 1.9 × 1.6 cm submucosal mass in the lower rectum. The incisional biopsy was performed and the pathological result reported it was a high-risk GIST. High-risk lower rectal GIST. IM was given for neoadjuvant therapy. Then TEM was adopted to resect the residual tumor. IM was restored 4 weeks after surgery. The final pathological results reported the margin was clear. After an 18-month follow up, no recurrence and metastasis was found and the patient had a satisfactory anal and urinal functions. TEM in combination with IM could be a practical strategy for the high-risk lower rectal GIST simultaneously to achieve curative resection and to preserve the anal and urinal functions that can significantly improve the life quality of the patients.

  2. The value of PET, CT and in-line PET/CT in patients with gastrointestinal stromal tumours: long-term outcome of treatment with imatinib mesylate

    Energy Technology Data Exchange (ETDEWEB)

    Goerres, G.W.; Hany, T.F.; Schulthess, G.K. von [University Hospital Zurich, Division of Nuclear Medicine, Zurich (Switzerland); Stupp, R.; Luthi, F.; Leyvraz, S. [University of Lausanne Medical Centre, Multidisciplinary Oncology Centre, Lausanne (Switzerland); Barghouth, G.; Schnyder, P. [University of Lausanne Medical Centre, Department of Radiology, Lausanne (Switzerland); Pestalozzi, B. [University Hospital Zurich, Department of Oncology, Zurich (Switzerland); Dizendorf, E. [University Hospital Zurich, Division of Nuclear Medicine, Zurich (Switzerland); International Tomography Center, Novosibirsk (Russian Federation)

    2005-02-01

    Gastrointestinal stromal tumours (GIST) are mesenchymal neoplasms of the gastrointestinal tract that are unresponsive to standard sarcoma chemotherapy. Imaging of GIST patients is done with structural and functional methods such as contrast-enhanced helical computed tomography (ceCT) and positron emission tomography (PET) with {sup 18}F-fluorodeoxyglucose (FDG). The aim of this study was to compare the prognostic power of PET and ceCT and to evaluate the clinical role of PET/CT imaging. All patients with GIST undergoing PET or PET/CT examinations were prospectively included in this study, and the median overall survival, time to progression and treatment duration were documented. The prognostic significance of PET and ceCT criteria of treatment response was assessed and PET/CT was compared with PET and ceCT imaging. Data for 34 patients (19 male, 15 female, 21-76 years) undergoing PET or PET/CT for staging or restaging were analysed. In 28 patients, PET/CT and ceCT were available after introduction of treatment with the tyrosine kinase inhibitor imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). Patients without FDG uptake after the start of treatment had a better prognosis than patients with residual activity. In contrast, ceCT criteria provided insufficient prognostic power. However, more lesions were found on ceCT images than on PET images, and FDG uptake was sometimes very variable. PET/CT delineated active lesions better than did the combination of PET and ceCT imaging. Both PET and PET/CT provide important prognostic information and have an impact on clinical decision-making in GIST patients. PET/CT precisely delineates lesions and thus allows for the correct planning of surgical interventions. (orig.)

  3. Imatinib mesylate attenuates myocardial remodeling through inhibition of platelet-derived growth factor and transforming growth factor activation in a rat model of hypertension.

    Science.gov (United States)

    Jang, Sung-Won; Ihm, Sang-Hyun; Choo, Eun-Ho; Kim, Ok-Ran; Chang, Kiyuk; Park, Chan-Seok; Kim, Hee-Yeol; Seung, Ki-Bae

    2014-06-01

    Imatinib mesylate is a specific tyrosine kinase inhibitor that may block the platelet-derived growth factor and transforming growth factor pathways. These pathways are known to provoke fibroblast activation. We evaluated whether imatinib, by inhibiting these pathways, prevents diastolic dysfunction and attenuates myocardial remodeling using spontaneously hypertensive rats (SHRs). Eight-week-old male SHRs were randomly assigned to either imatinib treatment group (30 mg/kg per day; n=10; SHR-I) or hypertensive control group (distilled water, n=10; SHR-C). Wistar-Kyoto rats were used as normal controls (n=10). At 16 weeks, all rats underwent hemodynamic studies and Doppler echocardiography and then were euthanized. Their hearts were extracted for histopathologic, immunoblotting, and quantitative reverse transcriptase polymerase chain reaction analyses. Although imatinib did not affect blood pressure, it markedly reduced perivascular and interstitial fibrosis in the hearts of SHR. Echocardiogram showed that imatinib significantly reduced the left ventricular wall thickness (septal/posterior wall; SHR-C versus SHR-I, 18±1/19±2 versus 15±1/15±1 mm; Pimatinib significantly reduced the mRNA expression of collagen type I, III, and platelet-derived growth factor receptor-β phosphorylation in the hearts of SHR. In addition, imatinib reduced collagen production by inhibiting the phosphorylation of c-abl and platelet-derived growth factor receptor-β in rat cardiac fibroblasts. In conclusion, these results suggest that imatinib could attenuate myocardial remodeling and improve left ventricular diastolic dysfunction in a hypertensive rat model by affecting platelet-derived growth factor and transforming growth factor-β1 pathway without the blood pressure-lowering effect.

  4. Effect of bromocriptine-QR (a quick-release formulation of bromocriptine mesylate) on major adverse cardiovascular events in type 2 diabetes subjects.

    Science.gov (United States)

    Gaziano, J Michael; Cincotta, Anthony H; Vinik, Aaron; Blonde, Lawrence; Bohannon, Nancy; Scranton, Richard

    2012-10-01

    Bromocriptine-QR (a quick-release formulation of bromocriptine mesylate), a dopamine D2 receptor agonist, is a US Food and Drug Administrration-approved treatment for type 2 diabetes mellitus (T2DM). A 3070-subject randomized trial demonstrated a significant, 40% reduction in relative risk among bromocriptine-QR-treated subjects in a prespecified composite cardiovascular (CV) end point that included ischemic-related (myocardial infarction and stroke) and nonischemic-related (hospitalization for unstable angina, congestive heart failure [CHF], or revascularization surgery) end points, but did not include cardiovascular death as a component of this composite. The present investigation was undertaken to more critically evaluate the impact of bromocriptine-QR on cardiovascular outcomes in this study subject population by (1) including CV death in the above-described original composite analysis and then stratifying this new analysis on the basis of multiple demographic subgroups and (2) analyzing the influence of this intervention on only the "hard" CV end points of myocardial infarction, stroke, and CV death (major adverse cardiovascular events [MACEs]). Three thousand seventy T2DM subjects on stable doses of ≤2 antidiabetes medications (including insulin) with HbA1c ≤10.0 (average baseline HbA1c=7.0) were randomized 2:1 to bromocriptine-QR (1.6 to 4.8 mg/day) or placebo for a 52-week treatment period. Subjects with heart failure (New York Heart Classes I and II) and precedent myocardial infarction or revascularization surgery were allowed to participate in the trial. Study outcomes included time to first event for each of the 2 CV composite end points described above. The relative risk comparing bromocriptine-QR with the control for the cardiovascular outcomes was estimated as a hazard ratio with 95% confidence interval on the basis of Cox proportional hazards regression. The statistical significance of any between-group difference in the cumulative percentage of

  5. Uso neoadjuvante do mesilato de imatinibe no tratamento de GIST retal volumoso: relato de caso Neoadjuvant use of imatinib mesylate for treatment of large rectal GIST: case report

    Directory of Open Access Journals (Sweden)

    Paulo Rocha França Neto

    2011-03-01

    and incomplete evacuation. Work-up revealed a large inferior rectal GIST located in the posterior wall, suspected on MRI and confirmed by immunohistochemical study of a parasacral biopsy guided by tomography. The supposed initial approach was an abdominoperineal resection, since tumor was compressing anal canal and sphincter complex. In order to save the sphincters, we have decided to refer patient to neoadjuvant treatment with imatinib mesylate (Glyvec®. After four months of treatment, a down staging of tumor was observed during rectal exam (about 50%, which was smaller on pelvic RNM. Patient was undergone to total mesorectal excision with manual coloanal anastomosis and protective ileostomy. He presented necrosis of mobilized left colon and underwent to resection, and terminal iliac colostomy. Subsequently, patient refused to undergo through a new coloanal anastomosis and remain with iliac colostomy after ileostomy takedown. In the treatment of unresectable or large rectal GISTs, the use of imantinib should be strongly considered, since that radical surgery is the main approach to reduce the possibility of local recurrence.

  6. Quantitative determination of two polymorphic forms of imatinib mesylate in a drug substance and tablet formulation by X-ray powder diffraction, differential scanning calorimetry and attenuated total reflectance Fourier transform infrared spectroscopy.

    Science.gov (United States)

    Bellur Atici, Esen; Karlığa, Bekir

    2015-10-10

    Imatinib has been identified as a tyrosine kinase inhibitor that selectively inhibits the Abl tyrosine kinases, including Bcr-Abl. The active substance used in drug product is the mesylate salt form of imatinib, a phenylaminopyrimidine derivative and chemically named as N-(3-(4-(pyridin-3-yl) pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl) methyl)-benzamide methanesulfonic acid salt. It exhibits many polymorphic forms and most stable and commercialized polymorphs are known as α and β forms. Molecules in α and β polymorphic forms exhibit significant conformational differences due to their different intra- and intermolecular interactions, which stabilize their molecular conformations and affect their physicochemical properties such as bulk density, melting point, solubility, stability, and processability. The manufacturing process of a drug tablet included granulation, compression, coating, and drying may cause polymorphic conversions. Therefore, polymorphic content of the drug substance should be controlled during quality control and stability testing. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) methods were evaluated for determination of the polymorphic content of the drug substance and drug product; and PXRD was the most accurate technique and selected as preferred method and validated. Prior to development of a quantification method, pure α and β polymorphs were characterized and used throughout the method development and validation studies. Mixtures with different ratios of α and β forms were scanned using X-ray diffractometer with a scan rate of 0.250°/min over an angular range of 19.5-21.0° 2θ and the peak heights for characteristic peak of β form at 20.5 ± 0.2° 2θ diffraction angle were used to generate a calibration curve. The detection limit of β polymorph in α form imatinib mesylate tablets was found as 4% and

  7. Desarrollo tecnológico de una formulación de dihidroergotoxina mesilato 0,3 mg/mL inyectable Technological development of an injectable formulation of dihydroergotoxine mesylate 0.3 mg/mL

    Directory of Open Access Journals (Sweden)

    Anna Karelia Collado Coello

    2008-08-01

    Full Text Available Los vasodilatadores cerebrales y periféricos son un conjunto de medicamentos muy heterogéneo, que tienen en común la capacidad de producir vasodilatación cerebral o periférica por mecanismos muy diferentes.Dentro de ese grupo se encuentra el fármaco que le da razón a este artículo, la dihidroergotoxina mesilato el cual estimula el ritmo del electroencefalograma e incrementa la utilización de glucosa en el cerebro. Se desarrolló una formulación inyectable estéril compuesta por dihidroergotoxina mesilato polvo, y cantidad suficiente del vehículo acuoso envasada en ampolletas de 1 mL de capacidad. Se desarrolló y validó una técnica analítica por cromatografía líquida de alta resolución para estudiar la estabilidad de la formulación y determinar la fecha de vencimiento de esta. Se comprobó la calidad microbiológica de la preparación, y se logró un producto que cumple satisfactoriamente con todas las especificaciones establecidas para preparaciones estériles. La tecnología obtenida fue fácilmente escalable.Cerebral and peripheral vasodilators are a group of very heterogeneous drugs that have in common the capacity to produce cerebral or peripheral vasodilatation by different mechanisms. The drug that gave rise to this paper, dihydroergotoxine mesylate, is within this group. It stimulates the rhythm of the electroencephalogram and increases the utilization of glucose in the brain. A sterile injectable formulation composed of dihydroergotoxine mesylate powder and enough amount of aqueous vehicle was developed and bottled in ampoules of 1 mL. An analytical technique was developed and validated by high resolution liquid chromatography to study the stability of the formulation and to determine its expiration date. The quality of the microbiological preparation was proved, and a product that satisfactorily meets all the specifications established for sterile preparations was obtained. The technology obtained was easily scalable

  8. Development and validation of a stability-indicating RP-HPLC method for the simultaneous estimation of process related impurities and degradation products of rasagiline mesylate in pharmaceutical formulation.

    Science.gov (United States)

    Reddy, P Sunil; Sudhakar Babu, K; Kumar, Navneet

    2013-03-01

    A sensitive, stability-indicating gradient reverse phase high-performance liquid chromatography-ultraviolet method has been developed for the quantitative determination of process-related impurities and forced degradation products of rasagiline mesylate in pharmaceutical formulation. Efficient chromatographic separation was achieved on an ACE C8, 150 × 4.6 mm, 3 µm column with mobile phase containing a gradient mixture of solvents A and B. The flow rate of the mobile phase was 0.8 mL/min with column temperature of 30°C and detection wavelength at 210 nm. Rasagiline was subjected to the stress conditions of oxidative, acid, base, hydrolytic, thermal and photolytic degradation. Rasagiline was found to degrade significantly in acid and thermal stress conditions. The degradation products were well resolved from rasagiline and its impurities. The peak purity test results confirmed that the rasagiline peak was homogenous and pure in all stress samples and the mass balance was found to be more than 97%, thus proving the stability-indicating power of the method. The developed method was validated according to the guidelines of the International Conference on Harmonization with respect to specificity, linearity, limits of detection and quantification, accuracy, precision and robustness.

  9. Therapy of chronic myeloid leukemia with imatinib mesylate in Brazil: a study of 98 cases Tratamento da leucemia mielóide crônica com imatinib mesilato no Brasil: estudo de 98 casos

    Directory of Open Access Journals (Sweden)

    Vaneuza A. M. Funke

    2005-09-01

    Full Text Available Chronic Myeloid Leukemia (CML is a clonal disease characterized by balanced translocation between chromosomes 9 and 22 (Philadelphia chromosome. The resulting BCR-ABL gene has tyrosine kinase activity which stimulates cellular growth. Imatinib mesylate is a potent and specific inhibitor of all ABL related kinases. Ninety-eight CML patients were treated with imatinib mesylate from October 2000 to January 2003. Disease stage was: late chronic phase resistant or intolerant to alpha-interferon (CP: 28; accelerated phase (AP: 55; blastic phase (BP: 15 patients. Dose: 400 mg for CP and 600 mg for AP or CB. The objectives were to evaluation the efficacy, safety and survival with imatinib mesylate therapy in all phases of CML. The median follow up time was 545 days (range: 7-862, complete hematologic response was 86% in CP, 47% in AP and 13% in BP. Complete cytogenetic response was 61%, 24% and 0% respectively. BCR-ABL was not detected by nested RT-PCR in 9% of patients. Grade 3-4 hematologic toxicity was seen in 21% of CP, 74% of AP and 87% of BP patients. Grade 3-4 non-hematologic toxicity was observed in 11% of CP, 51% of AP and 53% of BP patients. Two-year overall survival was 64% for all patients, 96% for CP and 36% for AP patients. All BP patients died within a median of 60 days. Imatinib mesylate induced cytogenetic responses in Brazilian patients with previously treated CML in chronic and accelerated phase. Adverse events are similar to those reported in the literature, except for lower rates of gastrointestinal symptoms and muscle cramps in our study group.INTRODUÇÃO: A Leucemia Mielóide Crônica (LMC é uma doença clonal caracterizada pela presença da translocação entre os cromossomos 9 e 22 (cromossomo Philadelphia. O gene resultante BCR-ABL possui atividade de tirosino-quinase, que estimula o crescimento celular. O mesilato de imatinibe é um inibidor potente e específico de todas as quinases relacionadas ao ABL. PACIENTES E M

  10. Is 3-years duration of adjuvant imatinib mesylate treatment sufficient for patients with high-risk gastrointestinal stromal tumor? A study based on long-term follow-up.

    Science.gov (United States)

    Lin, Jian-Xian; Chen, Qing-Feng; Zheng, Chao-Hui; Li, Ping; Xie, Jian-Wei; Wang, Jia-Bin; Lu, Jun; Chen, Qi-Yue; Cao, Long-Long; Lin, Mi; Tu, Ru-Hong; Huang, Chang-Ming

    2017-04-01

    The therapy for gastrointestinal stromal tumors (GIST) has changed significantly since the use of imatinib mesylate (IM). However, the appropriate duration of receiving adjuvant IM for patients with high-risk GIST who underwent R0 resection is still controversial. From January 2005 to December 2014, 234 patients who underwent R0 resection and were treated with adjuvant imatinib at our institution were identified from a prospectively collected database. The effect of the medication duration on the long-term outcomes was analyzed. In this study, 140 cases were male and 94 cases were female, and the mean age was 57.5 ± 11.4 years. The most common site was the stomach (103 cases, 44%), followed by the small intestine (81 cases, 34.6%). The 5 year recurrence-free survival (RFS) rate and overall survival (OS) rate in the whole groups were 76.2 and 83.4%, respectively. The patient's prognosis was improved due to the prolongation of the time of receiving the imatinib treatment (P  0.05). However, in the high-risk patients, the RFS rates of the 1-year group, 1-3-years group, 3-5-years group and more than 5 years group were 36.5, 68.7, 71.2 and 90.8%, respectively, and the OS rates were 36.7, 76.6, 84.0 and 97.4%, respectively (P imatinib treatment for at least 5 years.

  11. Rapid ionic liquid-supported nano-hybrid composite reinforced hollow-fiber electromembrane extraction followed by field-amplified sample injection-capillary electrophoresis: An effective approach for extraction and quantification of Imatinib mesylate in human plasma.

    Science.gov (United States)

    Forough, Mehrdad; Farhadi, Khalil; Eyshi, Ali; Molaei, Rahim; Khalili, Hedayat; Javan Kouzegaran, Vahid; Matin, Amir Abbas

    2017-09-22

    The focus of this study is development of a new, convenient, rapid and sensitive electromembrane extraction approach (based on an ionic liquid-supported MWCNTs/ZnO reinforced hollow fiber, for the first time) as an off-line sample clean-up/preconcentration method coupled with capillary electrophoresis (CE-UV) using field-amplified sample injection (FASI) for quantification of Imatinib mesylate in human plasma. The nano-hybrid sorbent, coated by 1-octyl-3-methylimidazolium bromide ionic liquid ([OMIm]Br) in this research, was prepared by a feasible basic catalyzed sol-gel method. Then, it was immobilized (supported by capillary forces and sonication) in pores of a segment of a polypropylene hollow fiber membrane as the extraction unit after dispersing in 2-nitrophenyl octyl ether (NPOE) solvent and subsequently served as the supported liquid membrane (SLM) composition. Significant variables affecting the proposed method were evaluated and optimized to achieve the maximum extraction performance. Optimal conditions were obtained by NPOE with 4mgmL -1 nano-sorbent as the SLM composition, 105V as the driving force, pH 2 and 1.8 of the donor and acceptor phases, respectively, an extraction time of 15min and an agitation rate of 800rpm. The developed method was validated according to FDA guidelines. Regarding the validation results, the method is proved to be linear (R 2 =0.998) over concentrations ranging from 25 to 1500ngmL -1 (LOD=6.24ngmL -1 ). The mean RSD values for intra- and inter-day precision studies were 6.83 and 7.71%, respectively and the mean recoveries ranged between 98 and 106%. Finally, the validated method was successfully applied for sensitive, selective and rapid determination of Imatinib in patient's plasma samples. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Concurrent effects of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp genetic polymorphisms with risk of cancer, clinical output, and response to treatment with imatinib mesylate in patients with chronic myeloid leukemia.

    Science.gov (United States)

    Salimizand, Hana; Amini, Sabrieh; Abdi, Mohammad; Ghaderi, Bayazid; Azadi, Namam-Ali

    2016-01-01

    There are a paucity and contradicted data about the impact of concurrent heredity of polymorphic genes and risk of chronic myeloid leukemia (CML). In the present study, the concurrent effects of three polymorphisms affecting the integrity of DNA consist of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp on development of chronic myeloid leukemia were studied. Furthermore, the role of these polymorphisms in clinical and laboratory outcomes of patients was evaluated. In this case-control study, 70 CML patients and 140 healthy individuals were enrolled in the study. The clinical features of patients such as phase of disease and response to treatment and laboratory data before and after treatment with imatinib mesylate were collected. ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp single nucleotide polymorphisms were evaluated by restriction fragment length polymorphism-polymerase chain reaction. The T allele of ABCB1 C3435T, T allele of XRCC1 Arg194Trp, and C allele of ABCG2 C421A polymorphisms were significantly higher in patients than controls. TT genotype of ABCB1 and TT genotype of XRCC1 were associated with higher risk of chronic myeloid leukemia development. CC421 ABCG2/TT3435 ABCB1 and CC421 ABCG2/TT27157 XRCC1 were also correlated with a higher risk of CML. Patients with C allele of ABCB1 had poor cytogenetic response, and correlation of CC421 ABCG2/TT3435 ABCB1 diplotype with accelerated phase of CML was significant. Patients with CC421 ABCG2/TT3435 ABCB1 and CC421 ABCG2/TT27157 XRCC1 diplotypes might be at higher risk to rapid and severe development of CML and have weaker response to treatments with imatinib.

  13. Predicting Effectiveness of Imatinib Mesylate in Tumors Expressing Platelet-Derived Growth Factors (PDGF-AA, PDGF-BB), Stem Cell Factor Ligands and Their Respective Receptors (PDGFR-α, PDGFR-β, and c-kit).

    Science.gov (United States)

    Moawad, Emad Y

    2015-09-01

    This research aims to optimize and predict the effectiveness of imatinib mesylate (imatinib) in tumors expressing platelet-derived growth factors (PDGF-AA, BB), kit/stem cell factor (SCF) ligands and their respective receptors (PDGFR-α, PDGFR-β, and c-kit). Samples of normal primary human T cells were incubated with graded concentrations of 1-5 μM imatinib. The energy yield by imatinib doses in those samples was identified in H-thymidine proliferation assay as described before in earlier studies. Tumor models of human pancreatic adenocarcinoma L3.6pl (PDGFAA/PDGFR-α-positive and KIT-negative), human male gonad Leydig tumor cells MA10 (PDGF-AA/PDGFR-α- positive and KIT-positive), human small-cell lung cancer [H209 (KIT-positive), NCI-H526 (PDGFR β-positive and KIT-positive), and NCI-H82 (PDGFR β-positive and KIT-negative)], and human neuroblastoma SMS-KCNR (PDGF-BB/PDGFR-β-positive and KIT-positive) in athymic nude mice were used. The antitumor activity of different doses of imatinib in different regimens in those xenografts was predicted as described before in earlier studies. The energy yield by drug doses was perfectly logarithmic correlated (r = 1) with the drug dose. An efficient dose-energy model with perfect fit (R = 1) estimating the energy yield by imatinib doses has been established to administer the personalized dose. Predictions for the antitumor activity of imatinib in those xenografts using the dose-energy model and the histologic grade of the control animals were 100 % identical to those actually induced. The effect of imatinib is transient and reversible, reduces tyrosine phosphorylation of tumor-derived PDGFR-α, PDGFR-β, and c-kit without affecting their levels of expression. A resumption of tumor growth nearly identical to the growth prior to therapy should be expected whenever the treatment is stopped. Tumors of PDGF-AA/PDGFR-α exhibit significant resistance to imatinib which requires administering imatinib three times a day, whereas

  14. 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

  15. Pharmacokinetic/pharmacodynamic evaluation of rasagiline mesylate for Parkinson's disease.

    Science.gov (United States)

    Müller, Thomas

    2014-10-01

    Oxidative stress reduction via monoamine oxidase-B (MAO-B) inhibition with rasagiline is under investigation to modify the course of Parkinson's disease (PD) progression. Rasagiline moderately improves motor symptoms and therefore reduces the predominant levodopa-associated wearing-off phenomena. Following a PubMed database search with the terms rasagiline and selegiline, this review describes the role of rasagiline in the treatment of Parkinson's disease, within a critical discussion of current treatment guidelines. This so-called evidence based research suggests that rasagiline is an alternative to the catechol-O-methyltransferase-inhibitor entacapone, in the treatment of wearing-off phenomena. There is some recent evidence to suggest rasagiline also has monoamine oxidase-A (MAO-A) inhibiting properties, as well as different clinical and pharmacodynamic properties when compared with selegiline, and clinical benefits when used in combination with a dopamine agonist monotherapy. Rasagiline is well tolerated and safe, however its use has not yet been fully exploited as an alternative to selegiline due to the availability of cheaper generics. When generic rasagiline is available in Europe, more widespread use should focus on the simultaneous administration with entacapone as an approach to delaying the onset of, and improving the severity of, motor complications in levodopa treated patients. The complimentary combination of the pharmacologic principles of rasagiline and entacapone may support the concept of continuous nigrostriatal dopaminergic stimulation.

  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. Eribulin Mesylate: A New Therapeutic Option for Metastatic Breast ...

    African Journals Online (AJOL)

    Asthenia, fatigue, neutropenia, alopecia, nausea, anorexia, and neuropathy are the most frequent adverse effects associated with this drug. The aim of this review was to highlight the importance of this drug in the management of breast cancer. Medline, Excerpta Medica database, cochrane database, medscape, Elsevier ...

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

    Science.gov (United States)

    2016-10-01

    sought access to Novartis Gleevec through Novartis, sought access to the now licensed (March 2016) generic imatinib by Sun Pharmaceuticals, and sought...anticipated. US prices offered to MUSC on 8/18/16 are $320.24 per pill for brand name Gleevec and $227.085 for generic drug. If we purchase generic...shared. • Inventions, patent applications, and/or licenses Identify inventions, patent applications with date, and/or licenses that have

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

    Science.gov (United States)

    2017-10-01

    exemption for this study and PI medical license so that a drug-only clinical trials agreement (CTA) between MUSC and Novartis can be fully executed...regulatory policies), or social actions; or • improving social, economic, civic, or environmental conditions. Nothing to Report. Nothing to Report...Inventions, patent applications, and/or licenses Identify inventions, patent applications with date, and/or licenses that have resulted from the research

  1. 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 ...

  2. Imatinib mesylate induced erythroderma: A rare case series.

    Science.gov (United States)

    Kumar, Sumir; Mahajan, Bharat Bhushan; Kaur, Sandeep; Banipal, Raja Paramjeet Singh; Singh, Amarbir

    2015-01-01

    Imatinib is a tyrosine kinase inhibitor approved as a first line treatment for chronic myeloid leukemia and gastrointestinal stromal tumors. Usually the drug is well-tolerated with hematological adverse effects being most commonly seen. Dermatological side effects are seen in 9.5-69% of patients on imatinib; majority of which are minor and self-limiting. We, hereby, report a case series of erythroderma occurring secondary to imatinib in two patients with chronic myeloid leukemia. Both the patients improved upon the discontinuation of the drug. The literature review revealed only six probable cases of erythroderma due to imatinib. So, this case series is being reported for the rarity of this adverse effect of imatinib.

  3. 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...

  4. Changes from imatinib mesylate to second generation tyrosine kinase inhibitors improve renal impairment with imatinib mesylate in chronic myelogenous leukemia.

    Science.gov (United States)

    Hino, Akihisa; Yoshida, Hitoshi; Tada, Yuma; Koike, Midori; Minami, Ryota; Masaie, Hiroaki; Ishikawa, Jun

    2016-11-01

    Understanding adverse events in long-term tyrosine kinase inhibitor (TKI) therapy for chronic myelogenous leukemia (CML) is important. We investigated changes in renal function during TKI therapy for CML. We retrospectively analyzed levels of serum creatinine (sCrn) and values of estimated glomerular filtration rate (eGFR) from June 2001 to March 2015. Sixty patients initially treated with imatinib were enrolled in this study. Continuous variables of sCrn and eGFR were compared by paired student's t test. Median age or duration of treatment with imatinib was 49 years (range 19-81) or 101 months (range 8-165), respectively. Mean levels of sCrn or mean values of eGFR had increased or decreased 1 year later from start of imatinib throughout observation with statistical significance (p imatinib to a second-generation TKI (nilotinib: 32; dasatinib: 6) for various reasons. We observed statistically significant (p imatinib has adverse effects on renal function and that changes from imatinib to a second-generation TKI should be considered as a therapeutic option in cases of renal impairment due to imatinib.

  5. 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.

  6. Pharmacokinetic interaction study between flavanones (hesperetin, naringenin) and rasagiline mesylate in wistar rats.

    Science.gov (United States)

    Pingili, Ravindrababu; Vemulapalli, Sridhar; Mullapudi, Surya Sandeep; Nuthakki, Siddhartha; Pendyala, Sivaprasad; Kilaru, Naveenbabu

    2016-01-01

    Cytochrome P-450 (CYP) enzymes and P-glycoprotein (P-gp) play an important role in the oral bioavailability and first-pass-metabolism (FPM) of many drugs. Rasagiline is a selective, monoamine oxidase-B inhibitor and it undergoes significant FPM in the liver prior to excretion by CYP1A2. Hesperetin and naringenin are naturally occurring flavanones and are reported as modulators of CYP enzymes and P-gp. The objective of the present investigation was to evaluate the effect of hesperetin and naringenin on the pharmacokinetics (PK) of rasagiline in rats. Rats were treated orally with rasagiline (2 mg/kg) alone and co-administered with hesperetin and naringenin (12.5 and 25 mg/kg) for 15 consecutive days. Blood samples were collected from tail vein on the 1st day in a single dose PK study (SDS) and on 15th day in the multiple dose PK study (MDS). Hesperetin and naringenin co-administration significantly enhanced the area under the curve (AUC), maximum plasma concentration (Cmax) and elimination half life (t1/2) of rasagiline with a concomitant reduction in clearance (CL/F) in both SDS and MDS. Rasagiline concentrations were significantly increased when co-administered with hesperetin and naringenin in the brain. No significant difference was found in rasagiline transport from mucosal to serosal side in the presence of hesperetin and naringenin ex vivo (rat everted gut sacs used). Our findings suggested that hesperetin and naringenin enhanced the systemic exposure of rasagiline might be through the inhibition of CYP1A2 but not P-gp. Further studies are needed on CYP1A2 and P-gp over expressed cells to confirm this interaction at cellular level.

  7. Inhibition of BCR/ABL protein expression by miR-203 sensitizes for imatinib mesylate.

    Directory of Open Access Journals (Sweden)

    Yajuan Li

    Full Text Available Selective inhibition of BCR/ABL expression by RNA interference has been demonstrated as an effective strategy in CML treatment and a reversal to imatinib resistance. microRNAs (miRNAs are small regulatory RNAs involved in post-transcriptional gene regulation. miR-203 is supposed to directly regulate ABL and BCR/ABL expression, however, the role of miR-203 in imatinib-resistant cells is not clear. Here, we report that overexpression of miR-203 in BaF3-BCR/ABL cells with T315I mutant inhibited cell growth and colony formation ability. Furthermore, miR-203 increased sensitivity to imatinib in BaF3-BCR/ABL(T315I cells, thereby antagonizing the main mechanism of resistance to imatinib.

  8. 75 FR 76017 - Determination That GLEEVEC (Imatinib Mesylate) Capsules, 50 Milligrams and 100 Milligrams, Were...

    Science.gov (United States)

    2010-12-07

    ... a variety of malignancies, including Ph+ chronic myeloid leukemia and acute lymphoblastic leukemia... eosinophilic leukemia, dermatofibrosarcoma protuberans, and gastrointestinal stromal tumors. FDA has moved...

  9. 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

    The FIP1L1-PDGFRA fusion gene is the most frequent genetic aberration in myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1. Affected patients in adult populations are very sensitive to imatinib therapy. Pediatric cases are rare and so far only one case...... 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...

  10. Effects of Repeated Oral Administration of Pazufloxacin Mesylate and Meloxicam on the Antioxidant Status in Rabbits

    Science.gov (United States)

    Khan, Adil Mehraj; Rampal, Satyavan

    2014-01-01

    Prolonged antibiotic and antiinflammatory therapy for complicated infections exposes the body to xenobiotics that can produce several adverse effects for which oxidative damage is the proposed underlying mechanism. In this context, we evaluated the effect of pazufloxacin, a fluoroquinolone antimicrobial, and meloxicam, a nonsteroidal antiinflammatory drug, on antioxidant parameters and lipid peroxidation in rabbits after oral administration for 21 d. Reduced glutathione levels were significantly decreased in rabbits (n = 4 per group) given pazufloxacin, meloxicam, or their combination. In addition, glutathione peroxidase activity was induced in the rabbits treated with pazufloxacin only. Administration of pazufloxacin and meloxicam, as single agents as well as in combination, produced significant lipid peroxidation compared with levels in untreated controls. In conclusion, both pazufloxacin and meloxicam potentially can induce oxidative damage in rabbits. PMID:25199097

  11. Complete pathological response to Imatinib mesylate in an extraintestinal gastrointestinal stromal tumor

    Directory of Open Access Journals (Sweden)

    Nicolás Quezada

    2014-01-01

    CONCLUSION: EGIST complete pathological response to Imatinib can be achieved. However, recommendation of systematic neoadjuvant therapy with Imatinib remains investigational and more studies are warranted in the future.

  12. Nose-to-brain transport of imatinib mesylate: A pharmacokinetic evaluation.

    Science.gov (United States)

    Hada, Nobuko; Netzer, William Joseph; Belhassan, Fanny; Wennogle, Lawrence Paul; Gizurarson, Sveinbjörn

    2017-05-01

    The delivery of drugs to the brain is a constant challenge due to limitations imposed by the blood-brain barrier (BBB). Various methods of bypassing the BBB are under investigation. One approach is intranasal administration, where the olfactory region of the nasal cavity extends up to the cranial cavity and provides direct access to the brain. The pharmacokinetics of this transport and factors that determine transport rates and capacity is of vital importance for evaluating the clinical value of this route. Here, the pharmacokinetics of intranasally administered imatinib has been explored. Imatinib is distributed into the brain following intravenous administration, and then rapidly removed. Following intravenous administration, the brain/plasma ratio for imatinib was calculated to be 2% and remained at this ratio for 30min. The brain/plasma ratio following intranasal administration, however, was found to be 5.3% and remained at this ratio for up to 90min. Imatinib was found to be rapidly transported into the brain via the olfactory region, by shutting down the nose-to-blood-to-brain transport with epinephrine. The increased brain concentration of imatinib (0.33μg/g tissue) achieved by intranasal administration, compared with an IV injection, is likely to provide a model for developing a wide range of CNS active molecules that were previously removed from consideration as drug candidates due to their lack of CNS access. Furthermore, brain imatinib levels were increased by co-administration of the p-gp substrates, elacridar and pantoprazole, showing that both compounds were able to inhibit the elimination of imatinib from the brain. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Target Therapy of Unresectable or Metastatic Dermatofibrosarcoma Protuberans With Imatinib Mesylate

    Science.gov (United States)

    Wang, Chunmeng; Luo, Zhiguo; Chen, Jie; Zheng, Biqiang; Zhang, Ruming; Chen, Yong; Shi, Yingqiang

    2015-01-01

    Abstract Dermatofibrosarcoma protuberans (DFSP) is a rare, plaque-like tumor of the cutaneous tissue occurring more on the trunk than the extremities and neck. More than 95% of DFSP present anomalies on the 17q22 and 22q13 chromosomal regions leading to the fusion of COL1A1 and PDGFB genes. Surgery is the optimal treatment for DFSP, but less effective in locally advanced or metastatic patients, as is the case with chemotherapy and radiotherapy. The aim of this study was to assess retrospectively the therapeutic activity and safety of imatinib on 22 Chinese patients with locally inoperative or metastatic DFSP at a single institution. In the collected data of 367 Chinese patients with DFSP, we analyzed retrospectively 22 patients with locally advanced or metastatic DFSP, all of whom received imatinib therapy at 1 center from January 2009 to October 2014. Patients were administered with imatinib at an initial dose of 400 mg and escalated to 800 mg daily after they developed imatinib resistance. The median follow-up time was 36 months, and the median treatment time was 15 months. The results showed that 10 locally advanced DFSP patients and 12 metastatic DFSP patients received imatinib therapy. Apart from 1 patient who developed primary imatinib resistance, 15 patients achieved partial remission (PR), and 6 patients achieved stable disease (SD). Both fibrosarcomatous DFSP and classic DFSP patients demonstrated similar response to imatinib. Median PFS was estimated to be 19 months. Median overall survival (OS) has not been reached, and estimated 1- and 3-year OS rates were 95.5% (21/22) and 77.3% (17/22), respectively. Four out of 10 patients with primarily unresectable DFSP received complete surgical resection after neoadjuvant treatment of imatinib. Imatinib therapy is well tolerated with a safety profile and is the therapy of choice in locally inoperative or metastatic DFSP. Neoadjuvant treatment of locally advanced or metastatic DFSP with imatinib improves surgical outcomes and may facilitate resection of difficult tumors. PMID:25929918

  14. Imatinib Mesylate Versus Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Chronic Myelogenous Leukemia.

    Science.gov (United States)

    Zhang, Gui-Fang; Zhou, Min; Bao, Xie-Bing; Qiu, Hui-Ying; Li, Zheng; Xue, Sheng-Li

    2016-01-01

    To compare the relative merits of imatinib and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia (CML). This cohort study was designed to compare the outcomes of imatinib (n=292) versus allo-HSCT (n=141) for CML, the clinical data of these patients being retrospectively analyzed so as to compare the event free survival (EFS) and overall survival (OS) between these two groups with patients in the chronic phase (CP) and advanced phases, including accelerate (AP) and blast phases (BP). (1) Patients treated with imatinib (278 in the CP) demonstrated superior EFS, OS, 5-year EFS and 5-year OS rates of 88.5% versus 70.0% (P0.05), 42.9% versus 57.1% (P>0.05), respectively, for imatinib (14 patients in the AP and BP) and allo-HSCT (21 patients in the AP and BP). Imatinib confers signi cant survival advantage (EFS and OS) for CML patients with CP compared with allo-HSCT treatment. However, the outcomes are equally good with both treatments in AP and BP patients.

  15. Long-term results of treatment of advanced dermatofibrosarcoma protuberans (DFSP) with imatinib mesylate - The impact of fibrosarcomatous transformation.

    Science.gov (United States)

    Rutkowski, P; Klimczak, A; Ługowska, I; Jagielska, B; Wągrodzki, M; Dębiec-Rychter, M; Pieńkowska-Grela, B; Świtaj, T

    2017-06-01

    Dermatofibrosarcoma protuberans (DFSP) is rare, infiltrating dermal neoplasm, characterized by indolent growth and low probability of metastases. The first effective systemic therapy in DFSP introduced into clinical practice was imatinib, demonstrating high activity in advanced cases. The aim of the study was to perform an analysis of patients with advanced DFSP treated with imatinib, with or without surgery, in routine clinical practice with long-term follow-up. We analyzed the data of 31 Caucasian patients (14 male, 17 female; median age 56 years) with locally advanced/initially inoperable and/or metastatic DFSP who started therapy with imatinib at initial dose 800 mg daily between 12/2004 and 07/2014. All diagnoses were confirmed cytogenetically for the presence of specific COL1A1-PDGFB fusion. Median follow-up time was 5.3 years. Metastases were present in 15 cases (8 - lungs, 5 - soft tissue, 2 - lymph nodes). Fibrosarcomatous transformation (FS-DFSP) was confirmed in 16 patients (52%). 5-year progression-free survival (PFS) rate was 58% (median 6.8 years), 5-year overall survival (OS) rate was 64% (median time for OS was not reached). The shorter PFS and OS correlated with FS-DFSP and presence of metastatic disease. 5-year PFS rate was 93% for classic DFSP and 33% for FS-DFSP. The best overall responses were: 21 partial responses (68%, including 8 FS-DFSP, but the responses were shorter than for classic DFSP), 6 stable disease (19%) and 4 progressive diseases (13%). Thirteen patients (47%) underwent resection of residual disease and nine of them remained free of disease, although imatinib was discontinued. Median survival after progression on imatinib was 19 months, and longer survival were observed only in cases were rescue surgery/radiotherapy was possible. Our results indicate the long-term activity of imatinib in therapy of inoperable and/or metastatic cases of DFSP, including FS-DFSP. Some DFSP patients initially evaluated as unresectable/metastatic or necessitating mutilating surgery turned resectable after imatinib therapy and this rational approach leading to complete remission maybe potentially curative. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

  16. Follow-up of gastro-intestinal stromal tumours (GIST) during treatment with imatinib mesylate by abdominal MRI

    Energy Technology Data Exchange (ETDEWEB)

    Stroszczynski, Christian; Jost, Dominik; Chmelik, Petra; Gaffke, Gunnar; Felix, Roland [Charite Universitaetsmedizin Berlin, Klinik und Poliklinik fuer Strahlenheilkunde, Berlin (Germany); Reichardt, Peter; Kretzschmar, Albrecht [Klinik fuer Haematologie, Onkologie und Tumorimmunologie CCB Robert-Roessle-Klinik, Berlin (Germany); Schneider, Ulrike [Institut fuer Pathologie CCB, Berlin (Germany); Hohenberger, Peter [Klinik fuer Chirurgie und Chirurgische Onkologie CCB Robert-Roessle-Klinik, Berlin (Germany)

    2005-12-01

    Typical MRI findings for gastro-intestinal stromal tumours (GIST) under treatment with imatinib were evaluated. MRI was performed in 45 patients (25 responders, 20 non-responders) with metastatic or locally advanced, unresectable GIST. Target lesions were selected and re-evaluated after 2, 4, and 6 months of therapy with imatinib. The target tumour response (TTR) was classified according to RECIST criteria. TTR, signal intensity in the centre and border of the lesion and the presence and the extension of a hypervascular rim were analysed. The mean diameter of the marker lesions decreased significantly (P<0.001) from 7.1{+-}2.6 cm to 5.9{+-}2.3 cm after 6 months. Accuracy of RECIST criteria was 51%, 69% and 73% on MRI 2, 4 and 6 months for response assessment. In addition, responders had higher signal-to-noise ratios on T2-w images after 2 months (P<0.05) and a decrease of vascularised areas in the lesion 4 and 6 months after treatment (each P<0.01), when compared with non-responders. Beyond the size measurement for response assessment, MRI provides additional information of tumour response using SI of T2-w images and quantification of vascularised areas of GIST manifestations. (orig.)

  17. Surgical treatment and prognostic analysis for gastrointestinal stromal tumors (GISTs of the small intestine: before the era of imatinib mesylate

    Directory of Open Access Journals (Sweden)

    Jan Yi-Yin

    2006-10-01

    Full Text Available Abstract Background Gastrointestinal stromal tumors (GISTs, the most common type of mesenchymal tumors of the gastrointestinal (GI tract, demonstrate positive kit staining. We report our surgical experience with 100 small intestine GIST patients and identify predictors for long-term disease-free survival (DFS and overall survival (OS to clarify the difference between high- and low-risk patients. Methods The clinicopathologic and follow-up records of 100 small intestine GIST patients who were treated at Chung Gung Memorial Hospital between 1983 and 2002 were retrospectively reviewed. Clinical and pathological factors were assessed for long-term DFS and OS by using a univariate log-rank test and a multivariate Cox proportional hazard model. Results The patients included 52 men and 48 women. Their ages ranged from 27 to 82 years. Among the 85 patients who underwent curative resection, 44 (51.8% developed disease recurrence (liver metastasis was the most common form of recurrence. The follow-up period ranged from 5 to 202 months (median: 33.2 months. The 1-, 3-, and 5-year DFS and OS rates were 85.2%, 53.8%, and 43.7%, and 91.5%, 66.6%, and 50.5%, respectively. Using multivariate analysis, it was found that high tumor cellularity, mitotic count >5/50 high-power field, and a Ki-67 index ≧10% were three independent factors that were inversely associated with DFS. However, absence of tumor perforation, mitotic count Conclusion Tumors with low cellularity, low mitotic count, and low Ki-67 index, which indicate low risk, predict a more favorable DFS for small intestine GIST patients undergoing curative resection. Absence of tumor perforation with low mitotic count and low cellularity, which indicates low risk, can predict long-term OS for small intestine GIST patients who have undergone curative resection.

  18. Target therapy of unresectable or metastatic dermatofibrosarcoma protuberans with imatinib mesylate: an analysis on 22 Chinese patients.

    Science.gov (United States)

    Wang, Chunmeng; Luo, Zhiguo; Chen, Jie; Zheng, Biqiang; Zhang, Ruming; Chen, Yong; Shi, Yingqiang

    2015-05-01

    Dermatofibrosarcoma protuberans (DFSP) is a rare, plaque-like tumor of the cutaneous tissue occurring more on the trunk than the extremities and neck. More than 95% of DFSP present anomalies on the 17q22 and 22q13 chromosomal regions leading to the fusion of COL1A1 and PDGFB genes. Surgery is the optimal treatment for DFSP, but less effective in locally advanced or metastatic patients, as is the case with chemotherapy and radiotherapy. The aim of this study was to assess retrospectively the therapeutic activity and safety of imatinib on 22 Chinese patients with locally inoperative or metastatic DFSP at a single institution.In the collected data of 367 Chinese patients with DFSP, we analyzed retrospectively 22 patients with locally advanced or metastatic DFSP, all of whom received imatinib therapy at 1 center from January 2009 to October 2014. Patients were administered with imatinib at an initial dose of 400 mg and escalated to 800 mg daily after they developed imatinib resistance. The median follow-up time was 36 months, and the median treatment time was 15 months.The results showed that 10 locally advanced DFSP patients and 12 metastatic DFSP patients received imatinib therapy. Apart from 1 patient who developed primary imatinib resistance, 15 patients achieved partial remission (PR), and 6 patients achieved stable disease (SD). Both fibrosarcomatous DFSP and classic DFSP patients demonstrated similar response to imatinib. Median PFS was estimated to be 19 months. Median overall survival (OS) has not been reached, and estimated 1- and 3-year OS rates were 95.5% (21/22) and 77.3% (17/22), respectively. Four out of 10 patients with primarily unresectable DFSP received complete surgical resection after neoadjuvant treatment of imatinib.Imatinib therapy is well tolerated with a safety profile and is the therapy of choice in locally inoperative or metastatic DFSP. Neoadjuvant treatment of locally advanced or metastatic DFSP with imatinib improves surgical outcomes and may facilitate resection of difficult tumors.

  19. 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

    Cancer Research, a biochemist with a research focus on tumor suppressor and cell cycle checkpoint signaling pathways. For more information about...the treatment of cancer. Cell Cycle . 2004;3:779-788. 12. Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K. Cotreatment with the histone...deacetylase inhibitors for the treatment of cancer. Cell Cycle . 2004;3:779-788. 26. Guo F, Sigua C, Tao J, et al. Cotreatment with histone deacetylase

  20. 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 induced a more pronounced colony growth inhibition than imatinib alone.Conclusion: NVP-BEZ235 effectively inhibited cell proliferation by G0/G1 cell cycle arrest and induced apoptosis through deregulating PI3K/Akt/mTOR pathway in CML cells; in addition, NVP-BEZ235 can enhance cell autophagy, and is conducive to raising CML cell sensitivity to imatinib to inhibit the growth of imatinib-resistant cells. Keywords: chronic myelogenous leukemia, NVP-BEZ235, phosphatidylinositol 3-kinase/Akt/mammalian pathway, imatinib, apoptosis, autophagy

  1. Effects of 1-methyl-5-guanylhydrazone-6-oxo-2,3,5,6-tetrahydroindole mesylate (S Adchnon 50) on radiation-induced leukopenia

    International Nuclear Information System (INIS)

    Tatsuno, Ikuro; Tada, Akira; Choutou, Shuichi

    1985-01-01

    S Adchnon 50 (300 mg/day) was administered, in combination with radiation therapy, to 30 patients with malignancy. Two patients were excluded from the study because one had side effects of S Adchnon 50 and another had leukopenia induced by other drugs. When the rate of decrease in WBC counts was 35 % or less or 45 % or less after the completion of radiation therapy (Criteria I) and when postirradiation WBC counts were 3,500/mm 3 or more (Criteria II), patients were regarded as responding to the drug. WBC counts decreased by 23.4 % during radiation therapy and by 22.5 % after the completion of radiation therapy. The response rates were 79 % for the Criteria I and 89 % for the Criteria II. It is therefore concluded that S Adchnon is an effective and safe drug in preventing leukopenia from radiation therapy. (Namekawa, K.)

  2. A multicenter phase I/II study of obatoclax mesylate administered as a 3- or 24-hour infusion in older patients with previously untreated acute myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Aaron D Schimmer

    Full Text Available An open-label phase I/II study of single-agent obatoclax determined a maximum tolerated dose (MTD and schedule, safety, and efficacy in older patients (≥ 70 yr with untreated acute myeloid leukemia (AML.Phase I evaluated the safety of obatoclax infused for 3 hours on 3 consecutive days (3 h × 3 d in 2-week cycles. Initial obatoclax dose was 30 mg/day (3 h × 3 d; n = 3. Obatoclax was increased to 45 mg/day (3 h × 3 d if ≤ 1 patient had a dose-limiting toxicity (DLT and decreased to 20 mg/day (3 h × 3 d if DLT occurred in ≥ 2 patients. In the phase II study, 12 patients were randomized to receive obatoclax at the dose identified during phase I (3 h × 3 d or 60 mg/day administered by continuous infusion over 24 hours for 3 days (24 h × 3 d to determine the morphologic complete response rate.In phase I, two of three patients receiving obatoclax 30 mg/day (3 h × 3 d experienced grade 3 neurologic DLTs (confusion, ataxia, and somnolence. Obatoclax was decreased to 20 mg/day (3 h × 3 d. In phase II, no clinically relevant safety differences were observed between the 20 mg/day (3 h × 3 d; n = 7 and 60 mg/day (24 h × 3 d; n = 5 arms. Neurologic and psychiatric adverse events were most common and were generally transient and reversible. Complete response was not achieved in any patient.Obatoclax 20 mg/day was the MTD (3 h × 3 d in older patients with AML. In the schedules tested, single-agent obatoclax was not associated with an objective response. Evaluation in additional subgroups or in combination with other chemotherapy modalities may be considered for future study.ClinicalTrials.gov NCT00684918.

  3. A multicenter phase I/II study of obatoclax mesylate administered as a 3- or 24-hour infusion in older patients with previously untreated acute myeloid leukemia.

    Science.gov (United States)

    Schimmer, Aaron D; Raza, Azra; Carter, Thomas H; Claxton, David; Erba, Harry; DeAngelo, Daniel J; Tallman, Martin S; Goard, Carolyn; Borthakur, Gautam

    2014-01-01

    An open-label phase I/II study of single-agent obatoclax determined a maximum tolerated dose (MTD) and schedule, safety, and efficacy in older patients (≥ 70 yr) with untreated acute myeloid leukemia (AML). Phase I evaluated the safety of obatoclax infused for 3 hours on 3 consecutive days (3 h × 3 d) in 2-week cycles. Initial obatoclax dose was 30 mg/day (3 h × 3 d; n = 3). Obatoclax was increased to 45 mg/day (3 h × 3 d) if ≤ 1 patient had a dose-limiting toxicity (DLT) and decreased to 20 mg/day (3 h × 3 d) if DLT occurred in ≥ 2 patients. In the phase II study, 12 patients were randomized to receive obatoclax at the dose identified during phase I (3 h × 3 d) or 60 mg/day administered by continuous infusion over 24 hours for 3 days (24 h × 3 d) to determine the morphologic complete response rate. In phase I, two of three patients receiving obatoclax 30 mg/day (3 h × 3 d) experienced grade 3 neurologic DLTs (confusion, ataxia, and somnolence). Obatoclax was decreased to 20 mg/day (3 h × 3 d). In phase II, no clinically relevant safety differences were observed between the 20 mg/day (3 h × 3 d; n = 7) and 60 mg/day (24 h × 3 d; n = 5) arms. Neurologic and psychiatric adverse events were most common and were generally transient and reversible. Complete response was not achieved in any patient. Obatoclax 20 mg/day was the MTD (3 h × 3 d) in older patients with AML. In the schedules tested, single-agent obatoclax was not associated with an objective response. Evaluation in additional subgroups or in combination with other chemotherapy modalities may be considered for future study. ClinicalTrials.gov NCT00684918.

  4. 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.

  5. Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium.

    Science.gov (United States)

    Geoerger, Birgit; Morland, Bruce; Ndiaye, Anna; Doz, Francois; Kalifa, Gabriel; Geoffray, Anne; Pichon, Fabienne; Frappaz, Didier; Chatelut, Etienne; Opolon, Paule; Hain, Sharon; Boderet, Francoise; Bosq, Jacques; Emile, Jean-Francois; Le Deley, Marie-Cecile; Capdeville, Renaud; Vassal, Gilles

    2009-09-01

    To explore imatinib efficacy and pharmacokinetics in children and adolescents with refractory/relapsing solid tumours, expressing imatinib-sensitive receptor tyrosine kinases. Exploratory study on imatinib in tumours expressing, at least, one of the receptors KIT or platelet-derived growth factor receptor (PDGFR). Standard radiological response evaluation, pharmacokinetics, gene mutations and positron emission tomography imaging were assessed. Thirty-six patients (median age: 13.7 years) with brain (12), mesenchymal/bone (14) or other solid tumours, received imatinib 340 mg/m(2)/d over a total of 255 months. Fifteen tumours expressed KIT in 30% cells, 19 expressed PDGFRA and 25 expressed PDGFRB. Twenty patients experienced grades 1-2 treatment-related toxicities. Ten patients achieved stable disease; one chordoma had metabolic response. Pharmacokinetic data showed high inter-patient variability (variation coefficient: 44% and 53% for plasma imatinib and CGP 74588 AUCs, respectively). Imatinib was tolerated well, but failed to show efficacy according to standard criteria in paediatric malignancies expressing KIT or PDGFR.

  6. Proteomic Analysis of Sera from Individuals with Diffuse Cutaneous Systemic Sclerosis Reveals a Multianalyte Signature Associated with Clinical Improvement during Imatinib Mesylate Treatment.

    Science.gov (United States)

    Haddon, D James; Wand, Hannah E; Jarrell, Justin A; Spiera, Robert F; Utz, Paul J; Gordon, Jessica K; Chung, Lorinda S

    2017-05-01

    Imatinib has been investigated for the treatment of systemic sclerosis (SSc) because of its ability to inhibit the platelet-derived growth factor receptor and transforming growth factor-β signaling pathways, which have been implicated in SSc pathogenesis. In a 12-month open-label clinical trial assessing the safety and efficacy of imatinib in the treatment of diffuse cutaneous SSc (dcSSc), significant improvements in skin thickening were observed. Here, we report our analysis of sera collected during the clinical trial. We measured the levels of 46 cytokines, chemokines, and growth factors in the sera of individuals with dcSSc using Luminex and ELISA. Autoantigen microarrays were used to measure immunoglobulin G reactivity to 28 autoantigens. Elastic net regularization was used to identify a signature that was predictive of clinical improvement (reduction in the modified Rodnan skin score ≥ 5) during treatment with imatinib. The signature was also tested using sera from a clinical trial of nilotinib, a tyrosine kinase inhibitor that is structurally related to imatinib, in dcSSc. The elastic net algorithm identified a signature, based on levels of CD40 ligand, chemokine (C-X-C motif) ligand 4 (CXCL4), and anti-PM/Scl-100, that was significantly higher in individuals who experienced clinical improvement than in those who did not (p = 0.0011). The signature was validated using samples from a clinical trial of nilotinib. Identification of patients with SSc with the greatest probability of benefit from treatment with imatinib has the potential to guide individualized treatment. Validation of the signature will require testing in randomized, placebo-controlled studies. Clinicaltrials.gov NCT00555581 and NCT01166139.

  7. Distribution and prognostic value of histopathologic data and immunohistochemical markers in gastrointestinal stromal tumours (GISTs): an analysis of the EORTC phase III trial of treatment of metastatic GISTs with imatinib mesylate

    DEFF Research Database (Denmark)

    Sciot, R.; biec-Rychter, M.; Daugaard, S.

    2008-01-01

    histological/immunohistochemical parameters correlate with clinical response to imatinib. PATIENTS AND METHODS: Pre-treatment samples of GISTs from 546 patients enroled in phase III study were analysed for immunohistochemical characteristics, correlations with clinicopathological data, with survival......RATIONALE: The 62005 EORTC phase III trial, comparing two doses of imatinib in patients with advanced GIST, reported a median progression-free survival of 25 months with a trend towards dose dependency for progression-free survival. The current analysis of that study aimed to assess whether...... and with tumours' genotype. RESULTS: There was no correlation between immunomorphological or clinical characteristics and response to treatment, PFS or OS. No correlations between immunophenotype of the tumour and PFS or OS in the two dose arms were observed. CONCLUSIONS: The results confirm the heterogeneity...

  8. 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 mass index, 24.3 (3.0) kg/m2. The mean (SD) of AUC(0-infinity) was 38,179 (15,504) ng/mL x h(-1) for the test formulation and 40,554 (17,027) ng/mL x h(-1) for the reference formulation. The mean of Cmax for the test formulation was 2472 (933) ng/mL, and the mean Tmax was 3.28 (0.93) hours. The mean of Cmax for the reference formulation was 2566 (963) ng/mL, and the mean T(max) was 3.63 (1.20) hours. The point estimates (90% CIs) for the test/reference ratios of the log-transformed AUC- and C(max) mean values were 0.95 (0.87-1.03) and 0.97 (0.89-1.05), respectively, which met the regulatory criteria for bioequivalence. Thirty-four mild to moderate adverse events were reported (13 with the test formulation and 21 with the reference formulation), and no serious or unexpected adverse events were observed during the study. The adverse events included 16 cases of headache, 13 cases of nausea, 4 cases of vomiting, and 1 episode of diarrhea. The results of this study suggest that the test formulation of imatinib met the regulatory criteria for bioequivalence to the reference formulation in these healthy fasting male volunteers. Both formulations were generally well tolerated and appeared to have a similar adverse-event profile.

  9. Survival advantage with imatinib mesylate therapy in chronic-phase chronic myelogenous ;eukemia (CML-CP) after IFN-alpha failure and in late CML-CP, comparison with historical controls.

    Science.gov (United States)

    Kantarjian, Hagop; O'Brien, Susan; Cortes, Jorge; Giles, Francis; Shan, Jianqin; Rios, Mary Beth; Faderl, Stefan; Verstovsek, Srdan; Garcia-Manero, Guillermo; Wierda, William; Kornblau, Steven; Ferrajoli, Alessandra; Keating, Michael; Talpaz, Moshe

    2004-01-01

    The purpose of this research was to compare the survival of patients with Philadelphia chromosome (Ph) -positive chronic myelogenous leukemia (CML) post-IFN-alpha failure treated with imatinib to historical experiences with standards of care or other therapies. The outcome of 261 patients with Ph-positive chronic phase CML post-IFN failure treated with imatinib was compared with 204 historical control patients treated for a similar disease status with existing therapies. A subset of 147 patients in late chronic phase CML and 100% Ph-positive status treated with imatinib was compared with 95 patients in a similar disease status treated with IFN. Multivariate analyses were conducted to assess the independent prognostic effect of therapy (imatinib versus other) on survival. In the first analysis involving 261 patients on imatinib plus 204 historical patients, the complete cytogenetic response rates were 62% and 19%, respectively (P < 0.001). A multivariate analysis identified pretreatment peripheral blasts and thrombocytosis to be independent poor prognostic factors for survival. Imatinib therapy (versus others) was a significant independent favorable prognostic factor for survival (hazard ratio, 0.17; P < 0.0001). In the second analysis involving the subset of 147 patients receiving imatinib plus 95 historical patients treated with IFN regimens, the complete cytogenetic response rates were 41% and 7%, respectively (P < 0.001). A multivariate analysis selected pretreatment anemia and peripheral blasts to be significant independent poor prognostic factors for survival. Imatinib therapy (versus IFN) was an independent favorable prognostic factor for survival (hazard ratio, 0.20; P < 0.0001). Three-month and 6-month landmark analyses showed that patients in all cytogenetic response categories (major, minor, and none) after imatinib therapy had survival outcomes better than the historical control population. Within each cytogenetic response category, survival was also better with imatinib than with other therapies. This analysis provides evidence for a survival advantage with imatinib versus other therapies in chronic-phase CML post-IFN failure, and for a survival advantage with imatinib versus IFN in late chronic-phase CML.

  10. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

    Science.gov (United States)

    Daver, Naval; Thomas, Deborah; Ravandi, Farhad; Cortes, Jorge; Garris, Rebecca; Jabbour, Elias; Garcia-Manero, Guillermo; Borthakur, Gautam; Kadia, Tapan; Rytting, Michael; Konopleva, Marina; Kantarjian, Hagop; O’Brien, Susan

    2015-01-01

    We have previously reported on the efficacy and tolerability of hyper-CVAD regimen (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) and imatinib followed by imatinib-based consolidation/maintenance therapy in 20 patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Here, we present the 13-year follow up of our study. Fifty-four patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia were enrolled: 39 (72%) with de novo disease, 6 (11%) whose disease was primary refractory after induction (without a tyrosine kinase inhibitor), and 9 (17%) in complete remission after one course of induction therapy (without tyrosine kinase inhibitor). Forty-two (93%) of the 45 patients treated for active disease achieved complete remission, one achieved complete remission with incomplete recovery of platelets, one achieved partial remission and one died during induction. Nineteen (35%) patients are alive and 18 are in complete remission. The 5-year overall survival rate for all patients was 43%. Significant negative predictors of overall survival were age over 60 years, p190 molecular transcript, and active disease at enrollment. Sixteen (30%) patients underwent allogeneic stem cell transplantation. Median overall survival was not significantly greater for patients who underwent transplant. Patients with residual molecular disease at three months had improved complete remission duration with transplant. The median time to hematologic recovery and severe toxicities with combination were not significantly different from those observed with conventional chemotherapy. Only one patient discontinued therapy due to toxicity. HyperCVAD chemotherapy and imatinib is an effective regimen for Philadelphia-positive acute lymphoblastic leukemia. Transplant may not be indicated in all patients with Philadelphia-positive acute lymphoblastic leukemia. (clinicaltrials.gov identifier: NCT00038610) PMID:25682595

  11. Dgroup: DG00865 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG00865 Chemical ... DGroup Rasagiline ... D08469 ... Rasagiline (USAN/INN) D02562 ... Rasagiline mesylate (USAN); Ras...agiline mesilate (JAN) ... D10829 ... Rasagiline tartrate Neuropsychiatric agent ... DG015

  12. Dgroup: DG01512 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available line (USAN/INN) ... D00785 ... Selegiline hydrochloride (JAN/USP) ... DG00865 ... Rasagiline ... D08469 ... Rasagiline (USAN/INN) ... D02562 ... Rasagil...ine mesylate (USAN); Rasagiline mesilate (JAN) ... D10829 ... Rasagiline tartrate DG01

  13. Dgroup: DG01967 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available line ... D03731 ... Selegiline (USAN/INN) ... D00785 ... Selegiline hydrochloride (JAN/USP) ... DG00865 ... Rasagiline ... D08469 ... Rasagiline... (USAN/INN) ... D02562 ... Rasagiline mesylate (USAN); Rasagiline mesilate (JAN) ... D10829 ... Rasagiline

  14. catalysed ortho-carboxylation of acetanilide with CO

    Indian Academy of Sciences (India)

    FG=functional group) utilize carbon monoxide as a carbon source for the formation of functionalized aromatic rings with a new. C-C bond. Carbonylation reactions of vinyl halides, aryl halides, mesylates, triflates, fluorosulphonates and.

  15. Dgroup: DG01619 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available AN) ... D06245 ... Trioxifene mesylate (USAN) ... D06551 ... Afimoxifene (USAN/INN) ... D09380 ... Sivifene (USAN/INN) DG01621 ... Cloimifene-type osteopo...rosis agent ... DG00476 ... Raloxifene ... D08465 ... Raloxifene (I

  16. 21 CFR 522.522 - Danofloxacin.

    Science.gov (United States)

    2010-04-01

    ... mesylate salt. (b) Sponsor. See No. 000069 in § 510.600(c) of this chapter. (c) Related tolerances. See... consumption should not be slaughtered within 4 days from the last treatment. Do not use in cattle intended for...

  17. Untitled

    Indian Academy of Sciences (India)

    bromo-6-tetrahydropyranyloxyhexane with the dianion of. 4-pentyn-1-ol yielded 11-tetrahydropyranyloxy-4-undecyn-1-ol (4) which upon catalytic hydrogenation and subsequent mesylation afforded (6). Li, CuCl4 catalysed the coupling of.

  18. Drugs Approved for Soft Tissue Sarcoma

    Science.gov (United States)

    ... Your Treatment Research Drugs Approved for Soft Tissue Sarcoma This page lists cancer drugs approved by the ... not listed here. Drugs Approved for Soft Tissue Sarcoma Cosmegen (Dactinomycin) Dactinomycin Doxorubicin Hydrochloride Eribulin Mesylate Gleevec ( ...

  19. Dgroup: DG00362 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG00362 Chemical ... DGroup Lomitapide ... D09637 ... Lomitapide (USAN/INN) D09638 ... Lomita...pide mesylate (USAN); Lomitapide mesilate (JAN) ... Cardiovascular agent ... DG01946 ... Hypolipidemic agent ATC co

  20. Dermatofibrosarcoma Protuberans (DFSP)

    Science.gov (United States)

    ... Advocacy priorities AADA Health System Reform Principles Drug pricing and availability CVS dermatologic formulary restrictions Access to ... Imatinib mesylate works differently. It is designed to target specific cancer-causing molecules. This gives it the ...

  1. Identification of Novel Genes and Candidate Targets in CML Stem Cells

    National Research Council Canada - National Science Library

    Eaves, Connie

    2008-01-01

    .... Though imatinib mesylate(IM) that targets BCR-ABL kinase activity is now widely used, its curative potential as a single agent is not sure, moreover it is unlikely to eliminate the CML stem cells either, which highlights...

  2. Imatinib-associated bilateral gynecomastia and unilateral testicular hydrocele in male patient with metastatic gastrointestinal stromal tumor: a literature review.

    Science.gov (United States)

    Tanriverdi, Ozgur; Unubol, Mustafa; Taskin, Fisun; Meydan, Nezih; Sargin, Gokhan; Guney, Engin; Barutca, Sabri

    2012-06-01

    Imatinib mesylate is a drug that has been approved for treatment of advanced gastrointestinal stromal tumors (GISTs) and patients with leukemia such as chronic myeloid or Philadelphia chromosome-positive acute lymphoblastic. Although it has been described only in one patient with testicular hydrocele and gynecomastia in the literature, several cases of male gynecomastia have been reported with the use of imatinib mesylate in chronic myeloid leukemia (GML). Generally, male mastoplasia resolves after discontinuation of imatinib treatment. We report a 73-year-old male with metastatic GISTs who developed gynecomastia and unilateral testicular hydrocele while receiving imatinib mesylate. Nine months after commencing imatinib treatment, gynecomastia and testicular hydrocele were determined. Hormone analyses requested showed serum testosterone levels below and serum estrogen levels above normal limits. During the first month after discontinuing imatinib mesylate treatment, serum testosterone level was normal and there was a partial regression in gynecomastia and testicular hydrocele. To our knowledge, this is the second report of male gynecomastia following imatinib mesylate treatment of a patient with GIST. In conclusion, male patients who are to receive treatment with imatinib mesylate may be monitored for serum testosterone levels and for other reproductive hormone profiles before initiation of the treatment and their breasts may be examined during follow-up visits.

  3. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity.

    Science.gov (United States)

    Yokota, Asumi; Kimura, Shinya; Masuda, Satohiro; Ashihara, Eishi; Kuroda, Junya; Sato, Kiyoshi; Kamitsuji, Yuri; Kawata, Eri; Deguchi, Yasuyuki; Urasaki, Yoshimasa; Terui, Yasuhito; Ruthardt, Martin; Ueda, Takanori; Hatake, Kiyohiko; Inui, Ken-ichi; Maekawa, Taira

    2007-01-01

    Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wild-type but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph+ leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.

  4. Investigation of the atypical glass transition and recrystallization behavior of amorphous prazosin salts.

    Science.gov (United States)

    Kumar, Lokesh; Popat, Dharmesh; Bansal, Arvind K

    2011-08-25

    This manuscript studied the effect of counterion on the glass transition and recrystallization behavior of amorphous salts of prazosin. Three amorphous salts of prazosin, namely, prazosin hydrochloride, prazosin mesylate and prazosin tosylate were prepared by spray drying, and characterized by optical-polarized microscopy, differential scanning calorimetry and powder X-ray diffraction. Modulated differential scanning calorimetry was used to determine the glass transition and recrystallization temperature of amorphous salts. Glass transition of amorphous salts followed the order: prazosin mesylate > prazosin tosylate ~ prazosin hydrochloride. Amorphous prazosin mesylate and prazosin tosylate showed glass transition, followed by recrystallization. In contrast, amorphous prazosin hydrochloride showed glass transition and recrystallization simultaneously. Density Functional Theory, however, suggested the expected order of glass transition as prazosin hydrochloride > prazosin mesylate > prazosin tosylate. The counterintuitive observation of amorphous prazosin hydrochloride having lower glass transition was explained in terms of its lower activation energy (206.1 kJ/mol) for molecular mobility at Tg, compared to that for amorphous prazosin mesylate (448.5 kJ/mol) and prazosin tosylate (490.7 kJ/mol), and was further correlated to a difference in hydrogen bonding strength of the amorphous and the corresponding recrystallized salts. This study has implications in selection of an optimal amorphous salt form for pharmaceutical development.

  5. Discovery of an L-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100.

    Science.gov (United States)

    Kim, Se-Ho; Tangallapally, Rajendra; Kim, In Chul; Trovato, Richard; Parker, Daniel; Patton, J Scott; Reeves, Leslie; Bradford, Chad; Wettstein, Daniel; Baichwal, Vijay; Papac, Damon; Bajji, Ashok; Carlson, Robert; Yager, Kraig M

    2015-11-15

    Various types of Hsp90 inhibitors have been and continue to undergo clinical investigation. One development candidate is the purine-based, synthetic Hsp90 inhibitor 1 (MPC-3100), which successfully completed a phase I clinical study. However, further clinical development of 1 was hindered by poor solubility and consequent formulation issues and promoted development of a more water soluble prodrug. Towards this end, numerous pro-moieties were explored in vitro and in vivo. These studies resulted in identification of L-alanine ester mesylate, 2i (MPC-0767), which exhibited improved aqueous solubility, adequate chemical stability, and rapid bioconversion without the need for solubilizing excipients. Based on improved physical characteristics and favorable PK and PD profiles, 2i mesylate was selected for further development. A convergent, scalable, chromatography-free synthesis for 2i mesylate was developed to support further clinical evaluation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Dgroup: DG01568 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available (JAN/USP) ... DG00865 ... Rasagiline ... D08469 ... Rasagiline (USAN/INN) ... D02562 ... Rasagiline mesylate (USAN); Rasagiline... mesilate (JAN) ... D10829 ... Rasagiline tartrate ... DG01259 ... Lazabemide ... D04...dase B inhibitor ... DG00864 ... Selegiline ... D03731 ... Selegiline (USAN/INN) ... D00785 ... Selegiline hydrochloride

  7. Kinetic spectrophotometric determination of some fluoroquinolone ...

    African Journals Online (AJOL)

    A simple and sensitive kinetic spectrophotometric method was developed for the determination of some fluoroquinolonea antibiotics; gemifloxacin mesylate, moxifloxacin hydrochloride and gatifloxacin in bulk and in pharmaceutical preparations. The method is based upon a kinetic investigation of the oxidation reaction of ...

  8. RESEARCH ARTICLE Association of GSTM1, GSTT1 and GSTP1 ...

    Indian Academy of Sciences (India)

    2017-01-12

    Jan 12, 2017 ... The detoxifying activity of GST enzymes not only protect cells from the adverse effects of xenobiotics, but also ... Kinase Inhibitors (TKIs) for Ph chromosome positive CML. ImatinibMesylate (IM) ... Polymorphisms in genes encoding drug metabolizing enzymes can vary in their enzymatic activity and can play ...

  9. Remarkably efficient synthesis of 2H-indazole 1-oxides and 2H-indazoles via tandem carbon-carbon followed by nitrogen-nitrogen bond formation.

    Science.gov (United States)

    Bouillon, Isabelle; Zajícek, Jaroslav; Pudelová, Nadĕzda; Krchnák, Viktor

    2008-11-21

    Base-catalyzed tandem carbon-carbon followed by nitrogen-nitrogen bond formations quantitatively converted N-alkyl-2-nitro-N-(2-oxo-2-aryl-ethyl)-benzenesulfonamides to 2H-indazoles 1-oxides under mild conditions. Triphenylphosphine or mesyl chloride/triethylamine-mediated deoxygenation afforded 2H-indazoles.

  10. Effect of ruboxistaurin in patients with diabetic macular edema : Thirty-month results of the randomized PKC-DMES clinical trial

    NARCIS (Netherlands)

    Aiello, Lloyd Paul; Ai, Everett; Aiello, Lloyd M.; Anand, Rajiv; Blumenkranz, Mark; Boyer, David; Brucker, Alexander J.; Chandler, Thomas; Chong, Lawrence; Connor, Thomas; Danis, Ron; Dehning, Doug; Dodson, Paul; Eaton, Alexander; Faber, David; Finkelstein, Dan; Forrester, John V.; Frank, Robert N.; Garcia, Charles; Gardner, Thomas W.; Gehrs, Karen M.; Goodart, Roy A.; Gottlieb, Justin; Greven, Craig M.; Guyer, David R.; Hainsworth, Dean; Hooper, Philip; Jackson, Willliam E.; Kinyoun, James L.; Kipnes, Mark; Klein, Michael L.; Kohner, Eva M.; Kuppermann, Baruch; Lewis, Hilel; Li, Helen K.; Lund-Anderson, Henrik; Ma, Colin; Martin, Daniel F.; Orellana, Juan; Paden, Philip Y.; Polak, Bettine; Ross, Stuart A.; Sharuk, George; Singerman, Lawrence J.; Smiddy, William E.; Trese, Michael; Tweeten, James P.; Vine, Andrew; Vora, Jiten; Wolffenbuttel, Bruce

    Objective: To evaluate the safety and efficacy of orally administered ruboxistaurin (RBX) as a mesylate salt in patients with diabetic macular edema (DME). 1 Design: Multicenter, double-masked, randomized, placebo-controlled study of 686 patients receiving placebo or RBX orally ( 4, 16, or 32 mg/d)

  11. Journal of Genetics | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics. RAVINDRAN ANKATHIL. Articles written in Journal of Genetics. Volume 96 Issue 4 September 2017 pp 633-639 RESEARCH ARTICLE. Association of GSTM1 , GSTT1 and GSTP1 Ile105Val polymorphisms with clinical response to imatinib mesylate treatment among Malaysian chronic ...

  12. 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...

  13. 77 FR 26288 - Determination of Regulatory Review Period for Purposes of Patent Extension; HALAVEN

    Science.gov (United States)

    2012-05-03

    ... market the human drug product and continues until FDA grants permission to market the drug product... marketing the human drug product HALAVEN (eribulin mesylate). HALAVEN is indicated for the treatment of... that the approval of HALAVEN represented the first permitted commercial marketing or use of the product...

  14. Receptor Tyrosine Kinases as Targets for Treatment of Peripheral Nerve Sheath Tumors in NF 1 Patients

    Science.gov (United States)

    2010-03-01

    additive effect of the drug and intrinsic survival disadvantage due to large size. Yang et al. [8] recently reported an effect of imatinib mesylate for...ethyl acetate extract of Bio 30 was analysed as described under Materials and Methods. The source of Bio 30 was Manuka Health, Auckland , New Zealand

  15. Polymorphism

    Indian Academy of Sciences (India)

    of the cancer 'chronic myeloid leukemia'. Novartis invented imatinib in 1992 and patented it in 1993 in US and other countries. The company applied for a patent in India in 1998 for β-crystalline form of imatinib mesylate, which led to a legal scrutiny of Patents Act 1970. suggested that virtually 'every compound has different ...

  16. Remarkably Efficient Synthesis of 2H-Indazole 1-oxides and 2H-Indazoles via Tandem Carbon–Carbon Followed by Nitrogen–Nitrogen Bond Formation

    Science.gov (United States)

    Bouillon, Isabelle; Zajíček, Jaroslav; Pudelová, Naděžda; Krchňák, Viktor

    2009-01-01

    Synthesis of Indazoles Base-catalyzed tandem carbon–carbon followed by nitrogen–nitrogen bond formations quantitatively converted N-alkyl-2-nitro-N-(2-oxo-2-aryl-ethyl)-benzenesulfonamides to 2H-indazoles 1-oxides under mild conditions. Triphenylphosphine or mesyl chloride/triethylamine-mediated deoxygenation afforded 2H-indazoles. PMID:18937414

  17. Journal of Genetics | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 96; Issue 4. Association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with clinical response to imatinib mesylate treatment among Malaysian chronic myeloid leukaemia patients. SITI MAZIRAS MAKHTAR AZLAN HUSIN ABDUL AZIZ BABA RAVINDRAN ANKATHIL.

  18. Dgroup: DG01260 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available on agent ATC code: N04BD03 MAO-B inhibitor, Antiparkinsonian agent MAOB [HSA:4129] [KO:K00274] ... ...mide mesylate (USAN) ... Neuropsychiatric agent ... DG01568 ... MAO inhibitor ... DG01512 ... Monoamine oxidase B inhibitor ... DG01967 ... Antiparkins

  19. 77 FR 35837 - Conditionally Approved New Animal Drugs for Minor Use and Minor Species; Masitinib

    Science.gov (United States)

    2012-06-15

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 516 [Docket No.... The supplemental CNADA provides for a revised indication for masitinib mesylate tablets in dogs. DATES... in dogs that have not previously received radiotherapy and/or chemotherapy except corticosteroids. In...

  20. 77 FR 4226 - Implantation or Injectable Dosage Form New Animal Drugs; Danofloxacin

    Science.gov (United States)

    2012-01-27

    ... danofloxacin mesylate injectable solution for the treatment of bovine respiratory disease in beef cattle. DATES... beef cattle. The supplemental NADA is approved as of December 16, 2011, and 21 CFR 522.522 is amended... environment. Therefore, neither an environmental assessment nor an environmental impact statement is required...

  1. Formulation and characterization of microspheres loaded with imatinib for sustained delivery

    NARCIS (Netherlands)

    Ramazani, F.; Chen, W.; van Nostrum, C.F.; Storm, Gerrit; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria; Hennink, Wim E.; Kok, R.J.

    2015-01-01

    The aim of this study was the development of imatinib-loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with high loading efficiency which can afford continuous release of imatinib over a prolonged period of time. Imatinib mesylate loaded PLGA microspheres with a size of 6–20 μm were

  2. Formulation and characterization of microspheres loaded with imatinib for sustained delivery

    NARCIS (Netherlands)

    Ramazani, F.; Chen, W.; Van Nostrum, C. F.; Storm, G.; Kiessling, F.; Lammers, T.; Hennink, W. E.; Kok, R. J.

    2015-01-01

    The aim of this study was the development of imatinib-loaded poly(d,l-lactide-co-glycolide) (PLGA) microspheres with high loading efficiency which can afford continuous release of imatinib over a prolonged period of time. Imatinib mesylate loaded PLGA microspheres with a size of 6-20 μm were

  3. Identification of Prognostic and Susceptibility Markers in Chronic ...

    African Journals Online (AJOL)

    2018-03-01

    Mar 1, 2018 ... ABSTRACT. BACKGROUND: Incidence of Chronic Myeloid Leukemia (CML) is continuously increasing and expected to reach 100,000 patients every year by 2030. Though the discovery of Imatinib Mesylate. (IM) has brought a paradigm shift in CML treatment, 20% patients show resistance to this tyrosine ...

  4. Concurrent inhibition of kit- and FcepsilonRI-mediated signaling: coordinated suppression of mast cell activation

    DEFF Research Database (Denmark)

    Jensen, Bettina M; Beaven, Michael A; Iwaki, Shoko

    2008-01-01

    characterized Kit inhibitor imatinib mesylate (imatinib). In contrast to imatinib, however, hypothemycin also effectively inhibited FcepsilonRI-mediated degranulation and cytokine production in addition to the potentiation of these responses via Kit. The effect of hypothemycin on Kit-mediated responses could...

  5. Efforts toward rapid construction of the cortistatin A carbocyclic core via enyne-ene metathesis

    KAUST Repository

    Baumgartner, Corinne

    2010-01-01

    Our efforts toward the construction of the carbocylic core of cortistatin A via an enyne-ene metathesis are disclosed. Interestingly, an attempted S N2 inversion of a secondary mesylate in our five-membered D-ring piece gave a product with retention of stereochemistry. © 2010 The Royal Society of Chemistry.

  6. Decarboxylative Aminomethylation of Aryl- and Vinylsulfonates through Combined Nickel- and Photoredox-Catalyzed Cross-Coupling

    KAUST Repository

    Fan, Lulu

    2016-09-23

    A mild approach for the decarboxylative aminomethylation of aryl sulfonates by the combination of photoredox and nickel catalysis through C−O bond cleavage is described for the first time. A wide range of aryl triflates as well as aryl mesylates, tosylates and alkenyl triflates afford the corresponding products in good to excellent yields.

  7. 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.

  8. 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...

  9. Phase I clinical trial of combination imatinib and ipilimumab in patients with advanced malignancies

    OpenAIRE

    Reilley, Matthew J.; Bailey, Ann; Subbiah, Vivek; Janku, Filip; Naing, Aung; Falchook, Gerald; Karp, Daniel; Piha-Paul, Sarina; Tsimberidou, Apostolia; Fu, Siqing; Lim, JoAnn; Bean, Stacie; Bass, Allison; Montez, Sandra; Vence, Luis

    2017-01-01

    Background Imatinib mesylate can induce rapid tumor regression, increase tumor antigen presentation, and inhibit tumor immunosuppressive mechanisms. CTLA-4 blockade and imatinib synergize in mouse models to reduce tumor volume via intratumoral accumulation of CD8+ T cells. We hypothesized that imatinib combined with ipilimumab would be tolerable and may synergize in patients with advanced cancer. Methods Primary objective of the dose-escalation study (3?+?3 design) was to establish the maximu...

  10. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome

    OpenAIRE

    Griffin, John H.; Leung, Joey; Bruner, Rebecca J.; Caligiuri, Michael A.; Briesewitz, Roger

    2003-01-01

    Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disease of unknown etiology. Recently, it has been reported that imatinib mesylate (Gleevec), an inhibitor of Bcr-Abl kinase useful in the treatment of chronic myeloid leukemia, is also effective in treating HES; however, the molecular target of imatinib in HES is unknown. This report identifies a genetic rearrangement in the eosinophilic cell line EOL-1 that results in the expression of a fusion protein comprising an N...

  11. Recent acquisitions in the management of iron overload.

    Science.gov (United States)

    Franchini, Massimo

    2005-10-01

    Chronically transfused patients develop iron overload, which leads to organ damage and ultimately to death. The introduction of the iron-chelating agent desferrioxamine mesylate dramatically improved the life expectancy of these patients. However, the very demanding nature of this treatment (subcutaneous, continuous infusion via a battery-operated portable pump) has been the motivation for attempts to develop alternative forms of treatment that would facilitate the patients' compliance. In this review, we describe the most important advances in iron-chelation therapy.

  12. Effects of chemotherapeutics on organotypic corticostriatal slice cultures identified by a panel of fluorescent and immunohistochemical markers

    DEFF Research Database (Denmark)

    Nørregaard, Annette; Jensen, Stine Skov; Kolenda, Jesper

    2012-01-01

    specific neuronal and glial degeneration induced by chemotherapeutics in organotypic rat corticostriatal slice cultures. The slice cultures were exposed to the alkylating agents temozolomide (TMZ) and nimustine (ACNU), the tyrosine kinase inhibitor imatinib mesylate (IM) and the microtubule......-destabilizing agent vincristine (VCR). Densitometric measurements of uptake of the fluorescent dye propidium iodide (PI) were used for quantifying cellular degeneration. Moreover, paraffin sections were hematoxylin eosine stained and immunostained for the neuronal marker microtubule-associated protein 2 (MAP2...

  13. Synthesis and anti-HIV activity of novel phenyl branched cyclopropyl nucleosides.

    Science.gov (United States)

    Wu, Ying; Hong, Joon Hee

    2005-09-01

    Novel phenyl branched cyclopropyl nucleoside analogues were designed and synthesized as potential antiviral agents. Cyclopropanation was performed via classical Simmons-Smith reaction using Zn(Et)2 and CH2I2. Coupling of the mesylates 11 and 12 with natural bases (A,C,T,U) and desilylation afforded a series of novel cyclopropyl nucleosides 21-28. The synthesized compounds were evaluated for their antiviral and antitumor activity against various viruses such as HIV, HSV-1, HSV-2 and HCMV.

  14. Transannulation of 1-Sulfonyl-1,2,3-Triazoles with Heterocumulenes

    Science.gov (United States)

    Chuprakov, Stepan; Kwok, Sen Wai; Fokin, Valery V.

    2013-01-01

    Readily available 1-mesyl-1,2,3-triazoles are efficiently converted into a variety of imidazolones and thiazoles by Rh(II)-catalyzed denitrogenative reactions with isocyanates and isothiocyanates, respectively. The proposed triazolediazoimine equilibrium results in the formation of highly reactive azavinyl metal-carbenes, which react with heterocumulenes causing an apparent swap of 1,2,3-triazole core for another heterocycle. PMID:23477345

  15. Efficacy and safety of rasagiline as an adjunct to levodopa treatment in Chinese patients with Parkinson's disease: a randomized, double-blind, parallel-controlled, multi-centre trial.

    Science.gov (United States)

    Zhang, Lina; Zhang, Zhiqin; Chen, Yangmei; Qin, Xinyue; Zhou, Huadong; Zhang, Chaodong; Sun, Hongbin; Tang, Ronghua; Zheng, Jinou; Yi, Lin; Deng, Liying; Li, Jinfang

    2013-08-01

    Rasagiline mesylate is a highly potent, selective and irreversible monoamine oxidase type B (MAOB) inhibitor and is effective as monotherapy or adjunct to levodopa for patients with Parkinson's disease (PD). However, few studies have evaluated the efficacy and safety of rasagiline in the Chinese population. This study was designed to investigate the safety and efficacy of rasagiline as adjunctive therapy to levodopa treatment in Chinese PD patients. This was a randomized, double-blind, placebo-controlled, parallel-group, multi-centre trial conducted over a 12-wk period that enrolled 244 PD patients with motor fluctuations. Participants were randomly assigned to oral rasagiline mesylate (1 mg) or placebo, once daily. Altogether, 219 patients completed the trial. Rasagiline showed significantly greater efficacy compared with placebo. During the treatment period, the primary efficacy variable--mean adjusted total daily off time--decreased from baseline by 1.7 h in patients treated with 1.0 mg/d rasagiline compared to placebo (p rasagiline treatment. Rasagiline was well tolerated. This study demonstrated that rasagiline mesylate is effective and well tolerated as an adjunct to levodopa treatment in Chinese PD patients with fluctuations.

  16. Multilayered Films Produced by Layer-by-Layer Assembly of Chitosan and Alginate as a Potential Platform for the Formation of Human Adipose-Derived Stem Cell aggregates

    Directory of Open Access Journals (Sweden)

    Javad Hatami

    2017-09-01

    Full Text Available The construction of multilayered films with tunable properties could offer new routes to produce biomaterials as a platform for 3D cell cultivation. In this study, multilayered films produced with five bilayers of chitosan and alginate (CHT/ALG were built using water-soluble modified mesyl and tosyl–CHT via layer-by-layer (LbL self-assembly. NMR results demonstrated the presences of mesyl (2.83 ppm and tosyl groups (2.39, 7.37 and 7.70 ppm in the chemical structure of modified chitosans. The buildup of multilayered films was monitored by quartz-crystal-microbalance (QCM-D and film thickness was estimated using the Voigt-based viscoelastic model. QCM-D results demonstrated that CHT/ALG films constructed using mesyl or tosyl modifications (mCHT/ALG were significantly thinner in comparison to the CHT/ALG films constructed with unmodified chitosan (p < 0.05. Adhesion analysis demonstrated that human adipose stem cells (hASCs did not adhere to the mCHT/ALG multilayered films and formed aggregates with sizes between ca. 100–200 µm. In vitro studies on cell metabolic activity and live/dead staining suggested that mCHT/ALG multilayered films are nontoxic toward hACSs. Multilayered films produced via LbL assembly of ALG and off-the-shelf, water-soluble modified chitosans could be used as a scaffold for the 3D aggregates formation of hASCs in vitro.

  17. Bio-analytical method development and validation of Rasagiline by high performance liquid chromatography tandem mass spectrometry detection and its application to pharmacokinetic study

    OpenAIRE

    Ravi Kumar Konda; Babu Rao Chandu; B.R. Challa; Chandrasekhar B. Kothapalli

    2012-01-01

    The most suitable bio-analytical method based on liquidâliquid extraction has been developed and validated for quantification of Rasagiline in human plasma. Rasagiline-13C3 mesylate was used as an internal standard for Rasagiline. Zorbax Eclipse Plus C18 (2.1 mmÃ50 mm, 3.5 μm) column provided chromatographic separation of analyte followed by detection with mass spectrometry. The method involved simple isocratic chromatographic condition and mass spectrometric detection in the positive ion...

  18. Desferrioxamine-related ocular toxicity: A case report

    Directory of Open Access Journals (Sweden)

    Sumu Simon

    2012-01-01

    Full Text Available A 29-year-old lady receiving repeated blood transfusions for β thalassemia since childhood, presented with rapidly deteriorating symptoms of night blindness and peripheral visual field loss. She was recently commenced on high-dose intravenous desferrioxamine for reducing the systemic iron overload. Clinical and investigative findings were consistent with desferrioxamine-related pigmentary retinopathy and optic neuropathy. Recovery was partial following cessation of desferrioxamine. This report highlights the ocular side-effects of desferrioxamine mesylate and the need to be vigilant in patients on high doses of desferrioxamine.

  19. Imatinib-induced Stevens-Johnsons syndrome.

    Science.gov (United States)

    Jha, Praveen; Himanshu, D; Jain, Nirdesh; Singh, Ajay Kumar

    2013-01-23

    Imatinib mesylate is a tyrosine kinase inhibitor used widely as the first-line treatment for chronic myeloid leukaemia (CML). The side-effect profile of this drug includes fluid retention, muscle cramps, diarrhoea, myelosuppression and skin rashes. Of these, rashes of the type maculo-papular eruptions and oedema developed most commonly. The cutaneous adverse reactions other than maculo-papular eruptions are rare with imatinib. Severe and life-threatening cutaneous reactions can occur in 5% cases. Here, the author reports a case of newly diagnosed CML that developed Steven-Johnsons syndrome due to imatinib therapy. Patient responded and discharged successfully on withdrawal of the culminating drug.

  20. Cadmium Removal from Water and Soil by a Cadmium-Resistant Rhizobacterium and Its Effect on Plant Root Elongation

    OpenAIRE

    Chirawee Sangthong; Siranan Duangboobpha; Benjaphorn Prapagdee

    2015-01-01

    A cadmium resistant rhizobacterium, Pseudomonas sp. PM2, was isolated from plant roots. It is highly resistant to cadmium toxicity. The minimum inhibitory concentrations of cadmium for Pseudomonas sp. PM2 is 2100 mg/L. Pseudomonas sp. PM2 produced high levels of siderophore and rhamnolipid biosurfactant in 74.88 µM of deferoxamine mesylate equivalents and 329.54 mg/L, respectively. It was able to remove cadmium ion in an aqueous solution by 69.84% at the initial cadmium ion concentration of 2...

  1. An activating mutation of GNB1 is associated with resistance to tyrosine kinase inhibitors in ETV6-ABL1-positive leukemia

    Czech Academy of Sciences Publication Activity Database

    Zimmermannova, O.; Doktorova, E.; Stuchlý, J.; Kanderová, V.; Kuzilkova, D.; Strnad, Hynek; Starková, J.; Alberich-Jorda, Meritxell; Falkenburg, J.H.F.; Trka, J.; Petrák, J.; Zuna, J.; Žaliová, M.

    2017-01-01

    Roč. 36, č. 43 (2017), s. 5985-5994 ISSN 0950-9232 R&D Projects: GA ČR(CZ) GBP302/12/G101; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:68378050 Keywords : acute lymphoblastic-leukemia * chronic myeloid-leukemia * bcr-abl * tel-abl * cytogenetic characterization * imatinib-mesylate * fusion proteins * blast crisis * rearrangement * patient Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Cell biology Impact factor: 7.519, year: 2016

  2. Clinical efficacy and safety of imatinib in the management of Ph+ chronic myeloid or acute lymphoblastic leukemia in Chinese patients

    Science.gov (United States)

    Zhu, Yu; Qian, Si-Xuan

    2014-01-01

    Imatinib mesylate is considered the standard first-line systemic treatment for patients with chronic myeloid leukemia (CML) and functions by targeting BCR-ABL tyrosine kinases. Imatinib has substantially changed the clinical management and improved the prognosis of CML and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL). Here, we review the pharmacology, mode of action, and pharmacokinetics of imatinib; Chinese efficacy studies in CML and Ph+ ALL; safety and tolerability; patient-focused perspectives, such as quality of life, patient satisfaction, acceptability, and adherence; and uptake of imatinib. PMID:24623982

  3. A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of neramexane in patients with moderate to severe subjective tinnitus

    OpenAIRE

    Jastreboff Pawel J; Görtelmeyer Roman; Gebauer Alexander; Ellers-Lenz Barbara; Althaus Michael; Suckfüll Markus; Moebius Hans J; Rosenberg Tanja; Russ Hermann; Wirth Yvonne; Krueger Hagen

    2011-01-01

    Abstract Background Neramexane is a new substance that exhibits antagonistic properties at α9α10 cholinergic nicotinic receptors and N-methyl-D-aspartate receptors, suggesting potential efficacy in the treatment of tinnitus. Methods A total of 431 outpatients with moderate to severe subjective tinnitus (onset 3-18 months before screening) were assigned randomly to receive either placebo or neramexane mesylate (25 mg/day, 50 mg/day and 75 mg/day) for 16 weeks, with assessment at 4-week interva...

  4. Bio-analytical method development and validation of Rasagiline by high performance liquid chromatography tandem mass spectrometry detection and its application to pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Ravi Kumar Konda

    2012-10-01

    Full Text Available The most suitable bio-analytical method based on liquid–liquid extraction has been developed and validated for quantification of Rasagiline in human plasma. Rasagiline-13C3 mesylate was used as an internal standard for Rasagiline. Zorbax Eclipse Plus C18 (2.1 mm×50 mm, 3.5 μm column provided chromatographic separation of analyte followed by detection with mass spectrometry. The method involved simple isocratic chromatographic condition and mass spectrometric detection in the positive ionization mode using an API-4000 system. The total run time was 3.0 min. The proposed method has been validated with the linear range of 5–12000 pg/mL for Rasagiline. The intra-run and inter-run precision values were within 1.3%–2.9% and 1.6%–2.2% respectively for Rasagiline. The overall recovery for Rasagiline and Rasagiline-13C3 mesylate analog was 96.9% and 96.7% respectively. This validated method was successfully applied to the bioequivalence and pharmacokinetic study of human volunteers under fasting condition. Keywords: High performance liquid chromatography, Mass spectrometry, Rasagiline, Liquid–liquid extraction

  5. Bio-analytical method development and validation of Rasagiline by high performance liquid chromatography tandem mass spectrometry detection and its application to pharmacokinetic study.

    Science.gov (United States)

    Konda, Ravi Kumar; Chandu, Babu Rao; Challa, B R; Kothapalli, Chandrasekhar B

    2012-10-01

    The most suitable bio-analytical method based on liquid-liquid extraction has been developed and validated for quantification of Rasagiline in human plasma. Rasagiline- 13 C 3 mesylate was used as an internal standard for Rasagiline. Zorbax Eclipse Plus C18 (2.1 mm×50 mm, 3.5 μm) column provided chromatographic separation of analyte followed by detection with mass spectrometry. The method involved simple isocratic chromatographic condition and mass spectrometric detection in the positive ionization mode using an API-4000 system. The total run time was 3.0 min. The proposed method has been validated with the linear range of 5-12000 pg/mL for Rasagiline. The intra-run and inter-run precision values were within 1.3%-2.9% and 1.6%-2.2% respectively for Rasagiline. The overall recovery for Rasagiline and Rasagiline- 13 C 3 mesylate analog was 96.9% and 96.7% respectively. This validated method was successfully applied to the bioequivalence and pharmacokinetic study of human volunteers under fasting condition.

  6. [Identification, evaluation and treatment of dementia patients in society].

    Science.gov (United States)

    Capildeo, R; Wallace, M G; Clifford Rose, F

    1983-12-29

    Patients with "mild to moderate" dementia might improve with appropriate drug therapy whereas patients with "severe" dementia are generally considered to have an irreversible condition, providing acute metabolic disorders have been excluded and appropriate investigations have been performed to exclude neurological conditions that might be amenable to neurosurgery. Since it is unlikely that this type of patient will be referred to the hospital outpatient clinics, it is necessary to identify these patients in the community. For this purpose, authors have used the Abbreviated Mental Test. A comparison between two observers (nurse and doctor) has been made. Subsequently, a 6 symptoms check-list, as abbreviated form of the Crichton Royal Rating Scale for geriatric patients, was used in an open pilot study on 260 patients completing a 12 weeks treatment by dihydroergotoxine mesylate (codergocrine mesylate, Hydergine) 4.5 mg once a day. Although this was an open pilot study, it does show that it is possible to identify and treat patients with "mild to moderate" dementia in the community. A single dose formulation in the elderly has obvious advantages. In this study, compliance was excellent and 88% of the patients showed significant improvement using the suggested rating scales.

  7. Gateways to clinical trials.

    Science.gov (United States)

    Tomillero, A; Moral, M A

    2009-05-01

    (-)-Gossypol; Abacavir sulfate/lamivudine, ACAM-1000, ACE-011, Agomelatine, AGS-004, Alemtuzumab, Alvocidib hydrochloride, AMG-317, Amlodipine, Aripiprazole, Atazanavir sulfate, Azacitidine; Becatecarin, Belinostat, Bevacizumab, BMS-387032, BMS-690514, Bortezomib; Casopitant mesylate, Cetuximab, Choline fenofibrate, CK-1827452, Clofarabine, Conivaptan hydrochloride; Dabigatran etexilate, DADMe-Immucillin-H, Darbepoetin alfa, Darunavir, Dasatinib, DC-WT1, Decitabine, Deferasirox, Degarelix acetate, Denenicokin, Denosumab, Dienogest, Duloxetine hydrochloride; Ecogramostim, Eculizumab, Edoxaban tosilate, Elacytarabine, Elesclomol, Eltrombopag olamine, Enfuvirtide, Enzastaurin hydrochloride, Eribulin mesilate, Erlotinib hydrochloride, Escitalopram oxalate, Eszopiclone, Etravirine; Flibanserin, Fludarabine, Fondaparinux sodium, Fosamprenavir calcium; Gefitinib, Genistein; I-131-L19-SIP, Idrabiotaparinux sodium, Imatinib mesylate, IMGN-901, Ipilimumab; Laromustine, Lenalidomide, Liposomal cisplatin, Liraglutide, Lisdexamfetamine mesilate, Lopinavir, Lopinavir/ritonavir; Maraviroc, MDV-3100, Mecasermin rinfabate, MP-470, Mycophenolic acid sodium salt; Naproxcinod, NB-002, Nesiritide, Nilotinib hydrochloride monohydrate, NK-012; Palonosetron hydrochloride, Panobinostat, Pegfilgrastim, Peginterferon alfa-2a, Pitavastatin calcium, PL-3994, Plerixafor hydrochloride, Plitidepsin, PM-10450; Raltegravir potassium, Recombinant human soluble thrombomodulin, ReoT3D, RHAMM R3 peptide, Rivaroxaban, Romiplostim, Rosuvastatin calcium, Rozrolimupab; Sabarubicin hydrochloride, Salinosporamide A, Sirolimus-eluting stent, Smallpox (Vaccinia) Vaccine, Live, Sorafenib; Tenofovir disoproxil fumarate, Tenofovir disoproxil fumarate/emtricitabine, Teriparatide, Tipifarnib, Tipranavir, Trabectedin, Trifluridine/TPI; Vardenafil hydrochloride hydrate, Vinflunine, Volociximab, Vorinostat; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Ziprasidone hydrochloride, Zoledronic acid monohydrate

  8. Expression of MDR1, MRP2 and BCRP mRNA in tissues of turkeys.

    Science.gov (United States)

    Haritova, A M; Schrickx, J; Lashev, L D; Fink-Gremmels, J

    2008-08-01

    MDR1, MRP2 and BCRP are members of the superfamily of ABC membrane transporters that export a large variety of structurally diverse substances out of the cell, hence being an integral part of various biological barriers. Here we report for the first time the tissue distribution of these ABC efflux transporters in the gastrointestinal tract (crop, proventriculus, duodenum, proximal and distal jejunum, ileum, caecum, colon) as well as in liver, kidney, lung, brain, adrenal gland, ovaries, oviduct and testes in BUT9 turkeys. MDR1 and BCRP mRNA expression was detected in all tissue samples, and the highest levels were measured in the small intestines. The tissue distribution of MRP2 mRNA was less consistent and some tissues seemed to lack any significant expression. Moreover, in consideration of previous findings suggesting that fluoroquinolones are substrates and modulators of ABC transporters, the effect of orally administered danofloxacin mesylate on the levels of MDR1, MRP2 and BCRP mRNA expression was investigated. Danofloxacin treatment resulted in a significant up-regulation of the measured transporters at the transcriptional level in the upper part of gastro-intestinal tract, liver and kidneys as well as in barrier-protected organs, such as the brain. However, despite this significant increase in the transcription levels, the pharmacokinetic parameters after repeated application of danofloxacin mesylate were not significantly altered.

  9. Novel and validated titrimetric method for determination of selected angiotensin-II-receptor antagonists in pharmaceutical preparations and its comparison with UV spectrophotometric determination

    Directory of Open Access Journals (Sweden)

    Shrikant H. Patil

    2012-12-01

    Full Text Available A novel and simple titrimetric method for determination of commonly used angiotensin-II-receptor antagonists (ARA-IIs is developed and validated. The direct acid base titration of four ARA-IIs, namely eprosartan mesylate, irbesartan, telmisartan and valsartan, was carried out in the mixture of ethanol:water (1:1 as solvent using standardized sodium hydroxide aqueous solution as titrant, either visually using phenolphthalein as an indicator or potentiometrically using combined pH electrode. The method was found to be accurate and precise, having relative standard deviation of less than 2% for all ARA-IIs studied. Also, it was shown that the method could be successfully applied to the assay of commercial pharmaceuticals containing the above-mentioned ARA-IIs. The validity of the method was tested by the recovery studies of standard addition to pharmaceuticals and the results were found to be satisfactory. Results obtained by this method were found to be in good agreement with those obtained by UV spectrophotometric method. For UV spectrophotometric analysis ethanol was used as a solvent and wavelength of 233 nm, 246 nm, 296 nm, and 250 nm was selected for determination of eprosartan mesylate, irbesartan, telmisartan, and valsartan respectively. The proposed titrimetric method is simple, rapid, convenient and sufficiently precise for quality control purposes. Keywords: Angiotensin-II-receptor antagonists, Titrimetric assay, UV spectrophotometry, Validation

  10. The inside mystery of jejunal gastrointestinal stromal tumor: a rare case report and review of the literature.

    Science.gov (United States)

    Dhull, A K; Kaushal, V; Dhankhar, R; Atri, R; Singh, H; Marwah, N

    2011-01-01

    Gastrointestinal stromal tumors (GISTs) are malignant and rare form of soft tissue sarcoma of the digestive tract. The incidence of gastrointestinal stromal tumors is very low Kramer et al. 2005 Jejunal GISTs are extremely rare. Here we present a rare case of jejunal GIST with unusually large size at presentation. The patient presented with severe abdomen pain, exophytic growth, and dimorphic anemia. Surgical resection of the tumor was carried out, and operative findings revealed a 15 × 10 cm growth, arising from serosal surface of jejunum, at the antimesenteric surface. Diagnosis in this case was made by subjecting the resected specimen to immunohistochemical analysis. In view of large size of the resected tumor, and high-risk histopathological features, imatinib mesylate 400 mg once daily was given as adjuvant chemotherapy. Patient is asymptomatic without any evidence of tumor recurrence after six months of postoperative followup. Imatinib as such is recommended in metastatic, residual or recurrent cases of GISTs or which are surgically not removable; however, recent recommendations suggests the use of imatinib mesylate after radical surgery in high-risk cases, because it has shown a significant decrease in the recurrence rate, and the Food and Drug Administration (FDA) has also approved the use of imatinib as adjuvant therapy after complete resection of localized, primary GIST.

  11. The Inside Mystery of Jejunal Gastrointestinal Stromal Tumor: A Rare Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    A. K. Dhull

    2011-01-01

    Full Text Available Gastrointestinal stromal tumors (GISTs are malignant and rare form of soft tissue sarcoma of the digestive tract. The incidence of gastrointestinal stromal tumors is very low Kramer et al. 2005 Jejunal GISTs are extremely rare. Here we present a rare case of jejunal GIST with unusually large size at presentation. The patient presented with severe abdomen pain, exophytic growth, and dimorphic anemia. Surgical resection of the tumor was carried out, and operative findings revealed a 15 × 10 cm growth, arising from serosal surface of jejunum, at the antimesenteric surface. Diagnosis in this case was made by subjecting the resected specimen to immunohistochemical analysis. In view of large size of the resected tumor, and high-risk histopathological features, imatinib mesylate 400 mg once daily was given as adjuvant chemotherapy. Patient is asymptomatic without any evidence of tumor recurrence after six months of postoperative followup. Imatinib as such is recommended in metastatic, residual or recurrent cases of GISTs or which are surgically not removable; however, recent recommendations suggests the use of imatinib mesylate after radical surgery in high-risk cases, because it has shown a significant decrease in the recurrence rate, and the Food and Drug Administration (FDA has also approved the use of imatinib as adjuvant therapy after complete resection of localized, primary GIST.

  12. In vivo brain dopaminergic receptor site mapping using 75Se-labeled pergolide analogs: the effects of various dopamine receptor agonists and antagonists

    International Nuclear Information System (INIS)

    Weaver, A.

    1986-01-01

    Perogolide mesylate is a new synthetic ergoline derivative which is reported to possess agonistic activity at central dopamine receptor sites in the brain. The authors have synthesized a [ 75 Se]-radiolabeled pergolide mesylate derivative, [ 75 Se]-pergolide tartrate, which, after i.v. administration to mature male rats, showed a time course differentiation in the uptake of this radiolabeled compound in isolated peripheral and central (brain) tissues that are known to be rich in dopamine receptor sites. Further studies were conducted in which the animals were preexposed to the dopamine receptor agonist SKF-38393, as well as the dopamine receptor antagonists (+)-butaclamol, (-)-butaclamol, (+/-)-butaclamol and (-)-chloroethylnorapomorphine, to substantiate the specific peripheral and central localization patterns of [ 75 Se]-pergolide tartrate. Further investigations were also conducted in which the animals received an i.v. administration of N-isopropyl-l-123-p-iodoamphetamine ([ 123 I]-iodoamphetamine). However, [ 123 I]-iodoamphetamine did not demonstrate a specific affinity for any type of receptor site in the brain. These investigations further substantiated the fact that [ 75 Se]-pergolide tartrate does cross the blood-brain barrier is quickly localized at specific dopamine receptor sites in the intact rat brain and that this localization pattern can be affected by preexposure to different dopamine receptor agonists and antagonists. Therefore, these investigations provided further evidence that [ 75 Se]-pergolide tartrate and other radiolabeled ergoline analogs might be useful as brain dopamine receptor localization radiopharmaceuticals

  13. Preformulation studies of a novel HIV protease inhibitor, AG1343.

    Science.gov (United States)

    Longer, M; Shetty, B; Zamansky, I; Tyle, P

    1995-09-01

    AG1343 is a novel human immunodeficiency virus (HIV) protease inhibitor designed using protein structure-based techniques and intended for chronic oral administration in the treatment of AIDS-related conditions. The compound is the mesylate salt of a basic amine with a molecular weight of 663.90, pKa of 6.0, and partition coefficient (log P) of 4.1. Examination of the physicochemical properties of a bench-scale lot of the bulk drug was undertaken in order to establish a preformulation database and to begin development of an oral formulation suitable for phase I clinical trials. A stability-indicating gradient HPLC method was developed, and initial stability studies indicated that the compound is relatively stable under accelerated conditions. Water solubility and intrinsic dissolution rate studies, however, revealed the potential for dissolution rate-limited absorption. Alternative salts were prepared and evaluated for water solubility relative to the mesylate. A pH-solubility profile for AG1343 was generated and its solubility in various pharmaceutical solvents was determined. Formulation into several prototypical oral dosage forms for in-vitro evaluation in animal models prior to phase I clinical trials resulted in a several-fold difference in bioavailability between these formulations.

  14. Synthesis and biodistribution of [sup 18]F-labeled fleroxacin. [Fluoroquinolone antibiotic

    Energy Technology Data Exchange (ETDEWEB)

    Livni, E.; Babich, J.; Alpert, N.M. (Massachusetts General Hospital, Boston, MA (United States). Radiology Dept.) (and others)

    1993-01-01

    [[sup 18]F]Fleroxacin (6,8-difluoro-1,4-dihydro-1-(2-[[sup 18]F] fluoroethyl)-4-oxo-7-(4-methyl-1-piperazinyl)-3-quinolinecarboxylic acid) was synthesized from its methylsulfonyl ester precursor. 6,7,8-Trifluoro-4-hydroxy-quinoline-3-carboxylic acid ethyl ester (Ro 19-7423) was alkylated with 2-bromoethanol to produce 6,7,8-trifluoro-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylic acid ethyl ester in 76% yield which was then condensed with 1-methyl-piperazine to produce 6,8-difluoro-1,4-dihydro-1-(2-hydroxyethyl)-7-(4-methyl-1-piperazi nyl)4-oxo-3-quinolinecarboxylic acid ethyl ester in 67% yield. This product was reacted with methanesulfonyl chloride to produce the mesylate precursor of fleroxacin in 66% yield. Nucleophilic substitution of the mesylate with [sup 18]F[sup -] in the presence of Kryptofix 2.2.2 followed by basic hydrolysis produced [[sup 18]F]fleroxacin with a radiochemical yield of 5-8% (EOS) within 90 min. The pattern of biodistribution of [[sup 18]F]fleroxacin was similar to the [sup 14]C-labeled drug. (Author).

  15. A LC-MS-MS method for determination of low doxazosin concentrations in plasma after oral administration to dogs.

    Science.gov (United States)

    Erceg, Marijana; Cindric, Mario; Pozaic Frketic, Lidija; Vertzoni, Maria; Cetina-Cizmek, Biserka; Reppas, Christos

    2010-02-01

    A rapid and sensitive reversed phase liquid chromatography- tandem mass spectrometry (LC-MS-MS) method is developed for the determination of doxazosin in canine plasma. The samples are prepared by precipitation of proteins using a mixture of methanol and acetonitrile, followed by freezing and evaporation of the organic solvent. The remaining dry residue is redissolved in mobile phase and analyzed by LC-MS-MS with positive electrospray ionization using the selected reactions monitoring mode. An XTerra MS C(18) column, a mobile phase composed of acetonitrile and 2mM ammonium acetate with gradient elution, and a flow rate of 400 microL/min are employed. The elution times for prazosin (internal standard) and doxazosin are approximately 8 and 10 min, respectively. Calibration curves are linear in the 1-20 ng/mL concentration range. Limits of detection and quantification are 0.4 ng/mL and 1.2 ng/mL, respectively. Recovery is higher than 94%. Intra- and inter-day relative standard deviations are below 7% and 8%, respectively. The method is applied for the determination of doxazosin plasma levels following a single administration of doxazosin base and doxazosin mesylate tablets (2 mg dose) to dogs in the fed state. The results indicate possible superiority of the mesylate salt on the plasma input rates of doxazosin.

  16. Gastrointestinal stromal tumors arising from the stomach: a report of three children.

    Science.gov (United States)

    Durham, Megan M; Gow, Kenneth W; Shehata, Bahig M; Katzenstein, Howard M; Lorenzo, Robert L; Ricketts, Richard R

    2004-10-01

    Gastrointestinal stromal tumors (GIST) are a unique subset of intestinal mesenchymal tumors that behave in an aggressive fashion. They have been commonly described in adults but have been rarely observed in children. The authors review the presentation, diagnostic workup, operative records, pathologic specimens, and outcomes of 3 children with GISTs that originated from the stomach. All 3 children presented after upper gastrointestinal bleeding from the gastric tumor. The first was a 10-year-old girl who underwent partial gastrectomy but had recurrence 8 years later requiring a second resection. She subsequently had a hepatic metastasis 8 years later requiring a third resection. The second patient was a 9-year-old girl who had an antrectomy with a Bilroth I reconstruction and was noted to have a synchronous liver metastasis that was also resected. Despite Imatinib Mesylate, she had further hepatic metastases. The third child was a 4-year-old boy who recently underwent a partial gastrectomy and has no signs of metastatic disease at this time. GISTs are unusual tumors that have been rarely described in children. When they arise in the stomach, they often present after upper gastrointestinal bleeding. Diagnosis can be made by endoscopy and biopsy. GISTs require resection and close observation for hepatic metastases. Current studies are ongoing for the potential role of Imatinib Mesylate for GISTs in children.

  17. PET imaging of liposomes labeled with an [18F]-fluorocholesteryl ether probe prepared by automated radiosynthesis

    DEFF Research Database (Denmark)

    Jensen, Andreas Tue Ingemann; Binderup, Tina; Andresen, Thomas Lars

    2012-01-01

    A novel [F-18]-labeled cholesteryl ether lipid probe was prepared by synthesis of the corresponding mesylate, which was [F-18]-fluorinated by a [F-18]KF, Kryptofix-222, K2CO3 procedure. Fluorination was done for 10 minutes at 165 degrees C and took place with conversion between 3 and 17%, depending......, was observed, corresponding to expected liposomal pharmacokinetics. The tumor accumulation 8 hours postinjection accounted for 2.25 +/- 0.23 (mean +/- standard error of the mean) percent of injected dose per gram (%ID/g), and the tumor-to-muscle ratio reached 2.20 +/- 0.24 after 8 hours, which...... on conditions. Radiolabelling of the probe and subsequent in situ purification on SEP-Paks were done on a custom-built, fully automatic synthesis robot. Long-circulating liposomes were prepared by hydration (magnetic stirring) of a lipid film containing the radiolabeled probe, followed by fully automated...

  18. 18F-fluorination by crown ether-metal fluoride

    International Nuclear Information System (INIS)

    Irie, T.; Fukushi, K.; Ido, T.; Kasida, Y.; Nozaki, T.

    1982-01-01

    18 F-Fluorination by ''naked'' 18 F - anion produced by complexing anhydrous K 18 F, which was prepared from aqueous 18 F, with 18 -Crown-6 was described for preparing 18 F-21-fluoroprogesterone. In order to find out optimum conditions in this labelling method, various factors were investigated such as the solubility of KF in organic solvents containing 18 -Crown-6 and its reactivity for the nucleophilic displacement of 21-mesylate of progesterone. Chloroform was a good solvent in solubilization of KF and its reactivity. Problems in this labelling procedure were also examined, such as a supporter for transferring the labelled anhydrous K 18 F and reaction vessels. Use of a Teflon reaction vessel resulted in a good radiochemical yield based on the starting activity of $ 18 water. (author)

  19. Competition of dipositive metal ions for Fe (III) binding sites in chelation therapy of Iron Load

    International Nuclear Information System (INIS)

    Rehmani, Fouzia S.

    2005-01-01

    Iron overload is a condition in which excessive iron deposited in the liver, kidney and spleen of human beings in the patients of beta thalassemia and sickle cell anemia. Instead of its importance iron could be toxic when in excess, it damages the tissues. For the treatment of iron overload, a drug desferrioxamine mesylate has been used. It is linear trihydroxamic acid, a natural siderophore produced by streptomyces which removes the extra iron from body. Salicylhydroxamate type siderphore. In present research salicylhydroxamate was used for the complexation with dipositive metal ions which are available in biological environments such as Mn (II), Co (II), Ni (II) and Cu (II). The aim of our work was to study the competition reactions between Fe (III) and other dipositive ions; to calculate the thermodynamic data of chelation of these metal ions complexes with hydroxamate by computer program and comparison with hydroxamate complexes. (author)

  20. Bone marrow necrosis secondary to imatinib usage, mimicking spinal metastasis on magnetic resonance imaging and FDG-PET/CT.

    Science.gov (United States)

    Aras, Yavuz; Akcakaya, Mehmet Osman; Unal, Seher N; Bilgic, Bilge; Unal, Omer Faruk

    2012-01-01

    Imatinib mesylate has become the treatment of choice for gastrointestinal stromal tumors (GISTs) and has made a revolutionary impact on survival rates. Bone marrow necrosis is a very rare adverse event in malignant GIST. Bone metastases are also rarely encountered in the setting of this disease. The authors report on a patient with malignant GIST who developed a bone lesion, mimicking spinal metastasis on both MR imaging and FDG-PET/CT. Corpectomy and anterior fusion was performed, but the pathology report was consistent with bone marrow necrosis. Radiological and clinical similarities made the distinction between metastasis and bone marrow necrosis challenging for the treating physicians. Instead of radical surgical excision, more conservative methods such as percutaneous or endoscopic bone biopsies may be more useful for pathological confirmation, even though investigations such as MR imaging and FDG-PET/CT indicate metastatic disease.

  1. Gemifloxacin Is Effective in Experimental Pneumococcal Meningitis

    Science.gov (United States)

    Smirnov, A.; Wellmer, A.; Gerber, J.; Maier, K.; Henne, S.; Nau, R.

    2000-01-01

    In a rabbit model of Streptococcus pneumoniae meningitis, 5 mg of gemifloxacin mesylate (SB-265805) per kg/h reduced the bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as 10 mg of ceftriaxone per kg/h (Δlog CFU/ml/h ± standard deviation [SD], −0.25 ± 0.09 versus −0.38 ± 0.11; serum and CSF concentrations of gemifloxacin were 2.1 ± 1.4 mg/liter and 0.59 ± 0.38 mg/liter, respectively, at 24 h). Coadministration of 1 mg of dexamethasone per kg did not affect gemifloxacin serum and CSF levels (2.7 ± 1.4 mg/liter and 0.75 ± 0.34 mg/liter, respectively, at 24 h) or activity (Δlog CFU/ml/h ± SD, −0.26 ± 0.11). PMID:10681354

  2. 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.

  3. Trace analysis of residual methyl methanesulfonate, ethyl methanesulfonate and isopropyl methanesulfonate in pharmaceuticals by capillary gas chromatography with flame ionization detection.

    Science.gov (United States)

    Li, Weiyong

    2004-08-13

    A capillary gas chromatographic method using flame ionization detection was developed and validated for the trace analysis (ppm level) of methyl methanesulfonate, ethyl methanesulfonate, and isopropyl methanesulfonate in pharmaceutical drug substance. The method utilizes a megabore capillary column with bonded and crosslinked polyethylene glycol stationary phase. A dissolve-and-injection approach was adopted for sample introduction in a splitless mode. The investigated sample solvents include acetonitrile, ethyl acetate, methylene chloride, 1,2-dichloromethane, and toluene. Aqueous mixtures of acetonitrile and water can also be used as sample solvent. A limit of detection of about 1 microg/g (1 ppm) and limit of quantitation of 5 microg/g (5 ppm) were achieved for the mesylate esters in drug substance samples. The method optimization and validation are also discussed in this paper.

  4. Assessment of the combined approach of N-alkylation and salt formation to enhance aqueous solubility of tertiary amines using bupivacaine as a model drug

    DEFF Research Database (Denmark)

    Nielsen, Anders Bach; Frydenvang, Karla Andrea; Liljefors, Tommy

    2005-01-01

    Quaternary prodrug types of poorly water-soluble tertiary amines have been shown to exhibit significantly enhanced solubilities as compared to the parent amine. In the present study the combined effect of N-alkylation and salt formation to enhance aqueous solubility of tertiary amines have been...... as their iodide salts. Chloride, mesylate, formate, acetate, glycolate, and tosylate salts were obtained by anion exchange of the N-methyl-bupivacaine derivative. N-Alkylation and salt formation afforded quaternary ammonium salts possessing pH-independent aqueous solubilities far exceeding that of the parent...... investigated using bupivacaine as a model compound. X-ray structure analyses of selected salts were included to investigate the potential existence of correlations between salt solubility and crystal packing modes. Alkyl groups were methyl, ethyl, propyl, and butyl and the derivatives were isolated...

  5. Improved and reliable synthesis of 3'-azido-2',3'-dideoxyguanosine derivatives.

    Science.gov (United States)

    Timoshchuk, Victor A; Hogrefe, Richard I; Vaghefi, Morteza M

    2004-01-01

    An improved synthesis of N2-protected-3'-azido-2',3'-dideoxyguanosine 20 and 23 is described. Deoxygenation of 2'-O-alkyl (and/or aryl) sulfonyl-5'-dimethoxytritylguanosine coupled with [1,2]-hydride shift rearrangement gave protected 9-(2-deoxythreo-pentofuranosyl)guanines (10, 12 and 16). This rearrangement was accomplished in high yield with a high degree of stereoselectivity using lithium triisobutylborohydride (L-Selectride). Compounds 10, 12 and 16 were transformed into 3'-O-mesylates (18 and 21), which can be used for 3'-substitution. The 3'-azido nucleosides were obtained by treatment of 18 and 21 with lithium azide. This procedure is reproducible with a good overall yield.

  6. Therapy for chronic myeloid leukemia: Past, present and future

    International Nuclear Information System (INIS)

    Tothova, E.

    2012-01-01

    Although chronic myeloid leukemia (CML) was probably first described in the early nineteenth century, there was little progress in understanding its biology until the discovery of the Philadelphia (Ph) chromosome in 1960. Subsequent important landmarks were the recognition that the Ph chromosome results from a t(9;22) translocation and subsequently of BCR-ABL fusion gene. Between 1980 and 2000, allo grafting, despite the risks of morbidity and mortality, was the recommended initial treatment for younger patients with HLA-matched donors. Therapy has now been „revolutionized“ by the introduction on imatinib mesylate (IM), the original Abl tyrosine kinase inhibitor (TKI) which was used first in the clinic in 1998. This paper will attempt to define approaches to management of the newly diagnosed patient with CML in chronic phase that are favored in 2012, but it is most probable these recommendations will need to be updated as further experience in gained with the use of TKI. (author)

  7. Experimental test on the use of MS-222 for ostracod anaesthesia: concentration, immersion period and recovery time

    Directory of Open Access Journals (Sweden)

    Francesc MEZQUITA

    2010-08-01

    Full Text Available Anaesthesia of animals may be useful for different purposes, particularly for veterinary reasons or in experimental research, for manipulation or treatment of immobilized but alive animals. Its use in crustaceans is not uncommon, but it has never been described for Ostracoda. We provide brief and preliminary guidelines on the use of the tricaine mesylate (MS-222 on the widespread freshwater ostracod Eucypris virens and we show that this compound is an effective anaesthetic used as a bath treatment at minimum concentrations of 500 mg L-1. This value is considerably higher than that recommended for other aquatic animals like fish. Recovery time, ranging from 5 to 15 minutes, is mostly determined by anaesthetic bath concentration, while bath duration influenced to a lesser extent. Anaesthesia induced with MS-222 can prove useful for minute manipulation of living ostracods e.g. for identification, marking or image capture under the microscope.

  8. Preparation of specifically dideuterated octadecanoates and oxooctadecanoates.

    Science.gov (United States)

    Tulloch, A P

    1977-01-01

    Sixteen methyl gem dideuterooctadecanoates with two deuterium atoms at positions 2- to 17- and seven oxo esters, 8-oxooctadecanoate-5,5-d(2), 8-oxooctadecanoate-11, 11-d(2), 11-oxooctadecanoate-8,8-d(2), 11-oxooctadecanoate-14,14-d(2), 12-oxooctadecanoate-9,9-d(2), 7-oxooctadecanoate-10,10-d(2) and 13-oxooctadecanoate-16,16-d(2) with two deuteriums on the carbon gamma to the oxo group, have been synthesized. Two prinicipal methods of introducing deuterium were used: preparation of 2,2-dideutero acids by exchange with deuterium oxide followed by chain extension giving dideuteroxooctadecanoates, which were then reduced, as tosylhydrazones, with sodium cyanoborohydride to dideuterooctadecanoates and stepwise introduction by reduction of oxooctadecanoates with sodium borodeuteride, formation of tosylate or mesylate, reduction with lithium aluminum deuteride to tetradeuterooctadecanol and oxidation to dideuterooctadecanoic acid.

  9. Biological treatment and chronic myeloid leukemia

    International Nuclear Information System (INIS)

    Tothova, E.

    2011-01-01

    Notwithstanding the considerable skepticism that prevailed at the beginning of nineties of the last century to the possible clinical significance of inhibitors of tyrosine kinase (TK), Druker et al. (1998) had developed a compound that inhibited the enzymatic activity of Abl protein and, consequently, increased activity of Bcr-Abl oncoprotein, whose presence is characteristic of chronic myeloid leukemia (CML). The TK inhibitor, imatinib mesylate (Glivec) has become the standard first-line therapy for all patients with newly diagnosed CML. Despite its high efficiency, part of patients is not responding to treatment with this preparation or is losing an already achieved response. In this case second-generation or third-generation tyrosine kinase inhibitors (TKIs) could be applied.. The paper presents an overview of treatment options for CML, focusing on biological therapy with TKIs. (author)

  10. A chiral synthesis of dapoxetine hydrochloride, a serotonin re-uptake inhibitor, and its 14C isotopomer

    International Nuclear Information System (INIS)

    Wheeler, W.J.; O'Bannon, D.D.

    1992-01-01

    The 14 C-isotopmer of dapoxetine-[ 14 C] HCl (S (+) -N,N-dimethyl-α[2-(1-naphthalenyloxy)ethyl-2- 14 C]benzenemeth a-n amine hydrochloride, 1a), a potent serotonin re-uptake inhibitor has been prepared by a chiral synthesis, starting with tert. -butyloxyphenylglycine (3). Borane reduction, followed by activation of the resulting alcohol 4 as its mesylate 5b, provided the chiral starting material. The radiolabel was introduced by reaction of 5b with sodium cyanide-[ 14 C]. The desired product (1) was then elaborated from nitrile 6a,b via a five step synthesis in an overall 19.5% radiochemical yield. (Author)

  11. The isolation and characterization of the rat liver glucocorticoid hormone receptor complex

    International Nuclear Information System (INIS)

    Hapgood, J.P.

    1986-06-01

    The untransformed rat liver glucocorticoid hormone receptor complex (GHRC) is purified by affinity chromatography and ion-exchange chromatography, with a 46% yield. The methodological problems encountered in the affinity purification of the highly labile GHRC were examined in detail. Some of the properties of the highly purified untransformed and transformed GHRC, such as size on SDS-gel electrophoresis, DNA-cellulose and nuclear binding, and sedimentation coefficients on sucrose gradients, is examined. A detailed investigation of protein kinase activity in purified GHRC preparations was performed. A preliminary investigation on the possible association of RNA with the GHRC was also conducted. The receptor protein was covalently modified with biotin and the properties of biotinyl-GHRC were examined. In order to identify the glucocorticoid receptor during isolation, the receptor was covalently labelled with 3 H dexamethasone-mesylate and the procedure described

  12. Antiproliferative activity of synthesized some new benzimidazole carboxamidines against MCF-7 breast carcinoma cells.

    Science.gov (United States)

    Karaaslan, Cigdem; Bakar, Filiz; Goker, Hakan

    2018-02-23

    Breast cancer is the most endemic cause of cancer among women in both developed and developing countries. Benzimidazole derivatives exemplify one of the chemical classes that show strong cytotoxic activity especially against breast cancer cells (MCF-7). Aromatic amidine derivatives are known as a group of DNA interactive compounds that bind minor groove of the genome, especially A-T base pairs, and show significant in vitro and in vivo toxicity toward cancer cells. In light of these studies, some new mono/dicationic amidino benzimidazole derivatives were synthesized and evaluated for cytotoxic activity on cultured MCF-7 breast cancer cells. Some of these compounds have strongly inhibited MCF-7 cell viability in a dose-dependent manner compared with clinically used reference compounds, imatinib mesylate and docetaxel. Among them, 4-[(5(6)-bromo-1H-benzimidazole-2-yl)amino]benzene-1-carboxamidine (30) showed the best inhibitory activity with IC50 value of 4.6 nM.

  13. A Gastrointestinal Stromal Tumor of the Stomach Demonstrating a Stepwise Progression from Low- to High-Grade Malignancy

    Directory of Open Access Journals (Sweden)

    Takahiko Nakajima

    2012-01-01

    Full Text Available We report a case of a gastrointestinal stromal tumor (GIST of the stomach that demonstrated a stepwise progression from low- to high-grade malignancy. The patient had been followed for a small gastric submucosal tumor that had turned malignant after 8 years of indolence, manifested by tarry stools. The tumor was enucleated, and gastric GIST was diagnosed. The most significant histological finding was that the tumor comprised two clearly demarcated areas, one with less aggressive characteristics and the other with highly aggressive characteristics. The patient exhibited multiple liver metastases 24 months after surgery. Imatinib mesylate was not administered throughout the clinical course because it was not available for clinical use at that time. The patient followed an unfavorable clinical course and died of liver dysfunction 55 months after surgery. Autopsy was performed. By comparing the immunohistochemical profiles of primary and metastatic tumors, it was established that only the tumor cells with highly aggressive characteristics had metastasized.

  14. Lack of effect of deferoxamine, dimethyl sulfoxide, and catalase on monocrotaline pyrrole pulmonary injury

    Energy Technology Data Exchange (ETDEWEB)

    Bruner, L.H.; Johnson, K.; Carpenter, L.J.; Roth, R.A.

    1987-01-01

    Monocrotaline pyrrole (MCTP) is a reactive metabolite of the pyrrolizidine alkaloid monocrotaline. MCTP given intravenously to rats causes pulmonary hypertension and right ventricular hypertrophy. Lesions in lungs after MCTP treatment contain macrophages and neutrophils, which may contribute to the damage by generation of reactive oxygen metabolites. Rats were treated with MCTP and agents known to protect against oxygen radical-mediated damage in acute models of neutrophil-dependent lung injury. Rats received MCTP and deferoxamine mesylate (DF), dimethyl sulfoxide (DMSO), or polyethylene glycol-coupled catalase (PEG-CAT). MCTP/vehicle-treated controls developed lung injury manifested as increased lung weight, release of lactate dehydrogenase into the airway, and sequestration of SVI-labeled bovine serum albumin in the lungs. Cotreatment of rats with DF, DMSO, or PEG-CAT did not protect against the injury due to MCTP. These results suggest that toxic oxygen metabolites do not play an important role in the pathogenesis of MCTP-induced pulmonary injury.

  15. Imatinib has deleterious effects on differentiating spermatogonia while sparing spermatogonial stem cell self renewal

    Science.gov (United States)

    Heim, Crystal; Minniear, Kayla; Dann, Christina Tenenhaus

    2011-01-01

    Imatinib mesylate is among a growing number of effective cancer drugs that provide molecularly targeted therapy; however, imatinib causes reproductive defects in rodents. The availability of an in vitro system for screening the effect of drugs on spermatogenesis would be beneficial. The imatinib targets, KIT and platelet-derived growth factor receptor beta (PDGFRB), were shown here to be expressed in “germline stem” (GS) cell cultures that contain spermatogonia, including spermatogonial stem cells (SSCs). GS cell cultures were utilized to determine whether imatinib affects SSC self renewal or differentiation. GS cells grown in imatinib retained self renewal based on multiple assays, including transplantation. However, growth in imatinib led to decreased numbers of differentiated spermatogonia and reduced culture growth consistent with the known requirement for KIT in survival and proliferation of spermatogonia. These results build upon the in vivo studies and support the possibility of utilizing GS cell cultures for preclinical drug tests. PMID:21295132

  16. Gastrointestinal stromal tumour: From the clinic to the molecules

    Directory of Open Access Journals (Sweden)

    Hapkova I

    2014-03-01

    Full Text Available GastroIntestional stromal tumours (GISTs, the most frequent sarcoma in the gastro-intestinal (GI tract, are highly resistant to conventional chemotherapy and radiotherapy. These tumours have activating mutations in two closely related genes, KIT (75-80% or/and PDGFRA (5-10%. Targeting these mutated activated proteins with imatinib mesylate has proven efficient in the treatment of GISTs. The median survival after diagnosis of GIST increased from 1.5 to 4.8 years with imatinib treatment. However, resistance to imatinib eventually develops and new-targeted therapies are needed. This paper reviews the medical, clinical and pathological aspects of GISTs based on latest research in human cell lines and animal models.

  17. Stability of dolasetron in two oral liquid vehicles.

    Science.gov (United States)

    Johnson, Cary E; Wagner, Deborah S; Bussard, Wendy E

    2003-11-01

    The stability of dolasetron 10 mg/mL over 90 days when prepared as an oral liquid formulation from commercially available tablets in both strawberry syrup and a sugar-free vehicle was studied. A liquid suspension of dolasetron mesylate 10 mg/mL was prepared from commercially available dolasetron tablets, OraPlus, and Ora-Sweet or strawberry syrup. Six samples of each formulation were prepared and stored in amber plastic bottles. Three samples of each formulation were refrigerated (3-5 degrees C) and three were stored at room temperature (23-25 degrees C). A 1-mL sample was withdrawn from each of the 12 bottles immediately and after 7, 14, 30, 60, and 90 days. After further dilution to an expected concentration of 10 micrograms/mL with sample diluent, the solutions were assayed in duplicate using high-performance liquid chromatography. The samples were also inspected for color and odor changes, and the pH of each sample was determined. The stability-indicating capability of the dolasetron assay was determined by forced degradation of four separate 10-mg/mL samples exposed to direct sunlight for 90 days. There were no detectable changes in color, odor, or taste and no visible microbial growth in any sample. At least 98% of the initial dolasetron concentration remained throughout the 90-day study period for all samples. An extemporaneously compounded oral liquid preparation of dolasetron mesylate 10 mg/mL in a 1:1 mixture of Ora-Plus and strawberry syrup or Ora-Sweet was stable for at least 90 days when stored at 3-5 or 23-25 degrees C.

  18. Diagnosis and treatment of small intestinal stromal tumor: an analysis of 45 cases

    Directory of Open Access Journals (Sweden)

    Yan ZENG

    2014-08-01

    Full Text Available Objective To study the clinical features, diagnosis and treatment of small intestinal stromal tumor (SIST. Methods Clinical data of 45 SIST patients admitted to our hospital from July 2007 to December 2013 were analyzed retrospectively. The diagnosis was confirmed pathologically in all the patients. Results The clinical manifestations of SIST were non-specific, and the most common manifestations were as follows: gastrointestinal bleeding in 29 patients (64.4 %, abdominal pain in 15 (33.3% and abdominal mass in 4 (8.9%. The most common predilection sites of SIST were jejunum (n=21, 46.7%, duodenum (n=13, 28.9% and ileum (n=9, 20.0%. The tumor was located at the jejunoileal junction in 2 patients (4.4%. The diagnostic rate of SIST by spiral CT was 73.7% (28/38, and it was the most accurate among all the examinations. Surgical operation was the most effective therapeutic method for SIST. All the 45 patients received surgical treatment, and according to Fletcher's criteria, there were 6 patients (13.3% at very low-risk, 16 (35.6% at low-risk, 8 (17.8% at moderate-risk and 15 (33.3% at highrisk of SIST. The postoperative immunohistochemistry showed that the positive rate of CD117 was 100%, while the positive rate of CD34 was 67.0% (30/45. Imatinib mesylate was helpful for patients who had palliative operation and for preventing postoperative recurrence. Reoperation could prolong the survival of patients who had a local recurrence or distant metastasis. Conclusions  Clinical manifestations of SIST are non-specific, and its early diagnosis is difficult. However, spiral CT has a high diagnostic value for SIST. The surgical operation is the main method for treatment of SIST, and long-time oral imatinib mesylate medication after surgery can attain a better result for a long duration. DOI: 10.11855/j.issn.0577-7402.2014.07.11

  19. 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

  20. Gateways to clinical trials.

    Science.gov (United States)

    Tomillero, A; Moral, M A

    2010-06-01

    [¹¹C]RAC; (18)F-Fluoromisonidazole; 89-12; 9-[¹⁸F]Fluoropropyl-(+)-dihydrotetrabenazine; Adalimumab, Adecatumumab, ADMVA, ADXS-11-001, Aflibercept, Agatolimod sodium, AGS-004, Alglucosidase alfa, Aliskiren fumarate, Alvocidib hydrochloride, AMG-108, AMG-853, Apixaban, Aripiprazole, Armodafinil, Atazanavir sulfate, Atomoxetine hydrochloride; Bevacizumab, BioMatrix Flex drug eluting stent, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, Cediranib, Cetuximab, ChimeriVax-Dengue, Choriogonadotropin alfa, Cinacalcet hydrochloride, Cizolirtine citrate, Clofarabine, Cocaine conjugate vaccine, CX-717; Darbepoetin alfa, Dasatinib, Decitabine, Denosumab, Desvenlafaxine succinate, Dexamethasone sodium phosphate, Dienogest, Diphencyprone, Doripenem, DTaP-HepB-IPV, Dutasteride; E-7010, Ecallantide, Ecstasy, Eicosapentaenoic acid/docosahexaenoic acid, Emtricitabine, Enfuvirtide, Erlotinib hydrochloride, Eszopiclone, Etonogestrel/ethinyl estradiol, Etoricoxib, Everolimus, Everolimus-eluting coronary stent EVT-201, Ezetimibe, Ezetimibe/simvastatin; Ferumoxytol, Fesoterodine fumavate, Figitumumab, Filgrastim, Fingolimod hydrochloride, Fluticasone furoate, Fluval P, Fluzone, Fondaparinux sodium, Fulvestrant, Fungichromin; Gamma-hydroxybutyrate sodium, Gefitinib, GHB-01L1, GLY-230, GSK-1349572; Hib-MenCY-TT, Hib-TT, HPV-6/11/16/18, Hydrocodone bitartrate; IC-51, Icatibant acetate, Imatinib mesylate, Immunoglobulin intravenous (human), Indetanib, Influenza A (H1N1) 2009 Monovalent Vaccine, Inhalable human insulin, Insulin glargine, Insulin glulisine, Interferon-beta, Ispinesib mesylate, Ixabepilone; Laromustine, Latanoprost/timolol maleate, L-Citrulline, Lenalidomide, Lexatumumab, Linezolid, Lopinavir/ritonavir, Lutropin alfa; Mapatumumab, MDX-066, MDX-1388, Mepolizumab, Methoxy polyethylene glycol-epoetin-beta, Metreleptin, Micafungin sodium, Mometasone furoate/oxymetazoline hydrochloride, Mx-dnG1, Mycophenolic acid sodium salt; Nabiximols, Natalizumab

  1. Brain penetrant small molecule 18F-GnRH receptor (GnRH-R) antagonists: Synthesis and preliminary positron emission tomography imaging in rats

    International Nuclear Information System (INIS)

    Olberg, Dag E.; Bauer, Nadine; Andressen, Kjetil W.; Hjørnevik, Trine; Cumming, Paul; Levy, Finn O.; Klaveness, Jo; Haraldsen, Ira; Sutcliffe, Julie L.

    2016-01-01

    Introduction: The gonadotropin releasing hormone receptor (GnRH-R) has a well-described neuroendocrine function in the anterior pituitary. However, little is known about its function in the central nervous system (CNS), where it is most abundantly expressed in hippocampus and amygdala. Since peptide ligands based upon the endogenous decapetide GnRH do not pass the blood–brain-barrier, we are seeking a high-affinity small molecule GnRH-R ligand suitable for brain imaging by positron emission tomography. We have previously reported the radiosynthesis and in vitro evaluation of two novel [ 18 F]fluorinated GnRH-R ligands belonging to the furamide class of antagonists, with molecular weight less than 500 Da. We now extend this work using palladium coupling for the synthesis of four novel radioligands, with putatively reduced polar surface area and hydrophilicity relative to the two previously described compounds, and report the uptake of these 18 F-labeled compounds in brain of living rats. Methods: We synthesized reference standards of the small molecule GnRH-R antagonists as well as mesylate precursors for 18 F-labeling. The antagonists were tested for binding affinity for both human and rat GnRH-R. Serum and blood stability in vitro and in vivo were studied. Biodistribution and PET imaging studies were performed in male rats in order to assess brain penetration in vivo. Results: A palladium coupling methodology served for the synthesis of four novel fluorinated furamide GnRH receptor antagonists with reduced heteroatomic count. Radioligand binding assays in vitro revealed subnanomolar affinity of the new fluorinated compounds for both human and rat GnRH-R. The 18 F-GnRH antagonists were synthesized from the corresponding mesylate precursors in 5–15% overall radiochemical yield. The radiolabeled compounds demonstrated good in vivo stability. PET imaging with the 18 F-radiotracers in naive rats showed good permeability into brain and rapid washout, but absence of

  2. 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.

  3. Malignant gastrointestinal stromal tumor presenting with hemoperitoneum in puerperium: report of a case with review of the literature

    Directory of Open Access Journals (Sweden)

    Vasilakaki Thivi

    2010-11-01

    Full Text Available Abstract Background Gastrointestinal stromal tumors (GISTs are mesenchymal tumors that develop in the wall of the gastrointestinal tract and their diagnosis during pregnancy or puerperium is extremely rare. Case A 28-year old patient presented with acute abdomen due to hemoperitoneum from a large mass arising of the small intestine with distended vessels on its top and a ruptured superficial vessel bleeding into the peritoneal cavity. The patient was at the tenth postpartum day of her first pregnancy. The preoperative diagnosis was a possible ovarian or uterine mass. After an emergency exploratory laparotomy a segmental bowel resection was performed, removing the tumor with a part of 3-cm of the small intestine. Histology revealed GIST with maximum diameter of 13 cm and mitotic rates more than 5 mitoses per 50 high power fields with some atypical forms, indicating a high risk malignancy. Immunohistochemical staining of the tumor tissue demonstrated strongly positive reactivity to CD 117 (c-kit and CD34 in almost all the tumor cells. The patient was treated with oral imatinib mesylate (Gleevec 400 mg daily for one year. Three years after surgery, the patient was alive without evidence of metastases or local recurrence. Conclusion Considering that only few patients with gastrointestinal stromal tumors have been reported in the obstetrical and gynecological literature, the awareness of such an entity by the obstetricians-gynecologists is necessary in order to facilitate coordinated approach with the general surgeons and oncologists for the optimal care of the patients.

  4. Simultaneous bioanalysis of rasagiline and its major metabolites in human plasma by LC-MS/MS: Application to a clinical pharmacokinetic study.

    Science.gov (United States)

    Wang, Ting; Yang, Leting; Hua, Jing; Xie, Huiru; Jiang, Xuehua; Wang, Ling

    2016-06-05

    Rasagiline is a selective, irreversible inhibitor of monoamine oxidase type-B (MAO-B) and has been used both as a monotherapy and in addition to levodopa in the treatment of Parkinson's disease (PD). Rasagiline is metabolized by the cytochrome P450 (CYP) system, and the following three major metabolites with potential neuroprotective activity have been identified: 1-aminoindan (AI), 3-hydroxy-N-propargyl-1-aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). In this study, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of rasagiline and its major metabolites in human plasma. This method was validated in terms of specificity, linearity, precision, accuracy, recovery, matrix effect and stability. The validated method was then applied to a clinical pharmacokinetic study after the oral administration of 1mg rasagiline mesylate tablets to six healthy Chinese volunteers. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Reversed-Phase UHPLC Enantiomeric Separation of Rasagiline Salts Using a Chiralpak®AGP Column.

    Science.gov (United States)

    Balaji, Nagarajan; Sultana, Sayeeda

    2017-07-19

    We report the first rapid ultra-high performance liquid chromatographic (UHPLC) enantiomeric reversed-phase separation of rasagiline mesylate and its tartrate salts using a Chiralpak ® AGP column (50 mm × 2.1 mm, 5 μm) as a stationary phase. This method was developed as an alternative to the usage of previously reported normal-phase chiral LC columns for isomer separation. Our method is based on an isocratic approach using a mixture of ammonium acetate and isopropyl alcohol (90:10, v/v ) as the mobile phase (0.6 mL/min flow rate). The detection limit (at a detection wavelength of 210 nm) and quantification limit for the rasagiline enantiomers were 0.06 and 0.2 μg/mL, respectively. This method is compatible with the UHPLC-MS technique. The successful separation of rasagiline and its enantiomer was confirmed by determining the corresponding specific optical rotation values. Our method will be applicable for detecting rasagiline enantiomers during the control of manufacturing processes, and for use in rapid analysis for quality control in pharmaceutical industry to obtain optically pure pharmaceutical substances. This method was validated in terms of its precision, limit of detection, limit of quantification, linearity, accuracy, robustness, ruggedness, specificity, forced degradation, and solution stability, according to International Council on Harmonization Validation Guidelines Q2 (R1).

  6. Reversed-Phase UHPLC Enantiomeric Separation of Rasagiline Salts Using a Chiralpak® AGP Column

    Directory of Open Access Journals (Sweden)

    Nagarajan Balaji

    2017-07-01

    Full Text Available We report the first rapid ultra-high performance liquid chromatographic (UHPLC enantiomeric reversed-phase separation of rasagiline mesylate and its tartrate salts using a Chiralpak® AGP column (50 mm × 2.1 mm, 5 μm as a stationary phase. This method was developed as an alternative to the usage of previously reported normal-phase chiral LC columns for isomer separation. Our method is based on an isocratic approach using a mixture of ammonium acetate and isopropyl alcohol (90:10, v/v as the mobile phase (0.6 mL/min flow rate. The detection limit (at a detection wavelength of 210 nm and quantification limit for the rasagiline enantiomers were 0.06 and 0.2 μg/mL, respectively. This method is compatible with the UHPLC-MS technique. The successful separation of rasagiline and its enantiomer was confirmed by determining the corresponding specific optical rotation values. Our method will be applicable for detecting rasagiline enantiomers during the control of manufacturing processes, and for use in rapid analysis for quality control in pharmaceutical industry to obtain optically pure pharmaceutical substances. This method was validated in terms of its precision, limit of detection, limit of quantification, linearity, accuracy, robustness, ruggedness, specificity, forced degradation, and solution stability, according to International Council on Harmonization Validation Guidelines Q2 (R1.

  7. Observation by flow 1H NMR and dimerization kinetics and products of reactive ortho-quinodimethanes and benzocyclobutadiene

    International Nuclear Information System (INIS)

    Fischer, D.

    1990-01-01

    The reactive o-quinodimethanes, 1,2-dimethylene-1,2-dihydronaphthalene (9) and o-xylylene (1) were observed by flow 1 H NMR spectroscopy at room temperature. The 1 H NMR spectrum of 9 was obtained in the absence of precursor and dimers. However, the 1 H NMR spectrum of the more reactive 1, generated in a similar manner from [o-((trimethylsilyl)methyl)benzyl]trimethylammonium iodide (5.) could be obtained only in the presence of its stable [4 + 2] and [4 + 4] dimers. The dimerization kinetics of 3-methyl- (5'), 3,6-dimethyl- (11), 3-isopropyl- (12), and 3,6-diisoproply-1,2-xylylene (13) in acetonitrile (CH 3 CN) were studied by stopped-flow UV-visible spectroscopy. Fluoride ion induced 1,2-elimination from 2-elimination from 2-trimethylsilylbenzocyclobutenyl-1 mesylate (26) was used to generate the reactive molecule benzocyclobutadiene (1') in CD 3 CN, which was observed by flow 1 H NMR spectroscopy at room temperature. The 1 H NMR spectrum (in CD 3 CN) of 1,2-dimethylene-1,2-dihydrothiophene (1 double-prime), obtained by fluoride ion induced 1,4-elimination from 3-(trimethylammoniummethyl)-2-(trimethylsilylmethyl)thiophene iodine was observed by flow 1 H NMR spectroscopy at room temperature. The dimerization rate of 1 double-prime in CH 3 CN, generated in the same manner, was measured by UV-visible spectroscopy. 166 refs., 7 figs., 7 tabs

  8. Effective melanoma cancer suppression by iontophoretic co-delivery of STAT3 siRNA and imatinib using gold nanoparticles.

    Science.gov (United States)

    Labala, Suman; Jose, Anup; Chawla, Sumeet Rajesh; Khan, Mohammed Shareef; Bhatnagar, Shubhmita; Kulkarni, Onkar Prakash; Venuganti, Venkata Vamsi Krishna

    2017-06-20

    Co-delivery of chemotherapeutic agents improve anti-tumor efficacy and reduce cancer resistance. Here, we report development of layer-by-layer assembled gold nanoparticles (LbL-AuNP) containing anti-STAT3 siRNA and imatinib mesylate (IM) to treat melanoma. The combination treatment with STAT3 siRNA and IM in B16F10 melanoma cells showed greater suppression of STAT3 protein, decreased cell viability and increased apoptotic events compared with LbL-AuNP containing either STAT3 siRNA or IM. In vivo efficacy studies in melanoma tumor bearing mice showed that non-invasive topical iontophoretic administration (0.5mA/cm 2 ) of LbL-AuNP was comparable with intratumoral administration. Co-delivery of STAT3 siRNA and IM using LbL-AuNP showed significant (p<0.05) reduction in percentage tumor volume, tumor weight and suppressed STAT3 protein expression compared with either STAT3 siRNA or IM loaded LbL-AuNP. Taken together, LbL-AuNP can be developed as nanocarrier system for co-delivery of siRNA and small molecule drugs for topical iontophoretic delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. 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

  10. pH-metric solubility. 3. Dissolution titration template method for solubility determination.

    Science.gov (United States)

    Avdeef, A; Berger, C M

    2001-12-01

    The main objective of this study was to develop an effective potentiometric saturation titration protocol for determining the aqueous intrinsic solubility and the solubility-pH profile of ionizable molecules, with the specific aim of overcoming incomplete dissolution conditions, while attempting to shorten the data collection time. A modern theory of dissolution kinetics (an extension of the Noyes-Whitney approach) was applied to acid-base titration experiments. A thermodynamic method was developed, based on a three-component model, to calculate interfacial, diffusion-layer, and bulk-water reactant concentrations in saturated solutions of ionizable compounds perturbed by additions of acid/base titrant, leading to partial dissolution of the solid material. Ten commercial drugs (cimetidine, diltiazem hydrochloride, enalapril maleate, metoprolol tartrate, nadolol, propoxyphene hydrochloride, quinine hydrochloride, terfenadine, trovafloxacin mesylate, and benzoic acid) were chosen to illustrate the new titration methodology. It was shown that the new method is about 10 times faster in determining equilibrium solubility constants, compared to the traditional saturation shake-flask methods.

  11. The HDAC inhibitor SB939 overcomes resistance to BCR-ABL kinase Inhibitors conferred by the BIM deletion polymorphism in chronic myeloid leukemia.

    Science.gov (United States)

    Rauzan, Muhammad; Chuah, Charles T H; Ko, Tun Kiat; Ong, S Tiong

    2017-01-01

    Chronic myeloid leukemia (CML) treatment has been improved by tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) but various factors can cause TKI resistance in patients with CML. One factor which contributes to TKI resistance is a germline intronic deletion polymorphism in the BCL2-like 11 (BIM) gene which impairs the expression of pro-apoptotic splice isoforms of BIM. SB939 (pracinostat) is a hydroxamic acid based HDAC inhibitor with favorable pharmacokinetic, physicochemical and pharmaceutical properties, and we investigated if this drug could overcome BIM deletion polymorphism-induced TKI resistance. We found that SB939 corrects BIM pre-mRNA splicing in CML cells with the BIM deletion polymorphism, and induces apoptotic cell death in CML cell lines and primary cells with the BIM deletion polymorphism. More importantly, SB939 both decreases the viability of CML cell lines and primary CML progenitors with the BIM deletion and restores TKI-sensitivity. Our results demonstrate that SB939 overcomes BIM deletion polymorphism-induced TKI resistance, and suggest that SB939 may be useful in treating CML patients with BIM deletion-associated TKI resistance.

  12. Hepcidin levels in hyperprolactinemic women monitored by nanopore thin film based assay: correlation with pregnancy-associated hormone prolactin.

    Science.gov (United States)

    Wang, Jing; Liu, Gang; Xu, Zi; Dai, Jiwei; Song, Ping; Shi, Jian; Hu, Ye; Hu, Zhongbo; Nie, Guangjun; Chang, Yan-Zhong; Zhao, Yuliang

    2015-05-01

    Hepcidin is a central regulator in human iron metabolism. Although it is often regarded as a promising indicator of iron status, the lack of effective quantification method has impeded the comprehensive assessment of its physiological and clinical significance. Herein we applied a newly established, nanopore film enrichment based hepcidin assay to examine the correlation between hepcidin and prolactin, the hormone with an important role during pregnancy and lactation. Women with pathologically elevated prolactin secretion (hyperprolactinemia) were found to have lower serum hepcidin compared to those with normal prolactin levels, without showing significant difference in other hepcidin-regulating factors. Moreover, prolactin-reducing drug bromocriptine mesylate resulted in elevated expression of the hepcidin in hyperprolactinemia patients. These findings suggest a possible role of prolactin in regulation of hepcidin, and may render hepcidin a useful biomarker for progress monitoring and treatment of iron-related diseases under hyperprolactinemic conditions. The level of hepcidin has been shown to reflect the underlying iron status of the patient. Nonentheless, there is an urgent need of reliable, fast and easy-to-do hepcidin assay in the clinical setting. In this paper, the authors described a further modification of their previously described nanopore silica film-based enrichment approach for quantification of hepcidin and found correlation between hepcidin and prolactin. This new knowledge may add to current understanding of iron homeostasis during pregnancy. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Equine pituitary pars intermedia dysfunction: current perspectives on diagnosis and management

    Directory of Open Access Journals (Sweden)

    Spelta CW

    2015-08-01

    Full Text Available Caroline W Spelta Townsville Vet Clinic, Townsville, QLD, Australia Abstract: Equine pituitary pars intermedia dysfunction (PPID is a neurodegenerative disease of the hypothalamus, resulting in the loss of dopaminergic inhibition of pars intermedia. An oxidative stress injury of unknown etiology has been suggested to initiate the neurodegeneration. While hypertrichosis (formerly known as hirsutism is considered pathognomic for advanced disease, the antemortem diagnosis of subclinical and early disease has continued to prove difficult. Numerous tests have been used with varying sensitivities and specificities. The overnight dexamethasone suppression test, originally documented to have 100% sensitivity and specificity in horses with advanced disease, has proven to be less valuable in identifying early disease. Basal plasma adrenocorticotropin concentrations have improved sensitivity and specificity when sampled during the autumn months, and α-melanocyte-stimulating hormone, while not yet commercially available, shows promise as a sensitive and specific single sample test. Recent advances in our knowledge include the strong association between laminitis and hyperinsulinemia, both common clinical signs associated with PPID. The pathogenesis of hyperinsulinemia, laminitis, and their association with this disease is a focus of current research. The dopamine agonist pergolide mesylate is still the mainstay of medical management, with studies on oral bioavailability, pharmacokinetics, and long-term survival rates now published. Keywords: PPID, ACTH, α-MSH, laminitis, pergolide, hypertrichosis, pars pituitary intermedia dysfunction

  14. The modulation of TRPM7 currents by nafamostat mesilate depends directly upon extracellular concentrations of divalent cations

    Directory of Open Access Journals (Sweden)

    Chen Xuanmao

    2010-12-01

    Full Text Available Abstract Concentrations of extracellular divalent cations (Ca2+ and Mg2+ fall substantially during intensive synaptic transmission as well as during some pathophysiological conditions such as epilepsy and brain ischemia. Here we report that a synthetic serine protease inhibitor, nafamostat mesylate (NM, and several of its analogues, block recombinant TRPM7 currents expressed in HEK293T cells in inverse relationship to the concentration of extracellular divalent cations. Lowering extracellular Ca2+ and Mg2+ also evokes a divalent-sensitive non-selective cation current that is mediated by TRPM7 expression in hippocampal neurons. In cultured hippocampal neurons, NM blocked these TRPM7-mediated currents with an apparent affinity of 27 μM, as well as the paradoxical Ca2+ influx associated with lowering extracellular Ca2+. Unexpectedly, pre-exposure to NM strongly potentiated TRPM7 currents. In the presence of physiological concentrations of extracellular divalent cations, NM activates TRPM7. The stimulating effects of NM on TRPM7 currents are also inversely related to extracellular Ca2+ and Mg2+. DAPI and HSB but not netropsin, blocked and stimulated TRPM7. In contrast, mono-cationic, the metabolites of NM, p-GBA and AN, as well as protease inhibitor leupeptin and gabexate failed to substantially modulate TRPM7. NM thus provides a molecular template for the design of putative modulators of TRPM7.

  15. Synthesis of no-carrier-added [{sup 18}F]fluoroacetate

    Energy Technology Data Exchange (ETDEWEB)

    Jaemin Jeong; Dongsoo Lee; Junekey Chung; Myungchul Lee; Changsoon Koh [Seoul National Univ. Hospital, Nuclear Medicine Dept., Seoul (Korea, Republic of); Samsik Kang [Seoul National Univ. Hospital, Natural Products Research Inst., Seoul (Korea, Republic of)

    1997-05-01

    To synthesize no-carrier-added potassium [{sup 18}F]fluoroacetate, Omesyl glycolate ethyl ester and O-tosyl glycolate ethyl ester were synthesized as prescursors. These precursors were radiolabeled by reacting with dried tetrabutylammonium [{sup 18}F]fluoride in the presence of tetrabutylammonium bicarbonate. O-Mesyl glycolate ethyl ester showed higher {sup 18}F incorporation (77.6% at 100{sup o}C) than O-tosyl glycolate ethyl ester (63.2% at 100{sup o}C). Resulting [{sup 18}F]fluoroacetate ethyl ester was hydrolyzed quantitatively by heating in 1 M potassium hydroxide solution. The [{sup 18}F]fluoroacetate was adsorbed to strong anion exchange resin and washed with excess water. Following elution with 1 M sodium bicarbonate solution and passing through Sep-Pak neutral aluminia column, the [{sup 18}F]fluoroacetate was obtained with 24.5% recovery (non-decay-corrected). Total labelling time from drying {sup 18}F to final product was 70 to 90 min. (author).

  16. Spectrophotometric methods for the determination of gemifloxacin in pharmaceutical formulations

    Directory of Open Access Journals (Sweden)

    Sara A.M. Ebraheem

    2011-12-01

    Full Text Available This paper describes two simple spectrophotometric methods for the determination of the antibiotic gemifloxacin mesylate (GFX in pharmaceutical formulations. The first (A is an indirect method in which oxidation of the drug with a known excess of cerium (IV sulphate is followed by determination of the residual oxidant by adding excess methyl orange and measuring residual dye at 507 nm. The second (B is a derivatisation method involving reaction of GFX with 1,2-naphthoquinone-4-sulphonate (NQS in alkaline medium (pH 11 to form an orange-coloured product exhibiting maximum absorption (λmax at 411 nm. The methods were linear in the concentration ranges 2–9 and 5–30 μg/mL for methods A and B, respectively, with intra-day precision (as RSD <1.5% for both. When applied to the determination of GFX in pharmaceutical tablets, the results were in good agreement with those obtained by capillary electrophoresis. The two methods are useful for routine analysis of GFX in quality control laboratories.

  17. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome.

    Science.gov (United States)

    Griffin, John H; Leung, Joey; Bruner, Rebecca J; Caligiuri, Michael A; Briesewitz, Roger

    2003-06-24

    Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disease of unknown etiology. Recently, it has been reported that imatinib mesylate (Gleevec), an inhibitor of Bcr-Abl kinase useful in the treatment of chronic myeloid leukemia, is also effective in treating HES; however, the molecular target of imatinib in HES is unknown. This report identifies a genetic rearrangement in the eosinophilic cell line EOL-1 that results in the expression of a fusion protein comprising an N-terminal region encoded by a gene of unknown function with the GenBank accession number NM_030917 and a C-terminal region derived from the intracellular domain of the platelet-derived growth factor receptor alpha (PDGFRalpha). The fusion gene was also detected in blood cells from two patients with HES. We propose naming NM_030917 Rhe for Rearranged in hypereosinophilia. Rhe-PDGFRalpha fusions result from an apparent interstitial deletion that links Rhe to exon 12 of PDGFRalpha on chromosome 4q12. The fusion kinase Rhe-PDGFRalpha is constitutively phosphorylated and supports IL-3-independent growth when expressed in BaF3 cells. Proliferation and viability of EOL-1 and BaF3 cells expressing Rhe-PDGFRalpha are ablated by the PDGFRalpha inhibitors imatinib, vatalanib, and THRX-165724.

  18. 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.

  19. Kinetic spectrophotometric determination of some fluoroquinolone antibiotics in bulk and pharmaceutical preparations

    Directory of Open Access Journals (Sweden)

    S. Abou Taleb

    2013-09-01

    Full Text Available A simple and sensitive kinetic spectrophotometric method was developed for the determination of some fluoroquinolonea antibiotics; gemifloxacin mesylate, moxifloxacin hydrochloride and gatifloxacin in bulk and in pharmaceutical preparations. The method is based upon a kinetic investigation of the oxidation reaction of the drugs with alkaline potassium permanganate at room temperature for a fixed time of 20 min for gemifloxacin and 15 min for moxifloxacin or gatifloxacin. The absorbance of the coloured manganate ion was measured at 610 nm. The absorbance–concentration plots were rectilinear over the ranges of 2.0-20, 4.0-24 and 4.0-40 µg mL−1 for gemifloxacin, moxifloxacin and gatifloxacin, respectively. The concentrations of the studied drugs were calculated using the corresponding calibration equations for the fixed-time method. The determination of the studied drugs by the fixed concentration and rate constant methods was also feasible with the calibration equations obtained but the fixed time method has been found to be more applicable. The different experimental parameters affecting the development and stability of the colors were carefully studied and optimized. The proposed method was applied to the determination of the studied drugs in pharmaceutical formulations.DOI: http://dx.doi.org/10.4314/bcse.v27i3.2

  20. Controlled study on the effect of pentoxifylline and an ergot alkaloid derivative on regional cerebral blood flow in patients with chronic cerebrovascular disease

    Energy Technology Data Exchange (ETDEWEB)

    Hartmann, A.; Tsuda, Y.

    1988-05-01

    Regional cerebral blood flow (rCBF) in 90 patients with CBF decreased due to vascular diseases was studied by using the xenon 133 inhalation technique and a 32-detector setup. Whereas 30 patients received their standard basic therapy only and were regarded as controls, 30 others received 3 x 2 mg/day of an ergot alkaloid (co-dergocrine mesylate), and 30 others received 3 x 400 mg pentoxifylline (slow-release formulation)/day orally. Therapy was performed for eight weeks and CBF measured before start of treatment, after a four-week treatment period, and at the end of the study. CBF did not change significantly in the control group; both the pentoxifylline and the ergot alkaloid group presented with a significant increase in the CBF. This positive effect was significantly more pronounced in the pentoxifylline group and affected more ischemic than other brain tissues. In addition, symptoms like sleep disturbances, vertigo, and tinnitus improved significantly during the pentoxifylline observation period.

  1. Controlled study on the effect of pentoxifylline and an ergot alkaloid derivative on regional cerebral blood flow in patients with chronic cerebrovascular disease

    International Nuclear Information System (INIS)

    Hartmann, A.; Tsuda, Y.

    1988-01-01

    Regional cerebral blood flow (rCBF) in 90 patients with CBF decreased due to vascular diseases was studied by using the xenon 133 inhalation technique and a 32-detector setup. Whereas 30 patients received their standard basic therapy only and were regarded as controls, 30 others received 3 x 2 mg/day of an ergot alkaloid (co-dergocrine mesylate), and 30 others received 3 x 400 mg pentoxifylline (slow-release formulation)/day orally. Therapy was performed for eight weeks and CBF measured before start of treatment, after a four-week treatment period, and at the end of the study. CBF did not change significantly in the control group; both the pentoxifylline and the ergot alkaloid group presented with a significant increase in the CBF. This positive effect was significantly more pronounced in the pentoxifylline group and affected more ischemic than other brain tissues. In addition, symptoms like sleep disturbances, vertigo, and tinnitus improved significantly during the pentoxifylline observation period

  2. Nuclear Medicine Program progress report for quarter ending June 30, 1996

    Energy Technology Data Exchange (ETDEWEB)

    Knapp, F.F. Jr.; Ambrose, K.R.; Beets, A.L.; Guhlke, S.; Luo, H.; McPherson, D.W.; Mirzadeh, S.

    1996-12-31

    The four stereoisomers of 1-azabicyclo[2.2.2]oct-3-yl {alpha}-(1fluoropent-5-yl)-{alpha}-hydroxy-{alpha}-phenylacetate (FQNPe, 4) have been resolved and were evaluated as potential candidates for PET imaging agents. Labeling with fluorine-18 involved a two-step synthesis via fluoride displacement of a mesylate intermediate at the ethyl ester stage followed by transesterification with (R)-quinuclidinol. In vitro data utilizing cloned human receptor subtypes demonstrated that while the (+,+)-isomer did not have significant receptor binding, the other stereoisomers of FNPe bound with high affinity to the various mA ChR subtypes tested (K{sub i}, nm: m1, ({minus},{minus}), 0.33; ({minus},+), 1.4; (+,{minus}), 3.8; m2, ({minus},{minus}), 0.1; ({minus},+), 4.2; +,{minus}), < 75% binding; m3, ({minus},{minus}), 0.34; ({minus},+), 3.1; (+;{minus}), 7.6. [{sup 18}F]-({minus},{minus})- and [{sup 18}F]-({minus},+)-FQNPe (4) were prepared in decay corrected radiochemical yields of 14% ([{sup 18}F]-({minus},{minus})-4) and 8% ([{sup 18}F]-({minus},+)-4). In vivo biodistribution studies were conducted in female rats with [18F]-({minus},{minus})- and (+,{minus})-FQNPe (4). [{sup 18}F]({minus},{minus})-4 demonstrated high uptake in mA ChR regions of the brain up to 3 hours post injection and low accumulation of radioactivity in the bone indicated good in vivo stability.

  3. Mitochondria-targeted molecules determine the redness of the zebra finch bill.

    Science.gov (United States)

    Cantarero, Alejandro; Alonso-Alvarez, Carlos

    2017-10-01

    The evolution and production mechanisms of red carotenoid-based ornaments in animals are poorly understood. Recently, it has been suggested that enzymes transforming yellow carotenoids to red pigments (ketolases) in animal cells may be positioned in the inner mitochondrial membrane (IMM) intimately linked to the electron transport chain. These enzymes may mostly synthesize coenzyme Q 10 (coQ 10 ), a key redox-cycler antioxidant molecularly similar to yellow carotenoids. It has been hypothesized that this shared pathway favours the evolution of red traits as sexually selected individual quality indices by revealing a well-adjusted oxidative metabolism. We administered mitochondria-targeted molecules to male zebra finches ( Taeniopygia guttata ) measuring their bill redness, a trait produced by transforming yellow carotenoids. One molecule included coQ 10 (mitoquinone mesylate, MitoQ) and the other one (decyl-triphenylphosphonium; dTPP) has the same structure without the coQ 10 aromatic ring. At the highest dose, the bill colour of MitoQ and dTPP birds strongly differed: MitoQ birds' bills were redder and dTPP birds showed paler bills even compared to birds injected with saline only. These results suggest that ketolases are indeed placed at the IMM and that coQ 10 antioxidant properties may improve their efficiency. The implications for evolutionary theories of sexual signalling are discussed. © 2017 The Author(s).

  4. Indirect comparisons of second-generation tyrosine kinase inhibitors in CML: case study using baseline population characteristics

    Directory of Open Access Journals (Sweden)

    Kimbach Tran Carpiuc

    2010-10-01

    Full Text Available Kimbach Tran Carpiuc1, Gianantonio Rosti2, Fausto Castagnetti2, Maarten Treur3, Jennifer Stephens11Pharmerit North America LLC, Bethesda, MD, USA; 2Department of Hematology and Oncology, S Orsola-Malpighi University Hospital, Bologna, Italy; 3Pharmerit Europe, Rotterdam, The NetherlandsAbstract: The use of indirect comparisons to evaluate the relative effectiveness between two or more treatments is widespread in the literature and continues to grow each year. Appropriate methodologies will be essential for integrating data from various published clinical trials into a systematic framework as part of the increasing emphasis on comparative effectiveness research. This article provides a case study example for clinicians using the baseline study population characteristics and response rates of the tyrosine kinase inhibitors in imatinib-resistant or imatinib-intolerant chronic myelogenous leukemia followed by a discussion of indirect comparison methods that are being increasingly implemented to address challenges with these types of comparisons.Keywords: comparative effectiveness research, meta-analysis, BCR–ABL-positive chronic myelogenous leukemia, imatinib mesylate, nilotinib, dasatinib 

  5. Human AQP5 plays a role in the progression of chronic myelogenous leukemia (CML.

    Directory of Open Access Journals (Sweden)

    Young Kwang Chae

    2008-07-01

    Full Text Available Aquaporins (AQPs have previously been associated with increased expression in solid tumors. However, its expression in hematologic malignancies including CML has not been described yet. Here, we report the expression of AQP5 in CML cells by RT-PCR and immunohistochemistry. While normal bone marrow biopsy samples (n = 5 showed no expression of AQP5, 32% of CML patient samples (n = 41 demonstrated AQP5 expression. In addition, AQP5 expression level increased with the emergence of imatinib mesylate resistance in paired samples (p = 0.047. We have found that the overexpression of AQP5 in K562 cells resulted in increased cell proliferation. In addition, small interfering RNA (siRNA targeting AQP5 reduced the cell proliferation rate in both K562 and LAMA84 CML cells. Moreover, by immunoblotting and flow cytometry, we show that phosphorylation of BCR-ABL1 is increased in AQP5-overexpressing CML cells and decreased in AQP5 siRNA-treated CML cells. Interestingly, caspase9 activity increased in AQP5 siRNA-treated cells. Finally, FISH showed no evidence of AQP5 gene amplification in CML from bone marrow. In summary, we report for the first time that AQP5 is overexpressed in CML cells and plays a role in promoting cell proliferation and inhibiting apoptosis. Furthermore, our findings may provide the basis for a novel CML therapy targeting AQP5.

  6. Effectiveness of a combination of cyclosporine A, suplatast tosilate and prednisolone on periodic oscillating hypereosinophilia

    Directory of Open Access Journals (Sweden)

    Imashuku S

    2011-11-01

    Full Text Available Shinsaku Imashuku1, Ikuyo Ueda2, Tohru Inaba3 1Divisions of Pediatrics and Hematology, Takasago-seibu Hospital, Takasago, Japan; 2Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan; 3Department of Infection Control and Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan Abstract: We report the treatment course of a 29-year-old man who has had unique oscillating FIP1L1-PDGFRA fusion gene-negative hypereosinophilic syndrome (HES for nearly 6 years. His periodic oscillating pattern of eosinophilia associated with angioedematous soft tissue swelling has shown two to three seasonal peaks (>15,000/µL absolute eosinophil counts [AEC] a year. Initially, the patient, who was thought to have distinct HES not compatible with previously described cases, did not respond to treatment except for a temporary response to imatinib mesylate. For 6 years, from 2005 to 2010, he was treated with a combination of oral cyclosporine A, suplatast tosilate, and a small dose of prednisolone, which significantly reduced the peak heights of AEC as well as blunting the oscillating patterns. Keywords: hypereosinophilic syndrome, eosinophilia, angioedema, IgM, sIL-2R, treatment, cyclosporin A, suplatast tosilate

  7. Cortisol and prolactin concentrations during repeated blood sample collection from freely moving, mouse-sized mammals (Phodopus spp.).

    Science.gov (United States)

    Reburn, C J; Wynne-Edwards, K E

    2000-04-01

    Validation of a method for obtaining blood samples that does not change cortisol or prolactin concentrations yet allows serial blood samples to be collected from animals under anesthesia, without prior handling, from freely interacting social groups of small mammals. Results from five experiments are reported. Male dwarf hamsters (Phodopus spp.) were housed in modified home cages under continuous flow of compressed air that could be switched to isoflurane in O2 vehicle without approaching the cages. Dwarf hamsters respond to manual restraint with behavioral distress and increase in the concentration of the dominant glucocorticoid, cortisol, and decrease in prolactin concentration. Both effects are evident within one minute. In contrast, when this new method was used, neither cortisol nor prolactin changed in response to repeated sample collection (up to 8 successive samples at 2 hour intervals), prolonged isoflurane exposure, or substantial blood volume reduction (30%). Prolactin concentration was suppressed and cortisol concentration was increased in response to stimuli from other hamsters tested without anesthesia. Suppression of prolactin concentration was graded in response to the degree of stress and equaled the pharmacologic reduction caused by bromocryptine mesylate (50 microg of CB154 x 3 days). The technique is superior to alternatives for studies of behavioral endocrinology of freely interacting small mammals.

  8. Treating the chronic-phase chronic myeloid leukemia patient: which TKI, when to switch and when to stop?

    Science.gov (United States)

    Patel, Ami B; Wilds, Brandon W; Deininger, Michael W

    2017-07-01

    With the discovery of imatinib mesylate nearly 20 years ago, tyrosine kinase inhibitors (TKIs) were found to be effective in chronic myeloid leukemia (CML). TKI therapy has since revolutionized the treatment of CML and has served as a paradigm of success for targeted drug therapy in cancer. Several new TKIs for CML have been approved over the last two decades that exhibit improved potency over imatinib and have different off-target profiles, providing options for individualized therapy selection. Areas covered: Current management of chronic phase CML, including guidance on the sequential use of imatinib and newer-generation TKIs and evolving treatment strategies such as TKI discontinuation. Relevant literature was identified by searching biomedical databases (i.e. PubMed) for primary research material. Expert commentary: Although survival outcomes have drastically improved for CML patients, treatment for CML has grown more complex with the introduction of next-generation TKIs and the advent of treatment-free remissions (TFR). Goals of therapy have shifted accordingly, with increased focus on improving quality of life, managing patient expectations and optimizing patient adherence.

  9. Synthesis, Molecular Structure and Reactivity of 5-Methylidene-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolines

    Directory of Open Access Journals (Sweden)

    Maria Gdaniec

    2004-02-01

    Full Text Available Synthesis of novel 5-methylidene-1,2,3,5-tetrahydro[2,1-b]-quinazolinederivatives 2-4 with potential biological activities mediated by α-adrenergic and/orimidazoline receptors was performed by reacting 2-chloro-4,5-dihydroimidazole (1 withthe corresponding 2-aminoacetophenones. Compound 2, which incorporates an enaminemoiety, underwent a 1,3-dipolar cycloaddition reaction with the appropriate nitrones 5-9to give 1,2,3,5-tetrahydro-imidazo[2,1-b]quinazolin-5,5'-spiro-2',3'-diphenylisoxazol-idines 10-14. Reactions of the title compounds 2 and 4 with dimethyl acetylene-dicarboxylate (DMAD afforded dimethyl 2-(2,3-dihydroimidazo[2,1-b]quinazolin-5(1H-ylidenemethylbut-2-enedioates 15, 16. Imidazo[2,1-b]quinazoline 2 was furthertreated with acetyl chloride, benzoyl chloride and mesyl chloride to give the 1-substitutedderivatives 17, 18 and 19, respectively. The structures of all new compounds obtainedwere confirmed by elemental analysis and spectral data (IR, 1H- and 13C-NMR as well asX-ray crystallographic analysis of 3 and 18.

  10. An optimal method of iron starvation of the obligate intracellular pathogen, Chlamydia trachomatis

    Directory of Open Access Journals (Sweden)

    Christopher C. Thompson

    2011-02-01

    Full Text Available Iron is an essential cofactor in a number of critical biochemical reactions, and as such, its acquisition, storage, and metabolism is highly regulated in most organisms. The obligate intracellular bacterium, Chlamydia trachomatis experiences a developmental arrest when iron within the host is depleted. The nature of the iron starvation response in Chlamydia is relatively uncharacterized because of the likely inefficient method of iron depletion, which currently relies on the compound deferoxamine mesylate (DFO. Inefficient induction of the iron starvation response precludes the identification of iron-regulated genes. This report evaluated DFO with another iron chelator, 2,2’-bipyridyl (Bpdl and presented a systematic comparison of the two across a range of criteria in a single-treatment time-of-infection regimen. We demonstrate that the membrane permeable Bpdl was superior to DFO in the inhibition of chlamydia development, the induction of aberrant morphology, and the induction of an iron starvation transcriptional response in both host and bacteria. Furthermore, iron starvation using Bpdl identified the periplasmic iron binding protein-encoding ytgA gene as iron- responsive. Overall, the data present a compelling argument for the use of Bpdl, rather than DFO, in future iron starvation studies of chlamydia and other intracellular bacteria.

  11. Oral picropodophyllin (PPP) is well tolerated in vivo and inhibits IGF-1R expression and growth of uveal melanoma.

    Science.gov (United States)

    Economou, Mario A; Andersson, Sandra; Vasilcanu, Diana; All-Ericsson, Charlotta; Menu, Eline; Girnita, Ada; Girnita, Leonard; Axelson, Magnus; Seregard, Stefan; Larsson, Olle

    2008-11-01

    The cyclolignan picropodophyllin (PPP) efficiently blocks the activity of insulin-like growth factor-1 receptor (IGF-1R) and inhibits growth of uveal melanoma cells in vitro and in vivo. In this study, we aimed to investigate the efficiency of orally administered PPP on growth of uveal melanoma xenografts. Further, we focused on the effect of PPP on vascular endothelial growth factor (VEGF) in vivo and evaluated its effects in combination with other established anti-tumor agents in vitro. Four different uveal melanoma cell lines (OCM-1, OCM-3, OCM-8, 92-1) were treated with PPP alone and in combination with imatinib mesylate, cisplatin, 5-FU and doxorubicin. Cell viability was determined by XTT assay. SCID mice xenografted with uveal melanoma cells were used to determine anti-tumor efficacy of oral PPP in vivo. Tumor samples obtained from the in vivo experiments were analyzed for VEGF and IGF-1R expression by western blotting. PPP was found to be superior to the other anti-tumor agents in killing uveal melanoma cells. Oral PPP inhibited uveal melanoma growth in vivo and was well tolerated by the animals. PPP decreased VEGF expression in the tumors. Oral PPP is well tolerated in vivo and caused total growth inhibition of uveal melanoma xenografts as well as it decreased the levels of VEGF in the tumors.

  12. The regulation of iron metabolism by hepcidin contributes to unloading-induced bone loss.

    Science.gov (United States)

    Xu, Zi; Sun, Weijia; Li, Yuheng; Ling, Shukuan; Zhao, Chenyang; Zhong, Guohui; Zhao, Dingsheng; Song, Jinping; Song, Hailin; Li, Jinqiao; You, Linhao; Nie, Guangjun; Chang, Yanzhong; Li, Yingxian

    2017-01-01

    Iron overload inhibits osteoblast function and promotes osteoclastogenesis. Hepcidin plays an important role in this process. The changes in iron content and the regulation of hepcidin under unloading-induced bone loss remain unknown. A hindlimb suspension model was adopted to simulate unloading-induced bone loss in mice. The results showed that iron deposition in both liver and bone was markedly increased in hindlimb unloaded mice, and was accompanied by the upregulation of osteoclast activity and downregulation of osteoblast activity. The iron chelator deferoxamine mesylate (DFO) reduced the iron content in bone and alleviated unloading-induced bone loss. The increased iron content in bone was mainly a result of the upregulation of transferrin receptor 1 (TfR1) and divalent metal transporter 1 with iron response element (DMT1+IRE), rather than changes in the iron transporter ferroportin 1 (FPN1). The hepcidin level in the liver was significantly higher, while the FPN1 level in the duodenum was substantially reduced. However, there were no changes in the FPN1 level in bone tissue. During hindlimb unloading, downregulation of hepcidin by siRNA increased iron uptake in bone and liver, which aggravated unloading-induced bone loss. In summary, these data show that unloading-induced bone loss was orchestrated by iron overload and coupled with the regulation of hepcidin by the liver. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Imaging in early phase childhood cancer trials

    Energy Technology Data Exchange (ETDEWEB)

    Adamson, Peter C. [Children' s Hospital of Philadelphia, Division of Clinical Pharmacology and Therapeutics, Philadelphia, PA (United States)

    2009-02-15

    Advances made in the treatment of childhood malignancies during the last four decades have resulted in overall cure rates of approximately 80%, but progress has slowed significantly during the last 10 years, underscoring the need for more effective and less toxic agents. Current research is focused on development of molecularly targeted agents, an era ushered in with the discovery of imatinib mesylate for the treatment of chronic myelogenous leukemia. Since imatinib's introduction into the clinic, an increasing number of tyrosine kinase inhibitors have been developed and entered into clinical trials and practice. Parallel to the initial advances made in molecularly targeted agents has been the development of a spectrum of novel imaging modalities. Future goals for imaging in childhood cancer research thus include (1) patient identification based on target identification or other biologic characteristics of the tumor, (2) assessing pharmacokinetic-pharmacodynamic (PK-PD) effects, and (3) predictive value with an early indication of patient benefit. Development and application of novel imaging modalities for children with cancer can serve to streamline development of molecularly targeted agents. (orig.)

  14. Analysis of Activated Platelet-Derived Growth Factor β Receptor and Ras-MAP Kinase Pathway in Equine Sarcoid Fibroblasts

    Directory of Open Access Journals (Sweden)

    Gennaro Altamura

    2013-01-01

    Full Text Available Equine sarcoids are skin tumours of fibroblastic origin affecting equids worldwide. Bovine papillomavirus type-1 (BPV-1 and, less commonly, type-2 are recognized as etiological factors of sarcoids. The transforming activity of BPV is related to the functions of its major oncoprotein E5 which binds to the platelet-derived growth factor β receptor (PDGFβR causing its phosphorylation and activation. In this study, we demonstrate, by coimmunoprecipitation and immunoblotting, that in equine sarcoid derived cell lines PDGFβR is phosphorylated and binds downstream molecules related to Ras-mitogen-activated protein kinase-ERK pathway thus resulting in Ras activation. Imatinib mesylate is a tyrosine kinase receptors inhibitor which selectively inhibits the activation of PDGFβR in the treatment of several human and animal cancers. Here we show that imatinib inhibits receptor phosphorylation, and cell viability assays demonstrate that this drug decreases sarcoid fibroblasts viability in a dose-dependent manner. This study contributes to a better understanding of the molecular mechanisms involved in the pathology of sarcoids and paves the way to a new therapeutic approach for the treatment of this common equine skin neoplasm.

  15. Asymmetric Synthesis and Antimicrobial Activity of Some New Mono and Bicyclic β-Lactams

    Directory of Open Access Journals (Sweden)

    A. Taslimi

    2004-11-01

    Full Text Available Reaction of the amino acid D-phenylalanine ethyl ester (4 with cinnamaldehyde gave chiral Schiff base 5, which underwent an asymmetric Staudinger [2+2] cycloaddition reaction with phthalimidoacetyl chloride to give the monocyclic β-lactam 6 as a single stereoisomer. Ozonolysis of 6 followed by reduction with lithium aluminum tri(tert-butoxy hydride afforded the hydroxymethyl β-lactam 8. Treatment of 8 with methansulfonyl chloride gave the mesylated monocyclic β-lactam 9, which was converted to the bicyclic β-lactam 10 upon treatment with 1,8-diazabicyclo[5,4.0] undec- 7-ene (DBU. Deprotection of the phthalimido group in β-lactams 6 and 10 by methylhydrazine and subsequent acylation of the free amino β-lactams with different acyl chlorides in the presence of pyridine afforded mono and bicyclic β-lactams 14a-d and 15a-d respectively. The compounds prepared were tested against Escherichia coli, Staphilococcus citrus, Klebsiella pneumanie and Bacillus subtillis. Some of these compounds showed potential antimicrobial activities.

  16. Targeting c-kit receptor in neuroblastomas and colorectal cancers using stem cell factor (SCF)-based recombinant bacterial toxins.

    Science.gov (United States)

    Choudhary, Swati; Pardo, Alessa; Rosinke, Reinhard; Batra, Janendra K; Barth, Stefan; Verma, Rama S

    2016-01-01

    Autocrine activation of c-kit (KIT receptor tyrosine kinase) has been postulated to be a potent oncogenic driver in small cell lung cancer, neuroblastoma (NB), and poorly differentiated colorectal carcinoma (CRC). Although targeted therapy involving tyrosine kinase inhibitors (TKIs) such as imatinib mesylate is highly effective for gastrointestinal stromal tumor carrying V560G c-kit mutation, it does not show much potential for targeting wild-type KIT (WT-KIT). Our study demonstrates the role of stem cell factor (SCF)-based toxin conjugates for targeting WT-KIT-overexpressing malignancies such as NBs and CRCs. We constructed SCF-based recombinant bacterial toxins by genetically fusing mutated form of natural ligand SCF to receptor binding deficient forms of Diphtheria toxin (DT) or Pseudomonas exotoxin A (ETA') and evaluated their efficacy in vitro. Efficient targeting was achieved in all receptor-positive neuroblastoma (IMR-32 and SHSY5Y) and colon cancer cell lines (COLO 320DM, HCT 116, and DLD-1) but not in receptor-negative breast carcinoma cell line (MCF-7) thereby proving specificity. While dose- and time-dependent cytotoxicity was observed in both neuroblastoma cell lines, COLO 320DM and HCT 116 cells, only an anti-proliferative effect was observed in DLD-1 cells. We prove that these novel targeting agents have promising potential as KIT receptor tyrosine kinase targeting system.

  17. Gateways to clinical trials. March 2003.

    Science.gov (United States)

    Bayés, M; Rabasseda, X; Prous, J R

    2003-03-01

    Gateways to clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and devlopment protal, http://integrity.prous.com. This issue focuses on the following selection of drugs: AAV-CF, adalimumab, ademetionine, afeletecan hydrochloride, agomelatine, alemtuzumab, almotriptan, amdoxovir, aplidine, aranose, arsenic sulfide, atazanavir, atlizumab; Bimatoprost, BMS-181176, BMS-188667, bortezomib, bryostatin 1; Combretastatin A-4 phosphate; Darbepoetin alfa, darusentan, deferasirox, desloratadine, DTaP-HBV-IPV/Hib-vaccine, DTI-0009; Eculizumab, edodekin alfa, emtricitabine, enfuvirtide, epoetin, esomeprazole magnesium etoricoxib; Fampridine, fenretinide, FR-146687; Galiximab, gamma-Hydroxybutyrate sodium, ganirelix acetate, gefitinib, Gemtuzumab ozogamicin, gimatecan; HEA125xOKT3, hIL-13-PE38QQR, HSV-2 theracine, Hu14.18-IL-2, human gammaglobulin; Idraparinux sodium, imatinib mesylate, IMiD3, insulin detemir, interleukin-4, irofulven, ISAtx-247; JT-1001; Levetiracetam, levosimendan, liposomal doxorubicin, liposomal vincristine sulfate, lixivaptan, lopinavir, lumiracoxib; Maxacalcitol, melatonin, midostaurin, MLN-518; Neridronic acid, nesiritide, nitronaproxen; Oblimersen sodium, oregovomab; PEG-filgrastim polyglutamate paclitaxel, prasterone, pregabalin; Rosuvastatin calcium, rotigotine hydrochloride; SGN-30; T-1249, tenofovir disoproxil fumarate, teriparatide, tiotropium bromide, tipranavir, TMC-114, trabectedin, transdermal selegiline; UK-427857; Valdecoxib, valganciclovir hydrochloride, vardenafil, vatalanib succinate, vincristine sulfate TCS; Zofenopril calcium.

  18. c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

    Science.gov (United States)

    Skartsis, Nikolaos; Martinez, Laisel; Duque, Juan Camilo; Tabbara, Marwan; Velazquez, Omaida C.; Asif, Arif; Andreopoulos, Fotios; Salman, Loay H.

    2014-01-01

    Stenosis of arteriovenous (A-V) fistulae secondary to neointimal hyperplasia (NIH) compromises dialysis delivery, which worsens patients' quality of life and increases medical costs associated with the maintenance of vascular accesses. In the present study, we evaluated the role of the receptor tyrosine kinase c-Kit in A-V fistula neointima formation. Initially, c-Kit was found in the neointima and adventitia of human brachiobasilic fistulae, whereas it was barely detectable in control veins harvested at the time of access creation. Using the rat A-V fistula model to study venous vascular remodeling, we analyzed the spatial and temporal pattern of c-Kit expression in the fistula wall. Interestingly, c-Kit immunoreactivity increased with time after anastomosis, which concurred with the accumulation of cells in the venous intima. In addition, c-Kit expression in A-V fistulae was positively altered by chronic kidney failure conditions. Both blockade of c-Kit with imatinib mesylate (Gleevec) and inhibition of stem cell factor production with a specific short hairpin RNA prevented NIH in the outflow vein of experimental fistulae. In agreement with these data, impaired c-Kit activity compromised the development of NIH in A-V fistulae created in c-KitW/Wv mutant mice. These results suggest that targeting of the c-Kit signaling pathway may be an effective approach to prevent postoperative NIH in A-V fistulae. PMID:25186298

  19. Stereoselective synthesis and pharmacological evaluation of [4.3.3]propellan-8-amines as analogs of adamantanamines.

    Science.gov (United States)

    Torres-Gómez, Héctor; Lehmkuhl, Kirstin; Frehland, Bastian; Daniliuc, Constantin; Schepmann, Dirk; Ehrhardt, Christina; Wünsch, Bernhard

    2015-08-01

    Amantadine (1) exerts its anti-Parkinson effects by inhibition of the NMDA associated cation channel and its antiviral activity by inhibition of the M2 protein channel of influenza A viruses. Herein the synthesis, NMDA receptor affinity and anti-influenza activity of analogous propellanamines 3 are reported. The key steps in the synthesis of the diastereomeric propellanamines syn-3 and anti-3 are diastereoselective reduction of the ketone 7 with L-Selectride to give anti-11, Mitsunobu inversion of the alcohol anti-13 into syn-13, and SN2 substitution of diastereomeric mesylates syn-14 and anti-14 with NaN3. The affinity of the propellanamines syn-3 and anti-3 to the PCP binding site of the NMDA receptor is similar to that of amantadine (Ki=11 μM). However, both propellanamines syn-3 and anti-3 do not exhibit activity against influenza A viruses. Compared to amantadine (1), the structurally related propellanamines syn-3 and anti-3 retain the NMDA antagonistic activity but loose the antiviral activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Functional and Structural Abnormalities in Deferoxamine Retinopathy: A Review of the Literature

    Directory of Open Access Journals (Sweden)

    Maura Di Nicola

    2015-01-01

    Full Text Available Deferoxamine mesylate (DFO is the most commonly used iron-chelating agent to treat transfusion-related hemosiderosis. Despite the clear advantages for the use of DFO, numerous DFO-related systemic toxicities have been reported in the literature, as well as sight-threatening ocular toxicity involving the retinal pigment epithelium (RPE. The damage to the RPE can lead to visual field defects, color-vision defects, abnormal electrophysiological tests, and permanent visual deterioration. The purpose of this review is to provide an updated summary of the ocular findings, including both functional and structural abnormalities, in DFO-treated patients. In particular, we pay particular attention to analyzing results of multimodal technologies for retinal imaging, which help ophthalmologists in the early diagnosis and correct management of DFO retinopathy. Fundus autofluorescence, for example, is not only useful for screening patients at high-risk of DFO retinopathy, but is also a prerequisite for identify specific high-risk patterns of RPE changes that are relevant for the prognosis of the disease. In addition, optical coherence tomography may have a clinical usefulness in detecting extent and location of different retinal changes in DFO retinopathy. Finally, this review wants to underline the need for universally approved guidelines for screening and followup of this particular disease.

  1. Cardiac and mood-related changes during short-term abstinence from crack cocaine: the identification of possible withdrawal phenomena.

    Science.gov (United States)

    Kajdasz, D K; Moore, J W; Donepudi, H; Cochrane, C E; Malcolm, R J

    1999-11-01

    Studies assessing withdrawal phenomenon during short-term abstinence from chronic cocaine use have been limited. Although cocaine abusers are reported to be at increased risk for cardiac disorders, little research has assessed cardiac parameters in cocaine abusers and subsequent changes in these parameters that may be associated with the discontinuation of cocaine use. In this study, we categorize 441 chronic cocaine abusers into three groups based on self-reported length of abstinence from cocaine use at entry into a trial approved by the National Institute on Drug Abuse (NIDA) assessing the use of pergolide mesylate in treating relapse and craving in crack cocaine abuse. Electrocardiogram (ECG) PR intervals were found to be correlated positively with length of abstinence, returning to normal population levels within 30 days. In addition, levels of generalized anxiety, nervousness, and heart racing were found to be correlated negatively with length of abstinence from crack cocaine. This work provides preliminary evidence of cardiac and mood-related parameters that are associated with cocaine abstinence and that may indicate specific withdrawal phenomena in chronic users. In addition, these results suggest that the risk of cardiomyopathies associated with abnormal atrial-ventricular polarization may dissipate relatively quickly in abusing individuals.

  2. Proliferation and differentiation of bone marrow stromal cells under hypoxic conditions

    International Nuclear Information System (INIS)

    Ren Hongying; Cao Ying; Zhao, Qinjun; Li Jing; Zhou Cixiang; Liao Lianming; Jia Mingyue; Zhao Qian; Cai Huiguo; Han Zhongchao; Yang Renchi; Chen Guoqiang; Zhao, R.C.

    2006-01-01

    Low oxygen tension is a potent differentiation inducer of numerous cell types and an effective stimulus of many gene expressions. Here, we described that under 8% O 2 , bone marrow stromal cells (MSCs) exhibited proliferative and morphologic changes. The level of differentiated antigen H-2Dd and the number of G 2 /S/M phase cells increased evidently under 8% O 2 condition. Also, the proportion of wide, flattened, and epithelial-like cells (which were alkaline phosphatase staining positive) in MSCs increased significantly. When cultured in adipogenic medium, there was a 5- to 6-fold increase in the number of lipid droplets under hypoxic conditions compared with that in normoxic culture. We also demonstrated the existence of MSC differentiation under hypoxic conditions by electron microscopy. Expression of Oct4 was inhibited under 8% O 2 condition, but after adipocyte differentiation in normoxic culture and hypoxia-mimicking agents cobalt chloride (CoCl 2 ) and deferoxamine mesylate (DFX) treatments, Oct4 was still expressed in MSCs. These results indicate hypoxia accelerates MSC differentiation and hypoxia and hypoxia-mimicking agents exert different effects on MSC differentiation

  3. Synthesis of [19- 2H3]-analogs of dehydroepiandrosterone and pregnenolone and their sulfates.

    Science.gov (United States)

    Cerný, Ivan; Pouzar, Vladimír; Budesínský, Milos; Bicíková, Marie; Hill, Martin; Hampl, Richard

    2004-03-01

    Deuterated analogs of pregnenolone and pregnenolone sulfate with three atoms of deuterium in position 19 were prepared. The synthetic approach was developed on derivatives of dehydroepiandrosterone, where initial intermediates were well characterized, and then applied to the pregnenolone series. Starting 19-hydroxy compounds were transformed into 3alpha,5-cycloderivatives to simplify the Jones oxidation into the corresponding 19-oic acids. After oxidation, rearrangement to 3-hydroxy-5-enes, and suitable protection, two deuterium atoms were introduced by lithium aluminum deuteride reduction. Mesylate exchange by iodide in the presence of zinc and deuterium oxide added third deuterium atom. Deprotection gave title analogs with about 93-95% content of d3-derivative, the rest was mainly not fully deuterated d2-analogue as followed from the mass spectra analysis. Thus, 3beta-hydroxy[19-2H3]androst-5-en-17-one was prepared in 14 steps from 19-hydroxy-17-oxoandrost-5-en-3beta-yl acetate in 8.9% yield, the analogous sequence in the pregnenolone series gave 3beta-hydroxy[19-2H3]pregn-5-en-20-one in 7.3% yield. Corresponding sulfates were prepared via pyridinium salts in 53 and 57% yields, respectively. Fully assigned NMR data of selected pregnenolone derivatives were given.

  4. Chemioxyexcitation (delta pO2/ROS)-dependent release of IL-1 beta, IL-6 and TNF-alpha: evidence of cytokines as oxygen-sensitive mediators in the alveolar epithelium.

    Science.gov (United States)

    Haddad, J J; Safieh-Garabedian, B; Saadé, N E; Kanaan, S A; Land, S C

    2001-02-07

    The signalling mechanisms in oxidative stress mediated by cytokines in the perinatal alveolar epithelium are not well known. In an in vitro model of fetal alveolar type II epithelial cells, we investigated the profile of cytokines in response to ascending Deltap O(2)regimen (oxyexcitation). The peak of TNF-alpha (4 h) preceded IL-1beta and IL-6 (6-9 h), indicating a positive feedback autocrine loop confirmed by exogenous rmTNF-alpha. Reactive oxygen species (ROS) induced a dose-dependent release of cytokines, an effect specifically obliterated by selective antioxidants of the hydroxyl radical (*OH) and superoxide anion (O(2)-). Actinomycin and cycloheximide blocked the induced production of cytokines, implicating transcriptional and translational control. Whilst the dismutating enzymes superoxide dismutase (SOD) and catalase were ineffective in reducing ROS-induced cytokines, MnP, a cell-permeating SOD mimetic, abrogated xanthine/xanthine oxidase-dependent cytokine release. Desferrioxamine mesylate, which inhibits the iron-catalysed generation of *OH via the Fenton reaction, exhibited a mild effect on the release of cytokines. Dynamic variation in alveolar p O(2)constitutes a potential signalling mechanism within the perinatal lung allowing upregulation of cytokines in an ROS-dependent manner. Copyright 2001 Academic Press.

  5. Low doses of imatinib induce myelopoiesis and enhance host anti-microbial immunity.

    Directory of Open Access Journals (Sweden)

    Ruth J Napier

    2015-03-01

    Full Text Available Imatinib mesylate (Gleevec inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics "emergency hematopoiesis," a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens.

  6. Macrolide-Resistance Selection in Tibetan Pigs with a High Load of Mycoplasma hyopneumoniae.

    Science.gov (United States)

    Qiu, Gang; Rui, Yapei; Zhang, Jialu; Zhang, Lihong; Huang, Shucheng; Wu, Qingxia; Li, Kun; Han, Zhaoqing; Liu, Suozhu; Li, Jiakui

    2017-12-22

    Currently, tylosin tartrate is the first-line treatment for Mycoplasma hyopneumoniae infections in China. However, the efficacy of tylosin tartrate and resistance to this treatment in M. hyopneumoniae infections of Tibetan pigs are unknown. In this study, we examined the prevalence of M. hyopneumoniae infection in Tibetan pigs at three intensive farms in Tibet, China. In addition, we investigated the efficacy of tylosin tartrate treatment for porcine enzootic pneumonia by monitoring M. hyopneumoniae DNA eradication dynamics and macrolide resistance (MR). Eighty-two of 450 (18.2%) Tibetan pigs tested positive for only M. hyopneumoniae, and most of these animals (85.1%) had symptoms and signs of pneumonia. The elimination of M. hyopneumoniae DNA was substantially faster in Tibetan pigs with a lower pretreatment M. hyopneumoniae load, and the total eradication rate was 97.4% (75/77). Two Tibetan pigs tested positive for M. hyopneumoniae that contained macrolide resistance-determining mutations in the 23S rRNA gene. Our results indicate that the pretreatment M. hyopneumoniae load may be an effective predictor of macrolide treatment efficacy (and possibly that of other antimicrobial agents) and MR. Moreover, our results suggest that danofloxacin mesylate can be used as an alternative drug for the treatment of macrolide-resistant M. hyopneumoniae infection acquired during intensive farming.

  7. [Determination of 25 quinolones in cosmetics by liquid chromatography-tandem mass spectrometry].

    Science.gov (United States)

    Lin, Li; Zhang, Yi; Tu, Xiaoke; Xie, Liqi; Yue, Zhenfeng; Kang, Haining; Wu, Weidong; Luo, Yao

    2015-03-01

    An analytical method was developed for the simultaneous determination of 25 quinolones, including danofloxacin mesylate, enrofloxacin, flumequine, oxloinic acid, ciprofloxacin, sarafloxacin, nalidixic acid, norfloxacin, and ofloxacin etc in cosmetics using direct extraction and liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Cosmetic sample was extracted by acidified acetonitrile, defatted by n-hexane and separated on Poroshell EC-C18 column with gradient elution program using acetonitrile and water (both containing 0. 1% formic acid) as the mobile phases and analyzed by LC-ESI-MS/MS under the positive mode using multiple reaction monitoring (MRM). The interference of matrix was reduced by the matrix-matched calibration standard curve. The method showed good linearities over the range of 1-200 mg/kg for the 25 quinolones with good linear correlation coefficients (r ≥ 0.999). The method detection limit of the 25 quinolones was 1.0 mg/kg, and the recoveries of all analytes in lotion, milky and cream cosmetics matrices ranged from 87.4% to 105% at the spiked levels of 1, 5 and 10 mg/kg with the relative standard deviations (RSD) of 4.54%-19.7% (n = 6). The results indicated that this method is simple, fast and credible, and suitable for the simultaneous determination of the quinolones in the above three types of cosmetics.

  8. Syntese af amino/hydroxypyrrolidines og -piperidiner fra kulhydratderivater

    DEFF Research Database (Denmark)

    Godskesen, Michael Anders

    Two aldonolactones and an aldonic acid methylester were used in the synthesis of three stereoisomeric 1,5-dideoxy-1,5-imino-pentitols with ribo-, L-lyxo- (L-arabino-), and xylo-configuration. The aldonic acid derivatives were mesylated at C-5 and subsequently reacted with ammonia. The corresponding...... lactams were reduced with sodium acetoxyborohydride or borane dimethyl sulfide to the 1,5-imino-1,5-pentitols.1,2,5-Trideoxy-1,5-imino-D-erythro-pentito l and 1,2,5-trideoxy-1,5-imino-D-threo-pentitol were synthesised from 2,5-difunctionalised aldonolactones by reduction of the 2-functionality...... with hydrazin. The hereby formed 5-functionalsed 2-deoxy-lactones were then reacted with ammonia to give the corresponding lactams. The lactams were reduced by borane dimethyl sulfid or lithium aluminium hydride to the 1,2,5-trideoxy-1,5-imino-pentitols.2,5-Difunctionalised aldonolactones were also used...

  9. Lack of effect of deferoxamine, dimethyl sulfoxide, and catalase on monocrotaline pyrrole pulmonary injury

    International Nuclear Information System (INIS)

    Bruner, L.H.; Johnson, K.; Carpenter, L.J.; Roth, R.A.

    1987-01-01

    Monocrotaline pyrrole (MCTP) is a reactive metabolite of the pyrrolizidine alkaloid monocrotaline. MCTP given intravenously to rats causes pulmonary hypertension and right ventricular hypertrophy. Lesions in lungs after MCTP treatment contain macrophages and neutrophils, which may contribute to the damage by generation of reactive oxygen metabolites. Rats were treated with MCTP and agents known to protect against oxygen radical-mediated damage in acute models of neutrophil-dependent lung injury. Rats received MCTP and deferoxamine mesylate (DF), dimethyl sulfoxide (DMSO), or polyethylene glycol-coupled catalase (PEG-CAT). MCTP/vehicle-treated controls developed lung injury manifested as increased lung weight, release of lactate dehydrogenase into the airway, and sequestration of 125 I-labeled bovine serum albumin in the lungs. Cotreatment of rats with DF, DMSO, or PEG-CAT did not protect against the injury due to MCTP. These results suggest that toxic oxygen metabolites do not play an important role in the pathogenesis of MCTP-induced pulmonary injury

  10. [Rapid detection of four antipertensive chemicals adulterated in traditional Chinese medicine for hypertension using TLC-SERS].

    Science.gov (United States)

    Zhu, Qing-Xia; Cao, Yong-Bing; Cao, Ying-Ying; Lu, Feng

    2014-04-01

    A novel facile method for on-site detection of antipertensive chemicals (e. g. nicardipine hydrochloride, doxazosin mesylate, propranolol hydrochloride, and hydrochlorothiazide) adulterated in traditional Chinese medicine for hypertension using thin layer chromatography (TLC) combined with surface enhanced Raman spectroscopy (SERS) was reported in the present paper. Analytes and pharmaceutical matrices was separated by TLC, then SERS method was used to complete qualitative identification of trace substances on TLC plate. By optimizing colloidal silver concentration and developing solvent, as well as exploring the optimal limits of detection (LOD), the initially established TLC-SERS method was used to detect real hypertension Chinese pharmaceuticals. The results showed that this method had good specificity for the four chemicals and high sensitivity with a limit of detection as lower as to 0.005 microg. Finally, two of the ten antipertensive drugs were detected to be adulterated with chemicals. This simple and fast method can realize rapid detection of chemicals illegally for doping in antipertensive Chinese pharmaceuticals, and would have good prospects in on-site detection of chemicals for doping in Chinese pharmaceuticals.

  11. Corrosion inhibition of iota-carrageenan natural polymer on aluminum in presence of zwitterion mediator in HCl media

    International Nuclear Information System (INIS)

    Fares, Mohammad M.; Maayta, A.K.; Al-Mustafa, Jamil A.

    2012-01-01

    Highlights: ► Inhibition of Al by ι-carrageenan in the presence of zwitterion mediator was investigated. ► Considerable improvement in inhibition efficiency observed in the presence of zwitterion mediator. ► Coherent physical adsorption layer was evidenced by kinetic and thermodynamic parameters. ► Small but consistent fractured island layers observed after acid exposure as revealed by SEM images. - Abstract: ι-Carrageenan a natural polymer has been used as corrosion inhibitor of aluminum in presence of pefloxacin mesylate, acting as zwitterionic mediator, in acidic medium. Considerable improvement in inhibition efficiency occurred in the presence of the mediator. Activation energy of corrosion and other thermodynamic parameters such as standard free energy, standard enthalpy, and standard entropy of the adsorption process revealed better and well-ordered physical adsorption layers in presence of pefloxacin. Adsorption isotherms in absence or presence of pefloxacin mediator appropriately fit in the Langmuir isotherms. The scanning electron microscope (SEM) images demonstrated smooth, glossy, and relatively coherent adsorption layers of the inhibitor on the metal surface in aqueous solution. After the exposure to 2.0 M HCl for 2 h, a smaller but consistent regular shaped fractured layer is obtained.

  12. Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas.

    Science.gov (United States)

    Tamborini, Elena; Miselli, Francesca; Negri, Tiziana; Lagonigro, M Stefania; Staurengo, Samantha; Dagrada, Gian Paolo; Stacchiotti, Silvia; Pastore, Elisa; Gronchi, Alessandro; Perrone, Federica; Carbone, Antonino; Pierotti, Marco A; Casali, Paolo G; Pilotti, Silvana

    2006-12-01

    We have previously shown the presence of an activated platelet-derived growth factor (PDGF) receptor (PDGFR) B and its ligand PDGFB in a limited number of patients with clinical and radiological responses to imatinib mesylate treatment. This article describes the results of comprehensive molecular/biochemical analyses of the three receptors targeted by the drug (PDGFRB, PDGFRA, and KIT) in a series of 31 chordoma patients. The presence and activation status of PDGFRB, PDGFRA, and KIT receptors were investigated by means of immunoprecipitation and Western blot analyses complemented by immunohistochemistry, their expression level was analyzed by means of real-time PCR, and the occurrence of activating point mutations was investigated by means of cDNA sequencing. The PDGFB, PDGFA, and stem cell factor cognate ligands were investigated by reverse transcription-PCR, and gene status was assessed by fluorescence in situ hybridization. The results show that PDGFRB was highly expressed and phosphorylated, whereas PDGFRA and KIT were less expressed but phosphorylated and thus activated. These findings, together with the absence of gain-of-function mutations and the presence of the cognate ligands, strongly support the hypothesis that the activation mechanism is the autocrine/paracrine loop. No role seems to be played by gene amplification. In the light of our findings, the clinical benefit observed in chordoma patients treated with imatinib seems to be attributable to the switching off of all three receptors.

  13. Myeloid Leukemia while on Dasatinib Therapy

    Directory of Open Access Journals (Sweden)

    Monika Conchon

    2010-01-01

    Full Text Available Here we report the case of an 18-year-old woman with chronic myeloid leukemia (CML who became pregnant while undergoing treatment with dasatinib. Before pregnancy, she received imatinib mesylate therapy but could not tolerate the treatment. The regimen was then changed to dasatinib at a dose of 70 mg b.i.d. While she was in hematological remission and on dasatinib therapy, she became pregnant. The unplanned pregnancy was identified after the patient had experienced four weeks of amenorrhea. Because the patient elected to continue the pregnancy to term, dasatinib was stopped immediately. Meanwhile, CML hematological relapse occurred and then she was treated with interferon- (IFN- (9 million IU/day throughout the pregnancy without a complete hematological response. She successfully gave birth to a male baby at 33 weeks by cesarean section delivery with no sequelae or malformations. Although this experience is limited to a single patient, it provides a useful contribution for counselling patients inadvertently exposed to dasatinib during pregnancy.

  14. UPPER GASTRO-INTESTINAL BLEEDING IN THE YOUNG - GASTRIC GIST TUMOR OR PEPTIC ULCER DISEASE?

    Directory of Open Access Journals (Sweden)

    Ayodele Atolagbe

    2015-09-01

    Full Text Available GIST tumors is very unusual in the young and middle aged and a high index of suspicion is needed for the diagnosis in young patients who present with upper gastrointestinal bleeding. Appropriate imaging such as a Computed tomographic scan (CT scan may identify this tumor which may easily be misdiagnosed as a bleeding Peptic Ulcer Disease in the young. We present a case of a healthy 38 year old man with no alcohol use who presented with epigastric pain and melena and subsequent torrential bleeding uncontrolled during endoscopy necessitating an emergency exploratory laparotomy by the general surgery team. The bleeding intraluminal component of the tumor with gross splenic and pancreatic involvement was identified and surgical management consisted of a wedge resection of the greater curvature of the stomach incorporating the tumor and the spleen with successful dissection of the tumor off the tail of the pancreas. Histology was positive for C-KIT and DOG-1 markers. Postoperative course was uneventful and he is presently on Imatinib Mesylate.

  15. 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.)

  16. Low Doses of Imatinib Induce Myelopoiesis and Enhance Host Anti-microbial Immunity

    Science.gov (United States)

    Swimm, Alyson; Giver, Cynthia R.; Harris, Wayne A. C.; Laval, Julie; Napier, Brooke A.; Patel, Gopi; Crump, Ryan; Peng, Zhenghong; Bornmann, William; Pulendran, Bali; Buller, R. Mark; Weiss, David S.; Tirouvanziam, Rabindra; Waller, Edmund K.; Kalman, Daniel

    2015-01-01

    Imatinib mesylate (Gleevec) inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs) and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics “emergency hematopoiesis,” a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens. PMID:25822986

  17. The Role of {sup 18}F-fluorodeoxyglucose Positron Emission Tomography in Gastrointestinal Stromal Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Yoo, Ie Ryung [College of Medicine, The Catholic University of Korea, Seoul (Korea, Republic of)

    2008-12-15

    Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasm of the gastrointestinal tract, and can be distinguished from the smooth muscle or neural tumors in approximately 95% of patients by expression of the KIT receptor tyrosine kinase (CD117). GISTs are known to have high malignant potential and none can be labeled definitely as benign. However, GISTs are unresponsive to standard sarcoma chemotherapy, and only complete surgical resection provides chance for cure. Although the imaging modality of choice is enhanced CT scan in patients with GIST, FDG PET can reflect the malignant potential of GIST. Clinical management of patients with GISTs has dramatically changed with the introduction of novel therapeutics, such as imatinib mesylate (Glivec). This has created a need to re-evaluate the existing criteria used to assess treatment response. FDG PET as functional imaging modality proved to be significantly more accurate than CT alone when assessing GIST response to imatinib. And, FDG PET and PET/CT have been found to be highly sensitive in detecting early response, and to be useful in predicting long-term response to imatinib in patients with recurrent or metastatic GISTs.

  18. Gastrointestinal stromal tumors: CT and MRI findings

    Energy Technology Data Exchange (ETDEWEB)

    Sandrasegaran, Kumaresan; Rydberg, Jonas; Akisik, Fatih M. [Indiana University Medical Center, Department of Radiology, Indianapolis, IN (United States); Rajesh, Arumugam [United Leicester Hospitals, Department of Radiology, Leicester (United Kingdom); Rushing, Daniel A. [Indiana University Medical Center, Department of Oncology, Indianapolis, Indiana (United States); Henley, John D. [Indiana University Medical Center, Department of Pathology, Indianapolis, Indiana (United States)

    2005-07-01

    The objective of this study was to report the CT and MRI appearances of primary and metastatic gastrointestinal stromal tumor (GIST). The clinical and imaging findings of 31 patients with histological and immunohistochemical diagnosis of GIST were reviewed. The CT and MRI findings were assessed independently for size, location, enhancement characteristics, and pattern of metastatic disease. The tumors were of enteric (n=13), gastric (n=12), duodenal (n=2), and rectal (n=3) origin. In one case the primary site was the mesentery, without involvement of bowel. Primary tumors were typically exophytic (79%), larger than 5 cm (84%), and inhomogeneously enhancing (84%). Central necrosis of all tumors (37%) and aneurysmal dilation of enteric tumors (33%) were less common. Metastases were most commonly to mesentery (26%) or liver (32%). Less common findings were ascites (7%) and omental caking (3%). Liver metastases were hypervascular in 92% of patients and rapidly became cystic following therapy with imatinib mesylate (Gleevec; Novartis, East Hanover, NJ, USA). Lung metastases, bowel obstruction, vascular invasion, and significant lymphadenopathy were not seen in any patient. GISTs have some specific CT findings which could help differentiate them from other gastrointestinal tumors. Liver metastases became cystic following therapy, mimicking simple cysts. MRI was better than single-phase CT for assessing liver metastases, while CT was more sensitive for mesenteric metastases. (orig.)

  19. Cytopathological Diagnosis of an Unusual Cause of Malignant Hydrocele.

    Science.gov (United States)

    Jain, Ankur; Khadwal, Alka; Prakash, Gaurav; Gupta, Nalini; Varma, Subhash; Malhotra, Pankaj

    2016-01-01

    Testicular involvement in a case of acute lymphoblastic leukemia (ALL) is well reported, but occurrence of "isolated" malignant hydrocele is extremely uncommon. We herein report a case of a 22-year-old man who presented to our hematology clinic with fever and easy fatiguability of 2 weeks' duration. Examination revealed pallor, cervical lymphadenopathy, and bilateral scrotal swellings. He was diagnosed as a case of Philadelphia-positive ALL (B-cell type) based on peripheral smear, bone marrow examination, and flow cytometry of the marrow aspirate. Ultrasonography of scrotum revealed bilateral hydrocele with normal testes. Cytopathological analysis of the hydrocele fluid showed the presence of lymphoblasts. The patient was treated with modified BFM-90 protocol along with imatinib mesylate (600 mg/day). He achieved complete remission with a minimal residual disease of hydrocele persisted and a repeat cytological examination of the aspirate did not reveal any lymphoblasts. The patient was treated with consolidation (high-dose methotrexate), bilateral testicular irradiation, and re-induction following which the hydrocele disappeared. The patient is currently on maintenance phase of BFM-90 protocol and is alive at one year of follow-up. Contiguous spread from the subclinical testicular involvement is hypothesized as the mechanism for development of hydrocele in the current case. The role of cytopathology in the early diagnosis of testicular involvement in ALL is emphasized here.

  20. Cytopathological Diagnosis of an Unusual Cause of Malignant Hydrocele

    Directory of Open Access Journals (Sweden)

    Ankur Jain

    2016-01-01

    Full Text Available Testicular involvement in a case of acute lymphoblastic leukemia (ALL is well reported, but occurrence of “isolated” malignant hydrocele is extremely uncommon. We herein report a case of a 22-year-old man who presented to our hematology clinic with fever and easy fatiguability of 2 weeks' duration. Examination revealed pallor, cervical lymphadenopathy, and bilateral scrotal swellings. He was diagnosed as a case of Philadelphia-positive ALL (B-cell type based on peripheral smear, bone marrow examination, and flow cytometry of the marrow aspirate. Ultrasonography of scrotum revealed bilateral hydrocele with normal testes. Cytopathological analysis of the hydrocele fluid showed the presence of lymphoblasts. The patient was treated with modified BFM-90 protocol along with imatinib mesylate (600 mg/day. He achieved complete remission with a minimal residual disease of <0.001% at the end of induction therapy. However, the hydrocele persisted and a repeat cytological examination of the aspirate did not reveal any lymphoblasts. The patient was treated with consolidation (high-dose methotrexate, bilateral testicular irradiation, and re-induction following which the hydrocele disappeared. The patient is currently on maintenance phase of BFM-90 protocol and is alive at one year of follow-up. Contiguous spread from the subclinical testicular involvement is hypothesized as the mechanism for development of hydrocele in the current case. The role of cytopathology in the early diagnosis of testicular involvement in ALL is emphasized here.

  1. Nanoporous capsules of block co-polymers of [(MeO-PEG-NH)-b-(L-GluA)]-PCL for the controlled release of anticancer drugs for therapeutic applications

    International Nuclear Information System (INIS)

    Amgoth, Chander; Paik, Pradip; Dharmapuri, Gangappa; Kalle, Arunasree M

    2016-01-01

    Herein, new nanoporous capsules of the block co-polymers of MeO-PEG-NH-(L-GluA) 10 and polycaprolactone (PCL) have been synthesized through a surfactant-free cost-effective self-assembled soft-templating approach for the controlled release of drugs and for therapeutic applications. The nanoporous polymer capsules are designed to be biocompatible and are capable of encapsulating anticancer drugs (e.g., doxorubicin hydrochloride (DOX) and imatinib mesylate (ITM)) with a high extent (∼279 and ∼480 ng μg −1 , respectively). We have developed a nanoformulation of porous MeO-PEG-NH-(L-GluA) 10 -PCL capsules with DOX and ITM. The porous polymer nanoformulations have been programmed in terms of the release of anticancer drugs with a desired dose to treat the leukemia (K562) and human carcinoma cells (HepG2) in vitro and show promising IC 50 values with a very high mortality of cancer cells (up to ∼96.6%). Our nanoformulation arrests the cell divisions due to ‘cellular scenescence’ and kills the cancer cells specifically. The present findings could enrich the effectiveness of idiosyncratic nanoporous polymer capsules for use in various other nanomedicinal and biomedical applications, such as for killing cancer cells, immune therapy, and gene delivery. (paper)

  2. Optimization of the tumor microenvironment and nanomedicine properties simultaneously to improve tumor therapy.

    Science.gov (United States)

    Zhang, Bo; Shi, Wei; Jiang, Ting; Wang, Lanting; Mei, Heng; Lu, Heng; Hu, Yu; Pang, Zhiqing

    2016-09-20

    Effective delivery of nanomedicines to tumor tissues depends on both the tumor microenvironment and nanomedicine properties. Accordingly, tumor microenvironment modification or advanced design of nanomedicine was emerging to improve nanomedicine delivery to tumors. However, few studies have emphasized the necessity to optimize the tumor microenvironment and nanomedicine properties simultaneously to improve tumor treatment. In the present study, imatinib mesylate (IMA) was used to normalize the tumor microenvironment including platelet-derived growth factor receptor-β expression inhibition, tumor vessel normalization, and tumor perfusion improvement as demonstrated by immunofluorescence staining. In addition, the effect of tumor microenvironment normalization on tumor delivery of nanomedicines with different sizes was carefully investigated. It was shown that IMA treatment significantly reduced the accumulation of nanoparticles (NPs) around 110 nm but enhanced the accumulation of micelles around 23 nm by in vivo fluorescence imaging experiment. Furthermore, IMA treatment limited the distribution of NPs inside tumors but increased that of micelles with a more homogeneous pattern. Finally, the anti-tumor efficacy study displayed that IMA pretreatment could significantly increase the therapeutic effects of paclitaxel-loaded micelles. All-together, a new strategy to improve nanomedicine delivery to tumor was provided by optimizing both nanomedicine size and the tumor microenvironment simultaneously, and it will have great potential in clinics for tumor treatment.

  3. Salt Stability - The Effect of pHmax on Salt to Free Base Conversion.

    Science.gov (United States)

    Hsieh, Yi-Ling; Merritt, Jeremy M; Yu, Weili; Taylor, Lynne S

    2015-09-01

    The aim of this study was to investigate how the disproportionation process can be impacted by the properties of the salt, specifically pHmax. Five miconazole salts and four sertraline salts were selected for this study. The extent of conversion was quantified using Raman spectroscopy. A mathematical model was utilized to estimate the theoretical amount of conversion. A trend was observed that for a given series of salts of a particular basic compound (both sertraline and miconazole are bases), the extent of disproportionation increases as pHmax decreases. Miconazole phosphate monohydrate and sertraline mesylate, although exhibiting significantly different pHmax values (more than 2 units apart), underwent a similar extent of disproportionation, which may be attributed to the lower buffering capacity of sertraline salts. This work shows that the disproportionation tendency can be influenced by pHmax and buffering capacity and thus highlights the importance of selecting the appropriate salt form during the screening process in order to avoid salt-to-free form conversion.

  4. The iron chelating agent, deferoxamine detoxifies Fe(Salen-induced cytotoxicity

    Directory of Open Access Journals (Sweden)

    Masanari Umemura

    2017-08-01

    Full Text Available Iron-salen, i.e., μ-oxo-N,N′-bis(salicylideneethylenediamine iron (Fe(Salen was a recently identified as a new anti-cancer compound with intrinsic magnetic properties. Chelation therapy has been widely used in management of metallic poisoning, because an administration of agents that bind metals can prevent potential lethal effects of particular metal. In this study, we confirmed the therapeutic effect of deferoxamine mesylate (DFO chelation against Fe(Salen as part of the chelator antidote efficacy. DFO administration resulted in reduced cytotoxicity and ROS generation by Fe(Salen in cancer cells. DFO (25 mg/kg reduced the onset of Fe(Salen (25 mg/kg-induced acute liver and renal dysfunction. DFO (300 mg/kg improves survival rate after systematic injection of a fatal dose of Fe(Salen (200 mg/kg in mice. DFO enables the use of higher Fe(Salen doses to treat progressive states of cancer, and it also appears to decrease the acute side effects of Fe(Salen. This makes DFO a potential antidote candidate for Fe(Salen-based cancer treatments, and this novel strategy could be widely used in minimally-invasive clinical settings.

  5. Versatile Route to Synthesize Heterobifunctional Poly(ethylene glycol of Variable Functionality for Subsequent Pegylation

    Directory of Open Access Journals (Sweden)

    Redouan Mahou

    2012-02-01

    Full Text Available Pegylation using heterotelechelic poly(ethylene glycol (PEG offers many possibilities to create high-performance molecules and materials. A versatile route is proposed to synthesize heterobifunctional PEG containing diverse combinations of azide, amine, thioacetate, thiol, pyridyl disulfide, as well as activated hydroxyl end groups. Asymmetric activation of one hydroxyl end group enables the heterobifunctionalization while applying selective monotosylation of linear, symmetrical PEG as a key step. The azide function is introduced by reacting monotosyl PEG with sodium azide. A thiol end group is obtained by reaction with sodium hydrosulfide. The activation of the hydroxyl end group and subsequent reaction with potassium carbonate/thioacetic acid yields a thioacetate end group. The hydrolysis of the thioester end group by ammonia in presence of 2,2′-dipyridyl disulfide provides PEG pyridyl disulfide. Amine terminated PEG is prepared either by reduction of the azide or by nucleophilic substitution of mesylate terminated PEG using ammonia. In all cases, >95% functionalization of the PEG end groups is achieved. The PEG derivatives particularly support the development of materials for biomedical applications. For example, grafting up to 13% of the Na-alg monomer units with α-amine-ω-thiol PEG maintains the gelling capacity in presence of calcium ions but simultaneous, spontaneous disulfide bond formation reinforces the initial physical hydrogel.

  6. A novel complex KIT mutation in a gastrointestinal stromal tumor of the vermiform appendix.

    Science.gov (United States)

    Vassos, Nikolaos; Agaimy, Abbas; Günther, Klaus; Hohenberger, Werner; Schneider-Stock, Regine; Croner, Roland S

    2013-04-01

    Gastrointestinal stromal tumors of the vermiform appendix are rare. To date, only 11 cases have been reported in the English literature. Here, we present a new case of appendiceal gastrointestinal stromal tumor associated with complete situs inversus. A 48-year-old man was operated on due to appendicitis-like symptoms. Laparotomy revealed a ruptured conglomerate tumor in the lower abdomen associated with extensive peritoneal adhesions. Histology showed a spindle cell gastrointestinal stromal tumor with prominent sclerosis and calcification without low mitotic activity. The tumor cells expressed strongly CD117 and CD34. The mutation analysis revealed a heterozygous deletion/insertion involving exon 11 of KIT (pK558_V559delNNins). Because the tumor was ruptured intraoperatively, a high risk was assigned according to the revised National Institute of Health criteria and adjuvant therapy with imatinib mesylate was recommended. The patient is currently alive without evidence of progression 27 months after surgery. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Admission of new oncological drugs to the Slovenian health care system and their accessibility to the patients

    Directory of Open Access Journals (Sweden)

    Mitja Kos

    2007-09-01

    shorter than 10 months. Exceptions are drugs which were first used, mostly in a limited amount, before the acquisition of trade permit in Slovenia or through centralized procedure at EMEA such as oxaliplatin, irinotecan, capecitabine, imatinib mesylate. Average difference between the first use in Slovenia and selected member states of EU for the chosen oncology drugs decreased with years. In recent period oncology drugs were more quickly accessed by patients than in the past. The drug market continuously increased from 1999 to 2005, with an average increase of 30 M EUR per year. The largest increase was demonstrated for the antitumor medications and imunomodulators (ATC = L. In 1999 their market amounted to 10 M EUR or 3.9 % of the whole drug market, in 2005 it amounted to 38 M EUR or 8.6 % of the whole drug market. The market of the targeted drugs has been progressively increasing from year 2000 onwards, and amounted to 6 M EUR in 2005, which represents 39 % of the market share of Antitumor medications (cytostatics (ATC = L01 group or 1.4 % of the market share for all of the drugs. The reason for this progressive increase is attributed to the increased use of mainly three drugs: imatinib mesylate trastuzumab, and rituximab.Conclusions: The discrepancies in admission and access to newer oncology drugs between Slovenia and other member states of EU are becoming smaller. The market of oncology drugs is increasing significantly faster compared to the whole drug market, mainly due to the new targeted drugs.

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

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    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

  9. Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine.

    Science.gov (United States)

    Chin, Bennett B; McDougald, Darryl; Weitzel, Douglas H; Hawk, Thomas; Reiman, Robert E; Zalutsky, Michael R; Vaidyanathan, Ganesan

    2017-01-01

    Amino acid transporters, such as LAT1, are overexpressed in aggressive prostate and breast carcinomas, directly influencing pathways of growth and proliferation. The purpose of this study was to synthesize and characterize a novel 18F labeled leucine analog, 5-[18F]fluoroleucine, as a potential imaging agent for aggressive tumors which may not be amenable to imaging by FDG PET. 5-fluoroleucine was synthesized and characterized, and its 18F-labeled analog was synthesized from a mesylate precursor. First, breast cancer cell line assays were performed to evaluate uptake of 3H- or 14C-labeled L-leucine and other essential amino acids. Both L-leucine and 5- [18F]fluoroleucine were tested for uptake and accumulation over time, and for uptake via LAT1. Biodistribution studies were performed to estimate radiation dosimetry for human studies. Small animal PET / CT studies of a breast cancer were performed to evaluate in vivo 5-[18F]fluoroleucine tumor uptake. Breast cancer cell lines showed increasing high net accumulation of L-[14C]leucine. Both L-leucine and 5-[18F]fluoroleucine showed increasing uptake over time in in vitro tumor cell assays, and uptake was also shown to occur via LAT1. The biodistribution study of 5-[18F]fluoroleucine showed rapid renal excretion, no significant in vivo metabolism, and acceptable dosimetry for use in humans. In vivo small animal PET / CT imaging of a breast cancer xenograft showed uptake of 5- [18F]fluoroleucine in the tumor, which progressively increased over time. 5-[18F]fluoroleucine is a leucine analog which may be useful in identifying tumors with high or upregulated expression of amino acid transporters, providing additional information that may not be provided by FDG PET. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1.

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    Jonathan T Sims

    Full Text Available Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec, reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline

  11. Fenoldopam use in a burn intensive care unit: a retrospective study

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    Cotant Casey L

    2010-06-01

    Full Text Available Abstract Background Fenoldopam mesylate is a highly selective dopamine-1 receptor agonist approved for the treatment of hypertensive emergencies that may have a role at low doses in preserving renal function in those at high risk for or with acute kidney injury (AKI. There is no data on low-dose fenoldopam in the burn population. The purpose of our study was to describe our use of low-dose fenoldopam (0.03-0.09 μg/kg/min infusion in critically ill burn patients with AKI. Methods We performed a retrospective analysis of consecutive patients admitted to our burn intensive care unit (BICU with severe burns from November 2005 through September 2008 who received low-dose fenoldopam. Data obtained included systolic blood pressure, serum creatinine, vasoactive medication use, urine output, and intravenous fluid. Patients on concomitant continuous renal replacement therapy were excluded. Modified inotrope score and vasopressor dependency index were calculated. One-way analysis of variance with repeated measures, Wilcoxson signed rank, and chi-square tests were used. Differences were deemed significant at p Results Seventy-seven patients were treated with low-dose fenoldopam out of 758 BICU admissions (10%. Twenty (26% were AKI network (AKIN stage 1, 14 (18% were AKIN stage 2, 42 (55% were AKIN stage 3, and 1 (1% was AKIN stage 0. Serum creatinine improved over the first 24 hours and continued to improve through 48 hours (p p p p = NS. Modified inotrope score and vasopressor dependency index both decreased over 48 hours (p p = 0.0012. Conclusions These findings suggest that renal function was preserved and that urine output improved without a decrease in systolic blood pressure, increase in vasoactive medication use, or an increase in resuscitation requirement in patients treated with low-dose fenoldopam. A randomized controlled trial is required to establish the efficacy of low-dose fenoldopam in critically ill burn patients with AKI.

  12. Morphological Changes in Bone Marrow Post Imatinib Therapy in Chronic Phase CML: A Follow up Study on Sequential Bone Marrow Aspirates and Biopsies.

    Science.gov (United States)

    Narang, Neha Chopra; Rusia, Usha; Sikka, Meera; Kotru, Mrinalini

    2017-04-01

    Imatinib mesylate is used extensively for first line treatment of Chronic Myeloid Leukemia (CML). However, not many studies have documented morphological changes in bone marrow biopsies produced during Imatinib therapy with reference to myelofibrosis. To document the morphological changes produced in the bone marrow during Imatinib therapy. This longitudinal study followed up 75 Philadelphia Chromosome Positive Chronic Myeloid Leukemia with chronic phase(Ph+ CML- CP) patients sequentially, receiving 400-600mg Imatinib over a period of 12 or more months. Haematologic parameters were measured at admission, 2 weeks, 1 month, 3 months, 6 months and 12 or more months. Morphologic changes in bone marrow aspirate and biopsy were evaluated at admission, 6 months and ≥12 months of treatment in accordance with National Comprehensive Cancer Network(NCCN) guidelines. Complete Haematologic Response (CHR) was seen in 47.1%, 80%, 85.4%, 90.4% at ≥1 month, 3 months, 6 months and 12 months respectively after therapy. It was noted that patients not showing CHR by 3 months were less likely to show CHR at 6 months and beyond. Bone marrow aspirates and biopsies showed reduction in cellularity and myeloid precursors with regeneration of erythroid precursors in 70-83% at ≥12 months. A significant decrease in myelofibrosis (p-value< 0.04) was noted as early as 6 months. Mild to moderate hypoplasia was noted in 31.8% of biopsies within 6 months. Pseudo gaucher cells and benign lymphoid nodules were also seen. Sequential analysis showed that Imatinib reduced the grade of myelofibrosis significantly (p-value< 0.04). It also prevented development of myelofibrosis in patients who did not have it at presentation. Hence Imatinib is effective when used early in the course of CML-CP.

  13. Observation by flow sup 1 H NMR and dimerization kinetics and products of reactive ortho-quinodimethanes and benzocyclobutadiene

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, D.

    1990-09-21

    The reactive o-quinodimethanes, 1,2-dimethylene-1,2-dihydronaphthalene (9) and o-xylylene (1) were observed by flow {sup 1}H NMR spectroscopy at room temperature. The {sup 1}H NMR spectrum of 9 was obtained in the absence of precursor and dimers. However, the {sup 1}H NMR spectrum of the more reactive 1, generated in a similar manner from (o-((trimethylsilyl)methyl)benzyl)trimethylammonium iodide (5.) could be obtained only in the presence of its stable (4 + 2) and (4 + 4) dimers. The dimerization kinetics of 3-methyl- (5{prime}), 3,6-dimethyl- (11), 3-isopropyl- (12), and 3,6-diisoproply-1,2-xylylene (13) in acetonitrile (CH{sub 3}CN) were studied by stopped-flow UV-visible spectroscopy. Fluoride ion induced 1,2-elimination from 2-elimination from 2-trimethylsilylbenzocyclobutenyl-1 mesylate (26) was used to generate the reactive molecule benzocyclobutadiene (1{prime}) in CD{sub 3}CN, which was observed by flow {sup 1}H NMR spectroscopy at room temperature. The {sup 1}H NMR spectrum (in CD{sub 3}CN) of 1,2-dimethylene-1,2-dihydrothiophene (1{double prime}), obtained by fluoride ion induced 1,4-elimination from 3-(trimethylammoniummethyl)-2-(trimethylsilylmethyl)thiophene iodine was observed by flow {sup 1}H NMR spectroscopy at room temperature. The dimerization rate of 1{double prime} in CH{sub 3}CN, generated in the same manner, was measured by UV-visible spectroscopy. 166 refs., 7 figs., 7 tabs.

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

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    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.

  15. A novel hyaluronidase produced by Bacillus sp. A50.

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    Xueping Guo

    Full Text Available Hyaluronidases are a family of enzymes that degrade hyaluronic acid (hyaluronan, HA and widely used in many fields. A hyaluronidase producing bacteria strain was screened from the air. 16S ribosomal DNA (16S rDNA analysis indicated that the strain belonged to the genus Bacillus, and the strain was named as Bacillus sp. A50. This is the first report of a hyaluronidase from Bacillus, which yields unsaturated oligosaccharides as product like other microbial hyaluronate lyases. Under optimized conditions, the yield of hyaluronidase from Bacillus sp. A50 could reach up to 1.5×10(4 U/mL, suggesting that strain A50 is a good producer of hyaluronidase. The hyaluronidase (HAase-B was isolated and purified from the bacterial culture, with a specific activity of 1.02×10(6 U/mg protein and a yield of 25.38%. The optimal temperature and pH of HAase-B were 44°C and pH 6.5, respectively. It was stable at pH 5-6 and at a temperature lower than 45°C. The enzymatic activity could be enhanced by Ca2+, Mg2+, or Ni2+, and inhibited by Zn2+, Cu2+, EDTA, ethylene glycol tetraacetic acid (EGTA, deferoxamine mesylate salt (DFO, triton X-100, Tween 80, or SDS at different levels. Kinetic measurements of HAase-B towards HA gave a Michaelis constant (Km of 0.02 mg/mL, and a maximum velocity (Vmax of 0.27 A232/min. HAase-B also showed activity towards chondroitin sulfate A (CSA with the kinetic parameters, Km and Vmax, 12.30 mg/mL and 0.20 A232/min respectively. Meanwhile, according to the sequences of genomic DNA and HAase-B's part peptides, a 3,324-bp gene encoding HAase-B was obtained.

  16. Psychosocial implications of Thalassemia Major.

    Science.gov (United States)

    Aydinok, Yesim; Erermis, Serpil; Bukusoglu, Nagihan; Yilmaz, Deniz; Solak, Ufuk

    2005-02-01

    Many causes including the chronicity of disease, burden of treatment modalities, morbidities, and the expectation of early death resulting from the disease complications, may lead to psychosocial burden in Thalassemia Major (TM) patients. A total of 38 patients with TM and their mothers were recruited to evaluate the psychosocial burden as well as to disclose whether the psychological status of the patients contribute to the compliance with the therapy or to the contrary. Demographic and disease variables were obtained. Child Behavior Check-list (CBCL) was completed by the mothers of the patients. A detailed psychiatric interview based on the 4th edition of the Diagnostic and Statistical Manual diagnostic criteria was performed for each patient. Symptom Distress Checklist 90 (SCL-90) scale was given to all mothers for evaluating their psychopathology. Although CBCL scores remained between the normal ranges, desferrioxamine mesylate (DFO)-compliant patients and the patients with lower ferritin values had significantly higher scores. A total of 24% of the patients had a psychiatric diagnosis including major depression, anxiety disorder, tic disorder, and enuresis nocturnal. The psychiatric diagnosis was significantly higher in the patients who were compliant with desferrioxamine compared with the non-compliant group (P = 0.007). The SCL-90 scores indicated that the mothers who had a child with good adherence to DFO had higher scale scores than the mothers with a poor adherent child. The increase risk of psychosocial and behavioral problems in thalassemics and their parents indicated the importance of a lifelong psychosocial support for the prevention of mental health issues. The patients and their parents, who were more conscious of the illness, were more worried but more compliant with the therapy and need stronger psychiatric support.

  17. Pondering Parotid Masses

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    Mark A Miller

    2001-01-01

    Full Text Available A49-year-old, human immunodeficiency virus (HIV- infected, Haitian-born woman presented with a left facial mass that she had noticed for the previous eight weeks. She was known to have been HIV-seropositive for the previous 11 years and had been on multiple antiretroviral therapies. Her past medical history was also significant for hypertension, disseminated varicella zoster virus and recurrent oral and buttock Herpes simplex episodes. She was taking the following medications at the time of her presentation with the facial mass: stavudine, lamivudine, didanosine, nelfinavir mesylate, famciclovir, hydrochlorothiazide and cotrimoxazole. She had no complaints of fever, chills, sweats, weight loss or anorexia. She denied any pain, redness or warmth at the site of the facial swelling. Her most recent CD4 lymphocyte count was 336 cells/µL, with an HIV viral load of log102.6 copies/mL. Physical examination revealed a 4 cm fluid-filled mass in the left parotid gland. There was no detectable induration, redness, warmth or tenderness, and no associated adenopathy. The rest of the examination was unremarkable. An aspirate of the mass was performed under sterile conditions and yielded 30 mL of turbid, yellow liquid. A Gram stain revealed no neutrophils, scant mononuclear cells and no visible organisms. An acid-fast stain was negative as well. Routine, mycobacterial and fungal cultures showed no growth. Cytological analysis showed scant reactive lymphocytes and no malignant cells. The patient was not given therapy and was observed for another two months. The fluid reaccumulated in the left parotid gland, and the patient?s only complaint concerned the unsightly appearance of the mass. The lesion was again aspirated for 30 mL of fluid and this time, the fluid had a turbid, brown appearance. All laboratory results were identical to the results from the first aspirate. What is your diagnosis, and how would you treat this patient?

  18. Nephrogenic systemic fibrosis

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    Bhushan Madke

    2011-01-01

    Full Text Available Nephrogenic systemic fibrosis (NSF is a relatively new fibrosing disorder which has caught the attention of various specialities in the past decade. NSF is an extremely disabling and often painful condition, affecting up to 13% of the individuals with chronic kidney disease. The administration of a gadolinium chelate contrast agent has been reported to induce the development of NSF, particularly in patients who have acute or chronic renal disease with a glomerular filtration rate (GFR lower than 30-mL/min/1.73 m 2 and in those with acute renal insufficiency. Mass spectroscopy studies have demonstrated particles of gadolinium in the lesional tissue. The exact pathogenesis of this curious sclerosing condition is unknown. The role of the aberrant targeting of ′circulating fibrocytes′ to the peripheral tissues and viscera has been hypothesized. NSF has distinct clinicopathological features in the setting of renal failure and needs to be looked upon as a new entity on the block. The condition is characterized by irregular indurated plaques, with amoeba-like projections and islands of sparing, chiefly on the trunk and extremities. Flexion contractures of fingers, knees, and elbow joints are known to occur in advanced cases of NSF. The course is frequently associated with painful episodes and loss of ambulation. Histopathology shows haphazard arrangement of thickened bundles of collagen, varying amount of mucin, and increased population of fibroblast-like cells in the dermis. Immunohistochemistry shows increased deposition of type-I procollagen and CD 34+ cells having fibroblastic activity. The condition is refractory to treatment with corticosteroids and immunosuppressive agents. Various modalities of therapy such as UVA1 phototherapy, imatinib mesylate, photodynamic therapy, plasmapheresis, extracorporeal photochemotherapy, and high-dose intravenous immunoglobulin have shown a moderate degree of improvement in skin thickness scores. A prudent

  19. Cannabinoid Modulation of Eukaryotic Initiation Factors (eIF2α and eIF2B1 and Behavioral Cross-Sensitization to Cocaine in Adolescent Rats

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    Philippe A. Melas

    2018-03-01

    Full Text Available Summary: Reduced eukaryotic Initiation Factor 2 (eIF2α phosphorylation (p-eIF2α enhances protein synthesis, memory formation, and addiction-like behaviors. However, p-eIF2α has not been examined with regard to psychoactive cannabinoids and cross-sensitization. Here, we find that a cannabinoid receptor agonist (WIN 55,212-2 mesylate [WIN] reduced p-eIF2α in vitro by upregulating GADD34 (PPP1R15A, the recruiter of protein phosphatase 1 (PP1. The induction of GADD34 was linked to ERK/CREB signaling and to CREB-binding protein (CBP-mediated histone hyperacetylation at the Gadd34 locus. In vitro, WIN also upregulated eIF2B1, an eIF2 activator subunit. We next found that WIN administration in vivo reduced p-eIF2α in the nucleus accumbens of adolescent, but not adult, rats. By contrast, WIN increased dorsal striatal levels of eIF2B1 and ΔFosB among both adolescents and adults. In addition, we found cross-sensitization between WIN and cocaine only among adolescents. These findings show that cannabinoids can modulate eukaryotic initiation factors, and they suggest a possible link between p-eIF2α and the gateway drug properties of psychoactive cannabinoids. : Melas et al. show that psychoactive cannabinoids modulate levels of two eukaryotic initiation factors (eIF2α and eIF2B1 known to be involved in protein synthesis, memory formation, and drug sensitivity. Cannabinoid modulation of eIF2α in vivo is only observed in adolescent animals, and is associated with cross-sensitization to cocaine. Keywords: drug use, addiction, cannabis, marijuana, cocaine, epigenetics, eIF2a, CREB, GADD34, gateway drugs

  20. Management of Menopausal Symptoms

    Science.gov (United States)

    Kaunitz, Andrew M.; Manson, JoAnn E.

    2015-01-01

    Most menopausal women experience vasomotor symptoms, with bothersome symptoms often lasting longer than one decade. Hormone therapy (HT) represents the most effective treatment for these symptoms, with oral and transdermal estrogen formulations having comparable efficacy. Findings from the Women’s Health Initiative and other recent randomized clinical trials have helped to clarify the benefits and risks of combination estrogen-progestin and estrogen-alone therapy. Absolute risks observed with HT tended to be small, especially in younger women. Neither regimen affected all-cause mortality rates. Given the lower rates of adverse events on HT among women close to menopause onset and at lower baseline risk of cardiovascular disease, risk stratification and personalized risk assessment appears to represent a sound strategy for optimizing the benefit: risk profile and safety of hormone therapy. Systemic HT should not be arbitrarily stopped at age 65; instead treatment duration should be individualized based on patients’ risk profiles and personal preferences. Genitourinary syndrome of menopause represents a common condition that adversely impacts the quality of life of many menopausal women. Without treatment, symptoms worsen over time. Low-dose vaginal estrogen represents highly effective treatment for this condition. Because custom-compounded hormones have not been tested for efficacy or safety, U.S. Food and Drug Administration (FDA)-approved HT is preferred. A low dose formulation of paroxetine mesylate currently represents the only nonhormonal medication FDA-approved to treat vasomotor symptoms. Gynecologists and other clinicians who remain abreast of data addressing the benefit: risk profile of hormonal and nonhormonal treatments can help menopausal women make sound choices regarding management of menopausal symptoms. PMID:26348174

  1. Inhibition of protein kinase Cbeta does not improve endothelial function in type 2 diabetes.

    Science.gov (United States)

    Beckman, Joshua A; Goldfine, Allison B; Goldin, Alison; Prsic, Adnan; Kim, Sora; Creager, Mark A

    2010-08-01

    Antagonism of protein kinase Cbeta (PKCbeta) restores endothelial function in experimental models of diabetes and prevents vascular dysfunction in response to hyperglycemia in healthy humans. We tested the hypothesis that PKCbeta antagonism would improve vascular function in subjects with type 2 diabetes compared with healthy control subjects. The effect of PKCbeta was evaluated in a randomized, placebo-controlled, double-blinded crossover trial. The study was performed in the outpatient setting of a university medical center. Thirteen subjects with type 2 diabetes without evidence of cardiovascular disease and 15 healthy control subjects were recruited via newspaper advertisement. Subjects underwent a randomized, double-blind, crossover, placebo-controlled trial of the selective PKCbeta antagonist ruboxistaurin mesylate. Subjects received each treatment for 14 d. Endothelium-dependent and endothelium-independent vasodilation of forearm resistance vessels was measured with mercury-in-silastic, strain-gauge plethysmography during intraarterial administration of methacholine chloride and verapamil, respectively. Markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress were measured after each treatment. Endothelium-dependent vasodilation of forearm resistance vessels was attenuated in diabetic subjects when compared with healthy subjects (P=0.001). Endothelium-independent vasodilation did not differ between groups (P value not significant). Ruboxistaurin did not significantly change endothelium-dependent or endothelium-independent vasodilation or blood-based markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress in either diabetic or healthy subjects. Endothelial dysfunction of forearm resistance vessels was not improved by 2 wk of selective PKCbeta inhibition in patients with diabetes. These results suggest that PKCbeta does not contribute significantly to vascular dysfunction in otherwise healthy patients with type 2

  2. Interferon γ is a STAT1-dependent direct inducer of BCL6 expression in imatinib-treated chronic myeloid leukemia cells.

    Science.gov (United States)

    Madapura, H S; Nagy, N; Ujvari, D; Kallas, T; Kröhnke, M C L; Amu, S; Björkholm, M; Stenke, L; Mandal, P K; McMurray, J S; Keszei, M; Westerberg, L S; Cheng, H; Xue, F; Klein, G; Klein, E; Salamon, D

    2017-08-10

    B-cell CLL/lymphoma 6 (BCL6) exerts oncogenic effects in several human hematopoietic malignancies including chronic myeloid leukemia (CML), where BCL6 expression was shown to be essential for CML stem cell survival and self-renewal during imatinib mesylate (IM) treatment. As several lines of evidence suggest that interferon γ (IFNγ) production in CML patients might have a central role in the response to tyrosine kinase inhibitor (TKI) therapy, we analyzed if IFNγ modulates BCL6 expression in CML cells. Although separate IFNγ or IM treatment only slightly upregulated BCL6 expression, combined treatment induced remarkable BCL6 upregulation in CML lines and primary human CD34+ CML stem cells. We proved that during combined treatment, inhibition of constitutive signal transducer and activator of transcription (STAT) 5 activation by IM allowed the specific enhancement of the STAT1 dependent, direct upregulation of BCL6 by IFNγ in CML cells. By using colony-forming assay, we found that IFNγ enhanced the ex vivo colony or cluster-forming capacity of human CML stem cells in the absence or presence of IM, respectively. Furthermore, inhibition of the transcriptional repressor function of BCL6 in the presence of IM and IFNγ almost completely blocked the cluster formation of human CML stem cells. On the other hand, by using small interfering RNA knockdown of BCL6, we demonstrated that in an IM-treated CML line the antiapoptotic effect of IFNγ was independent of BCL6 upregulation. We found that IFNγ also upregulated several antiapoptotic members of the BCL2 and BIRC gene families in CML cells, including the long isoform of MCL1, which proved to be essential for the antiapoptotic effect of IFNγ in an IM-treated CML line. Our results suggest that combination of TKIs with BCL6 and MCL1 inhibitors may potentially lead to the complete eradication of CML stem cells.

  3. A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of neramexane in patients with moderate to severe subjective tinnitus

    Directory of Open Access Journals (Sweden)

    Jastreboff Pawel J

    2011-01-01

    Full Text Available Abstract Background Neramexane is a new substance that exhibits antagonistic properties at α9α10 cholinergic nicotinic receptors and N-methyl-D-aspartate receptors, suggesting potential efficacy in the treatment of tinnitus. Methods A total of 431 outpatients with moderate to severe subjective tinnitus (onset 3-18 months before screening were assigned randomly to receive either placebo or neramexane mesylate (25 mg/day, 50 mg/day and 75 mg/day for 16 weeks, with assessment at 4-week intervals. The primary (intention-to-treat efficacy analysis was based on the change from baseline in Week 16 in the total score of the adapted German short version of the validated Tinnitus Handicap Inventory questionnaire (THI-12. Results Compared with placebo, the largest improvement was achieved in the 50 mg/d neramexane group, followed by the 75 mg/d neramexane group. This treatment difference did not reach statistical significance at the pre-defined endpoint in Week 16 (p = 0.098 for 50 mg/d; p = 0.289 for 75 mg/d neramexane, but consistent numerical superiority of both neramexane groups compared with placebo was observed. Four weeks after the end of treatment, THI-12 scores in the 50 mg/d group were significantly better than those of the controls. Secondary efficacy variables supported this trend, with p values of Conclusions This study demonstrated the safety and tolerability of neramexane treatment in patients with moderate to severe tinnitus. The primary efficacy variable showed a trend towards improvement of tinnitus suffering in the medium- and high-dose neramexane groups. This finding is in line with consistent beneficial effects observed in secondary assessment variables. These results allow appropriate dose selection for further studies. Trial Registration ClinicalTrials.gov NCT00405886

  4. Sodium hydrogen exchange 1 (NHE-1) regulates connexin 43 expression in cardiomyocytes via reverse mode sodium calcium exchange and c-Jun NH2-terminal kinase-dependent pathways.

    Science.gov (United States)

    Stanbouly, Seta; Kirshenbaum, Lorrie A; Jones, Douglas L; Karmazyn, Morris

    2008-10-01

    Connexin 43, the major connexin isoform in gap junctions of cardiac ventricular myocytes, undergoes changes in distribution and expression in cardiac diseases. The Na(+)-H(+) exchanger (NHE-1), a key mediator of hypertrophy and heart failure, has been shown to be localized in the cardiomyocyte gap junctional regions; however, whether NHE-1 regulates gap junction proteins in the hypertrophied cardiomyocyte is not known. To address this question, neonatal rat ventricular myocytes were treated with phenylephrine (PE) for 24 h to induce hypertrophy. Increased Cx43 expression observed with PE treatment (132.4 +/- 6.3% compared to control; P isopropyl-3-(methylsulfonyl)benzoyl-guanidine methanesulfonate]. PE-induced hypertrophy was associated with mitogen-activated protein kinase c-Jun NH(2)-terminal kinase (JNK) 1/2 activation, whereas inhibition of JNK1/2 with either SP600125 [anthra(1,9-cd)pyrazol-6(2H)-one 1,9-pyrazoloanthrone] or small interfering RNA significantly increased PE-induced up-regulation of Cx43 protein levels. Inhibition of reverse mode Na(+)-Ca(2+) exchange (NCX) with KB-R7943 [2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate] partially reversed JNK1/2 activation (195.2 +/- 21.4 versus 143.7 +/- 14.4% with KB-R7943; P < 0.05) and augmented up-regulation of Cx43 protein (121.1 +/- 8.3 versus 215.9 +/- 25.6% with KB-R7943; P < 0.05) in the presence of PE. Our results demonstrate that NHE-1 negatively regulates Cx43 protein expression in PE-induced cardiomyocyte hypertrophy via a JNK1/2-dependent pathway, which is probably activated by reverse mode NCX activity.

  5. Role of nitric oxide and free radicals in cardioprotection by blocking Na+/H+ and Na+/Ca2+ exchange in rat heart.

    Science.gov (United States)

    Maczewski, Michał; Beresewicz, Andrzej

    2003-02-14

    Inhibition of Na(+)/H(+) (NHE) and Na(+)/Ca(2+) (NCE) exchangers prevents myocardial ischemia/reperfusion injury by preventing cardiomyocyte Ca(2+) overload. We hypothesized that it may influence ischemic/reperfused myocardium also indirectly by preventing endothelial Ca(2+) accumulation, and thereby by attenuating reperfusion-induced formation of nitric oxide (NO) and/or oxygen free radicals. Langendorff-perfused rat hearts were subjected to 30-min ischemia and 30-min reperfusion. Myocardial outflow of NO (nitrite+nitrate) and hydroxyl radical (*OH, salicylate method), and functional recoveries were followed during reperfusion. In all groups, there was a transient rise in NO and *OH outflow upon reperfusion. An inhibitor of NHE, cariporide (10 microM) [(4-Isopropyl-3-methylsulfonyl-benzoyl)-quanidine methanesulfonate], and an inhibitor of the reverse mode of NCE, KB-R7943 (5 microM) (2-[4-(4-Nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate), decreased NO and *OH formation, reduced contracture, and improved the recovery of mechanical function during reperfusion, compared to the untreated hearts. The formation of NO was reduced by 40% by 100 microM N(G)-methyl-L-arginine acetate salt (L-NMMA, NO synthase inhibitor), and not affected by 50 microM L-NMMA. *OH formation, contracture, and the functional recoveries were affected neither by 50 nor by 100 microM L-NMMA. Also, the effects of cariporide and KB-R7943 were unaffected by 100 microM L-NMMA. This study shows for the first time that the inhibition of NHE and NCE attenuates post-ischemic myocardial formation of NO and *OH, suggesting that prevention of Ca(2+) overload is cardioprotective via these mechanisms. The results indicate, however, that NO synthase pathway did not interfere with the protection afforded by NHE or NCE in our model. Copyright 2003 Elsevier Science B.V.

  6. New developments in management of gastrointestinal stromal tumors: regorafenib, the new player in the team

    Directory of Open Access Journals (Sweden)

    Boichuk S

    2013-12-01

    Full Text Available Sergei Boichuk,1,2 Jessica L Rausch,1 Anette Duensing1,31Cancer Virology Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA; 2Department of Pathology, Kazan State Medical University, Kazan, Russia; 3Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USAAbstract: Gastrointestinal stromal tumors (GISTs are the most common mesenchymal tumors of the gastrointestinal tract and the most frequent single type of sarcoma, at least in some geographical regions. They arise from the interstitial cells of Cajal (or a common progenitor cell. The vast majority of GISTs are characterized by oncogenically activating mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA receptor tyrosine kinase genes. This molecular feature has been successfully exploited for therapeutic purposes, and as of a decade ago, GISTs have become the prototype of a solid tumor that can be targeted with small molecule kinase inhibitors. Imatinib mesylate (Gleevec®/Glivec® benefits more than 85% of patients with unresectable and/or metastatic GIST. Unfortunately, the majority of patients develop resistance to imatinib within the first 2 years of treatment and new therapeutic options are needed. Although the broad-range kinase inhibitor sunitinib malate (Sutent® has been the second-line therapy approved by the US Food and Drug Administration since 2006, it was not until recently (February 2013 that regorafenib (Stivarga® was approved as a third-line therapeutic agent for GIST. This review summarizes the development process of regorafenib for GIST and highlights its biochemical, pharmacologic, and clinical properties.Keywords: gastrointestinal stromal tumors, GIST, regorafenib

  7. Lipid peroxidation and cytotoxicity induced by respirable volcanic ash

    International Nuclear Information System (INIS)

    Cervini-Silva, Javiera; Nieto-Camacho, Antonio; Gomez-Vidales, Virginia; Ramirez-Apan, María Teresa; Palacios, Eduardo; Montoya, Ascención; Kaufhold, Stephan

    2014-01-01

    Highlights: • Respirable volcanic ash induces oxidative degradation of lipids in cell membranes. • Respirable volcanic ash triggers cytotoxicity in murin monocyle/macrophage cells. • Oxidative stress is surface controlled but not restricted by surface- Fe 3+ . • Surface Fe 3+ acts as a stronger inductor in allophanes vs phyllosilicates or oxides. • Registered cell-viability values were as low as 68.5 ± 6.7%. - Abstract: This paper reports that the main component of respirable volcanic ash, allophane, induces lipid peroxidation (LP), the oxidative degradation of lipids in cell membranes, and cytotoxicity in murin monocyle/macrophage cells. Naturally-occurring allophane collected from New Zealand, Japan, and Ecuador was studied. The quantification of LP was conducted using the Thiobarbituric Acid Reactive Substances (TBARS) assay. The cytotoxic effect was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide colorimetric assay. Electron-Paramagnetic Resonance (EPR) determinations of naturally-occurring allophane confirmed the incorporation in the structure and clustering of structural Fe 3+ , and nucleation and growth of small-sized Fe (oxyhydr)oxide or gibbsite. LP induced by allophane varied with time, and solid concentration and composition, reaching 6.7 ± 0.2 nmol TBARS mg prot −1 . LP was surface controlled but not restricted by structural or surface-bound Fe 3+ , because redox processes induced by soluble components other than perferryl iron. The reactivity of Fe 3+ soluble species stemming from surface-bound Fe 3+ or small-sized Fe 3+ refractory minerals in allophane surpassed that of structural Fe 3+ located in tetrahedral or octahedral sites of phyllosilicates or bulk iron oxides. Desferrioxamine B mesylate salt (DFOB) or ethylenediaminetetraacetic acid (EDTA) inhibited LP. EDTA acted as a more effective inhibitor, explained by multiple electron transfer pathways. Registered cell-viability values were as low as 68.5

  8. Combination of imatinib and clotrimazole enhances cell growth inhibition in T47D breast cancer cells.

    Science.gov (United States)

    Motawi, Tarek M K; Sadik, Nermin A H; Fahim, Sally A; Shouman, Samia A

    2015-05-25

    Imatinib mesylate (IM), a tyrosine kinase inhibitor, is used as targeted cancer therapy. However, mono-targeting by IM does not always achieve full tumor eradication and thus it is recommended to combine IM with other anticancer agents. Clotrimazole (CLT) is an antifungal azole derivative with promising anticancer effects due to inhibiting the activity of glycolytic enzymes. The present study aimed to evaluate the effect of combining CLT with IM on breast cancer cell line in an attempt to establish effective new combination. T47D human breast cancer cell line was treated with different concentrations of IM and/or CLT for 48 h. IM-CLT interaction was determined by isobologram equation and combination index. Cell viability was confirmed by measuring LDH activity. As indicators of glycolysis inhibition, the expression of hexokinase-2 (HK-2) and 6-phosphofructo-1-kinase (PFK-1) plus the activity of intracellular lactate dehydrogenase (LDH) and pyruvate kinase (PK) were determined. In addition, glucose consumption and adenosine triphosphate (ATP) production were measured. Moreover, nitric oxide (NO), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-α (HIF-α) were also determined as they are modulators for glycolysis. This study demonstrated that IM or CLT synergistically inhibited cell growth in T47D as shown by combination and dose reduction indices. The combination of 15 μM IM and 20 μM CLT significantly decreased glucose consumption, activity of both PK and intracellular LDH, while increased leaked LDH, VEGF and NO in the medium compared to each drug alone. Furthermore the combination decreased gene expression of HK-2, PFK-1 and ATP content compared to the control. In conclusion, the synergistic effect of CLT on IM cytotoxicity in T47D cell line maybe mediated through inhibition of glycolysis and increasing both NO and VEGF. Further studies are required to confirm the efficiency and safety of this combination. Copyright © 2015 Elsevier

  9. Identification of steroid-binding and phosphorylated sites within the glucocorticoid receptor

    Energy Technology Data Exchange (ETDEWEB)

    Smith, L.I.

    1989-01-01

    The primary goal of these studies was to localize the steroid-binding and phosphorylated sites of the glucocorticoid receptor. The synthetic steroid, dexamethasone 21-mesylate (DM) forms a covalent thioether bond via the sulfhydryl group of a cysteine residue in the receptor. To determine the covalent site of attachment of this ligand, receptors in WEHI-7 mouse thymoma cells were labeled with ({sup 3}H)DM and purified with a monoclonal antibody. The receptor was completely digested with trypsin and a single peptide covalently labeled with steroid identified by reversed-phase HPLC. This peptide was analyzed by automated Edman degradation to determine the location of the steroid-labeled residue. A similar analysis was performed on an overlapping peptide produced by Staphylococcus aureus protease digestion. Analysis of tryptic peptides from receptors labeled with both ({sup 3}H)DM and L-({sup 35}S)methionine indicated that this peptide contained methionine. These analyses, coupled with the published amino acid sequence of the receptor, identified Cysteine-644 in the steroid-binding domain of the mouse glucocorticoid receptor as the residue involved in covalent steroid-binding. A synthetic peptide representing amino acids 640-650 of the mouse receptor was prepared and analyzed to confirm the identification. These biochemical studies represent a direct demonstration of an amino acid important in receptor function. It has been proposed that the receptor functions through a phosphorylation-dephosphorylation cycle to explain the dependence of hormone binding capacity upon cellular ATP. The glucocorticoid receptor has been shown to be a phosphoprotein. As an initial step to identifying a role of phosphorylation in receptor action, phosphorylated sites within the functional domains of the protein were identified.

  10. Management of Menopausal Symptoms.

    Science.gov (United States)

    Kaunitz, Andrew M; Manson, JoAnn E

    2015-10-01

    Most menopausal women experience vasomotor symptoms with bothersome symptoms often lasting longer than one decade. Hormone therapy (HT) represents the most effective treatment for these symptoms with oral and transdermal estrogen formulations having comparable efficacy. Findings from the Women's Health Initiative and other recent randomized clinical trials have helped to clarify the benefits and risks of combination estrogen-progestin and estrogen-alone therapy. Absolute risks observed with HT tended to be small, especially in younger women. Neither regimen increased all-cause mortality rates. Given the lower rates of adverse events on HT among women close to menopause onset and at lower baseline risk of cardiovascular disease, risk stratification and personalized risk assessment appear to represent a sound strategy for optimizing the benefit-risk profile and safety of HT. Systemic HT should not be arbitrarily stopped at age 65 years; instead treatment duration should be individualized based on patients' risk profiles and personal preferences. Genitourinary syndrome of menopause represents a common condition that adversely affects the quality of life of many menopausal women. Without treatment, symptoms worsen over time. Low-dose vaginal estrogen represents highly effective treatment for this condition. Because custom-compounded hormones have not been tested for efficacy or safety, U.S. Food and Drug Administration (FDA)-approved HT is preferred. A low-dose formulation of paroxetine mesylate currently represents the only nonhormonal medication FDA-approved to treat vasomotor symptoms. Gynecologists and other clinicians who remain abreast of data addressing the benefit-risk profile of hormonal and nonhormonal treatments can help menopausal women make sound choices regarding management of menopausal symptoms.

  11. Use of deferasirox, an iron chelator, to overcome imatinib resistance of chronic myeloid leukemia cells.

    Science.gov (United States)

    Kim, Dae Sik; Na, Yoo Jin; Kang, Myoung Hee; Yoon, Soo-Young; Choi, Chul Won

    2016-03-01

    The treatment of chronic myeloid leukemia (CML) has achieved impressive success since the development of the Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate. Nevertheless, resistance to imatinib has been observed, and a substantial number of patients need alternative treatment strategies. We have evaluated the effects of deferasirox, an orally active iron chelator, and imatinib on K562 and KU812 human CML cell lines. Imatinib-resistant CML cell lines were created by exposing cells to gradually increasing concentrations of imatinib. Co-treatment of cells with deferasirox and imatinib induced a synergistic dose-dependent inhibition of proliferation of both CML cell lines. Cell cycle analysis showed an accumulation of cells in the subG1 phase. Western blot analysis of apoptotic proteins showed that co-treatment with deferasirox and imatinib induced an increased expression of apoptotic proteins. These tendencies were clearly identified in imatinib-resistant CML cell lines. The results also showed that co-treatment with deferasirox and imatinib reduced the expression of BcrAbl, phosphorylated Bcr-Abl, nuclear factor-κB (NF-κB) and β-catenin. We observed synergistic effects of deferasirox and imatinib on both imatinib-resistant and imatinib-sensitive cell lines. These effects were due to induction of apoptosis and cell cycle arrest by down-regulated expression of NF-κB and β-catenin levels. Based on these results, we suggest that a combination treatment of deferasirox and imatinib could be considered as an alternative treatment option for imatinib-resistant CML.

  12. Clinicopathologic features, management and outcome of ten cases of gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    Md. Nazmul Hoque

    2017-07-01

    Full Text Available Background and objectives:Gastrointestinal stromal tumor (GISTs is an uncommon and rare disease in Bangladesh. Our aims were to describe socio-demographic characteristics, clinical presentations, anatomical location, morphological variation, treatment and outcome of GIST in ten cases. Methods:This study included consecutive ten cases of GISTs diagnosed and treated in two tertiary level hospitals in Dhaka, Bangladesh from 2013 to 2016. Patients’ socio-demographic characteristics, clinical presentations, anatomical location, histological types, presence of CD117 markers were determined. Outcome of the treatment by surgical intervention and imatinib mesylate (400mg/day were evalauted. Results: Total 10 patients were included in the study. Among them 6 were male and 4 were female. The age range was 32-74 years. Abdominal pain, haematemesis, melaena, haematochezia and anaemia were the most common presentation. One patient had dysphagia and another had features of subacute intestinal obstruction. Five patients had GIST in the stomach (50%, two had in colon and one in esophagus, duodenum and ileum respectively. CD 117 was positive in 8 cases, majority had spindly type cell with low mitotic figure. Imatinib therapy was given in all the cases except two patients. Disease recurrence in the form liver metastasis was found in two cases and both died. Disease free survival for more than 2 years was observed in 4 cases. Conclusion: Haematemesis and melaena were common presentation of GISTs. Stomach was the most common site for GISTs and majority had spindle type of cells and positive CD117 marker. Surgical intervention and imatinib therapy was found effective. IMC J Med Sci 2017; 11(2: 45-49

  13. Simultaneous determination of phentermine and topiramate in human plasma by liquid chromatography-tandem mass spectrometry with positive/negative ion-switching electrospray ionization and its application in pharmacokinetic study.

    Science.gov (United States)

    Ni, Yang; Zhou, Ying; Xu, Mingzhen; He, Xiaomeng; Li, Huqun; Haseeb, Satter; Chen, Hui; Li, Weiyong

    2015-03-25

    A new method for simultaneous determination of phentermine and topiramate by liquid chromatography/electrospray tandem mass spectrometry (LC/MS/MS) operated in positive and negative ionization switching modes was developed and validated. Protein precipitation with acetonitrile was selected for sample preparation. Analyses were performed on a liquid chromatography system employing a Kromasil 60-5CN column (2.1 mm × 100 mm, 5 μm) and an isocratic elution with mixed solution of acetonitrile-20mM ammonium formate containing 0.3% formic acid (40:60, v/v), at a flow rate of 0.35 mL/min. Doxazosin mesylate and pioglitazone were used as the internal standard (IS) respectively for quantification. The determination was carried out on an API 4000 triple-quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode using the following transitions monitored simultaneously: positive m/z 150.0/91.0 for phentermine, m/z 452.1/344.3 for doxazosin, and negative m/z 338.3/77.9 for topiramate, m/z 355.0/41.9 for pioglitazone. The method was validated to be linear over the concentration range of 1-800 ng mL(-1) for phentermine, 1-1000 ng mL(-1) for topiramate. Within- and between-day accuracy and precision of the validated method at three different concentration levels were within the acceptable limits of <15% at all concentrations. Blood samples were collected into heparinized tubes before and after administration. The simple and robust LC/MS/MS method was successfully applied for the simultaneous determination of phentermine and topiramate in a pharmacokinetic study in healthy male Chinese volunteers. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. In situ salt screening--a useful technique for discovery support and preformulation studies.

    Science.gov (United States)

    Tong, W Q; Whitesell, G

    1998-05-01

    The purpose of this paper was to present an in situ salt screening technique which is applicable to most basic compounds. The theoretical aspects, experimental details, applications, and significance of this technique are illustrated through in situ salt screening studies performed on GW1818, an alpha 1A andrenergic receptor antagonist intended for treatment of benign prostatic hyperplasia (BPH). Generally, the in situ salt screening technique includes (i) acid selection, (ii) a solubility study, (iii) characterization of residual solids, and (iv) calculation of the Ksp and solubility of the salts. Six acids were screened for salt formation with GW1818. Excellent agreement was found between the solubility results determined using the authentic salts and solubility results obtained through in situ screening. Additional evidence of salt formation and some solid state properties of the salts formed in situ were obtained through microscopic examinations, differential scanning calorimetry (DSC), and x-ray powder diffraction studies. Four salts of GW1818, the phosphate, succinate, mesylate, and hydrochloride, were crystalline and demonstrated adequate solubility. These were selected for further evaluation. Adequate solubility was also observed in the case of citrate and tartrate salts, but these were considered only as potential backup candidates because they were difficult to crystallize. The results of the in situ salt screening experiments also led to the development of an IV formulation for use in pilot toxicological studies and pharmacological studies. In conclusion, the in situ salt screening technique offers a time- and compound-conserving approach for prioritizing salt selection and for providing solubility and stability information useful for formulation development both in the research and the development stages.

  15. "To patent or not to patent? the case of Novartis' cancer drug Glivec in India".

    Science.gov (United States)

    Gabble, Ravinder; Kohler, Jillian Clare

    2014-01-06

    Glivec (imatinib mesylate), produced by the pharmaceutical company Novartis, is prescribed in the case of chronic myeloid leukemia, one of the most common blood cancers in eastern countries. After more than a decade of legal battles surrounding its patentability, the Supreme Court of India gave its final decision on April 1st of 2013, rejecting the appeal of the Swiss giant drug manufacturer. In 2006, the Indian Patent Office first refused Glivec's patent under Section 3(d) of the Indian Patent Act arguing that it was only a modified version of an existing drug, Imatinib, and therefore that the drug was not innovative. Novartis replied filing legal challenges against the Indian government but the final verdict in April of 2013 ends the battle. Indeed, the Supreme Court stated that even if the bioavailability of the drug was improved, it did not demonstrate enhanced efficacy and that Glivec was not patentable. The research primarily focused on journal, newspaper and magazine articles relevant to the time frame of the lawsuit (from 1994 to 2013) as well as news searches through Google, Factiva, ProQuest, PubMed, and YouTube where press articles from court verdicts were obtained by using the following keywords: "India", "Novartis", "Glivec", "Patent", "Novartis Case", and "Supreme Court of India". The data sources were interpreted and analyzed according to the authors' own prior knowledge and understanding of the exigencies of the TRIPS Agreement. This case illuminates how India is interpreting international law to fit domestic public health needs. The Novartis case arguably sets an important precedent for the global pharmaceutical industry and ideally will help improve access to lifesaving medicines in the developing world by demanding that patient health needs supersede commercial interests. The Supreme Court of India's decision may affect the interpretation of the article of the TRIPS Agreement, which states members shall be free to determine the appropriate method

  16. Cleavage mechanism and anti-tumor activity of 3,6-epidioxy-1,10-bisaboladiene isolated from edible wild plants.

    Science.gov (United States)

    Kimura, Ken-ichi; Sakamoto, Yoshimi; Fujisawa, Nozomi; Uesugi, Shota; Aburai, Nobuhiro; Kawada, Manabu; Ohba, Shun-ichi; Yamori, Takao; Tsuchiya, Eiko; Koshino, Hiroyuki

    2012-06-15

    A bisabolane sesquiterpene endoperoxide compound, 3,6-epidioxy-1,10-bisaboladiene (EDBD), was isolated from edible wild plants grown in the northern area of Japan, Cacalia delphiniifolia and Cacalia hastata, using a mutant yeast (cdc2-1 rad9Δ). It showed cytotoxicity at IC(50) = 3.4 μM and induced apoptosis against the human promyelocytic leukemia cell line HL60 through a new stable rearrangement product (1) when in the presence of FeSO(4). This conversion mechanism is different from another sesquiterpene endoperoxide lactone compound, dihydroartemisinin (DHA), which is an anti-malarial drug. The cytotoxicity of EDBD decreased in the presence of the ferrous ion chelating drug deferoxamine mesylate (DFOM), and this suggested that the structural change of the drug caused by Fe(2+) may be responsible for its biological activities. EDBD induced apoptosis via phosphorylation of p38 mitogen-activated protein kinase (MAPK) in HL60 cells, and was detected by Western blot. EDBD resulted in an immediate increase in DCF fluorescence intensity in HL60 cells using DCFH-DA (2',7'-dichlorofluorescin diacetate) assay. The in vitro reaction of EDBD with FeSO(4) also increased DCF fluorescence intensity in a dose dependent manner. These results showed that the biological activity of EDBD involves an unstable carbon-centered radical intermediate. Furthermore, there was no similarity between the JFCR39 fingerprints of EDBD and DHA (correlation coefficient on COMPARE Analysis γ = 0.158). EDBD showed anti-tumor effects against a xenograft of Lox-IMVI cells in vivo. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Concentrations of danofloxacin 18% solution in plasma, milk and tissues after subcutaneous injection in dairy cows

    Energy Technology Data Exchange (ETDEWEB)

    Mestorino, N. [Pharmacology Department, Faculty of Veterinary Science, Universidad Nacional de La Plata, CC 296, 1900 La Plata, Buenos Aires (Argentina)], E-mail: nmestorino@yahoo.com; Marchetti, M.L.; Turic, E.; Pesoa, J.; Errecalde, J. [Pharmacology Department, Faculty of Veterinary Science, Universidad Nacional de La Plata, CC 296, 1900 La Plata, Buenos Aires (Argentina)

    2009-04-01

    Danofloxacin is a fluoroquinolone developed for use in veterinary medicine. Its concentrations and pharmacokinetic profile in plasma, milk and tissues of lactating dairy cows were determined, and its milk withdrawal time (WT) calculated. Twenty-one dairy cows received a single subcutaneous administration of 18% mesylate danofloxacin salt (6 mg kg{sup -1}). Plasma and milk samples were obtained at different times until 48 h. Groups of three animals were sacrificed at different post-administration times and tissue samples (mammary gland, uterus, duodenum, jejunum, ileum, colon and mesenteric lymph nodes) obtained. Danofloxacin concentrations were determined by liquid chromatography with fluorescence detection. The milk WT was calculated by the Time to Safe Concentration method (Software WTM 1.4, EMEA). Danofloxacin was rapidly absorbed and its distribution from plasma to all sampled tissues and milk was extensive. Milk and tissues concentrations were several times above those found in plasma. Plasma area under the curve (AUCp) was 9.69 {mu}g h mL{sup -1} and its elimination half life (T{sub {beta}}{sup 1/2}) was 12.53 h. AUC values for the various tissues and milk greatly exceeded AUCp. T{sub {beta}}{sup 1/2} from milk and tissues ranged between 4.57 and 21.91 h and the milk withdrawal time was 73.48 h. The reported results support the potential use of danofloxacin in the treatment of mastitis and other infections in milk cows with 3 days of withdrawal.

  18. Protective Effects of Imatinib on Ischemia/Reperfusion Injury in Rat Lung.

    Science.gov (United States)

    Tanaka, Satona; Chen-Yoshikawa, Toyofumi F; Kajiwara, Moto; Menju, Toshi; Ohata, Keiji; Takahashi, Mamoru; Kondo, Takeshi; Hijiya, Kyoko; Motoyama, Hideki; Aoyama, Akihiro; Masuda, Satohiro; Date, Hiroshi

    2016-11-01

    Ischemia/reperfusion injury (IRI) remains a significant complication after lung transplantation. Endothelial damage and inflammation contribute to its development. Imatinib has been reported to regulate vascular permeability by maintaining endothelial junctions and showing antiinflammatory effects through inhibition of the Abl kinases. We hypothesized that imatinib could have a protective effect against IRI. Male Lewis rats were heparinized and underwent left thoracotomy, and the left hilum was clamped for 90 minutes followed by reperfusion for 120 minutes. Imatinib mesylate (50 mg/kg) and a solvent were administered intraperitoneally 20 minutes before ischemia in the imatinib group and the vehicle group, respectively (n = 7 in each group). After reperfusion, lung function, lung wet to dry weight (W/D) ratio, and histologic findings were obtained. The expression of vascular endothelial cadherin (VEC), the phosphorylation level of CrkL (pCrkL) (an exclusive target of Abl kinases), and the cytokine level were evaluated using lung tissue lysate. The imatinib concentrations of plasma and lungs after reperfusion were measured in this hilar clamp model (n = 7). In the imatinib group, lung function was improved with a lower W/D ratio. Perivascular edema and neutrophil infiltration were ameliorated. The imatinib group demonstrated maintained expression of VEC, inhibition of pCrkL, and a significantly higher level of interleukin (IL)-10. The imatinib concentration in both lungs showed a strong correlation with plasma concentration. In a rat IRI model, imatinib attenuated lung injury by an antipermeability and antiinflammatory effect. The delivery and function of imatinib in the lung was also confirmed in this model. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  19. Determination of the side-reaction coefficient of desferrioxamine B in trace-metal-free seawater

    Directory of Open Access Journals (Sweden)

    Johan Schijf

    2016-07-01

    Full Text Available Electrochemical techniques like adsorptive cathodic stripping voltammetry with competitive ligand equilibration (ACSV-CLE can determine total concentrations of marine organic ligands and their conditional binding constants for specific metals, but cannot identify them. Individual organic ligands, isolated from microbial cultures or biosynthesized through genomics, can be structurally characterized via NMR and tandem MS analysis, but this is tedious and time-consuming. A complementary approach is to compare known properties of natural ligands, particularly their conditional binding constants, with those of model organic ligands, measured under suitable conditions. Such comparisons cannot be meaningfully interpreted unless the side-reaction coefficient (SRC of the model ligand in seawater is thoroughly evaluated.We conducted series of potentiometric titrations, in non-coordinating medium at seawater ionic strength (0.7 M NaClO4 over a range of metal:ligand molar ratios, to study complexation of the siderophore desferrioxamine B (DFOB with Mg and Ca, for which it has the highest affinity among the major seasalt cations. From similar titrations of acetohydroxamic acid in the absence and presence of methanesulfonate (mesylate, it was determined that Mg and Ca binding to this common DFOB counter-ion is not strong enough to interfere with the DFOB titrations. Stability constants were measured for all DFOB complexes with Mg and Ca including, for the first time, the bidentate complexes. No evidence was found for Mg and Ca coordination with the DFOB terminal amine. From the improved DFOB speciation, we calculated five SRCs for each of the five (deprotonated forms of DFOB in trace-metal-free seawater, yet we also present a more convenient definition of a single SRC that allows adjustment of all DFOB stability constants to seawater conditions, no matter which of these forms is selected as the 'component' (reference species. An example of Cd speciation in

  20. Is low-dose amitriptyline effective in the management of chronic low back pain? Study protocol for a randomised controlled trial.

    Science.gov (United States)

    Urquhart, Donna M; Wluka, Anita E; Sim, Malcolm R; van Tulder, Maurits; Forbes, Andrew; Gibson, Stephen J; Arnold, Carolyn; Fong, Chris; Anthony, Shane N; Cicuttini, Flavia M

    2016-10-22

    Low back pain is a major clinical and public health problem, with limited evidence-based treatments. Low-dose antidepressants are commonly used to treat pain in chronic low back pain. However, their efficacy is unproven. The aim of this pragmatic, double-blind, randomised, placebo-controlled trial is to determine whether low-dose amitriptyline (an antidepressant) is more effective than placebo in reducing pain in individuals with chronic low back pain. One hundred and fifty individuals with chronic low back pain will be recruited through hospital and private medical and allied health clinics, advertising in local media and posting of flyers in community locations. They will be randomly allocated to receive either low-dose amitriptyline (25 mg) or an active placebo (benztropine mesylate, 1 mg) for 6 months. The primary outcome measure of pain intensity will be assessed at baseline, 3 and 6 months using validated questionnaires. Secondary measures of self-reported low back disability, work absence and hindrance in the performance of paid/unpaid work will also be examined. Intention-to-treat analyses will be performed. This pragmatic, double-blind, randomised, placebo-controlled trial will provide evidence regarding the effectiveness of low-dose antidepressants compared with placebo in reducing pain, disability, work absenteeism and hindrance in work performance in individuals with chronic low back pain. This trial has major public health and clinical importance as it has the potential to provide an effective approach to the management of chronic low back pain. Australian New Zealand Clinical Trials Registry: ACTRN12612000131853 ; registered on 30 January 2012.

  1. 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.

  2. Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients

    International Nuclear Information System (INIS)

    Ferraresi, Virginia; Biagini, Roberto; Nuzzo, Carmen; Zoccali, Carmine; Marandino, Ferdinando; Vidiri, Antonello; Salducca, Nicola; Zeuli, Massimo; Giannarelli, Diana; Cognetti, Francesco

    2010-01-01

    Adequate surgery still remains the only curative treatment of chordoma. Interesting clinical data on advanced disease with molecularly targeted therapies were reported. We described the clinical outcome of a series of chordoma patients followed at Regina Elena National Cancer Centre of Rome from 2004 to 2008. Twenty-five consecutive patients with sacral (11 patients), spine (13 patients), and skull base (1 patient) chordoma went to our observation. Six patients (24%) had primary disease, 14(56%) a recurrent disease, and 5(20%) a metastatic spreading. Surgery was the primary option for treatment in 22 out of 25 patients. Surgical margins were wide in 5 (23%) and intralesional in 17(77%) patients; 3 out of 4 in-house treated patients obtained wide margins. After first surgery, radiotherapy (protons or high-energy photons) were delivered to 3 patients. One out of the 5 patients with wide margins is still without evidence of disease at 20 months from surgery; 2 patients died without evidence of disease after 3 and 36 months from surgery. Sixteen out of 17 (94%) patients with intralesional margins underwent local progression at a median time of 18 months with a 2-year local progression-free survival of 47%. The 5-year metastasis-free survival rate was 78.3%. Seventeen patients with locally advanced and/or metastatic disease expressing platelet-derived growth factor receptor (PDGFR) β were treated with imatinib mesylate. A RECIST stabilization of the disease was the best response observed in all treated cases. Pain relief with reduction in analgesics use was obtained in 6 out of 11 (54%) symptomatic patients. The 5- and 10-year survival rates of the entire series of patients were 76.7 and 59.7%, respectively. Despite progress of surgical techniques and the results obtained with targeted therapy, more effort is needed for better disease control. Specific experience of the multidisciplinar therapeutic team is, however, essential to succeed in improving patients

  3. The effects of chemotherapeutic agents on differentiated chordoma cells.

    Science.gov (United States)

    Bayrak, Omer Faruk; Aydemir, Esra; Gulluoglu, Sukru; Sahin, Fikrettin; Sevli, Serhat; Yalvac, Mehmet Emir; Acar, Hasan; Ozen, Mustafa

    2011-12-01

    Chordoma is a rare type of malignant bone tumor and is known to arise from the remnants of the notochord. Resistance to chemotherapy makes the treatment of chordoma difficult; therefore, new approaches need to be developed to cure this disease. Differentiation therapy, using various differentiating agents, is attracting oncologists as a common therapeutic method to treat other tumors. Based on forcing cells to mature into other lineages, differentiation therapy might be an available method to treat chordomas in addition to conventional therapies. In this study a chordoma cell line, U-CH1, was exposed to several chemotherapeutic agents including vincristine, doxorubicin, cisplatin, etoposide, fludarabine, methotrexate, nilotinib, and imatinib mesylate under appropriate conditions. The first group of U-CH1 cells was exposed to drugs only and the second group of cells was exposed to the simultaneous treatment of 1 μM all-trans retinoic acid (ATRA) and chemotherapeutic agents in differentiation therapy. The efficacy of the differentiation method was assessed by measuring the viability of U-CH1 cells. Vincristine, doxorubicin, etoposide, cisplatin, and fludarabine, each at a concentration of 10 μM, decreased the number of chordoma cells when given alone down to 11%, 0%, 30%, 67%, and 3%, respectively. Etoposide and cisplatin, each at a concentration of 10 μM, reduced the percentage of viable chordoma cells in a more effective way when given with 1 μM ATRA simultaneously, reducing the number of viable cells to 14% and 9%, respectively. On the other hand, imatinib and nilotinib, each at a concentration of 3 μM, as well as 10 μM methotrexate, showed no decrease in the number of cancer cells. The results suggest that chordoma cells may be treated using the differentiation method in a more effective way than when they are treated with chemotherapeutic agents alone. This new approach may be an alternative method to conventional therapies in the treatment of chordoma.

  4. Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients.

    Science.gov (United States)

    Ferraresi, Virginia; Nuzzo, Carmen; Zoccali, Carmine; Marandino, Ferdinando; Vidiri, Antonello; Salducca, Nicola; Zeuli, Massimo; Giannarelli, Diana; Cognetti, Francesco; Biagini, Roberto

    2010-01-28

    Adequate surgery still remains the only curative treatment of chordoma. Interesting clinical data on advanced disease with molecularly targeted therapies were reported. We described the clinical outcome of a series of chordoma patients followed at Regina Elena National Cancer Centre of Rome from 2004 to 2008. Twenty-five consecutive patients with sacral (11 patients), spine (13 patients), and skull base (1 patient) chordoma went to our observation. Six patients (24%) had primary disease, 14(56%) a recurrent disease, and 5(20%) a metastatic spreading. Surgery was the primary option for treatment in 22 out of 25 patients. Surgical margins were wide in 5 (23%) and intralesional in 17(77%) patients; 3 out of 4 in-house treated patients obtained wide margins. After first surgery, radiotherapy (protons or high-energy photons) were delivered to 3 patients. One out of the 5 patients with wide margins is still without evidence of disease at 20 months from surgery; 2 patients died without evidence of disease after 3 and 36 months from surgery. Sixteen out of 17 (94%) patients with intralesional margins underwent local progression at a median time of 18 months with a 2-year local progression-free survival of 47%. The 5-year metastasis-free survival rate was 78.3%. Seventeen patients with locally advanced and/or metastatic disease expressing platelet-derived growth factor receptor (PDGFR) beta were treated with imatinib mesylate. A RECIST stabilization of the disease was the best response observed in all treated cases. Pain relief with reduction in analgesics use was obtained in 6 out of 11 (54%) symptomatic patients. The 5- and 10-year survival rates of the entire series of patients were 76.7 and 59.7%, respectively. Despite progress of surgical techniques and the results obtained with targeted therapy, more effort is needed for better disease control. Specific experience of the multi-disciplinary therapeutic team is, however, essential to succeed in improving patients

  5. Cessation of tyrosine kinase inhibitors in patients with chronic-phase chronic myelogenous leukemia following durable complete molecular response: a single center facing the dilemma.

    Science.gov (United States)

    Iliakis, Theodoros; Papadopoulou, Vasiliki; Diamantopoulos, Panagiotis T; Panayiotidis, Panayiotis; Zervakis, Konstantinos; Giannakopoulou, Nefeli; Tilimidos, Gerassimos; Angelopoulou, Maria; Siakantaris, Marina P; Pangalis, Gerassimos; Mantzourani, Marina; Variami, Eleni; Viniou, Nora Athina

    2013-08-01

    Tyrosine kinase inhibitors (TKIs), namely imatinib mesylate (IM) and recently approved second-generation TKIs dasatinib and nilotinib, are currently considered the treatment of choice for newly-diagnosed chronic phase chronic myelogenous leukemia (CP-CML). Although treatment with TKIs has not yet been proven curative, it certainly accomplishes a sustained control of the disease in the vast majority of patients. More than a decade after the successful launching of IM in first-line treatment of CP-CML and the subsequent introduction of second-generation TKIs in this setting, the question of the possibility of TKI cessation in a specific subset of patients has emerged. Side-effects of TKIs, along with some patients' wish to abandon the drugs and the rising financial burden upon healthcare systems, have led to the dilemma whether IM can be safely withdrawn after achieving deep molecular remissions and which patients are suitable for this discontinuation. We examined the data of our patients with CML in search of potential canditates for cessation of TKI therapy and identified their characteristics. We also performed a thorough review of the relevant literature. Eight out of fifty patients were discriminated on grounds of sustained complete molecular response (CMR) exceeding 12 months, most of them with a low or intermediate Sokal score at diagnosis. The median interval from IM initiation to CMR was almost 2 years and the median duration of detected CMR reached 6.5 years. Based on the promising results of prospective clinical trials reporting successful cessation of treatment with TKIs on selected subgroups of patients, we decided to proceed to interruption of therapy in the specific subset of our patients and closely monitor their response.

  6. Caffeic acid, morin hydrate and quercetin partially attenuate sulfur mustard-induced cell death by inhibiting the lipoxygenase pathway.

    Science.gov (United States)

    Kim, Shin; Jeong, Kwang-Joon; Cho, Sung Kweon; Park, Joo-Won; Park, Woo-Jae

    2016-11-01

    Sulfur mustard (SM) is an alkylating agent, which has been used as in chemical warfare in a number of conflicts. As the generation of reactive oxygen species (ROS), and adducts in DNA and proteins have been suggested as the mechanism underlying SM‑induced cytotoxicity, the present study screened several antioxidant candidates, including tannic acid, deferoxamine mesylate, trolox, vitamin C, ellagic acid and caffeic acid (CA) to assess their potential as therapeutic agents for SM‑induced cell death. Among several antioxidants, CA partially alleviated SM‑induced cell death in a dose‑dependent manner. Although CA treatment decreased the phosphorylation of p38 mitogen‑activated protein (MAP) kinase and p53, p38 MAP kinase inhibition by SB203580 did not affect SM‑induced cell death. As CA has also been reported as a 15‑lipoxygenase (15‑LOX) inhibitor, the role of 15‑LOX in SM‑induced cytotoxicity was also examined. Similar to the results observed with CA, treatment with PD146176, a specific 15‑LOX inhibitor, decreased SM‑induced cytotoxicity, accompanied by decreases in the production of tumor necrosis factor‑α and 15‑hydroxyeicosatetraenoic acid. Furthermore, the present study investigated the protective effects of two natural 15‑LOX inhibitors, morin hydrate and quercetin, in SM‑induced cytotoxicity. As expected, these inhibitors had similar protective effects against SM‑induced cytotoxicity. These antioxidants also reduced the generation of ROS and nitrate/nitrite. Therefore, the results of the present study indicated that the natural products, CA, quercetin and morin hydrate, offer potential as adjuvant therapeutic agents for SM‑induced toxicity, not only by reducing inflammation mediated by the p38 and LOX signaling pathways, but also by decreasing the generation of ROS and nitrate/nitrite.

  7. Use of deferasirox, an iron chelator, to overcome imatinib resistance of chronic myeloid leukemia cells

    Science.gov (United States)

    Kim, Dae Sik; Na, Yoo Jin; Kang, Myoung Hee; Yoon, Soo-Young; Choi, Chul Won

    2016-01-01

    Background/Aims: The treatment of chronic myeloid leukemia (CML) has achieved impressive success since the development of the Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate. Nevertheless, resistance to imatinib has been observed, and a substantial number of patients need alternative treatment strategies. Methods: We have evaluated the effects of deferasirox, an orally active iron chelator, and imatinib on K562 and KU812 human CML cell lines. Imatinib-resistant CML cell lines were created by exposing cells to gradually increasing concentrations of imatinib. Results: Co-treatment of cells with deferasirox and imatinib induced a synergistic dose-dependent inhibition of proliferation of both CML cell lines. Cell cycle analysis showed an accumulation of cells in the subG1 phase. Western blot analysis of apoptotic proteins showed that co-treatment with deferasirox and imatinib induced an increased expression of apoptotic proteins. These tendencies were clearly identified in imatinib-resistant CML cell lines. The results also showed that co-treatment with deferasirox and imatinib reduced the expression of BcrAbl, phosphorylated Bcr-Abl, nuclear factor-κB (NF-κB) and β-catenin. Conclusions: We observed synergistic effects of deferasirox and imatinib on both imatinib-resistant and imatinib-sensitive cell lines. These effects were due to induction of apoptosis and cell cycle arrest by down-regulated expression of NF-κB and β-catenin levels. Based on these results, we suggest that a combination treatment of deferasirox and imatinib could be considered as an alternative treatment option for imatinib-resistant CML. PMID:26874514

  8. Exploratory evaluation of two-dimensional and three-dimensional methods of FDG PET quantification in pediatric anaplastic astrocytoma: a report from the Pediatric Brain Tumor Consortium (PBTC)

    Energy Technology Data Exchange (ETDEWEB)

    Williams, Gethin; Treves, S. Ted [Harvard Medical School, Joint Program in Nuclear Medicine, Children' s Hospital Boston, Boston, MA (United States); Fahey, Frederic H. [Harvard Medical School, Joint Program in Nuclear Medicine, Children' s Hospital Boston, Boston, MA (United States); Harvard Medical School, Division of Nuclear Medicine, Department of Radiology, Children' s Hospital Boston, Boston, MA (United States); Kocak, Mehmet; Boyett, James M.; Kun, Larry E. [St Jude Children' s Research Hospital, Memphis, TN (United States); Pollack, Ian F. [Children' s Hospital Pittsburgh, Pittsburgh, PA (United States); Young Poussaint, Tina [Harvard Medical School, Division of Neuroradiology, Department of Radiology, Children' s Hospital Boston, Boston, MA (United States)

    2008-09-15

    The rationale of this study was to investigate the feasibility of three-dimensional (3D) methods to analyze {sup 18}F-fluoro-deoxy-glucose (FDG) uptake in children with anaplastic astrocytoma (AA) in a multi-institutional trial, to compare 3D and two-dimensional (2D) methods and explore data associations with progression-free survival (PFS). 3D tumor volumes from pretreatment MR images (fluid attenuation inversion recovery and postgadolinium) of children with recurrent AA on a phase I trial of imatinib mesylate were coregistered to FDG positron emission tomography (PET) images. PET data were normalized. Four metrics were defined: the maximum ratio (maximum pixel value within the 3D tumor volume, normalized), the total ratio (cumulative pixel values within the tumor volume, normalized) and tumor mean ratio (total pixel value divided by volume, normalized). 2D analysis methods were compared. Cox proportional hazards models were used to estimate the association between these methods and PFS. Strongest correlations between 2D and 3D methods were with analyses using postcontrast T1 images for volume of interest (VOI). The analyses suggest 3D maximum tumor and mean tumor ratios, whether normalized by gray matter or white matter, were associated with PFS. This study of a series of pretreatment AA patients suggests that 3D PET methods using VOIs based on postcontrast T1 correlate with 2D methods and are related to PFS. These methods yield an estimate of metabolically active tumor burden and may add prognostic information after tumor grade is determined. Future rigorous multi-institutional protocols with larger numbers of patients will be required for validation. (orig.)

  9. Efficacy and Economic Value of Adjuvant Imatinib for Gastrointestinal Stromal Tumors

    Science.gov (United States)

    Gronchi, Alessandro

    2013-01-01

    Objective. This article presents the clinical effectiveness and cost-effectiveness of the use of adjuvant imatinib mesylate for treating patients with localized primary gastrointestinal stromal tumors (GISTs) and discusses the impact of prolonged treatment with adjuvant imatinib on health care costs. Methods. A systematic review of the medical literature was conducted to explore recently reported clinical trials demonstrating the clinical benefit of adjuvant imatinib in GISTs, along with analyses discussing the economic impact of adjuvant imatinib. Results. Two phase III trials have demonstrated a significant clinical benefit of adjuvant imatinib treatment in GIST patients at risk of recurrence after tumor resection. Guidelines now suggest adjuvant treatment for at least 3 years in patients at high risk of recurrence. Despite this clinical effectiveness, prolonged use of adjuvant imatinib can lead to an increase in the risk for adverse events and to increased costs for both patients and health care systems. However, the increased cost is partially offset by cost reductions associated with delayed or avoided GIST recurrences. Three years of adjuvant treatment in high-risk patients was concluded to be cost-effective. Therefore, the careful selection of patients who are most likely to benefit from treatment can lead to improved clinical outcomes and significant cost savings. Conclusion. Although introducing adjuvant imatinib has an economic impact on health plans, this effect seems to be limited. Several analyses have demonstrated that adjuvant imatinib is more cost-effective for treating localized primary GISTs than surgery alone. In addition, 3 years of adjuvant imatinib is more cost-effective than 1 year of adjuvant therapy. PMID:23709752

  10. Imatinib Reverses Doxorubicin Resistance by Affecting Activation of STAT3-Dependent NF-κB and HSP27/p38/AKT Pathways and by Inhibiting ABCB1

    Science.gov (United States)

    Sims, Jonathan T.; Ganguly, Sourik S.; Bennett, Holly; Friend, J. Woodrow; Tepe, Jessica; Plattner, Rina

    2013-01-01

    Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis. PMID:23383209

  11. microRNA expression signatures of gastrointestinal stromal tumours: associations with imatinib resistance and patient outcome

    Science.gov (United States)

    Akçakaya, P; Caramuta, S; Åhlen, J; Ghaderi, M; Berglund, E; Östman, A; Bränström, R; Larsson, C; Lui, W-O

    2014-01-01

    Background: Gastrointestinal stromal tumour (GIST) is mainly initialised by receptor tyrosine kinase gene mutations. Although the tyrosine kinase inhibitor imatinib mesylate considerably improved the outcome of patients, imatinib resistance still remains a major therapeutic challenge in GIST therapy. Herein we evaluated the clinical impact of microRNAs in imatinib-treated GISTs. Methods: The expression levels of microRNAs were quantified using microarray and RT–qPCR in GIST specimens from patients treated with neoadjuvant imatinib. The functional roles of miR-125a-5p and PTPN18 were evaluated in GIST cells. PTPN18 expression was quantified by western blotting in GIST samples. Results: We showed that overexpression levels of miR-125a-5p and miR-107 were associated with imatinib resistance in GIST specimens. Functionally, miR-125a-5p expression modulated imatinib sensitivity in GIST882 cells with a homozygous KIT mutation but not in GIST48 cells with double KIT mutations. Overexpression of miR-125a-5p suppressed PTPN18 expression, and silencing of PTPN18 expression increased cell viability in GIST882 cells upon imatinib treatment. PTPN18 protein levels were significantly lower in the imatinib-resistant GISTs and inversely correlated with miR-125a-5p. Furthermore, several microRNAs were significantly associated with metastasis, KIT mutational status and survival. Conclusions: Our findings highlight a novel functional role of miR-125a-5p on imatinib response through PTPN18 regulation in GIST. PMID:25349971

  12. Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    Seshadri Ramakrishnan

    2009-01-01

    Full Text Available Aim : To study the role of neoadjuvant imatinib mesylate in downsizing tumors in patients with locally advanced nonmetastatic gastrointestinal stromal tumors (GISTs, thus improving the possibility of complete resection. Materials and Methods : We used neoadjuvant imatinib in six patients with locally advanced GISTs, at a dose of 400 mg daily, given orally in all patients for a median period of 3.5 months (range 1-20 months. All patients had a computerized tomography scan (CT scan once before starting the treatment and a repeat CT scan 1 month after starting imatinib. Some patients had another CT scan done at 3 months. The tumor volume was calculated using the formula V=4/3 πr 3 . Results : Following imatinib therapy, the median reduction in the tumor volume was 40% (range 20-50%. Four of the six patients underwent successful complete resection of the tumor following neoadjuvant imatinib for a median period of 2 months, and are disease free after a median follow-up of 10.5 months (range 3-20 months. Two patients in whom the tumors were deemed to be operable after downsizing refused surgery and are continuing imatinib. Imatinib did not produce serious toxicity in any patient. Conclusion : Neoadjuvant imatinib can be used successfully in patients with locally advanced nonmetastatic GISTs to improve the rates of complete resection and reduce the chance of tumor spill. The optimal duration of neoadjuvant treatment needs to be tailored based on response assessment at frequent intervals to identify the ideal window period for surgery.

  13. Quantitative- and Phospho-Proteomic Analysis of the Yeast Response to the Tyrosine Kinase Inhibitor Imatinib to Pharmacoproteomics-Guided Drug Line Extension

    Science.gov (United States)

    dos Santos, Sandra C.; Mira, Nuno P.; Moreira, Ana S.

    2012-01-01

    Abstract Imatinib mesylate (IM) is a potent tyrosine kinase inhibitor used as front-line therapy in chronic myeloid leukemia, a disease caused by the oncogenic kinase Bcr-Abl. Although the clinical success of IM set a new paradigm in molecular-targeted therapy, the emergence of IM resistance is a clinically significant problem. In an effort to obtain new insights into the mechanisms of adaptation and tolerance to IM, as well as the signaling pathways potentially affected by this drug, we performed a two-dimensional electrophoresis-based quantitative- and phospho-proteomic analysis in the eukaryotic model Saccharomyces cerevisiae. We singled out proteins that were either differentially expressed or differentially phosphorylated in response to IM, using the phosphoselective dye Pro-Q® Diamond, and identified 18 proteins in total. Ten were altered only at the content level (mostly decreased), while the remaining 8 possessed IM-repressed phosphorylation. These 18 proteins are mainly involved in cellular carbohydrate processes (glycolysis/gluconeogenesis), translation, protein folding, ion homeostasis, and nucleotide and amino acid metabolism. Remarkably, all 18 proteins have human functional homologs. A role for HSP70 proteins in the response to IM, as well as decreased glycolysis as a metabolic marker of IM action are suggested, consistent with findings from studies in human cell lines. The previously-proposed effect of IM as an inhibitor of vacuolar H+-ATPase function was supported by the identification of an underexpressed protein subunit of this complex. Taken together, these findings reinforce the role of yeast as a valuable eukaryotic model for pharmacological studies and identification of new drug targets, with potential clinical implications in drug reassignment or line extension under a personalized medicine perspective. PMID:22775238

  14. Receptor tyrosine kinase inhibition causes simultaneous bone loss and excess bone formation within growing bone in rats

    International Nuclear Information System (INIS)

    Nurmio, Mirja; Joki, Henna; Kallio, Jenny; Maeaettae, Jorma A.; Vaeaenaenen, H. Kalervo; Toppari, Jorma; Jahnukainen, Kirsi; Laitala-Leinonen, Tiina

    2011-01-01

    During postnatal skeletal growth, adaptation to mechanical loading leads to cellular activities at the growth plate. It has recently become evident that bone forming and bone resorbing cells are affected by the receptor tyrosine kinase (RTK) inhibitor imatinib mesylate (STI571, Gleevec (registered) ). Imatinib targets PDGF, ABL-related gene, c-Abl, c-Kit and c-Fms receptors, many of which have multiple functions in the bone microenvironment. We therefore studied the effects of imatinib in growing bone. Young rats were exposed to imatinib (150 mg/kg on postnatal days 5-7, or 100 mg/kg on postnatal days 5-13), and the effects of RTK inhibition on bone physiology were studied after 8 and 70 days (3-day treatment), or after 14 days (9-day treatment). X-ray imaging, computer tomography, histomorphometry, RNA analysis and immunohistochemistry were used to evaluate bone modeling and remodeling in vivo. Imatinib treatment eliminated osteoclasts from the metaphyseal osteochondral junction at 8 and 14 days. This led to a resorption arrest at the growth plate, but also increased bone apposition by osteoblasts, thus resulting in local osteopetrosis at the osteochondral junction. The impaired bone remodelation observed on day 8 remained significant until adulthood. Within the same bone, increased osteoclast activity, leading to bone loss, was observed at distal bone trabeculae on days 8 and 14. Peripheral quantitative computer tomography (pQCT) and micro-CT analysis confirmed that, at the osteochondral junction, imatinib shifted the balance from bone resorption towards bone formation, thereby altering bone modeling. At distal trabecular bone, in turn, the balance was turned towards bone resorption, leading to bone loss. - Research highlights: → 3-Day imatinib treatment. → Causes growth plate anomalies in young rats. → Causes biomechanical changes and significant bone loss at distal trabecular bone. → Results in loss of osteoclasts at osteochondral junction.

  15. Structural organization of the human glucocorticoid receptor determined by one- and two-dimensional gel electrophoresis of proteolytic receptor fragments

    International Nuclear Information System (INIS)

    Smith, A.C.; Harmon, J.M.

    1987-01-01

    The structural organization of the steroid-binding protein of the IM-9 cell glucocorticoid receptor was investigated by using one- and two-dimensional gel electrophoresis of proteolytic receptor fragments. One-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of receptor fragments isolated after trypsin digestion of immunopurified [ 3 H]dexamethasone 21-mesylate ([ 3 H]DM-) labeled receptor revealed the presence of a stable 26.5-kilodalton (kDa) steroid-containing non-DNA-binding fragment, derived from a larger, less stable, 29-kDa fragment. The 26.5-kDa tryptic fragment appeared to be completely contained within a 41-kDa, steroid-containing, DNA-binding species isolated after chymotrypsin digestion of the intact protein. Two-dimensional electrophoretic analysis of the [ 3 H]DM-labeled tryptic fragments resolved two 26.5-kDa and two 29-kDa components. This was the same number of isoforms seen in the intact protein, indicating that the charge heterogeneity of the steroid-binding protein is the result of modification within the steroid-containing, non-DNA-binding, 26.5-kDa tryptic fragment. Two-dimensional analysis of the 41-kDa [ 3 H]DM-labeled chymotryptic species revealed a pattern of isoforms more complex than that seen either in the intact protein or in the steroid-containing tryptic fragments. These results suggest that the 41-kDa [ 3 H]DM-labeled species resolved by one-dimensional SDS-PAGE after chymotrypsin digestion may be composed of several distinct proteolytic fragments

  16. Safety and performance of targeted renal therapy: the Be-RITe! Registry.

    Science.gov (United States)

    Weisz, Giora; Filby, Steven J; Cohen, Mauricio G; Allie, David E; Weinstock, Barry S; Kyriazis, Dimitris; Walker, Craig M; Moses, Jeffrey W; Danna, Paolo; Fearon, William F; Sachdev, Naveen; Wiechmann, Bret N; Vora, Kishor; Findeiss, Laura; Price, Matthew J; Mehran, Roxana; Leon, Martin B; Teirstein, Paul S

    2009-02-01

    To evaluate the safety and patterns of use of targeted renal therapy (TRT) with the Benephit system. TRT, the delivery of therapeutic agents directly to the kidneys by renal arterial infusion, has the advantage of providing a higher local effective dose with potentially greater renal effects, while limiting systemic adverse effects due to renal first-pass elimination. The Benephit System Renal Infusion Therapy (Be-RITe!) Multicenter Registry was a post-market registry following patients treated using the Benephit systems for TRT. The registry enrolled 501 patients (332 men; mean age 72.2+/-9.5 years) at high risk for contrast-induced nephropathy (CIN) during coronary or peripheral angiography/intervention or cardiovascular surgery. The Mehran score was used to compare the actual to predicted incidence of CIN within 48 hours post procedure. Bilateral renal artery cannulation was successful in 94.2%, with a mean cannulation time of 2.0 minutes. Either fenoldopam mesylate, sodium bicarbonate, alprostadil, or B-type natriuretic peptide (BNP) was infused for 184+/-212 minutes. Mean creatinine levels did not change significantly (baseline, 24, and 48 hours post procedure: 1.95, 1.99, and 1.98 mg/dL, respectively; p = NS). In 285 patients who received TRT with fenoldopam and were followed for at least 48 hours, the incidence of CIN was 71% lower than predicted (8.1% actual CIN versus 28.0% predicted; p<0.0001). Only 4 (1.4%) patients required dialysis (versus the 2.6% predicted rate, p = NS). The Benephit system and TRT during coronary and endovascular procedures in patients at high risk for renal failure is simple to use and safe. With the infusion of intrarenal fenoldopam, the incidence of CIN was significantly lower than predicted by risk score calculations.

  17. Chiral multidentate oxazoline ligands based on cyclophosphazene cores: synthesis, characterization and complexation studies.

    Science.gov (United States)

    Kumar, Dheeraj; Singh, Jatinder; Elias, Anil J

    2014-10-07

    Chiral oxazoline based bi and hexadentate ligands built on cyclophosphazene cores have been synthesized and characterized. (NPPh2)2[NP(m-OC6H4C(O)OCH3)2] (1) was prepared by the reaction of gem-(NPPh2)2(NPCl2) with methyl-3-hydroxy benzoate in the presence of Cs2CO3. Compound 1 was converted to the dicarboxylic acid (NPPh2)2[NP(m-OC6H4C(O)OH)2] (2) by base promoted hydrolysis with KO(t-Bu). The dicarboxylic acid 2 on reaction with oxalyl chloride followed by (S)-(+)-2-amino-3-methyl-1-butanol, triethylamine and mesyl chloride was converted to the C2-symmetric phosphazene based chiral bisoxazoline ligand (NPPh2)2[NP{m-OC6H4(4-iPr-2-Ox)}2] (3) (Ox = oxazolinyl). A similar C2-symmetric bisoxazoline derivative having an oxazoline group attached to the para position of the phenyl ring was also synthesized starting from (NPPh2)2[NP(p-OC6H4C(O)OCH3)2] (4) which was first converted to the dicarboxylic acid (NPPh2)2[NP(p-OC6H4C(O)OH)2] (5) and finally to (NPPh2)2[NP{p-OC6H4(4-iPr-2-Ox)}2] (6) and (NPPh2)2[NP{p-OC6H4(4-Ph-2-Ox)}2] (7) under similar reaction conditions. Reaction of 6 with Pd(OAc)2 in acetic acid at room temperature and with PdCl2(C6H5CN)2 in refluxing benzene resulted in chiral palladium complexes Pd(OAc)2(NPPh2)2[NP{p-OC6H4(4-iPr-2-Ox)}2] (8) and PdCl2(NPPh2)2[NP{p-OC6H4(4-iPr-2-Ox)}2] (9), respectively. The utility of these palladium complexes as chiral catalysts for the asymmetric rearrangement of trichloroacetimidates to trichloroacetamides has been explored. The hexa(methylbenzoate) derivative of cyclophosphazene [PN(OC6H4COOCH3)2]3 (10) on treatment with KO(t-Bu) and H2O gave the hexacarboxylic acid derivative [PN(OC6H4COOH)2]3 (11), which on treatment with oxalyl chloride followed by (S)-(+)-2-amino-3-methyl-1-butanol/(S)-(+)-2-phenylglycinol, triethylamine and mesyl chloride was converted to the C3-symmetric cyclophosphazene based chiral hexaoxazoline ligands [PN{OC6H4(4-iPr-2-Ox)}2]3 (12) and [PN{OC6H4(4-Ph-2-Ox)}2]3 (13). The bis(phebox) derivative

  18. DETERMINANT VALUE OF THE CYTOGENETIC AND MOLECULAR IMATINIB THERAPEUTIC RESPONSE IN CHRONIC MYELOID LEUKEMIA

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    Angela Dascalescu

    2013-12-01

    Full Text Available The hallmark of chronic myeloid leukemia is the existence of the cytogenetic evidence of the Phyladelphia chromosome (reciprocal translocation between chromosome 9 and 22, and is specifically designated t(9;22(q34;q11. The result of the translocation is the oncogenic BCR-ABL gene fusion, located on the shorter derivative 22 chromosome. This gene encodes the Bcr-abl fusion protein the BCR-ABL tyrosine kinase - a protein that is continuously activated. The result of this unregulated  activation is an unregulated neoplastic type cell division - chronic myeloid leukemia.   The first targeted molecular treatment operating in cancer-  inhibitor of the BCR-ABL tyrosine kinase, Imatinib mesylate, is the standard of care for chronic myeloid leukemia (CML Methods. A retrospective review of patients in one department of hematology with a diagnosis of Ph/BCR-ABL positive CML and received imatinib.  Results. From 2002 to 2012, 66 patients in CML-CP received imatinib were introduced in the study. 22 (33% patients received imatinib as upfront therapy, the others as second or third line treatment. The cytogenetic response (CyR achieved was major in 62% with 56% complete cytogenetic response (CCR, no CyR in 17 patients (25%. The molecular response was complete in 13 (20% and major in 16 (24% patients. Better cytogenetic and molecular responses were achieved by those with low and intermediary risk (Sokal Seven patients developed under imatinib additional cytogenetic anomalies: supplemental chromosome 8 (6, duplication of Ph1 (2, trisomy 17 and 19 (1. The median of follow-up was 69 months (range 18-180 and under imatinib was 52 months (range 3-126. The Sokal score was a better predictor of survival than Hasford’s.  Conclusions. Imatinib remains the best  first line treatment, but there are still a significant number of patients who did not achieve a CyR. The responses and survival were not influenced by the previous treatments but the earlier introduction

  19. Treatment patterns, prescribing decision drivers, and predictors of complete response following disease recurrence in gastrointestinal stromal tumor patients-a chart extract-based approach.

    Science.gov (United States)

    Conley, Anthony Paul; Guerin, Annie; Sasane, Medha; Gauthier, Genevieve; Schwiep, Frances; Keir, Christopher Hunt; Wu, Eric Q

    2014-12-01

    The aim of this study was to investigate tumor characteristics, treatment patterns, and outcomes in recurrent KIT + GIST patients treated in a community practice setting. An online tool was used to retrieve data on 410 patients treated with adjuvant imatinib mesylate (IM) for primary resectable KIT + GIST, who discontinued, had a recurrence, and then restarted IM or initiated sunitinib. Tumor characteristics at recurrence, treatment patterns, and factors associated with post-recurrence complete response (CR) achievement were analyzed. About 72.7 % of patients did not have surgery post-recurrence as majority of them had unresectable (45 %), metastatic (40 %), or multifocal tumors (62.4 %). Following recurrence, 76.6 % of patients were re-started on IM and 23.4 % on sunitinib; patients were 7.37 times more likely to re-start IM if initial treatment duration was ≤18 months (p 12 months post-discontinuation, or they had a recurrence inside the GI system, lower or unknown Fletcher risk score at primary diagnosis, or lower mitotic rate, (odds ratio (OR) = 3.54, p < 0.001; OR = 2.64, p = 0.006; OR = 2.55, p = 0.007; and OR = 2.45, p = 0.002, respectively). About 22.4 % achieved CR; patients were more likely to achieve CR if they had unifocal tumor at recurrence, inside the GI system, of ≤2 cm, or had lower mitotic rate (OR = 2.61, p < 0.001; OR = 2.27, p = 0.036; OR = 2.16, p = 0.023, OR = 1.87, p = 0.017, respectively). IM treatment duration at primary diagnosis, time to develop recurrence after IM discontinuation, tumor location, and mitotic rate at recurrence were the main prescribing decision drivers. Tumor characteristics were the most important factor in achieving CR following c-KIT inhibitor retreatment.

  20. Dasatinib in chronic myeloid leukemia: a review

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    Dolly G Aguilera

    2009-03-01

    Full Text Available Dolly G Aguilera1, Apostolia M Tsimberidou21Department of Hematology-Oncology and Stem Cell Transplantation, Children’s Memorial Hospital, Northwestern University, Chicago, IL, USA; 2Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston Texas USAAbstract: Deregulated BCR-ABL tyrosine kinase (TK activity is the molecular marker for chronic myeloid leukemia (CML, which provides an identifiable target for developing therapeutic agents. Imatinib mesylate, a BCR-ABL TK inhibitor, is the frontline therapy for CML. Despite the stunning efficacy of this agent, a small number of patients develop a suboptimal response or resistance to imatinib. In newly diagnosed patients with chronic phase CML, the rate of resistance to imatinib at 4 years was up to 20%, increasing to 70% to 90% for patients in the accelerated/blastic phase. Resistance to imatinib led to the development of novel TK inhibitors such as dasatinib. Several clinical trials have reported more durable complete hematologic and cytogenetic responses with this agent in patients who are resistant or intolerant to imatinib. Dasatinib is well tolerated and has broad efficacy, resulting in durable responses in patients with any BCR-ABL mutation except for T3151 and mutations in codon 317 – most commonly F317L – including mutations that were highly resistant to imatinib, such as L248, Y253, E255, F359, and H396. Dasatinib is recommended for CML in chronic, blastic or accelerated phase that is resistant or intolerant to imatinib. Dasatinib was approved by the FDA at 100 mg once daily as the starting dose in patients with chronic phase CML and at 70 mg twice daily in patients with accelerated or blastic phase CML. Various clinical trial results provided evidence that resistance to one TK inhibitor can be reversed with the use of a different TK inhibitor (TKI. Other second-generation TKIs with activity in CML include nilotinib, bosutinib and

  1. Huntingtin cleavage product A forms in neurons and is reduced by gamma-secretase inhibitors

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    Betschart Claudia

    2010-12-01

    Full Text Available Abstract Background The mutation in Huntington's disease is a polyglutamine expansion near the N-terminus of huntingtin. Huntingtin expressed in immortalized neurons is cleaved near the N-terminus to form N-terminal polypeptides known as cleavage products A and B (cpA and cpB. CpA and cpB with polyglutamine expansion form inclusions in the nucleus and cytoplasm, respectively. The formation of cpA and cpB in primary neurons has not been established and the proteases involved in the formation of these fragments are unknown. Results Delivery of htt cDNA into the mouse striatum using adeno-associated virus or into primary cortical neurons using lentivirus generated cpA and cpB, indicating that neurons in brain and in vitro can form these fragments. A screen of small molecule protease inhibitors introduced to clonal striatal X57 cells and HeLa cells identified compounds that reduced levels of cpA and are inhibitors of the aspartyl proteases cathepsin D and cathepsin E. The most effective compound, P1-N031, is a transition state mimetic for aspartyl proteases. By western blot analysis, cathepsin D was easily detected in clonal striatal X57 cells, mouse brain and primary neurons, whereas cathepsin E was only detectible in clonal striatal X57 cells. In primary neurons, levels of cleavage product A were not changed by the same compounds that were effective in clonal striatal cells or by mRNA silencing to partially reduce levels of cathepsin D. Instead, treating primary neurons with compounds that are known to inhibit gamma secretase activity either indirectly (Imatinib mesylate, Gleevec or selectively (LY-411,575 or DAPT reduced levels of cpA. LY-411,575 or DAPT also increased survival of primary neurons expressing endogenous full-length mutant huntingtin. Conclusion We show that cpA and cpB are produced from a larger huntingtin fragment in vivo in mouse brain and in primary neuron cultures. The aspartyl protease involved in forming cpA has cathepsin

  2. Huntingtin cleavage product A forms in neurons and is reduced by gamma-secretase inhibitors.

    Science.gov (United States)

    Kegel, Kimberly B; Sapp, Ellen; Alexander, Jonathan; Reeves, Patrick; Bleckmann, Dorothee; Sobin, Linsday; Masso, Nicholas; Valencia, Antonio; Jeong, Hyunkyung; Krainc, Dimitri; Palacino, James; Curtis, Daniel; Kuhn, Rainer; Betschart, Claudia; Sena-Esteves, Miguel; Aronin, Neil; Paganetti, Paolo; Difiglia, Marian

    2010-12-14

    The mutation in Huntington's disease is a polyglutamine expansion near the N-terminus of huntingtin. Huntingtin expressed in immortalized neurons is cleaved near the N-terminus to form N-terminal polypeptides known as cleavage products A and B (cpA and cpB). CpA and cpB with polyglutamine expansion form inclusions in the nucleus and cytoplasm, respectively. The formation of cpA and cpB in primary neurons has not been established and the proteases involved in the formation of these fragments are unknown. Delivery of htt cDNA into the mouse striatum using adeno-associated virus or into primary cortical neurons using lentivirus generated cpA and cpB, indicating that neurons in brain and in vitro can form these fragments. A screen of small molecule protease inhibitors introduced to clonal striatal X57 cells and HeLa cells identified compounds that reduced levels of cpA and are inhibitors of the aspartyl proteases cathepsin D and cathepsin E. The most effective compound, P1-N031, is a transition state mimetic for aspartyl proteases. By western blot analysis, cathepsin D was easily detected in clonal striatal X57 cells, mouse brain and primary neurons, whereas cathepsin E was only detectible in clonal striatal X57 cells. In primary neurons, levels of cleavage product A were not changed by the same compounds that were effective in clonal striatal cells or by mRNA silencing to partially reduce levels of cathepsin D. Instead, treating primary neurons with compounds that are known to inhibit gamma secretase activity either indirectly (Imatinib mesylate, Gleevec) or selectively (LY-411,575 or DAPT) reduced levels of cpA. LY-411,575 or DAPT also increased survival of primary neurons expressing endogenous full-length mutant huntingtin. We show that cpA and cpB are produced from a larger huntingtin fragment in vivo in mouse brain and in primary neuron cultures. The aspartyl protease involved in forming cpA has cathepsin-D like properties in immortalized neurons and gamma

  3. 5-[{sup 18}F]Fluoroalkyl pyrimidine nucleosides: probes for positron emission tomography imaging of herpes simplex virus type 1 thymidine kinase gene expression

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    Chacko, Ann-Marie [Institute for Environmental Medicine, Targeted Therapeutics Program, University of Pennsylvania, Philadelphia, PA 19104 (United States); Blankemeyer, Eric; Lieberman, Brian P.; Qu, Wenchao [Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104 (United States); Kung, Hank F. [Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104 (United States); Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104 (United States)], E-mail: kunghf@gmail.com

    2009-01-15

    Introduction: The preliminary in vivo evaluation of novel 5-[{sup 18}F]fluoroalkyl-2'-deoxyuridines ([{sup 18}F]FPrDU, [{sup 18}F]FBuDU, [{sup 18}F]FPeDU; [{sup 18}F]1a-c, respectively) and 2'-fluoro-2'-deoxy-5-[{sup 18}F]fluoroalkyl-1-{beta}-D-arabinofuranosyl uracils ([{sup 18}F]FFPrAU, [{sup 18}F]FFBuAU, [{sup 18}F]FFPeAU; [{sup 18}F]1d-f, respectively) as probes for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression is described. Methods: [{sup 18}F]1a-f were successfully synthesized by a rapid and efficient two-step one-pot nucleophilic fluorination reaction using 5-O-mesylate precursors and [{sup 18}F]F{sup -}. For in vivo studies, tumor xenografts were grown in nude mice by implanting RG2 cells stably expressing HSV1-tk (RG2TK+) and wild-type cells (RG2). Results: Biodistribution studies at 2 h pi revealed that the uptake of [{sup 18}F]1a-b and [{sup 18}F]1d-e in RG2TK+ tumors was not significantly different from control tumors. However, [{sup 18}F]1c and [{sup 18}F]1f had an average 1.6- and 1.7-fold higher uptake in RG2TK+ tumors than control RG2 tumors. Blood activity curves for [{sup 18}F]1c and [{sup 18}F]1f highlight rapid clearance of radioactivity in the blood. Dynamic small animal PET (A-PET) imaging studies of tumor-bearing mice with [{sup 18}F]1c and [{sup 18}F]1f showed higher initial uptake (3.5- and 1.4-fold, respectively) in RG2TK+ tumors than in control tumors, with continued washout of activity from both tumors over time. Conclusions: Biological evaluations suggest that [{sup 18}F]1c and [{sup 18}F]1f may have limited potential for imaging HSV1-tk gene expression due to fast washout of activity from the blood, thus significantly decreasing sensitivity and specificity of tracer accumulation in HSV1-tk-expressing tumors.

  4. Molecular Characterization of PDGFR-α/PDGF-A and c-KIT/SCF in Gliosarcomas

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    Rui M. Reis

    2005-01-01

    Full Text Available Gliosarcomas are rare and poorly characterized malignant brain tumors that exhibit a biphasic tissue pattern with areas of gliomatous and sarcomatous differentiation. These tumors are histological variants of glioblastoma, displaying a similar genetic profile and dismal prognosis. Up-regulation of PDGFR subfamily of tyrosine kinase members, PDGFR-α and c-Kit, and their intracellular effectors RAS/RAF/MAPK has a crucial role in the cancer development. In addition, signal transduction mediated by activating mutations of c-Kit and PDGFR can be effectively blocked by specific tyrosine kinase inhibitors, such as Imatinib mesylate. The aim of this study was to characterize the molecular alterations of PDGFR signaling in gliosarcomas. Six cases were analyzed by immunohistochemistry for the expression of PDGFR-α, c-Kit and their ligands PDGF-A and SCF, respectively. The cases were further evaluated for the presence of activating mutations of PDGFR-α (exons 12 and 18 and c-kit (exons 9, 11, 13, and 17, as well as B-RAF (exons 11 and 15. Expression of PDGF-A was found in all cases and co-expression of PDGFR-α was observed in three cases. Four cases showed expression of SCF, and c-Kit was observed only in one case that also expressed SCF. Generally, immunoreaction predominates in the glial component. The mutational analysis of PDGFR-α showed the presence of an IVS17-50insT intronic insertion in two cases, one of them also with a 2472C > T silent mutation; this silent mutation was also found in another case. Glioma cell line analysis of IVS17-50insT insertion showed no influence on PDGFR-α gene splicing. No mutations were detected in c-kit and B-RAF oncogenes. Our Results indicate that activating mutations of PDGFR-α, c-kit and B-RAF are absent in gliosarcomas. Nevertheless, the presence of a PDGFR-a/PDGFA and c-Kit/SCF autocrine/paracrine stimulation loop in a proportion of cases, supports the potential role of specific tyrosine kinase inhibitors in

  5. Mefloquine in combination with hemin causes severe damage to adult Schistosoma japonicum in vitro.

    Science.gov (United States)

    Xiao, Shu-hua; Qiao, Chunhua; Xue, Jian; Wang, Lili

    2014-03-01

    In order to explore the interaction of mefloquine with hemin against adult Schistosoma japonicum in vitro, the 50% and 95% lethal concentration (LC50 and LC95) of mefloquine and hemin against schistosomes, some factors, such as other iron providing agents, iron chelaters, zinc protoporphyrin-IX, and biological relevant reductants, that might impact on antischistosomal activity induced by interaction of mefloquine with hemin, and preliminary analysis of chemical interaction of both compounds were undertaken. The LC50 and LC95 of mefloquine and hemin alone against schistosomes were determined to be 6.5μg/ml and 7.8μg/ml as well as 232μg/ml and 355μg/ml, respectively. The LC50 and LC95 of mefloquine in the presence of hemin 100μg/ml was 0.24μg/ml and 0.59μg/ml, respectively. On the other hand the LC50 and LC95 of hemin in the presence of mefloquine 1μg/ml was 23.2μg/ml and 77.2μg/ml, respectively. Meanwhile, mefloquine/hemin combinations showed potential synergistic effects against adult S. japonicum, with combination index (CI) values mefloquine exhibited no toxic effect against schistosomes. On the other hand, addition of iron chelators (deferiprone, desferrioxamine mesylate, or 2,2'-bipyridine) to the medium containing mefloquine-hemin resulted in no protective effect on the worms. Furthermore, biological reductants like glutathione, vitamine C or cysteine showed no apparent worm protection effect from toxic mefloquine-hemin even at higher concentrations (242.3-614.6μg/ml, i.e., 6.4-17.8-fold higher than the concentration of hemin). Chemical interaction of mefloquine with hemin was studied in 40% DMSO-Tris buffer solution. Both UV-Vis spectrum and mass spectrum demonstrated the strong interaction of mefloquine with hemin, which resulted in a reduction of hemin color and emergence of an adduct formed by mefloquine and hemin. The results confirm that mefloquine combined with hemin exhibits potential synergistic effect against adult S. japonicum in vitro

  6. R+-methanandamide inhibits tracheal response to endogenously released acetylcholine via capsazepine-sensitive receptors.

    Science.gov (United States)

    Nieri, Paola; Martinotti, Enrica; Testai, Lara; Adinolfi, Barbara; Calderone, Vincenzo; Breschi, Maria Cristina

    2003-01-10

    The effects of cannabinoid drugs on the cholinergic response evoked by electrical field stimulation (0.2 ms pulse width, 20 V amplitude, 10 Hz, 7.5 s train duration) in guinea-pig tracheal preparations were investigated. The stable analogue of the endocannabinoid anandamide, R(+)-methanandamide (10(-7)-10(-4) M), produced a dose-dependent inhibition (up to 27+/-5% of control) of electrical field stimulation-mediated atropine-sensitive response. This effect was not blocked by the selective cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide hydrochloride (SR 141716A; 10(-6) M), and was not reproduced with the cannabinoid CB(1)/CB(2) receptor agonist R(+)-[2,3-dihydro-5-methyl-[(morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)methanone mesylate) (WIN 55,212-2; 10(-8)-10(-5) M) or the cannabinoid CB(2) receptor selective agonist 1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015; 10(-8)-10(-5) M); it was, on the contrary, antagonized by the vanilloid antagonist 2-[2-(4-chlorophenyl)ethyl-amino-thiocarbonyl]-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-2 benzazepine (capsazepine; 10(-6) M). At the postjunctional level, neither R(+)-methanandamide nor WIN 55,212-2 nor JWH-015 did affect tracheal contractions induced by exogenous acetylcholine (10(-6) M). An inhibitory vanilloid receptor-mediated effect on the cholinergic response evoked by electrical stimulation was confirmed with the vanilloid agonist capsaicin, at doses (3-6 x 10(-8) M) which poorly influenced the basal smooth muscle tone of trachea. In conclusion, our data indicate that in guinea-pig trachea (a) neither CB(1) nor CB(2) cannabinoid receptor-mediated modulation of acetylcholine release occurs; (b) vanilloid VR1-like receptors appear involved in R(+)-methanandamide inhibitory activity on the cholinergic response to electrical field stimulation.

  7. Relaxation Responses of Trigonal Smooth Muscle from Rabbit by Alpha1-Adrenoceptor Antagonists Alfuzosin, Doxazosin and Tamsulosin

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    A. Karadeniz

    2008-01-01

    Full Text Available This study was performed to investigate the effects of alfuzosin, doxazosin and tamsulosin in vitro on trigone smooth muscle of rabbit. In this study, fifteen rabbits weighing 2.5 - 3 kg were used. One strip in the shape of a trigone was prepared for each of the isolated bladders. Firstly, an initial tension of 1 g was placed on each segment, and we waited for equilibration by constantly bubbling with 95% O2 and 5% CO2. Next, the determination level of electrical stimulation which created submaximal contraction and effective dosage were found for trigone and they were determined by applying different concentrations of phenylephrine (10-8 M, 10-7 M, 10-6 M, 10-5 M, respectively. Firstly 10-8 M dosage of alfuzosin (10-8 M, 10-7 M, 10-6 M, 10-5 M was added, then we waited for 20 min. Then, an effective dosage of phenylephrine (10-5 M was added into the solution and we waited for 7 min again. After this process, electrical stimulation was applied for the contraction of the tissue. After stimulation, the tissue was washed twice every two minutes and rested; we waited until the tissue reached its starting stretching value. The same processes were performed for the other dosages of alfuzosin (10-7 M, 10-6 M, 10-5 M, doxazosin (10-7 M, 10-6 M, 10-5 M and tamsulosin (10-7 M, 10-6 M, 10-5 M, respectively. In conclusion, when we compared the amplitudes of the responses of all concentrations of doxazosin, alfuzosin and tamsulosin in the trigone smooth muscle with amplitude of a response of effective concentration of phenylephrine, it was determined that the prevention level of contractions occurred after tamsulosin hydrochloride was higher than after alfuzosin hydrochloride and doxazosin mesylate. With these results, we showed that alfuzosin, doxazosin and tamsulosin inhibited noradrenalin-based contractions in the rabbit trigone smooth muscle and this result can be used both for in vitro and in vivo future studies.

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

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    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

  9. Preclinical evaluation and test-retest studies of [{sup 18}F]PSS232, a novel radioligand for targeting metabotropic glutamate receptor 5 (mGlu{sub 5})

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    Milicevic Sephton, Selena; Mueller Herde, Adrienne; Keller, Claudia; Ruedisuehli, Sonja; Schibli, Roger; Kraemer, Stefanie D.; Ametamey, Simon M. [Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Zurich (Switzerland); Mu, Linjing [University Hospital Zuerich, Department of Nuclear Medicine, Zuerich (Switzerland); Auberson, Yves [Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel (Switzerland)

    2015-01-15

    A novel, {sup 18}F-labelled metabotropic glutamate receptor subtype 5 (mGlu{sub 5}) derivative of [{sup 11}C]ABP688 ([{sup 11}C]1), [{sup 18}F]PSS232 ([{sup 18}F]5), was evaluated in vitro and in vivo for its potential as a PET agent and was used in test-retest reliability studies The radiosynthesis of [{sup 18}F]5 was accomplished via a one-step reaction using a mesylate precursor. In vitro stability was determined in PBS and plasma, and with liver microsomal enzymes. Metabolite studies were performed using rat brain extracts, blood and urine. In vitro autoradiography was performed on horizontal slices of rat brain using 1 and 8, antagonists for mGlu{sub 5} and mGlu{sub 1}, respectively. Small-animal PET, biodistribution, and test-retest studies were performed in Wistar rats. In vivo, dose-dependent displacement studies were performed using 6 and blocking studies with 7. [{sup 18}F]5 was obtained in decay-corrected maximal radiochemical yield of 37 % with a specific activity of 80 - 400 GBq/μmol. Treatment with rat and human microsomal enzymes in vitro for 60 min resulted in 20 % and 4 % of hydrophilic radiometabolites, respectively. No hydrophilic decomposition products or radiometabolites were found in PBS or plasma. In vitro autoradiography on rat brain slices showed a heterogeneous distribution consistent with the known distribution of mGlu{sub 5} with high binding to hippocampal and cortical regions, and negligible radioactivity in the cerebellum. Similar distribution of radioactivity was found in PET images. Under displacement conditions with 6, reduced [{sup 18}F]5 binding was found in all brain regions except the cerebellum. 7 reduced binding in the striatum by 84 % on average. Test-retest studies were reproducible with a variability ranging from 6.8 % to 8.2 %. An extended single-dose toxicity study in Wistar rats showed no compound-related adverse effects. The new mGlu{sub 5} radiotracer, [{sup 18}F]5, showed specific and selective in vitro and in vivo

  10. “To patent or not to patent? the case of Novartis’ cancer drug Glivec in India”

    Science.gov (United States)

    2014-01-01

    Background Glivec (imatinib mesylate), produced by the pharmaceutical company Novartis, is prescribed in the case of Chronic Myeloid Leukemia, one of the most common blood cancers in eastern countries. After more than a decade of legal battles surrounding its patentability, the Supreme Court of India gave its final decision on April 1st of 2013, rejecting the appeal of the Swiss giant drug manufacturer. In 2006, the Indian Patent Office first refused Glivec’s patent under Section 3(d) of the Indian Patent Act arguing that it was only a modified version of an existing drug, Imatinib, and therefore that the drug was not innovative. Novartis replied filing legal challenges against the Indian government but the final verdict in April of 2013 ends the battle. Indeed, the Supreme Court stated that even if the bioavailability of the drug was improved, it did not demonstrate enhanced efficacy and that Glivec was not patentable. Methods The research primarily focused on journal, newspaper and magazine articles relevant to the time frame of the lawsuit (from 1994 to 2013) as well as news searches through Google, Factiva, ProQuest, PubMed, and YouTube where press articles from court verdicts were obtained by using the following keywords: “India”, “Novartis”, “Glivec”, “Patent”, “Novartis Case”, and “Supreme Court of India”. The data sources were interpreted and analyzed according to the authors’ own prior knowledge and understanding of the exigencies of the TRIPS Agreement. Results This case illuminates how India is interpreting international law to fit domestic public health needs. Conclusions The Novartis case arguably sets an important precedent for the global pharmaceutical industry and ideally will help improve access to lifesaving medicines in the developing world by demanding that patient health needs supersede commercial interests. The Supreme Court of India’s decision may affect the interpretation of the article of the TRIPS Agreement

  11. Involvement of reactive oxygen species in brominated diphenyl ether-47-induced inflammatory cytokine release from human extravillous trophoblasts in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hae-Ryung, E-mail: heaven@umich.edu; Kamau, Patricia W.; Loch-Caruso, Rita

    2014-01-15

    Polybrominated diphenyl ethers (PBDEs) are widely used flame retardant compounds. Brominated diphenyl ether (BDE)-47 is one of the most prevalent PBDE congeners found in human breast milk, serum and placenta. Despite the presence of PBDEs in human placenta, effects of PBDEs on placental cell function are poorly understood. The present study investigated BDE-47-induced reactive oxygen species (ROS) formation and its role in BDE-47-stimulated proinflammatory cytokine release in a first trimester human extravillous trophoblast cell line, HTR-8/SVneo. Exposure of HTR-8/SVneo cells for 4 h to 20 μM BDE-47 increased ROS generation 1.7 fold as measured by the dichlorofluorescein (DCF) assay. Likewise, superoxide anion production increased approximately 5 fold at 10 and 15 μM and 9 fold at 20 μM BDE-47 with a 1-h exposure, as measured by cytochrome c reduction. BDE-47 (10, 15 and 20 μM) decreased the mitochondrial membrane potential by 47–64.5% at 4, 8 and 24 h as assessed with the fluorescent probe Rh123. Treatment with 15 and 20 μM BDE-47 stimulated cellular release and mRNA expression of IL-6 and IL-8 after 12 and 24-h exposures: the greatest increases were a 35-fold increased mRNA expression at 12 h and a 12-fold increased protein concentration at 24 h for IL-6. Antioxidant treatments (deferoxamine mesylate, (±)α-tocopherol, or tempol) suppressed BDE-47-stimulated IL-6 release by 54.1%, 56.3% and 37.7%, respectively, implicating a role for ROS in the regulation of inflammatory pathways in HTR-8/SVneo cells. Solvent (DMSO) controls exhibited statistically significantly decreased responses compared with non-treated controls for IL-6 release and IL-8 mRNA expression, but these responses were not consistent across experiments and times. Nonetheless, it is possible that DMSO (used to dissolve BDE-47) may have attenuated the stimulatory actions of BDE-47 on cytokine responses. Because abnormal activation of proinflammatory responses can disrupt trophoblast functions

  12. Involvement of reactive oxygen species in brominated diphenyl ether-47-induced inflammatory cytokine release from human extravillous trophoblasts in vitro

    International Nuclear Information System (INIS)

    Park, Hae-Ryung; Kamau, Patricia W.; Loch-Caruso, Rita

    2014-01-01

    Polybrominated diphenyl ethers (PBDEs) are widely used flame retardant compounds. Brominated diphenyl ether (BDE)-47 is one of the most prevalent PBDE congeners found in human breast milk, serum and placenta. Despite the presence of PBDEs in human placenta, effects of PBDEs on placental cell function are poorly understood. The present study investigated BDE-47-induced reactive oxygen species (ROS) formation and its role in BDE-47-stimulated proinflammatory cytokine release in a first trimester human extravillous trophoblast cell line, HTR-8/SVneo. Exposure of HTR-8/SVneo cells for 4 h to 20 μM BDE-47 increased ROS generation 1.7 fold as measured by the dichlorofluorescein (DCF) assay. Likewise, superoxide anion production increased approximately 5 fold at 10 and 15 μM and 9 fold at 20 μM BDE-47 with a 1-h exposure, as measured by cytochrome c reduction. BDE-47 (10, 15 and 20 μM) decreased the mitochondrial membrane potential by 47–64.5% at 4, 8 and 24 h as assessed with the fluorescent probe Rh123. Treatment with 15 and 20 μM BDE-47 stimulated cellular release and mRNA expression of IL-6 and IL-8 after 12 and 24-h exposures: the greatest increases were a 35-fold increased mRNA expression at 12 h and a 12-fold increased protein concentration at 24 h for IL-6. Antioxidant treatments (deferoxamine mesylate, (±)α-tocopherol, or tempol) suppressed BDE-47-stimulated IL-6 release by 54.1%, 56.3% and 37.7%, respectively, implicating a role for ROS in the regulation of inflammatory pathways in HTR-8/SVneo cells. Solvent (DMSO) controls exhibited statistically significantly decreased responses compared with non-treated controls for IL-6 release and IL-8 mRNA expression, but these responses were not consistent across experiments and times. Nonetheless, it is possible that DMSO (used to dissolve BDE-47) may have attenuated the stimulatory actions of BDE-47 on cytokine responses. Because abnormal activation of proinflammatory responses can disrupt trophoblast functions

  13. 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

  14. Toxicities of four anti-neoplastic drugs and their binary mixtures tested on the green alga Pseudokirchneriella subcapitata and the cyanobacterium Synechococcus leopoliensis.

    Science.gov (United States)

    Brezovšek, Polona; Eleršek, Tina; Filipič, Metka

    2014-04-01

    The residues of anti-neoplastic drugs are new and emerging pollutants in aquatic environments. This is not only because of their increasing use, but also because due to their mechanisms of action, they belong to a group of particularly dangerous compounds. However, information on their ecotoxicological properties is very limited. We tested the toxicities of four anti-neoplastic drugs with different mechanisms of action (5-fluorouracil [5-FU], cisplatin [CDDP], etoposide [ET], and imatinib mesylate [IM]), and some of their binary mixtures, against two phytoplankton species: the alga Pseudokirchneriella subcapitata, and the cyanobacterium Synechococcus leopoliensis. These four drugs showed different toxic potential, and the two species examined also showed differences in their susceptibilities towards the tested drugs and their mixtures. With P. subcapitata, the most toxic of these drugs was 5-FU (EC50, 0.13 mg/L), followed by CDDP (EC50, 1.52 mg/L), IM (EC50, 2.29 mg/L), and the least toxic, ET (EC50, 30.43 mg/L). With S. leopoliensis, the most toxic was CDDP (EC50, 0.67 mg/L), followed by 5-FU (EC50, 1.20 mg/L) and IM (EC50, 5.36 mg/L), while ET was not toxic up to 351 mg/L. The toxicities of the binary mixtures tested (5-FU + CDDP, 5-FU + IM, CDDP + ET) were predicted by the concepts of 'concentration addition' and 'independent action', and are compared to the experimentally determined toxicities. The measured toxicity of 5-FU + CDDP with P. subcapitata and S. leopoliensis was higher than that predicted, while the measured toxicity of CDDP + ET with both species was lower than that predicted. The measured toxicity of 5-FU + IM with P. subcapitata was higher, and with S. leopoliensis was lower, than that predicted. These data show that these mixtures can have compound-specific and species-specific synergistic or antagonistic effects, and they suggest that single compound toxicity data are not sufficient for the prediction of the aquatic

  15. Identification of novel target genes of nerve growth factor (NGF) in human mastocytoma cell line (HMC-1 (V560G c-Kit)) by transcriptome analysis.

    Science.gov (United States)

    Dutta, Priyanka; Koch, Alexandra; Breyer, Bjoern; Schneider, Heike; Dittrich-Breiholz, Oliver; Kracht, Michael; Tamura, Teruko

    2011-04-18

    Nerve growth factor (NGF) is a potent growth factor that plays a key role in neuronal cell differentiation and may also play a role in hematopoietic differentiation. It has been shown that NGF induced synergistic action for the colony formation of CD34 positive hematopoietic progenitor cells treated with macrophage-colony stimulating factor (M-CSF or CSF-1), or stem cell factor (SCF). However, the exact role of NGF in hematopoietic system is unclear. It is also not clear whether NGF mediated signals in hematopoietic cells are identical to those in neuronal cells. To study the signal transduction pathways induced by NGF treatment in hematopoietic cells, we utilized the mastocytoma cell line HMC-1(V560G c-Kit) which expresses the NGF receptor, tropomyosin-receptor-kinase (Trk)A, as well as the constitutively activated SCF receptor, V560G c-Kit, which can be inhibited completely by treatment with the potent tyrosine kinase inhibitor imatinib mesylate (imatinib). NGF rescues HMC-1(V560G c-Kit) cells from imatinib mediated cell death and promotes proliferation. To examine the NGF mediated proliferation and survival in these cells, we compared the NGF mediated upregulated genes (30 and 120 min after stimulation) to the downregulated genes by imatinib treatment (downregulation of c-Kit activity for 4 h) by transcriptome analysis. The following conclusions can be drawn from the microarray data: Firstly, gene expression profiling reveals 50% overlap of genes induced by NGF-TrkA with genes expressed downstream of V560G c-Kit. Secondly, NGF treatment does not enhance expression of genes involved in immune related functions that were down regulated by imatinib treatment. Thirdly, more than 55% of common upregulated genes are involved in cell proliferation and survival. Fourthly, we found Kruppel-like factor (KLF) 2 and Smad family member 7 (SMAD7) as the NGF mediated novel downstream genes in hematopoietic cells. Finally, the downregulation of KLF2 gene enhanced imatinib

  16. Antacid-induced hypermagnesemia in a patient with normal renal function and bowel obstruction.

    Science.gov (United States)

    McLaughlin, S A; McKinney, P E

    1998-03-01

    To report a case of severe hypermagnesemia caused by magnesium hydroxide in a woman with normal renal function. A 42-year-old Hispanic woman with schizophrenia and bipolar affective disorder was transported from jail to the emergency department with confusion, abdominal pain, vomiting, and constipation. She had been treated in jail with magnesium hydroxide, ordered as milk of magnesia 30 mL po each night and Maalox 30 mL po three times daily. Additional medications included lithium carbonate 300 mg po three times daily, chlorpromazine 150 mg po three times daily, benztropine mesylate 1 mg po twice daily, and docusate sodium 100 mg po each morning. Her temperature was 35.1 degrees C, blood pressure 108/58 mm Hg, heart rate 112 beats/min, and respiratory rate 24 breaths/min. She would respond only briefly to voice or painful stimuli. Her abdomen was distended and diffusely tender. Laboratory tests included serum magnesium concentration 9.1 mEq/L (normal 1.3-2), blood urea nitrogen 16 mg/dL (8-22), creatinine 0.9 mg/dL (0.5-1.1), calcium 3.9 mEq/L (4.2-5.2), and lithium 1.0 mEq/L. A laparotomy was performed, and an adhesive band from a previous oophorectomy was found to be compressing the sigmoid colon. Hypermagnesemia, hypothermia, and hypotension continued in the intensive care unit. Despite successful treatment of the hypermagnesemia with calcium, intravenous fluids, and furosemide, the patient's cardiac rhythm degenerated into fatal, pulseless electrical activity on postoperative day 2. This case of severe hypermagnesemia from magnesium hydroxide ingestion illustrates many of the risk factors for hypermagnesemia in patients with normal renal function. People using magnesium-containing medications for relief of gastrointestinal distress may be at increased risk for hypermagnesemia. A brief review of magnesium physiology, clinical effects, and treatment is provided. Frequent use of the laboratory to identify hypermagnesemia is encouraged because it is often a

  17. Gastrointestinal stromal tumors, somatic mutations and candidate genetic risk variants.

    Directory of Open Access Journals (Sweden)

    Katie M O'Brien

    Full Text Available Gastrointestinal stromal tumors (GISTs are rare but treatable soft tissue sarcomas. Nearly all GISTs have somatic mutations in either the KIT or PDGFRA gene, but there are no known inherited genetic risk factors. We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs in 279 participants from a clinical trial of adjuvant imatinib mesylate. Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or "signatures" in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci. As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response. We calculated adjusted odds ratios (ORs and 95% confidence intervals (CIs for the association between each variant and 7 categories of tumor mutation using logistic regression. We also evaluated gene-level effects using the sequence kernel association test (SKAT. Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836 and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836. CYP1B1 was also associated with these mutations categories in the SKAT analysis (p = 0.002 and p = 0.003, respectively. Other potential risk variants included GSTM1, RAD23B and ERCC2. This preliminary analysis of inherited genetic risk factors for GIST offers some clues about the disease's genetic

  18. Lipid peroxidation and cytotoxicity induced by respirable volcanic ash

    Energy Technology Data Exchange (ETDEWEB)

    Cervini-Silva, Javiera, E-mail: jcervini@correo.cua.uam.mx [Departamento de Procesos y Tecnología, Universidad Autónoma Metropolitana Unidad Cuajimalpa, México City (Mexico); Earth Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA (United States); Nieto-Camacho, Antonio [Laboratorio de Pruebas Biológicas, Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, México City (Mexico); Gomez-Vidales, Virginia [Laboratorio de Resonancia Paramagnética Electrónica, Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, México City (Mexico); Ramirez-Apan, María Teresa [Laboratorio de Pruebas Biológicas, Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, México City (Mexico); Palacios, Eduardo; Montoya, Ascención [Dirección de Investigación y Posgrado, Instituto Mexicano del Petróleo (Mexico); Kaufhold, Stephan [BGR Bundesansaltfür Geowissenschaften und Rohstoffe, Stilleweg 2, D-30655 Hannover (Germany); and others

    2014-06-01

    Highlights: • Respirable volcanic ash induces oxidative degradation of lipids in cell membranes. • Respirable volcanic ash triggers cytotoxicity in murin monocyle/macrophage cells. • Oxidative stress is surface controlled but not restricted by surface- Fe{sup 3+}. • Surface Fe{sup 3+} acts as a stronger inductor in allophanes vs phyllosilicates or oxides. • Registered cell-viability values were as low as 68.5 ± 6.7%. - Abstract: This paper reports that the main component of respirable volcanic ash, allophane, induces lipid peroxidation (LP), the oxidative degradation of lipids in cell membranes, and cytotoxicity in murin monocyle/macrophage cells. Naturally-occurring allophane collected from New Zealand, Japan, and Ecuador was studied. The quantification of LP was conducted using the Thiobarbituric Acid Reactive Substances (TBARS) assay. The cytotoxic effect was determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide colorimetric assay. Electron-Paramagnetic Resonance (EPR) determinations of naturally-occurring allophane confirmed the incorporation in the structure and clustering of structural Fe{sup 3+}, and nucleation and growth of small-sized Fe (oxyhydr)oxide or gibbsite. LP induced by allophane varied with time, and solid concentration and composition, reaching 6.7 ± 0.2 nmol TBARS mg prot{sup −1}. LP was surface controlled but not restricted by structural or surface-bound Fe{sup 3+}, because redox processes induced by soluble components other than perferryl iron. The reactivity of Fe{sup 3+} soluble species stemming from surface-bound Fe{sup 3+} or small-sized Fe{sup 3+} refractory minerals in allophane surpassed that of structural Fe{sup 3+} located in tetrahedral or octahedral sites of phyllosilicates or bulk iron oxides. Desferrioxamine B mesylate salt (DFOB) or ethylenediaminetetraacetic acid (EDTA) inhibited LP. EDTA acted as a more effective inhibitor, explained by multiple electron transfer pathways. Registered cell

  19. Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients

    Directory of Open Access Journals (Sweden)

    Giannarelli Diana

    2010-01-01

    Full Text Available Abstract Background Adequate surgery still remains the only curative treatment of chordoma. Interesting clinical data on advanced disease with molecularly targeted therapies were reported. Methods We described the clinical outcome of a series of chordoma patients followed at Regina Elena National Cancer Centre of Rome from 2004 to 2008. Results Twenty-five consecutive patients with sacral (11 patients, spine (13 patients, and skull base (1 patient chordoma went to our observation. Six patients (24% had primary disease, 14(56% a recurrent disease, and 5(20% a metastatic spreading. Surgery was the primary option for treatment in 22 out of 25 patients. Surgical margins were wide in 5 (23% and intralesional in 17(77% patients; 3 out of 4 in-house treated patients obtained wide margins. After first surgery, radiotherapy (protons or high-energy photons were delivered to 3 patients. One out of the 5 patients with wide margins is still without evidence of disease at 20 months from surgery; 2 patients died without evidence of disease after 3 and 36 months from surgery. Sixteen out of 17 (94% patients with intralesional margins underwent local progression at a median time of 18 months with a 2-year local progression-free survival of 47%. The 5-year metastasis-free survival rate was 78.3%. Seventeen patients with locally advanced and/or metastatic disease expressing platelet-derived growth factor receptor (PDGFR β were treated with imatinib mesylate. A RECIST stabilization of the disease was the best response observed in all treated cases. Pain relief with reduction in analgesics use was obtained in 6 out of 11 (54% symptomatic patients. The 5- and 10-year survival rates of the entire series of patients were 76.7 and 59.7%, respectively. Conclusions Despite progress of surgical techniques and the results obtained with targeted therapy, more effort is needed for better disease control. Specific experience of the multidisciplinar therapeutic team is

  20. Microbial mobilization of cesium from illite: Role of organic acids and siderophores

    Science.gov (United States)

    Hazotte, Alice; Peron, Olivier; Abdelouas, Abdesselam; Lebeau, Thierry

    2015-04-01

    Understanding the behavior of cesium (Cs) in soils and geological formations is interesting in the context of nuclear accidents and nuclear waste disposals. Indeed, this radionuclide with a 30-years half-life can contaminate crops and more generally the food chain. Cs with properties similar to potassium is known to be strongly accumulated in the clays of upper soil horizons. While excavation of contaminated soil cannot be feasible for the whole contaminated surfaces (huge volumes to be cleaned-up), in situ methods could provide a sustainable and low cost solution. Phytoextraction is one of a few solutions for in situ remediation of soils contaminated by trace elements and it preserves the quality of agricultural soils. However, many improvements are still needed to enhance phytoextraction effectiveness. The combination of bioaugmentation (soil inoculation with exogenous microorganisms) with phytoextraction is likely to increase the bioaccessibility of radionuclides and their accumulation in plants. The role of bacteria on soil-pollutants can be direct (direct metal complexation) and/or indirect (weathering of clays adsorbing Cs). This study aims to provide more specifically a mechanistic understanding of the bacterial mobilization of Cs from soil with the prospect of soil bioremediation. Bacterial metabolites of Pseudomonas fluorescens (ATCC 17400) were supplied to illite spiked with 0.1 and 1 mM of Cs. Purified siderophores including pyoverdine from P. fluorescens, or the whole metabolites from the bacterial culture supernatant were compared to low molecular weight organic acids (LMWOA) (citric and oxalic acids) at 0.04 mM, or synthetic chelants, i.e., acetohydroxamic acid (AHA) and desferrioxamine mesylate (DFOM) ranging from 50 µM up to 250 µM. The release of Cs and the structural alteration of illite (release of Al, Fe and Si) were monitored. When compared to the control, no release of Cs from illite was observed with LMWOA. On the contrary, a slight release

  1. Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Michele Tanturli

    Full Text Available We previously demonstrated that severe hypoxia inhibits growth of Chronic Myeloid Leukemia (CML cells and selects stem cells where BCR/Abl(protein is suppressed, although mRNA is not, so that hypoxia-selected stem cells, while remaining leukemic, are independent of BCR/Abl signaling and thereby refractory to Imatinib-mesylate. The main target of this study was to address the effects of the proteasome inhibitor Bortezomib (BZ on the maintenance of stem or progenitor cells in hypoxic primary cultures (LC1, by determining the capacity of LC1 cells to repopulate normoxic secondary cultures (LC2 and the kinetics of this repopulation. Unselected K562 cells from day-2 hypoxic LC1 repopulated LC2 with rapid, progenitor-type kinetics; this repopulation was suppressed by BZ addition to LC1 at time 0, but completely resistant to day-1 BZ, indicating that progenitors require some time to adapt to stand hypoxia. K562 cells selected in hypoxic day-7 LC1 repopulated LC2 with stem-type kinetics, which was largely resistant to BZ added at either time 0 or day 1, indicating that hypoxia-selectable stem cells are BZ-resistant per se, i.e. before their selection. Furthermore, these cells were completely resistant to day-6 BZ, i.e. after selection. On the other hand, hypoxia-selected stem cells from CD34-positive cells of blast-crisis CML patients appeared completely resistant to either time-0 or day-1 BZ. To exploit in vitro the capacity of CML cells to adapt to hypoxia enabled to detect a subset of BZ-resistant leukemia stem cells, a finding of particular relevance in light of the fact that our experimental system mimics the physiologically hypoxic environment of bone marrow niches where leukemia stem cells most likely home and sustain minimal residual disease in vivo. This suggests the use of BZ as an enhanced strategy to control CML. in particular to prevent relapse of disease, to be considered with caution and to need further deepening.

  2. The Rho-ROCK pathway as a new pathological mechanism of innate immune subversion in chronic myeloid leukaemia.

    Science.gov (United States)

    Basbous, Sara; Levescot, Anaïs; Piccirilli, Nathalie; Brizard, Françoise; Guilhot, François; Roy, Lydia; Bourmeyster, Nicolas; Gombert, Jean-Marc; Herbelin, André

    2016-11-01

    CD1d-restricted invariant natural killer T (iNKT) cells are believed to play a key role in cancer immune surveillance, and are functionally deficient in patients with chronic myeloid leukaemia (CML). Herein, we have hypothesized that this defect might originate from BCR-ABL-dependent dysfunctions in myeloid dendritic cells (mDCs). Indeed, flow cytometry and confocal microscopy revealed that cell surface expression of CD1d was downregulated in CML mDCs, relative to healthy donor (HD) controls. The decreased cell surface display of CD1d could not be ascribed to defective mDC differentiation, as attested by normal expression of HLA-DR and the CD86 maturation marker. On the other hand, reduced membrane expression was not associated with decreased intracytoplasmic levels of CD1d or its mRNA transcripts, consistent with intracellular retention. In vitro treatment of CML mDCs with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 partially restored both cell surface CD1d expression and CD1d-mediated antigen presentation, whereas it had no effect on HD mDCs. An inhibitor of BCR-ABL tyrosine kinase (TK), imatinib mesylate (IM), had no such activity. Similar recovery of CD1d expression occurred with fasudil, another ROCK inhibitor that is commonly used in clinical trials. Our data support the conclusion that BCR-ABL-dependent ROCK, but not TK, is involved in CD1d downregulation. We propose that ROCK, which is most likely activated by the DH/PH domain of BCR-ABL, mediates iNKT-cell immune subversion in CML patients by downregulating CD1d expression on CML mDCs. Our study reveals the ROCK-mDC axis as a new potential target to restore immune surveillance in patients with CML, offering new therapeutic perspectives for CML treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  3. Syntheses and Post-Polymerization Modifications of Well-Defined Styrenic Polymers Containing Three-Membered Heterocyclic Functionalities

    Science.gov (United States)

    McLeod, David Charles

    compositions, architectures, and thermal stabilities of the resulting ?-hydroxy ether-functionalized homopolymers were evaluated using NMR and FTIR spectroscopy, size exclusion chromatography, and thermal gravimetric analysis. Aziridines and thiiranes (saturated, three-membered heterocycles containing either a single nitrogen or sulfur atom, respectively) are also susceptible to nucleophilic ring-opening reactions, and functional materials derived from aziridine- or thiirane-containing polymers could potentially have many interesting properties as a result of their high amine or thiol content, such as the ability to form pH- or redox-responsive structures. The synthesis of polymers containing aziridines that are activated towards nucleophilic ring-opening by C-aryl and/or N-sulfonyl substituents is unprecedented in the literature. Efficient methods for synthesizing styrenic monomers that contain these highly-reactive functionalities, namely 2-(4-vinylphenyl)aziridine (VPA) and its sulfonyl-activated derivative, N-mesyl-2-(4-vinylphenyl)aziridine (NMVPA), were developed utilizing 4VPO as a starting material. VPA was polymerized under LCC ATRP and RAFT conditions, but these methods were ineffective at producing well-defined polymers due to side reactions between the aziridine groups and the polymerization mediating compounds. Nitroxide-mediated radical polymerization (NMRP) produced well-defined polyVPA at low to moderate conversions of monomer, but cross-linking side reactions were evident at higher monomer conversions. Nearly all undesirable side reactions were prevented by attaching a mesyl group to the aziridine nitrogen atom, and well-defined polyNMVPA was realized under RAFT and NMRP conditions. Under ATRP conditions, reactions between the aziridine groups and catalyst still occurred, so the polymerization of NMVPA was not controlled using this technique. The synthesis of thiirane-containing styrenic polymers from either 2-(4-vinylphenyl)thiirane (VPT) or 2

  4. Preparation and evaluation of ethyl [{sup 18}F]fluoroacetate as a proradiotracer of [{sup 18}F]fluoroacetate for the measurement of glial metabolism by PET

    Energy Technology Data Exchange (ETDEWEB)

    Mori, Tetsuya [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); Sun, Li-Quan [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); School of Life Science and Technology, Beijing Institute of Technology, Beijing 100081 (China); Kobayashi, Masato [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); Kiyono, Yasushi [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan)], E-mail: ykiyono@u-fukui.ac.jp; Okazawa, Hidehiko; Furukawa, Takako [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan); Kawashima, Hidekazu [Graduate School of Medicine, Kyoto University, Kyoto 606-8501 (Japan); Welch, Michael J. [Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Fujibayashi, Yasuhisa [Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193 (Japan)

    2009-02-15

    Introduction: Changes in glial metabolism in brain ischemia, Alzheimer's disease, depression, schizophrenia, epilepsy and manganese neurotoxicity have been reported in recent studies. Therefore, it is very important to measure glial metabolism in vivo for the elucidation and diagnosis of these diseases. Radiolabeled acetate is a good candidate for this purpose, but acetate has little uptake in the brain due to its low lipophilicity. We have designed a new proradiotracer, ethyl [{sup 18}F]fluoroacetate ([{sup 18}F]EFA), which is [{sup 18}F]fluoroacetate ([{sup 18}F]FA) esterified with ethanol, to increase the lipophilicity of fluoroacetate (FA), allowing the measurement of glial metabolism. Methods: The synthesis of [{sup 18}F]EFA was achieved using ethyl O-mesyl-glycolate as precursor. The blood-brain barrier permeability of ethyl [1-{sup 14}C]fluoroacetate ([{sup 14}C]EFA) was estimated by a brain uptake index (BUI) method. Hydrolysis of [{sup 14}C]EFA in the brain was calculated by the fraction of radioactivity in lipophilic and water fractions of homogenized brain. Using the plasma of five animal species, the stability of [{sup 14}C]EFA was measured. Biodistribution studies of [{sup 18}F]EFA in ddY mice were carried out and compared with [{sup 18}F]FA. Positron emission tomography (PET) scanning using common marmosets was performed for 90 min postadministration. At 60 min postinjection of [{sup 18}F]EFA, metabolite studies were performed. Organs were dissected from the marmosets, and extracted metabolites were analyzed with a thin-layer chromatography method. Results: The synthesis of [{sup 18}F]EFA was accomplished in a short time (29 min) and with a reproducible radiochemical yield of 28.6{+-}3.6% (decay corrected) and a high radiochemical purity of more than 95%. In the brain permeability study, the BUI of [{sup 14}C]EFA was 3.8 times higher than that of sodium [1-{sup 14}C]fluoroacetate. [{sup 14}C]EFA was hydrolyzed rapidly in rat brains. In stability

  5. Leucemia Mielóide Crônica em pediatria: perspectivas atuais Chronic Myeloid Leukemia in pediatrics patients: current approach

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    Maria Lucia M. Lee

    2008-04-01

    seen with imatinib mesylate was responsible for the approval of this drug in pediatric use for intolerant or refractory -interferon treated patients or relapsed patients after BMT. Currently, its use in pediatric patients with recently diagnosed CML, who have a compatible donor, has become a great dilemma. There is no agreement yet on which is the best way to use this drug or even whether it will ever replace BMT. Further studies with longer follow-up periods are still needed.

  6. Eosinofilia reacional, leucemia eosinofílica crônica e síndrome hipereosinofílica idiopática Reactive eosinophilia, chronic eosinophilic leukemia and idiopathic hypereosinophilic syndrome

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    Maria de Lourdes Lopes Ferrari Chauffaille

    2010-01-01

    conditions described as eosinophilia. Now these conditions are better understood due to the evolution of cellular and molecular biology. This knowledge has helped to characterize distinct disorders involving myeloid and lymphoid lineages. Hence, eosinophilia is categorized as reactive, clonal or idiopathic. With the introduction of anti-tyrosine kinase (imatinib mesylate therapy, which is effective for the FIP1L1/PDGFRa rearrangement, there is a possibility to control or cure chronic eosinophilic leukemia. For this reason, precise and fast diagnosis is necessary for ideal therapeutic decisions before organic lesions that are irreversible, such as heart injury, become established. The aim of this manuscript is to review eosinophilia and offer an update on diagnostic and therapeutic investigations.

  7. Gastrointestinal Stromal Tumors (GIST) of the Stomach: Retrospective Experience with Surgical Resection at the National Cancer Institute

    International Nuclear Information System (INIS)

    NAGUIB, Sh.F.; ZAGHLOUL, A.S.; El MARAKBY, H.

    2008-01-01

    Gastric Gist's account for more than half of all gastrointestinal stromal tumors and represent less than 5% of all gastric tumors. The peak age for harboring Gist of the stomach is around 60 years and a slight male preponderance is reported. These tumors are identified by expression of CD117 or CD34 antigen. Symptoms at presentation usually include bleeding, ab¬dominal pain or abdominal mass. Endoscopically, they typically appear as a submucosal mass with or without ulceration and on CT scans an extra gastric mass is usually seen. Complete surgical resection provides the only chance for cure, with only l-2 cm free margins needed. However, local recurrence and/or metastases supervene in almost half the patients treated with surgery alone, even when no gross residual is left. Thereby imatinib mesylate was advocated as an adjuvant to surgery, which appears to have improved disease-free and overall survival. Aim of the Work: The aim of this work was to assess clinico-pathological features of gastrointestinal stromal tumors (GIST) of the stomach and to appraise the results of treatment by surgery in patients treated at the National Cancer Institute (NCI) of Cairo between January 2002 and December 2007. Patients and Methods: Nineteen patients with histologically and immuno-histochemically proven GIST of the stomach were treated by surgery at the NCI during the 6-year study period. Preoperative assessment included detailed history, clinical examination, full laboratory tests, endoscopy, abdominal ultrasound and CT. General medical assessment included chest X-ray, ECG and echocardiography. Results: The patients' age ranged from 26 to 77 years with a median of 51 years. Obvious male/female preponderance was noticed (68.4% to 31.6%). Tumors were located at the upper 1/3 in 42.1%, at the middle 1/3 in 31.6% and at the lower 1/3 in 26.3%. The most common clinical presentation was related to bleeding (hematemesis, melena or anaemia) and was seen in 63.2%. No tumors were

  8. Tumores del estroma gastrointestinal (GIST: factores pronósticos de supervivencia tras citorreducción R0 Gastrointestinal stromal tumors (GIST: factors predictive of survival after R0-cytoreduction

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    J. M. Sánchez Hidalgo

    2007-12-01

    . Demographic, anatomical, clinical, pathological, and immunohistochemical variables were analyzed from a specific database. Survival and multivariate analyses were developed using Kaplan-Meier and multiple Cox regression models, respectively. Results: five-year overall survival was 77% with a mean survival of 52 months. Risk of malignant behaviour according to Fletcher's classification and tumor size higher than 10 cm had a significantly negative influence on overall survival in the univariate analysis (p 50% and currently alive. Conclusions: the poliferative Ki-67 index could represent an excellent predictive factor for survival in patients with c-kit-positive stromal gastrointestinal tumors. Confirmation and an adequate cut-off level should be the main objectives for future prospective studies, mostly focused on the appropriate selection of optimal candidates to imatinib-mesylate-based treatment.

  9. Leucemia mieloide crônica e outras doenças mieloproliferativas crônicas Chronic myeloid leukemia and other chronic myeloproliferative disorders

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    Vaneuza M. Funke

    2010-05-01

    HSCT have been restricted as a result of mortality related to this procedure and imatinib mesylate has become the new treatment of choice for this disease. In Brazil and possibly in other developing countries, socio-economic conditions make HSCT still feasible as first-line treatment in some situations. The HSCT remains indicated for Ph negative myeloproliferative disorders such as high risk myelofibrosis or patients with polycythemia vera or essential thrombocytosis that have evolved to myelofibrosis with high-risk features.

  10. Tumor Estromal Gastrintestinal de Localização Esofágica: Relato de Caso/ Gastrointestinal Stromal Tumor Location Esophageal: Case Report

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    Daniele Ribeiro Matsumoto

    2013-06-01

    the esophagus. Casuistry: We present a case of esophageal GIST location in a patient whose dysphagia for solid food and an intermitent character odynophagia, accompanied by nausea and vomiting. Were performed serioscopy contrasted esophagus, Upper endoscopy, CT scan of abdomen, the histopathological analysis of biopsy was inconclusive and the diagnosis was confirmed by immunohistochemistry that expressed CD117 (KIT by neoplastic cells. The oncology service reference directed the completion of surgery for tumor resection, but the patient opted for the use of Imatinib mesylate (IM, having presented progressive improvement of clinical picture. Discussion: The standard treatment for patients with non-metastatic GIST is complete resection of the lesion, as it offers the greatest chance for cure. However, the patient decided only by treatment with MI. Conclusion: We conclude that GIST should be considered in exophytic esophageal and that treatment only with MI may be considered, even though the recommended treatment in these cases is surgical resection, associated with MI as adjunctive therapy with improved survival.

  11. Tratamento adjuvante nos GISTs Adjuvant treatment in GISTs

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    Laercio Gomes Lourenço

    2011-09-01

    Full Text Available INTRODUÇÃO: O tumor estromal gastrointestinal (GIST é o sarcoma mais comum do aparelho digestivo. Essa neoplasia ocorre devido à mutação do gene KIT com consequente ativação constitutiva da proteína KIT. O tratamento primário é cirúrgico e consiste na sua ressecção completa. Entretanto, alguns grupos de pacientes apresentam risco elevado de recorrência mesmo após operação com ressecção completa (R0, indicando diferenças no comportamento biológico. Estudos clínicos comprovaram a atividade clínica do mesilato de imatinibe, fazendo dele a primeira linha de tratamento padrão nos GISTs metastáticos ou irressecáveis, mudando muito o desfecho clínico dessa doença em relação aos benefícios anteriormente obtidos com a quimioterapia antineoplásica. MÉTODO: Foi realizada revisão da literatura com consulta nos periódicos das bases Medline/Pubmed, Scielo e Lilacs cruzando os descritores: tumor estromal gastrointestinal, Gist, tratamento, adjuvância. Além desta revisão foi adicionada a experiência pessoal dos autores. CONCLUSÃO: Melhor refinamento dos critérios de prognóstico tem permitido selecionar de forma mais adequada pacientes para o tratamento adjuvante com imatinibe. Os resultados de maior evidência até o momento respaldam o tratamento adjuvante por um ano, o que produz benefício significativo na sobrevida livre de recidiva, mas não na sobrevida global desses pacientes.INTRODUCTION: Gastrointestinal stromal tumor (GIST is the most common sarcoma of the digestive tract. This cancer occurs due to mutation of the KIT gene resulting in constitutive activation of KIT protein. The primary treatment is surgical and consists of complete resection. However, some groups of patients at high risk of recurrence even after surgery with complete resection (R0, indicate differences in biological behavior. Clinical studies have demonstrated the clinical activity of imatinib mesylate, making it the standard first

  12. Leucemia eosinofílica crônica com expressão do rearranjo FIP1L1-PDGFRα: relato de caso e revisão da literatura Chronic eosinophilic leukemia with a FIP1L1-PDGFRα fusion: case report and literature review

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    Martha M. A. S. Arruda

    2010-01-01

    myeloproliferation or lymphoproliferation, alterations in peripheral blood and bone marrow and diffuse tissue injury due to the release of cytokines and humoral factors from eosinophilic granules. The presence of the PDGFR-α rearrangement is commonly related to chronic eosinophilic leukemia, with alterations in peripheral mastocytes and neutrophils, and rarely to acute myeloid leukemia or T lymphoblastic lymphoma with eosinophilia. The most prevalent PDGFR-α rearrangement is one resulting from an interstitial deletion in the long arm of chromosome 4, that allows the formation of a neogene from the fusion of the FIP1L1 and PDGFRα genes. This codes a constitutively active tyrosine kinase, which can be inhibited by imatinib mesylate. In 2002, the successful treatment of a patient using imatinib to treat hypereosinophilic syndrome was reported. Since then, this drug has been utilized with fast, complete and lasting clinical responses. Here we describe a case of chronic eosinophilic syndrome with expression of the FIP1L1-PDGFR-α rearrangement.

  13. 2-[F-18] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in uncommon malignancies

    International Nuclear Information System (INIS)

    Nair, N.; Basu, S.

    2004-01-01

    management strategy. In all these cases, unsuspected distant metastases were revealed by PET scan. 3 cases of anaplastic carcinoma of thyroid were evaluated. PET showed multiple unsuspected metastatic foci in the neck and mediastinal nodes. In one of them, the neck nodes were evaluated to be operable and underwent surgery. 2 cases of very rare neuroendocrine carcinoma were studied. One of them had a primary in the breast and presented with local recurrence. Patient was referred for consideration of 131-I MIBG therapy, which did not show any appreciable concentration in the diagnostic scan. PET revealed multiple metastatic foci in both lungs and mediastinum in addition to the local recurrence. In another case, the primary was in the sphenoid, which showed persistence post radiotherapy by MRI. However, PET showed no residual disease. In 4 cases of Gastrointestinal stromal tumour (GIST)/LMS, PET findings were concordant with the finding of other imaging modalities in 2 cases. There was change in decision-making process in the 2 cases, of which PET upstaged the disease in one case. In the remaining one, a case of advanced GIST who was Imatinib mesylate treatment; PET was done to evaluate the known hepatic metastases, where it demonstrated absence of disease in the cavitating lesions seen in morphologic imaging. In 2 cases of Angiosarcoma and 1 case of liposarcoma and 3 cases of synovial sarcoma, PET revealed multiple unsuspected metastatic foci in the body and upstaged the disease. In one case of synovial sarcoma, PET revealed an unsuspected metastasis to the male breast. 4 cases of Germ cell tumour and 5 cases of Carcinoma of Buccal mucosa, Oropharynx and tonsil were evaluated; the staging and management strategy were changed by PET in all of them. In conclusion, PET made a significant contribution in the decision making process in a wide variety of malignancies and studies with larger sample size are warranted to prove its efficacy in these tumours

  14. Radiolabeling of liposomes and polymeric micelles with PET-isotopes

    Energy Technology Data Exchange (ETDEWEB)

    Ingemann Jensen, A.T.

    2013-06-01

    glycerolipid and a cholesteryl ether were synthesized with free primary alcohols and a series of their sulphonates (Ms, Ts, Tf) were prepared. [18F]Radiofluorination of these substrates was performed on fully automated equipment using a classic Kryptofix222-mediated procedure in DMSO. Yields were poor, 3-17% depending on conditions. The [18F]fluorinated probes were purified in-situ on SEP-Paks. The cholesteryl ether mesylate performed best. This substrate was radiolabeled and formulated in long-circulating liposomes by drying the probe and the lipids together, followed by hydration by magnetic stirring. The liposomes were extruded through 100 nm filter on fully automated equipment. Animal studies were done in tumor-bearing mice, and PET-scans were performed over 8 hours. Clear tumor uptake, as well as hepatic and splenic uptake, was observed, corresponding to expected liposomal pharmacokinetics. Tumor uptake was quantifiable (tumor-tomuscle ratio at 8 h: 2.20), showing that the maximum scan duration with 18F is sufficient for visualizing tumor tissue. Because of the low [18F]radiofluorination yields obtained, we investigated ways of labeling lipophilic substrates in nonpolar solvents. This involved the transfer of [18]HF gas from a solution of concentrated sulphuric acid into a receiving vial containing the substrate in toluene. A phosphazene base was present to bind [18]HF and mediate fluorination. This procedure made it possible to fluorinate highly lipophilic substrates in 71% yields. Chapter 3. Radiolabeling of polymeric micelles with 64Cu (18% positron decay, T = 12.7 h) was investigated. 64Cu allows longer scans (up to 48 hours), which mirrors the duration of nanoparticle pharmacokinetics. It is a metal and must be attached to polymeric micelles by covalently conjugated chelators. DOTA and CB-TE2A are two such chelators, but DOTA is widely believed to be unstable in-vivo. DOTA and CB-TE2A were conjugated to triblock polymeric micelles in the shellregion. Here, they were

  15. Resultados maternos e perinatais em gestantes portadoras de leucemia Maternal and perinatal outcomes in pregnant women with leukemia

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    Roseli Mieko Yamamoto Nomura

    2011-08-01

    trimester opted for therapeutic abortion. Four patients with acute leukemia received chemotherapy during pregnancy, with a diagnosis established after the 20th week. In one case of ALL with a late diagnosis (30 weeks, chemotherapy was started after delivery. All pregnant women with acute leukemia developed anemia and thrombocytopenia, and four (57.1% developed febrile neutropenia. Of nine pregnant women with CML, four were treated with imatinib mesylate when they became pregnant, with treatment being interrupted in the first trimester in three of them and in the second trimester in one. During pregnancy, three patients (33.3% required no chemotherapy after discontinuation of imatinib, and six (66.7% were treated with the following drugs: interferon (n=5 and/or hydroxyurea (n=3 . In the group of pregnant women with CML, anemia occurred in four (44.4% cases and thrombocytopenia in one (11.1%. The perinatal outcomes of pregnancies complicated by acute leukemia were as follows: mean gestational age at delivery was 32 weeks (standard deviation - SD=4.4 and the mean birth weight was 1476 g (SD=657 g, there were 2 (40.0% perinatal deaths (a fetal one and a neonatal one. In pregnancies complicated by CML, the mean gestational age at delivery was 37.6 weeks (SD=1.1 and the mean birth weight was 2870 g (SD=516 g. There was no perinatal death and no fetal abnormality was detected. CONCLUSIONS: Maternal and fetal morbidity is high in pregnancies complicated by acute leukemia. Whereas, in pregnancies complicated by CML, the maternal and fetal prognosis appears to be more favorable, with greater ease in management of complications.

  16. Hurdles overcome in technology transfer for AIET and Positive outcome in Indian patients

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    Dedeepiya V

    2012-01-01

    perigastric peritoneal deposits with a marked decrease in the size of the inguinal lymph nodes from and no recurrence in the pelvic region. There was also improvement in appetite and quality of life of the patient. There were no adverse reactions following the AIET infusions. [8] The latest follow-up in May 2012 revealed static non progressive disease with all the parameters including tumor markers within normal range. Case 2: A 15 year old girl presented with complaints of diffuse bone pain for 3 months, intermittent fever for 1 month and increasing pallor in October 2004. On examination, she was found to have pallor with hepatosplenomegaly. A low haemoglobin level (9.3 mg/dl, low platelets (21000 and a WBC count of 13600 with 83% lymphoblasts was revealed in her blood picture. Bone marrow examination and flow cytometry were suggestive of Acute Lymphoblastic Leukemia – CD 10+ CD 19+. Cytogenetics revealed Philadelphia chromosome and BCR-ABL positivity. Qualitative BCR-ABL was done serially to assess disease status. She was started on chemotherapy as per UK MRC protocol – Regimen B along with Imatinib Mesylate (in view of her BCR-ABL positivity and prophylactic cranial radiotherapy of 12 Gy at the end of delayed intensification. She had persistent disease with low positive BCR-ABL at 0.04% at the end of delayed intensification. As there were no matched HLA donors as she had high risk disease she was suggested for AIET using autologous natural killer (NK cells (CD3-CD56+ in January 2007. 562 x 106 in vitro expanded NK cells were infused to the patient intravenously and four weeks later, the BCR-ABL in the PB turned negative. She completed her treatment in October 2007. She has been on regular follow up for the last five years and she continues to be in remission. Case 3: A female patient aged 64 years with advanced serous papillary Adenocarcinoma of both ovaries with liver metastasis underwent omentectomy and resection of the liver nodule in the month of January 2011 and