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Mesylate
Kinds of Mesylate Terms modified by Mesylate Selected AbstractsPalladium-Catalyzed Preparation of Propargylic or Allenylic Sulfides from Propargyl Halides or Mesylate and ThiolsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 3 2004Ken Tsutsumi Abstract In the presence of a catalytic amount of Pd0 -dppe complex [dppe: 1,2-bis(diphenylphosphanyl)ethane], generated in situ from [Pd2(dba)3·CHCl3] and dppe, propargylic bromide 1a reacted with an equimolar amount of propanethiol at 60 °C in DMF to afford propargylic sulfide 2 in an excellent yield. The reaction occurs readily when carried out in the presence of the weak base triethylamine. The choice of both the phosphane, which is employed as the palladium atom's ligand, and the solvent have a remarkable effect on this reaction. We found that the optimum conditions for the reaction are those using a bidentate phosphane ligand (dppe) in a polar solvent (DMF). Compound 1a reacted smoothly with both aromatic (PhSH) and secondary thiols (CySH) in high yields. The reactions with thiols bearing functional groups (OH or Cl) proceeded selectively in good to moderate yields. Primary chlorides 1b,e were readily converted into their corresponding propargylic sulfides 7,10 in high yields. The Pd0 -dppe catalyst was ineffective in the reaction of the bromide 1g bearing a tBu group at the propargylic position, but the reaction of the corresponding mesylate 1h using the Pd0 -DIOP catalyst [DIOP = O -isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphanyl)butane] at 100 °C afforded the product 11 in good yield. Allenylic sulfides were obtained from 1g,i. We suggest that a cationic ,3 -type complex may be a more reactive intermediate in this catalytic reaction than neutral ,1 - or ,3 -allenyl/propargylpalladium complexes. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source] Vitiligo-Like Lesions and Diffuse Lightening of the Skin in a Pediatric Patient Treated with Imatinib Mesylate: A Noninvasive Colorimetric AssessmentPEDIATRIC DERMATOLOGY, Issue 2 2006Valeria Brazzelli M.D. It acts as a potent and selective inhibitor of BCR-ABL tyrosine kinase. It also inhibits both c-kit and platelet-derived growth factor receptor tyrosine kinases. Hypopigmentation of the skin in patients receiving this drug has been recently reported. We report a 17-year-old Caucasian patient affected by chronic myeloid leukemia in therapy with imatinib mesylate who developed hypopigmented vitiligo-like patches and generalized lightening of the skin. In order to evaluate the lightening observed clinically, we measured the progressive skin color hypopigmentation by using a colorimeter over several months. The colorimetric evaluation confirmed the generalized and gradual lightening of patient's skin over treatment with imatinib mesylate. We believe that this is the first reported instance of vitiligo-like lesions in a pediatric patient treated with imatinib mesylate, and the second in a Caucasian patient. [source] Novel agents to override imatinib resistance mechanismsDRUG DEVELOPMENT RESEARCH, Issue 7 2008Asumi Yokota Abstract Chronic myelogenous leukemia (CML) is a disorder of hematopoietic stem cells that results from the Philadelphia chromosome (Ph) created through translocation of human chromosomes 9 and 22. The resulting Bcr-Abl fusion protein has constitutively high tyrosine kinase activity that causes transformation of hematopoietic stem cells. Imatinib mesylate (IM) was developed as a specific Bcr-Abl kinase inhibitor and is efficacious in treating Ph-chromosome-positive (Ph+) leukemias such as CML and Ph+ acute lymphoblastic leukemia (ALL). Within a few years of its introduction to the clinic, IM has dramatically altered the first-line therapy for CML. Although most newly diagnosed CML patients in the chronic phase (CP) achieved durable responses when treated with IM, resistance to IM has become a major problem in patients with advanced-stage disease. The most important mechanism of IM resistance are point mutations within the Abl kinase domain; therefore, there is an urgent need for novel agents that can inhibit mutated Bcr-Abl. In this review, we describe novel Bcr-Abl tyrosine kinase inhibitors, the so-called "Super Gleevec" inhibitors. Drug Dev Res 69:398,406, 2008. © 2008 Wiley-Liss, Inc. [source] Allogeneic haematopoietic cell transplantation for chronic myelogenous leukaemia in the era of imatinib: a retrospective multicentre studyEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2006Martin Bornhäuser Abstract:,Objective:,To analyse the results of allogeneic haematopoietic cell transplantation (HCT) in patients with advanced stages of Philadelphia chromosome-positive chronic myelogenous leukaemia (CML) who had previously been treated with imatinib mesylate (IM). Methods:,We analysed the outcome of 61 patients with CML who had received allogeneic HCT from sibling (n = 18) or unrelated (n = 43) donors after having been treated with IM. Forty-one patients had received IM because of accelerated or blast phase CML. Conditioning therapy contained standard doses of busulfan (n = 25) or total-body irradiation (n = 20) in conjunction with cyclophosphamide in the majority of cases. Sixteen patients received dose-reduced conditioning with fludarabine-based regimens. Results:,The incidence of grades II,IV and III,IV graft-versus-host disease was 66% and 38% respectively. The probability of overall survival (OS), disease-free survival (DFS) and relapse at 18 months for the whole patient cohort were 37%, 33% and 24% respectively. The probability of non-relapse mortality (NRM) at 100 d and 12 months was 30% and 46% respectively. Univariate analysis showed that fludarabine-based conditioning therapy, age ,40 yr and >12 months interval between diagnosis and transplantation were associated with a significantly lower OS and DFS and a higher NRM. Conclusion:,These data suggest that although pretreatment with IM is not an independent negative prognostic factor, it cannot improve the dismal prognosis of CML patients at high risk for transplant-related mortality. [source] First case of immune-mediated haemolytic anaemia associated to imatinib mesylateEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2003Marcia C. Zago Novaretti Abstract: Imatinib mesylate is a specific inhibitor of protein tyrosine kinase activity secondary to bcr-abl, mostly indicated for the treatment of patients with Philadelphia chromosome positive chronic myeloid leukaemia (CML). Generally, the undesirable effects of imatinib administration observed in clinical trials were of mild-to-moderate degree, and no haemolysis has been associated with this drug. We report here a case of immune-mediated haemolytic anaemia associated to imatinib mesylate successfully treated with prednisone in a patient with CML. Laboratory investigation showed anaemia [haemoglobin (Hb) of 59 g/L], reticulocyte of 61 × 109/L and a positive direct antiglobulin test. Anti-drug in vitro studies revealed a positive result with gel microcolumn assay by an adsorption mechanism. Seventy-four days after prednisone therapy, the patient's Hb level was of 110 g/L with negative direct antiglobulin test and drug in vitro studies. This case demonstrated that patients treated with imatinib mesylate can present immune-mediated haemolysis and adequate management of this event can be done maintaining the drug and associating corticosteroids. [source] Pergolide mesylate can improve sexual dysfunction in patients with Parkinson's disease: the results of an open, prospective, 6-month follow-upEUROPEAN JOURNAL OF NEUROLOGY, Issue 7 2004M. Pohanka One of the most disabling problems in males suffering from advanced Parkinson's disease (PD) is complex sexual dysfunction. The effect of dopamine replacement or dopaminergic stimulation on sexual dysfunction has been recently examined and described in patients treated by L-DOPA or apomorphine. Pergolide mesylate is another dopamine agonist with a known high affinity to hD(2S) subtype and a lower affinity to hD(2L) subtype of D2 dopaminergic receptors. It has been repeatedly shown to be a highly effective treatment of the complicated and advanced stages of PD. The current study has been designed to assess its efficacy in the treatment of sexual dysfunction, which frequently accompanies the complicated stage of PD in males. Fourteen male patients suffering from PD, each of whom had been treated with L-DOPA, and in whom additional treatment with peroral dopaminergic agonist (DA) was needed, were followed for a 6-month period. Pergolide mesylate (Permax) was given to each patient, and titrated to a total daily dose of 3 mg. All of the patients were taking L-DOPA. The assessments performed before the start of pergolide treatment consisted of a neurological examination, including Unified Parkinson's Disease Rating Scale (UPDRS) III and IV subscales scoring, Mini Mental State Examination (MMSE) scoring, the neuropsychological examination including Zung scale scoring to exclude depression, biochemical and haematological examinations including the examination of prolactine serum levels; and a sexological examination during which the patients filled-in the International Index of Erectile Function (IIEF) questionnaire. These examinations were repeated during the control assessments at months 1, 3 and 6. To compare the examination results, anova, Friedmann's anova (non-parametric) and Tukey post hoc tests were used. There were statistically significant differences between the values of UPDRS III motor subscale, UPDRS IV (complications of therapy) subscale and all subscales of IIEF when months 0 and 1 were compared with the results obtained at months 3 and 6. The differences between months 0 and 1 and months 3 and 6 (in these items) were virtually insignificant. In conclusion, pergolide substantially improved sexual function in the younger male patients who were still interested in sexual activities. In such cases, the introduction of pergolide might be a better choice than treatment with sildenafile, which usually meets several contraindications in common PD male population. [source] A Convenient Synthesis of (,)-ParoxetineEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 15 2004László Czibula Abstract A convenient synthesis of the antidepressant paroxetine starting from 1-benzyl-4-piperidone (2) is reported. A stereoselective reduction resulted in cis -piperidine-3-methanol [(+)- 6]. The reaction between cis -piperidine-3-methanol mesylate (7) and sesamol led to benzyl-protected trans -paroxetine (9) through an inversion reaction of the stereogenic center at position 3. The latter compound was deprotected by hydrogenolysis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source] Palladium-Catalyzed Preparation of Propargylic or Allenylic Sulfides from Propargyl Halides or Mesylate and ThiolsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 3 2004Ken Tsutsumi Abstract In the presence of a catalytic amount of Pd0 -dppe complex [dppe: 1,2-bis(diphenylphosphanyl)ethane], generated in situ from [Pd2(dba)3·CHCl3] and dppe, propargylic bromide 1a reacted with an equimolar amount of propanethiol at 60 °C in DMF to afford propargylic sulfide 2 in an excellent yield. The reaction occurs readily when carried out in the presence of the weak base triethylamine. The choice of both the phosphane, which is employed as the palladium atom's ligand, and the solvent have a remarkable effect on this reaction. We found that the optimum conditions for the reaction are those using a bidentate phosphane ligand (dppe) in a polar solvent (DMF). Compound 1a reacted smoothly with both aromatic (PhSH) and secondary thiols (CySH) in high yields. The reactions with thiols bearing functional groups (OH or Cl) proceeded selectively in good to moderate yields. Primary chlorides 1b,e were readily converted into their corresponding propargylic sulfides 7,10 in high yields. The Pd0 -dppe catalyst was ineffective in the reaction of the bromide 1g bearing a tBu group at the propargylic position, but the reaction of the corresponding mesylate 1h using the Pd0 -DIOP catalyst [DIOP = O -isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphanyl)butane] at 100 °C afforded the product 11 in good yield. Allenylic sulfides were obtained from 1g,i. We suggest that a cationic ,3 -type complex may be a more reactive intermediate in this catalytic reaction than neutral ,1 - or ,3 -allenyl/propargylpalladium complexes. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004) [source] Phentolamine mesylate relaxes rabbit corpus cavernosum by a nonadrenergic, noncholinergic mechanismFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2001Subbarao Vemulapalli The contribution of NO-cGMP dependent pathway to phentolamine mesylate-evoked nonadrenergic, noncholinergic relaxation of rabbit corpus cavernosum was investigated in vitro. Stimulation of nonadrenergic, noncholinergic neurons of the rabbit corpus cavernosum elicited frequency-related relaxation that was significantly attenuated by L-NAME (NO synthase inhibitor) or ODQ (an inhibitor of guanylate cyclase). Moreover, tetrodotoxin, a sodium channel blocker, abolished the electrical field stimulation-induced relaxation of rabbit corpus cavernosum, suggesting that neuronal release of NO mediates relaxation to electrical field stimulation. Phentolamine mesylate (30 and 100 nM) dose-dependently enhanced electrical field stimulation-induced relaxation of the rabbit corpus cavernosum. Prazosin (30 ,M) and yohimbine (30 ,M) failed to affect phentolamine mesylate-mediated nonadrenergic, noncholinergic rabbit penile smooth muscle relaxation, suggesting that phentolamine relaxes rabbit corpus cavernosum independent of ,-adrenergic receptor blockade. In contrast, pretreatment of the rabbit cavernosal strips with L-NAME significantly-attenuated electrical field stimulation produced relaxations to phentolamine mesylate, suggesting that phentolamine mesylate relaxes rabbit corpus cavernosum by activating NO synthase. The data suggest that phentolamine mesylate relaxes nonadrenergic noncholinergic neurons of the rabbit corpus cavernosum by activating NO synthase and is independent of ,-adrenergic receptor blockade. [source] Genetics of dermatofibrosarcoma protuberans family of tumors: From ring chromosomes to tyrosine kinase inhibitor treatmentGENES, CHROMOSOMES AND CANCER, Issue 1 2003Nicolas Sirvent Dermatofibrosarcoma protuberans (DP) is a rare, slow-growing, infiltrating dermal neoplasm of intermediate malignancy, made up of spindle-shaped tumor cells often positive for CD34. The preferred treatment is wide surgical excision with pathologically negative margins. At the cytogenetic level, DP cells are characterized by either supernumerary ring chromosomes, which have been shown by using fluorescence in situ hybridization techniques to be derived from chromosome 22 and to contain low-level amplified sequences from 17q22-qter and 22q10,q13.1, or t(17;22), that are most often unbalanced. Both the rings and linear der(22) contain a specific fusion of COL1A1 with PDGFB. Similar to other tumors, the COL1A1-PDGFB fusion is occasionally cryptic, associated with complex chromosomal rearrangements. Although rings have been mainly observed in adults, translocations have been reported in all pediatric cases. DP is therefore a unique example of a tumor in which (i) the same molecular event occurs either on rings or linear translocation derivatives, (ii) the chromosomal abnormalities display an age-related pattern, and (iii) the presence of the specific fusion gene is associated with the gain of chromosomal segments, probably taking advantage of gene dosage effects. In all DP cases that underwent molecular investigations, the breakpoint localization in PDGFB was found to be remarkably constant, placing exon 2 under the control of the COL1A1 promoter. In contrast, the COL1A1 breakpoint was found to be variably located within the exons of the ,-helical coding region (exons 6,49). No preferential COL1A1 breakpoint and no correlation between the breakpoint location and the age of the patient or any clinical or histological particularity have been described. The COL1A1-PDGFB fusion is detectable by multiplex RT-PCR with a combination of forward primers designed from a variety of COL1A1 exons and one reverse primer from PDGFB exon 2. Recent studies have determined the molecular identity of "classical" DP, giant cell fibroblastoma, Bednar tumor, adult superficial fibrosarcoma, and the granular cell variant of DP. In approximately 8% of DP cases, the COL1A1-PDGFB fusion is not found, suggesting that genes other than COL1A1 or PDGFB might be involved in a subset of cases. It has been proposed that PDGFB acts as a mitogen in DP cells by autocrine stimulation of the PDGF receptor. It is encouraging that inhibitory effects of the PDGF receptor tyrosine kinase antagonist imatinib mesylate have been demonstrated in vivo; such targeted therapies might be warranted in the near future for treatment of the few DP cases not manageable by surgery. © 2003 Wiley-Liss, Inc. [source] Synthesis, Mechanism, and Gas-Sensing Application of Surfactant Tailored Tungsten Oxide NanostructuresADVANCED FUNCTIONAL MATERIALS, Issue 11 2009Suman Pokhrel Abstract Widely applicable nonaqueous solution routes have been employed for the syntheses of crystalline nanostructured tungsten oxide particles from a tungsten hexachloride precursor. Here, a systematic study on the crystallization and assembly behavior of tungsten oxide products made by using the bioligand deferoxamine mesylate (DFOM) (product I), the two chelating ligands hexadecyltrimethylammoniumbromide (CTAB) (II) and poly(alkylene oxide) block copolymer (Pluronic P123) (III) is presented. The mechanistic pathways for the material synthesis are also discussed in detail. The tungsten oxide nanomaterials and reaction solutions are characterized by Fourier transform IR, 1H, and 13C NMR spectroscopies, powder X-ray diffraction, scanning electron microscopy, transmission electron microscopy (TEM), high-resolution TEM, and selected-area electron diffraction. The indexing of the line pattern suggests WO3 is in its monoclinic structure with a,=,0.7297,nm, b,=,0.7539,nm, c,=,0.7688,nm, and ,-i;,=,90.91,°. The nanoparticles formed have various architectures, such as chromosomal shapes (product I) and slates (II), which are quite different from the mesoporous one (III) that has internal pores or mesopores ranging from 5 to 15,nm. The nanoparticles obtained from all the synthetic procedures are in the range of 40,60,nm. The investigation of the gas-sensing properties of these materials indicate that all the sensors have good baseline stability and the sensors fabricated from material III present very different response kinetics and different CO detection properties. The possibility of adjusting the morphology and by that tuning the gas-sensing properties makes the preparation strategies used interesting candidates for fabricating gas-sensing materials. [source] Therapeutic targets in chronic myeloid leukaemiaHEMATOLOGICAL ONCOLOGY, Issue 2 2007Nicholas B. Heaney Abstract Chronic myeloid leukaemia (CML) is a clonal disorder of the haemopoietic stem cell arising as a consequence of the formation of the bcr-abl oncogene. The particular molecular basis of this condition has enabled the development of therapies that selectively target diseased cells. The success of the rationally designed first-line therapy imatinib mesylate (IM) is tempered by the problems of disease persistence and resistance. Novel strategies have been identified to take forward therapy in CML and these will be discussed in this review. This work is generated from a review of published literature and contains particular insight into the work performed by our group in this field. Copyright © 2007 John Wiley & Sons, Ltd. [source] Central nervous system is a sanctuary site for chronic myelogenous leukaemia treated with imatinib mesylateINTERNAL MEDICINE JOURNAL, Issue 6 2009Y. Isobe Abstract Imatinib mesylate (IM) is currently used as the first therapeutic choice against chronic myelogenous leukaemia (CML). Because IM poorly penetrates the blood-brain barrier, IM-treated CML patients may have a potential risk of central nervous system (CNS) involvement. Here we report a case with lymphoid blast crisis isolated only in CNS after bacterial meningitis, although the patient achieved and maintained complete cytogenetic response by IM therapy. It is important to consider isolated CNS blast crisis as a possible event in IM-treated CML patients. [source] Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signalsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Toru Hiraga Abstract Imatinib mesylate (imatinib) is a potent and selective inhibitor of the tyrosine kinases, Bcr-Abl, c-Kit and platelet-derived growth factor receptors (PDGFRs). Recently, it has been reported that imatinib also targets the macrophage colony-stimulating factor (M-CSF) receptor c-Fms. M-CSF signals are essential for the differentiation of osteoclasts. Bone metastases of breast cancer are frequently associated with osteoclastic bone destruction. Furthermore, several lines of evidence suggest that osteoclasts play central roles in the development and progression of bone metastases. Thus, in the present study, we examined the effects of imatinib on bone metastases of breast cancer. Coimmunoprecipitation assays showed that imatinib inhibited the M-CSF-induced phosphorylation of c-Fms in osteoclast precursor cells as well as the PDGF-induced PDGFR phosphorylation in MDA-MB-231 human breast cancer cells. Imatinib also markedly reduced osteoclast formation in vitro. In contrast, those concentrations of imatinib did not affect osteoblast differentiation. We then examined the effects of imatinib on bone metastases of MDA-MB-231 cells in a nude mouse model. Radiographic and histomorphometric analyses demonstrated that imatinib significantly decreased bone metastases associated with the reduced number of osteoclasts. In support of the notion that the inhibition of c-Fms acts to suppress the development of bone metastases, we found that a specific inhibitor of c-Fms Ki20227 also decreased bone metastases. In conclusion, these results collectively suggest that imatinib reduced bone metastases, at least in part, by inhibiting osteoclastic bone destruction through the blockade of c-Fms signals. Our results also suggest that imatinib may have a protective effect against cancer treatment-induced bone loss. © 2008 Wiley-Liss, Inc. [source] An unusual association of pemphigus vulgaris with hyperprolactinemiaINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 10 2002MNAMS, Sujay Khandpur MD A 21-year-old unmarried woman presented with oral ulcerations and generalized, itchy, fluid-filled, skin lesions of 10 days' duration. The lesions ruptured spontaneously, resulting in extensive denuded areas covered by crusts. One month prior to this, she experienced pain and enlargement of both breasts with galactorrhea. Her menstrual cycles were normal initially, but later she developed menstrual irregularities. No past history suggestive of any other systemic or skin disease, including atopy or drug allergies, could be obtained. Her family history was not contributory. Dermatologic examination revealed multiple, flaccid bullae and extensive denuded areas of skin covered with crusts over the scalp, face, trunk, and upper and lower limbs (Fig. 1). Bulla spread sign and Nikolsky's sign were positive. The oral mucosa, including the lips, buccal surface, tongue, and palate, showed multiple erosions covered with necrotic slough. The rest of the mucocutaneous and systemic examination was within normal limits. Figure 1. Extensive erosions and flaccid bullae over the trunk with breast enlargement The patient's diagnostic work-up revealed: hemoglobin, 11.2 g%; total leukocyte count, 7400/mm3; differential leukocyte count, P62L34E2M2; erythrocyte sedimentation rate, 34 mm/h. A peripheral blood smear examination, urinalysis, blood sugar, and renal and liver function tests were normal. Venereal Disease Research Laboratory (VDRL) test and enzyme-linked immunoabsorbent assay (ELISA) for human immunodeficiency virus (HIV) were nonreactive. Antinuclear antibody, lupus erythematosus (LE) cell, rheumatoid factor, and anti-dsDNA levels were normal. Serum protein electrophoresis demonstrated increased levels of immunoglobulin G (IgG) antibody. The serum prolactin level was significantly raised to 139.49 ng/mL (normal, 3.6,18.9 ng/mL). The sex hormone levels, however, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone, were within normal limits. The thyroid hormone profile was also unaltered. Chest X-ray was normal. Ultrasound of the abdomen and pelvis revealed no visceral abnormality and computerized tomography (CT) scan of the pituitary sella showed no adenoma. Mammography was negative for breast malignancy. A Tzanck smear prepared from the base of the erosion showed multiple acantholytic cells and lymphocytes. Histologic examination from an intact vesicle was suggestive of pemphigus vulgaris (PV), showing a suprabasal cleft with acantholytic cells and the basal layer demonstrating a "row of tombstones" appearance (Fig. 2). Direct immunofluorescence (DIF) revealed the intercellular deposition of IgG and C3 throughout the epidermis in a "fishnet pattern." Indirect immunofluorescence (IIF) test performed on rat esophagus for circulating IgG antibody was positive in a titer of 1 : 120. Figure 2. Photomicrograph showing suprabasal cleft with "row of tombstones" appearance, suggestive of pemphigus vulgaris (hematoxylin and eosin, × 40) Based on the clinical and immunohistological features, a diagnosis of PV with idiopathic hyperprolactinemia was made. The patient was treated with bromocriptine mesylate (Tablet Proctinal, Glaxo Wellcome Ltd, India) at a dose of 2.5 mg twice a day. After 2 months of therapy, significant improvement in the skin lesions was observed. The existing lesions re-epithelialized with a drastic reduction in the number and distribution of new vesicles. However, no change in the mucosal erosions was noticed. IIF test demonstrated a lower antibody titer (1 : 40). The breast complaints also improved with a reduction in serum prolactin level to 6.5 ng/mL. The patient refused further treatment as she experienced nausea and dizziness with bromocriptine. After 2 weeks, the disease relapsed with the appearance of new vesicles over the forearms, abdomen, back, and thighs. She again complained of breast tenderness and galactorrhea, and the serum prolactin level was 95 ng/mL. The IgG titer increased to 1 : 120. Hence, treatment with oral prednisolone (2 mg/kg/day) and bromocriptine (2.5 mg twice a day) with an antiemetic was initiated. After 6 weeks, the skin lesions had cleared completely, the breast symptoms had improved, menses had become regular, and the prolactin level had decreased to 4 ng/mL. IIF test was negative for circulating antibody. Steroids were tapered off and maintenance therapy with bromocriptine at a dose of 2.5 mg/day was continued. [source] Ligand Influence on Metathesis Activity of Ruthenium Carbene Catalysts: A DFT StudyADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 1-2 2007Bernd Abstract A survey of the concept of active and inactive ligand conformations in ruthenium alkene carbene complexes of the Grubbs catalyst type is presented. This concept is extended to a variety of anionic ligand atoms. Density functional theory calculations at the B3LYP/LACV3P**+//B3LYP/LACVP* level of theory were performed on the precatalyst, 14 valence-electron intermediate, alkene carbene conformers and ruthena(IV)cyclobutane model intermediates for several ligands, such as methoxide, methanethiolate, fluoride, mesylate, water, and ammonia. The rule of the superiority of metathesis catalysts with small and electron-withdrawing halogens does not apply to fluoride ligands. Alkoxides and thiolates also destabilize active carbene conformations, while mesylate ligands lead to a balanced energetic relation of active and inactive carbene orientations. Cationic ruthenium carbene species with aqua or ammine ligands are limited by unfavored ligand dissociation to 14 valence-electron intermediates. A guideline for the design of novel ligand systems for ruthenium carbene complexes as metathesis catalysts is proposed. [source] Practical [14C]-synthesis of molecules containing an acetic acid moiety: application to [14C]-labeled DP1 antagonistsJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 1 2007Carl Berthelette Abstract Efficient carbon-14 labeling of four potent and selective DP1 antagonists is reported. The synthetic sequence began with ,-hydroxylation, reduction of an ester, followed by oxidative diol cleavage and aldehyde reduction. The resulting alcohol 4 was converted to a mesylate then nucleophilic substitution with [14C]-sodium cyanide was performed to yield a nitrile, which upon basic hydrolysis provided the carbon-14 labeled acid 1. Compound 2 was obtained from the same alcohol intermediate 4 and two diastereomeric compounds 6 and 7 were easily prepared from compound 2. Carbon-14 synthesis of compounds 1, 2, 6 and 7 were achieved in good yields, high radiochemical purity (>99%) and with high specific activity (45 mCi/mmol). Copyright © 2006 John Wiley & Sons, Ltd. [source] Effect of chloride ion on dissolution of different salt forms of haloperidol, a model basic drugJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2005Shoufeng Li Abstract The effect of chloride ion (Cl,) on dissolution rates of hydrochloride, mesylate (methanesulfonate) and phosphate salt forms of a model drug, haloperidol, was investigated. The dissolution rates of the salts in 0.01M HCl from rotating disks followed the order of mesylate,,,phosphate,>,hydrochloride. With additional chloride ion, a decrease in dissolution rate of the hydrochloride salt was observed due to the common ion effect. Dissolution rates of mesylate and phosphate salts also decreased due to their conversion to the HCl salt form on the surfaces of dissolving disks, however, the dissolution rates of mesylate and phosphate salts under identical chloride ion concentrations were still higher than that of the HCl salt. In powder dissolution studies, it was observed that kinetics of nonhydrochloride-to-hydrochloride salt conversion play a major role in dissolution; the mesylate dissolved completely (<5 min) before its dissolution rate could be impeded by its conversion to the hydrochloride salt form. Therefore, despite the potential for conversion to a hydrochloride salt form, certain nonhydrochloride salt forms may still be preferred for dosage form development due to kinetic advantages during dissolution, such as higher apparent dissolution rate of a nonhydrochloride salt before it could completely convert to the hydrochloride form. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2224,2231, 2005 [source] Effects of imatinib mesylate (Glivec®) as a c-kit tyrosine kinase inhibitor in the guinea-pig urinary bladderNEUROUROLOGY AND URODYNAMICS, Issue 3 2006Yasue Kubota Abstract Aims In the gastrointestinal tract, slow wave activity in smooth muscle is generated by the interstitial cells of Cajal (ICC). Detrusor smooth muscle strips of most species show spontaneous contractions which are triggered by action potential bursts, however, the pacemaker mechanisms for the detrusor are still unknown. Recently, ICC-like cells have been found in guinea-pig bladder, using antibodies to the c-kit receptor. We have investigated the effects of Glivec, a c-kit tyrosine kinase inhibitor, on spontaneous action potentials in guinea-pig detrusor and intravesical pressure of isolated guinea-pig bladders. Methods Changes in the membrane potential were measured in guinea-pig detrusor smooth muscle using conventional microelectrode techniques. Pressure changes in the bladder were recorded using whole organ bath techniques. Results Smooth muscle cells in detrusor muscle bundles exhibited spontaneous action potentials, and spontaneous pressure rises occurred in isolated bladders. Glivec (10 ,M) converted action potential bursts into continuous firing with no effects on the shape of individual action potentials. Glivec (>50 ,M) reduced the amplitude of spontaneous pressure rises in the whole bladder in a dose dependent manner and abolished spontaneous action potentials in detrusor smooth muscle cells. Conclusions The results suggest that ICC-like cells may be responsible for generating bursts of action potentials and contractions in detrusor smooth muscle. Drugs inhibiting the c-kit receptor may prove useful for treating the overactive bladder. Neurourol. Urodynam. © 2006 Wiley-Liss, Inc. [source] Pathology of soft-tissue tumors: Daily diagnosis, molecular cytogenetics and experimental approachPATHOLOGY INTERNATIONAL, Issue 8 2009Hiroshi Iwasaki This article reviews problems in diagnostic pathology and molecular cytogenetics of soft-tissue tumors. Also discussed are the origin of soft-tissue sarcomas and the molecular basis of effective target therapy for sarcomas. Molecular cytogenetic analysis of tumor-specific chromosomal translocations and associated fusion gene transcripts offers a useful adjunct to the diagnosis of soft-tissue tumors, but recent studies have indicated a growing number of fusion gene variations in each tumor type. In pleomorphic sarcoma/malignant fibrous histiocytoma, the alternative lengthening of telomeres (ALT) mechanism may result in formation of anaphase bridges and marked nuclear pleomorphism. The histogenesis of soft-tissue sarcomas has been a matter of controversy. In the present experimental model using s.c. injection of 3-methylcholanthrene in C57BL/6 mice pretreated with bone marrow-transplantation from green fluorescent protein (GFP)-positive green mice, the bone marrow-derived mesenchymal stem cells as well as the tissue-resident mesenchymal cells in the peripheral soft tissues are possible originators of sarcomagenesis. Little is known about a molecular basis of target therapy for sarcomas. Platelet-derived growth factor-BB (PDGF-BB) enhances the invasive activity of malignant peripheral nerve sheath tumor (MPNST) cells through platelet-derived growth factor receptor (PDGFR) phosphorylation, whereas imatinib mesylate inhibited such activity, suggesting that targeting PDGFR-, may result in the establishment of novel treatment for MPNST. In addition, emmprin is a transmembrane glycoprotein on tumor cells that stimulates peritumoral fibroblasts to produce matrix metalloproteinases (MMP), playing a crucial role in tumor progression, invasion and metastasis. The MMP upregulation mechanism mediated by tumor-associated emmprin may be a potentially useful target in anti-tumor invasion therapy for sarcomas. [source] Pathology of gastrointestinal stromal tumorsPATHOLOGY INTERNATIONAL, Issue 1 2006Seiichi Hirota Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. It was found that most GIST expressed KIT, a receptor tyrosine kinase encoded by protooncogene c- kit. In normal gastrointestinal wall, KIT is expressed by interstitial cells of Cajal (ICC), which are a pacemaker for autonomous gastrointestinal movement. Because both GIST and ICC are double-positive for KIT and CD34, and because familial and multiple GIST appear to develop from diffuse hyperplasia of ICC, GIST are considered to originate from ICC or their precursor cells. It was also found that approximately 90% of the sporadic GIST have somatic gain-of-function mutations of the c- kit gene, and that the patients with familial and multiple GIST have germline gain-of-function mutations of the c- kit gene. These facts strongly suggest that the c- kit gene mutations are a cause of GIST. Approximately half of the sporadic GIST without c- kit gene mutations were demonstrated to have gain-of-function mutations in platelet-derived growth factor receptor-, (PDGFRA) gene that encodes another receptor tyrosine kinase. Because KIT is immunohistochemically negative in a minority of GIST, especially in PDGFRA gene mutation-harboring GIST, mutational analyses of c- kit and PDGFRA genes may be required to diagnose such GIST definitely. Imatinib mesylate was developed as a selective tyrosine kinase inhibitor. It inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for KIT-positive metastatic or unresectable GIST as a molecular target drug. Confirmation of KIT expression by immunohistochemistry is necessary for application of the drug. The effect of imatinib mesylate is different in various types of c- kit and PDGFRA gene mutations, and the secondary resistance against imatinib mesylate is often acquired by the second mutation of the identical genes. Mutational analyses of c- kit and PDGFRA genes are also significant for prediction of effectiveness of drugs including newly developed agents. [source] Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine,AMERICAN JOURNAL OF HEMATOLOGY, Issue 12 2009Ken H. Lim Cytoreductive therapy in systemic mastocytosis (SM) includes several drugs whose individual merit has not been well characterized. We retrospectively studied 108 Mayo Clinic patients who met the 2008 WHO diagnostic criteria for SM and received at least one cytoreductive drug. The numbers of patients who were evaluable for response to treatment with interferon-alpha with or without prednisone (IFN-,), hydroxyurea (HU), imatinib mesylate (IM) or 2-chlorodeoxyadenosine (2-CdA) were 40, 26, 22, and 22, respectively. The corresponding overall (major) response rates, according to recently published consensus criteria, were 53% (18%), 19% (0%), 18% (9%), and 55% (37%). The respective overall response rates in indolent SM, aggressive SM and SM associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD) were 60%, 60%, 45% for IFN-,, 0, 0, 21% for HU, 14%, 50%, 9% for IM and 56%, 50%, 55% for 2-CdA. The absence of mast cell mediator release symptoms in IFN-,-treated patients and presence of circulating immature myeloid cells in 2-CdA-treated patients predicted inferior response. TET2 mutational status did not influence treatment response. Although the major response rates with these four cytoreductive agents were still suboptimal and HU was mainly used in patients with SM-AHNMD, the current study favors 2-CdA or IFN-, as first-line current therapy in SM and identifies patients who are likely to respond to such therapy. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source] Treatment of CML in pediatric patients: Should imatinib mesylate (STI-571, Gleevec) or allogeneic hematopoietic cell transplant be front-line therapy?PEDIATRIC BLOOD & CANCER, Issue 5 2004Michael A. Pulsipher MD Abstract Background Long-term survival of pediatric patients with chronic myelogenous leukemia (CML) receiving myeloablative hematopoietic stem cell transplantation from fully-matched related and unrelated donors has been reported between 60 and 75%, but is associated with significant morbidity. Imatinib mesylate (STI-571, Gleevec) and reduced intensity conditioning stem cell transplantation (RIC) are two promising new tools that offer potential for decreasing therapy associated morbidity for patients with CML. Results Large trials have shown significant responses in chronic phase patients treated with imatinib and reasonable but short-lived responses in advanced phase CML. Data from adult studies is beginning to define populations likely to progress or have prolonged responses to imatinib, and some adult treatment paradigms are moving toward reserving transplantation until patients are at risk of failure with imatinib. Early trials of RIC transplantation in CML show decreased transplant related morbidity with efficacy similar to conventional transplantation, but the approach has yet to be verified in phase III studies. Data in pediatric patients with imatinib and RIC transplantation is limited. Conclusions Studies with imatinib are underway in pediatrics, but whether pediatric dosing schemes will lead to outcomes similar to adults is unknown. Because HLA-matched myeloablative transplantation offers a high rate of cure in the pediatric population, clinical studies assessing the role of imatinib mesylate and RIC transplantation should be planned carefully in order to avoid sub-optimal outcomes. © 2004 Wiley-Liss, Inc. [source] Chronic myeloid leukemia in a patient with chronic idiopathic thrombocytopenic purpura: Rapid response to imatinib mesylate (STI571)PEDIATRIC BLOOD & CANCER, Issue 2 2003Shinsaku Imashuku MD No abstract is available for this article. [source] Vitiligo-Like Lesions and Diffuse Lightening of the Skin in a Pediatric Patient Treated with Imatinib Mesylate: A Noninvasive Colorimetric AssessmentPEDIATRIC DERMATOLOGY, Issue 2 2006Valeria Brazzelli M.D. It acts as a potent and selective inhibitor of BCR-ABL tyrosine kinase. It also inhibits both c-kit and platelet-derived growth factor receptor tyrosine kinases. Hypopigmentation of the skin in patients receiving this drug has been recently reported. We report a 17-year-old Caucasian patient affected by chronic myeloid leukemia in therapy with imatinib mesylate who developed hypopigmented vitiligo-like patches and generalized lightening of the skin. In order to evaluate the lightening observed clinically, we measured the progressive skin color hypopigmentation by using a colorimeter over several months. The colorimetric evaluation confirmed the generalized and gradual lightening of patient's skin over treatment with imatinib mesylate. We believe that this is the first reported instance of vitiligo-like lesions in a pediatric patient treated with imatinib mesylate, and the second in a Caucasian patient. [source] Persistent neutropenia in chronic myelogenous leukemia in chronic phase treated with imatinib mesylate,,AMERICAN JOURNAL OF HEMATOLOGY, Issue 5 2009Yu-Yan Hwang First page of article [source] Surgery for gastrointestinal stromal tumour in the post-imatinib eraANZ JOURNAL OF SURGERY, Issue 3 2005Susan J. Neuhaus Gastrointestinal stromal tumour (GIST) is a rare tumour. Historically, surgery has been the only effective treatment. The prognosis of patients with gastrointestinal stromal tumour is poor. Even after apparently ,curative' surgical resection more than 50% of patients relapse. The development of an effective novel targeted therapy against GIST (imatinib mesylate) is a success story of molecular biology that has dramatically altered the management of patients with these tumours. However, as follow up of patients who have initially responded to imatinib has increased, it has become evident that such hopes of cure were premature because responses to imatinib are of limited duration. Unresolved issues include the role of imatinib as an induction (neo-adjuvant) therapy prior to surgery, or as adjuvant treatment after surgery, the role of surgery in patients with a differential or partial response and the role of surgery in patients with isolated metastatic disease. In the present paper the biology and natural history of GIST are reviewed, and the complexities of surgical management that exist in the context of an effective, but not curative, biological therapy, are addressed. [source] Molecular framework for response to imatinib mesylate in systemic sclerosis,ARTHRITIS & RHEUMATISM, Issue 2 2009Lorinda Chung Systemic sclerosis (SSc) is an autoimmune disease in which the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and Abl are hypothesized to contribute to the fibrosis and vasculopathy of the skin and internal organs. Herein we describe 2 patients with early diffuse cutaneous SSc (dcSSc) who experienced reductions in cutaneous sclerosis in response to therapy with the tyrosine kinase inhibitor imatinib mesylate. Immunohistochemical analyses of skin biopsy specimens demonstrated reductions of phosphorylated PDGFR, and Abl with imatinib therapy. By gene expression profiling, an imatinib-responsive signature specific to dcSSc was identified (P < 10,8). The response of these patients and the findings of the analyses suggest that PDGFR, and Abl play critical, synergistic roles in the pathogenesis of SSc, and that imatinib targets a gene expression program that is frequently dysregulated in dcSSc. [source] Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosisARTHRITIS & RHEUMATISM, Issue 1 2007Jörg H. W. Distler Objective Imatinib mesylate is a clinically well-tolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor , (TGF,) and platelet-derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc). Methods The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real-time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycin-induced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo. Results Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose-dependent manner. The induction of ECM proteins after stimulation with TGF, and PDGF was also strongly and dose-dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects. Conclusion These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc. [source] The successful management of two pregnancies with wild type metastatic gastrointestinal stromal tumorsASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 3 2009Thean Hsiang TAN Abstract Aim: To discuss the management of the uncommon situation of metastatic gastrointestinal tumour coexisting with pregnancy. Method: We describe two cases of women with metastatic gastrointestinal stromal tumor (GIST) who successfully achieved a full-term pregnancy without complications and with the delivery of healthy infants. In both cases, treatment with imatinib mesylate was withheld during pregnancy because of its unknown effects and questionable safety for the developing fetus. The available data in the medical literature regarding the use and safety of imatinib and pregnancy are reviewed. We also examine whether the knowledge of the exon mutational status would have influenced treatment decisions. Results: Both women had wild type GIST, but with different tumor growth characteristics, treatment responses and outcomes. The first patient deferred imatinib therapy to fall pregnant and her disease progressed rapidly off treatment. The second patient had a more indolent GIST where active surgical management allowed her to experience a long durable clinical response. She potentially belongs to a pediatric subgroup which carries a better prognosis despite being off imatinib. Conclusion: While we have successfully managed two pregnant women with metastatic GIST, the issue of initiating imatinib therapy in treatment-naive women, and treatment interruption in women already on therapy, remain difficult areas. Patients and their partners need to make an informed choice regarding the associated risks and the potential long-term sequelae if pregnancies are contemplated. Further research into the natural history of wild type GIST and how to tailor subsequent treatment are needed. [source] | |||||||||||||||||||||||||||||||