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Sample records for alkylated methotrexate analogues

  1. Liposomes containing alkylated methotrexate analogues for phospholipase A(2) mediated tumor targeted drug delivery

    DEFF Research Database (Denmark)

    Kaasgaard, Thomas; Andresen, Thomas Lars; Jensen, Simon Skøde;

    2009-01-01

    to the alpha-carboxylic acid. The cytotoxicity of the gamma-alkylated compound towards KATO III (IC50 = 55 nM) and HT-29 (IC50 = 400 nM) cell lines, Was unaffected by the alkylation, whereas the additional benzyl group on the alpha-carboxyl group made the Compound nontoxic. The gamma-derivative with promising...

  2. Methotrexate

    Science.gov (United States)

    Methotrexate is used to treat severe psoriasis (a skin disease in which red, scaly patches form on ... body) that cannot be controlled by other treatments. Methotrexate is also used along with rest, physical therapy, ...

  3. Stereochemistry analysis and comparison of two C(3)-alkyl substituted cyclohexonedicarboxylates with their C(3)-aryl substituted analogues

    Science.gov (United States)

    Chen, Chao-Yue; Wang, Qi; Zhu, Bing-Long; Zhao, Wen-Jie; Hu, Jin-Song

    2016-03-01

    Two representative C(3)-alkyl substituted cyclohexonedicarboxylates (4a and 4b) were synthesized and their conformational features were investigated by single crystal X-ray crystallography for the first time. These stereochemistry results of 4a and 4b were compared with those obtained from the earlier research of C(3)-aryl substituted analogues (1-3).

  4. 4-Alkylated homoibotenic acid (HIBO) analogues: versatile pharmacological agents with diverse selectivity profiles towards metabotropic and ionotropic glutamate receptor subtypes

    DEFF Research Database (Denmark)

    Madsen, Ulf; Pickering, Darryl S; Nielsen, Birgitte;

    2005-01-01

    4-Alkylated analogues of homoibotenic acid (HIBO) have previously shown high potency and selectivity at ionotropic and metabotropic glutamic acid receptor (iGluR and mGluR) subtypes. Compounds with different selectivity profiles are valuable pharmacological tools for neuropharmacological studies...

  5. QSAR analysis of N-Alkyl imidazole analogues as antibacterial agents

    Directory of Open Access Journals (Sweden)

    Khan Nazneen

    2006-01-01

    Full Text Available A quantitative structure activity relationship study on a series of N-alkyl imidazole analogues was made using combination of various thermodynamic electronic and spatial descriptors. Several statistical expressions were developed using stepwise multiple liner regression analysis. The best quantitative structure activity relationship models were further validated by leave-one-out method of cross-validation. The study revealed that the electronic property, i.e., dipole moment contributed positively, and spatial descriptor (principal moment of inertia at Y axis contributed negatively. The study suggested that substitution of group at R1 position on imidazole ring with hydrophobic nature and low bulkiness are favourable for the antibacterial activity in the concerned microbes. The quantitative structure activity relationship study provides important structural insights in designing of potent antibacterial agents.

  6. Revisiting AI-2 quorum sensing inhibitors: direct comparison of alkyl-DPD analogues and a natural product fimbrolide.

    Science.gov (United States)

    Lowery, Colin A; Abe, Takumi; Park, Junguk; Eubanks, Lisa M; Sawada, Daisuke; Kaufmann, Gunnar F; Janda, Kim D

    2009-11-04

    Quorum sensing (QS) systems have been discovered in a wide variety of bacteria, and mediate both intra- and interspecies communication. The AI-2-based QS system represents the most studied of these proposed interspecies systems and has been shown to regulate diverse functions such as bioluminescence, expression of virulence factors, and biofilm formation. As such, the development of modulatory compounds, both agonists and antagonists, is of great interest for the study of unknown AI-2-based QS systems and the potential treatment of bacterial infections. The fimbrolide class of natural products has exhibited excellent inhibitory activity against AI-2-based QS and as such may be considered the "gold standard" of AI-2 inhibitors. Thus, we sought to include a fimbrolide as a control compound for our recently developed alkyl-DPD panel of AI-2 modulators. Herein, we present a revised synthesis of a commonly studied fimbrolide as well as a direct comparison between the fimbrolide and alkyl-DPD analogues. We demonstrate that our alkyl-DPD analogues are more potent inhibitors of QS in both Vibrio harveyi and Salmonella typhimurium, the two organisms with defined AI-2 QS systems, and in doing so call into question the widely accepted use of fimbrolide-derived compounds as the "gold standard" of AI-2 inhibition.

  7. Synthesis and Cytotoxicity Evaluation of 13-n-Alkyl Berberine and Palmatine Analogues as Anticancer Agents

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    2012-09-01

    Full Text Available By introducing long carbon-chain alkyl groups at the C-13 position of berberine and palmatine, 13-n-hexyl/13-n-octyl berberine and palmatine chloride analogues 4ad were synthesized and examined by MTT assays for cytotoxic activity in seven human cancer cell lines (7701QGY, SMMC7721, HepG2, CEM, CEM/VCR, KIII, Lewis, yielding IC50 values of 0.02 ± 0.01–13.58 ± 2.84 μM. 13-n-Octyl palmatine (compound 4d gave the most potent inhibitor activity, with an IC50 of 0.02 ± 0.01 μM for SMMC7721. In all cases, the 13-n-alkyl berberine and palmatine analogues 4ad were more cytotoxic than berberine and palmatine. In addition, compounds 4ad also exhibited more potent cytotoxicity than berberine and palmatine in mice with S180 sarcoma xenografted in vivo. The primary screening results indicated that the 13-n-hexyl/13-n-octyl berberine and palmatine analogues might be valuable source for new potent anticancer drug candidates.

  8. Synthesis of alkylated deoxyno irimycin and 1,5-dideoxy-1,5-iminoxylitol analogues:

    DEFF Research Database (Denmark)

    Szczepina, M.G.; Johnston, B.D; Yuan, Y.

    2004-01-01

    The syntheses of N-alkylated deoxynojirimycin and 1,5-dideoxy-1,5-iminoxylitol derivatives having either a D- or an L-erythritol-3-sulfate functionalized N-substituent are reported. The alkylating agent used was a cyclic sulfate derivative, whereby selective attack of the nitrogen atom at the lea...

  9. Methotrexate Injection

    Science.gov (United States)

    Methotrexate injection is used alone or in combination with other medications to treat gestational trophoblastic tumors (a ... in bones) after surgery to remove the tumor. Methotrexate injection is also used to treat severe psoriasis ( ...

  10. APA-style human milk fat analogue from silkworm pupae oil: Enzymatic production and improving storage stability using alkyl caffeates.

    Science.gov (United States)

    Liu, Xi; Wang, Xudong; Pang, Na; Zhu, Weijie; Zhao, Xingyu; Wang, Fangqin; Wu, Fuan; Wang, Jun

    2015-12-08

    Silkworm pupae oil derived from reeling waste is a rich source of α-linolenic acid (ALA), which has multipal applications. ALAs were added in sn-1, 3 positions in a triacylglycerol (TAG) to produce an APA-human milk fat analogues (APA-HMFAs, A: α-linolenic acid, P: palmitic acid). The optimum condition is that tripalmitin to free fatty acids of 1:12 (mole ratio) at 65 °C for 48 h using lipase Lipozyme RM IM. Results show that, the major TAG species that comprised APA-HMFAs were rich in ALA and palmitic acid, which contained 64.52% total unsaturated fatty acids (UFAs) and 97.05% PA at the sn-2 position. The melting point of APA was -27.5 °C which is much lower than tripalmitin (40.5 °C) indicating more plastic character. In addition, the practical application of alkyl caffeates as liposoluble antioxidants in APA was developed. Alkyl caffeate showed a superior IC50 (1.25-1.66 μg/mL) compared to butyl hydroxy anisd (1.67 μg/mL) and L-ascorbic acid-6-palmitate (L-AP) (1.87 μg/mL) in DPPH analysis. The addition of ethyl caffeate to oil achieved a higher UFAs content (73.58%) at high temperatures. Overall, APA was obtained from silkworm pupae oil successfully, and the addition of caffeates extended storage ranges for APA-HMFAs.

  11. A 4-alkyl-substituted analogue of guaiacol shows greater repellency to savannah tsetse (Glossina spp.).

    Science.gov (United States)

    Saini, Rajindar K; Hassanali, Ahmed

    2007-05-01

    The responses of Glossina morsitans morsitans Westwood to guaiacol (2-methoxyphenol), a mild repellent constituent of bovid odors, and seven analogues comprising 2-methoxyfuran, 2,4-dimethylphenol, 2-methoxy-4-methylphenol (4-methylguaiacol), 4-ethyl-2-methoxyphenol (4-ethylguaiacol), 4-allyl-2-methoxyphenol (4-allylguaiacol; eugenol), 3,4-methylenedioxytoluene, and 3,4-dimethoxystyrene were compared in a two-choice wind tunnel. The 4-methyl-substituted derivative (2-methoxy-4-methylphenol) was found to elicit stronger repellent responses from the flies compared with guaiacol. None of the other analogues showed significant repellent effects on flies. 4-Methylguaiacol, guaiacol, and eugenol (which was included because of previous reports of its repellency against a number of arthropods) were further evaluated in the field with wild populations of predominantly Glossina pallidipes Austen. The presence of guaiacol or eugenol near odor-baited traps caused some nonsignificant reduction in the number of tsetse catches at relatively high release rates (approximately 50 mg/hr). In contrast, the 4-methyl derivative at three different release rates (2.2, 4.5, and 9.0 mg/hr) reduced trap catches of baited traps in a dose-response manner. At 10 mg/hr release rate, it reduced the catches of baited and unbaited traps by approximately 80 and approximately 70%, respectively. In addition, the compound not only reduced the number of tsetse attracted to natural ox odor (approximately 80%), but also had an effect on their feeding responses, reducing the proportion that fed on an ox by more than 80%. Our study shows that the presence of a methyl substituent at the 4-position of guaiacol enhances the repellency of the molecule to savannah tsetse and suggests that 4-methylguaiacol may represent a promising additional tool in the arsenal of techniques in trypanosomiasis control.

  12. Methotrexate osteopathy

    Energy Technology Data Exchange (ETDEWEB)

    Schwartz, A.M.; Leonidas, J.C.

    1984-01-01

    Methotrexate osteopathy is an uncommon complication of long-term oral maintenance therapy for childhood neoplasms, most commonly acute lymphocytic leukemia. It is characterized by severe lower extremity pain and by osteoporosis particularly involving the lower extremities and thick dense provisional zones of calcification and growth arrest lines resembling scurvy. Fractures may occur. The appearance must be distinguished from recurrent or metastatic disease.

  13. Solution- and solid-state conformations of C(α)-alkyl analogues of methylphenidate (Ritalin) salts: avoidance of gauche(+)gauche(-) interactions.

    Science.gov (United States)

    Steinberg, Avital; Froimowitz, Mark; Parrish, Damon A; Deschamps, Jeffrey R; Glaser, Robert

    2011-11-18

    Alkyl analogues of methylphenidate (Ritalin) salts are slow onset, long duration dopamine reuptake inhibitors with a potential use as a cocaine abuse pharmacotherapy. X-ray crystallographic studies and nuclear magnetic resonance (NMR) investigations strongly suggest that avoidance of sterically unfavorable gauche(-)gauche(+) orientations effectively influences both the C(α)-alkyl side chain conformation and the formation of a predominant rotamer about the CH-CH bond ligating piperidine and C(Ar)R moieties. The favored CH-CH rotamer in D(2)O and in CD(2)Cl(2) of the pharmacologically interesting i-Bu and CH(2)-cyc-Pnt (RS,RS)-salts has the same antiperiplanar arrangement that was found in the crystal structures, although there clearly is a fast equilibrium involving smaller amounts of synclinal partners. While the rotamer in the (RS,SR)-i-Bu HCl crystal structure exhibits a synclinal orientation for the vicinal pair of adjacent methine protons, the weighted time-averaged arrangement for these protons becomes almost completely antiperiplanar when the crystals are dissolved in D(2)O. Increased steric congestion around the CH-CH bond in the analogous N-methyl tertiary ammonium salts seems to augment the quantity of the preferred rotamer within the mixture. The stereochemistry of the species observed via NMR seems to arise from specific combinations of N-methyl orientation and avoidance of sterically unfavorable gauche(-)gauche(+) arrangements.

  14. Ring-alkyl connecting group effect on mesogenic properties of p-carborane derivatives and their hydrocarbon analogues

    Directory of Open Access Journals (Sweden)

    Aleksandra Jankowiak

    2009-12-01

    Full Text Available The effect of the phenyl–alkyl connecting group on mesogenic properties of several series of isostructural compounds containing p-carborane (A and B, bicyclo[2.2.2]octane (C, and benzene (D was investigated using thermal and optical methods. Results demonstrated that mesophase stability in the series containing A–D follows the order (AlkCH2CH2– < (AlkOOC– < (AlkCH2O– < (AlkCOO–. Surprisingly, the connecting groups (AlkCH2CH2– and (AlkOOC– destabilize the mesophase significantly stronger for carboranes (A and B than for carbocyclic derivatives (C and D. Analysis indicates that this effect may have quadrupolar and conformational origin.

  15. Erythrocyte-methotrexate and disease activity in children treated with oral methotrexate for juvenile chronic arthritis

    DEFF Research Database (Denmark)

    Kristensen, K; Nielsen, S; Karup Pedersen, F;

    2000-01-01

    The concentration of methotrexate (MTX) in erythrocytes (E-MTX) was measured twice with three months interval in 21 children suffering from juvenile chronic arthritis (JCA). At the same time joint score, visual analogue scale (VAS), and laboratory parameters (CRP, WBC, PMNs, and ALAT) were obtained...

  16. Methotrexate induced chronic hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Hemalatha Thiyagarajan

    2016-06-01

    Full Text Available 55 year old male patient diagnosed to have psoriasis 2.5 years ago and was started on methotrexate 5 mg thrice weekly. Patient was symptomatically better and continued methotrexate without proper follow up. 2 months ago patient experienced abdominal pain and distension. Skin lesions worsened on discontinuing methotrexate but later subsided with treatment. 1 week ago, patient had abdominal pain, bleeding and ascites. Cumulative dose of methotrexate 1.8g; Liver function tests: total bilirubin- 2.0; direct - 1.0; platelet count: 58,000 cells/cu.mm; ascitic tap done and fresh frozen plasma was infused. [Int J Basic Clin Pharmacol 2016; 5(3.000: 1138-1139

  17. Methotrexate for primary biliary cirrhosis

    DEFF Research Database (Denmark)

    Giljaca, Vanja; Poropat, Goran; Stimac, Davor;

    2010-01-01

    Methotrexate has been used to treat patients with primary biliary cirrhosis as it possesses immunosuppressive properties. The previously prepared version of this review from 2005 showed that methotrexate seemed to significantly increase mortality in patients with primary biliary cirrhosis. Since...

  18. Properties of Square-Pyramidal Alkyl-Thiolate FeIII-Complexes, Including an Analogue of the Unmodified Form of Nitrile Hydratase

    Science.gov (United States)

    Lugo-Mas, Priscilla; Taylor, Wendy; Schweitzer, Dirk; Theisen, Roslyn M.; Xu, Liang; Shearer, Jason; Swartz, Rodney D.; Gleaves, Morgan C.; DiPasquale, Antonio; Kaminsky, Werner; Kovacs, Julie A.

    2009-01-01

    The syntheses and structures of three new coordinatively unsaturated, monomeric, square pyramidal thiolate-ligated Fe(III) complexes are described, [FeIII((tame—N3)S2Me2)]+ (1), [FeIII(Et—N2S2Me2)(py)]1- (3), and [FeIII((tame—N2S)S2Me2)]2- (15). The anionic bis-carboxamide, tris-thiolate N2S3 coordination sphere of 15 is potentially similar to that of the yet-to-be characterized unmodified form of NHase. Comparison of the magnetic and reactivity properties of these reveals how anionic charge build-up (from cationic 1 to anionic 3 and dianionic 15) and spin-state influence apical ligand affinity. For all of the ligand-field combinations examined, an intermediate S= 3/2 spin-state was shown to be favored by a strong N2S2 basal plane ligand-field, and this was found to reduce the affinity for apical ligands, even when they are built-in. This is in contrast to the post-translationaly modified NHase active site, which is low-spin, and displays a higher affinity for apical ligands. Cationic 1 and its reduced FeII precursor are shown to bind NO and CO, respectively, to afford [FeIII((tame-N3)S2Me(NO)]+ (18, νNO= 1865 cm-1), an analogue of NO-inactivated NHase, and [FeII((tame-N3)S2Me)(CO)] (16; νCO stretch (1895 cm-1). Anions (N3-, CN-) are shown to be unreactive towards 1, 3 and 15, and neutral ligands unreactive towards 3 and 15, even when present in 100-fold excess, and at low—temperatures. The curtailed reactivity of 15, an analogue of the unmodified form of NHase, and its apical-oxygenated S= 3/2 derivative [FeIII((tame—N2SO2)S2Me2)]2- (20) suggests that regioselective post—translational oxygenation of the basal plane NHase cysteinate sulfurs plays an important role in promoting substrate binding. This is supported by previously reported theoretical (DFT) calculations.1 PMID:18989922

  19. Alkylating enzymes.

    Science.gov (United States)

    Wessjohann, Ludger A; Keim, Jeanette; Weigel, Benjamin; Dippe, Martin

    2013-04-01

    Chemospecific and regiospecific modifications of natural products by methyl, prenyl, or C-glycosyl moieties are a challenging and cumbersome task in organic synthesis. Because of the availability of an increasing number of stable and selective transferases and cofactor regeneration processes, enzyme-assisted strategies turn out to be promising alternatives to classical synthesis. Two categories of alkylating enzymes become increasingly relevant for applications: firstly prenyltransferases and terpene synthases (including terpene cyclases), which are used in the production of terpenoids such as artemisinin, or meroterpenoids like alkylated phenolics and indoles, and secondly methyltransferases, which modify flavonoids and alkaloids to yield products with a specific methylation pattern such as 7-O-methylaromadendrin and scopolamine.

  20. A review of methotrexate-associated hepatotoxicity.

    Science.gov (United States)

    Bath, Roopjeet K; Brar, Navkiran K; Forouhar, Faripour A; Wu, George Y

    2014-10-01

    Methotrexate is effective not only in treating psoriasis and rheumatoid arthritis but also various other disorders. The use of methotrexate has been somewhat limited by concerns regarding its adverse effects, including its potential for hepatotoxicity. The purpose of this article is to provide an overview of methotrexate-associated hepatotoxicity, including risk factors, pathogenesis and recommendations for monitoring it by US, UK and European guidelines, as well as providing a brief overview of its mechanism of action and of high-dose methotrexate.

  1. MEMBRANE-TRANSPORT OF METHOTREXATE IN A SQUAMOUS CARCINOMA CELL-LINE ADAPTED TO LOW FOLATE CONCENTRATIONS

    NARCIS (Netherlands)

    van der Laan, B.F.A.M.; Jansen, G; VANGESTEL, JA; SCHORNAGEL, JH; HORDIJK, GJ

    1991-01-01

    Membrane transport characteristics of the folate analogue methotrexate (MTX) were studied in a human squamous carcinoma cell line of the head and neck (HNSCC) adapted to grow in tissue culture media with nanomolar reduced folate concentrations (SCC-11B-LF), as compared to SCC-11B cells grown in stan

  2. Dipeptide analogues containing 4-ethoxy-3-pyrrolin-2-ones

    DEFF Research Database (Denmark)

    Hosseini, Masood; Kringelum, Henriette; Murray, A.;

    2006-01-01

    Pyrrolidine-2,4-diones (1) are naturally occurring analogues of amino acids. We herein present a facile synthesis of N-acylated, O-alkylated pyrrolin-2-ones (2) in high yield and excellent enantiopurity. Molecular mechanics calculations suggest that the resulting dipeptide analogues adopt a linea...

  3. Optimizing Methotrexate Treatment in Rheumatoid Arthritis: The Case for Subcutaneous Methotrexate Prior to Biologics.

    Science.gov (United States)

    Sharma, Poonam; Scott, David G I

    2015-11-01

    Methotrexate is the most common disease-modifying antirheumatic drug (DMARD) used in the treatment of rheumatoid arthritis (RA). Current evidence supports its efficacy in the treatment of RA, resulting in improved short-term disease control and long-term outcomes in terms of radiographic progression. Oral methotrexate has traditionally been used first-line due to various reasons, including ease of administration, low cost and easy availability. A methotrexate dose of >15 mg/week is generally required for disease control but oral methotrexate may be only partially effective or poorly tolerated in some patients. The rationale for using subcutaneous (SC) methotrexate is based on its improved bioavailability at higher doses and better tolerability in some patients who have side effects when receiving oral methotrexate. Current guidance advocates 'treating to target', with the aim of inducing remission in RA patients. In some patients, this can be achieved using methotrexate alone or in combination with other traditional DMARDs. Patients who have not responded to two DMARDs, including methotrexate, are eligible for biological therapy as per current National Institute for Health and Care Excellence (NICE) guidance in the UK. Biological treatments are expensive and using SC methotrexate can improve disease control in RA patients, thus potentially avoiding or delaying the requirement for future biological treatment.

  4. Methotrexate

    Science.gov (United States)

    ... at a lower dose. Should I get the flu vaccine? Yes. The flu (influenza) vaccine is recommended every year. Patients on MTX should be especially mindful of getting flu shots annually. Should I get the pneumococcal vaccine? Yes. The “pneumovax” shot helps protect against pneumonia ...

  5. [Hemiparesis and facial palsy caused by methotrexate].

    Science.gov (United States)

    Rueda Arenas, E; García Corzo, J; Franco Ospina, L

    2013-12-01

    Methotrexate used in the treatment of acute lymphocytic leukemia, can cause neurotoxicity, including a rare presentation with hemiparesis. We describe two teenagers, who during the implementation of the M phase of the protocol, suffered hemiparesis, facial paresis and dysarthria which quickly reversed. Leukemia involvement of the central nervous system and stroke, were ruled out. We briefly review the pathophysiology of methotrexate neurotoxicity, the characteristics of the focal paresis presentation and magnetic resonance image findings.

  6. Methotrexate induced sprue-like syndrome

    Institute of Scientific and Technical Information of China (English)

    Marta Maia Boscá; Ramon A(n)ón; Empar Hayordomo; Rosana Villagrasa; Nelly Balza; Cirilo Amorós; Juan Ramon Corts; Adolfo Benages

    2008-01-01

    A 52 year-old male patient diagnosed of ankylosing spondylitis presented with an iron deficiency anemia after a ten-month treatment of methotrexate. He did not respond to treatment with oral iron not a proton pump inhibitor and an upper endoscopy was performed. The histological study of the duodenal biopsies showed villus atrophy.After removing the methotrexate, administrating intramuscular iron and undertaking a gluten-free diet, the histological and analytical alterations progressively resolved.

  7. Impairment of Methotrexate Transport Is Common in Osteosarcoma Tumor Samples

    Directory of Open Access Journals (Sweden)

    Rebecca Sowers

    2011-01-01

    Full Text Available Osteosarcoma does not respond well to conventional dose methotrexate but does respond to high-dose methotrexate. Previous work has indicated that this resistance may be due to impaired transport of methotrexate across the cell membrane. In this study, the PT430 competitive displacement assay was adapted to evaluate methotrexate transport in 69 high-grade osteosarcoma tumor samples. All samples studied were shown to have relatively impaired methotrexate transport by PT430 assay. Ninety-nine percent of the samples had less than 20% PT430 displacement by methotrexate. Eighty-eight percent exhibited displacement by methotrexate at less than 50% of the displacement by trimetrexate. The high frequency of impaired transport suggests the presence of decreased functionality of the reduced folate carrier protein. The overwhelming presence of impaired transport may explain why methotrexate needs to be given in high doses to be effective in osteosarcoma therapy and suggests that reduced folate carrier-independent antifolates should be explored.

  8. Methotrexate information booklet study 2008.

    LENUS (Irish Health Repository)

    Mohammad, A

    2012-02-01

    INTRODUCTION: I n order to assess the value of using the methotrexate information booklet, we conducted a single blind prospective controlled trial of the patients attending two rheumatology services. METHODS: The active-arm (n=40) used the MTX information booklet for the patients\\' education and the control-arm (n=38) did not. Patients\\' interviews were conducted over a 6-month period using an MTX-questionnaire. RESULTS: The entire active-arm patients (100%) were taking folic-acid and 32 (80%) knew the reason why they were taking folic-acid vs. [30 (79%) and 10 (26%) in the control-arm]. In the active-arm 35 (88%) knew the reason for their monthly blood tests vs. 18 (47%) in the control-arm. The entire active-arm was aware of the need for contraception use and MTX-side effects vs. 23 (60%) and 15 (40%) in the control-arm respectively. CONCLUSIONS: The use of the MTX information booklet in our cohort improved their understanding of the treatment.

  9. Methotrexate-induced nitrosative stress may play a critical role in small intestinal damage in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Kolli, Viswa Kalyan; Abraham, Premila [Christian Medical College, Department of Biochemistry, Vellore, Tamil Nadu (India); Rabi, Suganthy [Christian Medical College, Department of Anatomy, Vellore, Tamil Nadu (India)

    2008-10-15

    Methotrexate (MTX), a structural analogue of folic acid, is widely used as a chemotherapeutic agent for leukemia and other malignancies. One of the major toxic effects of MTX is intestinal injury and enterocolitis.The mechanism of gastrointestinal toxicity of methotrexate has not been investigated completely. Therefore cancer chemotherapy has to be accompanied by symptomatic therapy such as antibiotics and anti-diarrheal drugs. It is important to investigate the mechanism by which methotrexate induces intestinal damage in order to perform cancer chemotherapy effectively by preventing the side effects. This study aimed at investigating whether nitrosative stress plays a role in methotrexate induced small intestinal damage using a rat model. Adult male rats were administered methotrexate at the dose of 7 mg/kg body weight intraperitoneally for 3 consecutive days and sacrificed 12 or 24 h after the final dose of methotrexate. Vehicle treated rats served as control. The intestinal tissue was used for light microscopic studies and markers of nitrosative stress including tissue nitrite level and nitrotyrosine. Myeloperoxidase (MPO) activity, a marker of neutrophil infiltration was also measured in intestinal homogenates. The villi were damaged at 12 h and the damage progressed and became severe at 24 h after the final dose of MTX. Biochemically, tissue nitrate was elevated fivefold at 12 h and fourfold at 24 h after the final dose of MTX as compared with control. Nitrotyrosine, measured immunohistochemically was detected in all the parts of the small intestine. Duodenum stained the most for nitrotyrosine, followed by ileum and then jejunum. The staining for nitrotyrosine was more intense at 24 h as compared with 12 h after the final dose of methotrexate. There was marked neutrophil infiltration as evidenced by increase in MPO activity in the small intestines. In conclusion, the results of the present study reveal that nitrosative stress may play a critical role in

  10. Adherence to methotrexate in rheumatoid arthritis

    DEFF Research Database (Denmark)

    Bliddal, Henning; Eriksen, Stine A; Christensen, Robin;

    2015-01-01

    Objectives. To study adherence to methotrexate (MTX) and factors of importance thereof in patients with rheumatoid arthritis (RA). Methods. Patients with a hospital diagnosis of RA (ICD10 codes M05.X or M06.X) after January 1, 1997, and aged ≥18 years at the date of first diagnosis/contact, with ......Objectives. To study adherence to methotrexate (MTX) and factors of importance thereof in patients with rheumatoid arthritis (RA). Methods. Patients with a hospital diagnosis of RA (ICD10 codes M05.X or M06.X) after January 1, 1997, and aged ≥18 years at the date of first diagnosis...

  11. Synthesis of a Cyclic Analogue of Galardin

    Institute of Scientific and Technical Information of China (English)

    马大为; 吴问根; 钱静; 郎深慧; 叶其壮

    2001-01-01

    A cyclic analogue 4 of galardin,a known MMP inhibitor,is designed to improve its selectivity.The synthesis of 4starts from dimethyl(S)-malate using diaselective alkylation and subsequent cyclization and amide formation as key steps.The compound 4 showed MMP inhibitory activity on all MMPs tested with IC50 ranging from 20.1 μM to 104 μM.

  12. Discovery – Methotrexate: Chemotherapy Treatment for Cancer

    Science.gov (United States)

    Prior to the 1950s, treatment for the majority of cancers was limited to either surgery or the use of radiation. The discovery of the use of methotrexate in curing a rare cancer marked the first time a cancer had been cured. This led to the development of many of today’s common cancer treatments.

  13. The combination of etanercept and methotrexate increases the effectiveness of treatment in active psoriasis despite inadequate effect of methotrexate therapy

    DEFF Research Database (Denmark)

    Zachariae, C.; Mork, N.J.; Reunala, T.;

    2008-01-01

    Many patients with moderate-to-severe plaque psoriasis do not respond adequately to methotrexate monotherapy. This pilot study, with a small patient population, was performed to evaluate the effectiveness and safety of etanercept and methotrexate combination in patients with plaque psoriasis...... and inadequate response to methotrexate. Outpatients with plaque psoriasis (Psoriasis Area and Severity Index >= 8 and/or body surface area > 10%), despite methotrexate treatment (>= 3 months; >= 7.5 mg/ week) were randomized to either etanercept with methotrexate tapered and discontinued (n = 28) or etanercept...... with continuous methotrexate (n = 31). Significantly more patients had a Physicians' Global Assessment of "clear"/"almost clear" in the combination group compared with etanercept/methotrexate taper (66.7 vs. 37.0%, respectively; p = 0.025). Adverse events were similar for both groups, with no cases...

  14. Structure-activity relationships of analogues of thapsigargin modified at O-11 and O-12

    DEFF Research Database (Denmark)

    Nielsen, S F; Thastrup, Ole; Pedersen, R;

    1995-01-01

    A number of analogues of thapsigargin have been synthesized by alkylating or acylating O-11 and O-12 in the lactol obtained by reducing thapsigargicin. Introduction of alpha-disposed substituents decreased the Ca(2+)-ATPase inhibitory potency of the analogue, whereas the enzyme was more tolerant ...

  15. Synthesis of Benzofuran Analogue of Go6976, an Isoform Selective Protein Kinase C Inhibitor

    Institute of Scientific and Technical Information of China (English)

    MA, Da-Wei; ZHANG, Xin-Rong; WU, Shi-Hui; TAO, Feng-Gang

    2001-01-01

    Based on the structure of Go6976, a known isoform-selective protein kinase C inhibitor, a benzofuran analogue (1) was designed. This analogue was synthesized by coupling of benzofuran 3-acetic acid and 8-oxo-tryptamine and subsequent intramolecular Dieckmann condensation, alkylation, oxidative photocyclization and cyanation reaction of mesylate.

  16. The combination of etanercept and methotrexate increases the effectiveness of treatment in active psoriasis despite inadequate effect of methotrexate therapy

    DEFF Research Database (Denmark)

    Zachariae, Claus; Mørk, Nils-Jørgen; Reunala, Timo;

    2008-01-01

    Many patients with moderate-to-severe plaque psoriasis do not respond adequately to methotrexate monotherapy. This pilot study, with a small patient population, was performed to evaluate the effectiveness and safety of etanercept and methotrexate combination in patients with plaque psoriasis...... and inadequate response to methotrexate. Outpatients with plaque psoriasis (Psoriasis Area and Severity Index > or = 8 and/or body surface area > 10%), despite methotrexate treatment (> or = 3 months; > or = 7.5 mg/week) were randomized to either etanercept with metho nottrexate tapered and discontinued (n = 28......) or etanercept with continuous methotrexate (n = 31). Significantly more patients had a Physicians' Global Assessment of "clear"/"almost clear" in the combination group compared with etanercept/methotrexate taper (66.7 vs. 37.0%, respectively; p = 0.025). Adverse events were similar for both groups...

  17. Method of making alkyl esters

    Science.gov (United States)

    Elliott, Brian

    2010-09-14

    Methods of making alkyl esters are described herein. The methods are capable of using raw, unprocessed, low-cost feedstocks and waste grease. Generally, the method involves converting a glyceride source to a fatty acid composition and esterifying the fatty acid composition to make alkyl esters. In an embodiment, a method of making alkyl esters comprises providing a glyceride source. The method further comprises converting the glyceride source to a fatty acid composition comprising free fatty acids and less than about 1% glyceride by mass. Moreover, the method comprises esterifying the fatty acid composition in the presence of a solid acid catalyst at a temperature ranging firm about 70.degree. C. to about 120.degree. C. to produce alkyl esters, such that at least 85% of the free fatty acids are converted to alkyl esters. The method also incorporates the use of packed bed reactors for glyceride conversion and/or fatty acid esterification to make alkyl esters.

  18. Methotrexate-induced acute toxic leukoencephalopathy

    Directory of Open Access Journals (Sweden)

    Parag R Salkade

    2012-01-01

    Full Text Available Acute lymphoblastic leukemia (ALL is one of the most common malignancies of childhood, which is treated with high doses of methotrexate (MTX, as it crosses the blood-brain barrier and can be administered intravenously and via intrathecal route to eradicate leukemic cells from central nervous system (CNS. Additionally, high doses of MTX not only prevent CNS recurrence but also hematologic relapses. Although, standard treatment protocol for ALL includes multimodality therapy, MTX is usually associated with neurotoxicity and affects periventricular deep white matter region. Methotrexate-induced ′acute toxic leukoencephalopathy′ has varying clinical manifestations ranging from acute neurological deficit to seizures or encephalopathy. Diffusion weighted magnetic resonance imaging (DW-MRI is widely available and routinely used in clinical practice to identify acute stroke and also to distinguish acute stroke from non-stroke like conditions. We report a local teenage Chinese girl who developed 2 discrete episodes of left upper and lower limb weakness with left facial nerve paresis after receiving the 2 nd and 3 rd cycle of high dose of intravenous and intrathecal methotrexate, without having cranial irradiation. After each episode of her neurological deficit, the DW-MRI scan showed focal restricted diffusion in right centrum semiovale. Her left sided focal neurological deficit and facial nerve paresis almost completely subsided on both these occasions within 3 days of symptom onset. Follow-up DW-MRI, after her neurological recovery, revealed almost complete resolution of previously noted restricted diffusion in right centrum semiovale, while the lesion was not evident on concurrent T2W (T2-weighted and FLAIR (Fluid-Attenuated Inversion recovery sequences, nor showed any post contrast enhancement on post gadolinium enhanced T1W (T1-weighted sequences. No residual neurological deficit or intellectual impairment was identified on clinical follow up

  19. Methotrexate-induced acute toxic leukoencephalopathy.

    Science.gov (United States)

    Salkade, Parag R; Lim, Teh Aun

    2012-01-01

    Acute lymphoblastic leukemia (ALL) is one of the most common malignancies of childhood, which is treated with high doses of methotrexate (MTX), as it crosses the blood-brain barrier and can be administered intravenously and via intrathecal route to eradicate leukemic cells from central nervous system (CNS). Additionally, high doses of MTX not only prevent CNS recurrence but also hematologic relapses. Although, standard treatment protocol for ALL includes multimodality therapy, MTX is usually associated with neurotoxicity and affects periventricular deep white matter region. Methotrexate-induced 'acute toxic leukoencephalopathy' has varying clinical manifestations ranging from acute neurological deficit to seizures or encephalopathy. Diffusion weighted magnetic resonance imaging (DW-MRI) is widely available and routinely used in clinical practice to identify acute stroke and also to distinguish acute stroke from non-stroke like conditions. We report a local teenage Chinese girl who developed 2 discrete episodes of left upper and lower limb weakness with left facial nerve paresis after receiving the 2 nd and 3 rd cycle of high dose of intravenous and intrathecal methotrexate, without having cranial irradiation. After each episode of her neurological deficit, the DW-MRI scan showed focal restricted diffusion in right centrum semiovale. Her left sided focal neurological deficit and facial nerve paresis almost completely subsided on both these occasions within 3 days of symptom onset. Follow-up DW-MRI, after her neurological recovery, revealed almost complete resolution of previously noted restricted diffusion in right centrum semiovale, while the lesion was not evident on concurrent T2W (T2-weighted) and FLAIR (Fluid-Attenuated Inversion recovery) sequences, nor showed any post contrast enhancement on post gadolinium enhanced T1W (T1-weighted) sequences. No residual neurological deficit or intellectual impairment was identified on clinical follow up over a 2 year

  20. Analogue computing methods

    CERN Document Server

    Welbourne, D

    1965-01-01

    Analogue Computing Methods presents the field of analogue computation and simulation in a compact and convenient form, providing an outline of models and analogues that have been produced to solve physical problems for the engineer and how to use and program the electronic analogue computer. This book consists of six chapters. The first chapter provides an introduction to analogue computation and discusses certain mathematical techniques. The electronic equipment of an analogue computer is covered in Chapter 2, while its use to solve simple problems, including the method of scaling is elaborat

  1. Drug Survival and reasons for discontinuation of intramuscular methotrexate: a study of 212 consecutive patients switching from oral methotrexate

    DEFF Research Database (Denmark)

    Linde, Louise; Hetland, Merete Lund; Østergaard, Mikkel

    2006-01-01

    Drug survival and reasons for discontinuation of intramuscular methotrexate: a study of 212 consecutive patients switching from oral methotrexate.Linde L, Hetland ML, Ostergaard M. Department of Rheumatology, Copenhagen University Hospital, Hvidovre Hospital, Hvidovre, Denmark. louiselinde......@dadlnet.dk OBJECTIVES: To assess the drug survival and reasons for discontinuation of intramuscular methotrexate (imMTX) in rheumatological patients who had switched to imMTX from oral methotrexate (oMTX). METHODS: Data from 212 consecutive patients who switched from oMTX to imMTX therapy at our outpatient clinic...... had stopped oMTX because of adverse events, 22% also withdrew from imMTX because of adverse events. CONCLUSION: Half of the patients benefited from switching from oral to intramuscular methotrexate for at least 6 months, but only a minority adhered to the treatment for years. Lack of efficacy...

  2. Nodulose por Metotrexato Methotrexate Induced Nodulosis

    Directory of Open Access Journals (Sweden)

    Fernanda Guidolin

    2005-08-01

    Full Text Available A nodulose por metotrexato (MTX é um dos efeitos colaterais pouco conhecidos do uso desse medicamento em doses baixas. Embora classicamente descrita em casos de artrite reumatóide, tem aparecido, também, em outras doenças reumáticas. Descreve-se aqui um caso de nodulose por MTX em uma paciente com artrite reumatóide soropositiva, que utilizava esse medicamento há um ano, com bom controle do processo articular. Segue-se uma breve revisão sobre o assunto.Methotrexate-induced nodulosis is a rare side effect of this drug when it is used in low doses. Although classically described in rheumatoid arthritis patients, it may also appear in other rheumatic disorders. We describe a seropositive rheumatoid arthritis patient who developed methotrexate-induced nodulosis after using this drug for a year, with good control of articular symptoms. This case presentation is followed by a brief revision on the subject.

  3. Synthesis of a Pseudodisaccharide α-C-Glycosidically Linked to an 8-Alkylated Guanine

    Directory of Open Access Journals (Sweden)

    Jan Duchek

    2013-04-01

    Full Text Available The synthesis of stable guanofosfocin analogues has attracted considerable attention in the past 15 years. Several guanofosfocin analogues mimicking the three constitutional elements of mannose, ribose, and guanine were designed and synthesized. Interest in ether-linked pseudodisaccharides and 8-alkylated guanines is increasing, due to their potential applications in life science. In this article, a novel guanofosfocin analogue 6, an ether-linked pseudodisaccharide connected α-C-glycosidically to an 8-alkylated guanine, was synthesized in a 10-longest linear step sequence from known diol 13, resulting in an overall yield of 26%. The key steps involve the ring-opening of cyclic sulfate 8 by alkoxide generated from 7 and a reductive cyclization of 4-N-acyl-2,4-diamino-5-nitrosopyrimidine 19 to form compound 6.

  4. Analogue MIMO Detection

    Directory of Open Access Journals (Sweden)

    McNamara Darren

    2006-01-01

    Full Text Available In this contribution we propose an analogue receiver that can perform turbo detection in MIMO systems. We present the case for a receiver that is built from nonlinear analogue devices, which perform detection in a "free-flow" network (no notion of iterations. This contribution can be viewed as an extension of analogue turbo decoder concepts to include MIMO detection. These first analogue implementations report reductions of few orders of magnitude in the number of required transistors and in consumed energy, and the same order of improvement in processing speed. It is anticipated that such analogue MIMO decoder could bring about the same advantages, when compared to traditional digital implementations.

  5. Enzymatic assay for methotrexate in erythrocytes

    DEFF Research Database (Denmark)

    Schrøder, H; Heinsvig, E M

    1985-01-01

    Methotrexate (MTX) accumulates in erythrocytes in MTX-treated patients. We present a modified enzymatic assay measuring MTX concentrations between 10 and 60 nmol/l in erythrocytes, adapted for a centrifugal analyser (Cobas Bio). About 40 patient's samples could be analysed within 1 h. The detection...... limit was 3 nmol/l. Within run and between-run precision was 7.4% and 13.5% for control 10 nmol/l and 1.2% and 3.2% for control 50 nmol/l. Recovery was 85-115% of MTX added to haemolysed erythrocytes. We found the method useful for pharmacokinetic studies of MTX in erythrocytes in MTX-treated patients...

  6. Effect of methotrexate on cerebellar development in infant rats.

    Science.gov (United States)

    Sugiyama, Akihiko; Sun, Jing; Ueda, Kota; Furukawa, Satoshi; Takeuchi, Takashi

    2015-07-01

    Six-day-old rats were treated intraperitoneal injections with methotrexate 1 mg/kg, and the cerebellum was examined. Both the length and width of the vermis decreased in the methotrexate-treated group instead of the control from 4 day after treatment (DAT) onward. A significant reduction in the width of the external granular layer was detected on 2 and 3 DAT in the methotrexate group. By 4 DAT, the width of the external granular layer of the methotrexate group was indistinguishable from the control, and by 8 DAT, it was greater than that of the control. The molecular layer of methotrexate group on 8 and 15 DAT was thinner than that of the control. On 1 DAT, in the methotrexate group, there were many TUNEL and cleaved caspase-3-positive granular cells throughout the external granular layer, and they decreased time-dependently. On 1 DAT, in the methotrexate group, phospho-histone H3-positive cells in the external granular layer were fewer than in the control and tended to increase on 2-4 DAT. The p21-positive-rate of the external granule cells in the MTX group was higher than in the control on 1-4 DAT. These results suggested that methotrexate exposure on postnatal day 6 induces a delay, slowing in the migration of external granular cells to the inner granular layer, attributed to decrease or inhibition in the production of external granular cells that had arisen from apoptosis and the decrease in cell proliferative activity, resulting in cerebellar hypoplasia.

  7. Enhancing Methotrexate Tolerance with Folate Tagged Liposomes in Arthritic Mice.

    Science.gov (United States)

    Nogueira, Eugénia; Lager, Franck; Le Roux, Delphine; Nogueira, Patrícia; Freitas, Jaime; Charvet, Celine; Renault, Gilles; Loureiro, Ana; Almeida, Catarina R; Ohradanova-Repic, Anna; Machacek, Christian; Bernardes, Gonçalo J L; Moreira, Alexandra; Stockinger, Hannes; Burnet, Michael; Carmo, Alexandre M; Gomes, Andreia C; Preto, Ana; Bismuth, Georges; Cavaco-Paulo, Artur

    2015-12-01

    Methotrexate is the first line of treatment of rheumatoid arthritis. Since many patients become unresponsive to methotrexate treatment, only very expensive biological therapies are effective and increased methotrexate tolerance strategies need to be identified. Here we propose the encapsulation of methotrexate in a new liposomal formulation using a hydrophobic fragment of surfactant protein conjugated to a linker and folate to enhance their tolerance and efficacy. In this study we aim to evaluate the efficiency of this system to treat rheumatoid arthritis, by targeting folate receptor β present at the surface of activated macrophages, key effector cells in this pathology. The specificity of our liposomal formulation to target folate receptor β was investigated both in vitro as in vivo using a mouse model of arthritis (collagen-induced arthritis in DBA/1J mice strain). In both systems, the liposomal constructs were shown to be highly specific and efficient in targeting folate receptor β. These liposomal formulations also significantly increase the clinical benefit of the encapsulated methotrexate in vivo in arthritic mice, together with reduced expression of CD39 and CD73 ectonucleotidases by joint-infiltrating macrophages. Thus, our formulation might be a promising cost effective way to treat rheumatoid arthritis and delay or reduce methotrexate intolerance.

  8. Curcumin and folic acid abrogated methotrexate induced vascular endothelial dysfunction.

    Science.gov (United States)

    Sankrityayan, Himanshu; Majumdar, Anuradha S

    2016-01-01

    Methotrexate, an antifolate drug widely used in rheumatoid arthritis, psoriasis, and cancer, is known to cause vascular endothelial dysfunction by causing hyperhomocysteinemia, direct injury to endothelium or by increasing the oxidative stress (raising levels of 7,8-dihydrobiopterin). Curcumin is a naturally occurring polyphenol with strong antioxidant and anti-inflammatory action and therapeutic spectra similar to that of methotrexate. This study was performed to evaluate the effects of curcumin on methotrexate induced vascular endothelial dysfunction and also compare its effect with that produced by folic acid (0.072 μg·g(-1)·day(-1), p.o., 2 weeks) per se and in combination. Male Wistar rats were exposed to methotrexate (0.35 mg·kg(-1)·day(-1), i.p.) for 2 weeks to induce endothelial dysfunction. Methotrexate exposure led to shedding of endothelium, decreased vascular reactivity, increased oxidative stress, decreased serum nitrite levels, and increase in aortic collagen deposition. Curcumin (200 mg·kg(-1)·day(-1) and 400 mg·kg(-1)·day(-1), p.o.) for 4 weeks prevented the increase in oxidative stress, decrease in serum nitrite, aortic collagen deposition, and also vascular reactivity. The effects were comparable with those produced by folic acid therapy. The study shows that curcumin, when concomitantly administered with methotrexate, abrogated its vascular side effects by preventing an increase in oxidative stress and abating any reduction in physiological nitric oxide levels.

  9. Methotrexate Hepatotoxicity; the Danger Not to Be Ignored

    Directory of Open Access Journals (Sweden)

    M Baghbanian

    2013-06-01

    Full Text Available Introduction: Methotrexate is used increasingly for treatment of some diseases such as rheumatoid arthritis, psoriasis and Crohn. Bone marrow suppression, mucocutaneous lesions, pneumonitis, and hepatotoxicity are major side effects of this drug. Since methotrexate toxicity is dose dependent and is usually administered with low dose via a weekly regimen, its side effects are not commonly seen. But due to long term prescription of this drug over the recent years especially for rheumatoid arthritis, growing cases of methotrexate hepatotoxicity are referred to Gastroenterologist. High dose of drug, high age, alcohol consumption, renal failure and preexisting liver disease are main risk factors for this toxicity. In this study, in addition to presenting two cases with cirrhosis and two cases with hepatitis linked to methotrexate, the clinical aspects on this field are discussed. Conclusions: Methotrexate hepatotoxicity is not a theoretical issue that can be ignored because it can lead to cirrhosis and liver failure. We can prevent the onset of this growing side effect with appropriate patient selection and investigating the patients’ liver function before and during Methotrexate therapy. Periodic testing the liver enzymes is used for monitoring the liver condition, but because interpretation of these tests is sometimes difficult, liver biopsy is needed in particular cases.

  10. Predictors of poor response to methotrexate in polyarticular-course juvenile idiopathic arthritis: analysis of the PRINTO methotrexate trial

    NARCIS (Netherlands)

    Vilca, I.; Munitis, P.G.; Pistorio, A.; Ravelli, A.; Buoncompagni, A.; Bica, B.; Campos, L.; Häfner, R.; Hofer, M.; Ozen, S.; Huemer, C.; Bae, S.C.; Sztajnbok, F.; Arguedas, O.; Foeldvari, I.; Huppertz, H.I.; Gamir, M.L.; Magnusson, B.; Dressler, F.; Uziel, Y.; van Rossum, M.A.J.; Hollingworth, P.; Cawkwell, G.; Martini, A.; Ruperto, N.

    2010-01-01

    Objectives To determine whether baseline demographic, clinical, articular and laboratory variables predict methotrexate (MTX) poor response in polyarticular-course juvenile idiopathic arthritis. Methods Patients newly treated for 6 months with MTX enrolled in the Paediatric Rheumatology Internationa

  11. Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis

    DEFF Research Database (Denmark)

    Hetland, Merete Lund; Stengaard-Pedersen, Kristian; Junker, Peter;

    2006-01-01

    OBJECTIVE: To investigate whether disease control can be achieved in early active rheumatoid arthritis (RA) by treatment with methotrexate and intraarticular betamethasone, and whether the addition of cyclosporine to the regimen has any additional effect. METHODS: Patients (n = 160) were randomized...... to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day (combination therapy) or methotrexate plus placebo-cyclosporine (monotherapy). At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 ml per visit......). Beginning at week 8, if synovitis was present, the methotrexate dosage was increased stepwise up to 20 mg/week, with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg. RESULTS: At 52 weeks, 20% improvement according to the American College of Rheumatology...

  12. Rechallenging With Intrathecal Methotrexate After Developing Subacute Neurotoxicity in Children With Hematologic Malignancies.

    Science.gov (United States)

    Badke, Colleen; Fleming, Amy; Iqbal, Asneha; Khilji, Ohmed; Parhas, Sophia; Weinstein, Joanna; Morgan, Elaine; Hijiya, Nobuko

    2016-04-01

    Methotrexate is associated with neurologic side effects. It is recommended that patients who developed neurotoxicity be rechallenged with methotrexate, but little is known about the safety of this approach. We performed a chart review to identify patients who received high-dose or intrathecal (IT) methotrexate. Twenty-one of 298 patients (7%) experienced neurologic symptoms attributed to methotrexate treatment in the premaintenance phase. Seventeen of these patients were rechallenged with IT methotrexate and 13 (76%) had no further neurotoxic events. No patients rechallenged during maintenance (n = 9) experienced recurrence of neurotoxic events. It is safe to rechallenge with IT methotrexate in maintenance.

  13. Mild Catalytic methods for Alkyl-Alkyl Bond Formation

    Energy Technology Data Exchange (ETDEWEB)

    Vicic, David A

    2009-08-10

    Overview of Research Goals and Accomplishments for the Period 07/01/06 – 06/30/07: Our overall research goal is to transform the rapidly emerging synthetic chemistry involving alkyl-alkyl cross-couplings into more of a mechanism-based field so that that new, rationally-designed catalysts can be performed under energy efficient conditions. Our specific objectives for the previous year were 1) to obtain a proper electronic description of an active catalyst for alkyl-alkyl cross-coupling reactions and 2) to determine the effect of ligand structure on the rate, scope, selectivity, and functional group compatibility of C(sp3)-C(sp3) cross-coupling catalysis. We have completed both of these initial objectives and established a firm base for further studies. The specific significant achievements of the current grant period include: 1) we have performed magnetic and computational studies on (terpyridine)NiMe, an active catalyst for alkyl-alkyl cross couplings, and have discovered that the unpaired electron resides heavily on the terpyridine ligand and that the proper electronic description of this nickel complex is a Ni(II)-methyl cation bound to a reduced terpyridine ligand; 2) we have for the first time shown that alkyl halide reduction by terpyridyl nickel catalysts is substantially ligand based; 3) we have shown by isotopic labeling studies that the active catalyst (terpyridine)NiMe is not produced via a mechanism that involves the formation of methyl radicals when (TMEDA)NiMe2 is used as the catalyst precursor; 4) we have performed an extensive ligand survey for the alkyl-alkyl cross-coupling reactions and have found that electronic factors only moderately influence reactivity in the terpyridine-based catalysis and that the most dramatic effects arise from steric and solubility factors; 5) we have found that the use of bis(dialkylphosphino)methanes as ligands for nickel does not produce active catalysts for cross-coupling but rather leads to bridging hydride

  14. Synthesis of triated N1`-alkyl derivatives of the delta opioid receptor ligand naltrindole

    Energy Technology Data Exchange (ETDEWEB)

    Lever, J.R.; Johnson, S.M. [Johns Hopkins Univ. School of Hygiene and Public Health, Environmental Health Sciences Dept., Baltimore, MD (United States)

    1997-02-01

    Tritiated N1`-methyl and N1`-ethyl analogues of naltrindole (NTI) have been synthesized for evaluation as radioligands for studies of delta opioid receptors. The two N1`-alkyl-5`,7`-dibromoNTI precursors for radiolabeling were prepared by base-promoted alkylation of 2,4-dibromophenylhydrazine with either iodomethane or iodoethane followed by condensation with naltrexone using the Fischer indole synthesis. Catalytic debromotritiation followed by HPLC purification afforded [{sup 3}H]MeNTI (17.3 Ci/mmol) and [{sup 3}H]EtNTI (22.5 Ci/mmol) with high chemical and radiochemical purities ({>=} 99.8%). (author).

  15. Synthesis and serotonin transporter activity of sulphur-substituted alpha-alkyl phenethylamines as a new class of anticancer agents

    DEFF Research Database (Denmark)

    Cloonan, Suzanne M.; Keating, John J.; Butler, Stephen G.

    2009-01-01

    transporters. In this study, a novel library of structurally diverse 4-MTA analogues were synthesised with or without N-alkyl and/or C-alpha methyl or ethyl groups so that their potential SERT-dependent antiproliferative activity could be assessed. Many of the compounds displayed SERT-binding activity as well...

  16. Primitive neuroectodermal tumor presenting as a delayed sequela to cranial irradiation and intrathecal methotrexate

    Energy Technology Data Exchange (ETDEWEB)

    Barasch, E.S.; Altieri, D.; Decker, R.E.; Ahmed, S.; Lin, J.

    1988-11-01

    A patient developed a primitive neuroectodermal tumor (PNET) many years after therapeutic cerebral radiation and methotrexate treatment for leukemia. The differential radiologic and histologic diagnoses, as well as the possible co-oncogenic effects of radiation and methotrexate, are evaluated.

  17. Carcinogenicity of insulin analogues

    NARCIS (Netherlands)

    Braak, Sebastiaan Johannes ter

    2015-01-01

    There is epidemiological evidence that the use of some insulin analogues by diabetic patients is correlated with an increased cancer risk. In vitro exposure experiments revealed that insulin glargine (LANTUS) was the only commercial insulin analogue with an increased mitogenic potential. In the huma

  18. Survey of analogue spacetimes

    CERN Document Server

    Visser, Matt

    2013-01-01

    Analogue spacetimes, (and more boldly, analogue models both of and for gravity), have attracted significant and increasing attention over the last decade and a half. Perhaps the most straightforward physical example, which serves as a template for most of the others, is Bill Unruh's model for a dumb hole, (mute black hole, acoustic black hole), wherein sound is dragged along by a moving fluid --- and can even be trapped behind an acoustic horizon. This and related analogue models for curved spacetimes are useful in many ways: Analogue spacetimes provide general relativists with extremely concrete physical models to help focus their thinking, and conversely the techniques of curved spacetime can sometimes help improve our understanding of condensed matter and/or optical systems by providing an unexpected and countervailing viewpoint. In this introductory chapter, I shall provide a few simple examples of analogue spacetimes as general background for the rest of the contributions.

  19. METHOTREXATE IN THE TREATMENT OF GLUCOCORTICOID-DEPENDENT ASTHMA

    Institute of Scientific and Technical Information of China (English)

    王国杨; 朱利文; 姚婉贞; 赵呜武

    2001-01-01

    To study how low-dose of methotrexate affects steroid use, asthma symptom scores and pulmonary function in glucocorticoid-dependent asthmatic patients.Methods 13 patients with severe, steroid-dependent asthma were enrolled in the prospective study, who received weekly oral methotrexate 20 mg for 12 months. Of these 13 patients, 12 finished 12 monthcourseResults The mean prednisone dose reduced from 20.63mg/d to 7.71mg/d (P<0.001) in the 12 patients treated with long-term methotrexate: Eight patients discontinued the regular use of prednisone, 10 patients reduced predaisone dosage by more than 50%. Measurement of forced vital capacity(FVC) and forced expiratory volume in one second (FEV1) showed that there was no deterioration due to methotrexate treatment and steroid reduction. Mean daily symptom scores for cough, wheezing, shortness of breath, and chest tightness remained unchanged.Conclusion Our study provides evidence supporting the long-term efficacy and safety of methotrexate in patients with severe bronchial asthma.

  20. Synthetic ganglioside analogues for sensitive biosensing : improved probes for antibodies and bacterial toxins

    NARCIS (Netherlands)

    Pukin, A.V.

    2010-01-01

    This thesis describes the synthesis of analogues of human gangliosides and applications thereof for the detection and inhibition of bacterial toxins and antibodies. An efficient glycosylation method was developed for the synthesis of ω-functionalized alkyl lactosides (Chapter 2). These lactosides we

  1. Cladribine Analogues via O6-(Benzotriazolyl Derivatives of Guanine Nucleosides

    Directory of Open Access Journals (Sweden)

    Sakilam Satishkumar

    2015-10-01

    Full Text Available Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxytris(dimethylaminophosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL, T-cell lymphoma (TCL and chronic lymphocytic leukemia (CLL, cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.

  2. 40 CFR 721.9892 - Alkylated urea.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkylated urea. 721.9892 Section 721... Alkylated urea. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as an alkylated urea (PMN P-93-1649) is subject to reporting under...

  3. MICROWAVE IRRADIATED ALKYLATION OF DIETHYL ACETAMIDOMALONATE

    Institute of Scientific and Technical Information of China (English)

    张雅文; 沈宗旋; 陆军

    1995-01-01

    Ethyl acetamidomalonate was alkylated using three alkylating agents, both by microtwave irradiation of a mixture of the malonate,the alkylating agent, potassium carbonate,TEBA,and DMF for 0.5 to 1.5 min and by heating a solution of the malonate, sodium ethoxide, and the alkylatlng agent in ethanol for several hours. The two metlmds gave comparable results.

  4. Preparation of the pyridinium salts differing in the length of the N-alkyl substituent.

    Science.gov (United States)

    Marek, Jan; Stodulka, Petr; Cabal, Jiri; Soukup, Ondrej; Pohanka, Miroslav; Korabecny, Jan; Musilek, Kamil; Kuca, Kamil

    2010-03-19

    Quaternary pyridinium salts with chains ranging from C8 to C20 belong in the large group of cationic surfactants. In this paper, the preparation of such cationic surface active agents based on the pyridinium moiety and differing in the length of the N-alkyl chain is described. Additionally, HPLC technique was established to distinguish each prepared pyridinium analogue. This study represents universal method for preparation and identification of quaternary pyridinium detergents.

  5. Preparation of the Pyridinium Salts Differing in the Length of the N-Alkyl Substituent

    Directory of Open Access Journals (Sweden)

    Kamil Musilek

    2010-03-01

    Full Text Available Quaternary pyridinium salts with chains ranging from C8 to C20 belong in the large group of cationic surfactants. In this paper, the preparation of such cationic surface active agents based on the pyridinium moiety and differing in the length of the N-alkyl chain is described. Additionally, HPLC technique was established to distinguish each prepared pyridinium analogue. This study represents universal method for preparation and identification of quaternary pyridinium detergents.

  6. Intravitreal methotrexate infusion for proliferative vitreoretinopathy

    Directory of Open Access Journals (Sweden)

    Sadaka A

    2016-09-01

    Full Text Available Ama Sadaka,1 Robert A Sisk,1–3 James M Osher,1,3 Okan Toygar,4 Melinda K Duncan,5 Christopher D Riemann1,3 1Department of Ophthalmology, University of Cincinnati College of Medicine, 2Department of Opthalmology, Cincinnati Children’s Hospital Medical Center, 3Cincinnati Eye Institute, Cincinnati, OH, USA; 4Department of Ophthalmology, Bahcesehir University Medical Faculty, Istanbul, Turkey; 5Department of Biological Sciences, University of Delaware, Newark, DE, USA Purpose: The purpose of this study was to evaluate intravitreal methotrexate infusion (IMI during pars plana vitrectomy (PPV for retinal detachment in patients with high risk for the development of proliferative vitreoretinopathy (PVR.Methods: Patients presenting with severe recurrent PVR with tractional retinal detachment and/or a history of severe ocular inflammation were treated with IMI. Clinical outcomes were determined from a retrospective medical chart review.Results: Twenty-nine eyes presenting with either tractional retinal detachment and recurrent PVR (n=22 or a history of severe inflammation associated with high PVR risk (n=7 received IMI during PPV. Best-corrected visual acuity at 6 months was ≥20/200 in 19 of 29 eyes (66% and remained stable or improved compared with initial presentation in 24 of 29 eyes (83%. At the last follow-up examination, the retinas of 26 of 29 eyes (90% remained attached after IMI while three eyes required another reattachment procedure. Three additional eyes (10% developed recurrent limited PVR without recurrent RD and were observed. No complications attributable to IMI occurred during a mean follow-up of 27 months.Conclusion: Eyes at high risk for PVR development due to a history of prior PVR or intraocular inflammation had a low incidence of PVR following IMI at the time of PPV for RD repair. No significant safety issues from IMI were observed in this series. Keywords: tractional retinal detachment, recurrent retinal detachment, pars

  7. Two interesting cases of gestational trophoblastic disease with methotrexate failure

    Directory of Open Access Journals (Sweden)

    Poonam Laul

    2016-09-01

    Full Text Available Gestational trophoblastic disease is group tumours that are more sensitive and respond well to a wide variety of chemotherapeutic regimes. Presented here are two interesting cases one with life threatening bleeding requiring hysterectomy and other with persistent disease post evacuation. Both being low risk were treated with single agent methotrexate, but failed to respond. They responded to alternative chemotherapy. Methotrexate resistant is seen even in low risk group. [Int J Reprod Contracept Obstet Gynecol 2016; 5(9.000: 3251-3253

  8. Methotrexate-induced misincorporation of uracil into DNA

    OpenAIRE

    Goulian, M; Bleile, B.; Tseng, B. Y.

    1980-01-01

    A line of human lymphoid cells was tested for the presence of dUMP in DNA with or without treatment with the dihydrofolate reductase inhibitor, methotrexate. Cells treated with methotrexate and labeled with [3H]dUrd contained dUMP in DNA in readily detectable amounts (≈0.8 pmol of dUMP per μmol of total DNA nucleotide), and this was increased ≈3-fold if the cells were also treated with Ura at the same time. No dUMP (

  9. Ulcerations due to methotrexate toxicity in a psoriasis patient*

    Science.gov (United States)

    Souza, Claudia Fernanda Dias; Suarez, Olga Milena Zarco; da Silva, Talita Fonseca Medeiros; Gorenstein, Ana Carolina Lourenço Araújo; Quintella, Leonardo Pereira; Avelleira, João Carlos Regazzi

    2016-01-01

    Methotrexate is one of the most used drugs in the treatment of psoriasis with indication of systemic therapy. Cutaneous and mucous side effects are described by pharmacological characteristics of the drug itself or due to overdose. We report the case of a patient with ulcerations in oral mucosa and psoriatic plaques after incorrect use of Methotrexate. Prescribed in a weekly dose, it was used continuously for 10 days and without simultaneous intake of folic acid. It is important to ensure correct comprehension of the prescription. PMID:27438211

  10. Effective Response of Methotrexate for Recurrent Idiopathic Hypertrophic Spinal Pachymeningitis

    Science.gov (United States)

    Park, Tae Joon; Seo, Won Deok; Kim, Sang Young; Cho, Jae Hoon; Kim, Dae Hyun

    2016-01-01

    Idiopathic hypertrophic spinal pachymeningitis (IHSP) is a chronic progressive and diffuse inflammatory fibrosis of the spinal dura mater. Though treatment of IHSP is surgical decompression with steroid therapy, treatment for recurrent IHSP is controversial. Our patient was diagnosed with IHSP based on magnetic resonance imaging (MRI) and underwent laminectomy for decompression following steroid pulse therapy. Despite maintenance of steroid therapy, the patient experienced 3 recurrences. As an alternative immunosuppressant medication, methotrexate was introduced with low-dose steroid. Fortunately, the symptom was resolved, and a decrease of dura thickening was revealed on MRI. We present the case and suggest that methotrexate might be an effective treatment modality for recurrent IHSP.

  11. Methotrexate-induced necrolysis in tumoral-stage mycosis fungoides: a challenging diagnosis.

    Science.gov (United States)

    Mna, Amira Ben; Souissi, Asmahene; Halouani, Slim; El Euch, Dalenda; Zahani, Alia; Kchir, Nidham; Zaraa, Ines; Mokni, Mourad

    2016-01-01

    Methotrexate-induced cutaneous ulceration is a rare but potentially serious drug adverse reaction. This adverse reaction of methotrexate therapy has been initially described in psoriasis patients and is unusual in patients with cutaneous T-cell lymphoma. In 1978, Mc Donald et al reported the first three cases of cutaneous ulcerations in patients treated for a mycosis fungoides with intravenous infusions of methotrexate. Since then, few cases of methotrexate-induced skin ulcers in patients with mycosis fungoides have been published. We report an additional patient with erythrodermic mycosis fungoides who developed cutaneous ulcerations as a sole manifestation of methotrexate toxicity.

  12. Synthesis of Tonghaosu Analogues

    Institute of Scientific and Technical Information of China (English)

    SUN Hai; LIN Yingjie; WU Yulin; WU Yikang

    2009-01-01

    Several new analogues of natural antifeedant tonghaosu were synthesized via m-CPBA (m-chloroperoxybenzoic acid) oxidation of corresponding 3-(a-furyl)propanols, Luche reduction of the resulting enone, epoxidation, acid-mediated spiroketalization, and radical mediated dehydration.

  13. Methotrexate use in rheumatoid arthritis. A Clinician's perspective.

    Science.gov (United States)

    Alarcón, G S

    2000-05-01

    Aminopterine, a precursor of methotrexate (MTX), was first used for the treatment of rheumatoid arthritis (RA) in 1951 [Gubner, R., 1951. Therapeutic suppression of tissue reactivity: I. Comparison of the effects of cortisone and aminopterin. Am. J. Med. Sci. 221, 169-175; Gubner, R., August, S., Ginsberg, V., 1951. Therapeutic suppression of tissue reactivity: II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am. J. Med. Sci. 221, 176-182.]. Corticosteroids, and to some extent cyclophosphamide, took MTX out of the rheumatologist's armamentarium until the late 1970s-early 1980s when the toxic profile of these compounds became apparent. By the mid 1980s, four randomized clinical trials (RCTs) had proven beyond doubt the beneficial effects of MTX when administered to patients with established disease who had failed to respond to other compounds such as gold salts and D-penicillamine [Thompson, R.N., Watts, C., Edelman, J., Esdaile, J., and Russell, A.S., 1984. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J. Rheumatol. 11, 760-763; Andersen, P.A., West, S.G., O'Dell, J.R., Via, C.S., Claypool, R.G., and Kotzin, B.L., 1985. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Ann. Intern. Med. 103, 489-496; Weinblatt, M.E., Coblyn, J.S., Fox, D.A., Fraser, P.A., Holdsworth, D.E., Glass, D.N., and Trentham, D.E., 1985. Efficacy of low-dose methotrexate in rheumatoid arthritis. N. Engl. J. Med. 312, 818-822; Williams, H.J., Willkens, R.F., Samuelson, C.O.J., Alarcón, G.S., Guttadauria, M., Yarboro, C., Polisson, R.P., Weiner, S.R., Luggen, M.E., Billingsley, L.M., Dahl, S.L., Egger, M.J., Reading, J.C., and Ward, J.R., 1985. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum. 28, 721-730.]. Subsequently, these four trials were included in

  14. Serum Creatinine Versus Plasma Methotrexate Levels to Predict Toxicities in Children Receiving High-dose Methotrexate.

    Science.gov (United States)

    Tiwari, Priya; Thomas, M K; Pathania, Subha; Dhawan, Deepa; Gupta, Y K; Vishnubhatla, Sreenivas; Bakhshi, Sameer

    2015-01-01

    Facilities for measuring methotrexate (MTX) levels are not available everywhere, potentially limiting administration of high-dose methotrexate (HDMTX). We hypothesized that serum creatinine alteration after HDMTX administration predicts MTX clearance. Overall, 122 cycles in 50 patients of non-Hodgkin lymphoma or acute lymphoblastic leukemia aged ≤18 years receiving HDMTX were enrolled prospectively. Plasma MTX levels were measured at 12, 24, 36, 48, 60, and 72 hours; serum creatinine was measured at baseline, 24, 48, and 72 hours. Correlation of plasma MTX levels with creatinine levels and changes in creatinine from baseline (Δ creatinine) were evaluated. Plasma MTX levels at 72 hours showed positive correlation with serum creatinine at 48 hours (P = .011) and 72 hours (P = .013) as also Δ creatinine at 48 hours (P = .042) and 72 hours (P = .045). However, cut-off value of either creatinine or Δ creatinine could not be established to reliably predict delayed MTX clearance. Greater than 50% Δ creatinine at 48 and 72 hours significantly predicted grade 3/4 leucopenia (P = .036 and P = .001, respectively) and thrombocytopenia (P = .012 and P = .009, respectively) but not mucositis (P = .827 and P = .910, respectively). Delayed MTX elimination did not predict any grade 3/4 toxicity. In spite of demonstration of significant correlation between serum creatinine and Δ creatinine with plasma MTX levels at 72 hours, cut-off value of either variable to predict MTX delay could not be established. Thus, either of these cannot be used as a surrogate for plasma MTX estimation. Interestingly, Δ creatinine effectively predicted hematological toxicities, which were not predicted by delayed MTX clearance.

  15. Failure Rate of Single Dose Methotrexate in Managment of Ectopic Pregnancy

    Directory of Open Access Journals (Sweden)

    Feras Sendy

    2015-01-01

    Full Text Available Background. One of the treatment modalities for ectopic pregnancy is methotrexate. The purpose of this study is to identify the failure rate of methotrexate in treating patients with ectopic pregnancy as well as the risk factors leading to treatment failure. Methods. A retrospective chart review of 225 patients who received methotrexate as a primary management option for ectopic pregnancy. Failure of single dose of methotrexate was defined as drop of BHCG level less than or equal to 14% in the seventh day after administration of methotrexate. Results. 225 patients had methotrexate. Most of the patients (151 (67% received methotrexate based on the following formula: f 50 mg X body surface area. Single dose of methotrexate was successful in 72% (162/225 of the patients. 28% (63/225 were labeled as failure of single dose of methotrexate because of suboptimal drop in BhCG. 63% (40/63 of failure received a second dose of methotrexate, and 37% (23/63 underwent surgical treatment. Among patient who received initial dose of methotrexate, 71% had moderate or severe pain, and 58% had ectopic mass size of more than 4 cm on ultrasound. Conclusion. Liberal use of medical treatment of ectopic pregnancy results in 71% success rate.

  16. Does switching from oral to subcutaneous administration of methotrexate influence on patient reported gastro-intestinal adverse effects?

    DEFF Research Database (Denmark)

    Kromann, Charles B; Lage-Hansen, Philip R; Koefoed, Mette

    2015-01-01

    INTRODUCTION: When treating patients with methotrexate (MTX) the most frequently reported adverse effects (AE) are gastrointestinal (GI) with nausea being reported by 10-20%. If intolerable AE of oral MTX persist, switching from oral to subcutaneous (SC) or intramuscular (IM) administration...... is common. However, this approach is largely empirical and the evidence is inconsistent. To our knowledge, this will be the first study to estimate the change in GI AE of switching from oral to SC MTX. METHODS: A retrospective postal survey was sent to patients who had changed from oral MTX to SC MTX. GI AE...... was rated by visual analogue scale (VAS) regarding frequency and intensity of nausea, frequency of vomiting and frequency of discomfort. All participants gave informed consent. No further ethical clearance was necessary according to national law. RESULTS: Of the sample 39/57 (68.4%) responded. Significant...

  17. Advances in individual prediction of methotrexate toxicity: a review

    DEFF Research Database (Denmark)

    Schmiegelow, K.

    2009-01-01

    As the cure rates for haematological malignancies have improved, the exploration of the balance between efficacy and side effects has become a major research target. The antifolate methotrexate is widely used in the treatment of acute lymphoblastic leukaemia, non-Hodgkin lymphoma, and osteosarcoma...

  18. Etanercept combined with methotrexate for high-need psoriasis.

    NARCIS (Netherlands)

    Driessen, R.J.B.; Kerkhof, P.C.M. van de; Jong, E.M.G.J. de

    2008-01-01

    BACKGROUND: For some high-need psoriatic patients, the efficacy of etanercept monotherapy is insufficient. In these cases it might be indicated to combine etanercept with other conventional treatments. Objectives To provide daily practice safety and efficacy data for etanercept and methotrexate comb

  19. Phase II trial of methotrexate in myasthenia gravis.

    Science.gov (United States)

    Pasnoor, Mamatha; He, Jianghua; Herbelin, Laura; Dimachkie, Mazen; Barohn, Richard J

    2012-12-01

    Prednisone is a frequently used treatment for myasthenia gravis (MG) but it has numerous side effects. Methotrexate is a selective inhibitor of dihydrofolate reductase and lymphocyte proliferation and is an effective immuosuppressive medication for autoimmune diseases. Given the negative results of the mycophenolate mofetil study, search for an effective immunosuppressant drug therapy is ongoing. The objective is to determine if oral methotrexate is safe and effective for MG patients who take prednisone. We have initiated a randomized, double-blind, placebo-controlled multicenter trial of methotrexate versus placebo in patients taking at least 10 mg/day of prednisone at enrollment. The methotrexate dose is increased to 20 mg and the prednisone dose is adjusted per protocol during the study. Clinical and laboratory evaluations are performed monthly for 12 months, with the primary efficacy measure being the nine-month prednisone area under the curve (AUC) from months 3 to 12. Secondary outcome measures include MG outcomes, quality of life measures, and a polyglutamation biomarker assay. A total of 18 U.S. sites and 2 Canadian sites are participating, with 48 screened cases, 42 enrolled, with 19 still active in the study.

  20. Methotrexate: should we start using it in clinical practice?

    Science.gov (United States)

    Miheller, Pal; Kiss, Lajos S; Mandel, Michael; Lakatos, Peter L

    2013-11-01

    Therapeutic approaches in inflammatory bowel disease have changed significantly in the past decade. Early aggressive immunosuppression has become the mainstay of therapy for patients at risk for complicated disease. Azathioprine is the most widely used immunosuppressant; however, a subgroup of patients is intolerant or refractory. Since the late 1990s, methotrexate (MTX) has become more widely used as an immunomodulator in patients with chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. Yet according to recent clinical data, methotrexate remained the second most commonly used immunosuppressive in inflammatory bowel diseases. Two landmark trials and subsequent studies provided evidence for the use of methotrexate in Crohn's disease, both for induction and maintenance of remission. The evidence is less solid in ulcerative colitis, for which results of further randomized controlled trials are pending (e.g. Meteor, Merit). A potential new indication of MTX could be combination therapy with biologicals. While this is state of the art therapy in rheumatoid arthritis, data in inflammatory bowel diseases are less clear. Some studies suggest that combination with immunosuppressants could prevent the development of anti-drug antibodies, while others suggested anti- TNF induced autoimmune disorders as a potential indication. In contrast, improved efficacy was not reported by one study (COMMIT). Limitations include frequent side effects, route of administration, pregnancy and concerns about long-term safety. This review summarizes current knowledge on the efficacy and side effects of methotrexate, and tries to reevaluate the drug in the current IBD armamentarium.

  1. Methods of making alkyl esters

    Science.gov (United States)

    Elliott, Brian

    2010-08-03

    A method comprising contacting an alcohol, a feed comprising one or more glycerides and equal to or greater than 2 wt % of one or more free fatty acids, and a solid acid catalyst, a nanostructured polymer catalyst, or a sulfated zirconia catalyst in one or more reactors, and recovering from the one or more reactors an effluent comprising equal to or greater than about 75 wt % alkyl ester and equal to or less than about 5 wt % glyceride.

  2. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis: development and validation of a methotrexate intolerance severity score

    NARCIS (Netherlands)

    Bulatovic, M.; Heijstek, M.W.; Verkaaik, M.; Dijkhuizen, E.H. van; Armbrust, W.; Hoppenreijs, E.P.A.H.; Kamphuis, S.; Kuis, W.; Egberts, T.C.; Sinnema, G.; Rademaker, C.M.A.; Wulffraat, N.M.

    2011-01-01

    OBJECTIVE: To design and validate a new questionnaire for identifying patients with methotrexate (MTX) intolerance, and to determine the prevalence of MTX intolerance in patients with juvenile idiopathic arthritis (JIA) using this questionnaire. METHODS: The MTX Intolerance Severity Score (MISS) que

  3. High prevalence of methotrexate intolerance in juvenile idiopathic arthritis : development and validation of a methotrexate intolerance severity score

    NARCIS (Netherlands)

    Bulatović, Maja; Heijstek, Marloes W; Verkaaik, Marleen; van Dijkhuizen, E H Pieter; Armbrust, Wineke; Hoppenreijs, Esther P A; Kamphuis, Sylvia; Kuis, Wietse; Egberts, Toine C G; Sinnema, Gerben; Rademaker, Carin M A; Wulffraat, Nico M

    2011-01-01

    OBJECTIVE: To design and validate a new questionnaire for identifying patients with methotrexate (MTX) intolerance, and to determine the prevalence of MTX intolerance in patients with juvenile idiopathic arthritis (JIA) using this questionnaire. METHODS: The MTX Intolerance Severity Score (MISS) que

  4. A case of delayed methotrexate clearance following administration of a complementary medication containing chlorophyll.

    Science.gov (United States)

    Brooks, Sally L; Sanders, Julie; Seymour, John F; Mellor, James D

    2014-06-01

    A 54-year-old male with relapsed primary cerebral lymphoma and normal renal function was treated with methotrexate (MTX) 3 g/m(2) monthly by intravenous infusion. Throughout treatment the patient self-administered a complementary medicine (Jason Winter's chlorophyll®), which he was advised to cease during methotrexate treatment due to the potential for unknown interactions. For the first four cycles, chlorophyll was ceased two days prior to commencement of methotrexate and withheld until clearance. These cycles were administered without complication, and the methotrexate level reduced to chlorophyll was not ceased and there were no changes to concomitant medications. A literature search found no documented interactions between methotrexate and chlorophyll and the chemotherapy was administered without a delay in treatment. The methotrexate level three days post-administration was 0.36 µmol/L and did not reduce to chlorophyll 48 h prior to methotrexate administration until clearance. There were no further episodes of delayed methotrexate clearance. No impurities were detected in a sample of Jason Winter's chlorophyll®. It is therefore likely that the patient's delayed methotrexate clearance was due to an interaction with chlorophyll. It is recommended that such chlorophyll containing preparations be avoided in patients treated with methotrexate.

  5. Methotrexate en radiotherapie. Een onderzoek naar de mogelijkheden van orale of intraveneuze toediening van methotrexate bij de radiotherapie van kanker in het hoofd-halsgebied

    NARCIS (Netherlands)

    Rietberg, Martinus

    1972-01-01

    Het doel van deze ,,pilotstudy" was om na te gaan a. of de kombinatie van methotrexate en radiotherapie van waarde kan zijn bij de behandeling van kanker in het hoofohals gebied; b. welke problemen zich voordoen bij deze gekombineerde behandeling en c. welke dosering methotrexate gewenst is en hoe d

  6. Combination of Mangifera indica L. extract supplementation plus methotrexate in rheumatoid arthritis patients: a pilot study.

    Science.gov (United States)

    López Mantecón, Ana M; Garrido, Gabino; Delgado-Hernández, René; Garrido-Suárez, Bárbara B

    2014-08-01

    The purpose of the present study was to evaluate the possible therapeutic effects and the safety of Mangifera indica extract (Vimang tablets, 300 mg) combined with methotrexate (MTX) on reducing disease activity in rheumatoid arthritis (RA). Twenty patients with active RA underwent a year of treatment with MTX (12.5 mg/week) associated to non-steroidal anti-inflammatory drugs (NSAIDs) and/or prednisone (5-10 mg/day) were randomly allocated to the experimental group (n=10), that received the extract supplementation (900 mg/day) or preceding usual treatment (n=10) during 180 days. RA activity was evaluated using the tender and swollen joint counts, erythrocyte sedimentation rate, disease activity score-28 (DAS 28), visual analogue scale (VAS) and health assessment questionnaire (HAQ). Treatment's efficacy was demonstrated with ACR criteria. Only the patients of MTX-Vimang group revealed statistically significant improvement in DAS 28 parameters with respect baseline data but no differences were observed between groups. ACR improvements amounted 80% only in MTX-Vimang group at the 90 days (p<0.001). In MTX-Vimang group, 100% of patients decreased NSAIDs administration (p<0.01) and 70% of those eradicated gastrointestinal side effects (p<0.01) ensuing of the preceding treatment. Other adverse effects were not reported.

  7. Subacute toxicopathological studies of methotrexate in Wistar rats

    Directory of Open Access Journals (Sweden)

    N. N. Patel

    2014-07-01

    Full Text Available Aim: A toxico-pathological study was undertaken to assess the effects of Methotrexate administration in Wistar rats by performing the hematology, serum biochemical analysis and associated histopathological changes in visceral organs. Materials and Methods: Rats in 4 treatment groups with 6 male and 6 female rats each were administered methotrexate (Group II to IV at the dose rate of 0.062, 0.125 and 0.250 mg/kg body weight respectively and distilled water (Group I as vehicle control for 28 days. Hematological parameters viz., total erythrocyte count, haemoglobin, packed cell volume, MCV, MCH and MCHC, total leukocyte count and differential leukocyte count and serum biochemical parameters viz., aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, serum creatinine, blood urea nitrogen, total protein, albumin, globulin (Calculated were estimated after 28 days. Necropsy examination was performed in all sacrificed animals and gross lesions were recorded. Tissue samples (lung, liver, kidney, intestine, testes and heart were collected in 10% formalin solution for histo-pathological examination. Results: The dose dependent reduction in body weight, feed consumption, RBCs count, packed cell volume, haemoglobin, total leucocyte count, neutrophil count, total protein and albumin was observed in animals of group II, III and IV along with significant increase in lymphocyte count, AST, ALT, AKP, creatinine and BUN in animals of methotrexate treated group IV followed by group III. No significant change in monocyte, eosinophil and basophil counts were observed in any treatment groups. All the rats exposed to methotrexate at three different dose levels revealed dose dependent pathological changes characterized by degeneration, necrosis, congestion, haemorrhage and vascular changes. The main target organs affected were liver, kidney, lungs and testes. Conclusion: It can be concluded from this study that sub-acute exposure to methotrexate

  8. Methotrexate Associated Renal Impairment Is Related to Delayed Elimination of High-Dose Methotrexate

    Directory of Open Access Journals (Sweden)

    Shi-Long Yang

    2015-01-01

    Full Text Available Although Methotrexate (MTX is an effective drug for the treatment of acute lymphoblastic leukemia (ALL, the toxicity remains a significant problem. In this prospective study, fifty-four patients with ALL were enrolled. 3 g or 5 g MTX/m2 was administered over 24 hours. Serum MTX concentrations were determined in 24, 48, and 96 hours after MTX infusion. Serum creatinine concentrations and creatinine clearance rate (CCR were determined before and 24 and 48 hours after MTX infusion. A total of 173 courses of MTX infusion were administered. The serum creatinine concentrations did not change much after MTX infusion while the CCR was gradually decreased. MTX clearance status was independently related to CCR decrease, with the risk of 8.07 to develop renal impairment in patients with delayed MTX elimination. Serum creatinine concentration, serum creatinine ratio, CCR, and CCR ratio at 24 hours were all related to MTX elimination delay. Patients with serum creatinine level >35.0 μmol/L, creatinine ratio >1.129, or CCR <100.0 mL/min were more likely to undergo MTX elimination delay. In conclusion, MTX could induce transient renal impairment and compromised renal function will delay MTX clearance. The serum creatinine concentration and the ratio and CCR are useful tools for evaluating MTX elimination status.

  9. A micelle-like structure of poloxamer-methotrexate conjugates as nanocarrier for methotrexate delivery.

    Science.gov (United States)

    Ren, Jin; Fang, Zhengjie; Yao, Li; Dahmani, Fatima Zohra; Yin, Lifang; Zhou, Jianping; Yao, Jing

    2015-06-20

    The purpose of this study was to develop a novel featured and flexible methotrexate (MTX) formulation, in which MTX was physically entrapped and chemically conjugated in the same drug delivery system. A series of poloxamer-MTX (p-MTX) conjugates was synthesized, wherein MTX was grafted to poloxamer through an ester bond. p-MTX conjugates could self-assemble into micelle-like structures in aqueous environment and the MTX end was in the inner-core of micelles. Moreover, free MTX could be physically entrapped into p-MTX micelles hydrophobic core region to increase the total drug loading. Importantly, the resulting MTX-loaded p-MTX micelles showed a biphasic release of MTX, with a relative fast release of the entrapped MTX (about 6-7h) followed by a sustained release of the conjugated MTX. The pharmacokinetics study showed that the mean residence time (MRT) was extended in the case of MTX-loaded p-MTX micelles, indicating a delayed MTX elimination from the bloodstream and prolonged in vivo residence time. Besides, the area under curve (AUC) of MTX-loaded p-MTX micelles was greater than free MTX, indicating a drug bioavailability improvement. Overall, MTX-loaded p-MTX micelles might be a promising nanosized drug delivery system for the cancer therapy.

  10. Pharmacogenomics of Methotrexate Membrane Transport Pathway: Can Clinical Response to Methotrexate in Rheumatoid Arthritis Be Predicted?

    Directory of Open Access Journals (Sweden)

    Aurea Lima

    2015-06-01

    Full Text Available Background: Methotrexate (MTX is widely used for rheumatoid arthritis (RA treatment. Single nucleotide polymorphisms (SNPs could be used as predictors of patients’ therapeutic outcome variability. Therefore, this study aims to evaluate the influence of SNPs in genes encoding for MTX membrane transport proteins in order to predict clinical response to MTX. Methods: Clinicopathological data from 233 RA patients treated with MTX were collected, clinical response defined, and patients genotyped for 23 SNPs. Genotype and haplotype analyses were performed using multivariate methods and a genetic risk index (GRI for non-response was created. Results: Increased risk for non-response was associated to SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G carriers; ABCC1 rs3784864 G carriers; CGG haplotype for ABCC1 rs35592, rs2074087 and rs3784864; and CGG haplotype for ABCC1 rs35592, rs246240 and rs3784864. GRI demonstrated that patients with Index 3 were 16-fold more likely to be non-responders than those with Index 1. Conclusions: This study revealed that SLC22A11 and ABCC1 may be important to identify those patients who will not benefit from MTX treatment, highlighting the relevance in translating these results to clinical practice. However, further validation by independent studies is needed to develop the field of personalized medicine to predict clinical response to MTX treatment.

  11. 40 CFR 721.1875 - Boric acid, alkyl and substituted alkyl esters (generic name).

    Science.gov (United States)

    2010-07-01

    ... alkyl esters (generic name). 721.1875 Section 721.1875 Protection of Environment ENVIRONMENTAL... esters (generic name). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance boric acid, alkyl and substituted alkyl esters (PMN P-86-1252) is subject to...

  12. ACTINOMYCIN D ANALOGUES

    DEFF Research Database (Denmark)

    1997-01-01

    The present invention relates to new compounds being structurally and functionally similar to Actinomycin D and to combinatorial libraries of such compounds. The Actinomycin D analogues according to the present invention comprise two linear or cyclic peptide moieties constituted by $g...

  13. Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate.

    OpenAIRE

    Boogerd, W.; vd Sande, J J; Moffie, D

    1988-01-01

    Nine out of 14 patients treated with intraventricular methotrexate (MTX) for meningeal carcinomatosis from breast carcinoma and surviving more than 4 months developed disseminated necrotising leukoencephalopathy (DNL). All four patients who had received both intraventricular MTX and whole brain radiotherapy developed DNL. Five of the six patients who experienced an acute febrile reaction with mild encephalopathic signs following intraventricular administration of MTX developed DNL after a mea...

  14. Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

    DEFF Research Database (Denmark)

    Schmiegelow, K.; Nielsen, Stine N; Frandsen, Thomas L;

    2014-01-01

    The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug...... intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments, extensive host genome profiling to understand diversity in treatment efficacy and toxicity, and alternative thiopurine dosing regimens...

  15. Beneficial effect of erdosteine on methotrexate-induced testicular toxicity in mice.

    Science.gov (United States)

    Oktar, Süleyman; Gökçe, Ahmet; Aydin, Mehmet; Davarci, Mürsel; Meydan, Sedat; Oztürk, Oktay Hasan; Koç, Ahmet

    2010-08-01

    Methotrexate is used to treat certain types of cancer of the breast, skin, head and neck, or lung. Methotrexate can cause serious or life-threatening side effects on liver, lungs, kidneys, and immune system. Methotrexate chemotherapy causes testicular damage in humans. The aim of this study was to investigate the possible protective role of erdosteine on testicular toxicity of methotrexate in mice. Twenty-six male mice were divided into four groups as follows: group 1, control; group 2, erdosteine-treated; group 3, methotrexate-treated; and group 4, methotrexate + erdosteine treated. On the first day of experiment, a single dose of methotrexate was intraperitoneally administered to groups 3 and 4, although a daily single dose of erdosteine was orally administered to group 2 and 4 for 7 days. At the end of the experiment, the testes of the animals were removed and weighed. The levels of total antioxidant capacity and total oxidative stress, and myeloperoxidase activity in the methotrexate group were higher than the control group (perdosteine could effectively protect the testes in methotrexate-induced toxicity.

  16. [The use of methotrexate for the treatment of sarcoidosis (data from a controlled prospective study)].

    Science.gov (United States)

    Vizel, A A; Vzel, I Yu

    2015-01-01

    We estimated the effectiveness and safety of methotrexate monotherapy of sarcoidosis in 63 patients refractory to the previous treatment. Methotrexate was given weekly at a dose of 5-20 mg. 54% of the patients reported improvement of their condition. Parameters of spirogram and the ray picture improved in 63.2 and 54% of the cases respectively. Methotrexate proved safe and had to be discontinued only in 12.6% of the patients. It is concluded that methotrexate can be used at least in half of the cases as a safe alternative to systemic steroid therapy.

  17. Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice

    Directory of Open Access Journals (Sweden)

    Andre Michael Mueller

    2013-10-01

    Full Text Available We previously showed that intrathecal administration of methotrexate slowed disability progression in multiple sclerosis patients with progressive disease. In general MS patients with progressive disease respond poorly to anti-inflammatory therapies. In order to better understand the mechanism by which methotrexate is protective in progressive MS, we analyzed its impact on the non-inflammatory cuprizone-induced demyelination model.When low-dose methotrexate was administered intracerebroventricularly it reduced demyelination and accumulation of GFAP+ reactive astrocytes in the corpus callosum. Administration of methotrexate after the withdrawal of cuprizone neither delayed remyelination nor influenced the number of astrocytes in the corpus callosum suggesting that methotrexate does not interfere with repair processes in the CNS. Moreover, methotrexate increased the expression of IGF1 in vitro and in vivo, a factor known to protect oligodendrocytes and limit the activation of astrocytes. Our studies show that methotrexate has an impact on pathogenic process in a demyelination model whose pathophysiological basis is not primarily related to inflammatory mechanisms, similar to neurodegenerative mechanisms associated with progressive MS. The pronounced inhibitory influence of methotrexate on the accumulation of astrocytes in the corpus callosum suggests that intrathecal methotrexate modulates astroglial activation in progressive MS possibly by promoting CNS production of IGF1.

  18. Relative bioavailability of oral low dose methotrexate. A comparison of 2 different formulations.

    Science.gov (United States)

    Fosså, S D; Tveit, K; Börmer, O; Moxnes, A; Jørgensen, N P; Orjaseter, H; Kristoffersen, D T

    1988-01-01

    In 39 patients the bioavailability of methotrexate from the two tablets Emthexat 2.5 mg and Methotrexate 2.5 mg was assessed in a double-blind study after a single oral dose of 30 mg/m2 Methotrexate. There was a considerable inter-individual variation of the serum pharmacokinetics in regard to Cmax and tmax, independent on the MTX formulation. Emthexat 2.5 mg tablets and Methotrexate 2.5 mg tablets were bioequivalent according to the definition (AUCE greater than or equal to AUCM X 80%).

  19. A liver fibrosis cocktail? Psoriasis, methotrexate and genetic hemochromatosis

    Directory of Open Access Journals (Sweden)

    Morley Nick

    2005-11-01

    Full Text Available Abstract Background Pathologists are often faced with the dilemma of whether to recommend continuation of methotrexate therapy for psoriasis within the context of an existing pro-fibrogenic risk factor, in this instance, patients with genetic hemochromatosis. Case presentations We describe our experience with two male psoriatic patients (A and B on long term methotrexate therapy (cumulative dose A = 1.56 gms and B = 7.88 gms with hetero- (A and homozygous (B genetic hemochromatosis. These patients liver function were monitored with routine biochemical profiling; apart from mild perivenular fibrosis in one patient (B, significant liver fibrosis was not identified in either patient with multiple interval percutaneous liver biopsies; in the latter instance this patient (B had an additional risk factor of partiality to alcohol. Conclusion We conclude that methotrexate therapy is relatively safe in patients with genetic hemochromatosis, with no other risk factor, but caution that the risk of fibrosis be monitored, preferably by non-invasive techniques, or by liver biopsy.

  20. [Acute toxicity by methotrexate used for abortion purpose. Case report].

    Science.gov (United States)

    Estrada-Altamirano, Ariel; Chacón-Solís, Rogerio Armando; Hernández-Pacheco, José Antonio; Belmont-Gómez, Aurora; Valenzuela-Jirón, Arlen; Carvajal-Valencia, Javier Andrés; Maya-Quiñones, José Luis

    2011-01-01

    We report the case of a 16 years old female patient, with a pregnancy history of 11.4 weeks by ultrasound and intrauterine fetal death. In a private clinic were prescribed methotrexate 500 mg intramuscular single dose, and vaginal misoprostol. She had a clinical feature of five days of evolution characterized by fever of 39 degrees C, nausea, general attack and vomiting. The initial diagnosis was severe sepsis secondary to septic abortion, oral candidiasis and acute poisoning by methotrexate. After that, she was referred to the Instituto Nacional de Perinatologia, where stayed with fever for four days, and was managed with hydration, antibiotics, folinic acid and alkalizing. Her recovery was gradual. She was discharged after 12 days with significant clinical improvement. The literature review describes that the use of methotrexate for abortion purpose with therapeutic-dose presents a similar adverse effects to those found in our patient, however there are no case reports that describe the use of this drug in macrodosis for the same purpose, and their cytotoxic effects. We present this case because the patient used a macrodosis of this antimetabolite and due to the premature and empirical management with folinic acid, joined with alkalinization of urine, is the ideal treatment and as it is illustrated in our case.

  1. Methotrexate for treatment of lichen planus: old drug, new indication.

    Science.gov (United States)

    Kanwar, A J; De, D

    2013-03-01

    Treatment of generalized lichen planus is often disappointing and is associated with relapses. Though reports have suggested a beneficial role of various immunosuppressive and immunomodulatory agents, most of these reports are retrospective series or anecdotes. Oral methotrexate has been found to be useful in recent studies. In this study, we prospectively evaluated the role of low-dose oral methotrexate (15 mg/week in adults or 0.25 mg/kg/week for children) in generalized lichen planus. Mean improvement in 24 evaluated patients (two of them were of paediatric age group) at the end of 14 weeks of treatment was 79%. By the end of 24 weeks treatment, 14 of 24 (58%) patients had complete remission of their disease. Side effects were observed in 12 of 24 (50%) patients. Most of these adverse effects were mild; only one requiring treatment discontinuation due to significantly deranged liver function test. During post-treatment follow-up of 3 months, none had relapse of lichen planus. Overall, low- dose methotrexate is effective and reasonably safe option in treatment of eruptive lichen planus, provided haematological and biochemical parameters are regularly monitored.

  2. Process for the preparation of alkyl glycosides

    NARCIS (Netherlands)

    De Goede, A.T.J.; Van der Leij, I.G.; Van der Heijden, A.M.; Van Rantwijk, F.; Van Bekkum, H.

    1996-01-01

    Abstract of WO 9636640 (A2) The present invention relates to a process for the preparation of alkyl glycosides by reacting an alcohol with a saccharide or a lower-alkyl glycoside in the presence of a catalyst, wherein the catalyst is a mesoporous silica-based molecular sieve material. This proce

  3. Synthesis of daidzin analogues as potential agents for alcohol abuse.

    Science.gov (United States)

    Gao, Guang-Yao; Li, Dian-Jun; Keung, Wing Ming

    2003-09-01

    Daidzin, the active principle of an herbal remedy for 'alcohol addiction', has been shown to reduce alcohol consumption in all laboratory animals tested to date. Correlation studies using structural analogues of daidzin suggests that it acts by raising the monoamine oxidase (MAO)/mitochondrial aldehyde dehydrogenase (ALDH-2) activity ratio (J. Med. Chem. 2000, 43, 4169). Structure-activity relationship (SAR) studies on the 7-O-substituted analogues of daidzin have revealed structural features important for ALDH-2 and MAO inhibition (J. Med. Chem. 2001, 44, 3320). We here evaluated effects of substitutions at 2, 5, 6, 8, 3' and 4' positions of daidzin on its potencies for ALDH-2 and MAO inhibition. Results show that analogues with 4'-substituents that are small, polar and with hydrogen bonding capacities are most potent ALDH-2 inhibitors, whereas those that are non-polar and with electron withdrawing capacities are potent MAO inhibitors. Analogues with a 5-OH group are less potent ALDH-2 inhibitors but are more potent MAO inhibitors. All the 2-, 6-, 8- and 3'-substituted analogues tested so far do not inhibit ALDH-2 and/or have decreased potencies for MAO inhibition. This, together with the results obtained from previous studies, suggests that a potent antidipsotropic analogue would be a 4',7-disubstituted isoflavone. The 4'-substituent should be small, polar, and with hydrogen bonding capacities such as, -OH and -NH(2); whereas the 7-substituent should be a straight-chain alkyl with a terminal polar function such as -(CH(2))(n)-OH with 2 or =4.

  4. Abatacept with methotrexate versus other biologic agents in treatment of patients with active rheumatoid arthritis despite methotrexate

    DEFF Research Database (Denmark)

    Guyot, Patricia; Taylor, Peter; Christensen, Robin;

    2011-01-01

    The goal of this study was to compare the efficacy in terms of Health Assessment Questionnaire change from baseline (HAQ CFB), 50% improvement in American College of Rheumatology criterion (ACR-50) and Disease Activity Score in 28 joints (DAS28) defined remission (<2.6) between abatacept and othe...... biologic disease modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) who have inadequate response to methotrexate (MTX-IR)....

  5. Gastric inhibitory polypeptide analogues

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2002-01-01

    of GIP and GLP-1 receptors, the incretin effect is essential for normal glucose tolerance. In patients with type 2 diabetes mellitus it turns out that the incretin effect is severely impaired or abolished. The explanation seems to be that both the secretion of GLP-1 and the effect of GIP are impaired...... (whereas both the secretion of GIP and the effect of GLP-1 are near normal). The impaired GLP-1 secretion is probably a consequence of diabetic metabolic disturbances. The known genetic variations in the GIP receptor sequence are not associated with type 2 diabetes mellitus, but a defective insulinotropic...... and its analogues are attractive as therapeutic agents for type 2 diabetes mellitus, analogues of GIP are unlikely to be effective. On the other hand, GIP seems to play an important role in lipid metabolism, promoting the disposal of ingested lipids, and mice with a targeted deletion of the GIP receptor...

  6. Aspartame and Its Analogues

    Science.gov (United States)

    Pavlova, L. A.; Komarova, T. V.; Davidovich, Yurii A.; Rogozhin, S. V.

    1981-04-01

    The results of studies on the biochemistry of the sweet taste are briefly reviewed. The methods of synthesis of "aspartame" — a sweet dipeptide — are considered, its structural analogues are described, and quantitative estimates are made of the degree of sweetness relative to sucrose. Attention is concentrated mainly on problems of the relation between the structure of the substance and its taste in the series of aspartyl derivatives. The bibliography includes 118 references.

  7. Quantum analogue computing.

    Science.gov (United States)

    Kendon, Vivien M; Nemoto, Kae; Munro, William J

    2010-08-13

    We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

  8. Mimicking cell membrane-like structures on alkylated silicon surfaces by peptide amphiphiles

    Energy Technology Data Exchange (ETDEWEB)

    Shamsi, Fahimeh, E-mail: neyayesh8@yahoo.com [Biophysics and Bioengineering, School of Chemical and Biomolecular Engineering, University of Sydney, Sydney, NSW 2006 (Australia); Coster, Hans G.L. [Biophysics and Bioengineering, School of Chemical and Biomolecular Engineering, University of Sydney, Sydney, NSW 2006 (Australia)

    2011-11-01

    Highlights: {yields} Lipidated peptide amphiphiles were hydrophobically attached onto an alkylated surface. {yields} Morphology of nanofibres of the peptide amphiles depended on the acyl chain length. {yields} We show that extended 2D analogues of the nanofibre surface can be constructed. {yields} Peptide amphiphiles with shorter acyl chains formed more homogeneous layers. - Abstract: We present a new strategy for flexible attachment of peptide amphiphiles on functionalized silicon surfaces. This method involves the production of an alkylated surface on which a lipidated peptide can then be attached through hydrophobic interaction. We applied this to two derivatives of amphiphilic peptide molecules with the same amino acid sequence (A-A-A-A-G-G-G-E-R-G-D) but different in alkyl chain lengths (palmitic acid, undecanoic acid). The basis of this work was to develop substrates which are more biocompatible and bioactive. The ultra-thin peptide amphiphile films were characterized using electrical impedance spectroscopy (EIS), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (ATR-FTIR) spectroscopy. The results demonstrated that the length of the alkyl chain in the peptide amphiphile affects the packing and coverage of the peptides on the silicon surface.

  9. Effects of methotrexate on rat P-450 cytochrome mono-oxygenases; Action du methotrexate sur les monooxygenases a cytochromes P-450 chez le rat

    Energy Technology Data Exchange (ETDEWEB)

    Guitton, J.; Guilluy, R.; Brazier, J.L. [Faculte de Pharmacie, 69 - Lyon (France); Souillet, G. [Hopital Debrousse, 69 - Lyon (France); Riviere, J.L. [INRA, 69 - Marcy l`Etoile (France); Gerard, F. [Institut Pasteur, 69 - Lyon (France)

    1994-12-31

    Methotrexate, an anti-cancerous agent, acts as an anti-metabolite of the nucleic acids which synthesis is then inhibited. Using aminopyrine breath test after methotrexate processing, the effects of the molecule on activities of the hepatocyte P-450 cytochrome mono-oxygenases, are studied. Breath micro-tests with carbon 13-labelled aminopyrine have been carried out to observe the metabolism evolution. Micro-test results have been compared to microsomal enzymatic activities for various substrates, and also to P-450 cytochrome ratio. Results show that methotrexate induces a reduction in the P-450 cytochrome ratio, and thus reduce the hepatic biotransformation process. 1 fig., 30 refs.

  10. Alkylation of organic aromatic compounds

    Science.gov (United States)

    Smith, L.A. Jr.

    1989-07-18

    Aromatic compounds are alkylated in a catalytic distillation, wherein the catalyst structure also serves as a distillation component by contacting the aromatic compound with a C[sub 2] to C[sub 10] olefin in the catalyst bed under 0.25 to 50 atmospheres of pressure and at temperatures in the range of 80 C to 500 C, using as the catalyst a mole sieve characterized as acidic or an acidic cation exchange resin. For example, ethyl benzene is produced by feeding ethylene below the catalyst bed while benzene is conveniently added through the reflux in molar excess to that required to react with ethylene, thereby reacting substantially all of the ethylene and recovering benzene as the principal overhead and ethyl benzene in the bottoms. 1 fig.

  11. Design, total synthesis, and evaluation of C13-C14 cyclopropane analogues of (+)-discodermolide.

    Science.gov (United States)

    Smith, Amos B; Xian, Ming; Liu, Fenghua

    2005-10-13

    [structure: see text] The design, total synthesis, and biological evaluation of two C13-C14-cyclopropyl analogues [(+)-1 and (+)-2] of (+)-discodermolide have been achieved. Key features of the syntheses include highly stereoselective, hydroxyl-directed cyclopropanations of vinyl iodides and higher order cuprate-mediated cross-coupling reactions between cyclopropyl iodides and alkyl iodides. Biological evaluation revealed that neither orientation of the cyclopropyl methylene completely substitutes for the C14 methyl found in (+)-discodermolide (3).

  12. Analogue Methods in Palaeoecology: Using the analogue Package

    OpenAIRE

    Simpson, Gavin L.

    2007-01-01

    Palaeoecology is an important branch of ecology that uses the subfossil remains of organisms preserved in lake, ocean and bog sediments to inform on changes in ecosystems and the environment through time. The analogue package contains functions to perform modern analogue technique (MAT) transfer functions, which can be used to predict past changes in the environment, such as climate or lake-water pH from species data. A related technique is that of analogue matching, which is concerned with i...

  13. SUCCESSFUL TREATMENT OF AN ADVANCED INTERSTITIAL PREGNANCY BY SEQUENTIAL SYSTEMIC AND LOCAL-ADMINISTRATION OF METHOTREXATE

    NARCIS (Netherlands)

    HOEK, A; BROEKMANS, FJ; VERHEIJEN, RHM; SCHATS, R

    1995-01-01

    A patient is presented with an advanced interstitial pregnancy, diagnosed by transvaginal ultrasound and confirmed by laparoscopy, Amenorrhoea at the time of diagnosis was 57 days, Methotrexate was given systemically (4x50 mg i.m.), Because of persisting viability of the fetus, systemic methotrexate

  14. Evidence-based recommendations for treatment with methotrexate in rheumatic disorders

    DEFF Research Database (Denmark)

    Madsen, Ole Rintek; Faurschou, Mikkel; Loft, Anne Gitte;

    2010-01-01

    The aim of this study was to develop 3E (Evidence, Expertise, Exchange) recommendations (RCs) on the use of methotrexate in rheumatic disorders and to assess the agreement among Danish rheumatologists.......The aim of this study was to develop 3E (Evidence, Expertise, Exchange) recommendations (RCs) on the use of methotrexate in rheumatic disorders and to assess the agreement among Danish rheumatologists....

  15. Indirect treatment comparison of abatacept with methotrexate versus other biologic agents for active rheumatoid arthritis despite methotrexate therapy in the United kingdom

    DEFF Research Database (Denmark)

    Guyot, Patricia; Taylor, Peter C; Christensen, Robin;

    2012-01-01

    To compare the efficacy of abatacept and alternative biologic disease-modifying antirheumatic drugs (DMARD) in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) in the United Kingdom.......To compare the efficacy of abatacept and alternative biologic disease-modifying antirheumatic drugs (DMARD) in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) in the United Kingdom....

  16. Uncommon toxicity of low-dose methotrexate: case report

    Directory of Open Access Journals (Sweden)

    Zohreh Yousefi

    2015-10-01

    Full Text Available Background: Standard treatment of Gestational Trophoblastic Disease (GTD is chemotherapy. Single-agent chemotherapy regime including Methotrexate (MTX or Actinomycin. Single-agent is widely used in treatment of persistent trophoblastic disease. We reported an uncommon toxicity of low-dose single-agent methotrexate in a patient. Case Presentation: A 20-year-old woman, primary gravid after two months missed period and spotting with diagnosis of incomplete abortion with uterine size equivalent of ten weeks pregnancy (8-10 cm underwent evacuation curettage. In serial follow-up, based on rise of beta-hCG titer and absence of metastatic disease, it was categorized as low-risk persistent trophoblastic disease. She was referred to gynecology oncology center of Ghaem Hospital, Mashhad University of Medical Sciences in May 2014. Because of rise of beta-hCG titer, after complete metastatic work-up and lack of disease in other sites, persistent disease was diagnosed and candidate for chemotherapy (single agent low-dose. The patient received first course of therapy with MTX (50 mg/m², intra muscular. Unfortunately, after two days of treatment she developed uncommon severe toxicity, fever, severe nausea and vomiting, tachycardia, and generalized weakness. Also, we found hematologic abnormality (WBC: -14000-15000 µI, platelet- 540 µI and sever neutropenia, and abnormal rising in liver function test (SGOT, SGPT (three to four times and renal function test (BUN and Creatinine (two times. In addition, she had disseminated erosive lesion in all of body especially in face. Due to the fatal side effects of chemotherapy, she was admitted to intensive care unit (ICU. Fortunately, after two to three weeks, she was improved by conservative management. After few weeks beta-hCG titer was in normal limit. However she had normal serial beta-hCG in one year of follow-up. Conclusion: It is important to emphasis unpredictable side effects of chemotherapy with low

  17. [Methotrexate to treat SAPHO syndrome with keloidal scars].

    Science.gov (United States)

    Azevedo, V F; Dal Pizzol, V I; Lopes, H; Coelho, S P; Czeczko, L E A

    2011-01-01

    SAPHO syndrome is an uncommon clinical entity, recently described in literature, which usually affects children, young adults and middle-aged people. It is defined by the association of skin lesions (severe acne, palmo-plantar pustulosis, supurative hidradenitis), synovitis, hiperosthosis and osteitis; however, not all manifestations are required for correct diagnosis. We report a currently forty-two year-old man who initiated follow-up in 1992 for severe acne. His diagnosis changed along the years and has been treated with antibiotics many times to control pustule formation and hidrosadenitis, which evolved to keloidal scars, requiring neck zethaplasty due to limitation of mobility. In 1996 isotretinoin was started, with good response to treatment but recurrence after its completion. Ten years later, isotretinoin was being used again due to worsening clinical picture when the patient developed polyarthritis, lost 11kg in 3 months and was found to have an elevated erythrocyte sedimentation rate. SAPHO syndrome was then diagnosed by the Rheumatology clinic, which started methotrexate at 10mg per week to a good clinical response. Several cutaneous and articular flares have occurred since, however he is now clinically stable with methotrexate 20mg per week and finasteride 5mg per day. SAPHO syndrome is a rare disease and its diagnosis is often late and difficult. In this case, skin lesions preceded arthritis in several years and have been resistant to other common treatments. The patient had a better improve after initiation of methotrexate. Although the skin disease has evolved to keloids, the patient has had excellent treatment response.

  18. Methotrexate in juvenile idiopathic arthritis: towards tailor-made treatment.

    Science.gov (United States)

    Ćalasan, Maja Bulatović; Wulffraat, Nico M

    2014-07-01

    Methotrexate (MTX) is the key treatment in juvenile idiopathic arthritis (JIA). Nevertheless, MTX is not always sufficiently efficacious and can lead to adverse effects, which compromises complete disease control. In such cases, combination therapies with biologicals are given, even at MTX start, before knowing the patients' MTX response. Ideally, clinicians should be able to practice precision medicine by knowing before or early after MTX start, which patients will benefit from MTX only and which patients will not, thus requiring addition of biologicals. To make such tailor-made treatment decisions, clinicians require tools to optimize MTX treatment. In this review, we focus on tools for tailor-made MTX treatment in JIA.

  19. The efficacy of methotrexate plus pioglitazone vs. methotrexate alone in the management of patients with plaque-type psoriasis: a single-blinded randomized controlled trial.

    Science.gov (United States)

    Lajevardi, Vahide; Hallaji, Zahra; Daklan, Soroush; Abedini, Robabeh; Goodarzi, Azadeh; Abdolreza, Mona

    2015-01-01

    Recently, thiazolidinediones have shown to be efficacious with a favorable safety profile when used in the treatment of chronic plaque-type psoriasis. The aim of this study was to evaluate and compare the efficacy and safety of a combination of methotrexate plus pioglitazone and methotrexate alone in plaque-type psoriasis. A total of 44 adult patients with plaque-type psoriasis were included in the study. Patients were randomized to treatment with methotrexate alone (group A) or methotrexate plus pioglitazone (group B) for 16 weeks. The primary efficacy outcome measure was psoriasis area and severity index (PASI) score change between the study groups at week 16 relative to baseline. The secondary efficacy outcome measure was dermatology life quality index (DLQI) score change between the two groups at week 16 relative to baseline. The PASI 75 score was also measured. After 16 weeks of therapy, the percentage of reduction in the mean PASI score was 70.3% in group B and 60.2% in group A. PASI 75 was achieved in 14 patients (63.6%) in group B compared with two patients (9.1%) in group A within 16 weeks, which was significant (P methotrexate in plaque-type psoriasis, as demonstrated by a reduction in the mean PASI scores. In terms of DLQI, there was no extra benefit by the addition of pioglitazone to methotrexate therapy.

  20. N-alkylated nitrogen-in-the-ring sugars: conformational basis of inhibition of glycosidases and HIV-1 replication.

    Science.gov (United States)

    Asano, N; Kizu, H; Oseki, K; Tomioka, E; Matsui, K; Okamoto, M; Baba, M

    1995-06-23

    The conformations of nitrogen-in-the-ring sugars and their N-alkyl derivatives were studied from 1H NMR analyses, mainly using 3J(H,H) coupling constants and quantitative NOE experiments. No significant difference was seen in the ring conformation of 1-deoxynojirimycin (1), N-methyl-1-deoxynojirimycin (2), and N-butyl-1-deoxynojirimycin (3). However, it was shown that the C6 OH group in 1 is predominantly equatorial to the piperidine ring, while that in 2 or 3 is predominantly axial, and its N-alkyl group is oriented equatorially. In the furanose analogues 1,4-dideoxy-1,4-imino-D-arabinitol (4) and its N-methyl (5) and N-butyl (6) derivatives, the five-membered ring conformation differed significantly by the presence or absence of the N-substituted group and the length of the N-alkyl chain. Compound 3 reduced its inhibitory effect on almost all glycosidases, resulting in an extremely specific inhibitor for processing alpha-glucosidase I since N-alkylation of 1 is known to enhance both the potency and specificity of this enzyme in vitro and in vivo. This preferred (C6 OH axial) conformation in 2 and 3 appears to be responsible for their strong alpha-glucosidase I activity. Compound 4 is a good inhibitor of intestinal alpha-glucohydrolases, alpha-glucosidase II, and Golgi alpha-mannosidases I and II, but its N-alkyl derivatives 5 and 6 markedly decreased inhibitory potential for all enzymes tested. In the case of 2,5-dideoxy-2,5-imino-D-mannitol (DMDP, 7), which is a potent beta-galactosidase inhibitor, its N-methyl (8) and N-butyl (9) derivatives completely lost potency toward beta-galactosidase as well. N-Alkylation of compounds 4 and 7, known well as potent yeast alpha-glucosidase inhibitors, resulted in a serious loss of inhibitory activity toward yeast alpha-glucohydrolases. Activity of these nine analogues against HIV-1 replication was determined, based on the inhibition of virus-induced cytopathogenicity in MT-4 and MOLT-4 cells. Compounds 2 and 3, which are

  1. Recurrent impetigo herpetiformis successfully treated with methotrexate: a case report.

    Science.gov (United States)

    Luewan, Suchaya; Sirichotiyakul, Supatra; Tongsong, Theera

    2011-06-01

    Impetigo herpetiformis is a rare disease and its occurrence is specific for pregnancy. The lesions are characterized by sterile, pustular eruptions. The disorder is usually seen in the third trimester, but cases of impetigo herpetiformis appearing in the first trimester have also been reported. The lesions are expected to disappear after birth, but the disorder may recur during subsequent pregnancies. In this case report we discuss a 28-year-old pregnant woman, G3P1011, with a history of impetigo herpetiformis in the first pregnancy, who presented with generalized pustular lesions at 30 weeks' gestation. Her disease responded poorly to corticosteroids and was more severe than in the previous pregnancy. She delivered prematurely at 34 weeks' gestation and then received aggressive postpartum treatment with methotrexate, resulting in a dramatic response. This case supports the current understanding that recurrent impetigo herpetiformis in subsequent pregnancy tends to be more severe and to have an earlier onset. Additionally, it provides additional evidence that methotrexate may be used as an alternative treatment for impetigo herpetiformis in the case of a poor response to corticosteroids.

  2. Collateral methotrexate resistance in cisplatin-selected murine leukemia cells

    Directory of Open Access Journals (Sweden)

    Bhushan A.

    1999-01-01

    Full Text Available Resistance to anticancer drugs is a major cause of failure of many therapeutic protocols. A variety of mechanisms have been proposed to explain this phenomenon. The exact mechanism depends upon the drug of interest as well as the tumor type treated. While studying a cell line selected for its resistance to cisplatin we noted that the cells expressed a >25,000-fold collateral resistance to methotrexate. Given the magnitude of this resistance we elected to investigate this intriguing collateral resistance. From a series of investigations we have identified an alteration in a membrane protein of the resistant cell as compared to the sensitive cells that could be the primary mechanism of resistance. Our studies reviewed here indicate decreased tyrosine phosphorylation of a protein (molecular mass = 66 in the resistant cells, which results in little or no transfer of methotrexate from the medium into the cell. Since this is a relatively novel function for tyrosine phosphorylation, this information may provide insight into possible pharmacological approaches to modify therapeutic regimens by analyzing the status of this protein in tumor samples for a better survival of the cancer patients.

  3. A Short Term Analogue Memory

    DEFF Research Database (Denmark)

    Shah, Peter Jivan

    1992-01-01

    A short term analogue memory is described. It is based on a well-known sample-hold topology in which leakage currents have been minimized partly by circuit design and partly by layout techniques. Measurements on a test chip implemented in a standard 2.4 micron analogue CMOS process show a droop...

  4. [A Case of Crohn's Disease Showing Favorable Response to Induction and Maintenance Therapy with Methotrexate after Failure of Anti-tumor Necrosis Factor Therapy].

    Science.gov (United States)

    Choi, Jung Ran; Yun, Gak Won; Park, Yoo Mi; Kim, Jie Hyun; Youn, Young Hoon; Park, Hyo Jin; Park, Jae Jun

    2015-10-01

    Thanks to the introduction of immumomodulators and biologics, therapeutic approaches in Crohn's disease have changed significantly during the past decade. Although new biologic therapy has dramatically improved the treatment of Crohn's disease, a substantial number of patients are refractory to these therapies or lose their initial response. Methotrexate (MTX) is a structural analogue of folic acid that can competitively inhibit the binding of dihydrofolic acid to the enzyme dihydrofolate reductase and has been widely used as immunomodulator in rheumatology area for patients with rheumatoid arthritis and psoriasis. Although MTX has also been shown to be an effective agent for remission induction and maintenance of remission in Crohn's disease, the use of MTX in Crohn's disease has not yet been reported in Korea. Herein, we report a case of Crohn's disease patient who was successfully treated with MTX after treatment failure with thiopurine and anti-tumor necrosis factor.

  5. Evaluation of the role of erythropoietin and methotrexate in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Sandipan Dasgupta

    2011-01-01

    Full Text Available Background : Erythropoietin, originally recognized for its role in erythropoiesis, has been shown to improve neurological outcome after stroke. Low-dose methotrexate is effective against certain inflammatory diseases, such as severe psoriasis and rheumatoid arthritis as well as Crohn′s disease. Immunosuppressive effect of methotrexate also reduces the proportion of patients with chronic progressive multiple sclerosis with modest clinical benefits. Combination of erythropoietin and methotrexate can target neuroinflammation along with immunosupression. Objective : To evaluate the role of erythropoietin and methotrexate in experimental autoimmune encephalomyelitis, a commonly used animal model of several degenerative human diseases like multiple sclerosis. Materials and Methods : In the present study, C57BL/J6 mice were immunized with 200 mg of myelin basic protein (MBP emulsified in complete Freund′s adjuvant (CFA supplemented with 1 mg/ml of killed mycobacterium tuberculosis (MBP: CFA in 1:1 ratio. These animals were given a combination of methotrexate and erythropoietin. Neurological function tests were scored daily by grading of clinical signs. Cerebral histopathology was performed to detect inflammatory infiltrates and demyelination. Results : Treatment with erythropoietin and methotrexate significantly improved the neurological function recovery, reduced inflammatory infiltrates, and demyelination as compared to controls possibly by stimulating oligodendrogenesis and down-regulating proinflammatory infiltrates. Conclusion : The findings suggest an adjunctive use of methotrexate in demyelinating disease.

  6. Nanoparticles of Conjugated Methotrexate-Human Serum Albumin: Preparation and Cytotoxicity Evaluations

    Directory of Open Access Journals (Sweden)

    Azade Taheri

    2011-01-01

    Full Text Available Methotrexate-human serum albumin conjugates were developed by a simple carbodiimide reaction. Methotrexate-human serum albumin conjugates were then crosslinked with 1-ethyl-3-(3-dimethylaminopropyl carbodiimide HCl (EDC to form nanoparticles. The size of nanoparticles determined by laser light scattering and TEM was between 90–150 nm. Nanoparticles were very stable at physiologic conditions (PBS pH 7.4, 37∘C and after incubation with serum. The effect of amount of EDC used for crosslinking on the particle size and free amino groups of nanoparticles was examined. The amount of crosslinker showed no significant effect on the size of nanoparticles but free amino groups of nanoparticles were decreased by increasing the crosslinker. The physicochemical interactions between methotrexate and human serum albumin were investigated by differential scanning calorimetry (DSC. Nanoparticles were more cytotoxic on T47D cells compared to free methotrexate. Moreover, methotrexate-human serum albumin nanoparticles decreased the IC50 value of methotrexate on T47D cells in comparison with free methotrexate.

  7. Methotrexate causes a change in intestinal 5-hydroxytryptamine metabolism in rats.

    Science.gov (United States)

    Takano, Yuho; Machida, Takuji; Obara, Yusuke; Hirano, Megumi; Kudo, Sae; Takagi, Minako; Hamaue, Naoya; Iizuka, Kenji; Hirafuji, Masahiko

    2014-10-01

    The effects of methotrexate on 5-hydroxytryptamine (5-HT) metabolism in the intestinal tissue of rats were investigated during the delayed phase after a single administration. Rats were i.p. injected with methotrexate or with saline as a control, and kaolin and food intakes were measured by an automatic monitoring apparatus. At 96 h after administration, dissected-out ileal tissue was frozen rapidly in liquid nitrogen for further analysis or fixed for immunohistochemical staining. Methotrexate at a dose of 50 mg/kg caused a time-dependent increase in kaolin intake lasting up to 72 h after administration, which returned to the control level at 96 h after administration. This dose of methotrexate caused a gradual decrease in body weight, food intake, and water intake lasting up to 72 h, which approached the control level at 96 h. Methotrexate caused pathologic changes, including a moderate inflammatory response in the ileal tissue and an increase in the number of L-tryptophan hydroxylase (TPH)-expressing cells in the ileal mucosa. Methotrexate also caused a significant increase in 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content and in TPH1 mRNA expression in the ileal tissues. It had no significant effects on mRNA expression of serotonin transporter, COX-1, or COX-2 or on myeloperoxidase activity. This study demonstrated, for the first time, that methotrexate caused a change in the ileal 5-HT metabolism associated with hyperplasia of mucosal enterochromaffin cells.

  8. Vorticity in analogue gravity

    CERN Document Server

    Cropp, Bethan; Turcati, Rodrigo

    2015-01-01

    In the analogue gravity framework, the acoustic disturbances in a moving fluid can be described by an equation of motion identical to a relativistic scalar massless field propagating in a curved spacetime. This description is possible only when the fluid under consideration is barotropic, inviscid and irrotational. In this case, the propagation of the perturbations is governed by an acoustic metric which depends algebrically on the local speed of sound, density and the background flow velocity, the latter assumed to be vorticity free. In this work we provide an straightforward extension in order to go beyond the irrotational constraint. Using a charged --- relativistic and non-relativistic --- Bose--Einstein condensate as a physical system, we show that in the low momentum limit and performing the eikonal approximation we can derive a d'Alembertian equation of motion for the charged phonons where the emergent acoustic metric depends on a flow velocity in the presence of vorticity.

  9. Design, synthesis, and biological evaluation of simplified analogues of (+)-discodermolide. Additional insights on the importance of the diene, the C7 hydroxyl, and the lactone.

    Science.gov (United States)

    Smith, Amos B; Xian, Ming

    2005-11-10

    [structure: see text] The design, synthesis, and biological evaluation of seven totally synthetic analogues of the antitumor agent (+)-discodermolide are reported. Saturation of the terminal diene system, alteration of the substituents on the lactone, and alkylation of the C7-hydroxyl group reveal significant structure-activity relationships.

  10. Acute methotrexate ingestions in adults: A review on ever-rising consumption of methotrexate since 1980s

    Directory of Open Access Journals (Sweden)

    Ranjita Santra(Dhali

    2015-01-01

    Full Text Available To review the possible association between methotrexate (MTX intake and increased toxicity. A MEDLINE literature search MEDLINE (1980-August 2014 was performed using the search terms MTX, antifolate, MTX toxicity, glucarpidase, and leucovorin. Additional references were identified from a review of literature citations. All English-language observational studies and case reports were considered. Methotrexate (meth" oh trex′ ate is an antifolate and antimetabolite that is used extensively in the therapy of leukemia, lymphoma, and several solid organ tumors. It also has potent activity against psoriasis and has immunomodulatory activity against inflammatory bowel disease and the inflammatory arthritidies. It exhibits a wide range of toxic effects profile. Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of MTX. In post marketing experience, overdose with MTX has generally occurred with oral and intrathecal administration, although intravenous and intramuscular overdose have also been reported. Supporting care strategies, extracorporeal measures, and glucarpidase are some of the means to overcome MTX overdosage. At present, pharmacogenomics tends to contribute toward the emergence of adverse effects following the widespread use of MTX for various indications.

  11. Surfactin analogues produced by Bacillus subtilis strains grown on rapeseed cake

    Science.gov (United States)

    Jajor, Paweł; Piłakowska-Pietras, Dorota; Krasowska, Anna; Łukaszewicz, Marcin

    2016-12-01

    Microbiologically produced surface acting compounds (biosurfactants) have very interesting properties with many potential industrial applications. Lipopeptides is a particularly promising group of biosurfactants in respect to the potentially huge number of various chemical structures. The chemical diversity results from fatty acid moiety (e.g. length, saturation, branching or hydroxylation) and type and sequence of the amino acids in the peptide chain. The limiting factor for the design and analysis of various lipopeptides is the ability of the targeted biosynthesis. Biosynthesis of particular lipopeptides may be potentially achieved by strain selection, culture conditions, or molecular engineering. The well-known lipopeptedes (surfactins, iturins, and fengycins) producer is B. subtilis. The aim of this study was to study targeted surfactin structural analogues biosynthesis in response to culture conditions in view of the design and production of tailor-made lipopeptides. Two B. subtilis strains (KB1 and #309) were tested for surfactin production. Both strains produced a mixture of five major surfactin analogues with the number of carbons in an alkyl chain ranging from 12 to 16. The two strains differed with respect to their oxygen demand for optimal surfactin biosynthesis (lower oxygen demand for KB1). The amount of air influenced the relative ratios of surfactin analogues. Lower oxygen amount decreased the share of C15 analogues while it increased the share of C12 analogues. Thus, the biosynthesis of a desired surfactin analogue may controlled by both strain and culture conditions.

  12. Yellow fever vaccine used in a psoriatic arthritis patient treated with methotrexate: a case report.

    Science.gov (United States)

    Stuhec, Matej

    2014-01-01

    The yellow fever vaccines on the market are contraindicated for immunocompromised and elderly patients. A case of yellow fever vaccine used in a 27-year-old Slovenian male with psoriatic arthritis during treatment with methotrexate is described. We demonstrate a positive case, since there were no adverse effects in concurrent administration of yellow fever vaccine and methotrexate. This patient did not show severe adverse reactions and did not contract yellow fever despite potential exposure. More research is needed on possible adverse effects of concurrent administration of yellow fever vaccine and methotrexate to determine the potential of this method for more frequent use.

  13. NASA/ESMD Analogue Mission Plans

    Science.gov (United States)

    Hoffman, Stephen J.

    2007-01-01

    A viewgraph presentation exploring Earth and its analogues is shown. The topics include: 1) ESMD Goals for the Use of Earth Analogues; 2) Stakeholders Summary; 3) Issues with Current Analogue Situation; 4) Current state of Analogues; 5) External Implementation Plan (Second Step); 6) Recent Progress in Utilizing Analogues; 7) Website Layout Example-Home Page; 8) Website Layout Example-Analogue Site; 9) Website Layout Example-Analogue Mission; 10) Objectives of ARDIG Analog Initiatives; 11) Future Plans; 12) Example: Cold-Trap Sample Return; 13) Example: Site Characterization Matrix; 14) Integrated Analogue Studies-Prerequisites for Human Exploration; and 15) Rating Scale Definitions.

  14. Biodegradation of alkylates under less agitated aquifer conditions

    Institute of Scientific and Technical Information of China (English)

    Jay J.Cho; Makram T.Suidan; Albert D.Venosa

    2013-01-01

    The biodegradability of three alkylates (2,3-dimethylpentane,2,4-dimethylpentane and 2,2,4-trimethylpentane) under less agitated aquifer conditions was investigated in this study.All three alkylates biodegraded completely under these conditions regardless of the presence or absence of ethanol or benzene,toluene,ethylbenzene,and xylenes (BTEX) in the feed.In the presence of ethanol,alkylates degradation was not inhibited by ethanol.However,alkylates degraded more slowly in the presence of BTEX suggesting competitive inhibition to microbial utilization of alkylates.In the sterile controls,alkylates concentrations remained unchanged throughout the experiments.

  15. Clinical outcomes of primary intraocular lymphoma patients treated with front-line systemic high-dose methotrexate and intravitreal methotrexate injection.

    Science.gov (United States)

    Ma, Wei-Li; Hou, Hsin-An; Hsu, Ya-Jui; Chen, Yin-Kai; Tang, Jih-Luh; Tsay, Woei; Yeh, Po-Ting; Yang, Chung-May; Lin, Chang-Ping; Tien, Hwei-Fang

    2016-03-01

    A standard treatment for patients with primary intraocular lymphoma (PIOL) remains unclear. This study retrospectively analyzed the clinical features and outcomes of 19 patients with PIOL who were treated with a first-line therapy comprising combined intravenous high-dose methotrexate and intravitreal methotrexate between January 2003 and December 2013. Thirteen (68.4 %) patients were female, and the median age at diagnosis was 57 (39-77 years). Diagnoses were based on the identification of abnormal lymphoid cells in vitreous fluid. Ten (52.6 %) patients had bilateral eye involvement, and six had concurrent central nervous system (CNS) involvement. All 19 patients achieved complete remission (CR) as confirmed by cytological examination of vitreous and cerebrospinal fluid and brain imaging if CNS was involved. Patients with concurrent brain involvement required a longer time to achieve CR. However, the duration of complete remission did not differ between patients with and without CNS involvement. The 5-year overall survival rate was 55.8 % for the total cohort and was higher (68.8 %) in patients with isolated PIOL than in those with concurrent CNS involvement. In all patients, methotrexate treatment was well tolerated, with manageable side effects. We conclude that combined intravitreal methotrexate and systemic high-dose methotrexate treatment is effective in patients with PIOL.

  16. Synthesis and Antiangiogenic Activity of N-Alkylated Levamisole Derivatives

    Science.gov (United States)

    Sylvest, Lene; Friis, Tina; Staerk, Dan; Jørgensen, Flemming Steen; Olsen, Christian A.; Houen, Gunnar

    2012-01-01

    Inhibition of angiogenesis is a promising addition to current cancer treatment strategies. Neutralization of vascular endothelial growth factor by monoclonal antibodies is clinically effective but may cause side effects due to thrombosis. Low molecular weight angiogenesis inhibitors are currently less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S)-Levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure–activity relationships with regard to inhibition of angiogenesis. N-Methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S)-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with normal human dermal fibroblasts. Interestingly, the cluster morphology caused by N-methyllevamisole was different than the clusters observed for levamisole, and a third “cord-like” morphology resembling that of the known drug suramin was observed for an aniline-containing derivative. New chemotypes exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted. PMID:23024819

  17. Synthesis and antiangiogenic activity of N-alkylated levamisole derivatives.

    Directory of Open Access Journals (Sweden)

    Anders N Hansen

    Full Text Available Inhibition of angiogenesis is a promising addition to current cancer treatment strategies. Neutralization of vascular endothelial growth factor by monoclonal antibodies is clinically effective but may cause side effects due to thrombosis. Low molecular weight angiogenesis inhibitors are currently less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S-levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure-activity relationships with regard to inhibition of angiogenesis. N-methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with normal human dermal fibroblasts. Interestingly, the cluster morphology caused by N-methyllevamisole was different than the clusters observed for levamisole, and a third "cord-like" morphology resembling that of the known drug suramin was observed for an aniline-containing derivative. New chemotypes exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted.

  18. The redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Susana Barros

    Full Text Available BACKGROUND: Methotrexate is a chemotherapeutic agent used to treat a variety of cancers. However, the occurrence of resistance limits its effectiveness. Cytochrome c in its reduced state is less capable of triggering the apoptotic cascade. Thus, we set up to study the relationship among redox state of cytochrome c, apoptosis and the development of resistance to methotrexate in MCF7 human breast cancer cells. RESULTS: Cell incubation with cytochrome c-reducing agents, such as tetramethylphenylenediamine, ascorbate or reduced glutathione, decreased the mortality and apoptosis triggered by methotrexate. Conversely, depletion of glutathione increased the apoptotic action of methotrexate, showing an involvement of cytochrome c redox state in methotrexate-induced apoptosis. Methotrexate-resistant MCF7 cells showed increased levels of endogenous reduced glutathione and a higher capability to reduce exogenous cytochrome c. Using functional genomics we detected the overexpression of GSTM1 and GSTM4 in methotrexate-resistant MCF7 breast cancer cells, and determined that methotrexate was susceptible of glutathionylation by GSTs. The inhibition of these GSTM isoforms caused an increase in methotrexate cytotoxicity in sensitive and resistant cells. CONCLUSIONS: We conclude that overexpression of specific GSTMs, GSTM1 and GSTM4, together with increased endogenous reduced glutathione levels help to maintain a more reduced state of cytochrome c which, in turn, would decrease apoptosis, thus contributing to methotrexate resistance in human MCF7 breast cancer cells.

  19. Chiral Alkyl Halides: Underexplored Motifs in Medicine

    Directory of Open Access Journals (Sweden)

    Bálint Gál

    2016-11-01

    Full Text Available While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation.

  20. Hydroxyethylated graphene oxide as potential carriers for methotrexate delivery

    Energy Technology Data Exchange (ETDEWEB)

    Du Libo, E-mail: dulibo@iccas.ac.cn; Suo Siqingaowa [Chinese Academy of Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Sciences, Institute of Chemistry (China); Luo Dan [Peking University, Single-molecule and Nanobiology Laboratory, Department of Biophysics, School of Basic Medical Sciences and Biomed-X Center (China); Jia Hongying [Chinese Academy of Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Sciences, Institute of Chemistry (China); Sha Yinlin [Peking University, Single-molecule and Nanobiology Laboratory, Department of Biophysics, School of Basic Medical Sciences and Biomed-X Center (China); Liu Yang, E-mail: yliu@iccas.ac.cn [Chinese Academy of Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Center for Molecular Sciences, Institute of Chemistry (China)

    2013-06-15

    In this study, we presented a simple approach to prepare hydroxyethylated graphene oxide (HE-GO) with high water solubility and physiological stability. The successful synthesis of HE-GO was confirmed by UV-Vis spectroscopy, Fourier transform infrared spectroscopy, and atomic force microscopy. The loading of anticancer drug methotrexate (MTX) onto this nanocarrier (MTX/HE-GO) was investigated. The results of in vitro drug release experiment showed that the rate of MTX release from MTX/HE-GO was pH dependent. Moreover, cell viability assay demonstrated that HE-GO loaded with MTX exhibits higher anticancer activity against human lung adenocarcinoma epithelial cell line than non-vehicle MTX.

  1. Pharmacology and optimization of thiopurines and methotrexate in inflammatory bowel disease

    DEFF Research Database (Denmark)

    Coskun, Mehmet; Steenholdt, Casper; de Boer, Nanne K.;

    2016-01-01

    Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease...

  2. HER2 specific delivery of methotrexate by dendrimer conjugated anti-HER2 mAb

    Energy Technology Data Exchange (ETDEWEB)

    Shukla, Rameshwer; Thomas, Thommey P; Desai, Ankur M; Kotlyar, Alina; Park, Steve J; Baker, James R Jr [Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, 9220 MSRB III, Box 0648, Ann Arbor, MI 48109 (United States)], E-mail: rameshwe@umich.edu, E-mail: jbakerjr@med.umich.edu

    2008-07-23

    Herceptin, a humanized monoclonal antibody that binds to human growth factor receptor-2 (HER2), was covalently attached to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. The specific binding and internalization of this conjugate labeled with FITC was clearly demonstrated in cell lines overexpressing HER2 by flow cytometry as well as confocal microscopic analysis. In addition, binding and uptake of antibody conjugated dendrimers was completely blocked by excess non-conjugated herceptin. The dendrimer conjugate was also shown to inhibit the dihydrofolate reductase with similar activity to methotrexate. Co-localization experiments with lysotracker red indicate that antibody conjugate, although internalized efficiently into cells, has an unusually long residence time in the lysosome. Somewhat lower cytotoxicity of the conjugate in comparison to free methotrexate was attributed to the slow release of methotrexate from the conjugate and its long retention in the lysosomal pocket.

  3. Evidence-based recommendations for treatment with methotrexate in rheumatic disorders

    DEFF Research Database (Denmark)

    Madsen, Ole Rintek; Faurschou, Mikkel; Loft, Anne Gitte;

    2010-01-01

    The aim of this study was to develop 3E (Evidence, Expertise, Exchange) recommendations (RCs) on the use of methotrexate in rheumatic disorders and to assess the agreement among Danish rheumatologists....

  4. Selective sparing of goblet cells and paneth cells in the intestine of methotrexate-treated rats

    NARCIS (Netherlands)

    M. Verburg (Melissa); I.B. Renes (Ingrid); H.P. Meijer; J.A. Taminiau; H.A. Büller (Hans); A.W.C. Einerhand (Sandra); J. Dekker (Jan)

    2000-01-01

    textabstractProliferation, differentiation, and cell death were studied in small intestinal and colonic epithelia of rats after treatment with methotrexate. Days 1-2 after treatment were characterized by decreased proliferation, increased apoptosis, and decreased numbers and depths

  5. Alkylation of Chitosan as Nerve Conduit Biomaterial

    Institute of Scientific and Technical Information of China (English)

    邓劲光; 公衍道; 程明愚; 赵南明; 张秀芳

    2002-01-01

    Chitosan under physiological conditions is a degradable and biocompatible biomaterial with a wide variety of useful physicochemical properties. However, as a nerve conduit biomaterial, its solubility was very low, so chitosan was modified chemically to enhance its solubility. The free amino groups of long molecular chains in chitosan are responsible for its solubility, and the solubility could be adjusted by controlling the free amidogen capacity with N-alkylation. The results show that the solubility of N-alkylation chitosan is increased to 10%, which is an increase of 500%.

  6. Nano-self-assemblies based on synthetic analogues of mycobacterial monomycoloyl glycerol and DDA: Supramolecular structure and adjuvant efficacy

    DEFF Research Database (Denmark)

    Martin-Bertelsen, Birte; Korsholm, Karen Smith; Christensen, Dennis

    2016-01-01

    responses. In the present study, we investigated the supramolecular structure and in vivo adjuvant activity of dispersions based on binary mixtures of DDA and an array of synthetic MMG-1 analogues (MMG- 2/3/5/6) displaying longer (MMG-2) or shorter (MMG-3) alkyl chain lengths, or polar headgroup (MMG-5......-adsorbed to DDA:MMG-1/3/6 dispersions revealed that all tested adjuvants were immunoactive and induced strong Th1 and Th17 responses with a potential for a central effector memory profile. The MMG-1 and MMG-6 analogues were equally immunoactive in vivo upon incorporation into DDA liposomes, despite the reported...

  7. Yellow fever vaccine used in a psoriatic arthritis patient treated with methotrexate

    OpenAIRE

    Štuhec, Matej

    2015-01-01

    The yellow fever vaccines on the market are contraindicated for immunocompromised and elderly patients. A case of yellow fever vaccine used in a 27-year-old Slovenian male with psoriatic arthritis during treatment with methotrexate is described. We demonstrate a positive case, since there were noadverse effects in concurrent administration of yellow fever vaccine and methotrexate. This patient did not show severe adverse reactions and did not contract yellow fever despite potential exposure. ...

  8. Yellow fever vaccine used in a psoriatic arthritis patient treated with methotrexate: a case report:

    OpenAIRE

    Štuhec, Matej

    2014-01-01

    The yellow fever vaccines on the market are contraindicated for immunocompromised and elderly patients. A case of yellow fever vaccine used in a 27-year-old Slovenian male with psoriatic arthritis during treatment with methotrexate is described. We demonstrate a positive case, since there were noadverse effects in concurrent administration of yellow fever vaccine and methotrexate. This patient did not show severe adverse reactions and did not contract yellow fever despite potential exposure. ...

  9. Enhancement of alkylation catalysts for improved supercritical fluid regeneration

    Science.gov (United States)

    Ginosar, Daniel M.; Petkovic, Lucia

    2009-09-22

    A method of modifying an alkylation catalyst to reduce the formation of condensed hydrocarbon species thereon. The method comprises providing an alkylation catalyst comprising a plurality of active sites. The plurality of active sites on the alkylation catalyst may include a plurality of weakly acidic active sites, intermediate acidity active sites, and strongly acidic active sites. A base is adsorbed to a portion of the plurality of active sites, such as the strongly acidic active sites, selectively poisoning the strongly acidic active sites. A method of modifying the alkylation catalyst by providing an alkylation catalyst comprising a pore size distribution that sterically constrains formation of the condensed hydrocarbon species on the alkylation catalyst or by synthesizing the alkylation catalyst to comprise a decreased number of strongly acidic active sites is also disclosed, as is a method of improving a regeneration efficiency of the alkylation catalyst.

  10. Effect of proanthocyanidin, arginine and glutamine supplementation on methotrexate-induced gastrointestinal toxicity in rats.

    Science.gov (United States)

    Gulgun, M; Karaoglu, A; Kesik, V; Kurt, B; Erdem, O; Tok, D; Kismet, E; Koseoglu, V; Ozcan, O

    2010-11-01

    Methotrexate is a folate antagonist that is commonly used as an antitumor and antiarthritic drug. The aim of this study was to investigate the possible roles of exogenous glutamine (Glu), arginine (Arg) and proanthocyanidin (PA) on gut protection from methotrexate-induced intestinal damage in rats. Experimental rats were separated into eight groups. The first (sham) group received a 0.9% NaCl solution alone. The second group received intraperitoneal injections of methotrexate (20 mg/kg/day) administered on day 4 of the experiment and continued for 5 days. Rats in the other six groups were administered PA, Glu, Arg, Glu+PA, Arg+PA or Glu+Arg orally by gavage together with methotrexate and animals were sacrificed on day 8 of the experiment. All animals were sacrificed 4 days after methotrexate injection for histopathological analysis, tissue glutathione peroxidase, malondialdehyde and superoxide dismutase assays. Proanthocyanidin and Glu decreased the severity of intestinal injury and oxidant injury as evident by histopathology and changes in malondialdehyde levels. Histological analysis confirmed that PA and to a lesser extent Glu supplementation were more favorable than Arg for the protection of the small intestine from methotrexate-induced injury.

  11. The Synthesis of 6-Alkyl-5-Fluorouracil Derivatives

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    6-alkyl-5-fluorouracil derivatives (5a~5f) were synthesized by facile alkylation of lithiation of 5-fluorouracil derivatives with mthyl iodide (MeI) or alkyl trifluoromethanesulfonate (ROTf) in yield of 42~58%. We found that the methylated product was ethyl-substituted derivatives, not methyl-substituted derivatives.

  12. Amberlyst-15 catalyzed synthesis of alkyl/aryl/heterocyclic phosphonates

    Institute of Scientific and Technical Information of China (English)

    U.M. Rao Kunda; V.N. Reddy Mudumala; C.S. Reddy Gangireddy; B.R. Nemallapudi; K.N. Sandip; S.R. Cirandur

    2011-01-01

    A novel and efficient procedure for the synthesis of alkyl phosphonates through one pot condensation of alkyl halide and tri-alkyl/aryl phosphite in the presence of Amberlyst-15 as catalyst under solvent free conditions was applied. It demonstrated several advantages such as good yields of products, simple operation, convenient separation and inexpensive catalyst.

  13. IONIC LIQUID-CATALYZED ALKYLATION OF ISOBUTANE WITH 2-BUTENE

    Science.gov (United States)

    A detailed study of the alkylation of isobutane with 2-butene in ionic liquid media has been conducted using 1-alkyl-3-methylimidazolium halides?aluminum chloride encompassing various alkyl groups (butyl-, hexyl-, and octyl-) and halides (Cl, Br, and I) on its cations and anions,...

  14. 40 CFR 721.10087 - Substituted alkyl phosphine oxide (generic).

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Substituted alkyl phosphine oxide... Specific Chemical Substances § 721.10087 Substituted alkyl phosphine oxide (generic). (a) Chemical... as substituted alkyl phosphine oxide (PMN P-06-332) is subject to reporting under this section...

  15. 40 CFR 721.5769 - Mixture of nitrated alkylated phenols.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Mixture of nitrated alkylated phenols... Substances § 721.5769 Mixture of nitrated alkylated phenols. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as a mixture of nitrated alkylated...

  16. 40 CFR 721.2825 - Alkyl ester (generic name).

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkyl ester (generic name). 721.2825... Substances § 721.2825 Alkyl ester (generic name). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance alkyl ester (PMN P-84-968) is subject to reporting under this...

  17. 40 CFR 721.8700 - Halogenated alkyl pyridine.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Halogenated alkyl pyridine. 721.8700... Substances § 721.8700 Halogenated alkyl pyridine. (a) Chemical substances and significant new uses subject to reporting. (1) The chemical substance identified generically as halogenated alkyl pyridine (PMN P-83-237)...

  18. Polypyrrole Doped with Alkyl Benzene Sulphonates

    DEFF Research Database (Denmark)

    Bay, Lasse; Mogensen, Naja; Skaarup, Steen;

    2002-01-01

    The properties of polypyrrole (PPy) are to a large extent determined by the condition of synthesis and especially by the counterion incorporated as dopant during synthesis. In this work, PPy doped with different alkyl benzenesulfonates are compared. The polymer films are prepared by constant curr...

  19. Dicentrine Analogue-Induced G2/M Arrest and Apoptosis through Inhibition of Topoisomerase II Activity in Human Cancer Cells.

    Science.gov (United States)

    Lin, Huei-Fang; Huang, Huey-Lan; Liao, Jyh-Fei; Shen, Chien-Chang; Huang, Ray-Ling

    2015-07-01

    Lindera megaphylla has been traditionally used as an antineoplastic and wound healing remedy. We previously demonstrated the antitumor effects of D-dicentrine, a natural aporphine alkaloid from the root of L. megaphylla. To generate analogues, series of phenanthrene alkaloids from D-dicentrine were synthesized by degradation with ethyl chloroformate in pyridine, base hydrolysis, and N-alkylation. In this study, we demonstrated that one of the synthesized D-dicentrine analogues (here after designated as analogue 1) exhibited more potent cytotoxic effects than D-dicentrine in colon adenocarcinoma, hepatoma, leukemia, and epidermoid carcinoma cells. We performed cell cycle and apoptotic analysis by flow cytometry, an apoptotic DNA detection ELISA assay, and topoisomerase II activity by the kinetoplast DNA concatenation assay for studying their cytotoxic mechanisms. We found that both D-dicentrine and analogue 1 induced apoptosis and G2/M arrest in HL-60 leukemia cells. The percentage of apoptotic cells induced by analogue 1 was 4.5-fold higher than that induced by D-dicentrine as evident from measuring the amount of histone-bound DNA fragments. Moreover, we found that analogue 1 was 28-fold more potent than D-dicentrine for inhibition of topoisomerase II activity by the kinetoplast DNA concatenation assay. Our findings indicate that D-dicentrine analogue 1 is very promising as a potential antitumor agent for future study.

  20. Maternal Exposure to Methotrexate and Birth Defects: a Population-Based Study

    Science.gov (United States)

    Dawson, April L.; Riehle-Colarusso, Tiffany; Reefhuis, Jennita; Arena, J. Fernando

    2015-01-01

    Methotrexate is an anti-folate medication that is associated with increased risk of multiple birth defects. Using data from the National Birth Defects Prevention Study, a case-control study of major birth defects in the United States, we examined mothers exposed to methotrexate. The study population included mothers of live-born infants without major birth defects (controls) and mothers of fetuses or infants with a major birth defect (cases), with expected dates of delivery between October 1997 and December 2009. Mothers of cases and controls were asked detailed questions concerning pregnancy history, demographic information, and exposures in a telephone interview. Approximately 0.06% (n=16/27,623) of case and 0.04% (n=4/10,113) of control mothers reported exposure to methotrexate between three months prior to conception through the end of pregnancy. Of the 16 case infants, 11 (68.8%) had a congenital heart defect (CHD). The observed CHDs included atrial septal defects, tetralogy of Fallot, valvar pulmonary stenosis, ventricular septal defects (VSDs), and total anomalous pulmonary venous return. One case infant had microtia in addition to a VSD and another had VACTER association. Exposed cases without a CHD had one of the following birth defects: cleft palate, hypospadias, congenital diaphragmatic hernia, or craniosynostosis. Based on a limited number of methotrexate-exposed mothers, our findings support recent case reports suggesting an association between early pregnancy exposure to methotrexate and CHDs. Because of the rarity of maternal periconceptional exposure to methotrexate, long-term, population-based case-control studies are needed to confirm these findings and better evaluate the association between methotrexate and birth defects. PMID:24898111

  1. The combined application of biological therapy and methotrexate in case of escape phenomenon progressing

    Directory of Open Access Journals (Sweden)

    Ponich E.S.

    2015-09-01

    Full Text Available Aim: the study of the efficacy of methotrexate in patients with the "escape effect" during the ustekinumab therapy. Materials and Methods. The results of methotrexate at a dose of 15-20mg/week in treatment of 4 patients receiving biologic and developed "escape effect". Ustekinumab is used as a hypodermic injection at a dose of 45 mg for a body weight of a patient no more than 100 kg, and 90 mg of body weight over 100 kg, at the zero week, the 4th week and then every 12 weeks. Patients control meets the standard management of patients in biological therapy. Results. The study shows that in the case of the resistance progressing when applying preparations of biological therapy, methotrexate is useful at a dose of 15-20mg/week for up to 6 months. The combined use of biologic therapy and methotrexate in the treatment of patients with psoriasis vulgaris, "escape effect" contributes to the marked regression of clinical symptoms and allows to control the process long enough, which is confirmed by the dynamics of the index PASI, BRS and DLQI. The combined method is highly safe, as evidenced by the lack of inhibition of hematopoiesis, the normal level of hepatic transaminases and serum creatinine, which greatly improves patient compliance in this type of therapy. Conclusion. The article presents the data of the combined application of biological medication therapy (ustekinumab and methotrexate for the treatment of patients with the common form of psoriasis vulgaris. In the case of the development of resistance of biological therapy recommended the appointment of methotrexate. The combined use of methotrexate and biologic therapy in the treatment of patients with psoriasis vulgaris contributes to marked regression of clinical symptoms and allows to control the process for a long time.

  2. Maternal exposure to methotrexate and birth defects: a population-based study.

    Science.gov (United States)

    Dawson, April L; Riehle-Colarusso, Tiffany; Reefhuis, Jennita; Arena, J Fernando

    2014-09-01

    Methotrexate is an anti-folate medication that is associated with increased risk of multiple birth defects. Using data from the National Birth Defects Prevention Study, a case-control study of major birth defects in the United States, we examined mothers exposed to methotrexate. The study population included mothers of live-born infants without major birth defects (controls) and mothers of fetuses or infants with a major birth defect (cases), with expected dates of delivery between October 1997 and December 2009. Mothers of cases and controls were asked detailed questions concerning pregnancy history, demographic information, and exposures in a telephone interview. Approximately 0.06% (n = 16/27,623) of case and 0.04% (n = 4/10,113) of control mothers reported exposure to methotrexate between 3 months prior to conception through the end of pregnancy. Of the 16 case infants, 11 (68.8%) had a congenital heart defect (CHD). The observed CHDs included atrial septal defects, tetralogy of Fallot, valvar pulmonary stenosis, ventricular septal defects (VSDs), and total anomalous pulmonary venous return. One case infant had microtia in addition to a VSD and another had VACTER association. Exposed cases without a CHD had one of the following birth defects: cleft palate, hypospadias, congenital diaphragmatic hernia, or craniosynostosis. Based on a limited number of methotrexate-exposed mothers, our findings support recent case reports suggesting an association between early pregnancy exposure to methotrexate and CHDs. Because of the rarity of maternal periconceptional exposure to methotrexate, long-term, population-based case-control studies are needed to confirm these findings and better evaluate the association between methotrexate and birth defects.

  3. Prediction of methotrexate CNS distribution in different species - influence of disease conditions.

    Science.gov (United States)

    Westerhout, Joost; van den Berg, Dirk-Jan; Hartman, Robin; Danhof, Meindert; de Lange, Elizabeth C M

    2014-06-16

    Children and adults with malignant diseases have a high risk of prevalence of the tumor in the central nervous system (CNS). As prophylaxis treatment methotrexate is often given. In order to monitor methotrexate exposure in the CNS, cerebrospinal fluid (CSF) concentrations are often measured. However, the question is in how far we can rely on CSF concentrations of methotrexate as appropriate surrogate for brain target site concentrations, especially under disease conditions. In this study, we have investigated the spatial distribution of unbound methotrexate in healthy rat brain by parallel microdialysis, with or without inhibition of Mrp/Oat/Oatp-mediated active transport processes by a co-administration of probenecid. Specifically, we have focused on the relationship between brain extracellular fluid (brainECF) and CSF concentrations. The data were used to develop a systems-based pharmacokinetic (SBPK) brain distribution model for methotrexate. This model was subsequently applied on literature data on methotrexate brain distribution in other healthy and diseased rats (brainECF), healthy dogs (CSF) and diseased children (CSF) and adults (brainECF and CSF). Important differences between brainECF and CSF kinetics were found, but we have found that inhibition of Mrp/Oat/Oatp-mediated active transport processes does not significantly influence the relationship between brainECF and CSF fluid methotrexate concentrations. It is concluded that in parallel obtained data on unbound brainECF, CSF and plasma concentrations, under dynamic conditions, combined with advanced mathematical modeling is a most valid approach to develop SBPK models that allow for revealing the mechanisms underlying the relationship between brainECF and CSF concentrations in health and disease.

  4. Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis

    DEFF Research Database (Denmark)

    Conaghan, Philip G; Østergaard, Mikkel; Bowes, Michael A;

    2016-01-01

    OBJECTIVES: To explore the effects of tofacitinib-an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)-with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand. METHODS: In this exploratory...

  5. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors

    Science.gov (United States)

    Westhovens, R; Robles, M; Ximenes, A C; Nayiager, S; Wollenhaupt, J; Durez, P; Gomez-Reino, J; Grassi, W; Haraoui, B; Shergy, W; Park, S-H; Genant, H; Peterfy, C; Becker, J-C; Covucci, A; Helfrick, R; Bathon, J

    2009-01-01

    Objectives: To assess the efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis (RA) and poor prognostic factors. Methods: In this double-blind, phase IIIb study, patients with RA for 2 years or less were randomly assigned 1 : 1 to receive abatacept (∼10 mg/kg) plus methotrexate, or placebo plus methotrexate. Patients were methotrexate-naive and seropositive for rheumatoid factor (RF), anti-cyclic citrullinated protein (CCP) type 2 or both and had radiographic evidence of joint erosions. The co-primary endpoints were the proportion of patients achieving disease activity score in 28 joints (DAS28)-defined remission (C-reactive protein) and joint damage progression (Genant-modified Sharp total score; TS) at year 1. Safety was monitored throughout. Results: At baseline, patients had a mean DAS28 of 6.3, a mean TS of 7.1 and mean disease duration of 6.5 months; 96.5% and 89.0% of patients were RF or anti-CCP2 seropositive, respectively. At year 1, a significantly greater proportion of abatacept plus methotrexate-treated patients achieved remission (41.4% vs 23.3%; p<0.001) and there was significantly less radiographic progression (mean change in TS 0.63 vs 1.06; p = 0.040) versus methotrexate alone. Over 1 year, the frequency of adverse events (84.8% vs 83.4%), serious adverse events (7.8% vs 7.9%), serious infections (2.0% vs 2.0%), autoimmune disorders (2.3% vs 2.0%) and malignancies (0.4% vs 0%) was comparable for abatacept plus methotrexate versus methotrexate alone. Conclusions: In a methotrexate-naive population with early RA and poor prognostic factors, the combination of abatacept and methotrexate provided significantly better clinical and radiographic efficacy compared with methotrexate alone and had a comparable, favourable safety profile. PMID:19124524

  6. Nail psoriasis successfully treated with intralesional methotrexate: case report.

    Science.gov (United States)

    Sarıcaoglu, Hayriye; Oz, Arife; Turan, Hakan

    2011-02-01

    Psoriasis is a common, chronic disease which affects nearly 3% of the population. The lifetime incidence of nail involvement increases up to 80-90% for psoriatic patients. Nail psoriasis is considered a significant social problem. Many topical agents have been used for psoriatic nails with various side effects and some benefits; management is currently inconclusive. Methotrexate (MTX) is a folic acid analog, which irreversibly binds to dehydrofolate reductase and blocks deoxyribonucleic acid synthesis. It is considered a potential treatment option for rapidly growing cells and has an anti-inflammatory effect through inhibition of the polyamine pathway in autoimmune diseases. Intralesional MTX has been used successfully for various indications. We present a case successfully treated with low-dose intralesional MTX with no observed side effects in a 26-year-old female psoriatic patient suffering from nail dystrophy. In contrast, conventional topical and systemic therapies have various side effects, which limit their use. We conclude that intralesional MTX injection seems to be a safe and effective treatment option for nail psoriasis; however, large controlled studies are needed.

  7. Effect of methotrexate on the mandibular development of arthritic rabbits

    Science.gov (United States)

    Meyer, Philipp; Rafayelyan, Smbat; Minden, Kirsten; Jost-Brinkmann, Paul-Georg

    2015-01-01

    Summary Introduction: Juvenile idiopathic arthritis affecting the temporomandibular joint (TMJ) can cause severe disturbances of the mandibular development. Methotrexate (MTX) is often administered as a common used remission-inducing agent to treat this disease. The aim of this study was to investigate the effect of low dose MTX on the mandibular growth in arthritic rabbits. Subjects and methods: Eighteen 10-week-old female New Zealand white rabbits were randomly assigned to three groups with six animals in each group. After being sensitized to ovalbumin (OA), the first and the second group received intra-articular injections with OA. The first group remained untreated, the second was treated by weekly injections of MTX. Cephalograms were taken from each animal at 10, 13, 16, 19, and 22 weeks of age and six mandibular distances measured. Results: All distances showed an increase between 10 and 20 per cent, whereas growth was more accentuated in the sagittal dimension. Significant differences in the overall growth could be observed between the arthritic and the control animals and less accentuated between the arthritic and the MTX animals. In contrast, existing differences between the groups were not significant during the intervals, but time had the greatest influence on mandibular growth. Conclusions: MTX seems to have a positive impact on growth in rabbits suffering from experimental arthritis of the TMJ. PMID:25518996

  8. Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate.

    Science.gov (United States)

    Boogerd, W; vd Sande, J J; Moffie, D

    1988-10-01

    Nine out of 14 patients treated with intraventricular methotrexate (MTX) for meningeal carcinomatosis from breast carcinoma and surviving more than 4 months developed disseminated necrotising leukoencephalopathy (DNL). All four patients who had received both intraventricular MTX and whole brain radiotherapy developed DNL. Five of the six patients who experienced an acute febrile reaction with mild encephalopathic signs following intraventricular administration of MTX developed DNL after a mean time of 5 months and a low mean dose of 44 mg MTX. DNL was also noted in two patients without a previous febrile reaction or whole brain radiotherapy, following prolonged intraventricular MTX therapy after a mean time of 19.5 months and a mean dose of 147 mg MTX. These findings confirm the hazards of (1) high cumulative doses of intrathecal MTX and (2) combined intrathecal chemotherapy and whole brain radiotherapy. This study also suggests a possible relationship between an early and transient febrile reaction during intraventricular administration of MTX and the development of DNL.

  9. Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate.

    Science.gov (United States)

    Boogerd, W; vd Sande, J J; Moffie, D

    1988-01-01

    Nine out of 14 patients treated with intraventricular methotrexate (MTX) for meningeal carcinomatosis from breast carcinoma and surviving more than 4 months developed disseminated necrotising leukoencephalopathy (DNL). All four patients who had received both intraventricular MTX and whole brain radiotherapy developed DNL. Five of the six patients who experienced an acute febrile reaction with mild encephalopathic signs following intraventricular administration of MTX developed DNL after a mean time of 5 months and a low mean dose of 44 mg MTX. DNL was also noted in two patients without a previous febrile reaction or whole brain radiotherapy, following prolonged intraventricular MTX therapy after a mean time of 19.5 months and a mean dose of 147 mg MTX. These findings confirm the hazards of (1) high cumulative doses of intrathecal MTX and (2) combined intrathecal chemotherapy and whole brain radiotherapy. This study also suggests a possible relationship between an early and transient febrile reaction during intraventricular administration of MTX and the development of DNL. Images PMID:3225584

  10. Methotrexate intercalated ZnAl-layered double hydroxide

    Science.gov (United States)

    Chakraborty, Manjusha; Dasgupta, Sudip; Soundrapandian, Chidambaram; Chakraborty, Jui; Ghosh, Swapankumar; Mitra, Manoj K.; Basu, Debabrata

    2011-09-01

    The anticancerous drug methotrexate (MTX) has been intercalated into an ZnAl-layered double hydroxide (LDH) using an anion exchange technique to produce LDH-MTX hybrids having particle sizes in the range of 100-300 nm. X-ray diffraction studies revealed increases in the basal spacings of ZnAl-LDH-MTX hybrid on MTX intercalation. This was corroborated by the transmission electron micrographs, which showed an increase in average interlayer spacing from 8.9 Å in pristine LDH to 21.3 Å in LDH-MTX hybrid. Thermogravimetric analyses showed an increase in the decomposition temperature for the MTX molecule in the LDH-MTX hybrid indicating enhanced thermal stability of the drug molecule in the LDH nanovehicle. The cumulative release profile of MTX from ZnAl-LDH-MTX hybrids in phosphate buffer saline (PBS) at pH 7.4 was successfully sustained for 48 h following Rigter-Peppas model release kinetics via diffusion.

  11. Introduction to electronic analogue computers

    CERN Document Server

    Wass, C A A

    1965-01-01

    Introduction to Electronic Analogue Computers, Second Revised Edition is based on the ideas and experience of a group of workers at the Royal Aircraft Establishment, Farnborough, Hants. This edition is almost entirely the work of Mr. K. C. Garner, of the College of Aeronautics, Cranfield. As various advances have been made in the technology involving electronic analogue computers, this book presents discussions on the said progress, including some acquaintance with the capabilities of electronic circuits and equipment. This text also provides a mathematical background including simple differen

  12. Analogue Methods in Palaeoecology: Using the analogue Package

    Directory of Open Access Journals (Sweden)

    Gavin L. Simpson

    2007-08-01

    Full Text Available Palaeoecology is an important branch of ecology that uses the subfossil remains of organisms preserved in lake, ocean and bog sediments to inform on changes in ecosystems and the environment through time. The analogue package contains functions to perform modern analogue technique (MAT transfer functions, which can be used to predict past changes in the environment, such as climate or lake-water pH from species data. A related technique is that of analogue matching, which is concerned with identifying modern sites that are floristically and faunistically similar to fossil samples. These techniques, and others, are increasingly being used to inform public policy on environmental pollution and conservation practices. These methods and other functionality in analogue are illustrated using the Surface Waters Acidification Project diatom:pH training set and diatom counts on samples of a sediment core from the Round Loch of Glenhead, Galloway, Scotland. The paper is aimed at palaeoecologists who are familiar with the techniques described but not with R.

  13. Alkyl- and fluoroalkyltrialkoxysilanes for wettability modification

    Energy Technology Data Exchange (ETDEWEB)

    Dopierala, Katarzyna, E-mail: katarzyna.dopierala@put.poznan.pl [Institute of Chemical Technology and Engineering, Poznan University of Technology, Pl. Marii Skłodowskiej-Curie 2, Poznań 60-965 (Poland); Maciejewski, Hieronim [Poznań Science and Technology Park, Rubież 46, Poznań 61-612 (Poland); Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, Poznań 60-780 (Poland); Karasiewicz, Joanna [Poznań Science and Technology Park, Rubież 46, Poznań 61-612 (Poland); Prochaska, Krystyna [Institute of Chemical Technology and Engineering, Poznan University of Technology, Pl. Marii Skłodowskiej-Curie 2, Poznań 60-965 (Poland)

    2013-10-15

    Alkyl- and fluoroalkyltriethoxysilanes were investigated as potential surface modifiers. Many aspects concerning trialkoxysilanes were discussed, starting from hydrolysis of silanes in water solutions, the effect of this hydrolysis on the surface tension, wettability of the modified surface to the morphology of the modified surface. Surface tension and contact angle measurements as well as scanning electron microscopy were used to characterise alkyl- and fluoroalkyltriethoxysilanes and their ability to modify the wettability of glass. The effect of such modification was superhydrophobic surface with high values of contact angles. Superhydrophobic behaviour was observed as a result of two-step modification providing increased surface roughness thanks to the use of different size silica particles and surface chemical modification with fluorosilane molecules.

  14. Effect of biologic therapy on radiological progression in rheumatoid arthritis: what does it add to methotrexate?

    Directory of Open Access Journals (Sweden)

    Jones G

    2012-07-01

    Full Text Available Graeme Jones, Erica Darian-Smith, Michael Kwok, Tania WinzenbergMenzies Research Institute, University of Tasmania, Tasmania, AustraliaAbstract: There have been substantial advances in the treatment of rheumatoid arthritis in recent years. Traditional disease-modifying antirheumatic drugs (DMARDs have been shown to have small effects on the progression of radiographic damage. This quantitative overview summarizes the evidence for biologic DMARDS and radiographic damage either alone or in combination with methotrexate. Two outcomes were used (standardized mean difference and odds of progression. A total of 21 trials were identified of which 18 had useable data. For biologic monotherapy, tocilizumab, adalimumab, and etanercept were significantly better than methotrexate, with tocilizumab ranking first in both outcomes while golimumab was ineffective in both outcomes. For a biologic in combination with methotrexate compared with methotrexate alone, most therapies studied (etanercept, adalimumab, infliximab, certolizumab, tocilizumab, and rituximab were effective at slowing X-ray progression using either outcome, with infliximab ranking first in both outcomes. The exceptions to this were golimumab (no effect on standardized mean difference and abatacept (no effect on odds of progression. This effect was additional to methotrexate; thus, the overall benefit is moderate to large in magnitude, which is clearly of major clinical significance for sufferers of rheumatoid arthritis and supports the use of biologic DMARDs in those with a poor disease prognosis.Keywords: rheumatoid, trials, meta-analysis, radiographs, biologic, disease-modifying antirheumatic drugs, DMARDs

  15. IN SILICO AND IN VITRO STUDIES: TRYPAREDOXIN PEROXIDASE INHIBITOR ACTIVITY OF METHOTREXATE FOR ANTILEISHMANIAL ACTIVITY

    Directory of Open Access Journals (Sweden)

    Ravi Kumar Gundampati

    2013-01-01

    Full Text Available In order to understand the mechanism of molecular interactions at the active site of Tryparedoxin Peroxidase (Try P, homology modeling and docking studies were performed. We generated a Three-Dimensional (3D model of target protein based on the Crystal structure of Leishmania Major Try PI (PDB ID: 3TUE using modeler software. Docking analysis was carried out to study the effects of methotrexate on Tryparedoxin Peroxidase (Try P. Inhibition of the Tryparedoxin peroxidase interaction has become a new therapeutic strategy in treating leishmaniasis. Docking analysis was carried out to study the effects of methotrexate on Tryparedoxin Peroxidase (TryP. Tryparedoxin peroxidase of Trypanosomatidae family functions as antioxidant through their peroxidase and peroxynitrite reductase activities. The theoretical docking study, conducted on a sample previously reported for anti-cancer properties of Methotrexate at the binding site of 3D models of Tryparedoxin Peroxidase of Leishmania braziliensis (L. braziliensis Try P examine interaction energy. Our studies indicate that Methotrexate displays potent activity against Try P with lowest binding energy and RMSD values to be -14.5879 Kcal/Mol and 2.0 A. The results of the present study clearly demonstrated the Tryparedoxin Peroxidase inhibitory activity by methotrexate in in silico docking analysis and in vitro assay which contributes towards understanding the mechanism of antileishmanial activity.

  16. Rational design of novel N-alkyl-N capped biostable RNA nanostructures for efficient long-term inhibition of gene expression

    Science.gov (United States)

    Terrazas, Montserrat; Ivani, Ivan; Villegas, Núria; Paris, Clément; Salvans, Cándida; Brun-Heath, Isabelle; Orozco, Modesto

    2016-01-01

    Computational techniques have been used to design a novel class of RNA architecture with expected improved resistance to nuclease degradation, while showing interference RNA activity. The in silico designed structure consists of a 24–29 bp duplex RNA region linked on both ends by N-alkyl-N dimeric nucleotides (BCn dimers; n = number of carbon atoms of the alkyl chain). A series of N-alkyl-N capped dumbbell-shaped structures were efficiently synthesized by double ligation of BCn-loop hairpins. The resulting BCn-loop dumbbells displayed experimentally higher biostability than their 3′-N-alkyl-N linear version, and were active against a range of mRNA targets. We studied first the effect of the alkyl chain and stem lengths on RNAi activity in a screen involving two series of dumbbell analogues targeting Renilla and Firefly luciferase genes. The best dumbbell design (containing BC6 loops and 29 bp) was successfully used to silence GRB7 expression in HER2+ breast cancer cells for longer periods of time than natural siRNAs and known biostable dumbbells. This BC6-loop dumbbell-shaped structure displayed greater anti-proliferative activity than natural siRNAs. PMID:26975656

  17. A New Synthesis Method and GABA Transporters Inhibitory Activities of Tiagabine and Its Analogues

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    A new synthetic method and GABA transporter inhibitory activities of Tiagabine and its analogues are described.The key intermediates 4-tosyl-1,1-diaryl/heteroaryl-1-butene 10a-10e were synthesized by Wittig reaction, and followed by N-alkylation with (R)-3-piperidinecarboxylate. The resultingN-diheterocyclylalkenylpiperidine-3-carboxylic acid ester 11a-11e were saponified and then acidified toget the target compounds 1a-1e. The preliminary bioassays show that compound 1a-1e exhibited excellent inhibition of [3H]-GABA uptake in vitro of culture cells.

  18. Extended duration of prehydration does not prevent nephrotoxicity or delayed drug elimination in high-dose methotrexate infusions

    DEFF Research Database (Denmark)

    Mikkelsen, Torben Stamm; Mamoudou, Aissata Diop; Tuckuviene, Ruta;

    2014-01-01

    Alkalized hydration is used as supportive care to prevent renal toxicity during infusions with high-dose methotrexate (HDMTX). In children with acute lymphoblastic leukemia (ALL), the hydration is commonly initiated 4 hours before start of the methotrexate (MTX) infusion. To test if longer duration...

  19. Enzymatic Synthesis of Palm Alkyl Ester Using Dialkyl Carbonate as an Alkyl Donors

    Directory of Open Access Journals (Sweden)

    Roila Awang

    2010-01-01

    Full Text Available Problem statement: Though efficient in terms of reaction yield and time, the chemical approach to synthesizing alkyl ester has drawback such as difficulties in the recovery of glycerol and the need for removal of salt residue. On the other hand, biocatalyst allow for synthesis of specific alkyl esters and easy recovery of glycerol. However, the solvent-free alcoholysis, does not give high conversion. The same problem was also found when ethyl or methyl acetate was used as acyl acceptors. Approach: Lipase catalyzed transesterification of oil and dialkyl carbonate was predicted to give higher conversion in solvent free reaction system. Results: Alkyl esters were synthesized enzymatically to overcome the problems associated with chemical processes. In this study, dialkyl carbonates were used as an alkyl donor for the production of alkyl ester. Nine commercial lipases were tested for their suitability for the reaction system. Among the lipase tested, Novozym 435 was chosen for optimization study because of their higher activity. In a solvent-free reaction system, the ester formation using dialkyl carbonate was 6 times higher than using ethanol and methanol. The effect of various reaction parameters such as temperature, amount of enzyme, organic solvent and structure of substrates were studied to determine optimal condition. The optimal conditions of ester formation were reaction temperature at 60°C, reaction time at 8 h, enzyme amount of 10% (w/w of oil and 0.2% wt added water. Conclusion: Solvent-free lipase catalyzed transesterification of palm kernel oil and dialkyl carbonates gave higher conversion of ester compared to the reaction using short chain alcohol as an alkyl donors.

  20. Semicircular lipoatrophy in a child with systemic lupus erythematosus after subcutaneous injections with methotrexate.

    Science.gov (United States)

    Haas, Norbert; Henz, Beate M; Bunikowski, Rita; Keitzer, Rolf

    2002-01-01

    Lipoatrophia semicircularis, a rare entity which presents as atrophic cutaneous indentations exclusively on the anterior thighs of women, is thought to result from physical trauma. Localized lipoatrophies are common following injection with drugs and occur in patients with collagen disease. We report a 10-year-old girl who developed semicircular lipoatrophy on the anterior thighs after treatment of systemic lupus erythematosus (SLE) with subcutaneous injections of methotrexate. Until now, subcutaneously administered methotrexate has not been reported to cause lipoatrophy. Other possible causes include underlying autoimmune disease, the predisposition for females to be affected, and local trauma, also from the injections, at the specific body site. We suggest that subcutaneous injections with methotrexate on the anterior thighs should be avoided or monitored closely in female patients with SLE.

  1. Reduced folate carrier: biochemistry and molecular biology of the normal and methotrexate-resistant cell.

    Science.gov (United States)

    Bosson, Geoffrey

    2003-01-01

    The cytotoxic drug methotrexate uses the reduced folate carrier for transport into the cell, where it inhibits key enzymes in nucleotide biosynthesis. Resistance to methotrexate can be achieved by altering the genetic code of the reduced folate carrier gene and thus change the structure and function of the protein. Our understanding of RFC structure and function is based on the information gained from studying the uptake of folates and antifolates in living cells and the application of molecular techniques to determine gene expression and genetic mutations. The aim of this essay is to explain the structure and function of the reduced folate carrier, review the molecular biology of the reduced folate carrier gene and the mutations and polymorphisms that can result in methotrexate resistance.

  2. Bilateral septic knee arthritis after treatment of an ectopic pregnancy with methotrexate

    Directory of Open Access Journals (Sweden)

    Karaaslan F

    2015-01-01

    Full Text Available Fatih Karaaslan,1 Musa Uğur Mermerkaya,1 Emre Yurdakul,2 Özlem Tanin3 1Department of Orthopaedics and Traumatology, Faculty of Medicine, Bozok University, Yozgat, Turkey; 2Department of Orthopaedics and Traumatology, Osmaniye State Hospital, Osmaniye, Turkey; 3Department of Gynecology and Obstetrics, Faculty of Medicine, Bozok University, Yozgat, Turkey Abstract: We describe a case of bilateral septic knee arthritis that followed the administration of methotrexate for nonsurgical termination of an ectopic pregnancy. We believe that methotrexate is a relatively effective alternative to surgery in patients with early unruptured tubal pregnancies, but suggest that it be used with caution in view of possible septic events. Keywords: bilateral septic arthritis, methotrexate, ectopic pregnancy, immunsupression

  3. Use of methotrexate in inflammatory bowel disease in 2014: A User’s Guide

    Institute of Scientific and Technical Information of China (English)

    Arun; Swaminath; Raja; Taunk; Garrett; Lawlor

    2014-01-01

    Methotrexate has been used an immunomodulator in many autoimmune diseases,including inflammatory bowel disease. However,many physicians are unfamiliar or uncomfortable with its use in the management of inflammatory bowel disease. We summarize the data for use of methotrexate in common clinical scenarios:(1) steroid dependant Crohn’s disease(CD);(2) maintenance of remission in steroid free CD;(3) azathioprine failures in CD;(4) in combination therapy with Anti-TNF agents in CD;(5) decreasing antibody formation to Anti-TNF therapy in CD;(6) management of fistulizing disease in CD; and(7) as well as induction and maintenance of remission in ulcerative colitis. An easy to use algorithm is provided for the busy clinician to access and safely prescribe methotrexate for their inflammatory bowel disease patients.

  4. Local Methotrexate Injection as the First-line Treatment for Cesarean Scar Pregnancy: Review of the Literature.

    Science.gov (United States)

    Cheung, Vincent Y T

    2015-01-01

    The objective of this study was to determine the outcome of using ultrasound-guided local methotrexate injection as the first-line treatment of cesarean scar pregnancy (CSP). A literature review was performed on all eligible reports using this modality as the first-line treatment of CSP. Relevant publications were obtained from the PubMed electronic database from inception to December 2014. Ninety-six cases from 95 women reported in 17 articles were reviewed. The success rate was 73.9% after a single local methotrexate injection. An accumulated success rate of 88.5% could be achieved after additional local or intramuscular methotrexate administration. Eleven cases (11.5%) failed methotrexate treatment and required surgical interventions. Except for women with serum human chorionic gonadotropin levels higher than 100 000 IU/L, ultrasound-guided local methotrexate injection could be considered as a first-line treatment modality for CSP.

  5. Multivalent polyglycerol supported imidazolidin-4-one organocatalysts for enantioselective Friedel–Crafts alkylations

    Directory of Open Access Journals (Sweden)

    Tommaso Pecchioli

    2015-05-01

    Full Text Available The first immobilization of a MacMillan’s first generation organocatalyst onto dendritic support is described. A modified tyrosine-based imidazolidin-4-one was grafted to a soluble high-loading hyperbranched polyglycerol via a copper-catalyzed alkyne–azide cycloaddition (CuAAC reaction and readily purified by dialysis. The efficiency of differently functionalized multivalent organocatalysts 4a–c was tested in the asymmetric Friedel–Crafts alkylation of N-methylpyrrole with α,β-unsaturated aldehydes. A variety of substituted enals was investigated to explore the activity of the catalytic system which was also compared with monovalent analogues. The catalyst 4b showed excellent turnover rates and no loss of activity due to immobilization, albeit moderate enantioselectivities were observed. Moreover, easy recovery by selective precipitation allowed the reuse of the catalyst for three cycles.

  6. Measuring Mental Imagery with Visual Analogue Scales.

    Science.gov (United States)

    Quilter, Shawn M.; Band, Jennie P.; Miller, Gary M.

    1999-01-01

    Investigates some of the psychometric characteristics of the results from visual-analogue scales used to measure mental imagery. Reports that the scores from visual-analogue scales are positively related to scores from longer pencil-and-paper measures of mental imagery. Implications and limitations for the use of visual-analogue scales to measure…

  7. Germline Genetic Variation in an Organic Anion Transporter Polypeptide Associated With Methotrexate Pharmacokinetics and Clinical Effects

    Science.gov (United States)

    Treviño, Lisa R.; Shimasaki, Noriko; Yang, Wenjian; Panetta, John C.; Cheng, Cheng; Pei, Deqing; Chan, Diana; Sparreboom, Alex; Giacomini, Kathleen M.; Pui, Ching-Hon; Evans, William E.; Relling, Mary V.

    2009-01-01

    Purpose Methotrexate plasma concentration is related to its clinical effects. Our aim was to identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL). Patients and Methods We performed a genome-wide analysis of 500,568 germline single-nucleotide polymorphisms (SNPs) to identify how inheritance affects methotrexate plasma disposition among 434 children with ALL who received 3,014 courses of methotrexate at 2 to 5 g/m2. SNPs were validated in an independent cohort of 206 patients. Results Adjusting for age, race, sex, and methotrexate regimen, the most significant associations were with SNPs in the organic anion transporter polypeptide, SLCO1B1. Two SNPs in SLCO1B1, rs11045879 (P = 1.7 × 10−10) and rs4149081 (P = 1.7 × 10−9), were in linkage disequilibrium (LD) with each other (r2 = 1) and with a functional polymorphism in SLCO1B1, T521C (rs4149056; r2 > 0.84). rs11045879 and rs4149081 were validated in an independent cohort of 206 patients (P = .018 and P = .017), as were other SLCO1B1 SNPs residing in different LD blocks. SNPs in SLCO1B1 were also associated with GI toxicity (odds ratio, 15.3 to 16.4; P = .03 to .004). Conclusion A genome-wide interrogation identified inherited variations in a plausible, yet heretofore low-priority candidate gene, SLCO1B1, as important determinants of methotrexate's pharmacokinetics and clinical effects. PMID:19901119

  8. Effects of alkyl parabens on plant pathogenic fungi.

    Science.gov (United States)

    Ito, Shinsaku; Yazawa, Satoru; Nakagawa, Yasutaka; Sasaki, Yasuyuki; Yajima, Shunsuke

    2015-04-15

    Alkyl parabens are used as antimicrobial preservatives in cosmetics, food, and pharmaceutical products. However, the mode of action of these chemicals has not been assessed thoroughly. In this study, we determined the effects of alkyl parabens on plant pathogenic fungi. All the fungi tested, were susceptible to parabens. The effect of linear alkyl parabens on plant pathogenic fungi was related to the length of the alkyl chain. In addition, the antifungal activity was correlated with the paraben-induced inhibition of oxygen consumption. The antifungal activity of linear alkyl parabens likely originates, at least in part, from their ability to inhibit the membrane respiratory chain, especially mitochondrial complex II. Additionally, we determined that some alkyl parabens inhibit Alternaria brassicicola infection of cabbage.

  9. Long-term survival of methotrexate in psoriatic arthritis

    Directory of Open Access Journals (Sweden)

    N. Battafarano

    2011-06-01

    Full Text Available Objective. The purpose of this study was to evaluate the long-term survival rate of Methotrexate (MTX in the peripheral joint involvement of psoriatic arthritis (PsA in a setting of everyday clinical practice. Methods. This was an observational restrospective study performed using the data from a dermatological-rheumatological PsA clinic. All of the patients evaluated at this clinic from March 1997 to December 2007 who were started on MTX alone, had a three-year follow-up time or had discontinued the therapy were included into the survey. Results. Of the 174 evaluable patients, 104 (59.8% were still taking MTX after three years of treament. The reasons of therapy discontinuation in the remaining 70 (40.2% patients were: 34 (19.5% lost-to-follow-up, 18 (10.3% adverse events, 14 (8% inefficacies, and 4 (2.3% deaths (none related to the therapy. MTX was effective in controlling joint inflammation but not in preventing their deterioration. Overall, adverse events were recorded in 43 patients (36.4% of the 114 patients with a three-year follow-up. No serious side effect occurred in the study population. Conclusions. The results of this study showed that, in a setting of clinical pratice, MTX had a good three-year performance in patients with peripheral PsA. Almost 60% of them were still taking this drug at the end of the study period and the toxicity was more than acceptable. In our opinion, MTX might be considered the non-biological DMARD of choice for the treatment of this condition. However it should be used earlier and at higher doses.

  10. Reversible acute methotrexate leukoencephalopathy: atypical brain MR imaging features

    Energy Technology Data Exchange (ETDEWEB)

    Ziereisen, France; Damry, Nash; Christophe, Catherine [Queen Fabiola Children' s University Hospital, Department of Radiology, Brussels (Belgium); Dan, Bernard [Queen Fabiola Children' s University Hospital, Department of Neurology, Brussels (Belgium); Azzi, Nadira; Ferster, Alina [Queen Fabiola Children' s University Hospital, Department of Paediatrics, Brussels (Belgium)

    2006-03-15

    Unusual acute symptomatic and reversible early-delayed leukoencephalopathy has been reported to be induced by methotrexate (MTX). We aimed to identify the occurrence of such atypical MTX neurotoxicity in children and document its MR presentation. We retrospectively reviewed the clinical findings and brain MRI obtained in 90 children treated with MTX for acute lymphoblastic leukaemia or non-B malignant non-Hodgkin lymphoma. All 90 patients had normal brain imaging before treatment. In these patients, brain imaging was performed after treatment completion and/or relapse and/or occurrence of neurological symptoms. Of the 90 patients, 15 (16.7%) showed signs of MTX neurotoxicity on brain MRI, 9 (10%) were asymptomatic, and 6 (6.7%) showed signs of acute leukoencephalopathy. On the routine brain MRI performed at the end of treatment, all asymptomatic patients had classical MR findings of reversible MTX neurotoxicity, such as abnormal high-intensity areas localized in the deep periventricular white matter on T2-weighted images. In contrast, the six symptomatic patients had atypical brain MRI characterized by T2 high-intensity areas in the supratentorial cortex and subcortical white matter (n=6), cerebellar cortex and white matter (n=4), deep periventricular white matter (n=2) and thalamus (n=1). MR normalization occurred later than clinical recovery in these six patients. In addition to mostly asymptomatic classical MTX neurotoxicity, MTX may induce severe but reversible unusual leukoencephalopathy. It is important to recognize this clinicoradiological presentation in the differential diagnosis of acute neurological deterioration in children treated with MTX. (orig.)

  11. Receptor binding characteristics and cytotoxicity of insulin-methotrexate

    Institute of Scientific and Technical Information of China (English)

    Xiao-Hong Ou; An-Ren Kuang; Zheng-Lu Liang; Xian Peng; Yu-Guo Zhong

    2004-01-01

    AIM: To characterize the receptor binding affinity and cytotoxicity of insulin-methotrexate (MTX) for the potential utilization of insulin as carriers for carcinoma target drugs.METHODS: MTX was covalently linked to insulin. InsulinMTX conjugate was purified by Sephadex G-25 column and analyzed by high performance liquid chromatography.Hepatocellular carcinoma cell membrane fractions were isolated by sucrose density gradient centrifugation.Competitive displacement of 125I-insulin with insulin and insulin-MTX binding to insulin receptors were carried out.Cytoreductive effect of insulin-MTX on human hepatoma BEL7402 cells and human hepatocyte cell line HL7702 was evaluated using the MTT assay.RESULTS: Insulin-MTX competed as effectively as insulin with 125I-insulin for insulin receptors. The values of Kd for insulin-MTX and insulin were 93.82±19.32 nmol/L and 5.01±1.24 nmol/L, respectively. The value of Kd for insulinMTX was significantly increased in comparison with insulin (t=7.2532,n=4, P<0.005). Insulin-MTX inhibited the growth of human hepatoma cells (BEL7402) almost as potently as MTX. The inhibitory effect reached a peak on the 5 th day when the growth of cells was inhibited by 79% at a concentration of 5.0 μg/mL insulin-MTX. Treatment with 5.0 μg/mL of MTX and 5.0 μg/mL of insulin-MTX merely resulted in inhibition of HL7702 cells by 31.5% and 7.8%on the 5 th day.CONCLUSION: Insulin-MTX specifically recognizes insulin receptors and inhibits the growth of BEL7402 cells. These results suggest that insulin can be used as a carrier in receptor mediated carcinoma-targeting therapy.

  12. Sequential Proximal Tibial Stress Fractures associated with Prolonged usage of Methotrexate and Corticosteroids: A Case Report

    Directory of Open Access Journals (Sweden)

    Tan TJL

    2015-11-01

    Full Text Available Stress fractures of the proximal tibia metaphysis are rare in the elderly. We present a case of a 65-year old male who developed sequential proximal tibia stress fractures associated with prolonged usage of methotrexate and prednisolone within a span of 18 months. Magnetic Resonance Imaging revealed an incomplete stress fracture involving the medial proximal tibial region. The patient was treated with stemmed total knee arthroplasty (TKA bilaterally. Stress fractures should be considered in patients with atypical knee pain who have a history of methotrexate and prednisolone usage. TKA is an effective treatment in stress fractures of the proximal tibia.

  13. [High-dosage intralumbar methotrexate administration. A report on clinical experience].

    Science.gov (United States)

    Schöck, V

    1983-06-01

    In therapy and prophylaxis of meningeal leucemia, more than 400 injections of methotrexate, in doses between 15 mg and 50 mg (sometimes up to 75 mg) have been administered to 71 children without severe neurotoxic sequelae. This high dosage was applied repeatedly from 1970 to 1980 in 45 children suffering from acute lymphoblastic leucemia as CNS prophylaxis during a course of cobalt 60 irradiation of the skull. Since then primary CNS relapses have not been observed in these patients. The astonishing fact that these high intrathecal doses of methotrexate have been tolerated without adverse side effects may be attributed to the long intervals of at least 7 days between the individual applications.

  14. Oxidative Umpolung α‐Alkylation of Ketones

    DEFF Research Database (Denmark)

    Shneider, O. Svetlana; Pisarevsky, Evgeni; Fristrup, Peter;

    2015-01-01

    We disclose a hypervalent iodine mediated α-alkylative umpolung reaction of carbonyl compounds with dialkylzinc as the alkyl source. The reaction is applicable to all common classes of ketones including 1,3-dicarbonyl compounds and regular ketones via their lithium enolates. The α......-alkylated carbonyl products are formed in up to 93% yield. An ionic mechanism is inferred based on meticulous analysis, NMR studies, trapping and crossover experiments, and computational studies....

  15. Influence of pre-hydration and pharmacogenetics on plasma methotrexate concentration and renal dysfunction following high-dose methotrexate therapy.

    Science.gov (United States)

    Yanagimachi, Masakatsu; Goto, Hiroaki; Kaneko, Tetsuji; Naruto, Takuya; Sasaki, Koji; Takeuchi, Masanobu; Tanoshima, Reo; Kato, Hiromi; Yokosuka, Tomoko; Kajiwara, Ryosuke; Fujii, Hisaki; Tanaka, Fumiko; Goto, Shoko; Takahashi, Hiroyuki; Mori, Masaaki; Kai, Sumio; Yokota, Shumpei

    2013-12-01

    High-dose methotrexate therapy (HD-MTX) has been well established for the treatment of childhood acute lymphoblastic leukemia (ALL). The aims of this study were to investigate whether clinical and pharmacogenetic factors influence plasma MTX concentration and renal dysfunction in patients treated with HD-MTX. In a total of 127 courses of HD-MTX in 51 patients with childhood ALL, influence of clinical and pharmacogenetic factors on plasma MTX concentration and HD-MTX-related renal dysfunction was evaluated. Clinical factors included age, gender, duration of HD-MTX continuous-infusion and duration of pre-hydration before HD-MTX. Pharmacogenetic factors included 5 gene polymorphisms within the MTX pathway genes, namely, SLC19A1, MTHFR, ABCC2 and ABCG2. Short duration of pre-hydration before HD-MTX is the most important risk factor for prolonged high MTX concentration (p < 0.001, OR 6.40, 95 % CI 2.39-17.16) and renal dysfunction (p = 0.013, OR 3.15, 95 % CI 1.27-7.80). The T allele at MTHFR C677T was the risk factor for prolonged high MTX concentration (p = 0.009, OR 5.54, 95 % CI 1.54-19.85), but not for renal dysfunction. We found the influence of MTHFR C677T polymorphism on prolonged high MTX concentration. We reconfirmed the importance of adequate pre-hydration before HD-MTX to prevent prolonged high MTX concentration and MTX-related renal dysfunction.

  16. Efficacy of golimumab plus methotrexate in methotrexate-naïve patients with severe active rheumatoid arthritis.

    Science.gov (United States)

    Emery, Paul; Fleischmann, Roy M; Hsia, Elizabeth C; Xu, Stephen; Zhou, Yiying; Baker, Daniel

    2014-09-01

    The purpose of this study was to assess the treatment benefit of golimumab + methotrexate (MTX) vs. MTX monotherapy in MTX-naïve patients with severe active rheumatoid arthritis (RA). This was a post hoc analysis of MTX-naïve RA patients in the GO-BEFORE trial who were randomized to receive placebo + MTX (n = 160), golimumab 50 mg + MTX (n = 159), or golimumab 100 mg + MTX (n = 159). Subsets of patients with severe disease were identified using these baseline criteria: C-reactive protein (CRP) ≥1.5 mg/dL, CRP ≥3.0 mg/dL, swollen joint count (SJC) ≥10 and tender joint count (TJC) ≥12, SJC ≥ 20/TJC ≥ 12, 28-joint count Disease Activity Score using CRP (DAS28-CRP) >5.1, and anti-cyclic citrullinated peptide antibody-positive status. The treatment effect of golimumab + MTX vs. MTX alone was evaluated for these outcomes: the proportions of patients achieving ≥20, 50, and 70 % improvement in the American College of Rheumatology criteria; DAS28-CRP European League Against Rheumatism response; DAS28-CRP golimumab + MTX groups vs. placebo + MTX for all of the outcomes evaluated. Furthermore, the treatment effect of golimumab + MTX was consistently greater among patients in the severe disease subsets when compared with the overall GO-BEFORE trial population. The treatment benefit of golimumab + MTX vs. MTX monotherapy was most pronounced within the subsets of patients with CRP ≥3.0 mg/dL and SJC ≥ 20/TJC ≥ 12. Following treatment with golimumab + MTX, improvements in RA signs/symptoms and in progression of structural damage were evident for the overall GO-BEFORE population, with the treatment effect more pronounced among patients with severe active disease.

  17. High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma.

    Science.gov (United States)

    Akiyama, Hiroki; Takase, Hiroshi; Kubo, Fumito; Miki, Tohru; Yamamoto, Masahide; Tomita, Makoto; Mochizuki, Manabu; Miura, Osamu; Arai, Ayako

    2016-10-01

    In order to prevent central nervous system (CNS) involvement and improve the prognosis of primary intraocular lymphoma (PIOL), we prospectively evaluated the efficacy of combined therapy using intravitreal methotrexate (MTX) and systemic high-dose MTX on treatment-naïve PIOL. Patients with newly diagnosed PIOL whose lymphoma was limited to the eyes were enrolled. The patients were treated with weekly intravitreal MTX until the ocular lesions were resolved, followed by five cycles of systemic high-dose MTX (3.5 g/m(2) ) every other week. Ten patients were enrolled in this study and completed the treatment. All patients achieved complete response for their ocular lesions with rapid decrease of intravitreal interleukin-10 concentration. Adverse events of intravitreal and systemic high-dose MTX were mild and tolerable. With a median follow-up of 29.5 months, four patients (40%) experienced the CNS disease development and the mean CNS lymphoma-free survival (CLFS) time was 51.1 months. Two-year CLFS, which was the primary end-point of the study, was 58.3% (95% confidence interval, 23.0-82.1%). In contrast, eight patients were treated with intravitreal MTX alone in our institute, and their 2-year CLFS was 37.5% (95% confidence interval, 8.7-67.4%). In conclusion, systemic high-dose MTX following intravitreal MTX is feasible and might be effective in preventing CNS involvement of PIOL. Further arrangements are worth considering in order to improve the effects. This study was registered with UMIN Clinical Trials Registry (UMIN000003921).

  18. Isolation of a Cyclic (Alkyl(aminogermylene

    Directory of Open Access Journals (Sweden)

    Liliang Wang

    2016-07-01

    Full Text Available A 1,4-addition of a dichlorogermylene dioxane complex with α,β-unsaturated imine 1 gave a dichlorogermane derivative 2 bearing a GeC3N five-membered ring skeleton. By reducing 2 with KC8, cyclic (alkyl(aminogermylene 3 was synthesized and fully characterized. Germylene 3 readily reacted with TEMPO, N2O and S8, producing the 1:2 adduct 4, the oxo-bridged dimer 5 and the sulfido-bridged dimer 6, respectively.

  19. New Bioactive Alkyl Sulfates from Mediterranean Tunicates

    Directory of Open Access Journals (Sweden)

    Marialuisa Menna

    2012-10-01

    Full Text Available Chemical investigation of two species of marine ascidians, Aplidium elegans and Ciona edwardsii, collected in Mediterranean area, led to isolation of a series of alkyl sulfates (compounds 1–5 including three new molecules 1–3. Structures of the new metabolites have been elucidated by spectroscopic analysis. Based on previously reported cytotoxic activity of these type of molecules, compounds 1–3 have been tested for their effects on the growth of two cell lines, J774A.1 (BALB/c murine macrophages and C6 (rat glioma in vitro. Compounds 1 and 2 induced selective concentration-dependent mortality on J774A.1 cells.

  20. Neuronal Analogues of Conditioning Paradigms

    Science.gov (United States)

    1984-04-24

    Although the mechanisms of interneuronal communication have been well established, the changes underlying most forms of learning have thus far eluded...stimulating electrodes on one of the connectives was adjusted so as to produce a small excitatory postsynaptic potential ( EPSP ) in the impaled cell...two stimuli would constitute a neuronal analogue of conditioning by producing an increased EPSP in response to the test stimulus alone. If so, then

  1. Novel acetylcholine and carbamoylcholine analogues

    DEFF Research Database (Denmark)

    Hansen, Camilla Petrycer; Jensen, Anders Asbjørn; Christensen, Jeppe K.;

    2008-01-01

    A series of carbamoylcholine and acetylcholine analogues were synthesized and characterized pharmacologically at neuronal nicotinic acetylcholine receptors (nAChRs). Several of the compounds displayed low nanomolar binding affinities to the alpha 4beta 2 nAChR and pronounced selectivity for this ......A series of carbamoylcholine and acetylcholine analogues were synthesized and characterized pharmacologically at neuronal nicotinic acetylcholine receptors (nAChRs). Several of the compounds displayed low nanomolar binding affinities to the alpha 4beta 2 nAChR and pronounced selectivity...... for this subtype over alpha 3beta 4, alpha 4beta 4, and alpha 7 nAChRs. The high nAChR activity of carbamoylcholine analogue 5d was found to reside in its R-enantiomer, a characteristic most likely true for all other compounds in the series. Interestingly, the pronounced alpha 4beta 2 selectivities exhibited......AChR agonists published to date. Ligand-protein docking experiments using homology models of the amino-terminal domains of alpha 4beta 2 and alpha 3beta 4 nAChRs identified residues Val111(beta 2)/Ile113(beta 4), Phe119(beta 2)/Gln121(beta 4), and Thr155(alpha 4)/Ser150(alpha 3) as possible key determinants...

  2. Substrate analogues for isoprenoid enzymes

    Energy Technology Data Exchange (ETDEWEB)

    Stremler, K.E.

    1987-01-01

    Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

  3. CAN INITIAL βHCG VALUES PREDICT THE NEED FOR SECOND DOSE OF METHOTREXATE IN MEDICAL MANAGEMENT OF ECTOPIC PREGNANCY?

    Directory of Open Access Journals (Sweden)

    Priya Narayanan

    2016-09-01

    Full Text Available INTRODUCTION Prediction of requirement of second dose of methotrexate in patients treated with single dose would help in guiding treatment and counseling. The aim of this study is to determine whether pretreatment beta HCG values can predict the need for second dose of methotrexate in medically managed ectopic pregnancy. MATERIALS AND METHODS 46 women with ectopic pregnancies who were managed medically were included. The median of beta HCG titres on day 1, day 4 and day 7 was assessed in patients who responded to single dose methotrexate and those who required a second dose. RESULTS Out of the 46 patients studied, 41 responded to medical treatment (success 91%. 14 out of 41 required second dose of methotrexate (34%. Two patients required third dose of methotrexate. Five patients required surgery. DISCUSSION The median of day 1 and day 4 beta HCG values were not statistically different between those who responded to single dose methotrexate and those who required a second dose. Only day 7 values were found to be different. CONCLUSION The beta-hCG titre on day 1 and day 4 is not a predictor of requirement of second dose of methotrexate.

  4. Methotrexate decreases hippocampal cell proliferation and induces memory deficits in rats

    NARCIS (Netherlands)

    Seigers, Riejanne; Schagen, Sanne B.; Coppens, Caroline M.; van der Most, Peter J.; van Dam, Frits S. A. M.; Koolhaas, Jaap M.; Buwalda, Bauke

    2009-01-01

    Methotrexate (MTX) is a cytostatic agent used in adjuvant chemotherapy for treatment of breast cancer and is associated with cognitive impairment in a subgroup of patients. The aim of this paper is to test whether MTX can rapidly affect various brain structures resulting in decreased hippocampal cel

  5. Encapsulation of methotrexate loaded magnetic microcapsules for magnetic drug targeting and controlled drug release

    Energy Technology Data Exchange (ETDEWEB)

    Chakkarapani, Prabu [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Subbiah, Latha, E-mail: lathasuba2010@gmail.com [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Palanisamy, Selvamani; Bibiana, Arputha [Department of Pharmaceutical Technology & Centre for Excellence in Nanobio Translational Research, Anna University, Bharathidasan Institute of Technology Campus, Tiruchirappalli 620024, Tamil Nadu (India); Ahrentorp, Fredrik; Jonasson, Christian; Johansson, Christer [Acreo Swedish ICT AB, Arvid Hedvalls backe 4, SE-411 33 Göteborg (Sweden)

    2015-04-15

    We report on the development and evaluation of methotrexate magnetic microcapsules (MMC) for targeted rheumatoid arthritis therapy. Methotrexate was loaded into CaCO{sub 3}-PSS (poly (sodium 4-styrenesulfonate)) doped microparticles that were coated successively with poly (allylamine hydrochloride) and poly (sodium 4-styrenesulfonate) by layer-by-layer technique. Ferrofluid was incorporated between the polyelectrolyte layers. CaCO{sub 3}-PSS core was etched by incubation with EDTA yielding spherical MMC. The MMC were evaluated for various physicochemical, pharmaceutical parameters and magnetic properties. Surface morphology, crystallinity, particle size, zeta potential, encapsulation efficiency, loading capacity, drug release pattern, release kinetics and AC susceptibility studies revealed spherical particles of ~3 µm size were obtained with a net zeta potential of +24.5 mV, 56% encapsulation and 18.6% drug loading capacity, 96% of cumulative drug release obeyed Hixson-Crowell model release kinetics. Drug excipient interaction, surface area, thermal and storage stability studies for the prepared MMC was also evaluated. The developed MMC offer a promising mode of targeted and sustained release drug delivery for rheumatoid arthritis therapy. - Highlights: • Development of methotrexate magnetic microcapsules (MMC) by layer-by-layer method. • Characterization of physicochemical, pharmaceutical and magnetic properties of MMC. • Multiple layers of alternative polyelectrolytes prolongs methotrexate release time. • MMC is capable for targeted and sustained release rheumatoid arthritis therapy.

  6. Localized and systemic scleroderma show different histological responses to methotrexate therapy.

    NARCIS (Netherlands)

    Seijger, M.M.B.; Hoogen, F.H.J. van den; Vlijmen-Willems, I.M.J.J. van; Kerkhof, P.C.M. van de; Jong, E.M.G.J. de

    2001-01-01

    Although morphoea (localized scleroderma) and systemic sclerosis are distinct disease entities, the skin lesions show identical histological characteristics and both diseases respond favourably to low-dose treatment with methotrexate (MTX). The aim of this study was to find out whether MTX treatment

  7. Apoptosis and electroretinogram after intravitreal injection of methotrexate in an experimental rabbit model.

    Science.gov (United States)

    Aly, Eman; Ebrahim, Amal

    2016-04-01

    The aim of this study was to explore the changes in electroretinogram of rabbit retina and apoptosis in methotrexate-induced toxicity. Rabbits were divided into 5 groups. Group I served as control in which saline solutions was injected intravitreally. Methotrexate (800 μg, 1.76 μmol) was injected into the vitreous of both eyes of rabbits groups II, III, IV and V by an insulin injector with a 26 gauge needle under general anesthesia. Retinal function was assessed by electroretinogram (ERG) after 2, 4, 10 days and one month then animals were decapitated. The eyes were enucleated and processed for DNA fragmentation studies by gel electrophoresis to retinae and measurement of caspase-3 activities. The results indicated a significant reduction (p ˂ 0.05) in a- and b-wave, a time-dependent appearance of the typical ladder pattern of internucleosomal fragmentation, a characteristic of apoptosis and increase of relative caspase-3 activity after methotrexate intravitreal injection. Methotrexate lead to apoptosis, increase of caspase-3 and affect retinal function.

  8. Mg–Al layered double hydroxide–methotrexate nanohybrid drug delivery system: Evaluation of efficacy

    Energy Technology Data Exchange (ETDEWEB)

    Chakraborty, Jui [Central Glass and Ceramic Research Institute, CSIR, 196 Raja S.C. Mullick Road, Kolkata-700032 (India); Roychowdhury, Susanta [Indian Institute of Chemical Biology, CSIR, Kolkata-700032 (India); Sengupta, Somoshree [Central Glass and Ceramic Research Institute, CSIR, 196 Raja S.C. Mullick Road, Kolkata-700032 (India); Ghosh, Swapankumar, E-mail: swapankumar.ghosh2@mail.dcu.ie [Central Glass and Ceramic Research Institute, CSIR, 196 Raja S.C. Mullick Road, Kolkata-700032 (India)

    2013-05-01

    Mg–Al layered double hydroxide nanoparticles were synthesized by one-pot co-precipitation method and anticancerous drug methotrexate was incorporated into it by in-situ ion exchange. The LDH–MTX nanohybrid produced moderately stable suspension in water, as predicted by zeta potential measurement. X-ray diffraction revealed that the basal spacing increased to nearly twice the same for pristine LDH on MTX intercalation. Thermogravimetric analyses confirmed an increase in thermal stability of the intercalated drug in the LDH framework. A striking enhancement in efficacy/sensitivity of MTX on the HCT-116 cells was obtained when intercalated within the LDH layers, as revealed by the attainment of half maximal inhibitory concentration of LDH–MTX nanohybrid by 48 h, whereas, bare MTX required 72 h for the same. The MTX release from MgAl-LDH–MTX hybrids in phosphate buffer saline at pH 7.4 followed a relatively slow, first order kinetics and was complete within 8 days following diffusion and crystal dissolution mechanism. Highlights: ► MgAl-LDH–methotrexate nanohybrid synthesized by one-pot synthetic strategy ► IC{sub 50} for LDH–MTX indicates the efficacy of nanohybrid as an efficient drug carrier. ► XRD and TEM study on nanohybrid revealed successful intercalation of methotrexate. ► TG analyses showed ∼ 13.1 wt.% of methotrexate loading into the nanohybrid.

  9. Inhibition of cytokine production by methotrexate. Studies in healthy volunteers and patients with rheumatoid arthritis.

    NARCIS (Netherlands)

    Gerards, A.H.; Lathouder, de S; Groot, E.R.; Dijkmans, B.A.C.; Aarden, L.A.

    2003-01-01

    OBJECTIVES: To analyse whether the beneficial effects of methotrexate in rheumatoid arthritis (RA) could be due to inhibition of inflammatory cytokine production. METHODS: Cytokine production was studied using whole blood (WB) and mononuclear cells (MNC) of healthy volunteers and RA patients. Cultur

  10. Synthesis of novel methotrexate derivatives with inhibition activity of nitric oxide synthase

    Institute of Scientific and Technical Information of China (English)

    Ming Sheng Feng; Ping Guo; Li Xun Jiang; Jing Bo Shi; Yu Ping Cao; Qi Zheng Yao

    2009-01-01

    Seventeen 4-alkylamino/arylamino-substituted methotrexate(MTX)derivatives 6a-14a were designed and synthesized.Their inhibition activities against inducible nitric oxide synthase(iNOS)were evaluated in vitro.The pharmacological results showed that most of the prepared compounds displayed the potent inhibitory effects on iNOS.

  11. Reduced folate carrier mutations are not the mechanism underlying methotrexate resistance in childhood acute lymphoblastic leukemia.

    NARCIS (Netherlands)

    Kaufman, Y; Drori, S.; Cole, PD; Kamen, BA; Sirota, J; Ifergan, I; Arush, MW; Elhasid, R; Sahar, D; Kaspers, G.J.L.; Jansen, G.; Matherly, LH; Rechavi, G; Toren, A; Assaraf, Y.G.

    2004-01-01

    BACKGROUND: Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with combination chemotherapy containing methotrexate (MTX), drug resistance contributes to treatment failure for a substantial fraction of patients. The primary transporter for folates and MTX is the red

  12. Use of Mycophenolate Mofetil in Patients with Severe Localized Scleroderma Resistant or Intolerant to Methotrexate

    NARCIS (Netherlands)

    Mertens, J.S.; Marsman, D.; Kerkhof, P.C.M. van de; Hoppenreijs, E.P.A.H.; Knaapen, H.K.A.; Radstake, T.R.D.J.; Jong, E.M.G.J. de; Seyger, M.M.B.

    2016-01-01

    To assess the efficacy and safety of mycophenolate mofetil (MMF) in patients with localized scleroderma (LoS) resistant or intolerant to previous treatment with methotrexate (MTX). A case series of patients with LoS treated with MMF. Outcome was assessed through clinical examination. Adverse events

  13. Use of mycophenolate mofetil in patients with severe localized scleroderma resistant or intolerant to methotrexate

    NARCIS (Netherlands)

    Mertens, Jorre S.; Marsman, Diane; van de Kerkhof, Peter C M; Hoppenreijs, Esther P A H; Knaapen, Hanneke K A; Radstake, Timothy R D; de Jong, Elke M G J; Seyger, Marieke M B

    2016-01-01

    To assess the efficacy and safety of mycophenolate mofetil (MMF) in patients with localized scleroderma (LoS) resistant or intolerant to previous treatment with methotrexate (MTX). A case series of patients with LoS treated with MMF. Outcome was assessed through clinical examination. Adverse events

  14. Inadvertent yellow fever vaccination of a patient with Crohn's disease treated with infliximab and methotrexate

    DEFF Research Database (Denmark)

    Ekenberg, C.; Friis-Møller, N.; Ulstrup, Thomas

    2016-01-01

    We present a case of a 56-year-old woman with Crohn's disease, treated with methotrexate and infliximab, who inadvertently received yellow fever vaccination (YFV) prior to a journey to Tanzania. She was not previously vaccinated against YF. YFV contains live-attenuated virus, and is contraindicated...

  15. Lactose maldigestion during methotrexate-induced gastrointestinal mucositis in a rat model

    NARCIS (Netherlands)

    Fijlstra, M.; Rings, E. H. H. M.; Verkade, H. J.; van Dijk, T. H.; Kamps, W. A.; Tissing, W. J. E.

    2011-01-01

    Fijlstra M, Rings EH, Verkade HJ, van Dijk TH, Kamps WA, Tissing WJ. Lactose maldigestion during methotrexate-induced gastrointestinal mucositis in a rat model. Am J Physiol Gastrointest Liver Physiol 300: G283-G291, 2011. First published November 18, 2010; doi:10.1152/ajpgi.00462.2010.-Patients wit

  16. Diacyltransferase Activity and Chain Length Specificity of Mycobacterium tuberculosis PapA5 in the Synthesis of Alkyl β-Diol Lipids

    Energy Technology Data Exchange (ETDEWEB)

    Touchette, Megan H.; Bommineni, Gopal R.; Delle Bovi, Richard J.; Gadbery, John; Nicora, Carrie D.; Shukla, Anil K.; Kyle, Jennifer E.; Metz, Thomas O.; Martin, Dwight W.; Sampson, Nicole S.; Miller, W. T.; Tonge, Peter J.; Seeliger, Jessica C.

    2015-09-08

    Although classified as Gram-positive bacteria, Corynebacterineae possess an asymmetric outer membrane that imparts structural and thereby physiological similarity to more distantly related Gram-negative bacteria. Like lipopolysaccharide in Gram-negative bacteria, lipids in the outer membrane of Corynebacterineae have been associated with the virulence of pathogenic species such as Mycobacterium tuberculosis (Mtb). For example, Mtb strains that lack long, branched-chain alkyl esters known as dimycocerosates (DIMs) are significantly attenuated in model infections. The resultant interest in the biosynthetic pathway of these unusual virulence factors has led to the elucidation of many of the steps leading to the final esterification of the alkyl beta-diol, phthiocerol, with branched-chain fatty acids know as mycocerosates. PapA5 is an acyltransferase implicated in these final reactions. We here show that PapA5 is indeed the terminal enzyme in DIM biosynthesis by demonstrating its dual esterification activity and chain-length preference using synthetic alkyl beta-diol substrate analogues. Applying these analogues to a series of PapA5 mutants, we also revise a model for the substrate binding within PapA5. Finally, we demonstrate that the Mtb Ser/Thr kinase PknB modifies PapA5 on three Thr residues, including two (T196, T198) located on an unresolved loop. These results clarify the DIM biosynthetic pathway and suggest possible mechanisms by which DIM biosynthesis may be regulated by the post-translational modification of PapA5.

  17. Functionalized gold nanoparticles for topical delivery of methotrexate for the possible treatment of psoriasis.

    Science.gov (United States)

    Bessar, Hagar; Venditti, Iole; Benassi, Luisa; Vaschieri, Cristina; Azzoni, Paola; Pellacani, Giovanni; Magnoni, Cristina; Botti, Elisabetta; Casagrande, Viviana; Federici, Massimo; Costanzo, Antonio; Fontana, Laura; Testa, Giovanna; Mostafa, Fawzia Farag; Ibrahim, Samia Ali; Russo, Maria Vittoria; Fratoddi, Ilaria

    2016-05-01

    Gold nanoparticles (AuNPs) represent an effective choice for topical drug delivery systems thanks to their small size, general non-toxicity, ease of functionalization and high surface to volume ratio. Even if systemic, methotrexate still plays an important role in psoriasis treatment: its topical use shows insufficient percutaneus penetration owing to limited passive diffusion, high molecular weight and dissociation at physiological pH. The aim of our study was to design a new drug delivery nanocarrier for Methotrexate and to improve its solubility, stability and biodistribution. AuNPs were on purpose prepared with a hydrophilic stabilizing layer, in order to improve the colloidal stability in water. Water-soluble gold nanoparticles functionalized by sodium 3-mercapto-1-propansulfonate (Au-3MPS) were prepared and loaded with methotrexate (MTX). The loading efficiency of MTX on Au-3MPS was assessed in the range 70-80%, with a fast release (80% in one hour). The release was studied up to 24h reaching the value of 95%. The Au-3MPS@MTX conjugate was fully characterized by spectroscopic techniques (UV-vis, FTIR) and DLS. Preliminary toxicity tests in the presence of keratinocytes monolayers allowed to assess that the used Au-3MPS are not toxic. The conjugate was then topically used on C57BL/6 mouse normal skin in order to trace the absorption behavior. STEM images clearly revealed the distribution of gold nanoparticles inside the cells. In vitro studies showed that Methotrexate conjugated with Au-3MPS is much more efficient than Methotrexate alone. Moreover, DL50, based on MTT analysis, is 20 folds reduced at 48 h, by the presence of nanoparticles conjugation. UV-vis spectra for in vivo tracing of the conjugate on bare mouse skin after 24h of application, show increased delivery of Methotrexate in the epidermis and dermis using Au-3MPS@MTX conjugate, compared to MTX alone. Moreover we observed absence of the Au-3MPS in the dermis and in the epidermis, suggesting that

  18. An overview of the properties of fatty acid alkyl esters

    Science.gov (United States)

    Fatty acid alkyl esters of plant oils, especially in the form of methyl esters, have numerous applications with fuel use having received the most attention in recent times due to the potential high volume. Various properties imparted by neat fatty acid alkyl esters have been shown to influence fuel ...

  19. 40 CFR 721.840 - Alkyl substituted diaromatic hydrocarbons.

    Science.gov (United States)

    2010-07-01

    ... hydrocarbons. 721.840 Section 721.840 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Specific Chemical Substances § 721.840 Alkyl substituted diaromatic hydrocarbons. (a) Chemical substance... alkyl substituted di-aro-matic hydrocarbons (PMN P-91-710) is subject to reporting under this...

  20. 40 CFR 721.2155 - Alkoxyamino-alkyl-coumarin (generic).

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkoxyamino-alkyl-coumarin (generic... Substances § 721.2155 Alkoxyamino-alkyl-coumarin (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as...

  1. 40 CFR 721.10073 - Modified alkyl acrylamide (generic).

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Modified alkyl acrylamide (generic... Specific Chemical Substances § 721.10073 Modified alkyl acrylamide (generic). (a) Chemical substance and... acrylamide (PMN P-05-536) is subject to reporting under this section for the significant new uses...

  2. Polyfluorinated alkyl phosphate ester surfactants - current knowledge and knowledge gaps

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Rosenmai, Anna Kjerstine; Vinggaard, Anne Marie

    2014-01-01

    information on fluorochemicals. Polyfluorinated alkyl phosphate ester surfactants (PAPs) belong to the group of polyfluorinated alkyl surfactants. They have been detected in indoor dust and are widely used in food-contact materials, from which they have the ability to migrate into food. Toxicological data...

  3. Alternating hemiparesis and orolingual apraxia as manifestations of methotrexate neurotoxicity in a paediatric case of acute lymphoblastic leukaemia.

    Science.gov (United States)

    Yap, Siew Mei; MacEneaney, Peter; Ryan, Clodagh; O'Toole, Orna

    2016-04-25

    A 15-year-old girl with a recent diagnosis of acute lymphoblastic leukaemia was admitted to hospital with pancytopaenia after having received high-dose intrathecal methotrexate 1 day prior. During the next week she had intermittent episodes of alternating hemiparesis associated with speech arrest lasting minutes to hours at a time. The episodes were not associated with altered level of consciousness or headache. MRI of the brain showed features consistent with methotrexate encephalopathy. This report discusses the typical clinical and radiological features of methotrexate neurotoxicity in addition to differential diagnoses and the proposed pathophysiological mechanisms.

  4. Temporal profiles of synaptic plasticity-related signals in adult mouse hippocampus with methotrexate treatment.

    Science.gov (United States)

    Yang, Miyoung; Kim, Juhwan; Kim, Sung-Ho; Kim, Joong-Sun; Shin, Taekyun; Moon, Changjong

    2012-07-25

    Methotrexate, which is used to treat many malignancies and autoimmune diseases, affects brain functions including hippocampal-dependent memory function. However, the precise mechanisms underlying methotrexate-induced hippocampal dysfunction are poorly understood. To evaluate temporal changes in synaptic plasticity-related signals, the expression and activity of N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, extracellular signal-regulated kinase 1/2, cAMP responsive element-binding protein, glutamate receptor 1, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor were examined in the hippocampi of adult C57BL/6 mice after methotrexate (40 mg/kg) intraperitoneal injection. Western blot analysis showed biphasic changes in synaptic plasticity-related signals in adult hippocampi following methotrexate treatment. N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, and glutamate receptor 1 were acutely activated during the early phase (1 day post-injection), while extracellular signal-regulated kinase 1/2 and cAMP responsive element-binding protein activation showed biphasic increases during the early (1 day post-injection) and late phases (7-14 days post-injection). Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression increased significantly during the late phase (7-14 days post-injection). Therefore, methotrexate treatment affects synaptic plasticity-related signals in the adult mouse hippocampus, suggesting that changes in synaptic plasticity-related signals may be associated with neuronal survival and plasticity-related cellular remodeling.

  5. Evaluation of efficacy of combination of methotrexate and hydroxychloroquine with leflunomide in active rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Shashikumar N

    2010-01-01

    Full Text Available Background: Several new drugs for rheumatoid arthritis are available including leflunomide. Comparative studies of treatment with leflunomide (against methotrexate report a better quality of life. Aim: This study was designed to evaluate the efficacy of combination of methotrexate and hydroxychloroquine with leflunomide, a new disease modifying antirheumatoid drug. Analysis was of intent to treat group. Materials and Methods: This was an open labeled, randomized, comparative clinical trial in the department of rheumatology and immunology, at a tertiary care center in Bangalore. Patients who have diagnosed with rheumatoid arthritis as per American College of Rheumatology aged between 18 and 60 years were recruited and randomized to receive leflunomide (10 mg/day p.o. or a combination of methotrexate and hydroxychloroquine (7.5 mg/week p.o. and 200 mg/day p.o., respectively along with folate supplementation for 12 weeks. The European League Against Rheumatism criteria of improvement according to disease activity score 28 was considered as the primary efficacy variable. Baseline and end of study values were evaluated. The duration of the study period was 1 year. Analysis of variance (ANOVA and Wilcoxon Signed rank test were used for statistical analysis. Results: After 12 weeks, improvement noted in patients treated with leflunomide was similar to those treated with a combination of methotrexate and hydroxychloroquine. There was no statistical significance in improvement in disease activity between the two groups (P = 0.377. Conclusion: Combination of methotrexate and hydroxychloroquine is equivalent to leflunomide in terms of efficacy in reducing disease activity in the initial treatment of severe rheumatoid arthritis.

  6. [Intrathecal methotrexate in breast cancer meningeal carcinomatosis - Experience with a new administration schedule].

    Science.gov (United States)

    Cochereau, Delphine; Da Costa, Sabrina; Le Maignan, Christine; Gauthier, Hélène; Cochereau, Jérôme; Espié, Marc; Giacchetti, Sylvie; Teixeira, Luis

    2016-05-01

    Methotrexate represents the standard intrathecal treatment of breast cancer meningeal carcinomatosis. However, its optimal schedule remains undefined. The aim of the present study was to evaluate results obtained with the methotrexate schedule used in Saint-Louis hospital (Paris). Patients followed in Saint-Louis hospital for breast cancer and who received intrathecal methotrexate were included in this retrospective monocentric study. Intrathecal treatment received contained methotrexate 12 mg/day (days: 1-5) and then 15 mg/week until progression or toxicity. Between 2003 and 2015, 41 patients were included. Primitive tumours were RH+/HER2-, HER2+ and triple-negative in respectively 66%, 14%, 5% and 15% of patients, 22% of them had meningeal carcinomatosis as metastatic disease initial manifestation. Objective response rate was 54%, median overall survival was 4.0 mois [CI 95%: 3-7.3] and 1-year survival rate was 15.2% (11.4%, 50% et 0% in RH+/HER2-, HER2+ and triple-negative subgroups; HR=0.45 [0.21-0.97] between HER2+ and RH+/HER2-). In univariate analysis, prognostic factors were brain involvement (p=0.049), initial cerebrospinal fluid protein level (p=0.0002) and concomitant systemic treatment received (p=0.049). This intrathecal methotrexate schedule demonstrates a similar median overall survival as the one obtained with a dose-dense schedule and an improved quality of life. Nevertheless, as the objective response and 1-year survival rates are slightly inferior, a dose-dense schedule remains still preferred in HER2+ patients or in those harboring a mainly meningeal progression.

  7. Temporal profiles of synaptic plasticity-related signals in adult mouse hippocampus with methotrexate treatment

    Institute of Scientific and Technical Information of China (English)

    Miyoung Yang; Juhwan Kim; Sung-Ho Kim; Joong-Sun Kim; Taekyun Shin; Changjong Moon

    2012-01-01

    Methotrexate, which is used to treat many malignancies and autoimmune diseases, affects brain functions including hippocampal-dependent memory function. However, the precise mechanisms underlying methotrexate-induced hippocampal dysfunction are poorly understood. To evaluate temporal changes in synaptic plasticity-related signals, the expression and activity of N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, extracellular signal-regulated kinase 1/2, cAMP responsive element-binding protein, glutamate receptor 1, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor were examined in the hippocampi of adult C57BL/6 mice after methotrexate (40 mg/kg) intraperitoneal injection. Western blot analysis showed biphasic changes in synaptic plasticity-related signals in adult hippocampi following methotrexate treatment. N-methyl-D-aspartic acid receptor 1, cal-cium/calmodulin-dependent protein kinase II, and glutamate receptor 1 were acutely activated dur-ing the early phase (1 day post-injection), while extracellular signal-regulated kinase 1/2 and cAMP responsive element-binding protein activation showed biphasic increases during the early (1 day post-injection) and late phases (7-14 days post-injection). Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression increased significantly during the late phase (7-14 days post-injection). Therefore, methotrexate treatment affects synaptic plasticity-related signals in the adult mouse hippocampus, suggesting that changes in synaptic plasticity-related signals may be associated with neuronal survival and plasticity-related cellular remodeling.

  8. Microbubbles coupled to methotrexate-loaded liposomes for ultrasound-mediated delivery of methotrexate across the blood-brain barrier.

    Science.gov (United States)

    Wang, Xiang; Liu, Ping; Yang, Weixiao; Li, Lu; Li, Peijing; Liu, Zheng; Zhuo, Zhongxiong; Gao, Yunhua

    2014-01-01

    Methotrexate (MTX) is the single most effective agent for the treatment of primary central nervous system lymphoma. Currently, the delivery of MTX to the brain is achieved by high systemic doses, which cause severe long-term neurotoxicity, or intrathecal administration, which is highly invasive and may lead to infections or hemorrhagic complications. Acoustically active microbubbles have been developed as drug carriers for the noninvasive and brain-targeted delivery of therapeutics. However, their application is limited by their low drug-loading capacity. To overcome this limitation, we prepared microbubbles coupled to MTX-loaded liposomes using ZHIFUXIAN, a novel type of microbubbles with a superior safety profile and long circulation time. MTX-liposome-coupled microbubbles had a high drug-loading capacity of 8.91%± 0.86%, and their size (2.64 ± 0.93 μm in diameter) was suitable for intravenous injection. When used with ultrasound, they showed more potent in vitro cytotoxicity against Walker-256 cancer cells than MTX alone or MTX-loaded liposomes. When Sprague-Dawley rats were exposed to sonication, administration of these MTX-liposome-coupled microbubbles via the tail vein led to targeted disruption of the blood-brain barrier without noticeable tissue or capillary damage. High-performance liquid chromatography analysis of the brain MTX concentration showed that MTX delivery to the brain followed the order of MTX-liposome-coupled microbubbles + ultrasound (25.3 ± 2.4 μg/g) > unmodified ZHIFUXIAN + MTX + ultrasound (18.6 ± 2.2 μg/g) > MTX alone (6.97 ± 0.75 μg/g) > MTX-liposome-coupled microbubbles (2.92 ± 0.39 μg/g). Therefore, treatment with MTX-liposome-coupled microbubbles and ultrasound resulted in a significantly higher brain MTX concentration than all other treatments (Pliposome-coupled microbubbles may hold great promise as new and effective therapies for primary central nervous system lymphoma and other central nervous system malignancies.

  9. Substitution of methotrexate with corticosteroid for acute graft-versus-host disease prevention in transplanted patients who develop methotrexate toxicity.

    Science.gov (United States)

    Kim, Sung-Yong; Kim, Ah Ran; Yoon, So Young; Cho, Yo-Han; Lee, Mark Hong

    2016-02-01

    Methotrexate (MTX) toxicity can hamper the administration of all planned doses in acute graft-versus-host disease (GVHD) prophylaxis following allogeneic hematopoietic stem cell transplantation. Reduction or omission of MTX doses results in an increased risk of acute GVHD. In this prospective observational study, we compared the incidence of GVHD and the transplant outcomes between patients who received the full treatment course of MTX (group 1), patients in whom MTX doses were omitted if MTX toxicity developed (group 2), and patients receiving corticosteroid instead of MTX if MTX toxicity developed (group 3). The cumulative incidence of grades II-IV acute GVHD at 100 days post-transplantation was 22.2 % in group 1, 43.6 % in group 2, and 25.0 % in group 3 (P = 0.132). The risk of grades II-IV acute GVHD in group 2 was higher than that in group 1 (hazard ratio (HR) 3.262, P = 0.016), but the risk in group 3 was similar to that in group 1 (HR 0.960, P = 0.890). Group 3 also showed a trend towards a lower risk of chronic GVHD compared to the other groups. The cumulative risk of chronic GVHD at 2 years was 73.9, 71.6, and 33.3 % in groups 1, 2, and 3, respectively (P = 0.084). However, a likely higher relapse incidence and infection-related mortality in group 3 produced a trend towards the lowest relapse-free survival (2-year RFS, 46.3, 49.3, and 25.0 % in groups 1, 2, and 3, respectively; P = 0.329) and overall survival (2-year OS, 45, 52.3, and 25 %, respectively; P = 0.322) in group 3. Although the substitution of MTX with corticosteroid ameliorates the increased risk of GVHD in patients in which it is imperative to omit its dose, its negative impact on relapse and infection risk does not result in favorable transplant outcomes.

  10. One-step selective synthesis of branched 1-O-alkyl-glycerol/diglycerol monoethers by catalytic reductive alkylation of ketones

    Institute of Scientific and Technical Information of China (English)

    DAYOUB; Wissam; LEMAIRE; Marc

    2010-01-01

    Branched 1-O-alkyl glycerol and diglycerol monoethers were obtained in good yields and high selectivity by a straightforward catalytic reductive alkylation of glycerol with relevant ketones in the presence of 0.5 mol% of Pd/C under 10 bar of hydrogen pressure using a Brφnsted acid as the co-catalyst.

  11. Systematic review and network meta-analysis of the efficacy and safety of tumour necrosis factor inhibitor–methotrexate combination therapy versus triple therapy in rheumatoid arthritis

    Science.gov (United States)

    Fleischmann, Roy; Tongbram, Vanita; van Vollenhoven, Ronald; Tang, Derek H; Chung, James; Collier, David; Urs, Shilpa; Ndirangu, Kerigo; Wells, George; Pope, Janet

    2017-01-01

    Objective Clinical trials have not consistently demonstrated differences between tumour necrosis factor inhibitor (TNFi) plus methotrexate and triple therapy (methotrexate plus hydroxychloroquine plus sulfasalazine) in rheumatoid arthritis (RA). The study objective was to estimate the efficacy, radiographic benefits, safety and patient-reported outcomes of TNFi–methotrexate versus triple therapy in patients with RA. Methods A systematic review and network meta-analysis (NMA) of randomised controlled trials of TNFi–methotrexate or triple therapy as one of the treatment arms in patients with an inadequate response to or who were naive to methotrexate was conducted. American College of Rheumatology 70% response criteria (ACR70) at 6 months was the prespecified primary endpoint to evaluate depth of response. Data from direct and indirect comparisons between TNFi–methotrexate and triple therapy were pooled and quantitatively analysed using fixed-effects and random-effects Bayesian models. Results We analysed 33 studies in patients with inadequate response to methotrexate and 19 in patients naive to methotrexate. In inadequate responders, triple therapy was associated with lower odds of achieving ACR70 at 6 months compared with TNFi–methotrexate (OR 0.35, 95% credible interval (CrI) 0.19 to 0.64). Most secondary endpoints tended to favour TNFi–methotrexate in terms of OR direction; however, no clear increased likelihood of achieving these endpoints was observed for either therapy. The odds of infection were lower with triple therapy than with TNFi−methotrexate (OR 0.08, 95% CrI 0.00 to 0.57). There were no differences observed between the two regimens in patients naive to methotrexate. Conclusions In this NMA, triple therapy was associated with 65% lower odds of achieving ACR70 at 6 months compared with TNFi–methotrexate in patients with inadequate response to methotrexate. Although secondary endpoints numerically favoured TNFi–methotrexate, no

  12. Ecstasy analogues found in cacti.

    Science.gov (United States)

    Bruhn, Jan G; El-Seedi, Hesham R; Stephanson, Nikolai; Beck, Olof; Shulgin, Alexander T

    2008-06-01

    Human interest in psychoactive phenethylamines is known from the use of mescaline-containing cacti and designer drugs such as Ecstasy. From the alkaloid composition of cacti we hypothesized that substances resembling Ecstasy might occur naturally. In this article we show that lophophine, homopiperonylamine and lobivine are new minor constituents of two cactus species, Lophophora williamsii (peyote) and Trichocereus pachanoi (San Pedro). This is the first report of putatively psychoactive phenethylamines besides mescaline in these cacti. A search for further biosynthetic analogues may provide new insights into the structure-activity relationships of mescaline. An intriguing question is whether the new natural compounds can be called "designer drugs."

  13. Antimicrobial evaluation of mangiferin analogues

    Directory of Open Access Journals (Sweden)

    Singh S

    2009-01-01

    Full Text Available The naturally occurring xanthone glycoside mangiferin has been isolated by column chromatography from the ethanol extract of stem bark of Mangifera indica. Mangiferin was further converted to 5-(N-phenylaminomethylenomangiferin, 5-(N-p-chlorophenylaminomethyleno mangiferin, 5-(N-2-methylphenylaminomethyleno mangiferin, 5-(N-p-methoxyphenylaminomethyleno mangiferin, 5-(N,N-diphenylaminomethyleno mangiferin, 5-(N--napthylaminomethyleno mangiferin and 5-(N-4-methylphenylaminomethyleno mangiferin. Mangiferin and its analogues were characterized by melting point and R f value determination and through spectral technique like UV, IR, and NMR spectral analysis. The synthesized compounds were screened for antimicrobial activity.

  14. Antimicrobial Evaluation of Mangiferin Analogues

    Science.gov (United States)

    Singh, S. K.; Kumar, Y.; Kumar, S. Sadish; Sharma, V. K.; Dua, K.; Samad, A.

    2009-01-01

    The naturally occurring xanthone glycoside mangiferin has been isolated by column chromatography from the ethanol extract of stem bark of Mangifera indica. Mangiferin was further converted to 5-(N-phenylaminomethyleno)mangiferin, 5-(N-p-chlorophenylaminomethyleno) mangiferin, 5-(N-2-methylphenylaminomethyleno) mangiferin, 5-(N-p-methoxyphenylaminomethyleno) mangiferin, 5-(N, N-diphenylaminomethyleno) mangiferin, 5-(N--napthylaminomethyleno) mangiferin and 5-(N-4-methylphenylaminomethyleno) mangiferin. Mangiferin and its analogues were characterized by melting point and Rf value determination and through spectral technique like UV, IR, and NMR spectral analysis. The synthesized compounds were screened for antimicrobial activity. PMID:20490307

  15. A graphical approach to analogue behavioural modelling

    OpenAIRE

    Moser, Vincent; Nussbaum, Pascal; Amann, Hans-Peter; Astier, Luc; Pellandini, Fausto

    2007-01-01

    In order to master the growing complexity of analogue electronic systems, modelling and simulation of analogue hardware at various levels is absolutely necessary. This paper presents an original modelling method based on the graphical description of analogue electronic functional blocks. This method is intended to be automated and integrated into a design framework: specialists create behavioural models of existing functional blocks, that can then be used through high-level selection and spec...

  16. Carbonyl Alkyl Nitrates as Trace Constituents in Urban Air

    Science.gov (United States)

    Woidich, S.; Gruenert, A.; Ballschmiter, K.

    2003-04-01

    Organic nitrates, esters of nitric acid, significantly contribute to the entire pool of odd nitrogen (NOY) in the atmosphere. Organic nitrates are formed in NO rich air by degradation of alkanes and alkenes initiated by OH and NO3 radicals during daytime and nighttime, respectively. Bifunctional organonitrates like the alkyl dinitrates and hydroxy alkyl nitrates are formed primarily from alkenes. The two main sources for Alkenes are traffic emissions and naturally occurring terpenes. So far a broad spectrum of alkyl dinitrates and hydroxy alkyl nitrates including six different isoprene nitrates has been identified in urban and marine air (1-3). We report here for the first time about the group of C4 C7 carbonyl alkyl nitrates as trace constituents in urban air collected on the campus of the University of Ulm Germany, and in the downtown area of Salt Lake City, Utah. Air sampling was done by high volume sampling (flow rate 25 m3/h) using a layer of 100 g silica gel (particle diameter 0.2 - 0.5 mm) as adsorbent. The organic nitrates were eluted from the silica gel by pentane/acetone (4:1, w/w) and the extract was concentrated to a volume of 500 µL for a group separation using normal phase HPLC. Final analysis was performed by high resolution capillary gas chromatography with electron capture detection as well as by mass selective detection in the (CH4)NCI mode using NO2- = m/e 46 as the indicator mass. The carbonyl alkyl nitrates were identified by self synthesized reference standards . So far we have identified eight non-branched a-carbonyl alkyl nitrates (vicinal carbonyl alkyl nitrates), two b-carbonyl alkyl nitrates and one g-carbonyl alkyl nitrate with carbon chains ranging from C4 to C7. The mixing ratios are between 0.05 and 0.30 ppt(v) for daytime samples and are two to three times higher for samples taken at night. (1) M. Schneider, O. Luxenhofer, Angela Deißler, K. Ballschmiter: 2C1-C15 Alkyl Nitrates, Benzyl Nitrate, and Bifunctional Nitrates

  17. Laser-assisted delivery of topical methotrexate - in vitro investigations.

    Science.gov (United States)

    Taudorf, Elisabeth Hjardem

    2016-06-01

    Ablative fractional lasers (AFXL) are increasingly used to treat dermatological disorders and to facilitate laser-assisted topical drug delivery. In this thesis, laser-tissue interactions generated by stacked pulses with a miniaturized low-power 2,940 nm AFXL were characterized (study I). Knowledge of the correlation between laser parameters and tissue effects was used to deliver methotrexate (MTX) topically through microscopic ablation zones (MAZs) of precise dimensions. MTX is a well-known chemotherapeutic and anti-inflammatory drug that may cause systemic adverse effects, and topical delivery is thus of potential benefit. The impact of MAZ depth (study II) and transport kinetics (study III) on MTX deposition in skin as well as transdermal permeation was determined in vitro. Quantitative analyses of dermal and transdermal MTX concentrations were performed by high performance liquid chromatography (HPLC) (study II & III), while qualitative analyses of MTX biodistribution in skin were illustrated and semi-quantified by fluorescence microscopy (study II & III) and desorption electro spray mass spectrometry imaging (DESI-MSI) (study III). Laser-tissue interactions generated by AFXL: AFXL-exposure generated a variety of MAZ-dimensions. MAZ depth increased linearly with the logarithm of total energy delivered by stacked pulses, but was also affected by variations in power, pulse energy, pulse duration, and pulse repetition rate. Coagulation zones lining MAZs increased linearly with the applied total energy, while MAZ width increased linearly with the logarithm of stacked pulses. Results were gathered in a mathematical model estimating relations between laser parameters and specific MAZ dimensions. Impact of MAZ depth on AFXL-assisted topical MTX delivery: Pretreatment by AFXL facilitated topical MTX delivery to all skin layers. Deeper MAZs increased total MTX deposition in skin compared to superficial MAZs and altered the intradermal biodistribution profile towards

  18. What Can We Learn From Analogue Experiments?

    CERN Document Server

    Thebault, Karim P Y

    2016-01-01

    In 1981 Unruh proposed that fluid mechanical experiments could be used to probe key aspects of the quantum phenomenology of black holes. In particular, he claimed that an analogue to Hawking radiation could be created within a fluid mechanical `dumb hole', with the event horizon replaced by a sonic horizon. Since then an entire sub-field of `analogue gravity' has been created. In 2016 Steinhauer reported the experimental observation of quantum Hawking radiation and its entanglement in a Bose-Einstein condensate analogue black hole. What can we learn from such analogue experiments? In particular, in what sense can they provide evidence of novel phenomena such as black hole Hawking radiation?

  19. Valutazione dell'efficacia di methotrexate e sua influenza sui titoli anticorpali patogenetici nei pazienti affetti da pemfigoide bolloso

    OpenAIRE

    Balestri, Riccardo

    2015-01-01

    Studio osservazionale condotto presso la Dermatologia dell'Università di Bologna atto a valutare l'efficacia di methotrexate e, in particolare, la sua influenza sui titoli degli autoanticorpi patogeni nei pazienti affetti dalla malattia rara Pemfigoide Bolloso

  20. Cytoprotective effects of amifostine, ascorbic acid and N-acetylcysteine against methotrexate-induced hepatotoxicity in rats

    OpenAIRE

    Akbulut, Sami; Elbe, Hulya; Eris, Cengiz; Dogan, Zumrut; Toprak, Gulten; Otan, Emrah; Erdemli, Erman; Turkoz, Yusuf

    2014-01-01

    AIM: To investigate the potential role of oxidative stress and the possible therapeutic effects of N-acetyl cysteine (NAC), amifostine (AMF) and ascorbic acid (ASC) in methotrexate (MTX)-induced hepatotoxicity.

  1. Combination treatment with metrotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis

    DEFF Research Database (Denmark)

    Hetland, Merete; Stengaard-Pedersen, Kristian; Junker, Peter;

    2006-01-01

    OBJECTIVE: To investigate whether disease control can be achieved in early active rheumatoid arthritis (RA) by treatment with methotrexate and intraarticular betamethasone, and whether the addition of cyclosporine to the regimen has any additional effect. METHODS: Patients (n = 160) were randomized...... to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day (combination therapy) or methotrexate plus placebo-cyclosporine (monotherapy). At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 ml per visit......). Beginning at week 8, if synovitis was present, the methotrexate dosage was increased stepwise up to 20 mg/week, with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg. RESULTS: At 52 weeks, 20% improvement according to the American College of Rheumatology...

  2. The Valles natural analogue project

    Energy Technology Data Exchange (ETDEWEB)

    Stockman, H.; Krumhansl, J.; Ho, C. [Sandia National Labs., Albuquerque, NM (United States); McConnell, V. [Alaska Univ., Fairbanks, AK (United States). Geophysical Inst.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  3. Organomontmorillonites Modified with 2-Methacryloyloxy Ethyl Alkyl Dimethyl Ammonium Bromide

    Institute of Scientific and Technical Information of China (English)

    WANG Jian-quan; WU Wen-hui

    2007-01-01

    Organomontmorillonites (organo-MMT) were synthesized by means of montmorillonites (MMT) modified with a series of 2-methacryloyloxy ethyl alkyl dimethyl ammonium bromide (MAAB) having different alkyl chain lengths as cationic surfactants through a cationic exchanging reaction, and were characterized by FTIR, TG, elemental analysis, and XRD. The microenvironment of the organic interlayer such as the orientation and arrangement of the alkyl chains of MAAB, as well as the properties of nanocomposite hydrogels, were also investigated. The amount of organic components absorbed on interlayer and the basal spacing of organo-MMT both increase with the increasing of alkyl length of MAAB. When carbon number of alkyl chain is in the region of 8 to 14, the alkyl chains between layers would adopt a disordered gauche conformation; while the carbon number is 16, an ordered all-trans conformation with a vertical orientation would be found together with the disordered gauche conformation according to the results of XRD and FTIR. Due to the difference of microenvironment of organic interlayer, the Young's moduli of the nanocomposite hydrogels increased as the alkyl chains of MAAB became longer.

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

    Science.gov (United States)

    Inamo, Yasuji; Ochiai, Toyoko

    2013-01-01

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

  5. Structure, Stability and Interaction Studies on Nucleotide Analogue Systems

    Directory of Open Access Journals (Sweden)

    R. Kanakaraju

    2003-08-01

    Full Text Available Abstract: Most of the biological molecules have a good interaction with water molecules. The hydrogen bonding interactions with the structural analogues of nucleic acid phosphate group namely dimethyl phosphate anion (DMP and diethyl phosphate anion (DEP are studied employing the ab initio and density functional theory methods. Inspections have been made to locate the reactive sites for the interactions of isomeric forms of mono, di and tri hydrates of alkyl phosphate anion using the above theories. It reveals, water molecules have a very strong interaction with the phosphate group in both the molecules and their interactions induce the changes in the structural parameters of the PO4 group for both the DMP and DEP anions. The optimized structural parameters, total energy, dipole moment and rotational constants are calculated and are compared with the available experimental values. The chemical hardness and chemical potential for these complexes have been calculated at HF/6-31G* level of theory and discussed the conformational stability of these complexes.

  6. Population PK/PD model of homocysteine concentrations after high-dose methotrexate treatment in patients with acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Hauke Rühs

    Full Text Available Elevated homocysteine concentrations have been associated with methotrexate-induced neurotoxicity. Based on methotrexate and homocysteine plasma concentrations of 494 children with acute lymphoblastic leukemia treated with high-dose methotrexate in the TOTAL XV study, a pharmacokinetic/pharmacodynamic (PK/PD model was built with NONMEM. Several compartment and indirect response models were investigated. The pharmacokinetic disposition of methotrexate was best described by a two-compartment model. Homocysteine concentrations were included by an indirect response model where methotrexate inhibition of the homocysteine elimination rate was described by an E(max model. The homocysteine baseline level was found to be age-dependent. Simulations revealed that folinate rescue therapy does not affect peak concentrations of homocysteine but leads to a modestly reduced homocysteine exposure. In conclusion, our PK/PD model describes the increase of methotrexate-induced HCY concentrations with satisfactory precision and can be applied to assess the effect of folinate regimens on the HCY concentration-time course.

  7. PREVALENCE OF PULMONARY FUNCTION DEFECTS IN PSORIASIS PATIENTS RECEIVING METHOTREXATE IN A TERTIARY CARE HOSPITAL IN TAMIL NADU, INDIA

    Directory of Open Access Journals (Sweden)

    Allwyn Vijay

    2015-10-01

    Full Text Available Methotrexate is an anti - metabolite widely used in malignancy, rheumatoid arthritis and refractory cases of psoriasis . 1 The value of low dose methotrexate is well established . 2 - 4 There are evidences of pulmonary function defects in patients on long term low dose methotrexate in rheumatoid arthritis patients. Because methotrexate is frequently used in patients suffering from conditions such as RA, dermatomyositis or sarcoidosis, which can be associated wi th interstitial lung disease, determining the exact role of methotrexate in the development of pulmonary complications in these patients seems to be difficult. Therefore, we conducted a cross - sectional study to analyse the findings found on chest x - rays, h igh resolution computed tomography (HRCT and pulmonary function tests (PFT in a cohort of patients without previous recognized interstitial lung disease who were taking methotrexate as a treatment for psoriatic arthritis, a condition not associated with pleuro pulmonary disease. RESULTS: In this study 154 patients from the outpatient department of psoriasis clinic of dermatology department of government general hospital, Chennai who were receiving methotrexate for psoriasis were screened. Out of which 30 patients who were eligible as per inclusion criteria were included in the study. In this study 9 patients showed normal radiology and pulmonary function test. 21 patients had pulmonary function abnormalities. In this study there were 13(43% patients with restrictive pulmonary function defect. Belzenegui . 14 et al reported 2 cases with mild restriction among 27 patients in a similar study. There were 10(33% patients with diffusion defect in this study. Belzenegui et al reported 2 cases among 27 patients in a similar study. There were 5(16% patients with small airway disease as suggested by decrease in mean mid expiratory flow. Belzenegui et al reported 5 cases among 27 patients in a similar study. There were 3(3% patients with

  8. Complex of Burkholderia cepacia lipase with transition state analogue of 1-phenoxy-2-acetoxybutane: biocatalytic, structural and modelling study.

    Science.gov (United States)

    Luić, M; Tomić, S; Lescić, I; Ljubović, E; Sepac, D; Sunjić, V; Vitale, L; Saenger, W; Kojic-Prodić, B

    2001-07-01

    In a series of four racemic phenoxyalkyl-alkyl carbinols, 1-phenoxy-2-hydroxybutane (1) is enantioselectively acetylated by Burkholderia cepacia (formerly Pseudomonas cepacia) lipase with an E value > or = 200, whereas for the other three racemates E was found to be analogue with a tetrahedral P-atom, (R(P),S(P))-O-(2R)-(1-phenoxybut-2-yl)methylphosphonic acid chloride was prepared and crystallized in complex with B. cepacia lipase. The X-ray structure of the complex was determined, allowing to compare the conformation of the inhibitor with results of molecular modelling.

  9. Synthesis and antitumor activity of a new class of pyrazolo[4,3-e]pyrrolo[1,2-a][1,4]diazepinone analogues of pyrrolo[1,4][2,1-c]benzodiazepines.

    Science.gov (United States)

    Baraldi, P G; Leoni, A; Cacciari, B; Manfredini, S; Simoni, D; Bergomi, M; Menta, E; Spinelli, S

    1994-12-09

    A new class of pyrrolo[1,4]benzodiazepine (PBD) analogues featuring a pyrazolo[4,3-e]pyrrolo[1,2-a][1,4]diazepinone ring system has been designed and synthesized. These compounds, 2a-o, are characterized by the substitution of the aromatic A ring, characteristic of the PBDs, with a disubstituted pyrazole ring bearing alkyl and benzyl substituents at N6 or N7 and alkyl or carbomethoxy substituents at C8. Biological evaluation revealed an appreciable in vitro cytotoxic activity for compounds 2a,b,f-i.

  10. Palladium-catalyzed regioselective decarboxylative alkylation of arenes and heteroarenes with aliphatic carboxylic acids.

    Science.gov (United States)

    Premi, Chanchal; Dixit, Ankit; Jain, Nidhi

    2015-06-05

    An unprecedented Pd(OAc)2-catalyzed decarboxylative alkylation of unactivated arenes, with aliphatic carboxylic acids as inexpensive alkyl sources, is reported. The alkylation, controlled by the directing group, is regioselective, shows high functional group tolerance, and provides mild access to alkylated indolines, 2-phenylpyridines, and azobenzenes under solvent-free conditions in moderate to high yields.

  11. Strategy and methodology of dynamical analogue prediction

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    In order to effectively improve numerical prediction level by using current models and data, the strategy and methodology of dynamical analogue prediction (DAP) is deeply studied in the present paper. A new idea to predict the prediction errors of dynamical model on the basis of historical analogue information is put forward so as to transform the dynamical prediction problem into the estimation problem of prediction errors. In terms of such an idea, a new prediction method of final analogue correction of errors (FACE) is developed. Furthermore, the FACE is applied to extra-seasonal prediction experiments on an operational atmosphere-ocean coupled general circulation model. Prediction results of summer mean circulation and total precipitation show that the FACE can to some extent reduce prediction errors, recover prediction variances, and improve prediction skills. Besides, sensitive experiments also show that predictions based on the FACE are evidently influenced by the number of analogues, analogue-selected variables and analogy metric.

  12. The future of somatostatin analogue therapy.

    Science.gov (United States)

    Stewart, P M; James, R A

    1999-10-01

    Since its discovery almost 30 years ago, the mode of action and therapeutic applications of somatostatin have been defined. In particular the cloning and characterization of somatostatin receptor subtypes has facilitated the development of high affinity analogues. In the context of pituitary disease, long-acting somatostatin analogues (octreotide, lanreotide) have been used to treat a variety of pituitary tumours but are most efficacious for the treatment of GH and TSH-secreting adenomas. In patients with acromegaly, depot preparations of these analogues are administered intramuscularly every 10-28 days and provide consistent suppression of GH levels to < 5 mU/l in approximately 50-65% of all cases. Even more specific somatostatin receptor analogues are under development. Finally, radiolabelled somatostatin analogue scintigraphy and, in larger doses, therapy, are now established tools in the evaluation and treatment of neuroendocrine tumours.

  13. [A case of pseudomembranous colitis in a juvenile rheumatoid arthritis patient taking methotrexate].

    Science.gov (United States)

    Yu, Ji Han; Kim, Na Young; Lee, Hae Min; Lee, Ha Ni; Ahn, Hyo Jun; Kim, Sang Woo; Choi, Kyu Yong

    2010-12-01

    Pseudomembranous colitis is mainly caused by antibiotics and Clostridium difficile infection. But conditions such as gastrointestinal surgery, antacid medication, anti-neoplastic agent or immunosuppressive agent which influences the normal flora of colon can induce colitis without the administration of any antibiotics. We experienced a 13 year-old male who was taking low-dose methotrexate for juvenile rheumatoid arthritis complained diarrhea and abdominal pain for 3 weeks. Sigmoidoscopic findings revealed diffuse patch yellowish pseudomembranes on the rectum. Histologic finding was compatible to pseudomembranous colitis. His symptom was improved after stop taking methotrexate and the administration of metronidazole. If a patient treated with immunosuppressive agents or antineoplastic agents complains diarrhea, fever or abdominal pain and has not improved with conservative care, pseudomembranous colitis should be taken into account as a differential diagnosis and prompt treatment is required for better prognosis.

  14. A Case of Diverticular Perforation in a Young Patient with Rheumatoid Arthritis on Methotrexate

    Directory of Open Access Journals (Sweden)

    Ian Chang

    2015-01-01

    Full Text Available Background. Disease-modifying antirheumatic drugs (DMARDs, such as methotrexate (MTX, are associated with gastrointestinal toxicity. MTX inhibits dihydrofolate reductase, but it is unclear if polymorphisms of the methylenetetrahydrofolate reductase (MTHFR gene predict toxicity. Case. We describe a 33-year-old male with polyarticular rheumatoid arthritis who developed sigmoid diverticular perforation while receiving methotrexate, folic acid, prednisone, and naproxen. He tested heterozygous for the C677T allele MTHFR gene. Discussion. Rheumatoid arthritis and its treatments are associated with increased risk of gastrointestinal disease. In one study, perforation was highest among individuals with concomitant exposure to NSAIDs, nonbiologic DMARDs, and glucocorticoids. Multiple mutations of the MTHFR gene have been identified, but their association with MTX toxicity is unclear. This case adds to a growing body of literature that could help inform the treatment of others in the future.

  15. Interaction of anticancer drug methotrexate with nucleic acids analyzed by multi-spectroscopic method

    Science.gov (United States)

    Cai, Changqun; Chen, Xiaoming; Gong, Hang

    2009-02-01

    Methotrexate (MTX) as an antifolate, which is widely used as chemotherapeutic drugs. A high-dose MTX therapy has a direct toxicity influence on the non-germinal cells, especially the liver cells. It is known that the inject dose for adults is 10-30 mg and is half for children for routine use, while our experiments showed that the optimum dosage of MTX which enhanced the RLS intensities to the maximum is 4.54 ng ml -1. The interaction of methotrexate (MTX) with nucleic acids in aqueous solution in the presence of cetyltrimethylammonium bromide (CTMAB), a kind of cationic surfactant similar to the Human cells, were investigated based on the measurements of resonance light scattering (RLS), UV-vis, fluorescence and NMR spectra, etc. The interaction has been proved to give a ternary complex of MTX-CTMAB-DNA in BR buffer (pH 9.30), which exhibits strong enhanced RLS signals at 339.5 nm.

  16. Teratogenicity studies with methotrexate, aminopterin, and acetylsalicylic acid in domestic cats.

    Science.gov (United States)

    Khera, K S

    1976-08-01

    Pregnancy was timed in cats following induced ovulation. Methotrexate, (0.5 mg/kg), aminopterin, (0.1 mg/kg), and acetylsalicylic acid, (25 or 50 mg/kg) were administered orally in gelatin capsules in single daily doses on different days of gestation, methotrexate (MTX) on days 11-14, 14-17, or 17-20, aminopterin on day 12, 14, or 16, and acetylsalicylic acid (ASA) on days 10-15 or 15-20. Maternal toxicity was produced only by MTX. MTX given on days 11-14 and 14-17 produced high frequencies of malformations including umbilical hernia. Aminopterin caused no conclusive teratogenic response. An overall increased frequency of anomalies occurred after 50 mg/kg ASA but no single anomaly predominated.

  17. Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Wojtuszkiewicz, Anna; Peters, Godefridus J; van Woerden, Nicole L;

    2015-01-01

    BACKGROUND: Methotrexate (MTX) eradicates leukemic cells by disrupting de novo nucleotide biosynthesis and DNA replication, resulting in cell death. Since its introduction in 1947, MTX-containing chemotherapeutic regimens have proven instrumental in achieving curative effects in acute lymphoblastic...... leukemia (ALL). However, drug resistance phenomena pose major obstacles to efficacious ALL chemotherapy. Moreover, clinically relevant molecular mechanisms underlying chemoresistance remain largely obscure. Several alterations in MTX metabolism, leading to impaired accumulation of this cytotoxic agent...

  18. METHOTREXATE IN THE TREATMENT OF COXITIS IN EARLY SPONDYLOARTHRITIS: ARE THERE PROSPECTS?

    Directory of Open Access Journals (Sweden)

    T. V. Dubinina

    2015-01-01

    Full Text Available Hip joint injury, coxitis, is a characteristic manifestation of ankylosing spondylitis. Coxitis therapy has not been elaborated so far. There are few publications on the efficacy of tumor necrosis factor-α inhibitors. Alternative pharmacotherapies, including use of methotrexate, have not fully been studied. The study describes clinical cases of coxitis treated in patients with early spondyloarthritis.

  19. Percutaneous delivery of methotrexate in the absence and presence of natural permeation enhancers / Mariska H. Pretorius

    OpenAIRE

    Pretorius, Mariska Heleen

    2003-01-01

    The transdermal delivery of drugs has a lot of advantages above other routes of delivery, such as the avoidance of first-pass hepatic and intestinal metabolism, the non-invasive infusion of drugs, etc. However, the transdermal delivery of drugs, especially hydrophilic drugs, is limited due to the lipophilic nature of the stratum corneum. Methotrexate is a folic acid antagonist with antineoplastic activity and is used for the treatment of psoriasis and Kaposi's sarcoma. The perm...

  20. The efficacy and safety of methotrexate in refractory Crohn’s disease

    Institute of Scientific and Technical Information of China (English)

    徐萍萍

    2014-01-01

    Objective To assess the efficacy and safety of methotrexate(MTX)on refractory Crohn’s disease(CD).Methods A total of 35 consecutive refractory CD patients in the First Affiliated Hospital of Sun Yat-Sen University treated with MTX were retrospectively analyzed.Clinical data from June 2004 to December 2012 were collected from the database of inflammatory bowel disease(IBD)center.Clinical responses and drug side effects were recorded and analyzed.Results Thirty-five refractory CD

  1. A Putative Case of Methotrexate-Related Lymphoma: Clinical Course and PET/CT Findings

    OpenAIRE

    Rachel C. Jankowitz; James Ganon; Todd Blodgett; Christine Garcia; Samuel Jacobs

    2009-01-01

    Patients with autoimmune conditions develop lymphoproliferative disorders (LPDs) at a higher frequency than normal both in association with and independent of Methotrexate (MTX). We describe a case of MTX-associated lymphoma in a patient with psoriasis on long-standing MTX. The case is notable for the initial tumor burden, the dramatic disappearance of the PET-CT findings on discontinuation of MTX, and the subsequent early regrowth of disease. Our case report is illustrative of an MTX-related...

  2. 21 CFR 176.120 - Alkyl ketene dimers.

    Science.gov (United States)

    2010-04-01

    ... derived from the fatty acids of animal or vegetable fats and oils. (b) The alkyl ketene dimers are used as... HUMAN CONSUMPTION (CONTINUED) INDIRECT FOOD ADDITIVES: PAPER AND PAPERBOARD COMPONENTS Substances...

  3. Alkyl resorcinols in grains from plants from the family Gramineae

    Directory of Open Access Journals (Sweden)

    Grzegorz Kubus

    2014-02-01

    Full Text Available 5-n-alkylresorcinols were found in 22 of the 27 studied species of grasses. In Agropyron caninum and Bromus macrostachys only the content of alkyl resorcinols was determined, in Agropyron repens, Bromus mollis and Elymus arenarius the composition of alkyl resorcinol homologues was also established. When calculated per gram of dry mass of air-dried grains, the content of alkyl resorcinols was found to be: in the genus Agropyron - approximately 715 µg, in the genus Bromus approximately 60 µg and in Elymus arenarius, 272 µg. The homologues of alkyl resorcinods in the studied genera of grasses differ from the homologues found in wheat or rye by their greater content of long-chain fractions.

  4. Safety assessment of alkyl benzoates as used in cosmetics.

    Science.gov (United States)

    'Becker, Lillian C; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2012-01-01

    The functions of alkyl benzoates in cosmetics include fragrance ingredients, skin-conditioning agents--emollient, skin-conditioning agents--miscellaneous, preservatives, solvents, and plasticizers. The Cosmetic Ingredient Review Expert Panel reviewed the relevant animal and human data and noted gaps in the available safety data for some of the alkyl benzoates. Similar structure activity relationships, biologic functions, and cosmetic product usage allowed the available data of many of the alkyl benzoates to be extended to the entire group. Carcinogenicity data were not available, but available data indicated that these alkyl benzoate cosmetic ingredients are not genotoxic. Also benzoic acid and tested component alcohols were not reproductive or developmental toxicants, are not genotoxic in almost all assays, and are not carcinogenic. These ingredients were determined to be safe in the present practices of use and concentration.

  5. Fluorinated Alkyl Ether Epoxy Resin Compositions and Applications Thereof

    Science.gov (United States)

    Wohl, Christopher J. (Inventor); Connell, John W. (Inventor); Smith, Joseph G. (Inventor); Siochi, Emilie J. (Inventor); Gardner, John M. (Inventor); Palmieri, Frank M. (Inventor)

    2017-01-01

    Epoxy resin compositions prepared using amino terminated fluoro alkyl ethers. The epoxy resin compositions exhibit low surface adhesion properties making them useful as coatings, paints, moldings, adhesives, and fiber reinforced composites.

  6. Alkyl chains acting as entropy reservoir in liquid crystalline materials.

    Science.gov (United States)

    Sorai, Michio; Saito, Kazuya

    2003-01-01

    The roles played by the conformational disordering of alkyl chains in determining the aggregation states of matter are reviewed for liquid crystalline materials from a thermodynamic perspective. Entropy, which is one of the most macroscopic concepts but which has a clear microscopic meaning, provides crucial microscopic information for complex systems for which a microscopic description is hard to establish. Starting from structural implication by absolute (third-law) entropy for crystalline solids, the existence of successive phase transitions caused by the successive conformational melting of alkyl chains in discotic mesogens is explained. An experimental basis is given for the "quasi-binary picture" of thermotropic liquid crystals, i.e., the highly disordered alkyl chains behave like a second component (solvent). A novel entropy transfer between the "components" of a molecule and the resulting "alkyl chains as entropy reservoir" mechanism are explained for cubic mesogens.

  7. Iminium Salts by Meerwein Alkylation of Ehrlich’s Aldehyde

    Directory of Open Access Journals (Sweden)

    Gerhard Laus

    2013-03-01

    Full Text Available 4-(Dimethylaminobenzaldehyde is alkylated at the N atom by dialkyl sulfates, MeI, or Me3O BF4. In contrast, ethylation by Et3O BF4 occurs selectively at the O atom yielding a quinoid iminium ion. 4-(Diethylaminobenzaldehyde is alkylated only at O by either Et or Me oxonium reagent. The iminium salts are prone to hydrolysis giving the corresponding hydrotetrafluoroborates. Five crystal structures were determined.

  8. Early rheumatoid arthritis therapy: comparative characteristic of delagil, sulphasalazine and methotrexate

    Directory of Open Access Journals (Sweden)

    T S Salnikova

    2003-01-01

    Full Text Available Objective. To assess early administration and efficacy of 3 disease modifying antirheumatic drugs. Material and methods. 92 pts with rheumatoid arthritis (RA aged 17 to 45 years (mean age 34,9±8,5 years were included. Disease duration did not exceed 6 months (mean 3,5±1,9 months. All had 2-3 activity degree and did not received glucocorticoid therapy (systemic or local and did not have severe concomitant diseases of internal organs. Results. Diagnosis of RA was confirmed during follow up in 90 pts. In 2 pts after 6 months diagnosis was changed to systemic lupus erythematosus. 30 pts received delagil for 3 months without improvement. Treatment with sulphasalazine for 3 months was not effective in 23 from 30 pts. 7 pts had subjective improvement during first 3 months but at 6 month effect was lost. Methotrexate administration provided improvement (DAS change 1,6. Clinical and laboratory remission was achieved in 6 pts. Number of bone erosions in pts treated with methotrexate was significantly less and depended on time of therapy beginning and features of disease onset. Conclusion. Methotrexate was most effective from the 3 drugs in early RA particularly when administered during first 3 months of the disease.

  9. Microemulsions for Colorectal Cancer Treatments. General Considerations and Formulation of Methotrexate.

    Science.gov (United States)

    Flores, Sergio E; Rial-Hermida, M Isabel; Ramirez, Jorge C; Pazos, Alejandro; Concheiro, Angel; Alvarez-Lorenzo, Carmen; Peralta, René D

    2016-01-01

    Microemulsions combine the advantages of emulsions with those of nanocarriers, overcoming the stability problems of the former and providing facile scalable systems with compartments adequate for high drug loadings. Recently, microemulsions are gaining attention in the formulation of anticancer drugs not only for topical treatment, but also for systemic delivery as well as for the development of theranostic systems. The aim of this paper is two-fold. First, an updated review about general features, preparation, characterization and pharmaceutical applications, with a special focus on colorectal cancer, is provided. Second, a case study of formulation of methotrexate in microemulsions is presented. Various essential oils (menthol, trans-anethole, α-tocopherol) and surfactants (TPGS-1000, Maxemul 6112, Noigen RN-20) were investigated for the preparation of o/w microemulsions for the delivery of methotrexate, and the ability of methotrexate-loaded microemulsions to inhibit cancer cell growth was then evaluated. Disregarding the surfactants used, menthol and trans-anethole led to cytotoxic microemulsions, whereas α-tocopherol based-formulations induced cell proliferation. These findings highlight the role that the oily component may play in the efficacy and safety of the microemulsions.

  10. Mechanisms and Implications of Dual-Acting Methotrexate in Folate-Targeted Nanotherapeutic Delivery

    Directory of Open Access Journals (Sweden)

    Pamela T. Wong

    2015-01-01

    Full Text Available The rational design of a nanoplatform in drug delivery plays a crucial role in determining its targeting specificity and efficacy in vivo. A conventional approach relies on the surface conjugation of a nanometer-sized particle with two functionally distinct types of molecules, one as a targeting ligand, and the other as a therapeutic agent to be delivered to the diseased cell. However, an alternative simplified approach can be used, in which a single type of molecule displaying dual function as both a targeting ligand and therapeutic agent is conjugated to the nanoparticle. In this review, we evaluate the validity of this new strategy by using methotrexate, which displays multifunctional mechanisms of action. Methotrexate binds to the folate receptor, a surface biomarker frequently overexpressed in tumor cells, and also inhibits dihydrofolate reductase, an enzyme critical for cell survival and division. Thus we describe a series of fifth generation poly(amido amine dendrimers conjugated with methotrexate, and discuss several lines of evidence supporting the efficacy of this new platform strategy based on surface plasmon resonance spectroscopy, enzyme activity assays, and cell-based studies with folate receptor (+ KB cancer cells.

  11. Persistent Human Chorionic Gonadotropin After Methotrexate Treatment and an Emergency Surgical Procedure for Ectopic Pregnancy.

    Science.gov (United States)

    Kurt-Mangold, Michelle; Van Voorhis, Bradley J; Krasowski, Matthew D

    2015-01-01

    The case study is a 33-year-old white female with persistently elevated serum human chorionic gonadotropin (hCG) levels following methotrexate treatment and emergency surgery for ectopic pregnancy. At the time of the first methotrexate dose, the serum hCG concentration was 27,995 IU/L. The laboratory was consulted 3.5 months after the surgery, because serum hCG levels had stopped declining and had leveled off to around 80 to 90 IU/L but with negative urine pregnancy tests. Laboratory studies ruled out heterophile antibody interference and hook effect by multiple methods including analysis by different serum hCG assays, treatment with heterophile antibody blocking agents, and dilution studies. Three additional doses of methotrexate over six months were required for serum hCG concentrations to decline to undetectable levels. This case illustrates challenges that may arise with serum hCG measurements in management of ectopic pregnancies. Close collaboration between the laboratory and clinical service is key for optimal patient care.

  12. Protective effect of propolis on methotrexate-induced kidney injury in the rat.

    Science.gov (United States)

    Ulusoy, Hasan Basri; Öztürk, İsmet; Sönmez, Mehmet Fatih

    2016-06-01

    Objectives Propolis is a potent antioxidant and a free radical scavenger. Pharmacological induction of heat shock proteins (HSPs) has been investigated for restoring normal cellular function following an injury. In this study, effect of propolis on HSP-70 expression in methotrexate-induced nephrotoxicity and direct preventive effect of propolis in this toxicity were investigated. Material and methods A total of 40 male Wistar albino rats were divided into four groups: Group 1 was the untreated control. On the eighth day of the experiment, groups 2 and 3 received single intraperitoneal injections of methotrexate (MTX) at 20 mg/kg. Groups 3 and 4 received 100 mg/kg/day propolis (by oral gavage) for 15 d by the first day of the experimental protocol. Then the rats were decapitated under ketamine esthesia and their kidney tissues were removed. HSP-70 expression, apoptosis, and histopathological damage scores were then compared. Results MTX caused epithelial desquamation into the lumen of the tubules, dilatation, and congestion of the peritubular vessels and renal corpuscles with obscure Bowman's space. The number of apoptotic cells (p = 0.000) and HSP-70 (p = 0.002) expression were increased in group 2. Propolis prevented the rise in number of apoptotic cells (p = 0.017), HSP-70 (p = 0.000) expression, and improved kidney morphology. Conclusions It was found that methotrexate gives rise to serious damage in the kidney and propolis is a potent antioxidant agent in preventing kidney injury.

  13. Protective effects of propolis on methotrexate-induced testis injury in rat.

    Science.gov (United States)

    Sönmez, Mehmet Fatih; Çilenk, Kübra Tuğçe; Karabulut, Derya; Ünalmış, Sunay; Deligönül, Erkan; Öztürk, İsmet; Kaymak, Emin

    2016-04-01

    Propolis is an adhesive substance which is collected and used by honeybees. Propolis is a potent antioxidant and a free radical scavenger. This study was designed to determine whether propolis could protect against dysfunction and oxidative stress induced by methotrexate-induced injury in rat testis. A total of 40 male Wistar albino rats were divided into four groups: group 1 was the untreated control. On the eighth day of the experiment, groups 2 and 3 received single intraperitoneal injections of methotrexate (MTX) at 20mg/kg. Groups 3 and 4 received 100mg/kg/day propolis (by oral gavage) for 15 days by the first day of the experimental protocol. Then the rats were decapitated under anesthesia, and their testes were removed. The histopathological and biochemical analysis along with apoptosis assessment of testis tissues were compared. Immunohistochemical analysis of Heat shock protein-70 (HSP-70) and Proliferating Cell Nuclear Antigen (PCNA) were performed. The phenolic characterization of propolis was performed by Liquid chromatography-mass spectrometry (LC-MS/MS). Methotrexate caused tended to increase in malondialdehyde level and in the number of apoptotic cells; it also caused a decrease in MSTD and JTBS, PCNA and HSP-70 expression and xanthine oxidase levels in group 2. Propolis prevented the rise in malondialdehyde, xanthine oxidase levels and HSP-70 expression and improved testicular morphology and JTBS. It was found that, methorexate gives rise to serious damage in the testes and propolis is a potent antioxidant agent in preventing testicular injury.

  14. Screening of cytoprotectors against methotrexate-induced cytogenotoxicity from bioactive phytochemicals

    Directory of Open Access Journals (Sweden)

    Shaobin Gu

    2016-05-01

    Full Text Available As a well known anti-neoplastic drug, the cytogenotoxicity of methotrexate (MTX has received more attention in recent years. To develop a new cytoprotector to reduce the risk of second cancers caused by methotrexate, an umu test combined with a micronucleus assay was employed to estimate the cytoprotective effects of ten kinds of bioactive phytochemicals and their combinations. The results showed that allicin, proanthocyanidins, polyphenols, eleutherosides and isoflavones had higher antimutagenic activities than other phytochemicals. At the highest dose tested, the MTX genetoxicity was suppressed by 34.03%∼67.12%. Of all the bioactive phytochemical combinations, the combination of grape seed proanthocyanidins and eleutherosides from Siberian ginseng as well as green tea polyphenols and eleutherosides exhibited stronger antimutagenic effects; the inhibition rate of methotrexate-induced genotoxicity separately reached 74.7 ± 6.5% and 71.8 ± 4.7%. Pretreatment of Kunming mice with phytochemical combinations revealed an obvious reduction in micronucleus and sperm abnormality rates following exposure to MTX (p < 0.01. Moreover, significant increases in thymus and spleen indices were observed in cytoprotector candidates in treated groups. The results indicated that bioactive phytochemicals combinations had the potential to be used as new cytoprotectors.

  15. Role of methotrexate in the treatment of bullous pemphigoid in the elderly.

    Science.gov (United States)

    Patton, Timothy; Korman, Neil

    2008-01-01

    Bullous pemphigoid (BP) is an autoimmune blistering disease that commonly occurs in the elderly. Immunosuppressive medications are effective at controlling the disease in the majority of cases. Mortality can occur as a consequence of severe disease or as a result of the therapies that are frequently employed as treatment. Commonly employed therapies include systemic corticosteroids, azathioprine and mycophenolate mofetil. In a small subset of patients, these first- and second-line therapies do not control disease or are not tolerated by the patients. Optional therapies include nicotinamide (niacinamide), tetracycline, intravenous immunoglobulin, cyclophosphamide, dapsone and methotrexate. The majority of BP patients are elderly, and several considerations need to be taken into account before a specific therapy is chosen. Methotrexate provides several advantages in the elderly population in terms of practicality, cost and tolerability. Several retrospective and prospective studies have evaluated its effectiveness in the treatment of BP in the elderly population. The results of these studies indicate that methotrexate is an effective therapy for BP and is a reasonable option for treatment in the elderly population, although maybe not as a first- or second-line therapy.

  16. Screening of cytoprotectors against methotrexate-induced cytogenotoxicity from bioactive phytochemicals.

    Science.gov (United States)

    Gu, Shaobin; Wu, Ying; Yang, Jianbo

    2016-01-01

    As a well known anti-neoplastic drug, the cytogenotoxicity of methotrexate (MTX) has received more attention in recent years. To develop a new cytoprotector to reduce the risk of second cancers caused by methotrexate, an umu test combined with a micronucleus assay was employed to estimate the cytoprotective effects of ten kinds of bioactive phytochemicals and their combinations. The results showed that allicin, proanthocyanidins, polyphenols, eleutherosides and isoflavones had higher antimutagenic activities than other phytochemicals. At the highest dose tested, the MTX genetoxicity was suppressed by 34.03%∼67.12%. Of all the bioactive phytochemical combinations, the combination of grape seed proanthocyanidins and eleutherosides from Siberian ginseng as well as green tea polyphenols and eleutherosides exhibited stronger antimutagenic effects; the inhibition rate of methotrexate-induced genotoxicity separately reached 74.7 ± 6.5% and 71.8 ± 4.7%. Pretreatment of Kunming mice with phytochemical combinations revealed an obvious reduction in micronucleus and sperm abnormality rates following exposure to MTX (p phytochemicals combinations had the potential to be used as new cytoprotectors.

  17. Development and validation of a turbulent flow chromatography and tandem mass spectrometry method for the quantitation of methotrexate and its metabolites 7-hydroxy methotrexate and DAMPA in serum.

    Science.gov (United States)

    Schofield, Ryan C; Ramanathan, Lakshmi V; Murata, Kazunori; Grace, Marie; Fleisher, Martin; Pessin, Melissa S; Carlow, Dean C

    2015-10-01

    A rapid and simple turbulent flow liquid chromatography (TFC-LC) method implementing positive heated electrospray ionization (HESI) for the accurate and precise determination of methotrexate (MTX), 7-hydroxy methotrexate (7-OH MTX), and 4-amino-4-deoxy-N(10)-methylpteroic acid (DAMPA) concentrations in serum was developed. MTX was isolated from serum samples (100μL) after protein precipitation with methanol containing formic acid and internal standard (MTX-D3) followed by centrifugation. The supernatant was injected into the turbulent flow liquid chromatography which is followed by electrospray positive ionization tandem mass spectrometry (TFC-LC-MS/MS) and quantified using a six-point calibration curve. For MTX and DAMPA the assays were linear from 10 to 1000nmol/L and for 7-OH MTX from 20 to 2000nmol/L. Dilutions of 10, 100 and 1000-fold were validated giving a clinically reportable range of 10nmol/L to 5×10(5)nmol/L. Within-day and between-day precisions at concentrations spanning the analytical measurement ranges were less than 10% for all three analytes. MTX, DAMPA and 7-OH MTX were sufficiently stable under all relevant analytical conditions. No significant matrix effect was observed during the method validation. The TFC-LC-MS/MS MTX method was also compared with three other clinically validated MTX assays: a dihydrofolate reductase (DHFR) inhibition assay, an immunoassay based on fluorescence polarization and a previously developed LC-MS/MS assay.

  18. Alkyl and phenolic glycosides from Saussurea stella.

    Science.gov (United States)

    Wang, Tian-Min; Wang, Ru-Feng; Chen, Hu-Biao; Shang, Ming-Ying; Cai, Shao-Qing

    2013-07-01

    One alkyl glycoside, saussurostelloside A (1), two phenolic glycosides, saussurostellosides B1 (2) and B2 (3), and 27 known compounds, including eleven flavonoids, seven phenolics, six lignans, one neolignan, one phenethyl glucoside and one fatty acid, were isolated from an ethanol extract of Saussurea stella (Asteraceae). Their structures were elucidated by NMR, MS, UV, and IR spectroscopic analysis. Of the known compounds, (+)-medioresinol-di-O-β-D-glucoside (7), picraquassioside C (10), and diosmetin-3'-O-β-D-glucoside (27) were isolated from the Asteraceae family for the first time, while (+)-pinoresinol-di-O-β-D-glucoside (6), di-O-methylcrenatin (11), protocatechuic acid (14), 1,5-di-O-caffeoylquinic acid (17), formononetin (28), and phenethyl glucoside (29) were isolated from the Saussurea genus for the first time. The anti-inflammatory activities of three new compounds (1-3), five lignans ((-)-arctiin (4), (+)-pinoresinol-4-O-β-D-glucoside (5), (+)-pinoresinol-di-O-β-D-glucoside (6), (+)-medioresinol-di-O-β-D-glucoside (7) and (+)-syringaresinol-4-O-β-D-glucoside (8)), one neolignan (picraquassioside C (10)), and one phenolic glycoside (di-O-methylcrenatin (11)) were evaluated by testing their inhibition of the release of β-glucuronidase from PAF-stimulated neutrophils. Only compound 5 showed moderate inhibition of the release of β-glucuronidase, with an inhibition ratio of 39.1%.

  19. Effects of alkyl substituents of xanthine on phosphodiesterase isoenzymes.

    Science.gov (United States)

    Miyamoto, K; Sakai, R; Kurita, M; Ohmae, S; Sanae, F; Sawanishi, H; Hasegawa, T; Takagi, K

    1995-03-01

    The structure-activity relationships of a series of alkylxanthine derivatives were investigated. The partition coefficient of alkylxanthines enlarged with an elongation of the alkyl chain at the 1-, 3-, or 7-position of xanthine. There was a mild correlation between the apparent partition coefficient and the tracheal relaxant activity or the inhibitory activity on phosphodiesterase (PDE) IV isoenzyme, while the tracheal relaxant activity closely correlated with the PDE IV inhibitory activity. Regarding substituents at different positions, the alkylation at the 3-position increased the inhibitory activity on every PDE isoenzyme. The alkylation at the 1-position potentiated the inhibitory activity on PDE IV with the alkyl chain length, but decreased the activities on other PDE isoenzymes. The alkylation at the 7-position was characteristic in its decrease in inhibitory activity on PDE III. These results suggested that the potency of the inhibitory activity of xanthine derivatives on PDE isoenzymes is not dependent simply upon their hydrophobicity but upon change in the affinity for the active sites on PDE isoenzymes by the introduction of the alkyl group at particular positions of the xanthine skeleton.

  20. Final Technical Report [Development of Catalytic Alkylation and Fluoroalkylation Methods

    Energy Technology Data Exchange (ETDEWEB)

    Vicic, David A.

    2014-05-01

    In the early stages of this DOE-funded research project, we sought to prepare and study a well-defined nickel-alkyl complex containing tridentate nitrogen donor ligands. We found that reaction of (TMEDA)NiMe2 (1) with terpyridine ligand cleanly led to the formation of (terpyridyl)NiMe (2), which we also determined to be an active alkylation catalyst. The thermal stability of 2 was unlike that seen for any of the active pybox ligands, and enabled a number of key studies on alkyl transfer reactions to be performed, providing new insights into the mechanism of nickel-mediated alkyl-alkyl cross-coupling reactions. In addition to the mechanistic studies, we showed that the terpyridyl nickel compounds can catalytically cross-couple alkyl iodides in yields up to 98% and bromides in yields up to 46 %. The yields for the bromides can be increased up to 67 % when the new palladium catalyst [(tpy’)Pd-Ph]I is used. The best route to the targeted [(tpy)NiBr] (1) was found to involve the comproportionation reaction of [(dme)NiBr{sub 2}] and [Ni(COD){sub 2}] in the presence of two equivalents of terpyridine. This reaction was driven to high yields of product formation (72 % isolated) by the precipitation of 1 from THF solvent.

  1. Has increased clinical experience with methotrexate reduced the direct costs of medical management of ectopic pregnancy compared to surgery?

    Directory of Open Access Journals (Sweden)

    Westaby Daniel T

    2012-09-01

    Full Text Available Abstract Background There is a debate about the cost-efficiency of methotrexate for the management of ectopic pregnancy (EP, especially for patients presenting with serum human chorionic gonadotrophin levels of >1500 IU/L. We hypothesised that further experience with methotrexate, and increased use of guideline-based protocols, has reduced the direct costs of management with methotrexate. Methods We conducted a retrospective cost analysis on women treated for EP in a large UK teaching hospital to (1 investigate whether the cost of medical management is less expensive than surgical management for those patients eligible for both treatments and (2 to compare the cost of medical management for women with hCG concentrations 1500–3000 IU/L against those with similar hCG concentrations that elected for surgery. Three distinct treatment groups were identified: (1 those who had initial medical management with methotrexate, (2 those who were eligible for initial medical management but chose surgery (‘elected’ surgery and (3 those who initially ‘required’ surgery and did not meet the eligibility criteria for methotrexate. We calculated the costs from the point of view of the National Health Service (NHS in the UK. We summarised the cost per study group using the mean, standard deviation, median and range and, to account for the skewed nature of the data, we calculated 95% confidence intervals for differential costs using the nonparametric bootstrap method. Results Methotrexate was £1179 (CI 819–1550 per patient cheaper than surgery but there were no significant savings with methotrexate in women with hCG >1500 IU/L due to treatment failures. Conclusions Our data support an ongoing unmet economic need for better medical treatments for EP with hCG >1500 IU/L.

  2. Methotrexate administration directly into the fourth ventricle in children with malignant fourth ventricular brain tumors: a pilot clinical trial.

    Science.gov (United States)

    Sandberg, David I; Rytting, Michael; Zaky, Wafik; Kerr, Marcia; Ketonen, Leena; Kundu, Uma; Moore, Bartlett D; Yang, Grace; Hou, Ping; Sitton, Clark; Cooper, Laurence J; Gopalakrishnan, Vidya; Lee, Dean A; Thall, Peter F; Khatua, Soumen

    2015-10-01

    We hypothesize that chemotherapy can be safely administered directly into the fourth ventricle to treat recurrent malignant brain tumors in children. For the first time in humans, methotrexate was infused into the fourth ventricle in children with recurrent, malignant brain tumors. A catheter was surgically placed into the fourth ventricle and attached to a ventricular access device. Cerebrospinal fluid (CSF) flow was confirmed by CINE MRI postoperatively. Each cycle consisted of 4 consecutive daily methotrexate infusions (2 milligrams). Disease response was monitored with serial MRI scans and CSF cytologic analysis. Trough CSF methotrexate levels were sampled. Five patients (3 with medulloblastoma and 2 with ependymoma) received 18, 18, 12, 9, and 3 cycles, respectively. There were no serious adverse events or new neurological deficits attributed to methotrexate. Two additional enrolled patients were withdrawn prior to planned infusions due to rapid disease progression. Median serum methotrexate level 4 h after infusion was 0.04 µmol/L. Range was 0.02-0.13 µmol/L. Median trough CSF methotrexate level 24 h after infusion was 3.18 µmol/L (range 0.53-212.36 µmol/L). All three patients with medulloblastoma had partial response or stable disease until one patient had progressive disease after cycle 18. Both patients with ependymoma had progressive disease after 9 and 3 cycles, respectively. Low-dose methotrexate can be infused into the fourth ventricle without causing neurological toxicity. Some patients with recurrent medulloblastoma experience a beneficial anti-tumor effect both within the fourth ventricle and at distant sites.

  3. Effect of methotrexate on the temporomandibular joint and facial morphology in juvenile rheumatoid arthritis patients.

    Science.gov (United States)

    Ince, D O; Ince, A; Moore, T L

    2000-07-01

    Juvenile rheumatoid arthritis is a disease characterized by chronic inflammation in one or more joints; it affects children and adolescents up to 18 years of age. This disease may cause significant skeletal joint destruction, and the temporomandibular joint, like other joints, may become severely affected resulting in aberrant mandibular growth, abnormal dentofacial development, and/or altered orofacial muscle function. Methotrexate is the most common remittive agent used in juvenile rheumatoid arthritis to modify the course of inflammatory destruction of peripheral joints. The purpose of this study was: (1) to evaluate the effect of methotrexate therapy on the prevalence of temporomandibular joint lesions and aberration in craniofacial development in children afflicted with juvenile rheumatoid arthritis; (2) to further examine the relationship between the temporomandibular joint/cephalometric findings and rheumatologic data (ie, age at onset, duration of disease); and (3) to evaluate further pauciarticular- and polyarticular-onset disease in juvenile rheumatoid arthritis and the prevalence of temporomandibular joint lesions and facial dysmorphology. The following information was obtained from 45 patients with juvenile rheumatoid arthritis: (1) routine rheumatologic clinical examination data; (2) anamnestic temporomandibular joint evaluation data; (3) clinical temporomandibular joint examination data; (4) lateral cephalometric measurement data; (5) posteroanterior cephalometric measurement data; and (6) individually corrected axial tomographic data. The results demonstrated the following: (1) radiographic evidence of condylar degeneration was apparent in 63% of all patients with juvenile rheumatoid arthritis with pauciarticular patients showing less temporomandibular involvement than polyarticular patients; (2) polyarticular juvenile rheumatoid arthritis patients receiving methotrexate showed less severe temporomandibular joint involvement than the polyarticular

  4. Depolymerization of coal by oxidation and alkylation; Sanka bunkai to alkyl ka ni yoru sekitan kaijugo

    Energy Technology Data Exchange (ETDEWEB)

    Tomita, H.; Isoda, T.; Kusakabe, K.; Morooka, S. [Kyushu University, Fukuoka (Japan). Faculty of Engineering; Hayashi, J. [Hokkaido University, Sapporo (Japan). Center for Advanced Research of Energy Technology

    1996-10-28

    Change in depolymerization degree and coal structure was studied for depolymerization treatment of coal in various alcohol containing aqueous hydrogen peroxide. In experiment, the mixture of Yallourn coal, alcohol and aqueous hydrogen peroxide was agitated in nitrogen atmosphere of normal pressure at 70{degree}C for 12 hours. As the experimental result, the methanol solubility of only 5% of raw coal increased up to 35.2% by hydrogen peroxide treatment, while the yield of insoluble matters also decreased from 94% to 62%. Most of the gas produced during treatment was composed of inorganic gases such as CO and CO2, and its carbon loss was extremely decreased by adding alcohol. From the analytical result of carbon loss in hydrogen peroxide treatment, it was clarified that alkylation advances with introduction of alkyl group derived from alcohol into coal by hydrogen peroxide treatment under a coexistence of alcohol, and depolymerization reaction of coal itself is thus promoted by alcohol. 4 refs., 7 figs., 1 tab.

  5. Combustion Pathways of the Alkylated Heteroaromatics: Bond Dissociation Enthalpies and Alkyl Group Fragmentations

    Science.gov (United States)

    Hayes, Carrigan J.; Hadad, Christopher M.

    2009-04-01

    The bond dissociation enthalpies (BDEs) of the alkyl groups of the alkyl-substituted heterocycles have been studied and compiled using DFT methodology, with the intent of modeling the larger heterocyclic functionalities found in coal. DFT results were calibrated against CBS-QB3 calculations, and qualitative trends were reproduced between these methods. Loss of hydrogen at the benzylic position provided the most favorable route to radical formation, for both the azabenzenes and five-membered heterocycles. The ethyl derivatives had lower BDE values than the methyl derivatives due to increased stabilization of the corresponding radicals. Calculated spin densities correlated well with bond dissociation enthalpies for these compounds, while geometric effects were minimal with respect to the heterocycles themselves. Temperature effects on the bond dissociation enthalpies were minor, ranging by about 5 kcal/mol from 298 to 2000 K; the free energies of reaction dropped significantly over the same range due to entropic effects. Monocyclic heteroaromatic rings were seen to replicate the chemistry of multicyclic heteroaromatic systems.

  6. Well-Defined Molybdenum Oxo Alkyl Complex Supported on Silica by Surface Organometallic Chemistry: A Highly Active Olefin Metathesis Precatalyst.

    Science.gov (United States)

    Merle, Nicolas; Le Quéméner, Frédéric; Bouhoute, Yassine; Szeto, Kai C; De Mallmann, Aimery; Barman, Samir; Samantaray, Manoja K; Delevoye, Laurent; Gauvin, Régis M; Taoufik, Mostafa; Basset, Jean-Marie

    2017-02-15

    The well-defined silica-supported molybdenum oxo alkyl species (≡SiO-)MoO(CH2(t)Bu)3 was selectively prepared by grafting of MoO(CH2(t)Bu)3Cl onto partially dehydroxylated silica (silica700) using the surface organometallic chemistry approach. This surface species was fully characterized by elemental analysis and DRIFT, solid-state NMR, and EXAFS spectroscopy. This new material is related to the active species of industrial supported MoO3/SiO2 olefin metathesis catalysts. It displays very high activity in propene self-metathesis at mild (turnover number = 90 000 after 25 h). Remarkably, its catalytic performance outpaces those of the parent imido derivative and its tungsten oxo analogue.

  7. Assessing usability, label comprehension, pen robustness and pharmacokinetics of a self-administered prefilled autoinjector pen of methotrexate in patients with rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Jaime A Pachon

    2014-12-01

    Full Text Available Objective: To assess usability, bioavailability, and safety of subcutaneous self-administration of 0.3 mL of methotrexate 50 mg/mL solution via a prefilled autoinjector pen (methotrexate pen in patients with rheumatoid arthritis. Methods: The study enrolled methotrexate-naïve and methotrexate-experienced patients aged ≥16 years. Visit 1 (Day 1 included methotrexate pen usage training with documentation, patient self-injection, and a patient-training questionnaire completed by the healthcare professional. Visit 2 (Days 8–10 included evaluation of patient self-injection through four scenarios: holding needle in place for 5 s, confirming methotrexate delivery, skin pinch, and pen disposal. At Visit 2, patient opinion and training retention (since Visit 1 were also assessed. Pharmacokinetic parameters were assessed in 25 patients, who were stratified by body weight and randomized to receive injections in the abdomen or the upper thigh. Results: At Visit 1, 12 of 106 patients had questions about the pen, and 4 required self-injection assistance. At Visit 2, the mean performance rating for all scenarios was ≥9.8 (scale: 1 (very difficult−10 (very easy. Successful completion rates were 96.2%–100%; 91.3%–100% of patients required no assistance. Impressions of the pen were favorable; 98.1% of patients passed the written examination. All methotrexate pens effectively delivered 0.3 mL methotrexate and were intact after use. Body weight >100 kg significantly decreased total and peak methotrexate exposure when administered abdominally. No adverse effects resulted in drug discontinuation. Conclusion: The methotrexate pen was used with a high degree of effectiveness, satisfaction, and safety, indicating that this delivery system may be a viable option for patients requiring subcutaneous methotrexate.

  8. Space analogue studies in Antarctica

    Science.gov (United States)

    Lugg, D.; Shepanek, M.

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  9. Condensed matter analogues of cosmology

    Science.gov (United States)

    Kibble, Tom; Srivastava, Ajit

    2013-10-01

    It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the

  10. Antimicrobial Activity of Resveratrol Analogues

    Directory of Open Access Journals (Sweden)

    Malik Chalal

    2014-06-01

    Full Text Available Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew. Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold. The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups and antimicrobial activity.

  11. Four-way calibration applied to the simultaneous determination of folic acid and methotrexate in urine samples.

    Science.gov (United States)

    Muñoz de la Peña, A; Durán Merás, I; Jiménez Girón, A

    2006-08-01

    First-, second- and third-order calibration methods were investigated for the simultaneous determination of folic acid and methotrexate. The interest in the determination of these compounds is related to the fact that methotrexate inhibits the body's absorption of folic acid and prolonged treatment with methotrexate may lead to folic acid deficiency, and to the use of folic acid to cope with toxic side effects of methotrexate. Both analytes were converted into highly fluorescent compounds by oxidation with potassium permanganate, and the kinetics of the reaction was continuously monitored by recording the kinetics curves of fluorescence emission, the evolution with time of the emission spectra and the excitation-emission matrices (EEMs) of the samples at different reaction times. Direct determination of mixtures of both drugs in urine was accomplished on the basis of the evolution of the kinetics of EEMs by fluorescence measurements and four-way parallel-factor analysis (PARAFAC) or multiway partial least squares (N-PLS) chemometric calibration. The core consistency diagnostic (CORCONDIA) was employed to determine the correct number of factors in PARAFAC and the procedure converged to a choice of three factors, attributed to folic acid, methotrexate and to the sum of fluorescent species present in the urine.

  12. Sulfur analogues of psychotomimetic agents. Monothio analogues of mescaline and isomescaline.

    Science.gov (United States)

    Jacob, P; Shulgin, A T

    1981-11-01

    Two monothio analogues of mescaline and three monothio analogues of 2,3,4-trimethoxyphenethylamine (isomescaline) have been synthesized and characterized. Only the two mescaline analogues (3-and 4-thiomescaline) were found to be psychotomimetics in man, being 6 and 12 times more potent than mescaline, respectively. All five compounds can serve as substrates for bovine plasma monoamine oxidase in vitro, but no positive correlation is apparent between the extent of enzymatic degradation and human psychotomimetic potency.

  13. Heterocyclic chalcone analogues as potential anticancer agents.

    Science.gov (United States)

    Sharma, Vikas; Kumar, Vipin; Kumar, Pradeep

    2013-03-01

    Chalcones, aromatic ketones and enones acting as the precursor for flavonoids such as Quercetin, are known for their anticancer effects. Although, parent chalcones consist of two aromatic rings joined by a three-carbon α,β-unsaturated carbonyl system, various synthetic compounds possessing heterocyclic rings like pyrazole, indole etc. are well known and proved to be effective anticancer agents. In addition to their use as anticancer agents in cancer cell lines, heterocyclic analogues are reported to be effective even against resistant cell lines. In this connection, we hereby highlight the potential of various heterocyclic chalcone analogues as anticancer agents with a brief summary about therapeutic potential of chalcones, mechanism of anticancer action of various chalcone analogues, and current and future prospects related to the chalcones-derived anticancer research. Furthermore, some key points regarding chalcone analogues have been reviewed by analyzing their medicinal properties.

  14. Total Synthesis of the Analogue of Icogenin

    Institute of Scientific and Technical Information of China (English)

    Shu Jie HOU; Peng XU; Liang ZHOU; De Quan YU; Ping Sheng LEI; Chuan Chun ZOU

    2006-01-01

    One of the analogues of icogenin, a natural furostanol saponin showing strong cytotoxic effect on cancer cell, was first synthesized via convergent strategy by using diosgenin and available monosaccharides as starting materials,

  15. Second-Generation Fluorescent Quadracyclic Adenine Analogues

    DEFF Research Database (Denmark)

    Dumat, Blaise; Bood, Mattias; Wranne, Moa S.;

    2015-01-01

    Fluorescent base analogues comprise a group of increasingly important molecules for the investigation of nucleic acid structure, dynamics, and interactions with other molecules. Herein, we report on the quantum chemical calculation aided design, synthesis, and characterization of four new putativ...

  16. Novel enterobactin analogues as potential therapeutic chelating agents: Synthesis, thermodynamic and antioxidant studies

    Science.gov (United States)

    Zhang, Qingchun; Jin, Bo; Shi, Zhaotao; Wang, Xiaofang; Liu, Qiangqiang; Lei, Shan; Peng, Rufang

    2016-09-01

    A series of novel hexadentate enterobactin analogues, which contain three catechol chelating moieties attached to different molecular scaffolds with flexible alkyl chain lengths, were prepared. The solution thermodynamic stabilities of the complexes with uranyl, ferric(III), and zinc(II) ions were then investigated. The hexadentate ligands demonstrate effective binding ability to uranyl ion, and the average uranyl affinities are two orders of magnitude higher than 2,3-dihydroxy-N1,N4-bis[(1,2-hydroxypyridinone-6-carboxamide)ethyl]terephthalamide [TMA(2Li-1,2-HOPO)2] ligand with similar denticity. The high affinity of hexadentate ligands could be due to the presence of the flexible scaffold, which favors the geometric agreement between the ligand and the uranyl coordination preference. The hexadentate ligands also exhibit higher antiradical efficiency than butylated hydroxyanisole (BHA). These results provide a basis for further studies on the potential applications of hexadentate ligands as therapeutic chelating agents.

  17. The structure activity relationship of discodermolide analogues.

    Science.gov (United States)

    Shaw, Simon J

    2008-03-01

    The marine polyketide discodermolide is a member of a class of natural products that stabilize microtubules. Many analogues have been synthesized suggesting that few changes can be made to the internal carbon backbone. Both ends of the molecule, however, can be modified. The majority of analogues have been generated via modification of the lactone region. This suggests that significant simplifications can be made in this region provided that the lactone moiety is maintained.

  18. A Study on Alkyl Polyglycosides of the Starch

    Institute of Scientific and Technical Information of China (English)

    Wang Qing-ning; Li Chun-lei; Feng Hui-xia; Kang Wen-shu

    2004-01-01

    The alkyl polyglycosides (APG) is new type the surfactants that is made by regenerationresource of the starch and the grease, since the nineties of 20th century it is energetically exploited ininternational extent. APG not only good in surface activity, but also plenty on bubble, thin greasyand stabilization, there are good decontamination, compatibility, innocuity, not incitation and uniquefunction that organism decomposition of swiftness and downrightness, and so on.APG is to get production that loses one molecule water with half condensation aldehyde hydroxyand sebum alcohol hydroxy under acid catalysis. The production not is one simplicity compound, butis one of sugar polymerization degree, so it is mixture of the alkyl single glucoside, the alkyl twoglucoside and the alkyl three glucoside.Author synthesizes the surfactants of the alkyl polyglycosides, with the oleaster and potato starchand sebum alcohol, that was chosen to use duality system activator of plant acid and p-toluene-sulfoacid for the first time. The adoption way is that the lower alkyl polyglycosides is firstly formed byreaction of lower alcohol with starch then exchanged with high alcohol to obtain APG. The study isto make certain most technics condition, determining capillary tension and the pastern sheafdeepness of critical, calculating HLB value, determining construction by 1R.To synthesize principium:Peroration :[1]Duality system activator of plant acid and p-toluene-sulfo acid is compare idea activator that was the lower alkyl polyglycosides is firstly formed by reaction of lower alcohol with glucose then exchanged with high alcohol to obtain high alkyl polyglycosides. The advantage is that it overcomes agglomeration, there is reaction entirety, high of sugar transform ratio, reaction time short.[2]Most good reaction temperature is 90~ 170℃, the dosage of activator is 0.5%~0.9%, the mated ratio: The APG of glucose basic butane ratio starch is 5:1, the APG of potato starch basic glycol

  19. Assessment by MRI of inflammation and damage in rheumatoid arthritis patients with methotrexate inadequate response receiving golimumab: results of the GO-FORWARD trial

    DEFF Research Database (Denmark)

    Conaghan, Philip G; Emery, Paul; Østergaard, Mikkel;

    2011-01-01

    To evaluate golimumab's effect on MRI-detected inflammation and structural damage in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX).......To evaluate golimumab's effect on MRI-detected inflammation and structural damage in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX)....

  20. Role of Caveolin 1, E-Cadherin, Enolase 2 and PKCalpha on resistance to methotrexate in human HT29 colon cancer cells

    DEFF Research Database (Denmark)

    Selga, Elisabet; Morales Torres, Christina; Noé, Véronique;

    2008-01-01

    with methotrexate is limited by the development of drug resistance, which may be acquired through different ways. To get insights into the mechanisms associated with drug resistance and sensitization we performed a functional analysis of genes deregulated in methotrexate resistant cells, either due to its co...

  1. Interaction between alkyl radicals and single wall carbon nanotubes.

    Science.gov (United States)

    Denis, Pablo A

    2012-06-30

    The addition of primary, secondary, and tertiary alkyl radicals to single wall carbon nanotubes (SWCNTs) was studied by means of dispersion corrected density functional theory. The PBE, B97-D, M06-L, and M06-2X functionals were used. Consideration of Van der Waals interactions is essential to obtain accurate addition energies. In effect, the enthalpy changes at 298 K, for the addition of methyl, ethyl, isopropyl, and tert-butyl radicals onto a (5,5) SWCNT are: -25.7, -25.1, -22.4, and -16.6 kcal/mol, at the M06-2X level, respectively, whereas at PBE/6-31G* level they are significantly lower: -25.0, -19.0, -16.7, and -5.0 kcal/mol respectively. Although the binding energies are small, the attached alkyl radicals are expected to be stable because of the large desorption barriers. The importance of nonbonded interactions was more noticeable as we moved from primary to tertiary alkyl radicals. Indeed, for the tert-butyl radical, physisorption onto the (11,0) SWCNT is preferred rather than chemisorption. The bond dissociation energies determined for alkyl radicals and SWCNT follow the trend suggested by the consideration of radical stabilization energies. However, they are in disagreement with some degrees of functionalization observed in recent experiments. This discrepancy would stem from the fact that for some HiPco nanotubes, nonbonded interactions with alkyl radicals are stronger than covalent bonds.

  2. Effects of alkyl substitutions of xanthine skeleton on bronchodilation.

    Science.gov (United States)

    Sakai, R; Konno, K; Yamamoto, Y; Sanae, F; Takagi, K; Hasegawa, T; Iwasaki, N; Kakiuchi, M; Kato, H; Miyamoto, K

    1992-10-30

    Structure-activity relationships in a series of 1,3,7-trialkyl-xanthine were studied with guinea pigs. Relaxant actions in the tracheal muscle were increased with alkyl chain length at the 1- and 3-positions of the xanthine skeleton, but decreased by alkylation at the 7-position. Positive chronotropic actions in the right atrium were potentiated with 3-alkyl chain length but tended to decrease with 1-alkylation and diminish by 7-substitution. Consequently, while the 1- and 3-substitutions were equally important for the tracheal smooth muscle relaxation, the substitution at the 1-position was more important than the 3-substitution for bronchoselectivity. The 7-alkylation may be significant to cancel heart stimulation. There were good correlations between the smooth muscle relaxant action and the cyclic AMP-PDE inhibitory activity in 3-substituents and the affinity for adenosine (A1) receptors in 1-, 3-, and 7-substituents. This suggests that not only the cyclic AMP-PDE inhibitory activity but also the adenosine antagonistic activity is important in the bronchodilatory effects of alkylxanthines. Among these xanthine derivatives, 1-butyl-3-propylxanthine and its 7-methylated derivative showed high bronchoselectivity in the in vitro and in vivo experiments compared to theophylline and enprofylline and may be new candidates for bronchodilator.

  3. Primary therapy of Waldenström macroglobulinemia with nucleoside analogue-based therapy.

    Science.gov (United States)

    Souchet-Compain, Laetitia; Nguyen, Stéphanie; Choquet, Sylvain; Leblond, Véronique

    2013-04-01

    Waldenström macroglobulinemia is a rare chronic lymphoproliferative disorder. Treatments are currently reserved for symptomatic patients and usually consist of nucleoside analogues (NAs), alkylating agents, bortezomib, and monoclonal antibodies, alone or in combination. Fludarabine and 2-chlorodeoxyadenosine (2-CdA) have been studied in first-line treatment of Waldenström macroglobulinemia (WM) since the end of the 1990s. In monotherapy, response rates vary between 36% and 94%. In a phase III trial, fludarabine in monotherapy was more efficient than chlorambucil for progression-free survival (PFS) (37.8 vs. 27.1 months), duration of response (DOR) (38.5 vs. 21.3 months) and overall survival (OS) (median not reached vs. 69.8 months), but the overall response rate (ORR) was similar (45.6% and 35.9%). NAs have been studied in combination with rituximab and/or alkylating agents for increasing the quality and duration of the response. Hematologic toxicities are a major concern, limiting the indication for NAs in first-line treatment to patients who are not candidates for autologous stem cell transplantation, those in need of rapid control of the disease, or those with poor prognostic factors.

  4. Safety Assessment of Alkyl PEG Sulfosuccinates as Used in Cosmetics.

    Science.gov (United States)

    Johnson, Wilbur; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2015-09-01

    The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the safety of alkyl polyethylene glycol (PEG) sulfosuccinates, which function in cosmetics mostly as surfactants/cleansing agents. Although these ingredients may cause ocular and skin irritation, dermal penetration is unlikely because of the substantial polarity and molecular size of these ingredients. The Panel considered the negative oral carcinogenicity and reproductive and developmental toxicity data on chemically related laureths (PEG lauryl ethers) and negative repeated dose toxicity and skin sensitization data on disodium laureth sulfosuccinate supported the safety of these alkyl PEG sulfosuccinates in cosmetic products, but. The CIR Expert Panel concluded that the alkyl PEG sulfosuccinates are safe in the present practices of use and concentration when formulated to be nonirritating.

  5. Safety Assessment of Alkyl Ethylhexanoates as Used in Cosmetics.

    Science.gov (United States)

    Fiume, Monice; Heldreth, Bart; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2015-01-01

    The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) assessed the safety of 16 alkyl ethylhexanoates for use in cosmetics, concluding that these ingredients are safe in cosmetic formulations in the present practices of use and concentrations when formulated to be nonirritating. The alkyl ethylhexanoates primarily function as skin-conditioning agents in cosmetics. The highest concentration of use reported for any of the alkyl ethylhexanoates is 77.3% cetyl ethylhexanoate in rinse-off formulations used near the eye, and the highest leave-on use reported is 52% cetyl ethylhexanoate in lipstick formulations. The Panel reviewed available animal and clinical data related to these ingredients, and the similarities in structure, properties, functions, and uses of ingredients from previous CIR assessments on constituent alcohols that allowed for extrapolation of the available toxicological data to assess the safety of the entire group.

  6. Alkylation of imidazole under ultrasound irradiation over alkaline carbons

    Energy Technology Data Exchange (ETDEWEB)

    Costarrosa, L. [Dpto. de Quimica Inorganica y Quimica Tecnica, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia (UNED), C/Senda del Rey, 9, E-28040 Madrid (Spain); Calvino-Casilda, V. [Dpto. de Quimica Inorganica y Quimica Tecnica, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia (UNED), C/Senda del Rey, 9, E-28040 Madrid (Spain); Ferrera-Escudero, S. [Dpto. de Quimica Inorganica y Quimica Tecnica, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia (UNED), C/Senda del Rey, 9, E-28040 Madrid (Spain); Duran-Valle, C.J. [Dpto. de Quimica Inorganica, Facultad de Ciencias, Universidad de Extremadura, Avenida de Elvas s/n, 06071 Badajoz (Spain); Martin-Aranda, R.M. [Dpto. de Quimica Inorganica y Quimica Tecnica, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia (UNED), C/Senda del Rey, 9, E-28040 Madrid (Spain)]. E-mail: rmartin@ccia.uned.es

    2006-06-30

    N-Alkyl-imidazole has been synthesized by sonochemical irradiation of imidazole and 1-bromobutane using alkaline-promoted carbons (exchanged with the binary combinations of Na, K and Cs). The catalysts were characterized by X-ray photoelectron spectroscopy, thermal analysis and N{sub 2} adsorption isotherms. Under the experimental conditions, N-alkyl-imidazoles can be prepared with a high activity and selectivity. It is observed that imidazole conversion increases in parallel with increasing the basicity of the catalyst. The influence of the alkaline promoter, the reaction temperature, and the amount of catalyst on the catalytic activity has been studied. For comparison, the alkylation of imidazole has also been performed in a batch reactor system under thermal activation.

  7. Adipose-derived stem cells retain their regenerative potential after methotrexate treatment

    Energy Technology Data Exchange (ETDEWEB)

    Beane, Olivia S. [Center for Biomedical Engineering, Brown University, Providence, RI (United States); Fonseca, Vera C. [Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI (United States); Darling, Eric M., E-mail: Eric_Darling@brown.edu [Center for Biomedical Engineering, Brown University, Providence, RI (United States); Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI (United States); Department of Orthopaedics, Brown University, Providence, RI (United States); School of Engineering, Brown University, Providence, RI (United States)

    2014-10-01

    In musculoskeletal tissues like bone, chemotherapy can impair progenitor cell differentiation and proliferation, resulting in decreased bone growth and mineralization throughout a patient's lifetime. In the current study, we investigated the effects of chemotherapeutics on adipose-derived stem cell (ASC) function to determine whether this cell source could be a candidate for repairing, or even preventing, chemotherapy-induced tissue damage. Dose-dependent proliferation rates of ASCs and normal human fibroblasts (NHFs) were quantified after treatment with cytarabine (CY), etoposide (ETO), methotrexate (MTX), and vincristine (VIN) using a fluorescence-based assay. The influence of MTX on the multipotency of ASCs and freshly isolated stromal vascular fraction (SVF) cells was also evaluated using lineage-specific stains and spectrophotometry. ASC and NHF proliferation were equally inhibited by exposure to CY and ETO; however, when treated with MTX and VIN, ASCs exhibited greater resistance. This was especially apparent for MTX-treated samples, with ASC proliferation showing no inhibition for clinically relevant MTX doses ranging from 0.1 to 50 μM. Additional experiments revealed that the differentiation potential of ASCs was not affected by MTX treatment and that upregulation of dihydrofolate reductase possibly contributed to this response. Moreover, SVF cells, which include ASCs, exhibited similar resistance to MTX impairment, with respect to cellular proliferation, clonogenicity, and differentiation capability. Therefore, we have shown that the regenerative properties of ASCs resist the cytotoxicity of MTX, identifying these cells as a potential key for repairing musculoskeletal damage in patients undergoing chemotherapy. - Highlights: • Long-term effects of chemotherapeutics can include musculoskeletal dysfunction. • A screen of common drugs showed disparate effects on ASCs and fibroblasts. • One drug, methotrexate, did not impair ASC growth

  8. Medical ozone increases methotrexate clinical response and improves cellular redox balance in patients with rheumatoid arthritis.

    Science.gov (United States)

    León Fernández, Olga Sonia; Viebahn-Haensler, Renate; Cabreja, Gilberto López; Espinosa, Irainis Serrano; Matos, Yanet Hernández; Roche, Liván Delgado; Santos, Beatriz Tamargo; Oru, Gabriel Takon; Polo Vega, Juan Carlos

    2016-10-15

    Medical ozone reduced inflammation, IL-1β, TNF-α mRNA levels and oxidative stress in PG/PS-induced arthritis in rats. The aim of this study was to investigate the medical ozone effects in patients with rheumatoid arthritis treated with methotrexate and methotrexate+ozone, and to compare between them. A randomized clinical study with 60 patients was performed, who were divided into two groups: one (n=30) treated with methotrexate (MTX), folic acid and Ibuprophen (MTX group) and the second group (n=30) received the same as the MTX group+medical ozone by rectal insufflation of the gas (MTX+ozone group). The clinical response of the patients was evaluated by comparing Disease Activity Score 28 (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), Anti-Cyclic Citrullinated (Anti-CCP) levels, reactants of acute phase and biochemical markers of oxidative stress before and after 20 days of treatment. MTX+ozone reduced the activity of the disease while MTX merely showed a tendency to decrease the variables. Reactants of acute phase displayed a similar picture. MTX+ozone reduced Anti-CCP levels as well as increased antioxidant system, and decreased oxidative damage whereas MTX did not change. Glutathione correlated with all clinical variables just after MTX+ozone. MTX+ozone increased the MTX clinical response in patients with rheumatoid arthritis. No side effects were observed. These results suggest that ozone can increase the efficacy of MTX probably because both share common therapeutic targets. Medical ozone treatment is capable of being a complementary therapy in the treatment of rheumatoid arthritis.

  9. Shortening Infusion Time for High-Dose Methotrexate Alters Antileukemic Effects: A Randomized Prospective Clinical Trial

    Science.gov (United States)

    Mikkelsen, Torben S.; Sparreboom, Alex; Cheng, Cheng; Zhou, Yinmei; Boyett, James M.; Raimondi, Susana C.; Panetta, John C.; Bowman, W. Paul; Sandlund, John T.; Pui, Ching-Hon; Relling, Mary V.; Evans, William E.

    2011-01-01

    Purpose To determine whether shortening the infusion duration of high-dose methotrexate (HDMTX; 1 g/m2) affects the in vivo accumulation of active methotrexate polyglutamates (MTXPG1-7) in leukemia cells and whether this differs among major acute lymphoblastic leukemia (ALL) subtypes. Methods From June 2000 through October 2007, 356 children with ALL were randomly assigned to receive initial single-agent treatment with HDMTX (1 g/m2) as either a 24-hour infusion or a 4-hour infusion at two pediatric hospitals in the United States. The primary outcome measures were the accumulation of MTXPG1-7 in leukemia cells and the antileukemic effects (eg, inhibition of de novo purine synthesis in bone marrow ALL cells, and decrease in circulating ALL cells). Results The 24-hour infusion resulted in significantly higher amounts of MTXPG1-7 in bone marrow leukemia cells (median: 1,695 v 1,150 pmol/109 cells, P = .0059), and better antileukemic effects. The 24-hour infusion had the greatest effect on MTXPG1-7 accumulation in hyperdiploid ALL (median: 3,919 v 2,417 pmol/109 cells, P = .0038); T-cell ALL exhibited smaller differences in MTXPG1-7 but greater antileukemic effects with the longer infusion (median decrease in leukemia cells: 88.4% v 51.8%, P = .0075). In contrast, infusion duration had no significant impact on MTXPG1-7 accumulation or antileukemic effects in ALL with the t(12;21)/(ETV6-RUNX1) chromosomal translocation. Conclusion Shortening the infusion time of HDMTX reduces accumulation of active methotrexate in leukemia cells and decreases antileukemic effects, with differing consequences among major ALL subtypes. PMID:21444869

  10. A qualitative analysis of methotrexate self-injection education videos on YouTube.

    Science.gov (United States)

    Rittberg, Rebekah; Dissanayake, Tharindri; Katz, Steven J

    2016-05-01

    The aim of this study is to identify and evaluate the quality of videos for patients available on YouTube for learning to self-administer subcutaneous methotrexate. Using the search term "Methotrexate injection," two clinical reviewers analyzed the first 60 videos on YouTube. Source and search rank of video, audience interaction, video duration, and time since video was uploaded on YouTube were recorded. Videos were classified as useful, misleading, or a personal patient view. Videos were rated for reliability, comprehensiveness, and global quality scale (GQS). Reasons for misleading videos were documented, and patient videos were documented as being either positive or negative towards methotrexate (MTX) injection. Fifty-one English videos overlapped between the two geographic locations; 10 videos were classified as useful (19.6 %), 14 misleading (27.5 %), and 27 personal patient view (52.9 %). Total views of videos were 161,028: 19.2 % useful, 72.8 % patient, and 8.0 % misleading. Mean GQS: 4.2 (±1.0) useful, 1.6 (±1.1) misleading, and 2.0 (±0.9) for patient videos (p videos (p videos (p = 0.0027). This study demonstrates a minority of videos are useful for teaching MTX injection. Further, video quality does not correlate with video views. While web video may be an additional educational tool available, clinicians need to be familiar with specific resources to help guide and educate their patients to ensure best outcomes.

  11. Simultaneous Quantification of Baricitinib and Methotrexate in Rat Plasma by LC-MS/MS: Application to a Pharmacokinetic Study.

    Science.gov (United States)

    Veeraraghavan, Sridhar; Thappali, Satheeshmanikandan R S; Viswanadha, Srikant; Vakkalanka, Swaroop; Rangaswamy, Manivannan

    2016-01-01

    Efficacy assessments using a combination of baricitinib and methotrexate necessitate the development of an analytical method for the determination of both drugs in plasma with precision. A high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of baricitinib and methotrexate in rat plasma. Extraction of baricitinib, methotrexate, and tolbutamide (internal standard; IS) from 50 µL of rat plasma was carried out by protein precipitation with methanol. Chromatographic separation of the analytes was performed on the YMC pack ODS AM (150 mm × 4.6 mm, 5 µm) column under gradient conditions with methanol: 2.0 mM ammonium acetate buffer as the mobile phases at a flow rate of 1 mL/min. The precursor ion and product ion transition for both analytes and IS were monitored on a triple quadrupole mass spectrometer, operated with selective reaction monitoring in positive ionization mode. The method was validated over a concentration range of 0.5-250.00 ng/mL for baricitinib and methotrexate. Mean extraction recoveries for baricitinib, methotrexate, and IS of 86.8%, 89.4%, and 91.8% were consistent across low, medium, and high QC levels, respectively. Precision and accuracy at low, medium, and high quality control levels were less than 15% across the analytes. Benchtop, wet, freeze-thaw, and long-term stability were evaluated for both of the analytes. The analytical method was applied to support the pharmacokinetic study of simultaneous estimation of baricitinib and methotrexate in Wistar rats. Assay reproducibility was demonstrated by reanalysis of 18 incurred samples.

  12. Improved Pharmacy Department Workflow with New Method of Order Entry for Single-Agent, High-Dose Methotrexate

    Science.gov (United States)

    VanDyke, Thomas H.; Athmann, Paul W.; Mills, Lisa B.; Bonter, Michael P.; Bremer, Matthew W.; Dougherty, Mary L.; Foster, Ryan W.; Knight, Sandra K.; Slot, Martha G.; Steinmetz-Malato, Laura L.

    2014-01-01

    Purpose: To determine whether a process change impacted the proportion of orders for single-agent, high-dose methotrexate entered by chemotherapy pharmacists instead of general pharmacy staff. Coordination of antiemetic premedication and leucovorin rescue with the new method of order entry was evaluated. Methods: Adults treated with single-agent, high-dose methotrexate were identified retrospectively. Order entry of methotrexate and ancillary medications was examined to determine whether the old or new method was used and whether it was performed by a chemotherapy pharmacist. The fundamental difference between the old and new methods for order entry is use of the “unscheduled” frequency of medication administration to replace the administration frequency of “once” with a specified date and time. Timing of antiemetic premedication and leucovorin rescue relative to methotrexate administration were tallied for the new method. Chi-square analysis was performed for the primary objective. Observational statistics were performed otherwise. Results: The number of evaluable encounters identified was 158. A chemotherapy pharmacist entered a greater proportion of orders when the new method was utilized (P < .0001). The proportion of orders entered by a chemotherapy pharmacist increased during the hours of 0700 and 2259 with the new method. Appropriate coordination of antiemetic and leucovorin administration was documented for 96% and 100% of cases with the new method of order entry. Conclusion: The proportion of orders for single-agent, high-dose methotrexate entered by a chemotherapy pharmacist was significantly greater with the use of the new method. Administration of antiemetic premedication and leucovorin rescue were appropriately coordinated with the use of the new method for order entry of single-agent, high-dose methotrexate. PMID:25673893

  13. Prevention of methotrexate-induced nephrotoxicity by concomitantadministration of garlic aqueous extract in rat

    OpenAIRE

    Ahmed, Walaa; ZAKI, AMR; NABIL, TAGHRED

    2015-01-01

    Background/aim: Methotrexate (MTX) has been widely used for treatment of cancer and rheumatoid arthritis, but its use has been limited by its nephrotoxicity. This study was carried out to determine whether garlic exerts a protective effect against MTX-induced nephrotoxicity. Materials and methods: Nephrotoxicity was induced in rats after a single i.p. injection of MTX (20 mg/kg). Garlic extract (1 mL/100 g b.w.) was given orally for 7 days before and after MTX administration. Serum samples ...

  14. A Putative Case of Methotrexate-Related Lymphoma: Clinical Course and PET/CT Findings

    Directory of Open Access Journals (Sweden)

    Rachel C. Jankowitz

    2009-01-01

    Full Text Available Patients with autoimmune conditions develop lymphoproliferative disorders (LPDs at a higher frequency than normal both in association with and independent of Methotrexate (MTX. We describe a case of MTX-associated lymphoma in a patient with psoriasis on long-standing MTX. The case is notable for the initial tumor burden, the dramatic disappearance of the PET-CT findings on discontinuation of MTX, and the subsequent early regrowth of disease. Our case report is illustrative of an MTX-related NHL in an autoimmune patient. Conclusion. Withdrawal of MTX in a patient with lymphoma is reasonable before initiating chemotherapy, but observation for early regrowth of disease is necessary.

  15. A Putative Case of Methotrexate-Related Lymphoma: Clinical Course and PET/CT Findings.

    Science.gov (United States)

    Jankowitz, Rachel C; Ganon, James; Blodgett, Todd; Garcia, Christine; Jacobs, Samuel

    2009-01-01

    Patients with autoimmune conditions develop lymphoproliferative disorders (LPDs) at a higher frequency than normal both in association with and independent of Methotrexate (MTX). We describe a case of MTX-associated lymphoma in a patient with psoriasis on long-standing MTX. The case is notable for the initial tumor burden, the dramatic disappearance of the PET-CT findings on discontinuation of MTX, and the subsequent early regrowth of disease. Our case report is illustrative of an MTX-related NHL in an autoimmune patient. Conclusion. Withdrawal of MTX in a patient with lymphoma is reasonable before initiating chemotherapy, but observation for early regrowth of disease is necessary.

  16. Autoimmune hepatitis as an adverse effect of long-term methotrexate therapy

    Directory of Open Access Journals (Sweden)

    Kamilia Ksouda

    2014-01-01

    Full Text Available Methotrexate (MTX is one of the most commonly used medicines in the treatment of psoriatic arthritis. The drug can produce steatosis and cirrhosis. Autoimmune hepatitis is a rare and serious adverse effect. We describe the case of a 53-year-old woman who developed autoimmune hepatitis after a long-term use of MTX for psoriatic arthritis. Hepatitis was completely resolved 4 months after stopping this drug. The pathophysiologic mechanisms of a drug-induced autoimmunity are unclear and complex. This report confirms the need to monitor liver enzymes carefully in patients using long-term treatment with MTX for psoriasis or rheumatoid arthritis.

  17. Diacyltransferase Activity and Chain Length Specificity of Mycobacterium tuberculosis PapA5 in the Synthesis of Alkyl β-Diol Lipids.

    Science.gov (United States)

    Touchette, Megan H; Bommineni, Gopal R; Delle Bovi, Richard J; Gadbery, John E; Nicora, Carrie D; Shukla, Anil K; Kyle, Jennifer E; Metz, Thomas O; Martin, Dwight W; Sampson, Nicole S; Miller, W Todd; Tonge, Peter J; Seeliger, Jessica C

    2015-09-08

    Although they are classified as Gram-positive bacteria, Corynebacterineae possess an asymmetric outer membrane that imparts structural and thereby physiological similarity to more distantly related Gram-negative bacteria. Like lipopolysaccharide in Gram-negative bacteria, lipids in the outer membrane of Corynebacterineae have been associated with the virulence of pathogenic species such as Mycobacterium tuberculosis (Mtb). For example, Mtb strains that lack long, branched-chain alkyl esters known as dimycocerosates (DIMs) are significantly attenuated in model infections. The resultant interest in the biosynthetic pathway of these unusual virulence factors has led to the elucidation of many of the steps leading to the final esterification of the alkyl β-diol, phthiocerol, with branched-chain fatty acids known as mycocerosates. PapA5 is an acyltransferase implicated in these final reactions. Here, we show that PapA5 is indeed the terminal enzyme in DIM biosynthesis by demonstrating its dual esterification activity and chain-length preference using synthetic alkyl β-diol substrate analogues. By applying these analogues to a series of PapA5 mutants, we also revise a model for the substrate binding within PapA5. Finally, we demonstrate that the Mtb Ser/Thr kinases PknB and PknE modify PapA5 on three overlapping Thr residues and that a fourth Thr is unique to PknE phosphorylation. These results clarify the DIM biosynthetic pathway and indicate post-translational modifications that warrant further elucidation for their roles in the regulation of DIM biosynthesis.

  18. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis

    DEFF Research Database (Denmark)

    Visser, K; Katchamart, W; Loza, E

    2009-01-01

    OBJECTIVES: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders. METHODS: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007-8 consisting of three separate rounds of di......-sparing agent in other rheumatic diseases. CONCLUSIONS: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use....

  19. ‘Short-term treatment with methotrexate does not affect microvascular endothelial function in patients with psoriasis’

    DEFF Research Database (Denmark)

    Gyldenløve, M; Jensen, Peter; Løvendorf, M B

    2015-01-01

    BACKGROUND: Psoriasis is associated with increased risk of cardiovascular disease (CVD), possibly due to chronic low-grade systemic inflammation. Systemic anti-inflammatory treatment might reduce the risk of CVD. OBJECTIVE: Our aim was to investigate if short-term treatment with methotrexate...... of treatment with methotrexate. At the same time points, we recorded anamnestic information, measured body mass index (BMI), waist and hip circumferences and blood pressure, and drew blood samples (lipid profile, HbA1 and hs-CRP). Psoriasis severity was evaluated by psoriasis area and severity index (PASI...

  20. Between Analogue and Digital Diagrams

    Directory of Open Access Journals (Sweden)

    Zoltan Bun

    2012-10-01

    Full Text Available This essay is about the interstitial. About how the diagram, as a method of design, has lead fromthe analogue deconstruction of the eighties to the digital processes of the turn of the millennium.Specifically, the main topic of the text is the interpretation and the critique of folding (as a diagramin the beginning of the nineties. It is necessary then to unfold its relationship with immediatelypreceding and following architectural trends, that is to say we have to look both backwards andforwards by about a decade. The question is the context of folding, the exchange of the analogueworld for the digital. To understand the process it is easier to investigate from the fields of artand culture, rather than from the intentionally perplicated1 thoughts of Gilles Deleuze. Both fieldsare relevant here because they can similarly be used as the yardstick against which the era itselfit measured. The cultural scene of the eighties and nineties, including performing arts, movies,literature and philosophy, is a wide milieu of architecture. Architecture responds parallel to itsera; it reacts to it, and changes with it and within it. Architecture is a medium, it has always beena medium, yet the relations are transformed. That’s not to say that technical progress, for exampleusing CAD-software and CNC-s, has led to the digital thinking of certain movements ofarchitecture, (it is at most an indirect tool. But the ‘up-to-dateness’ of the discipline, however,a kind of non-servile reading of an ‘applied culture’ or ‘used philosophy’2 could be the key.(We might recall here, parenthetically, the fortunes of the artistic in contemporary mass society.The proliferation of museums, the magnification of the figure of the artist, the existence of amassive consumption of printed and televised artistic images, the widespread appetite for informationabout the arts, all reflect, of course, an increasingly leisured society, but also relateprecisely to the fact

  1. Analysis of association between polymorphisms of MTHFR, MTHFD1 and RFC1 genes and efficacy and toxicity of methotrexate in rheumatoid arthritis patients

    Directory of Open Access Journals (Sweden)

    Vejnovic Dubravka

    2016-01-01

    Full Text Available A folate analogue methotrexate (MTX is the most commonly used disease-modifying drug in the treatment of rheumatoid arthritis. However, the clinical response of RA patients treated with MTX shows interindividual differences and 30% of patients discontinue therapy due to the side effects. In a group of 184 RA patients treated with MTX we have investigated whether polymorphisms in MTHFR (rs1801133, rs1801131, MTHFD1 (rs2236225 and RFC1 (rs144320551 genes may have impact on MTX efficacy and/or adverse drugs effects (ADEs. The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR based on EULAR criteria and relative DAS28 values (rDAS28 and all adverse drug events were recorded. Patients were genotyped for selected polymorphism by PCR-RFLP method. According to the EULAR response criteria after 6 months of MTX therapy 146 (79.3% patients were classified as responders, (17 patients (11.6% were good and 129 patients (88.4% were moderate responders and 38 patients (20.7% as non-responders. ADEs were observed in 53 (28.8% patients. The majority of ADEs were mild (36 (19.56% patients to moderate (12 (6.25% patients. Five patients (2.7% had serious ADEs. Association studies have been conducted between obtained genotypes and the efficacy and toxicity of MTX. We have observed no association between polymorphisms and efficacy or toxicity of MTX in RA patients. [Projekat Ministarstva nauke Republike Srbije, br. 175091

  2. Phosphine-free conversion of alcohols into alkyl thiocyanates using trichloroisocyanuric acid/NH4SCN

    Institute of Scientific and Technical Information of China (English)

    Roya Azadi; Babak Mokhtari; Mohamad-Ali Makaremi

    2012-01-01

    A convenient and efficient phosphine-free procedure for the one-pot conversion of primary,secondary and tertiary alcohols into the corresponding alkyl thiocyanates or alkyl isothiocyanates is described using trichloroisocyanuric acid/NH4SCN.

  3. Immobilization of lipases on alkyl silane modified magnetic nanoparticles: effect of alkyl chain length on enzyme activity.

    Directory of Open Access Journals (Sweden)

    Jiqian Wang

    Full Text Available BACKGROUND: Biocatalytic processes often require a full recycling of biocatalysts to optimize economic benefits and minimize waste disposal. Immobilization of biocatalysts onto particulate carriers has been widely explored as an option to meet these requirements. However, surface properties often affect the amount of biocatalysts immobilized, their bioactivity and stability, hampering their wide applications. The aim of this work is to explore how immobilization of lipases onto magnetite nanoparticles affects their biocatalytic performance under carefully controlled surface modification. METHODOLOGY/PRINCIPAL FINDINGS: Magnetite nanoparticles, prepared through a co-precipitation method, were coated with alkyl silanes of different alkyl chain lengths to modulate their surface hydrophobicity. Candida rugosa lipase was then directly immobilized onto the modified nanoparticles through hydrophobic interaction. Enzyme activity was assessed by catalytic hydrolysis of p-nitrophenyl acetate. The activity of immobilized lipases was found to increase with increasing chain length of the alkyl silane. Furthermore, the catalytic activities of lipases immobilized on trimethoxyl octadecyl silane (C18 modified Fe(3O(4 were a factor of 2 or more than the values reported from other surface immobilized systems. After 7 recycles, the activities of the lipases immobilized on C18 modified nanoparticles retained 65%, indicating significant enhancement of stability as well through hydrophobic interaction. Lipase immobilized magnetic nanoparticles facilitated easy separation and recycling with high activity retaining. CONCLUSIONS/SIGNIFICANCE: The activity of immobilized lipases increased with increasing alkyl chain length of the alkyl trimethoxy silanes used in the surface modification of magnetite nanoparticles. Lipase stability was also improved through hydrophobic interaction. Alkyl silane modified magnetite nanoparticles are thus highly attractive carriers for

  4. Does intraperitoneal medical ozone preconditioning and treatment ameliorate the methotrexate induced nephrotoxicity in rats?

    Science.gov (United States)

    Aslaner, Arif; Çakır, Tuğrul; Çelik, Betül; Doğan, Uğur; Mayir, Burhan; Akyüz, Cebrail; Polat, Cemal; Baştürk, Ahmet; Soyer, Vural; Koç, Süleyman; Şehirli, Ahmet Özer

    2015-01-01

    Methotrexate is a chemotherapeutic agent used for many cancer treatments. It leads to toxicity with its oxidative injury. The purpose of our study is investigating the medical ozone preconditioning and treatment has any effect on the methotrexate-induced kidneys by activating antioxidant enzymes in rats. Eighteen rats were divided into three equal groups; control, Mtx without and with medical ozone. Nephrotoxicity was performed with a single dose of 20 mg/kg Mtx intraperitoneally at the fifteenth day of experiment on groups 2 and 3. Medical ozone preconditioning was performed at a dose of 25 mcg/ml (5 ml) intraperitoneally everyday in the group 3 and treated with medical ozone for five more days while group 2 was received only 5 ml of saline everyday for twenty days. All rats were sacrificed at the end of third week and the blood and kidney tissue samples were obtained to measure the levels of TNF-α, IL-1β, malondialdehyde, glutathione and myeloperoxidase. Kidney injury score was evaluated histolopatologically. Medical ozone preconditioning and treatment ameliorated the biochemical parameters and kidney injury induced by Mtx. There was significant increase in tissue MDA, MPO activity, TNF-α and IL-1β (Pnephrotoxicity induced by Mtx in rats by activating antioxidant enzymes and prevented renal tissue.

  5. Tailoring folic acid and methotrexate-attributed quantum dots for integrated cancer cell imaging and therapy

    Science.gov (United States)

    Fahmi, Mochamad Zakki; Chang, Jia-Yaw

    2016-03-01

    Potential application of folic acid and methotrexate-attributed AgInS2-ZnS quantum dots on both detection and therapeutic of cancer cell were intensively investigated on this study. In the initial step, the bright luminescent of QDs, with % QY up to 55.3, were synthesized with one-pot two-step process resulting narrow particle distribution and successfully transferred to water phase without significant effect on optical properties. The water-soluble AgInS2-ZnS quantum dots (QDs) encapsulated with oleylamine have been successfully prepared by ultrasonication assisting. Several aspect including QDs characterization, pH stability, ionic strength, and bonding properties were investigated to reach desired condition of water-soluble AgInS2-ZnS QDs. Folic acid was further conjugated to QDs for HeLa and MCF7 cancer cell imaging to performs the targeting capability. Moreover, folic acid is efficiently internalized into cell through the receptor-mediated endocytosis even when conjugated with a wide variety of molecules. Confocal imaging characterization further informs folic acid-conjugated AgInS2-ZnS QDs could most specific targeted to the human cervical (HeLa) cells. The therapeutic feature of QDs on HeLa cancer cell was conjugated by attributing methotrexate on the QDs, instead of folic acid, and the design could improve on inhibiting the cancer cell viability as well as its fluorescent intensity.

  6. Fucose decorated solid-lipid nanocarriers mediate efficient delivery of methotrexate in breast cancer therapeutics.

    Science.gov (United States)

    Garg, Neeraj K; Singh, Bhupinder; Jain, Ashay; Nirbhavane, Pradip; Sharma, Rajeev; Tyagi, Rajeev K; Kushwah, Varun; Jain, Sanyog; Katare, Om Prakash

    2016-10-01

    The present study is designed to engineer fucose anchored methotrexate loaded solid lipid nanoparticles (SLNs) to target breast cancer. The developed nano-carriers were characterized with respect to particle size, PDI, zeta potential, drug loading and entrapment, in-vitro release etc. The characterized formulations were used to comparatively assess cellular uptake, cell-viability, apoptosis, lysosomal membrane permeability, bioavailability, biodistribution, changes in tumor volume and animal survival. The ex-vivo results showed greater cellular uptake and better cytotoxicity at lower IC50 of methotrexate in breast cancer cells. Further, we observed increased programmed cell death (apoptosis) with altered lysosomal membrane permeability and better rate of degradation of lysosomal membrane in-vitro. On the other hand, in-vivo evaluation showed maximum bioavailability and tumor targeting efficiency with minimum secondary drug distribution in various organs with formulated and anchored nano-carrier when compared with free drug. Moreover, sizeable reduction in tumor burden was estimated with fucose decorated SLNs as compared to that seen with free MTX and SLNs-MTX. Fucose decorated SLNs showed promising results to develop therapeutic interventions for breast cancer, and paved a way to explore this promising and novel nano-carrier which enables to address breast cancer.

  7. Delayed High-dose Methotrexate Excretion and Influencing Factors in Osteosarcoma Patients

    Institute of Scientific and Technical Information of China (English)

    Wei Zhang; Qing Zhang; Ting-Ting Zheng; Jian-Cun Zhen; Xiao-Hui Niu

    2016-01-01

    Background:High-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is "gold standard" therapy for osteosarcoma.Plasma concentrations of methotrexate (MTX) are closely related to its efficacy and toxicity.Delayed excretion of MTX can lead to serious adverse reactions that may result in treatment cessation,irreversible organ damage,and death.This study focused on the incidence of delayed excretion of MTX in Chinese osteosarcoma patients.Methods:A total of 1277 osteosarcoma patients were treated with HD-MTX chemotherapy (4291 cycles) from 2010 to 2015.Factors that could influence delayed excretion of MTX (gender,age,number of chemotherapy cycles,and serum concentration of MTX) were analyzed.Results:The incidence of delayed excretion of MTX (serum concentrations at 24 h [C24 h] >5 μmol/L) and severe delayed excretion of MTX (C24 h >20 μmol/L) were 6.19% and 0.86% per patient,and 2.31% and 0.26% per cycle of treatment,respectively.The incidence of severe delayed excretion of MTX was associated with gender,age,and C24 h.Conclusions:Precaution of delayed excretion of MTX is needed during osteosarcoma treatment using HD-MTX.An optimal individualized rescue strategy can be created with consideration of gender,age,and C24 h.

  8. Methotrexate for the Treatment of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Amr Nassar

    2014-01-01

    Full Text Available Glucocorticoids have been the primary treatment of graft-versus-host disease (GVHD over the past decade. Complete responses to steroid therapy are usually expected in almost one-third of aGVHD cases and partial response is anticipated in another one-third of patients. However, for those patients not responding to corticosteroid treatment, there is no standard second-line therapy for acute or chronic GVHD. Methotrexate (MTX for treatment of steroid refractory GVHD has been evaluated in a number of studies. Results from peer-reviewed original articles were identified and the pooled data analyzed. Despite several limitations in data collection and analysis, weekly administration of methotrexate at a median dose of 7.5 mg/m2 seems to be safe with minimal toxicities in the context of both aGVHD and cGVHD treatments. The observed overall response (OR in patients with aGVHD to MTX treatment in the published studies was 69.9%, with complete response (CR in 59.2% and PR in 10.6%. In cGVHD the OR was 77.6%, with CR reported in 49.6% and PR in 28% of patients. Predictors of better responses were lower grade GVHD, cutaneous involvement, and isolated organ involvement. MTX as a steroid sparing agent might reduce long-term complications and improve the quality of life of GVHD affected individuals.

  9. Bio-modified carbon nanoparticles loaded with methotrexate Possible carrier for anticancer drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Muthukumar, Thangavelu [Bio-Products Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, Tamil Nadu (India); Prabhavathi, Sundaram [Department of Biotechnology, SRM University, Kattankulathur, Chennai 603 203 (India); Chamundeeswari, Munusamy [St. Joseph' s College of Engineering, Sholinganallur, Chennai 600119 (India); Sastry, Thotapalli Parvathaleswara, E-mail: sastrytp@hotmail.com [Bio-Products Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, Tamil Nadu (India)

    2014-03-01

    The modification of carbon nanoparticles (CNPs) using biological molecules is important in the field of chemical biology, as the CNPs have the potential to deliver the drugs directly to the targeted cells and tissues. We have modified the CNPs by coating bovine serum albumin (BSA) on their surfaces and loaded with methotrexate (Mtx). Infrared spectra have revealed the coating of BSA and Mtx on CNP (CBM). Scanning electron microscopy (SEM) and atomic force microscope (AFM) pictures have exhibited the spherical nature of the composite and coating of the proteins on CNPs. The prepared CBM biocomposite has exhibited a sustained release of drug. MTT assay using A549 lung cancer cell lines has revealed 83% cell death at 150 μg/ml concentration of CBM. These results indicate that CNPs based biocomposites may be tried as therapeutic agents in treatment of cancer like diseases. - Highlights: • It's a cost effective method with maximum anticancer activity. • Maximum drug loading (methotrexate) and release have been achieved. • The prepared CBM was found to be biocompatible and hemocompatible. • About 83% of A549 lung cancer cell line apoptosis was observed with CBM.

  10. A histological evaluation on osteogenesis and resorption of methotrexate-loaded calcium phosphate cement in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Li Dong; Yang Zhiping; Li Xin; Li Zhenfeng; Li Jianmin [Department of Orthopedics, Qilu Hospital of Shandong University, Shandong (China); Yang Jingyan, E-mail: yangzhiping@medmail.com.c [Department of Pathology, 2nd Affiliated Hospital of Shandong University, Shandong (China)

    2010-04-15

    In this study, we investigated the resorption of in vivo methotrexate-loaded calcium phosphate cement (MTX-CPC) implants and their effect on osteogenesis. MTX-CPC implants containing 1% methotrexate (MTX) (weight/weight) were preset and implanted into the femoral condyle of rabbits. Calcium phosphate cement (CPC) without MTX was used as the control. The femurs were harvested at day 1 and at 1, 3 and 6 months after implantation and radiological examination were performed. Decalcified sections were examined by hematoxylin and eosin (HE) staining, alkaline phosphatase (ALPase) immunohistochemistry and tartrate-resistant acid phosphatase (TRAPase) enzyme histochemistry. Then, we performed histomorphometric analysis, including determination of the percentage of newly formed bone and osteoblast and osteoclast counts. The results indicated that MTX-CPC implants were biocompatible, biodegradable and osteoconducive. However, MTX release from the implantation site inhibited osteogenesis in the initial period; this inhibition weakened with time, and no difference was observed between CPC and MTX-CPC at 6 months after implantation. Hence, MTX-CPC is an excellent material for filling defects and can be used for preparing effective drug delivery systems to achieve local control of invasive bone tumors.

  11. Role of inducible nitric oxide synthase pathway on methotrexate-induced intestinal mucositis in rodents

    Directory of Open Access Journals (Sweden)

    Siqueira Francisco JWS

    2011-08-01

    Full Text Available Abstract Background Methotrexate treatment has been associated to intestinal epithelial damage. Studies have suggested an important role of nitric oxide in such injury. The aim of this study was to investigate the role of nitric oxide (NO, specifically iNOS on the pathogenesis of methotrexate (MTX-induced intestinal mucositis. Methods Intestinal mucositis was carried out by three subcutaneous MTX injections (2.5 mg/kg in Wistar rats and in inducible nitric oxide synthase knock-out (iNOS-/- and wild-type (iNOS+/+ mice. Rats were treated intraperitoneally with the NOS inhibitors aminoguanidine (AG; 10 mg/Kg or L-NAME (20 mg/Kg, one hour before MTX injection and daily until sacrifice, on the fifth day. The jejunum was harvested to investigate the expression of Ki67, iNOS and nitrotyrosine by immunohistochemistry and cell death by TUNEL. The neutrophil activity by myeloperoxidase (MPO assay was performed in the three small intestine segments. Results AG and L-NAME significantly reduced villus and crypt damages, inflammatory alterations, cell death, MPO activity, and nitrotyrosine immunostaining due to MTX challenge. The treatment with AG, but not L-NAME, prevented the inhibitory effect of MTX on cell proliferation. MTX induced increased expression of iNOS detected by immunohistochemistry. MTX did not cause significant inflammation in the iNOS-/- mice. Conclusion These results suggest an important role of NO, via activation of iNOS, in the pathogenesis of intestinal mucositis.

  12. Geomagnetic properties of Proxima Centauri b analogues

    CERN Document Server

    Zuluaga, Jorge I

    2016-01-01

    The recent discovery of a planet around the closest star, Proxima Centauri, could represent a quantum leap on the testability of models in exoplanet sciences. Unlike any other discovered exoplanet, models of planetary processes in Proxima b could be contrasted against near future telescopic observations and far future in-situ measurements. In this paper we study the geomagnetic properties of Proxima b analogues, namely, solid planets with masses close but larger than Earth's mass, periods of rotation of several days and habitable surface conditions. Assuming different planetary masses, bulk compositions and periods of rotations, we calculate for each planetary analogue its radius, heat flux, time of inner core formation, dynamo lifetime and minimum dipole magnetic moment. We find that most ($\\gtrsim$70\\%) Proxima b analogues develop intrinsic dynamos that last at least 3 Gyr, although only half of them are older than the present age of the host star ($4-6$ Gyr). Relying in our planetary evolution models, we p...

  13. Synthesis and anticancer evaluation of spermatinamine analogues

    KAUST Repository

    Moosa, Basem

    2016-02-04

    Spermatinamine was isolated from an Australian marine sponge, Pseudoceratina sp. as an inhibitor of isoprenylcystiene carboxyl methyltransferase (Icmt), an attractive and novel anticancer target. Herein, we report the synthesis of spermatinamine analogues and their cytotoxic evaluation against three human cancer cell lines i.e. cervix adenocarcinoma (HeLa), breast adenocarcinoma (MCF-7), and prostate carcinoma (DU145). Analogues 12, 14 and 15 were found to be the most potent against one or more cell lines with the IC50 values in the range of 5 - 10 μM. The obtained results suggested that longer polyamine linker along with aromatic oxime substitution provided the most potent analogue compounds against cancer cell lines.

  14. 40 CFR 721.3900 - Alkyl polyethylene glycol phosphate, potassium salt.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkyl polyethylene glycol phosphate... Specific Chemical Substances § 721.3900 Alkyl polyethylene glycol phosphate, potassium salt. (a) Chemical... as alkyl polyethylene glycol phosphate, potassium salt (P-90-481), is subject to reporting under...

  15. 40 CFR 721.5380 - Mixed alkyl phenolic novolak resin (generic).

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Mixed alkyl phenolic novolak resin... Specific Chemical Substances § 721.5380 Mixed alkyl phenolic novolak resin (generic). (a) Chemical... as mixed alkyl phenolic novolak resin (PMN P-98-718) is subject to reporting under this section...

  16. 40 CFR 721.6475 - Alkyl polycarboxylic acids, esters with ethoxylated fatty alcohols.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkyl polycarboxylic acids, esters... Significant New Uses for Specific Chemical Substances § 721.6475 Alkyl polycarboxylic acids, esters with... chemical substances identified generically as alkyl polycarboxylic acids, esters with ethoxylated...

  17. Synthesis and Performance of a Biomimetic Indicator for Alkylating Agents.

    Science.gov (United States)

    Provencher, Philip A; Love, Jennifer A

    2015-10-02

    4-(4-Nitrobenzyl)pyridine (NBP) is a colorimetric indicator compound for many types of carcinogenic alkylating agents. Because of the similar reactivity of NBP and guanine in DNA, NBP serves as a DNA model. NBP assays are used in the toxicological screening of pharmaceutical compounds, detection of chemical warfare agents, environmental hygiene technology, preliminary toxicology tests, mutagenicity of medicinal compounds, and other chemical analyses. Nevertheless, the use of NBP as a DNA model suffers from the compound's low water solubility, its lack of reactive oxygen sites, and dissimilar steric encumbrance compared to DNA. We report herein the design and synthesis of NBP derivatives that address some of these issues. These derivatives have been tested in solution and found to be superior in the colorimetric assay of the alkylating anticancer drug cyclophosphamide. The derivatives have also been integrated into a polymeric silica material which changes color upon the exposure to dangerous alkylating agents, such as iodomethane vapor, without the need for an exogenous base. This material modernizes the NBP assay from a time-consuming laboratory analysis to a real-time solid state sensor, which requires neither solvent nor additional reagents and can detect both gas- and solution-phase alkylating agents.

  18. Ionic liquid containing hydroxamate and N-alkyl sulfamate ions

    Energy Technology Data Exchange (ETDEWEB)

    Friesen, Cody A.; Wolfe, Derek; Johnson, Paul Bryan

    2016-03-15

    Embodiments of the invention are related to ionic liquids and more specifically to ionic liquids used in electrochemical metal-air cells in which the ionic liquid includes a cation and an anion selected from hydroxamate and/or N-alkyl sulfamate anions.

  19. Ruthenium-Catalyzed Alkylation of Oxindole with Alcohols

    DEFF Research Database (Denmark)

    Jensen, Thomas; Madsen, Robert

    2009-01-01

    An atom-economical and solvent-free catalytic procedure for the mono-3-alkylation of oxindole with alcohols is described. The reaction is mediated by the in situ generated catalyst from RuCl3 center dot xH(2)O and PPh3 in the presence of sodium hydroxide, The reactions proceed in good to excellent...

  20. Students' Understanding of Alkyl Halide Reactions in Undergraduate Organic Chemistry

    Science.gov (United States)

    Cruz-Ramirez de Arellano, Daniel

    2013-01-01

    Organic chemistry is an essential subject for many undergraduate students completing degrees in science, engineering, and pre-professional programs. However, students often struggle with the concepts and skills required to successfully solve organic chemistry exercises. Since alkyl halides are traditionally the first functional group that is…

  1. Synthesis of Hydroxytyrosyl Alkyl Ethers from Olive Oil Waste Waters

    Directory of Open Access Journals (Sweden)

    Juan Fernández-Bolaños

    2009-05-01

    Full Text Available The preparation of a new type of derivatives of the naturally occurring antioxidant hydroxytyrosol is reported. Hydroxytyrosyl alkyl ethers were obtained in high yield by a three-step procedure starting from hydroxytyrosol isolated from olive oil waste waters. Preliminary results obtained by the Rancimat method have shown that these derivatives retain the high protective capacity of free hydroxytyrosol.

  2. On the Boiling Points of the Alkyl Halides.

    Science.gov (United States)

    Correia, John

    1988-01-01

    Discusses the variety of explanations in organic chemistry textbooks of a physical property of organic compounds. Focuses on those concepts explaining attractive forces between molecules. Concludes that induction interactions play a major role in alkyl halides and other polar organic molecules and should be given wider exposure in chemistry texts.…

  3. Effect of alkyl substitutions on self-assembly

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The self-assemblies of 4-hexadecyloxybenzoic acid and 3,4,5-trihexadecyloxybenzoic acid have been studied by using scanning tunneling microscopy (STM). The well-ordered assemblies with different arrangement have been investigated. The structural change is attributed to the different number of substituted alkyl chains on periphery.

  4. Alkyl Radicals as Hydrogen Bond Acceptors: Computational Evidence

    DEFF Research Database (Denmark)

    Hammerum, Steen

    2009-01-01

    , and gives rise to pronounced shifts of IR stretching frequencies and to increased absorption intensities. The hydrogen bond acceptor properties of alkyl radicals equal those of many conventional acceptors, e.g., the bond length changes and IR red-shifts suggest that tert-butyl radicals are slightly better...

  5. Research progress in ionic liquids catalyzed isobutane/butene alkylation

    Institute of Scientific and Technical Information of China (English)

    Panxue Gan; Shengwei Tang

    2016-01-01

    The complicated reaction mechanism and the character of competitive reactions lead to a stringent requirement for the catalyst of C4 alkylation process. Due to their unique properties, ionic liquids (ILs) are thought to be new potential acid catalysts for C4 alkylation. An analysis of the regular and modified chloroaluminate ILs, novel Brønsted ILs and composite ILs used in isobutane/butene alkylation shows that the use of either ILs or ILs coupled with mineral acid as homogeneous catalysts can help to greatly adjust the acid strength. By modifying the struc-tural parameters of the cations and anions of the ILs, the solubility of the reactants could also be adjusted, which in turn displays a positive effect on improving the activity of ILs. Immobilization of ILs is an effective way to mod-ulate the surface adsorption/desorption properties and acid strength distribution of the solid acid catalysts. Such a process has a tremendous potential to reduce the deactivation of catalyst and enhance the activity of the solid acid catalyst. The development of novel acid catalysts for C4 alkylation is a comprehensive consideration of acid strength and its distribution, interfacial properties and transport characteristics.

  6. Benzoylphenylurea sulfur analogues with potent antitumor activity.

    Science.gov (United States)

    Hallur, Gurulingappa; Jimeno, Antonio; Dalrymple, Susan; Zhu, Tao; Jung, M Katherine; Hidalgo, Manuel; Isaacs, John T; Sukumar, Saraswati; Hamel, Ernest; Khan, Saeed R

    2006-04-06

    A novel series of BPU analogues were synthesized and evaluated for antitumor activity. In particular, BPU sulfur analogues 6n and 7d were shown to possess up to 10-fold increased potency, when compared to 1 (NSC-639829), against cancer cell lines. 6n was more effective than 1 in causing apoptosis of MCF-7 cells. When compared to other drugs with a similar mechanism of action, 6n retained significant ability to inhibit tubulin assembly, with an IC(50) of 2.1 microM.

  7. Review of the bioanalytical methods for the determination of methotrexate and its metabolites in in vitro, preclinical and clinical studies

    DEFF Research Database (Denmark)

    Patel, Harilal; Giri, Poonam; Ghoghari, Ashok

    2016-01-01

    Methotrexate is an old drug that has found use in several therapeutic areas, such as cancer to treat various malignancies, rheumatoid arthtritis and inflammatory bowel disease. Owing to its structural properties of possessing two carboxylic acid groups and having low native fluorescence, it has p...

  8. Temperature-responsive polymeric nanospheres containing methotrexate and gold nanoparticles: A multi-drug system for theranostic in rheumatoid arthritis.

    Science.gov (United States)

    Costa Lima, Sofia A; Reis, Salette

    2015-09-01

    Inflammation plays a crucial role in rheumatoid arthritis progress. In the present work, a novel stealth polymeric nanospheres platform able to carry anti-inflammatory drugs and an imaging agent was developed. Incorporation of gold nanoparticles will allow photoacoustic imaging and near infra-red photothermal application. Through emulsion-diffusion evaporation technique methotrexate and gold nanoparticles were incorporated in the pegylated-poly(DL-lactic-co-glycolic acid) nanospheres. In vitro drug release assays revealed pH and temperature-dependence on gold nanoparticles. Blank nanospheres exhibited negligible in vitro cytotoxicity, while methotrexate-loaded nanospheres hampered monocytes and macrophages viability at a higher level than free methotrexate. Confocal fluorescent microscopy and flow cytometry revealed effective nanospheres internalization, and that their cellular uptake was energy dependent mediated by caveolae and clathrin-endocytosis mechanism. Finally, MTX-loaded multifunctional nanospheres containing gold lead to a significant reduction of IL-1β, IL-6 and TNF-α inflammatory cytokines produced by monocytes and macrophages upon in vitro inflammatory stimulation, suggesting a favorable anti-inflammatory activity. These results confirm that the multifunctional nanospheres represent a promising theranostic platform for RA diagnosis and intracellular treatment, by combining methotrexate and gold nanoparticles for a highly effective targeted chemo-photothermal therapy.

  9. Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial

    NARCIS (Netherlands)

    P.P. Tak; W.F. Rigby; A. Rubbert-Roth; C.G. Peterfy; R.F. van Vollenhoven; W. Stohl; E. Hessey; A. Chen; H. Tyrrell; T.M. Shaw

    2011-01-01

    Objectives Rituximab is an effective treatment in patients with established rheumatoid arthritis (RA). The objective of the IMAGE study was to determine the efficacy of rituximab in the prevention of joint damage and its safety in combination with methotrexate (MTX) in patients initiating treatment

  10. Compliance with methotrexate treatment in patients with rheumatoid arthritis: influence of patients' beliefs about the medicine. A prospective cohort study

    DEFF Research Database (Denmark)

    de Thurah, Annette; Nørgaard, Mette; Harder, Ingegerd;

    2010-01-01

    Objective of the study is to investigate how compliance during the first year of methotrexate (MTX) treatment in rheumatoid arthritis (RA) is influenced by the patients' perception of the necessity for and concern about MTX, the patients' functional disability, and the dose of MTX. A total of 126...

  11. Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine

    NARCIS (Netherlands)

    Gelinck, L. B. S.; Van der Bijl, A. E.; Visser, L. G.; Huizinga, T. W. J.; Van Hogezand, R. A.; Rijkers, G. T.

    2008-01-01

    introduction: The efficacy of the immune response upon vaccination in patients treated with anti-tumor necrosis factor-alpha (anti-TNF) with or without methottexate is the subject of debate. We studied the effect of immuncisuppressive treatment, including anti-TNF and methotrexate, on the response t

  12. Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis : a randomised trial

    NARCIS (Netherlands)

    Ruperto, Nicolino; Pistorio, Angela; Oliveira, Sheila; Zulian, Francesco; Cuttica, Ruben; Ravelli, Angelo; Fischbach, Michel; Magnusson, Bo; Sterba, Gary; Avcin, Tadej; Brochard, Karine; Corona, Fabrizia; Dressler, Frank; Gerloni, Valeria; Apaz, Maria T; Bracaglia, Claudia; Cespedes-Cruz, Adriana; Cimaz, Rolando; Couillault, Gerard; Joos, Rik; Quartier, Pierre; Russo, Ricardo; Tardieu, Marc; Wulffraat, Nico; Bica, Blanca; Dolezalova, Pavla; Ferriani, Virginia; Flato, Berit; Bernard-Medina, Ana G; Herlin, Troels; Trachana, Maria; Meini, Antonella; Allain-Launay, Emma; Pilkington, Clarissa; Vargova, Veronika; Wouters, Carine; Angioloni, Simona; Martini, Alberto

    2016-01-01

    BACKGROUND: Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with

  13. Relapse rates after two versus three consolidation courses of methotrexate in the treatment of low-risk gestational trophoblastic neoplasia.

    NARCIS (Netherlands)

    Lybol, C.; Sweep, F.C.; Harvey, R.; Mitchell, H.; Short, D.; Thomas, C.M.G.; Ottevanger, P.B.; Savage, P.M.; Massuger, L.F.A.G.; Seckl, M.J.

    2012-01-01

    OBJECTIVE: Methotrexate (MTX) alternating with folinic acid is a commonly used treatment regimen for low-risk gestational trophoblastic neoplasia (GTN). In The Netherlands, two courses of MTX are administered after normalization of serum human chorionic gonadotrophin (hCG) levels (consolidation cour

  14. Continuous enteral administration can overcome the limited capacity to absorb glucose in rats with methotrexate-induced gastrointestinal mucositis

    NARCIS (Netherlands)

    Fijlstra, Margot; Rings, Edmond H. H. M.; van Dijk, Theo H.; Plosch, Torsten; Verkade, Henkjan J.; Tissing, Wim J. E.

    2013-01-01

    Patients with chemotherapy-induced gastrointestinal mucositis often suffer from weight loss. It is not well known how to enterally feed mucositis patients, potentially experiencing malabsorption. Recently, we showed in a rat model of methotrexate (MTX)-induced mucositis that intestinal absorption of

  15. Success and spontaneous pregnancy rates following systemic methotrexate versus laparoscopic surgery for tubal pregnancies: A randomized trial

    DEFF Research Database (Denmark)

    Møller, Lars Bo Krag; Moeller, Charlotte; Thomsen, Sten Grove;

    2009-01-01

    Objective. To determine which treatment should be offered to women with a non-ruptured tubal pregnancy: a single dose of methotrexate (MTX) or laparoscopic surgery. Design. Prospective, randomized, open multicenter study. Setting. Seven Danish departments of obstetrics and gynecology. Sample...

  16. Open-label trial of anti-TNF-alpha in dermato- and polymyositis treated concomitantly with methotrexate

    DEFF Research Database (Denmark)

    Hengstman, G.J.; Bleecker, J.L. De; Feist, E.

    2008-01-01

    BACKGROUND/AIMS: To determine the efficacy of infliximab combined with weekly methotrexate in drug-naive recent-onset dermatomyositis and polymyositis. METHODS: A multicentre open-label controlled trial was conducted. Disease activity was assessed using patient's and physician's disease activity...

  17. Changes in serum lipids in patients with rheumatoid arthritis treated with a combination of tocilizumab and methotrexate compared with methotrexate alone for 24 weeks of observation

    Directory of Open Access Journals (Sweden)

    E. V. Udachkina

    2015-11-01

    Full Text Available Background. According to the some studies tocilizumab therapy (TCZ in patients with rheumatoid arthritis (RA is accompanied by deterioration of blood lipid profile. Aim. To study changes in serum lipid parameters in patients with RA treated with a combination of tocilizumab and methotrexate compared with methotrexate alone for 24 weeks of observation. Material and methods. Patients (n=72 with RA were included into the pilot non-randomized 24-week study and divided in two groups: 1 TCZ+MTX group (n=39; women 30; median age 51 [43-55] years; 6 i.v. infusions of TCZ 8 mg/kg + МТX 10-20 mg/week; 2 MTX group (n=33; women 23; mеdian age 56 [48-63] years; MTX 7.5-20 mg/week. Results. At the baseline, similar proatherogenic blood profile was observed in both groups. The patients of MTX group more frequently took statins (n=19; 57.6% compared with the group TCZ+MTX (n=7; 18%, (p<0.05. The lipid levels correlated positively with traditional risk factors (p<0.05. RA activity and duration correlated negatively with high density lipoprotein cholesterol (HDL-C, (p<0.05. Good/satisfactory anti-inflammatory effect was achieved in both groups after 24 weeks of treatment. Patients of TCZ+MTX group showed an increase in total cholesterol and HDL-C levels by 11% and 110%, respectively and decrease in plasma atherogenic index (PAI by 47%, (p<0.05. HDL-C level increased by 22% and PAI decreased by 16% in patients of MTX group (p<0.05. Among patients of MTX group without statin therapy HDL-C as well as non-HDL-C levels were increased by 24% and 27%, respectively (p<0.05; PAI did not change significantly in this subgroup. Among patients of MTX group treated with statins isolated increase in HDL-C level by 22% and decrease in PAI by 37.3% (p<0.05 were observed. A number of patients with achieved target levels of all studied lipid parameters did not change significantly in both groups. Conclusions. TCZ+MTX combined therapy as well as MTX monotherapy are associated

  18. Analogue alternative the electronic analogue computer in Britain and the USA, 1930-1975

    CERN Document Server

    Small, James S

    2013-01-01

    We are in the midst of a digital revolution - until recently, the majority of appliances used in everyday life have been developed with analogue technology. Now, either at home or out and about, we are surrounded by digital technology such as digital 'film', audio systems, computers and telephones. From the late 1940s until the 1970s, analogue technology was a genuine alternative to digital, and the two competing technologies ran parallel with each other. During this period, a community of engineers, scientists, academics and businessmen continued to develop and promote the analogue computer.

  19. EFFECT OF ALKYL CHAIN ASYMMETRY ON THE FUSION AND CRYSTALLIZATION BEHAVIOR OF VESICLES FORMED FROM DI-N-ALKYL PHOSPHATES

    NARCIS (Netherlands)

    STREEFLAND, L; WAGENAAR, A; HOEKSTRA, D; ENGBERTS, JBFN

    1993-01-01

    Fusion of vesicles formed from synthetic, asymmetric (i.e mixed-chain) sodium di-n-alkyl phosphates (1-6) has been studied with a resonance energy transfer assay for lipid mixing and with transmission electron microscopy. Fusion was induced by Ca2+ ions above the Lalpha --> Lbeta phase transition te

  20. Levels and pattern of alkyl nitrates, multifunctional alkyl nitrates, and halocarbons in the air over the Atlantic Ocean

    Science.gov (United States)

    Fischer, Ralf G.; Kastler, Jürgen; Ballschmiter, Karlheinz

    2000-06-01

    The Albatross Campaign was a research cruise of the German research vessel RV Polarstern (cruise ANT XFV/1) in October and November 1996 across the Atlantic Ocean. The cruise started in Bremerhaven, Germany, reached the polar region at 67°N, followed the 30°W meridian longitude, crossed the equatorial region, and ended at 50°S at Punta Quilla, Argentina. A second cruise leg closer to the African continent started from Capetown, South Africa, passed the Canary Island, and ended through the English Channel at Bremerhaven, Germany, in May/June 1998. Measurements of atmospheric levels of C1-C13 alkyl mononitrates, 24 alkyl dinitrates (C3-C6), 19 hydroxy alkyl nitrates (C2-C6), and benzyl nitrate, as well as the halocarbons tetrachloroethene, hexachloroethane, and bromoform are presented in this work. The halocarbons are used to assess the origin of the air parcels analyzed. Levels and patterns of multifunctional alkyl nitrates in the marine air are described here for the first time. The air masses include polluted air from the northern Europe, as well as highly degraded air masses of the South Atlantic trade wind region that represent global baseline levels. Two independent analytical methods were used in combination to cover the whole range of organic nitrates. First, the low-volume adsorptive enrichment of organic traces on Tenax, followed by thermodesorption cold trap HRGC-ECD and thermodesorption cold trap HRGC-(EI)MSD was used. Second, high-volume adsorptive enrichment of organic traces on silica gel was applied followed by solvent desorption, NP-HPLC group separation, and HRGC-(EI)-MSD. Short-chain alkyl nitrates (C4-C6) showed mixing ratios in the range of 0.2-2.5 parts per trillion by volume (pptv), with a local minimum for the tropical regions and significantly lower ratios for the Southern Hemisphere. The mixing ratio of the sum of 36 long-chain alkyl mononitrates (C7-C13) ranged from 0.02-0.43 pptv, the mixing ratio of the sum of 23 alkyl dinitrates (C3-C

  1. Synthesis and antimicrobial activity of squalamine analogue.

    Science.gov (United States)

    Kim, H S; Choi, B S; Kwon, K C; Lee, S O; Kwak, H J; Lee, C H

    2000-08-01

    Synthesis and antimicrobial activity of squalamine analogue 2 are reported. The synthesis of 2 was accomplished from bisnoralcohol 3. The spermidine moiety was introduced via reductive amination of an appropriately functionalized 3beta-aminosterol with spermidinyl aldehyde 17 utilizing sodium triacetoxyborohydride as the reducing agent. Compound 2 shows weaker antimicrobial activity than squalamine.

  2. Dumb holes: analogues for black holes.

    Science.gov (United States)

    Unruh, W G

    2008-08-28

    The use of sonic analogues to black and white holes, called dumb or deaf holes, to understand the particle production by black holes is reviewed. The results suggest that the black hole particle production is a low-frequency and low-wavenumber process.

  3. Solanapyrone analogues from a Hawaiian fungicolous fungus

    Science.gov (United States)

    Four new solanayrone analogues (solanapyrones J-M; 1-4) have been isolated from an unidentified fungicolous fungus collected in Hawaii. The structures and relative configurations of these compounds were determined by analysis of ID NMR, 2D NMR, and MS data. Solanapyrone J(1) showed antifungal acti...

  4. Prussian Blue Analogues of Reduced Dimensionality

    NARCIS (Netherlands)

    Gengler, Regis Y. N.; Toma, Luminita M.; Pardo, Emilio; Lloret, Francesc; Ke, Xiaoxing; Van Tendeloo, Gustaaf; Gournis, Dimitrios; Rudolf, Petra

    2012-01-01

    Mixed-valence polycyanides (Prussian Blue analogues) possess a rich palette of properties spanning from room-temperature ferromagnetism to zero thermal expansion, which can be tuned by chemical modifications or the application of external stimuli (temperature, pressure, light irradiation). While mol

  5. Inhibitory Activities of Alkyl Syringates and Related Compounds on Aflatoxin Production

    Directory of Open Access Journals (Sweden)

    Tomohiro Furukawa

    2016-06-01

    Full Text Available Inhibitors of aflatoxin production of aflatoxigenic fungi are useful for preventing aflatoxin contamination in crops. As methyl syringate weakly inhibits aflatoxin production, aflatoxin production inhibitory activities of additional alkyl syringates with alkyl chains from ethyl to octyl were examined. Inhibitory activity toward aflatoxin production of Aspergillus flavus became stronger as the length of the alkyl chains on the esters became longer. Pentyl, hexyl, heptyl, and octyl syringates showed strong activity at 0.05 mM. Heptyl and octyl parabens, and octyl gallate also inhibited aflatoxin production as strongly as octyl syringate. Alkyl parabens and alkyl gallates inhibit the complex II activity of the mitochondrial respiration chain; thus, whether alkyl syringates inhibit complex II activity was examined. Inhibitory activities of alkyl syringates toward complex II also became stronger as the length of the alkyl chains increased. The complex II inhibitory activity of octyl syringate was comparable to that of octyl paraben and octyl gallate. These results suggest that alkyl syringates, alkyl parabens, and alkyl gallates, including commonly used food additives, are useful for aflatoxin control.

  6. Inhibitory Activities of Alkyl Syringates and Related Compounds on Aflatoxin Production

    Science.gov (United States)

    Furukawa, Tomohiro; Iimura, Kurin; Kimura, Taichi; Yamamoto, Toshiyoshi; Sakuda, Shohei

    2016-01-01

    Inhibitors of aflatoxin production of aflatoxigenic fungi are useful for preventing aflatoxin contamination in crops. As methyl syringate weakly inhibits aflatoxin production, aflatoxin production inhibitory activities of additional alkyl syringates with alkyl chains from ethyl to octyl were examined. Inhibitory activity toward aflatoxin production of Aspergillus flavus became stronger as the length of the alkyl chains on the esters became longer. Pentyl, hexyl, heptyl, and octyl syringates showed strong activity at 0.05 mM. Heptyl and octyl parabens, and octyl gallate also inhibited aflatoxin production as strongly as octyl syringate. Alkyl parabens and alkyl gallates inhibit the complex II activity of the mitochondrial respiration chain; thus, whether alkyl syringates inhibit complex II activity was examined. Inhibitory activities of alkyl syringates toward complex II also became stronger as the length of the alkyl chains increased. The complex II inhibitory activity of octyl syringate was comparable to that of octyl paraben and octyl gallate. These results suggest that alkyl syringates, alkyl parabens, and alkyl gallates, including commonly used food additives, are useful for aflatoxin control. PMID:27338472

  7. Inadequate response or intolerability to oral methotrexate: Is it optimal to switch to subcutaneous methotrexate prior to considering therapy with biologics?

    Science.gov (United States)

    Yadlapati, Sujani; Efthimiou, Petros

    2016-05-01

    Methotrexate (MTX) is considered an anchor drug in the treatment of rheumatoid arthritis. It is also the first-line therapy in a multitude of rheumatologic conditions. Low-dose oral MTX is the preliminary modality of treatment for rheumatoid arthritis due to its affordability, favorable outcomes, and limited risks. However, patients refractory to low-dose MTX therapy may require larger doses of oral MTX. Several studies in the past have demonstrated variability in bioavailability of oral MTX at high doses. This warrants a subsequent switch to parenteral MTX. Widely used among the parenteral preparations of MTX is subcutaneous (SC) MTX. SC MTX provides dependable efficacy, predictable bioavailability, sustained clinical outcomes, and minimal GI adverse effects. It is useful either singularly or in combination therapy regimens. Although SC MTX and intramuscular MTX have similar pharmacokinetics, SC MTX may be preferred by most patients. Development of prefilled syringes and auto-injectors have enabled self-administration of the medication providing the patients with a sense of independence and improved general well-being. Hence, SC MTX can prove to be more efficacious in patients refractory to oral MTX therapy or in patients experiencing severe gastrointestinal adverse effects.

  8. Development of an Assay for Methotrexate and Its Metabolites 7-Hydroxy Methotrexate and DAMPA in Serum by LC-MS/MS.

    Science.gov (United States)

    Schofield, Ryan C; Ramanathan, Lakshmi V; Murata, Kazunori; Fleisher, Martin; Pessin, Melissa S; Carlow, Dean C

    2016-01-01

    Methotrexate (MTX) is a folic acid antagonist that is widely used as an immunosuppressant and chemotherapeutic agent. After high-dose administration of MTX serum levels must be monitored to determine when to administer leucovorin, a folic acid analog that bypasses the enzyme inhibition caused by MTX and reverses its toxicity. We describe a rapid and simple turbulent flow liquid chromatography (TFLC) method implementing positive heated electrospray ionization (HESI) for the accurate and precise determination of MTX, 7-hydroxymethotrexate (7-OH MTX), and 4-amino-4-deoxy-N(10)-methylpteroic acid (DAMPA) concentrations in serum. MTX is isolated from serum samples (100 μL) after protein precipitation with a methanolic solution containing internal standard (MTX-D3) followed by centrifugation. The supernatant is injected into the turbulent flow liquid chromatography which is followed by electrospray positive ionization tandem mass spectrometry (TFLC-ESI-MS/MS) and quantified using a six-point calibration curve. For MTX, 7-OH MTX, and DAMPA the assays were linear from 20 to 1000 nmol/L. Dilutions of 10-, 100-, and 1000-fold were validated giving a clinically reportable range of 20 to 1.0 × 10(6) nmol/L. Within-day and between-day precisions at concentrations spanning the analytical measurement ranges were less than 10 % for all three analytes.

  9. [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1.

    Science.gov (United States)

    Cai, Yunxin; Lu, Dandan; Chen, Zhen; Ding, Yi; Chung, Nga N; Li, Tingyou; Schiller, Peter W

    2016-08-01

    Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity were prepared by replacing Dmt with various 2',6'-dialkylated Tyr analogues, including 2',4',6'-trimethyltyrosine (Tmt), 2'-ethyl-6'-methyltyrosine (Emt), 2'-isopropyl-6'-methyltyrosine (Imt) and 2',6'-diethyltyrosine (Det). All compounds were selective μ opioid agonists and the Tmt(1)-, Emt(1) and Det(1)-analogues showed subnanomolar μ opioid receptor binding affinities. The Tmt(1)- and Emt(1)-analogues showed improved antioxidant activity compared to the Dmt(1)-parent peptide in the DPPH radical-scavenging capacity assay, and thus are of interest as drug candidates for neuropathic pain treatment.

  10. A q-analogue of the four functions theorem

    OpenAIRE

    Christofides, Demetres

    2009-01-01

    In this article we give a proof of a q-analogue of the celebrated four functions theorem. This analogue was conjectured by Bjorner and includes as special cases both the four functions theorem and also Bjorner's q-analogue of the FKG inequality.

  11. Tryptophan analogues. 1. Synthesis and antihypertensive activity of positional isomers.

    Science.gov (United States)

    Safdy, M E; Kurchacova, E; Schut, R N; Vidrio, H; Hong, E

    1982-06-01

    A series of tryptophan analogues having the carboxyl function at the beta-position was synthesized and tested for antihypertensive activity. The 5-methoxy analogue 46 exhibited antihypertensive activity in the rat via the oral route and was much more potent than the normal tryptophan analogue. The methyl ester was found to be a critical structural feature for activity.

  12. Analogue VLSI for probabilistic networks and spike-time computation.

    Science.gov (United States)

    Murray, A

    2001-02-01

    The history and some of the methods of analogue neural VLSI are described. The strengths of analogue techniques are described, along with residual problems to be solved. The nature of hardware-friendly and hardware-appropriate algorithms is reviewed and suggestions are offered as to where analogue neural VLSI's future lies.

  13. Methotrexate bioavailability

    NARCIS (Netherlands)

    van Roon, E. N.; van de Laar, M. A. F. J.

    2010-01-01

    The clinical relevance of the concept of bioavailability rests on two main principles. First, that measurement of the active component at the site of action is generally not possible and, secondly, that a relationship exists between on the one hand efficacy and/or safely and on the other hand concen

  14. 肌酐清除率对大剂量甲氨蝶呤化疗中血药浓度的影响%Influence of creatinine clearance on serum methotrexate concentration in high-dose methotrexate therapy

    Institute of Scientific and Technical Information of China (English)

    林晓雯; 邵宏; 聂小燕; 孙迎琪; 张乐萍; 李玉珍; 顾健

    2009-01-01

    AIM: To study the influence of creati-nine clearance on serum methotrexate ( MTX) concentration in high-dose methotrexate ( HDMTX) therapy. METHODS: The data was collected from 44 children who were diagnosed of acute lymphocytic leukemia (ALL) or non-Hodgkin lymphoma (NHL), and were administered with 106 doses of HDMTX from Feb, 2006 to May, 2008. The association between creatinine clearance and serum methotrexate concentration at 24 and 42 h were retrospectively analyzed, by SPSS 12.0 format. RESULTS: There was a significant correlation between creatinine clearance and 24 h serum methotrexate concentration (P 0.05) . CONCLUSION: Creatinine clearance can be related with 24 h serum methotrexate concentration, and can be referenced in estimating 24 h serum methotrexate concentration .%目的:研究肌酐清除率对于大剂量甲氨蝶呤(HDMTX)化疗中甲氨蝶呤(MTX)血药浓度的影响.方法:收集2006年2月至2008年5月住院期间使用HDMTX化疗方案化疗的44名急性淋巴细胞白血病或非霍奇金淋巴瘤患儿共106次化疗资料,使用SPSS 12.0版本回顾性地分析了肌酐清除率和24、42 h的血药浓度的相关性.结果:肌酐清除率和24 h血药浓度有显著相关性(P<0.05).肌酐清除率和42 h血药浓度无相关性(P>0.05).结论:肌酐清除率对于24 h MTX血药浓度有影响,对于预计24 h MTX血药浓度有一定参考价值.

  15. Effect of growth hormone on testicular dysfunction induced by methotrexate in rats.

    Science.gov (United States)

    Nouri, H Serati; Azarmi, Y; Movahedin, M

    2009-04-01

    Methotrexate (MTX) is a chemotherapeutic agent causing defective oogenesis and spermatogenesis. This study was performed to assess the role of human growth hormone (GH) on testis recovery after treatment with MTX. Forty male Wistar rats were selected and randomly divided into four groups (n = 10): control (vehicle), GH group (0.3 mg kg(-1) GH for 28 days, IP), MTX group (MTX 1 mg kg(-1) week(-1) for 4 weeks, IP) and GH/MTX group (0.3 mg kg(-1) GH for 28 day plus 1 mg kg(-1) week(-1) MTX for 4 weeks, IP). On days 14 and 28, five rats from each group were killed, testes of rats of all groups were removed, spermatozoa were collected from epididymis and then prepared for analysis. MTX caused significant increase in interstitial tissue and capsular thickness and decrease of testicular and body weight (P rat testes and thus improved sperm parameters.

  16. Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours

    DEFF Research Database (Denmark)

    Sengeløv, Lisa; von der Maase, Hans; Lundbeck, Finn

    2002-01-01

    This prospective, randomized study based on two associated trials was designed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b, NX-3, MO transitional cell carcinoma...... was 12.9 months. Median time to progression was 14.2 months with chemotherapy and 11.4 months without chemotherapy. The actuarial 5-year overall survival rate for all 153 patients was 29%, and 29% for both treatment groups. Multivariate analyses showed that T-stage, tumour size and serum creatinine were...... independent prognostic factors for survival. The cystectomy trial included 33 patients. Median survival was 78.9 months, 82.5 months with chemotherapy and 45.8 months without chemotherapy (p = 0.76). The radiotherapy trial included 120 patients. The median survival was 17.6 months. Median survival was 19...

  17. Markers of Treatment Response to Methotrexate in Rheumatoid Arthritis: Where Do We Stand?

    Directory of Open Access Journals (Sweden)

    Karina I. Halilova

    2012-01-01

    Full Text Available Methotrexate (MTX is the most commonly used disease-modifying antirheumatic drug (DMARD for the treatment of rheumatoid arthritis (RA. However, despite its efficacy and affordability, additional DMARDs or biologic agents are often required in order to achieve the recommended goals of low disease activity or remission. Although well tolerated by most, some patients develop important side effects such as cytopenias, gastrointestinal adverse events (stomatitis, nausea, or abnormal liver function tests, which may limit its use and may result in additional health care costs. Given the clinical implications of widespread use of MTX in RA, various studies have evaluated the role of potential biomarkers in predicting treatment effectiveness of MTX. These biomarkers include RBC MTX polyglutamate (PG levels; genetic variation in genes from relevant biological and metabolic pathways; gene expression profiles; serum proteins. This paper provides an update on the current data regarding biomarkers of treatment response to MTX.

  18. Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes.

    Science.gov (United States)

    Bateman, D Nicholas; Page, Colin B

    2016-03-01

    Some toxins cause their effects by affecting physiological processes that are fundamental to cell function or cause systemic effects as a result of cellular interaction. This review focuses on four examples, coumarin anticoagulants, isoniazid, methotrexate and thyroxine from the context of management of overdose as seen in acute general hospitals. The current basic clinical pharmacology of the toxin, the clinical features in overdose and evidence base for specific antidotes are discussed. The treatment for this group is based on an understanding of the toxic mechanism, but studies to determine the optimum dose of antidote are still required in all these toxins except thyroxine, where treatment dose is based on symptoms resulting from the overdose.

  19. Influence of methylene tetrahydrofolate reductase polymorphisms and coadministration of antimetabolites on toxicity after high dose methotrexate

    DEFF Research Database (Denmark)

    Niekerk, P.B. van Kooten; Schmiegelow, K.; Schroeder, H.

    2008-01-01

    BACKGROUND AND OBJECTIVE: Through interruption of maintenance treatment with 6-mercaptopurine (6MP), toxicity after high-dose methotrexate (HDMTX) may compromise the efficiency of the treatment of children with acute lymphocytic leukaemia (ALL). We investigated the influence of polymorphisms......-intensity co-treatment (6MP 75 mg/m(2)/d + MTX 20 mg/m(2)/wk) was found associated with increased odds of haematological toxicity (OR's: 3.47-7.88; P's: fever (OR = 2.2; P = 0.004) and interruption maintenance treatment (OR = 15.9; P ....006-0.027), fever (OR = 2.65; P = 0.037) and interruption of maintenance treatment (OR = 3.04; P = 0.032). No convincing associations were found between the MTHFR C677T or A1298C polymorphisms and toxicity. CONCLUSION: Our findings demonstrate that toxicity after HDMTX is influenced by coadministrated...

  20. Involvement of Multiple Transporters-mediated Transports in Mizoribine and Methotrexate Pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Teruo Murakami

    2012-08-01

    Full Text Available Mizoribine is administered orally and excreted into urine without being metabolized. Many research groups have reported a linear relationship between the dose and peak serum concentration, between the dose and AUC, and between AUC and cumulative urinary excretion of mizoribine. In contrast, a significant interindividual variability, with a small intraindividual variability, in oral bioavailability of mizoribine is also reported. The interindividual variability is mostly considered to be due to the polymophisms of transporter genes. Methotrexate (MTX is administered orally and/or by parenteral routes, depending on the dose. Metabolic enzymes and multiple transporters are involved in the pharmacokinetics of MTX. The oral bioavailability of MTX exhibits a marked interindividual variability and saturation with increase in the dose of MTX, with a small intraindividual variability, where the contribution of gene polymophisms of transporters and enzymes is suggested. Therapeutic drug monitoring of both mizoribine and MTX is expected to improve their clinical efficacy in the treatment of rheumatoid arthritis.

  1. Pharmacogenetics and pharmacogenomics for rheumatoid arthritis responsiveness to methotrexate treatment: the 2013 update.

    Science.gov (United States)

    Zhu, Hong; Deng, Fei-Yan; Mo, Xing-Bo; Qiu, Ying-Hua; Lei, Shu-Feng

    2014-03-01

    Rheumatoid arthritis (RA) is a complex, systemic autoimmune disease characterized by chronic inflammation of multiple peripheral joints, which leads to serious destruction of cartilage and bone, progressive deformity and severe disability. Methotrexate (MTX) is one of the first-line drugs commonly used in RA therapy owing to its excellent long-term efficacy and cheapness. However, the efficacy and toxicity of MTX treatment have significant interpatient variability. Genetic factors contribute to this variability. In this review, we have summarized and updated the progress of RA response to MTX treatment since 2009 by focusing on the fields of pharmacogenetics and pharmacogenomics. Identification of genetic factors involved in MTX treatment response will increase the understanding of RA pathology and the development of new personalized treatments.

  2. Clinical Observation on Methotrexate Combined with Chinese Preparations in Treating Rheumatoid Arthritis Patients

    Institute of Scientific and Technical Information of China (English)

    陈洪滔; 张晓

    2002-01-01

    @@ Rheumatoid arthritis (RA) is an auto-immune disease, the cause of which is not clear. It manifested joint change as chief lesion, is a frequently encountered, common disease. In recent years the disease modifying antirheumatic drugs (DMARDs) combined application in treating RA has conducted many studies in domestic study and abroad, indicating that it can effectively retard the progressing of the disease. Meanwhile the domestic reports on the Chinese medicine (CM) in treating RA has obtained some efficacy, but the long-term efficacy was not sure. From May 1999 to August, 2001, the authors have applied and observed methotrexate (MTX) combined with CM preparation and MTX combined with western medicine (WM) in treating 43 cases of RA, the report is as follows.

  3. Inadvertent yellow fever vaccination of a patient with Crohn's disease treated with infliximab and methotrexate.

    Science.gov (United States)

    Ekenberg, Christina; Friis-Møller, Nina; Ulstrup, Thomas; Aalykke, Claus

    2016-08-29

    We present a case of a 56-year-old woman with Crohn's disease, treated with methotrexate and infliximab, who inadvertently received yellow fever vaccination (YFV) prior to a journey to Tanzania. She was not previously vaccinated against YF. YFV contains live-attenuated virus, and is contraindicated in patients treated with immunosuppressive drugs. Following vaccination, the patient fell ill with influenza-like illness. Elevated transaminase levels and YF viremia were detected. Despite being immunocompromised, the patient did not develop more severe adverse effects. Neutralising antibodies to YF virus were detected on day 14 following vaccination and remained protective at least 10 months after vaccination. Limited data is available on outcomes of YFV in patients receiving immunosuppressive therapy, including biologics, and we report this case as a reminder of vigilance of vaccine recommendations in this population.

  4. Methotrexate-induced pneumonitis in Crohn's disease. Case report and review of the literature

    Directory of Open Access Journals (Sweden)

    D'Andrea Nadia

    2010-10-01

    Full Text Available Abstract Methotrexate (MTX is a folate-antagonist used in several neoplastic and inflammatory diseases. Reports of pulmonary complications in patients given low-dose MTX therapy are increasing. Pulmonary toxicity from MTX has a variable frequency and can present with different forms. Most often MTX-induced pneumonia in patients affected by rheumatoid arthritis (RA is reported. In this paper we describe a case of MTX-related pneumonitis in a relatively young woman affected by Crohn's disease who presented non-productive cough, fever and dyspnea on exercise. Chest X-ray demonstrated bilateral interstitial infiltrates and at computed tomography (CT ground-glass opacities appeared in both lungs. At spirometry an obstructive defect was demonstrated. A rapid improvement of symptoms and the regression of radiographic and spirometric alterations was achieved through MTX withdrawal and the introduction of corticosteroid therapy.

  5. Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic diseases.

    Science.gov (United States)

    Stamp, Lisa K; Roberts, Rebecca L

    2011-10-01

    Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis and is frequently used in the management of other forms of inflammatory arthritis. It is currently challenging to predict which patients will achieve adequate disease control and which patients will develop adverse effects while taking MTX. As an analog of dihydrofolic acid, MTX enters cells through the reduced folate carrier-1 protein, and is polyglutamated. MTX polyglutamates inhibit key enzymes in the folate pathway to produce an anti-inflammatory effect. It has been suggested that genetic polymorphisms in the folate pathway may influence intracellular folate and MTX polyglutamates pools, and thus MTX response. However, studies to identify genetic predictors have yielded inconclusive results. Nonreplication across studies has been attributed to insufficient statistical power as well as pharmacological and clinical confounders. Prospective studies, standardizing the definitions of response and toxicity, and application of genome-wide approaches may advance the search for genetic predictors of MTX response.

  6. Topically applied methotrexate is rapidly delivered into skin by fractional laser ablation

    DEFF Research Database (Denmark)

    Taudorf, Elisabeth Hjardem; Lerche, Catharina; Vissing, Anne-Cathrine

    2015-01-01

    Objectives: Methotrexate (MTX) is a chemotherapeutic and anti-inflammatory drug that may cause systemic adverse effects. This study investigated kinetics and biodistribution of MTX delivered topically by ablative fractional laser (AFXL). Methods: In vitro passive diffusion of 10 mg/ml MTX (1 w...... of 690 µm ablation depth, lined by the 47 µm thermal coagulation zone (CZ). Quantitatively, MTX was detectable by HPLC in mid-dermis after 15 min, significantly exceeded deposition in intact skin after 1.5 h, and saturated skin after 7 h at a 10-fold increased MTX-deposition versus intact skin (3.08 vs 0.......30 mg/cm3, p = 0.002). Transdermal permeation was saturation, and increased up to 8.0% after 24 h. Qualitatively, MTX distributed into CZ within 15 min (p = 0.015) and further into surrounding dermal tissue after 1.5 h (p = 0.004). After skin saturation at 7 h, MTX...

  7. Detection of methotrexate in a flow system using electrochemical impedance spectroscopy and multivariate data analysis.

    Science.gov (United States)

    Tesfalidet, Solomon; Geladi, Paul; Shimizu, Kenichi; Lindholm-Sethson, Britta

    2016-03-31

    Methotrexate (MTX), a common pharmaceutical drug in cancer therapy and treatment of rheumatic diseases, is known to cause severe adverse side effects at high dose. As the side effect may be life threatening, there is an urgent need for a continuous, bed-side monitoring of the nominal MTX serum level in a patient while the chemical is being administered. This article describes a detection of MTX using a flow system that consists two modified gold electrodes. Interaction of MTX with the antibodies fixed on the electrode surface is detected by electrochemical impedance spectroscopy and evaluated using singular value decomposition (SVD). The key finding of this work is that the change in the electrode capacitance is found to be quantitative with respect to the concentration of MTX. Moreover a calibration curve constructed using the principal component regression method has a linear range of six orders of magnitude and a detection limit of 1.65 × 10(-10) M.

  8. Prenyl sulfates as alkylating reagents for mercapto amino acids.

    Science.gov (United States)

    Maltsev, Sergey; Sizova, Olga; Utkina, Natalia; Shibaev, Vladimir; Chojnacki, Tadeusz; Jankowski, Wieslaw; Swiezewska, Ewa

    2008-01-01

    A new methodology for prenylation of thiol compounds has been developed. The approach is based on the use of prenyl sulfates as new reagents for S-prenylation of benzenethiol and cysteamine in aqueous systems. The C(10)-prenols geraniol and nerol that differ in the configuration (E or Z, correspondingly) of the alpha-isoprene unit were efficiently O-sulfated in the presence of a pyridine-SO(3') complex. The obtained geranyl and neryl sulfates were tested as alkylating agents. These compounds were chosen to reveal the influence of the alpha-isoprene unit configuration on their alkylation (prenylation) ability. S-Geranyl cysteine was prepared to demonstrate the applicability of this method for prenylation of peptides containing mercapto amino acids.

  9. Safety Assessment of Alkyl Esters as Used in Cosmetics.

    Science.gov (United States)

    Fiume, Monice M; Heldreth, Bart A; Bergfeld, Wilma F; Belsito, Donald V; Hill, Ronald A; Klaassen, Curtis D; Liebler, Daniel C; Marks, James G; Shank, Ronald C; Slaga, Thomas J; Snyder, Paul W; Andersen, F Alan

    2015-09-01

    The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of 237 alkyl esters for use in cosmetics. The alkyl esters included in this assessment have a variety of reported functions in cosmetics, with skin-conditioning agent being the most common function. The Panel reviewed available animal and clinical data in making its determination of safety on these ingredients, and where there were data gaps, similarity in structure, properties, functions, and uses of these ingredients allowed for extrapolation of the available toxicological data to assess the safety of the entire group. The Panel concluded that these ingredients are safe in cosmetic formulations in the present practices of use and concentration when formulated to be nonirritating.

  10. Synthesis and Antioxidant Activity of Alkyl Nitroderivatives of Hydroxytyrosol

    Directory of Open Access Journals (Sweden)

    Elena Gallardo

    2016-05-01

    Full Text Available A series of alkyl nitrohydroxytyrosyl ether derivatives has been synthesized from free hydroxytyrosol (HT, the natural olive oil phenol, in order to increase the assortment of compounds with potential neuroprotective activity in Parkinson’s disease. In this work, the antioxidant activity of these novel compounds has been evaluated using Ferric Reducing Antioxidant Power (FRAP, 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid diammonium salt (ABTS, and Oxygen Radical Scavenging Capacity (ORAC assays compared to that of nitrohydroxytyrosol (NO2HT and free HT. New compounds showed variable antioxidant activity depending on the alkyl side chain length; compounds with short chains (2–4 carbon atoms maintained or even improved the antioxidant activity compared to NO2HT and/or HT, whereas those with longer side chains (6–8 carbon atoms showed lower activity than NO2HT but higher than HT.

  11. Molecular simulation of alkyl monolayers on the Si(111)surface

    Institute of Scientific and Technical Information of China (English)

    YUAN; Shiling; (苑世领); CAI; Zhengting; (蔡政亭); XIAO; Li; (肖莉); XU; Guiying; (徐桂英); LIU; Yongjun; (刘永军)

    2003-01-01

    The structure of twelve-carbon monolayers on the H-terminated Si(111) surface is investigated by molecular simulation method. The best substitution percent on Si(111) surface obtained via molecular mechanics calculation is equal to 50%, and the (8×8) simulated cell can be used to depict the structure of alkyl monolayer on Si surface. After two-dimensional cell containing alkyl chains and four-layer Si(111) crystal at the substitution 50% is constructed, the densely packed and well-ordered monolayer on Si(111) surface can be shown through energy minimization in the suitable-size simulation cell. These simulation results are in good agreement with the experiments. These conclusions show that molecular simulation can provide otherwise inaccessible mesoscopic information at the molecular level, and can be considered as an adjunct to experiments.

  12. Effectiveness of disease-modifying antirheumatic drug co-therapy with methotrexate and leflunomide in rituximab-treated rheumatoid arthritis patients

    DEFF Research Database (Denmark)

    Chatzidionysiou, Katerina; Lie, Elisabeth; Nasonov, Evgeny

    2012-01-01

    OBJECTIVES: To compare the effectiveness and safety of rituximab alone or in combination with either methotrexate or leflunomide.METHODS: 10 European registries submitted anonymised datasets with baseline, 3, 6, 9 and 12-month clinical data from patients who started rituximab.RESULTS: 1195 patients...... were treated with rituximab plus methotrexate, 177 with rituximab plus leflunomide and 505 with rituximab alone. Significantly more patients achieved a European League Against Rheumatism good response at 6 months when treated with rituximab plus leflunomide (29.1%) compared with rituximab plus...... methotrexate (21.1%) and rituximab alone (19.3%; p=0.02 and p=0.01, respectively). Similar results were observed at 12 months. Adverse events occurred in 10.2%, 13.2% and 13.9% of patients on rituximab plus leflunomide, rituximab plus methotrexate and rituximab alone, respectively.CONCLUSIONS: Leflunomide...

  13. Folate Receptor-Targeted Dendrimer-Methotrexate Conjugate for Inflammatory Arthritis.

    Science.gov (United States)

    Qi, Rong; Majoros, Istvan; Misra, Asish C; Koch, Alisa E; Campbell, Phil; Marotte, Hubert; Bergin, Ingrid L; Cao, Zhengyi; Goonewardena, Sascha; Morry, Jingga; Zhang, Shuai; Beer, Michael; Makidon, Paul; Kotlyar, Alina; Thomas, Thommey P; Baker, James R

    2015-08-01

    Generation 5 (G5) poly(amidoamide) (PAMAM) dendrimers are synthetic polymers that have been broadly applied as drug delivery carriers. Methotrexate (MTX), an anti-folate metabolite, has been successfully used as an anti-inflammatory drug to treat rheumatoid arthritis (RA) in the clinic. In this study, we examine the therapeutic efficacy of G5 PAMAM dendrimer methotrexate conjugates (G5-MTX) that also have folic acid (FA) conjugated to the G5-MTX (G5-FA-MTX) to target inflammation-activated folate receptors overexpressing macrophages. These cells are thought to play an important role in the development of RA. With G5 serving as a control, the in vitro binding affinities of G5-FA-MTX and G5-MTX to activated macrophages were assessed in RAW264.7, NR8383 and primary rat peritoneal macrophages. The results indicated that the binding of either conjugate to macrophages was concentration- and temperature-dependent and could be blocked by the presence of 6.25 mM free FA (p < 0.005). The preventive effects of G5-MTX and G5-FA-MTX conjugates on the development of arthritis were explored on an adjuvant-induced inflammatory arthritis model and had similar preventive effects in inflammatory arthritis at a MTX equivalent dose of 4.95 μmol/kg. These studies indicated that when multiples of MTX are conjugated on dendritic polymers, they specifically bind to folate receptor overexpressing macrophages and have comparable anti-inflammatory effects to folate targeted MTX conjugated polymers.

  14. Anti-TNFα agents and methotrexate in spondyloarthritis related uveitis in a Chinese population.

    Science.gov (United States)

    Lian, Fan; Zhou, Jun; Wei, Cui; Wang, Yu; Xu, Hanshi; Liang, Liuqin; Yang, Xiuyan

    2015-11-01

    This study seeks to evaluate the clinical characteristics of spondyloarthritis (SpA)-related uveitis in a cohort from South China and to assess the efficacy and safety of therapies based on TNF blockers. SpA patients with uveitis admitted to a south China hospital were enrolled. Demographic information, clinical characteristics, laboratory findings, intraocular inflammation, visual acuity, macular thickness, and treatments were documented. Of the 1,036 SpA patients reviewed, 182 had uveitis. Ankylosing spondylitis (AS) was the most common subtype. Unilateral uveitis was found in 51 cases (51/182, 28.0%), and unilateral alternating uveitis was found in 75 cases (75/182, 41.2%). Half of the cases were recurrent uveitis (52.2%), and acute onset was common (76.4%). The most serious complication was vision loss (0.5%). No significant difference in disease activity was found between the SpA patients with or without uveitis. Predominant improvements were found in cases treated with all three anti-TNFs (infliximab, adalimumab, and etanercept) and anti-TNFs plus methotrexate (MTX). Monotherapy of methotrexate was not adequate for inducing remission. Monotherapy of etanercept was not as effective as adalimumab and infliximab, mainly in the prevention of recurrence. No significant difference in effectiveness was found among the three anti-TNFs if MTX was added. Etanercept plus MTX were well tolerated. Infliximab and adalimumab were associated with more tuberculosis and/or hepatitis flares. Uveitis is common in SpA patients. Severe complications may develop in prolonged and intractable cases. Treatments based on anti-TNFs had good clinical response, and better safety documentation were observed in etanercept plus MTX compared to the other two anti-TNF monoclonal antibodies plus MTX.

  15. USE OF SUBCUTANEOUS METHOTREXATE FOR THE TREATMENT OF PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: THE REMARCA TRIAL

    Directory of Open Access Journals (Sweden)

    D. E. Karateev

    2016-01-01

    Full Text Available The early administration of methotrexate (MTX and the use of its high (by the rheumatology practice standards doses contribute to the enhanced efficiency of therapy and the reduced severity of rheumatoid arthritis (RA. One of the important merits of MTX in the treatment of RA is the possibility of adjusting its dose and choosing its (oral or subcutaneous administration routes, which makes it possible to individualize treatment. Particular emphasis has been recently placed just on a subcutaneous MTX formulation that creates prerequisites for substantially improving the efficiency of RA therapy. The paper gives the data of the REMARCA (Russian investigation of methotrexate and biologicals for early active arthritis trial assessing the results of RA treatment in the use of the subcutaneous MTX dosage form as a first-line drug and in the elaboration of management tactics for this disease.Subjects and methods. The investigation included 191 patients (34 men and 157 women with active RA; of whom 51.8% had very early RA (< 6 months' disease duration. 115 patients with RA completed a 24-month follow-up period; and their data were analyzed in more detail.Results and discussion. The findings may substantiate treatment policy based on the prescription of subcutaneous MTX (without previously administering its oral formulation in patients with early RA and high disease activity, starting the drug at 15 mg/week and rapidly escalating with the highest tolerable doses during 4-8 weeks, which allows remission (or low disease activity in the majority of patients without using glucocorticoids and biological agents.

  16. Short time administration of antirheumatic drugs - Methotrexate as a strong inhibitor of osteoblast's proliferation in vitro

    Directory of Open Access Journals (Sweden)

    Annussek Tobias

    2012-09-01

    Full Text Available Abstract Introduction Due to increasing use of disease modifying antirheumatic drugs (DMARDs as first line therapy in rheumatic diseases, dental and maxillofacial practitioner should be aware of drug related adverse events. Especially effects on bone-metabolism and its cells are discussed controversially. Therefore we investigate the in vitro effect of short time administration of low dose methotrexate (MTX on osteoblasts as essential part of bone remodelling cells. Methods Primary bovine osteoblasts (OBs were incubated with various concentrations of MTX, related to tissue concentrations, over a period of fourteen days by using a previously established standard protocol. The effect on cell proliferation as well as mitochondrial activity was assessed by using 3-(4, 5-dimethylthiazol-2-yl 2, 5-diphenyltetrazolium bromide (MTT assay, imaging and counting of living cells. Additionally, immunostaining of extracellular matrix proteins was used to survey osteogenic differentiation. Results All methods indicate a strong inhibition of osteoblast`s proliferation by short time administration of low dose MTX within therapeutically relevant concentrations of 1 to 1000nM, without affecting cell differentiation of middle-stage differentiated OBs in general. More over a significant decrease of cell numbers and mitochondrial activity was found at these MTX concentrations. The most sensitive method seems to be the MTT-assay. MTX-concentration of 0,01nM and concentrations below had no inhibitory effects anymore. Conclusion Even low dose methotrexate acts as a potent inhibitor of osteoblast’s proliferation and mitochondrial metabolism in vitro, without affecting main differentiation of pre-differentiated osteoblasts. These results suggest possible negative effects of DMARDs concerning bone healing and for example osseointegration of dental implants. Especially the specifics of the jaw bone with its high vascularisation and physiological high tissue metabolism

  17. Safety of methotrexate in rheumatoid arthritis: a retrospective cohort study in clinical practice

    Directory of Open Access Journals (Sweden)

    G. Mennillo

    2011-09-01

    Full Text Available Objective. To evaluate the treatment duration with MTX monotherapy or in association with DMARDs or anti TNFa inhibitors and the incidence and typology of adverse events (AE occurred in rheumatoid arthritis (RA patients. Methods. A retrospective large cohort study of RA outpatients, consecutively seen from January 2000 to June 2005 was performed. Study group were RA patients classified according to the 1984 ACR criteria for the classification of rheumatoid arthritis. The patients were divided in 3 groups according to the treatment regimen: MTX monotherapy, MTX in combination with DMARD or with anti TNFa agents. We analyzed 348 therapeutic cycles, 177 of whom using MTX monotherapy. Results. The 224 RA patients accumulated 800 person-years of follow up. Follow up for each of the groups was: MTX monotherapy 479.4 person-years, MTX in combination with DMARDs 244.5, or with anti TNFa inhibitors, 75.7 person- years. From the Kaplan-Meier analysis, the probability of patients remaining on treatment 5 years was 58.5 after starting MTX. The incidence of any AE was 8.87 per 100 person-years. From all, 69 (97.2% AE were no severe. Among those, more frequently were observed at gastrointestinal tract (31%, liver (19.7%, skin (15.5%. Incidence of severe AE (lung adenocarcinoma, 1 case; pancreatitis, 1 case was 0.25 per 100 person-years, occurring in patients taking MTX monotherapy or MTX in combination with DMARDs, respectively. Conclusions. These data confirm that methotrexate is well tolerated in clinical practice in the medium-long term. Nevertheless, the occurrence of severe AE require an accurate vigilance for methotrexate toxicity.

  18. Isolation of a Cyclic (Alkyl)(amino)germylene.

    Science.gov (United States)

    Wang, Liliang; Lim, Yi Shan; Li, Yongxin; Ganguly, Rakesh; Kinjo, Rei

    2016-07-29

    A 1,4-addition of a dichlorogermylene dioxane complex with α,β-unsaturated imine 1 gave a dichlorogermane derivative 2 bearing a GeC₃N five-membered ring skeleton. By reducing 2 with KC₈, cyclic (alkyl)(amino)germylene 3 was synthesized and fully characterized. Germylene 3 readily reacted with TEMPO, N₂O and S₈, producing the 1:2 adduct 4, the oxo-bridged dimer 5 and the sulfido-bridged dimer 6, respectively.

  19. Neurobehavioral teratogenicity of perfluorinated alkyls in an avian model

    OpenAIRE

    Pinkas, Adi; Slotkin, Theodore A.; Brick-Turin, Yael; Van der Zee, Eddy A.; Yanai, Joseph

    2010-01-01

    Perfluorinated alkyls are widely-used agents that accumulate in ecosystems and organisms because of their slow rate of degradation. There is increasing concern that these agents may be developmental neurotoxicants and the present study was designed to develop an avian model for the neurobehavioral teratogenicity of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Fertilized chicken eggs were injected with 5 or 10 mg/kg of either compound on incubation day 0. On the day of h...

  20. New potential of the reductive alkylation of amines

    Science.gov (United States)

    Gusak, K. N.; Ignatovich, Zh V.; Koroleva, E. V.

    2015-03-01

    Available data on the reductive alkylation of amines with carbonyl compounds — a key method for the preparation of secondary and tertiary amines — are described systematically. The review provides information on the relevant reducing agents and catalysts and on the use of chiral catalysts in stereo- and enantiocontrolled reactions of amine synthesis. The effect of the reactant and catalyst structures on the reaction rates and chemo- and stereo(enantio)selectivity is considered. The bibliography includes 156 references.

  1. Alkylation of Benzene with Propylene Catalyzed by Ionic Liquids

    Institute of Scientific and Technical Information of China (English)

    Sun Xuewen; Zhao Suoqi

    2006-01-01

    The alkylation of benzene with propylene catalyzed by ionic liquids to obtain cumene was investigated. Propylene conversion and cumene selectivity under mild reaction conditions were improved greatly after the ionic liquid was modified with HCl. Under the conditions of 20 oC, 0.1MPa, 5 min of reaction time, and a molar ratio of benzene to propylene of 10:1, propylene conversion increased from 83.6% to 100%, and cumene selectivity increased from 90.86% to 98.47%. In addition, it was found that the reaction could be carried out in two different stages so as to obtain a better result. At the first stage, the key reaction was alkylation and a higher propylene conversion was obtained at a lower temperature;At the second stage, the key reaction was transalkylation and a higher temperature was used to improve cumene selectivity. The reaction temperature, pressure and the amount of catalyst used in this work were lower than those used in traditional alkylation processes.

  2. Chemotherapy-induced pulmonary hypertension: role of alkylating agents.

    Science.gov (United States)

    Ranchoux, Benoît; Günther, Sven; Quarck, Rozenn; Chaumais, Marie-Camille; Dorfmüller, Peter; Antigny, Fabrice; Dumas, Sébastien J; Raymond, Nicolas; Lau, Edmund; Savale, Laurent; Jaïs, Xavier; Sitbon, Olivier; Simonneau, Gérald; Stenmark, Kurt; Cohen-Kaminsky, Sylvia; Humbert, Marc; Montani, David; Perros, Frédéric

    2015-02-01

    Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.

  3. Synthesis and Antioxidant Activity of Hydroxytyrosol Alkyl-Carbonate Derivatives.

    Science.gov (United States)

    Fernandez-Pastor, Ignacio; Fernandez-Hernandez, Antonia; Rivas, Francisco; Martinez, Antonio; Garcia-Granados, Andres; Parra, Andres

    2016-07-22

    Three procedures have been investigated for the isolation of tyrosol (1) and hydroxytyrosol (2) from a phenolic extract obtained from the solid residue of olive milling. These three methods, which facilitated the recovery of these phenols, were chemical or enzymatic acetylation, benzylation, and carbomethoxylation, and subsequent carbonylation or acetonation reactions. Several new lipophilic alkyl-carbonate derivatives of hydroxytyrosol have been synthesized, coupling the primary hydroxy group of this phenol, through a carbonate linker, using alcohols with different chain lengths. The antioxidant properties of these lipophilic derivatives have been evaluated by different methods and compared with free hydroxytyrosol (2) and also with the well-known antioxidants BHT and α-tocopherol. Three methods were used for the determination of this antioxidant activity: FRAP and ABTS assays, to test the antioxidant power in hydrophilic media, and the Rancimat test, to evaluate the antioxidant capacity in a lipophilic matrix. These new alkyl-carbonate derivatives of hydroxytyrosol enhanced the antioxidant activity of this natural phenol, with their antioxidant properties also being higher than those of the commercial antioxidants BHT and α-tocopherol. There was no clear influence of the side-chain length on the antioxidant properties of the alkyl-carbonate derivatives of 2, although the best results were achieved mainly by the compounds with a longer chain on the primary hydroxy group of this natural phenolic substance.

  4. Polycyclic aromatic acids are primary metabolites of alkyl-PAHs - a case study with Nereis diversicolor

    DEFF Research Database (Denmark)

    Malmquist, Linus Mattias Valdemar; Selck, Henriette; Jørgensen, Kåre Bredeli;

    2015-01-01

    Although concentrations of alkylated polycyclic aromatic hydrocarbons (alkyl-PAHs) in oil-contaminated sediments are higher than those of unsubstituted PAHs, only little attention has been given to metabolism and ecotoxicity of alkyl-PAHs. In this study we demonstrated that metabolism of alkyl-PA...... that carboxylic acid metabolites of alkyl-PAHs have the potential of constituting a new class of contaminants in marine waters that needs attention in relation to ecological risk assessments....

  5. Low-Dose Whole Brain Radiotherapy with Tumor Bed Boost after Methotrexate-Based Chemotherapy for Primary Central Nervous System Lymphoma

    OpenAIRE

    Kim, Byoung Hyuck; Kim, Il Han; Park, Sung-Hye; Park, Chul Kee; Jung, Hee Won; Kim, Tae Min; Lee, Se-Hoon; Heo, Dae Seog

    2014-01-01

    Purpose The purpose of this study is to evaluate the outcome of low-dose whole brain radiotherapy (WBRT) with tumor bed boost after methotrexate-based chemotherapy in the management of primary central nervous system lymphoma (PCNSL). Materials and Methods We retrospectively analyzed 64 patients with pathologically proven PCNSL between 2000 and 2011. Methotrexate-based chemotherapy with a median of five cycles was followed by radiotherapy to the whole brain and to the initial tumor bed. The me...

  6. UV absorption spectra, kinetics and mechanism for alkyl and alkyl peroxy radicals originating from t-butyl alcohol

    DEFF Research Database (Denmark)

    Langer, S.; Ljungström, E.; Sehested, J.

    1994-01-01

    Alkyl and alkyl peroxy radicals from 1-butyl alcohol (TBA), HOC (CH3)2CH2. and HOC(CH3)2CH2O2. have been studied in the ps phase at 298 K. Two techniques were used: pulse radiolysis UV absorption to measure the spectra and kinetics, and long path-length Fourier transform infrared spectroscopy (FTIR......) to identify and quantify the reaction products. Absorption cross sections were quantified over the wavelength range 220-320 nm. At 240 nm, sigma(HOC(CH3)2CH2) = (2.4 +/- 0.3) x 10(-18) and sigma(HOC(CH3)2CH2O2) = (3.4 +/- 0.5) X 10(-18) cm2 molecule-1 have been obtained. Observed rate constants for the self...

  7. Molecularly imprinted solid-phase extraction combined with electrochemical oxidation fluorimetry for the determination of methotrexate in human serum and urine.

    Science.gov (United States)

    Chen, Suming; Zhang, Zhujun

    2008-06-01

    The method of synthesis and evaluation of molecularly imprinted polymers was reported. As a selective solid-phase extraction sorbent, the polymers were coupled with electrochemical fluorimetry detection for the efficient determination of methotrexate in serum and urine. Methotrexate was preconcentrated in the molecularly imprinted solid-phase extraction microcolumn packed with molecularly imprinted polymers, and then eluted. The eluate was detected by fluorescence spectrophotometer after electrochemical oxidation. The conditions of preconcentration, elution, electrochemical oxidation and determination were carefully studied. Under the selected experimental conditions, the calibration graph of the fluorescence intensity versus methotrexate concentration was linear from 4x10(-9) g mL(-1) to 5x10(-7) g mL(-1), and the detection limit was 8.2x10(-10) g mL(-1) (3sigma). The relative standard deviation was 3.92% (n=7) for 1x10(-7) g mL(-1) methotrexate. The experiments showed that the selectivity and sensitivity of fluorimetry could be greatly improved by the proposed method. This method has been successfully applied to the determination of methotrexate. At the same time, the binding characteristics of the polymers to the methotrexate were evaluated by batch and dynamic methods.

  8. Optimization of propafenone analogues as antimalarial leads.

    Science.gov (United States)

    Lowes, David J; Guiguemde, W Armand; Connelly, Michele C; Zhu, Fangyi; Sigal, Martina S; Clark, Julie A; Lemoff, Andrew S; Derisi, Joseph L; Wilson, Emily B; Guy, R Kiplin

    2011-11-10

    Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug's potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogues was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multidrug resistant K1 strain of P. falciparum compared to the 3D7 strain.

  9. Spectroscopic study of solar twins and analogues

    CERN Document Server

    Datson, Juliet; Portinari, Laura

    2014-01-01

    Context. Many large stellar surveys have been and are still being carried out, providing huge amounts of data, for which stellar physical parameters will be derived. Solar twins and analogues provide a means to test the calibration of these stellar catalogues because the Sun is the best-studied star and provides precise fundamental parameters. Solar twins should be centred on the solar values. Aims. This spectroscopic study of solar analogues selected from the Geneva-Copenhagen Survey (GCS) at a resolution of 48,000 provides effective temperatures and metallicities for these stars. We test whether our spectroscopic parameters, as well as the previous photometric calibrations, are properly centred on the Sun. In addition, we search for more solar twins in our sample. Methods. The methods used in this work are based on literature methods for solar twin searches and on methods we developed in previous work to distinguish the metallicity-temperature degeneracies in the differential comparison of spectra of solar ...

  10. Holographic Fluids with Vorticity and Analogue Gravity

    CERN Document Server

    Leigh, Robert G; Petropoulos, P Marios

    2012-01-01

    We study holographic three-dimensional fluids with vorticity in local equilibrium and discuss their relevance to analogue gravity systems. The Fefferman-Graham expansion leads to the fluid's description in terms of a comoving and rotating Papapetrou-Randers frame. A suitable Lorentz transformation brings the fluid to the non-inertial Zermelo frame, which clarifies its interpretation as moving media for light/sound propagation. We apply our general results to the Lorentzian Kerr-AdS_4 and Taub-NUT-AdS_4 geometries that describe fluids in cyclonic and vortex flows respectively. In the latter case we associate the appearance of closed timelike curves to analogue optical horizons. In addition, we derive the classical rotational Hall viscosity of three-dimensional fluids with vorticity. Our formula remarkably resembles the corresponding result in magnetized plasmas.

  11. Confirmation via Analogue Simulation: A Bayesian Analysis

    CERN Document Server

    Dardashti, Radin; Thebault, Karim P Y; Winsberg, Eric

    2016-01-01

    Analogue simulation is a novel mode of scientific inference found increasingly within modern physics, and yet all but neglected in the philosophical literature. Experiments conducted upon a table-top 'source system' are taken to provide insight into features of an inaccessible 'target system', based upon a syntactic isomorphism between the relevant modelling frameworks. An important example is the use of acoustic 'dumb hole' systems to simulate gravitational black holes. In a recent paper it was argued that there exists circumstances in which confirmation via analogue simulation can obtain; in particular when the robustness of the isomorphism is established via universality arguments. The current paper supports these claims via an analysis in terms of Bayesian confirmation theory.

  12. {sup 18}F-Labelled metomidate analogues as adrenocortical imaging agents

    Energy Technology Data Exchange (ETDEWEB)

    Erlandsson, Maria; Karimi, Farhad [Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, S-751 23 Uppsala (Sweden); Lindhe, Orjan [Uppsala Imanet, GE Healthcare, Box 967, S-751 09 Uppsala (Sweden); Langstroem, Bengt [Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, S-751 23 Uppsala (Sweden)], E-mail: bengt.langstrom@biorg.uu.se

    2009-05-15

    Introduction: Two- and one-step syntheses of {sup 18}F-labelled analogues of metomidate, such as 2-[{sup 18}F]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (1), 2-[{sup 18}F]fluoroethyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate (2), 2-[{sup 18}F]fluoroethyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (3), 3-[{sup 18}F]fluoropropyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (4) and 3-[{sup 18}F]fluoropropyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (5) are presented. Methods: Analogues 1-5 were prepared by a two-step reaction sequence that started with the synthesis of either 2-[{sup 18}F]fluoroethyl 4-methylbenzenesulfonate or 3-[{sup 18}F]fluoropropyl 4-methylbenzenesulfonate. These were used as {sup 18}F-alkylating agents in the second step, in which they reacted with the ammonium salt of a 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. One-step-labelling syntheses of 1, 2 and 5 were also explored. Analogues 1-4 were biologically validated by frozen-section autoradiography and organ distribution. Metabolite analysis was performed for 2 and 3. Results: The radiochemical yield of the two-step synthesis was in the range of 10-29% and that of the one-step synthesis was 25-37%. Using microwave irradiation in the one-step synthesis of 1 and 2 increased the radiochemical yield to 46{+-}3% and 79{+-}30%, respectively. Conclusion: Both the frozen-section autoradiography and organ distribution results indicated that analogue 2 has a potential as an adrenocortical imaging agent, having the highest degree of specific adrenal binding and best ratio of adrenal to organ uptake among the compounds studied.

  13. Changes in plasma IL-6, plasma VEGF and serum YKL-40 during Treatment with Etanercept and Methotrexate or Etanercept alone in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy

    DEFF Research Database (Denmark)

    Knudsen, Lene Surland; Hetland, Merete Lund; Johansen, Julia Sidenius

    2009-01-01

    Changes in plasma IL-6, plasma VEGF and serum YKL-40 were determined in rheumatoid arthritis (RA) patients during treatment with etanercept alone or in combination with methotrexate. Twenty-five patients with active RA (DAS28 >/= 3.2) were randomized to receive etanercept (25 mg sc. biweekly) plus...... methotrexate (n = 12) or etanercept alone (n = 13). Plasma IL-6, plasma VEGF and serum YKL-40 were determined by ELISA. The 3 biomarkers and DAS28 scores were evaluated at baseline and after 4, 8, 12 and 16 weeks of treatment. At inclusion all patients had significantly (p plasma IL-6, plasma...... VEGF and serum YKL-40 compared to healthy subjects. Eighteen patients responded to treatment (pooled data from both treatment groups), and they had significant (p plasma IL-6, plasma VEGF, serum YKL-40, ESR and DAS28 after 4 weeks of treatment and throughout the study...

  14. A novel dried blood spot-LCMS method for the quantification of methotrexate polyglutamates as a potential marker for methotrexate use in children.

    Directory of Open Access Journals (Sweden)

    Ahmed F Hawwa

    Full Text Available OBJECTIVE: Development and validation of a selective and sensitive LCMS method for the determination of methotrexate polyglutamates in dried blood spots (DBS. METHODS: DBS samples [spiked or patient samples] were prepared by applying blood to Guthrie cards which was then dried at room temperature. The method utilised 6-mm disks punched from the DBS samples (equivalent to approximately 12 µl of whole blood. The simple treatment procedure was based on protein precipitation using perchloric acid followed by solid phase extraction using MAX cartridges. The extracted sample was chromatographed using a reversed phase system involving an Atlantis T3-C18 column (3 µm, 2.1 × 150 mm preceded by Atlantis guard column of matching chemistry. Analytes were subjected to LCMS analysis using positive electrospray ionization. KEY RESULTS: The method was linear over the range 5-400 nmol/L. The limits of detection and quantification were 1.6 and 5 nmol/L for individual polyglutamates and 1.5 and 4.5 nmol/L for total polyglutamates, respectively. The method has been applied successfully to the determination of DBS finger-prick samples from 47 paediatric patients and results confirmed with concentrations measured in matched RBC samples using conventional HPLC-UV technique. CONCLUSIONS AND CLINICAL RELEVANCE: The methodology has a potential for application in a range of clinical studies (e.g. pharmacokinetic evaluations or medication adherence assessment since it is minimally invasive and easy to perform, potentially allowing parents to take blood samples at home. The feasibility of using DBS sampling can be of major value for future clinical trials or clinical care in paediatric rheumatology.

  15. Association of erythrocyte methotrexate-polyglutamate levels with the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a 76-week prospective study

    Science.gov (United States)

    Kaneko, Yuko; Okano, Yutaka; Taguchi, Hiroaki; Oshima, Hisaji; Izumi, Keisuke; Yamaoka, Kunihiro; Takeuchi, Tsutomu

    2017-01-01

    Objective To assess the utility of erythrocyte methotrexate-polyglutamate (MTX-PG) concentrations in determining the safety and efficacy of MTX in patients with rheumatoid arthritis (RA). Methods 79 MTX-naïve patients with RA were enrolled in this prospective 76-week cohort study. MTX was initiated, and a predefined dose-escalation protocol was followed. Erythrocyte MTX-PG concentrations were measured using liquid chromatography. The associations of MTX-PG concentrations with disease activity and adverse events were analysed. Results Dose escalation of MTX resulted in increased MTX-PG concentrations and a decrease in the mean Disease Activity Score in 28 joints (DAS28). A significant association was observed between total MTX-PG concentrations and ΔDAS28 at week 12 (β=−0.013, p=0.003) and at week 24 (β=−0.014, p=0.003). The maximum MTX-PG levels were significantly higher in patients presenting with elevated transaminases (≥100 IU/L) than in those without (146 vs 106 nmol/L, p=0.009). Receiver operating characteristic curve analysis revealed that a total MTX-PG concentrations of 83 nmol/L at week 12 was the threshold for a DAS28 improvement of ≥1.2 at week 24, and 105 nmol/L was the threshold for transaminases of ≥50 IU/L and 131 nmol/L for transaminases of ≥100 IU/L. MTX-PG concentrations were strongly influenced by body mass index and a serum albumin level. Conclusions MTX-PG concentrations are a useful biomarker in MTX therapy, in terms of efficacy and safety.

  16. Polyamine analogues targeting epigenetic gene regulation.

    Science.gov (United States)

    Huang, Yi; Marton, Laurence J; Woster, Patrick M; Casero, Robert A

    2009-11-04

    Over the past three decades the metabolism and functions of the polyamines have been actively pursued as targets for antineoplastic therapy. Interactions between cationic polyamines and negatively charged nucleic acids play a pivotal role in DNA stabilization and RNA processing that may affect gene expression, translation and protein activity. Our growing understanding of the unique roles that the polyamines play in chromatin regulation, and the discovery of novel proteins homologous with specific regulatory enzymes in polyamine metabolism, have led to our interest in exploring chromatin remodelling enzymes as potential therapeutic targets for specific polyamine analogues. One of our initial efforts focused on utilizing the strong affinity that the polyamines have for chromatin to create a backbone structure, which could be combined with active-site-directed inhibitor moieties of HDACs (histone deacetylases). Specific PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) polyamine analogues have demonstrated potent inhibition of the HDACs, re-expression of p21 and significant inhibition of tumour growth. A second means of targeting the chromatin-remodelling enzymes with polyamine analogues was facilitated by the recent identification of flavin-dependent LSD1 (lysine-specific demethylase 1). The existence of this enzyme demonstrated that histone lysine methylation is a dynamic process similar to other histone post-translational modifications. LSD1 specifically catalyses demethylation of mono- and di-methyl Lys4 of histone 3, key positive chromatin marks associated with transcriptional activation. Structural and catalytic similarities between LSD1 and polyamine oxidases facilitated the identification of biguanide, bisguanidine and oligoamine polyamine analogues that are potent inhibitors of LSD1. Cellular inhibition of LSD1 by these unique compounds led to the re-activation of multiple epigenetically silenced genes important in tumorigenesis. The use of

  17. Benchmarking analogue models of brittle thrust wedges

    Science.gov (United States)

    Schreurs, Guido; Buiter, Susanne J. H.; Boutelier, Jennifer; Burberry, Caroline; Callot, Jean-Paul; Cavozzi, Cristian; Cerca, Mariano; Chen, Jian-Hong; Cristallini, Ernesto; Cruden, Alexander R.; Cruz, Leonardo; Daniel, Jean-Marc; Da Poian, Gabriela; Garcia, Victor H.; Gomes, Caroline J. S.; Grall, Céline; Guillot, Yannick; Guzmán, Cecilia; Hidayah, Triyani Nur; Hilley, George; Klinkmüller, Matthias; Koyi, Hemin A.; Lu, Chia-Yu; Maillot, Bertrand; Meriaux, Catherine; Nilfouroushan, Faramarz; Pan, Chang-Chih; Pillot, Daniel; Portillo, Rodrigo; Rosenau, Matthias; Schellart, Wouter P.; Schlische, Roy W.; Take, Andy; Vendeville, Bruno; Vergnaud, Marine; Vettori, Matteo; Wang, Shih-Hsien; Withjack, Martha O.; Yagupsky, Daniel; Yamada, Yasuhiro

    2016-11-01

    We performed a quantitative comparison of brittle thrust wedge experiments to evaluate the variability among analogue models and to appraise the reproducibility and limits of model interpretation. Fifteen analogue modeling laboratories participated in this benchmark initiative. Each laboratory received a shipment of the same type of quartz and corundum sand and all laboratories adhered to a stringent model building protocol and used the same type of foil to cover base and sidewalls of the sandbox. Sieve structure, sifting height, filling rate, and details on off-scraping of excess sand followed prescribed procedures. Our analogue benchmark shows that even for simple plane-strain experiments with prescribed stringent model construction techniques, quantitative model results show variability, most notably for surface slope, thrust spacing and number of forward and backthrusts. One of the sources of the variability in model results is related to slight variations in how sand is deposited in the sandbox. Small changes in sifting height, sifting rate, and scraping will result in slightly heterogeneous material bulk densities, which will affect the mechanical properties of the sand, and will result in lateral and vertical differences in peak and boundary friction angles, as well as cohesion values once the model is constructed. Initial variations in basal friction are inferred to play the most important role in causing model variability. Our comparison shows that the human factor plays a decisive role, and even when one modeler repeats the same experiment, quantitative model results still show variability. Our observations highlight the limits of up-scaling quantitative analogue model results to nature or for making comparisons with numerical models. The frictional behavior of sand is highly sensitive to small variations in material state or experimental set-up, and hence, it will remain difficult to scale quantitative results such as number of thrusts, thrust spacing

  18. Electromagnetic wave analogue of electronic diode

    OpenAIRE

    Shadrivov, Ilya V.; Powell, David A.; Kivshar, Yuri S.; Fedotov, Vassili A.; Zheludev, Nikolay I.

    2010-01-01

    An electronic diode is a nonlinear semiconductor circuit component that allows conduction of electrical current in one direction only. A component with similar functionality for electromagnetic waves, an electromagnetic isolator, is based on the Faraday effect of the polarization state rotation and is also a key component of optical and microwave systems. Here we demonstrate a chiral electromagnetic diode, which is a direct analogue of an electronic diode: its functionality is underpinned by ...

  19. Synthesis of constrained analogues of tryptophan

    Directory of Open Access Journals (Sweden)

    Elisabetta Rossi

    2015-10-01

    Full Text Available A Lewis acid-catalysed diastereoselective [4 + 2] cycloaddition of vinylindoles and methyl 2-acetamidoacrylate, leading to methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate derivatives, is described. Treatment of the obtained cycloadducts under hydrolytic conditions results in the preparation of a small library of compounds bearing the free amino acid function at C-3 and pertaining to the class of constrained tryptophan analogues.

  20. The Brookhaven electron analogue, 1953--1957

    Energy Technology Data Exchange (ETDEWEB)

    Plotkin, M.

    1991-12-18

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary.

  1. Thymidine analogues for tracking DNA synthesis.

    Science.gov (United States)

    Cavanagh, Brenton L; Walker, Tom; Norazit, Anwar; Meedeniya, Adrian C B

    2011-09-15

    Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into replicating DNA, effectively tagging dividing cells allowing their characterisation. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU) and related halogenated analogues, detected using antibodies. Their detection required the denaturation of DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 reviewed biomedical studies. A recent breakthrough in "tagging DNA synthesis" is the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU). The alkyne group in EdU is readily detected using a fluorescent azide probe and copper catalysis using 'Huisgen's reaction' (1,3-dipolar cycloaddition or 'click chemistry'). This rapid, two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in more experimental assays than previously possible with other "unnatural bases". These include physiological, anatomical and molecular biological experimentation in multiple fields including, stem cell research, cancer biology, and parasitology. The full potential of EdU and related molecules in biomedical research remains to be explored.

  2. Thymidine Analogues for Tracking DNA Synthesis

    Directory of Open Access Journals (Sweden)

    Brenton L. Cavanagh

    2011-09-01

    Full Text Available Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into replicating DNA, effectively tagging dividing cells allowing their characterisation. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU and related halogenated analogues, detected using antibodies. Their detection required the denaturation of DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 reviewed biomedical studies. A recent breakthrough in “tagging DNA synthesis” is the thymidine analogue 5-ethynyl-2′-deoxyuridine (EdU. The alkyne group in EdU is readily detected using a fluorescent azide probe and copper catalysis using ‘Huisgen’s reaction’ (1,3-dipolar cycloaddition or ‘click chemistry’. This rapid, two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in more experimental assays than previously possible with other “unnatural bases”. These include physiological, anatomical and molecular biological experimentation in multiple fields including, stem cell research, cancer biology, and parasitology. The full potential of EdU and related molecules in biomedical research remains to be explored.

  3. A Fatal Case of Acute Myeloid Leukaemia-Methotrexate Related or Primary Autoimmune Disease Related: A Rare Case Report.

    Science.gov (United States)

    Agarwal, Saurabh; Kaeley, Nidhi; Gupta, Priyanka; Gupta, Vibha; Bhatia, Rohan

    2016-03-01

    Methotrexate is being used for many years in the treatment of chronic medical disorders e.g. rheumatoid arthritis since 1951. It has been associated with various systemic toxicities and complications including bone marrow suppression and lymphomas. The development of leukaemia in a patient of chronic rheumatoid arthritis is either related with the primary disease or due to the drugs which are used in the treatment like cyclophosphamide. In our present case, a 70-year-old female who was a known case of Rheumatoid Arthritis (RA) and was on methotrexate once a week orally for the past 20 years presented with complaints of loss of appetite, loss of weight and anaemia since 2 months. After thorough examination and investigation, she was diagnosed with acute myeloid leukaemia (AML-M4) with bilateral chest consolidation.

  4. Actuarial risk of isolated CNS involvement in Ewing's sarcoma following prophylactic cranial irradiation and intrathecal methotrexate

    Energy Technology Data Exchange (ETDEWEB)

    Trigg, M.E.; Makuch, R.; Glaubiger, D.

    1985-04-01

    Records of 154 patients with Ewing's sarcoma treated at the National Cancer Institute were reviewed to assess the incidence and risk of developing isolated central nervous system (CNS) Ewing's sarcoma. Sixty-two of the 154 patients had received CNS irradiation and intrathecal (i.t.) methotrexate as part of their initial therapy to prevent the occurrence of isolated CNS Ewing's sarcoma. The risk of developing isolate CNS Ewing's sarcoma was greatest within the first two years after diagnosis and was approximately 10%. The overall risk of CNS recurrence in the group of patients receiving DNS treatment was similar to the group receiving no therapy directed to the CNS. The occurrence of isolated CNS involvement was not prevented by the use of CNS irradiation and i.t. methotrexate. Because of a lack of efficacy to the CNS irradiation regimen, current treatment regimens do not include therapy directed to CNS.

  5. Topical coal tar alone and in combination with oral methotrexate in management of psoriasis : a retrospective analysis

    Directory of Open Access Journals (Sweden)

    Prasad PVS

    1997-01-01

    Full Text Available Thirty five patients admitted with psoriasis were analysed. 16 patients received 20% crude coal tar and 19 patients received 20% crude coal tar along with methotrexate in a weekly oral schedule (15mg/wk. After 4 weeks of therapy there was total clearence in 52.6% of the patients with combination therapy, whereas only 12.5% of the patients with conventional therapy achieved this.

  6. Palonosetron for the prevention of nausea and vomiting in children with acute lymphoblastic leukemia treated with high dose methotrexate

    DEFF Research Database (Denmark)

    Nadaraja, Sambavy; Mamoudou, Aissata Diop; Thomassen, Harald;

    2012-01-01

    High dose methotrexate (HD-MTX), used in the treatment of children with acute lymphoblastic leukemia (ALL), is moderately emetogenic. First generation 5-HT(3) receptor antagonists are effective prophylactic agents but require multiple administrations. Palonosetron has a half life of 36-42 hours a...... of palonosetron (5 µg/kg) for the prevention of chemotherapy-induced nausea and vomiting in children 18 years of age with ALL treated with HD-MTX, 5 g/m(2)....

  7. St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Shih-Ying [Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan (China); Juang, Shin-Hun [Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan (China); Department of Medical Research, China Medical University Hospital, Taichung, Taiwan (China); Tsai, Shang-Yuan; Chao, Pei-Dawn Lee [School of Pharmacy, China Medical University, Taichung, Taiwan (China); Hou, Yu-Chi, E-mail: hou5133@gmail.com [School of Pharmacy, China Medical University, Taichung, Taiwan (China); Department of Medical Research, China Medical University Hospital, Taichung, Taiwan (China)

    2012-08-15

    St. John's wort (SJW, Hypericum perforatum) is one of the popular nutraceuticals for treating depression. Methotrexate (MTX) is an immunosuppressant with narrow therapeutic window. This study investigated the effect of SJW on MTX pharmacokinetics in rats. Rats were orally given MTX alone and coadministered with 300 and 150 mg/kg of SJW, and 25 mg/kg of diclofenac, respectively. Blood was withdrawn at specific time points and serum MTX concentrations were assayed by a specific monoclonal fluorescence polarization immunoassay method. The results showed that 300 mg/kg of SJW significantly increased the AUC{sub 0−t} and C{sub max} of MTX by 163% and 60%, respectively, and 150 mg/kg of SJW significantly increased the AUC{sub 0−t} of MTX by 55%. In addition, diclofenac enhanced the C{sub max} of MTX by 110%. The mortality of rats treated with SJW was higher than that of controls. In conclusion, coadministration of SJW significantly increased the systemic exposure and toxicity of MTX. The combined use of MTX with SJW would need to be with caution. -- Highlights: ► St. John's wort significantly increased the AUC{sub 0−t} and C{sub max} of methotrexate. ► Coadministration of St. John's wort increased the exposure and toxicity of methotrexate. ► The combined use of methotrexate with St. John's wort will need to be with caution.

  8. The effect of vitamin E and L-carnitine against methotrexate-induced injury in rat testis

    OpenAIRE

    YÜNCÜ, MEHMET; BÜKÜCÜ, NEZAHAT; BAYAT, NURAY; SENCAR, LEMAN; Tarakçioğlu, Mehmet

    2015-01-01

    Background/aim: Methotrexate (MTX), used commonly as an antimetabolite drug in cancer therapy, leads to acute toxic side effects in tissues or organs containing rapidly dividing cells, such as bone marrow, gastrointestinal mucosa, and seminiferous tubules. In this study, we investigated the protective effects of vitamin E and L-carnitine against MTX-induced injury in rat testis. Materials and methods: Rats were divided into 4 groups, including the control group. The study took 17 days and th...

  9. Cerebral venous and sinus thrombosis with cerebrospinal fluid circulation block after the first methotrexate administration by lumbar puncture

    Energy Technology Data Exchange (ETDEWEB)

    Bienfait, H.P. [Gelre Hospital, location Lukas, Apeldoorn, Department of Neurology, Albert Schweitzerlaan 31, PO Box 9014, 7300 DS Apeldoorn (Netherlands); Department of Neuro-Oncology, Daniel den Hoed Kliniek, Academisch Ziekenhuis Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam (Netherlands); Gijtenbeek, J.M.M. [Department of Neuro-Oncology, Daniel den Hoed Kliniek, Academisch Ziekenhuis Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam (Netherlands); Department of Neurology, University Medical Center Nijmegen, St Radboud, Postlaan 4, 6525 GC Nijmegen (Netherlands); Bent, M.J. van [Department of Neuro-Oncology, Daniel den Hoed Kliniek, Academisch Ziekenhuis Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam (Netherlands); Bruin, H.G. de [Department of Radiology, Daniel den Hoed Kliniek, Academisch Ziekenhuis Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam (Netherlands); Voogt, P.J. [Department of Hematology, Daniel den Hoed Kliniek, Academisch Ziekenhuis Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam (Netherlands); Pillay, M. [Department of Nuclear Medicine, Daniel den Hoed Kliniek, Academisch Ziekenhuis Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam (Netherlands)

    2002-11-01

    We report a patient treated for small lymphocytic lymphoma/leukemia with cerebral venous and sinus thrombosis (CVST) after lumbar puncture with intrathecal administration of methotrexate (MTX). He also developed a cerebrospinal fluid flow block. This is the first report of an association between lumbar puncture and intrathecally administered MTX and the development of CVST. Intrathecal treatment in this patient was discontinued and he was successfully treated with high-dose low-molecular-weight heparin subcutaneously. (orig.)

  10. Analogue to Digital and Digital to Analogue Converters (ADCs and DACs): A Review Update

    CERN Document Server

    Pickering, J

    2015-01-01

    This is a review paper updated from that presented for CAS 2004. Essentially, since then, commercial components have continued to extend their performance boundaries but the basic building blocks and the techniques for choosing the best device and implementing it in a design have not changed. Analogue to digital and digital to analogue converters are crucial components in the continued drive to replace analogue circuitry with more controllable and less costly digital processing. This paper discusses the technologies available to perform in the likely measurement and control applications that arise within accelerators. It covers much of the terminology and 'specmanship' together with an application-oriented analysis of the realisable performance of the various types. Finally, some hints and warnings on system integration problems are given.

  11. A facile and convenient method for synthesis of alkyl thiocyanates under homogeneous phase transfer catalyst conditions

    Institute of Scientific and Technical Information of China (English)

    Ali Reza Kiasat; Rashid Badri; Soheil Sayyahi

    2008-01-01

    A simple and environmentally friendly method is described for the efficient conversion of alkyl halide to alkyl thiocyanate using tetrabutylammonium bromide (TBAB) as a phase transfer catalyst.The reactions occur in water and furnish the corresponding alkyl thiocyanate in high yields.No evidence for the formation of isothiocyanates as by-product of the reaction was observed and the products were obtained in pure form without further purification.

  12. Highly enantio- and diastereoselective allylic alkylation of Morita-Baylis-Hillman carbonates with allyl ketones

    KAUST Repository

    Tong, Guanghu

    2013-05-17

    The asymmetric allylic alkylation of Morita-Baylis-Hillman (MBH) carbonates with allyl ketones has been developed. The α-regioselective alkylation adducts, containing a hexa-1,5-diene framework with important synthetic value, were achieved in up to 83% yield, >99% ee, and 50:1 dr by using a commercially available Cinchona alkaloid as the catalyst. From the allylic alkylation adduct, a cyclohexene bearing two adjacent chiral centers was readily prepared. © 2013 American Chemical Society.

  13. A Versatile Approach for the Asymmetric Synthesis of 3-Alkyl-isoindolin-1-ones

    Institute of Scientific and Technical Information of China (English)

    CHEN,Ming-De(陈明德); HE,Ming-Zhu(贺明珠); HUANG,Li-Qiang(黄利强); RUAN, Yuan-Ping( 阮源萍 ); HUANG, Pei-Qiang (黄培强)

    2002-01-01

    A flexxible approach to(R)-3-alkyl-isoindolin-1-ones and (R)-3-aryl-isoindolin-1-ones via a diastereoselective-alkylation is described. Present method is versatile in scope, allowing the easy introduction of various C-3 substituents by Grignard addition to phthalimide derived from (R)-phenylglycinol.3-Alkyl-3-hydroxy-isoindolin-1-ones can also be obtained in the first step of the present method.

  14. In situ synthesized BSA capped gold nanoparticles: Effective carrier of anticancer drug Methotrexate to MCF-7 breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Murawala, Priyanka [Physical and Materials Chemistry Division, National Chemical Laboratory, Pune 411008 (India); Tirmale, Amruta [Physical and Materials Chemistry Division, National Chemical Laboratory, Pune 411008 (India); National Centre for Cell Science, NCCS, Pune 411007 (India); Shiras, Anjali, E-mail: anjalishiras@nccs.res.in [National Centre for Cell Science, NCCS, Pune 411007 (India); Prasad, B.L.V., E-mail: pl.bhagavatula@ncl.res.in [Physical and Materials Chemistry Division, National Chemical Laboratory, Pune 411008 (India)

    2014-01-01

    The proficiency of MTX loaded BSA capped gold nanoparticles (Au-BSA-MTX) in inhibiting the proliferation of breast cancer cells MCF-7 as compared to the free drug Methotrexate (MTX) is demonstrated based on MTT and Ki-67 proliferation assays. In addition, DNA ladder gel electrophoresis studies, flow cytometry and TUNEL assay confirmed the induction of apoptosis by MTX and Au-BSA-MTX in MCF-7 cells. Notably, Au-BSA-MTX was found to have higher cytotoxicity on MCF-7 cells compared with an equivalent dose of free MTX. The enhanced activity is attributed to the preferential uptake of Au-BSA-MTX particles by MCF-7 cells due to the presence of BSA that acts as a source of nutrient and energy to the rapidly proliferating MCF-7 cells. Moreover, the targeting ability of the drug MTX to the over expressed folate receptors on MCF-7 cells also contributes to the enhanced uptake and activity. Taken together, these results unveil that Au-BSA-MTX could be more effective than free drug for cancer treatment. - Highlights: • Gold nanoparticles prepared using bovine serum albumin as a reducing and capping agent. • These gold nanoparticles are extremely stable under strong electrolyte and pH conditions. • The anticancer drug methotrexate has been loaded on the Au-BSA nanoparticles. • Due to BSA loading these are taken up by cancerous cells preferentially. • Better proficiency in inhibiting MCF-7 cells as compared to the free drug Methotrexate is demonstrated.

  15. [Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: experience with six pediatric patients. Potential efficacy of methotrexate].

    Science.gov (United States)

    Bravo-Oro, Antonio; Abud-Mendoza, Carlos; Quezada-Corona, Arturo; Dalmau, Josep; Campos-Guevara, Verónica

    2013-11-01

    INTRODUCTION. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a condition that is increasingly more frequently diagnosed in the paediatric age. Unlike adults, in many cases it is not associated to tumours and the most common initial manifestations in children are seizures and movement disorders, while in adults there is a predominance of psychiatric alterations. CASE REPORTS. We present six confirmed paediatric cases with antibodies against the subunit NR1 of the NMDA receptor in serum and cerebrospinal fluid. Five of the cases began with seizures as the initial clinical symptom prior to the development of the classical clinical features of this condition. In all cases, steroids were used as the first line of treatment, although these only brought about control over the manifestations in one of them; the other patients therefore required second-line immunomodulators. All the patients received methotrexate as immunomodulator treatment to prevent relapses, and in all cases there was an improvement in the patients' situation. CONCLUSIONS. In our series of patients with anti-NMDA receptor encephalitis, none were associated with tumours. All of them were given methotrexate for at least one year and no adverse clinical or analytical events were observed; likewise, there were no neurological sequelae or relapses during treatment. Although it is a small series and it would be advisable to increase the number and time to progression, we see methotrexate as an excellent alternative immunomodulator treatment for this pathology.

  16. Towards understanding the mechanism of action of antibacterial N-alkyl-3-hydroxypyridinium salts: Biological activities, molecular modeling and QSAR studies.

    Science.gov (United States)

    Dolezal, Rafael; Soukup, Ondrej; Malinak, David; Savedra, Ranylson M L; Marek, Jan; Dolezalova, Marie; Pasdiorova, Marketa; Salajkova, Sarka; Korabecny, Jan; Honegr, Jan; Ramalho, Teodorico C; Kuca, Kamil

    2016-10-01

    In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software.

  17. Methods of producing alkylated hydrocarbons from an in situ heat treatment process liquid

    Science.gov (United States)

    Roes, Augustinus Wilhelmus Maria; Mo, Weijian; Muylle, Michel Serge Marie; Mandema, Remco Hugo; Nair, Vijay

    2009-09-01

    A method for producing alkylated hydrocarbons is disclosed. Formation fluid is produced from a subsurface in situ heat treatment process. The formation fluid is separated to produce a liquid stream and a first gas stream. The first gas stream includes olefins. The liquid stream is fractionated to produce at least a second gas stream including hydrocarbons having a carbon number of at least 3. The first gas stream and the second gas stream are introduced into an alkylation unit to produce alkylated hydrocarbons. At least a portion of the olefins in the first gas stream enhance alkylation.

  18. Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergistic effects with pyrimidine analogues in lymphoid malignancies.

    Directory of Open Access Journals (Sweden)

    Nobuya Hiraoka

    Full Text Available Bendamustine has shown considerable clinical activity against indolent lymphoid malignancies as a single agent or in combination with rituximab, but combination with additional anti-cancer drugs may be required for refractory and/or relapsed cases as well as other intractable tumors. In this study, we attempted to determine suitable anti-cancer drugs to be combined with bendamustine for the treatment of mantle cell lymphoma, diffuse large B-cell lymphoma, aggressive lymphomas and multiple myeloma, all of which are relatively resistant to this drug, and investigated the mechanisms underlying synergism. Isobologram analysis revealed that bendamustine had synergistic effects with alkylating agents (4-hydroperoxy-cyclophosphamide, chlorambucil and melphalan and pyrimidine analogues (cytosine arabinoside, gemcitabine and decitabine in HBL-2, B104, Namalwa and U266 cell lines, which represent the above entities respectively. In cell cycle analysis, bendamustine induced late S-phase arrest, which was enhanced by 4-hydroperoxy-cyclophosphamide, and potentiated early S-phase arrest by cytosine arabinoside (Ara-C, followed by a robust increase in the size of sub-G1 fractions. Bendamustine was able to elicit DNA damage response and subsequent apoptosis faster and with shorter exposure than other alkylating agents due to rapid intracellular incorporation via equilibrative nucleoside transporters (ENTs. Furthermore, bendamustine increased the expression of ENT1 at both mRNA and protein levels and enhanced the uptake of Ara-C and subsequent increase in Ara-C triphosphate (Ara-CTP in HBL-2 cells to an extent comparable with the purine analog fludarabine. These purine analog-like properties of bendamustine may underlie favorable combinations with other alkylators and pyrimidine analogues. Our findings may provide a theoretical basis for the development of more effective bendamustine-based combination therapies.

  19. Investigation of nano lipid vesicles of methotrexate for anti-rheumatoid activity

    Directory of Open Access Journals (Sweden)

    Prabhu P

    2012-01-01

    Full Text Available Prabhakara Prabhu1, Rakshith Shetty1, Marina Koland1, K Vijayanarayana3, KK Vijayalakshmi2, M Harish Nairy1, GS Nisha11Department of Pharmaceutics, Nitte University, NGSM Institute of Pharmaceutical Sciences, Paneer, Deralakatte, Mangalore, Karnataka, India; 2Department of Applied Zoology, Mangalore University, Konaje, Mangalore, Karnataka, India; 3Department of Pharmacy Practice, Manipal University, Manipal College of Pharmaceutical Sciences, Manipal, Karnataka, IndiaBackground: The purpose of this study was to formulate and evaluate nano lipid vesicles of methotrexate (MTX for its anti-rheumatoid activity.Methods: In this study the principle of both active as well as passive targeting using MTX-loaded stealth liposomes as per the magic gun approach was followed. Stealth liposomes of MTX were prepared by thin-film hydration method using a PEGylated phospholipid-like DSPE-MPEG 2000. Similarly, conventional liposomes were prepared using phospholipids like DPPC and DSPC. Conventional liposomes were coated with a hydrophilic biocompatible polymer like chitosan. They were investigated for their physical properties and in vitro release profile. Further, in vivo screening of the formulations for their anti-rheumatoid efficacy was carried out in rats. Rheumatoid arthritis was induced in male Wistar-Lewis rats using complete Freund’s adjuvant (1 mg/mL Mycobacterium tuberculosis, heat killed in mineral oil.Results: It was found that chitosan coating of the conventional liposomes increased the physical stability of the liposomal suspension as well as its entrapment efficiency. The size of the unsonicated lipid vesicles was found to be in the range of 8–10 µm, and the sonicated lipid vesicles in the range of 210–260 nm, with good polydispersity index. Further, chitosan-coated conventional liposomes and the PEGylated liposomes released the drug for a prolonged period of time, compared to the uncoated conventional liposomes. It was found that there

  20. Use of biotin targeted methotrexate–human serum albumin conjugated nanoparticles to enhance methotrexate antitumor efficacy

    Directory of Open Access Journals (Sweden)

    Taheri A

    2011-09-01

    Full Text Available Azade Taheri1, Rassoul Dinarvand1,2, Faranak Salman Nouri1, Mohammad Reza Khorramizadeh3, Atefeh Taheri Borougeni4, Pooria Mansoori5, Fatemeh Atyabi1,21Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical sciences, Tehran, Iran; 3Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; 4Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Tehran University of Medical Sciences, Tehran, Iran; 5Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IranAbstract: Biotin molecules could be used as suitable targeting moieties in targeted drug delivery systems against tumors. To develop a biotin targeted drug delivery system, we employed human serum albumin (HSA as a carrier. Methotrexate (MTX molecules were conjugated to HSA. MTX-HSA nanoparticles (MTX-HSA NPs were prepared from these conjugates by cross-linking the HSA molecules. Biotin molecules were then conjugated on the surface of MTX-HSA NPs. The anticancer efficacy of biotin targeted MTX-HSA NPs was evaluated in mice bearing 4T1 breast carcinoma. A single dose of biotin targeted MTX-HSA NPs showed stronger in vivo antitumor activity than non-targeted MTX-HSA NPs and free MTX. By 7 days after treatment, average tumor volume in the biotin targeted MTX-HSA NPs-treated group decreased to 17.6% of the initial tumor volume when the number of attached biotin molecules on MTX-HSA-NPs was the highest. Average tumor volume in non-targeted MTX-HSA NPs-treated mice grew rapidly and reached 250.7% of the initial tumor volume. Biotin targeted MTX-HSA NPs increased the survival of tumor-bearing mice to 47.5 ± 0.71 days and increased their life span up to 216.7%. Mice treated with biotin targeted MTX-HSA NPs showed slight body weight loss (8% 21 days after treatment, whereas non-targeted MTX

  1. Facile synthesis of methotrexate intercalated layered double hydroxides: Particle control, structure and bioassay explore

    Energy Technology Data Exchange (ETDEWEB)

    Tian, De-Ying; Liu, Zhen-Lei [Jiangsu Key Laboratory of Biofunctional Material, College of Chemistry and Material Science, Nanjing Normal University, Nanjing 210023 (China); Li, Shu-Ping, E-mail: lishuping@njnu.edu.cn [Jiangsu Key Laboratory of Biofunctional Material, College of Chemistry and Material Science, Nanjing Normal University, Nanjing 210023 (China); Li, Xiao-Dong [Jiangsu Key Laboratory of Biofunctional Material, College of Chemistry and Material Science, Nanjing Normal University, Nanjing 210023 (China); Shenzhen Research Institute of Xiamen University, Shenzhen 518057 (China)

    2014-12-01

    To study the influence of particle size on drug efficacy and other properties, a series of methotrexate intercalated layered double hydroxides (MTX/LDHs) were synthesized through the traditional coprecipitation method, using a mixture of water and polyethylene glycol (PEG-400) as the solvent. To adjust the particle size of MTX/LDHs, the dropping way, the volume ratio of water to PEG-400 and different hydrothermal treatment time changed accordingly, and the results indicate that the particle size can be controlled between 90 and 140 nm. Elemental C/H/N and inductive coupled plasma (ICP) analysis indicated that different synthesis conditions almost have no effect on the compositions of the nanohybrids. X-ray diffraction (XRD) patterns manifested the successful intercalation of MTX anions into the LDH interlayers, and it's also found out that different volume ratios of water to PEG-400 and variable dropping way can affect the crystallinity of the final samples, i.e., the volume ratio of 3:1 and pH decreasing are proved to be optimum conditions. Furthermore, both antiparallel monolayer and bilayers adopting different orientations are suggested for four samples from XRD results. Fourier transform infrared spectroscopy (FTIR) investigations proved the coexistence of CO{sub 3}{sup 2−} and MTX anions in the interlayer of the nanohybrids. MTX/LDH particles exhibited hexagonal platelet morphology with round corner and different dropping ways can affect the morphology greatly. Moreover, a DSC study indicated that longer time treatment can weaken the bond between the MTX anions and LDH layers. The kinetic release profiles told us that larger MTX/LDH particles have enhanced the ability of LDH layers to protect interlayer molecules. At last, the bioassay study indicated that the nanohybrids with larger diameters have higher tumor suppression efficiency. - Graphical abstract: A series of methotrexate intercalated layered double hydroxides were synthesized by changing the

  2. Differential alkylation-based redox proteomics - Lessons learnt

    DEFF Research Database (Denmark)

    Wojdyla, Katarzyna; Rogowska-Wrzesinska, Adelina

    2015-01-01

    is a critical evaluation of differential alkylation-based strategies for the analysis of S-nitrosylation and S-sulfenylation. The aim is to assess the current status and to provide insights for future directions in the dynamically evolving field of redox proteomics. To achieve that we collected 35 original......, including the amount of starting material required for analysis. The results of this meta-analysis are the core of this review, complemented by issues related to biological models and sample preparation in redox proteomics, including conditions for free thiol blocking and labelling of target cysteine...

  3. Synthesis and cytotoxic activity of some derivatives of alkyl piperidine.

    Science.gov (United States)

    Jahan, Sarwat; Akhtar, Shamim; Saify, Zafar Saied; Mushtaq, Nousheen; Sial, Ali Akbar; Kamil, Arfa; Arif, Muhammed

    2013-05-01

    Synthesis of novel phenacyl derivatives of alkyl piperidine as cytotoxic agents via simple and single step reaction procedure is going to be reported here. Twelve new compounds were successfully synthesized in moderate yield and in solid form. Their synthesis was confirmed by TLC, melting point, CHN analysis and through different spectral studies such as UV, IR, Mass and proton NMR. The advantages of this synthetic route are simple operation, mild reaction conditions and good yields. These newly synthesized derivatives were extensively explored for their cytotoxicity by brine shrimp lethality assay.

  4. Alkyl polyglycoside-sorbitan ester formulations for improved oil recovery

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Y.; Iglauer, S.; Shuler, P.; Tang, Y. [Power Environmental Energy Research Institute (PEERI), Covina, CA (United States); Goddard, W.A. III [California Inst. of Technology, Pasadena, CA (US). Div. of Chemistry and Chemical Engineering, Materials and Process Simulation Center (MSC)

    2010-09-15

    We measured interfacial tensions (IFT) of aqueous alkyl polyglucoside (APG) systems formulated with sorbitan ester-type cosurfactants against n-octane. The study focused on low to ultra-low IFT systems which are relevant for enhanced oil recovery (EOR). In addition, we measured equilibrium adsorption concentrations of these surfactants and cosurfactants onto kaolinite clay, commonly found in oil reservoirs. We present one surfactant EOR laboratory flood experiment with one selected APG-sorbitan ester formulation with which we recovered 94% of initial oil in place (IOIP). (orig.)

  5. Formation of methotrexate-PLLA-PEG-PLLA composite microspheres by microencapsulation through a process of suspension-enhanced dispersion by supercritical CO2

    Directory of Open Access Journals (Sweden)

    Chen AZ

    2012-06-01

    Full Text Available Ai-Zheng Chen,1,2 Guang-Ya Wang,1 Shi-Bin Wang,1,2 Li Li,1 Yuan-Gang Liu,1,2 Chen Zhao11College of Chemical Engineering, 2Institute of Pharmaceutical Engineering, Institute of Biomaterials and Tissue Engineering, Huaqiao University, Xiamen 361021, ChinaBackground: The aim of this study was to improve the drug loading, encapsulation efficiency, and sustained-release properties of supercritical CO2-based drug-loaded polymer carriers via a process of suspension-enhanced dispersion by supercritical CO2 (SpEDS, which is an advanced version of solution-enhanced dispersion by supercritical CO2 (SEDS.Methods: Methotrexate nanoparticles were successfully microencapsulated into poly (L-lactide-poly(ethylene glycol-poly(L-lactide (PLLA-PEG-PLLA by SpEDS. Methotrexate nanoparticles were first prepared by SEDS, then suspended in PLLA-PEG-PLLA solution, and finally microencapsulated into PLLA-PEG-PLLA via SpEDS, where an "injector" was utilized in the suspension delivery system.Results: After microencapsulation, the composite methotrexate (MTX-PLLA-PEG-PLLA microspheres obtained had a mean particle size of 545 nm, drug loading of 13.7%, and an encapsulation efficiency of 39.2%. After an initial burst release, with around 65% of the total methotrexate being released in the first 3 hours, the MTX-PLLA-PEG-PLLA microspheres released methotrexate in a sustained manner, with 85% of the total methotrexate dose released within 23 hours and nearly 100% within 144 hours.Conclusion: Compared with a parallel study of the coprecipitation process, microencapsulation using SpEDS offered greater potential to manufacture drug-loaded polymer microspheres for a drug delivery system.Keywords: drug loading, encapsulation efficiency, methotrexate, nanoparticles, poly(L-lactide, supercritical CO2 sustained release

  6. A randomized placebo-controlled double-blind pilot study of methotrexate in the treatment of H1 antihistamine-resistant chronic spontaneous urticaria

    Directory of Open Access Journals (Sweden)

    Vinod K Sharma

    2014-01-01

    Full Text Available Background: Chronic urticaria not responsive to antihistamines is a difficult disease to manage. Methotrexate has been used in difficult chronic urticarias with some benefit. Objective: To evaluate the efficacy of methotrexate in the treatment of chronic spontaneous urticaria poorly responsive to H1 antihistaminics. Methods: In a randomized double-blind trial at the Department of Dermatology and Venereology of a tertiary care centre, 29 patients with chronic spontaneous urticaria not responding well to H1 antihistaminics were recruited. Patients were randomly allocated to receive either a weekly dose of oral methotrexate 15 mg or placebo (calcium carbonate for a total duration of 12 weeks, after which treatment was stopped and patients were followed up for relapse of urticaria. Each group also received levocetrizine 5 mg once daily for symptom control. Primary outcome measured was a reduction by >2/3 rd of baseline urticaria scores after 12 week therapy. Secondary outcome was a reduction in antihistamine requirement after stopping therapy. Results: Fourteen patients were randomized to the methotrexate group and fifteen patients to the placebo group. Out of 17 patients who completed therapy, the primary outcome was achieved by 3.5 ± 1.9 (out of 10 patients in the methotrexate group and by 3.67 ± 1.03 (out of 7 patients in the placebo group (P > 0.05. Ten patients followed up, after stopping therapy, for a mean period of 3.5 ± 2.4 months; 3 remained in remission and 7 had relapsed. One patient had uncontrollable nausea and vomiting after taking methotrexate and was withdrawn from the study. The placebo group did not experience any side effects. Conclusions: Methotrexate 15 mg weekly for 3 months did not provide any additional benefit over H1 antihistamines in this study but an adequately powered study with longer follow up is required to assess its utility.

  7. The Advantage of Cyclosporine A and Methotrexate Rotational Therapy in Long-Term Systemic Treatment for Chronic Plaque Psoriasis in a Real World Practice

    Science.gov (United States)

    Choi, Chong Won; Kim, Bo Ri; Ohn, Jungyoon

    2017-01-01

    Background Psoriasis is a chronic inflammatory disease. In the treatment of psoriasis, cyclosporine is commonly prescribed systemic agents. However, long-term use of cyclosporine is not recommended because of side effects such as nephrotoxicity or hypertension. Objective To ascertain the improved safety of rotational therapy using cyclosporine and methotrexate, we investigated the frequency of abnormal results in laboratory test after long term rotational therapy using cyclosporine and methotrexate. Methods From January 2009 to June 2014, patients who were treated with cyclosporine or methotrexate were enrolled. The clinical data and usage of medications were reviewed. Laboratory tests were conducted before starting the treatment and regularly follow-up. The occurrences of any laboratory abnormalities during the treatments were investigated. Results A total of 21 psoriatic patients were enrolled. The mean of medication period and cumulative dose of cyclosporine and methotrexate were 497.81±512.06 days and 115.68±184.34 g in cyclosporine and 264.19±264.71 days and 448.71±448.63 mg in methotrexate. Laboratory abnormalities were found in total two patients after rotational therapy: two patients (9.5%) in aspartate aminotransferase/alanine aminotransferase and one patient (4.8%) in uric acid. No laboratory abnormalities were found in renal function test. Conclusion We found that the rotational approaches using cyclosporine and methotrexate reduced the possibility of the development of nephrotoxicity. In addition to other advantage such as quick switching from one agent to another, the rotational therapy using cyclosporine and methotrexate can minimize the adverse events during the systemic treatment of chronic plaque psoriasis. PMID:28223747

  8. Safety and efficacy of ocrelizumab in rheumatoid arthritis patients with an inadequate response to methotrexate or tumor necrosis factor inhibitors: a systematic review and meta-analysis.

    Science.gov (United States)

    Abushouk, Abdelrahman Ibrahim; Ahmed, Hussien; Ismail, Ammar; Elmaraezy, Ahmed; Badr, Ahmed Said; Gadelkarim, Mohamed; Elnenny, Mohammed

    2017-02-24

    We conducted this systematic reviews and meta-analysis to investigate the safety and efficacy of ocrelizumab in patients with active rheumatoid arthritis (RA) who exhibited resistance or intolerance to methotrexate or biological therapy. We performed a web-based literature search of PubMed, Google Scholar, EBSCO, Scopus, Embase, and Web of science for studies that compared ocrelizumab plus methotrexate versus methotrexate plus placebo in RA patients. Data were extracted from eligible studies and pooled as risk ratios (RR), using RevMan software. Pooling data from four RCTs (2230 patients) showed that ocrelizumab plus methotrexate were superior to methotrexate plus placebo at 24 weeks in terms of improvement on the American college of rheumatology (ACR20, ACR50, and ACR70) criteria (p < 0.00001), disease activity score 28-ESR (RR = 3.77, 95% CI [2.47, 5.74], p < 0.00001), and Sharp/van der Heijde radiological score (RR = 1.63, 95% CI [1.43, 1.85], p < 0.00001). These effects were consistent among all ocrelizumab doses. The rates of serious adverse events were comparable between the ocrelizumab and placebo containing groups (RR = 1, 95% CI [0.78, 1.28], p = 0.98). However, infusion related reactions were significantly higher in ocrelizumab group (RR = 2.13, 95% CI [1.69, 2.68], p < 0.00001), compared to placebo group. The combination of ocrelizumab plus methotrexate was superior to methotrexate plus placebo on all clinical and radiographic improvement scales. The incidence of adverse events, including serious adverse events, was comparable between both groups. Future trials should investigate the efficacy of ocrelizumab alone and develop strategies to alleviate its related infusion reactions.

  9. The Greenland analogue project. Yearly report 2010

    Energy Technology Data Exchange (ETDEWEB)

    Harper, J.; Brinkerhoff, D.; Johnson, J. [University of Montana, Missoula (United States); Ruskeeniemi, T.; Engstroem, J.; Kukkonen, I. [Geological Survey of Finland (Finland)] [and others

    2012-04-15

    A four-year field and modelling study of the Greenland ice sheet and subsurface conditions, Greenland Analogue Project (GAP), has been initiated collaboratively by SKB, Posiva and NWMO to advance the understanding of processes associated with glaciation and their impact on the long-term performance of a deep geological repository. The study site encompasses a land terminus portion of the Greenland ice sheet, east of Kangerlussuaq, and is in many ways considered to be an appropriate analogue of the conditions that are expected to prevail in much of Canada and Fennoscandia during future glacial cycles. The project begins in 2009 and is scheduled for completion in 2012. Our current understanding of the hydrological, hydrogeological and hydrogeochemical processes associated with cold climate conditions and glacial cycles, and their impact on the long-term performance of deep geological repositories for spent nuclear fuel, will be significantly improved by studying a modern analogue. The GAP will conduct the first in situ investigations of some of the parameters and processes needed to achieve a better understanding of how an ice sheet may impact a deep repository, and will provide measurements, observations and data that may significantly improve our safety assessments and risk analyses of glaciation scenarios. This report was produced by the GAP team members and presents an overview of the activities within the GAP during the interval January 1 to December 31, 2010, as well as research results obtained during this time frame. Research for the GAP is ongoing, and additional results related to the data presented here may become available in the future and will be presented in subsequent annual reports. (orig.)

  10. Technical Considerations in Magnetic Analogue Models

    CERN Document Server

    Adams, Patrick W M

    2016-01-01

    The analogy between vorticity and magnetic fields has been a subject of interest to researchers for a considerable period of time, mainly because of the structural similarities between the systems of equations that govern the evolution of the two fields. We recently presented the analysis of magnetic fields and hydrodynamics vorticity fields and argued for a formal theory of analogue magnetism. This article provides in depth technical details of the relevant considerations for the simulation procedures and extends the analyses to a range of fluids.

  11. Analogues of Euler and Poisson Summation Formulae

    Indian Academy of Sciences (India)

    Vivek V Rane

    2003-08-01

    Euler–Maclaurin and Poisson analogues of the summations $\\sum_{a < n ≤ b}(n)f(n), \\sum_{a < n ≤ b}d(n) f(n), \\sum_{a < n ≤ b}d(n)(n) f(n)$ have been obtained in a unified manner, where (()) is a periodic complex sequence; () is the divisor function and () is a sufficiently smooth function on [, ]. We also state a generalised Abel's summation formula, generalised Euler's summation formula and Euler's summation formula in several variables.

  12. Analogue cosmology in a hadronic fluid

    Directory of Open Access Journals (Sweden)

    Bilić Neven

    2014-01-01

    Full Text Available Analog gravity models of general relativity seem promising routes to providing laboratory tests of the foundation of quantum field theory in curved space-time. In contrast to general relativity, where geometry of a spacetime is determined by the Einstein equations, in analog models geometry and evolution of analog spacetime are determined by the equations of fluid mechanics. In this paper we study the analogue gravity model based on massless pions propagating in a expanding hadronic fluid. The analog expanding spacetime takes the form of an FRW universe, with the apparent and trapping horizons defined in the standard way.

  13. Satellite television analogue and digital reception techniques

    CERN Document Server

    Benoit, Herve

    1999-01-01

    Satellite television is part of the lives of millions of television viewers worldwide and its influence is set to increase significantly with the launch of digital satellite television services.This comprehensive reference book, written by the author of the highly successful 'Digital Television', provides a technical overview of both analogue and digital satellite TV. Written concisely and thoroughly, it covers all aspects of satellite TV necessary to understand its operation and installation. It also covers the evolution of satellite television, and contains a detailed glossary of tec

  14. U.S. Nuclear Regulatory Commission natural analogue research program

    Energy Technology Data Exchange (ETDEWEB)

    Kovach, L.A.; Ott, W.R. [Nuclear Regulatory Commission, Washington, DC (United States)

    1995-09-01

    This article describes the natural analogue research program of the U.S. Nuclear Regulatory Commission (US NRC). It contains information on the regulatory context and organizational structure of the high-level radioactive waste research program plan. It also includes information on the conditions and processes constraining selection of natural analogues, describes initiatives of the US NRC, and describes the role of analogues in the licensing process.

  15. Co-association of methotrexate and SPIONs into anti-CD64 antibody-conjugated PLGA nanoparticles for theranostic application

    Directory of Open Access Journals (Sweden)

    Moura CC

    2014-10-01

    Full Text Available Catarina Costa Moura,1,2 Marcela A Segundo,1 José das Neves,3,4 Salette Reis,1 Bruno Sarmento3,4 1REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; 2Faculty of Engineering, University of Porto, Porto, Portugal; 3CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto de Ciências da Saúde-Norte, Gandra PRD, Portugal; 4INEB – Instituto de Engenharia Biomédica, University of Porto, Porto, Portugal Background: Rheumatoid arthritis (RA is an autoimmune disease with severe consequences for the quality of life of sufferers. Regrettably, the inflammatory process involved remains unclear, and finding successful therapies as well as new means for its early diagnosis have proved to be daunting tasks. As macrophages are strongly associated with RA inflammation, effective diagnosis and therapy may encompass the ability to target these cells. In this work, a new approach for targeted therapy and imaging of RA was developed based on the use of multifunctional polymeric nanoparticles. Methods: Poly(lactic-co-glycolic acid nanoparticles were prepared using a single emulsion-evaporation method and comprised the co-association of superparamagnetic iron oxide nanoparticles (SPIONs and methotrexate. The nanoparticles were further functionalized with an antibody against the macrophage-specific receptor, CD64, which is overexpressed at sites of RA. The devised nanoparticles were characterized for mean particle size, polydispersity index, zeta potential, and morphology, as well as the association of SPIONs, methotrexate, and the anti-CD64 antibody. Lastly, the cytotoxicity of the developed nanoparticles was assessed in RAW 264.7 cells using standard MTT and LDH assays.Results: The nanoparticles had a mean diameter in the range of 130–200 nm and zeta potential values ranging from -32 mV to -16 mV. Association with either methotrexate or SPIONs did not

  16. Self-assembly Polyrotaxanes Nanoparticles as Carriers for Anticancer Drug Methotrexate Delivery

    Institute of Scientific and Technical Information of China (English)

    Longgui Zhang; Ting Su; Bin He; Zhongwei Gu∗

    2014-01-01

    α-Cyclodextrin/poly(ethylene glycol) (α-CD/PEG) polyrotaxane nanoparticles were prepared via a self-assembly method. Anticancer drug methotrexate (MTX) was loaded in the nanoparticles. The interaction between MTX and polyrotaxane was investigated. The formation, morphology, drug release and in vitro anticancer activity of the MTX loaded polyrotaxane nanoparticles were studied. The results show that the MTX could be efficiently absorbed on the nanoparticles, and hydrogen bonds were formed between MTX andα-CDs. The typical channel-type stacking assembly style of polyrotaxane nanoparticles was changed after MTX was loaded. The mean diameter of drug loaded polyrotaxane nanoparticles were around 200 nm and the drug loading content was as high as about 20%. Drug release profiles show that most of the loaded MTX was released within 8 hours and the cumulated release rate was as high as 98%. The blank polyrotaxane nanoparticles were nontoxicity to cells. The in vitro anticancer activity of the MTX loaded polyrotaxane nanoparticles was higher than that of free MTX.

  17. Methotrexate-conjugated quantum dots: synthesis, characterisation and cytotoxicity in drug resistant cancer cells.

    Science.gov (United States)

    Johari-Ahar, Mohammad; Barar, Jaleh; Alizadeh, Ali Mohammad; Davaran, Soodabeh; Omidi, Yadollah; Rashidi, Mohammad-Reza

    2016-01-01

    Methotrexate (MTX), a folic acid derivative, is a potent anticancer used for treatment of different malignancies, but possible initiation of drug resistance to MTX by cancer cells has limited its applications. Nanoconjugates (NCs) of MTX to quantum dots (QDs) may favour the cellular uptake via folate receptors (FRs)-mediated endocytosis that circumvents the efflux functions of cancer cells. We synthesised MTX-conjugated l-cysteine capped CdSe QDs (MTX-QD nanoconjugates) and evaluated their internalisation and cytotoxicity in the KB cells with/without resistancy to MTX. The NCs were fully characterised by high resolution transmission electron microscopy (HR-TEM), atomic force microscopy (AFM), dynamic light scattering (DLS) and optical spectroscopy. Upon conjugation with MTX, the photoluminescence (PL) properties of QDs altered, while an obvious quenching in PL of QDs was observed after physical mixing. The MTX-QD nanoconjugates efficiently internalised into the cancer cells, and induced markedly high cytotoxicity (IC50, 12.0 µg/mL) in the MTX-resistant KB cells as compared to the free MTX molecules (IC50,105.0 µg/mL), whereas, these values were respectively about 7.0 and 0.6 µg/mL in the MTX-sensitive KB cells. Based on these findings, the MTX-QD nanoconjugates are proposed for the targeted therapy of MTX-resistant cancers, which may provide an improved outcome in the relapsed FR-overexpressing cancers.

  18. Effect of ketoprofen and indomethacin on methotrexate pharmacokinetics in mice plasma and tumor tissues.

    Science.gov (United States)

    Elmorsi, Yasmine M; El-Haggar, Sahar M; Ibrahim, Osama M; Mabrouk, Mokhtar M

    2013-03-01

    Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs in the treatment of inflammatory diseases as well as malignancies. Severe adverse effects with this combination may occur, usually resulting from inhibition of renal transporters. Solid Ehrlich carcinoma was experimentally induced by implantation of Ehrlich ascites Carcinoma cells subcutaneously into the thigh of mice, and after 30 days, mice were divided into three groups: Group I that served as control group received MTX (50 mg/kg, i.p.); Group II received ketoprofen (100 mg/kg, i.p.) and then after half an hour received MTX (50 mg/kg, i.p.); Group III received indomethacin (10 mg/kg, i.p.) and then after half an hour received MTX (50 mg/kg, i.p.). Plasma and tissue samples were collected at different time points and then MTX concentrations were determined by HPLC. The injection of ketoprofen or indomethacin before MTX injection resulted in significant increase in the AUC and CPmax of MTX (p ketoprofen. The study showed that administration of ketoprofen or indomethacin prior to MTX caused significant decrease in MTX elimination and significant increase in MTX extent of absorption which may lead to severe adverse effects if coadministered in human.

  19. Induction of pulmonary fibrosis by methotrexate treatment in mice lung in vivo and in vitro.

    Science.gov (United States)

    Ohbayashi, Masayuki; Suzuki, Masanori; Yashiro, Yoshiki; Fukuwaka, Sayaka; Yasuda, Masako; Kohyama, Noriko; Kobayashi, Yasuna; Yamamoto, Toshinori

    2010-10-01

    Methotrexate (MTX) has been used as the first-line disease-modifying antirheumatic drug (DMARD) in patients with early progressive rheumatoid arthritis (RA). Several severe side effects such as myelosuppression, hepato-, nephro-, and pulmonary toxicities have been reported. However, the pathogenic mechanism of MTX-induced pulmonary fibrosis is still unknown. Here, we evaluated the morphological and biological changes of the pulmonary fibrosis in mice treated with MTX. Three, four and five weeks after consecutive administration of MTX (3 mg/kg/day), hydroxyproline content in the lung tissues increased significantly to about 2 times higher that of the control level. This result closely reflected to the results of hematoxylin and eosin (HE) and Azan stains. Immunohistochemical analysis revealed that MTX treatment resulted in a decrease of alveolar epithelial cells and an increase of fibroblast cells in the mouse lung tissues. When we examined the effects of MTX on primary mouse alveolar epithelial cell (MAEC) and mouse lung fibroblast (MLF) survival in vitro, the efficiency of MTX-induced cytotoxicity and apoptosis in MAEC was more sensitive than MLF cells. Thus, our results indicate that the administration of MTX by an oral route could induce a fibrotic response with cell dysfunction of the alveolar epithelium by which MTX-induced apoptosis. Our results thus suggest that MTX could induce alveolar epithelial cell injury and resulted in the loss of integrity of the alveolar-capillary barrier basement membranes followed by the recruitment and proliferation of myofibroblasts with the deposition of collagens.

  20. INVESTIGATION OF NEPFROPROTECTIVE EFFECT OF SILYMARIN AGAINST METHOTREXATE AND IFOSFAMIDE INDUCED TOXICITY IN RATS.

    Directory of Open Access Journals (Sweden)

    MANOHAR NAIK K

    2015-01-01

    Full Text Available The present study was undertaken to investigate the Nephroprotective effect of silymarin against Methotrexate (MTX induced nephrotoxicity in rats. In MTX model rats of either sex (n=6 were pre-treated with silymarin (50mg/kg, p.o. for 6 days in MTX model, MTX toxicity was induced by administering MTX (20mg/kg on third day by intra-peritoneal route. The influence of prophylactic treatment was analyzed by quantification of Serum/Urinary biomarkers and antioxidants and histopathological observations. Silymarin treatment in presence of MTX was responsible for significant reduction in Serum; Urea, Creatinine, Aspartate transaminase (AST, Alanine transaminase (ALT and Urinary; Total Protein, Sodium and Potassium compared to MTX control group. Silymarin treatment was also responsible for significant increase in Serum Albumin and antioxidants such as superoxide dismutase (SOD, Glutathione (GSH and Catalase activities in kidney tissue homogenate compared to MTX control group. Similarly, there was an increase in the urine volume and decrease in the kidney weight in the silymarin treated groups compared to the MTX control group. Results were further supported by histopathological studies. Investigation witnessed the administration of silymarin 50mg/kg dose was effective in normalizing the abnormal conditions of kidney induced by MTX. Thus investigational finding conclude that silymarin possess potential benefits in treating animals with nephrotoxicity.

  1. Beneficial effects of Chrysin against Methotrexate-induced hepatotoxicity via attenuation of oxidative stress and apoptosis.

    Science.gov (United States)

    Ali, Nemat; Rashid, Summya; Nafees, Sana; Hasan, Syed Kazim; Sultana, Sarwat

    2014-01-01

    Methotrexate (MTX), a folic acid antagonist, an effective chemotherapeutic agent is used in the treatment of a wide range of tumors and autoimmune diseases. Moreover, hepatotoxicity limits its clinical use. Several studies have already confirmed that the oxidative stress plays a major role in the pathogenesis of MTX-induced damage in the various organs especially in liver. The aim of this study was to determine the protective effect of Chrysin against MTX-induced hepatic oxidative stress and apoptosis in rats. In the present study, efficacy of Chrysin was investigated against hepatotoxicity caused by MTX in terms of biochemical investigations of antioxidant enzymes, apoptosis, and histopathological alteration in rat liver. In the MTX-treated group there was a significant increase in alanine transaminase, aspartate aminotransferase, lactate dehydrogenase activity and malondialdehyde content as well as decreased glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase activities and reduced glutathione content were also observed compared to the control group as a marker of oxidative stress. Histopathological alterations and apoptosis through the immunopositive staining of p53, cleaved caspases-3 and Bcl-2-associated X protein in rat liver were observed. Pretreatment of Chrysin at both doses prevents the hepatotoxicity by ameliorating oxidative stress, histopathological alterations, and apoptosis and thus our results suggest that Chrysin has a protective effect against hepatotoxicity induced by MTX and it may, therefore, improve the therapeutic index of MTX if co-administration is done.

  2. The protective effect of intraperitoneal medical ozone preconditioning and treatment on hepatotoxicity induced by methotrexate.

    Science.gov (United States)

    Aslaner, Arif; Çakır, Tuğrul; Çelik, Betül; Doğan, Uğur; Akyüz, Cebrail; Baştürk, Ahmet; Polat, Cemal; Gündüz, Umut; Mayir, Burhan; Şehirli, Ahmet Özer

    2015-01-01

    The aim of this study is to determine the effects of medical ozone preconditioning and treatment on the methotrexate acute induced hepatotoxicity in rats that has not reports elsewhere. Eighteen rats were randomly assigned into three equal groups; control, Mtx and Mtx with ozone. Hepatotoxicity was performed with a single dose of 20 mg/kg Mtx to group 2 and group 3 at the fifteenth day. The medical ozone preconditioning was administered intraperitonealy in group 3 for fifteen days and more five days after inducing Mtx. The other rats of the group 1 and 2 received saline injection. At the twentyfirst day the blood and the liver tissue samples were obtained to measure the levels of liver enzymes ALT and AST, proinflamatory cytokines TNF-α, IL-1β, malondialdehyde, glutathione and myeloperoxidase. And the histolopatological examination was evaluated for injury score. In our study Mtx administration caused a significant increase on the liver enzymes ALT and AST, the tissue MDA and MPO activity and significant decrease in the tissue GSH. Moreover the both pro-inflammatory cytokines were significantly increased in the Mtx group. Medical ozone preconditioning and treatment reversed all these biochemical parameters and histopathological changes of the hepatotoxicity induced by Mtx. We conclude that medical ozone ameliorates Mtx induced hepatotoxicity in rats.

  3. Intervention of ginger or propolis ameliorates methotrexate-induced ileum toxicity.

    Science.gov (United States)

    Abdul-Hamid, Manal; Salah, Marwa

    2016-02-01

    The long-term clinical use of methotrexate (MTX) is restricted due to its severe intestinal toxicity. The protective effect of ginger or propolis on the toxicity induced by MTX is relatively less understood, so the possible protective effect of ginger or propolis, used separately, was investigated. A total of 60 male albino rats were divided into six groups as follows: (1) control group; (2) ginger group; (3) propolis group; (4) MTX group; (5) ginger + MTX group; and (6) propolis + MTX group. The present results show that MTX caused ileum injury, including shortening and fusion of the villi, inflammatory cell infiltration and goblet cell depletion. Administration of ginger or propolis ameliorated the MTX-induced ileum injury as shown by histological, immunohistochemical and ultrastructural investigations and statistical analysis. This is revealed by intact villi, which shows marked increase in brown colouration of proliferating cell nuclear antigen positive nuclei in the crypts region, improvement in the number of goblet cells and brush border length of ileum. The current results conclude the efficacy and safety of ginger and propolis, which may be due to their antioxidant properties.

  4. Methotrexate for the treatment of juvenile idiopathic arthritis: process to approval for JIA indication in Japan.

    Science.gov (United States)

    Mori, Masaaki; Naruto, Takuya; Imagawa, Tomoyuki; Murata, Takuji; Takei, Syuji; Tomiita, Minako; Itoh, Yasuhiko; Fujikawa, Satoshi; Yokota, Shumpei

    2009-01-01

    Methotrexate (MTX), the primary treatment for the articular-type juvenile idiopathic arthritis (JIA), is effective and brings about radiological improvement. Patient compliance is good, and it is recognized that its known side effects, namely, disruption of liver function and induction of pulmonary lesions, are unlikely to be severe at the low MTX doses that are administered. In Japan, MTX was granted approval in 1999 by the then Ministry of Health and Welfare specifically for treating rheumatoid arthritis in adult patients, allowing it be generally used in medical institutions for patients having National Health Insurance. However, in the pediatric field, its use outside the indications has so far been unavoidable, and has been left to the discretion of the physician. Finally, at the present conference, expansion of the indications of MTX for JIA was approved in Japan. It is noteworthy that this expansion of indications was achieved without requiring clinical trials on children sponsored by the pharmaceutical company: it was achieved rather by collecting necessary information through ongoing efforts (including collection and analysis of information about approval status in foreign countries, adequate evidence from the literature, implementation of a clinical use survey in Japan, etc.). It also merits attention that the maximum dose (10 mg/m2) was set on the basis of pharmacokinetic data from children, rather than relying on the dosing method and dose for adults.

  5. Triethanolamine Stabilization of Methotrexate-β-Cyclodextrin Interactions in Ternary Complexes

    Science.gov (United States)

    Barbosa, Jahamunna A. A.; Zoppi, Ariana; Quevedo, Mario A.; de Melo, Polyanne N.; de Medeiros, Arthur S. A.; Streck, Letícia; de Oliveira, Alice R.; Fernandes-Pedrosa, Matheus F.; Longhi, Marcela R.; da Silva-Júnior, Arnóbio A.

    2014-01-01

    The interaction of methotrexate (MTX) with beta-cyclodextrin (β-CD) in the presence of triethanolamine (TEA) was investigated with the aim to elucidate the mechanism whereby self-assembly cyclodextrin systems work in association with this third component. Solubility diagram studies showed synergic increment of the MTX solubility to be about thirty-fold. Experiments using 2D ROESY and molecular modeling studies revealed the inclusion of aromatic ring III of the drug into β-CD cavity, in which TEA contributes by intensifying MTX interaction with β-CD and stabilizes MTX:β-CD:TEA ternary complex by electrostatic interaction. The maintenance of these interactions in solid phase was also studied in ternary MTX:β-CD:TEA and comparisons were made with freeze dried binary MTX:β-CD and physical mixtures. FTIR studies evidenced that MTX–β-CD interaction remained in solid ternary complexes, which was also supported by thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TG)/first derivative of TG analysis (DTG) and C,N,H elementary analysis) and structural (X-ray diffraction analysis, (XRD)) studies, mainly regarding the increment of drug stability. The efficient in vitro drug dissolution studies successfully demonstrated the contribution of ternary complexes, which highlights the importance of this possible new raw material for further applications in drug delivery systems. PMID:25257529

  6. Polymorphisms and pharmacogenomics for the toxicity of methotrexate monotherapy in patients with rheumatoid arthritis

    Science.gov (United States)

    Qiu, Qi; Huang, Jing; Lin, Yang; Shu, Xiaoming; Fan, Huizheng; Tu, Zhihua; Zhou, Youwen; Xiao, Cheng

    2017-01-01

    Abstract Background: Methotrexate (MTX) is widely used and considered a first-line disease modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, 10% to 30% of patients discontinue therapy within a year of starting the treatment, usually because of undesirable side effects. Many of the relevant genes have been investigated to estimate the association between gene polymorphisms and MTX toxicity in RA patients, although inconsistent results have been reported. Methods: We searched EMBASE and PubMed in February 2016 for polymorphisms and pharmacogenomics study of the toxicity of MTX monotherapy in RA patients. The meta-analysis was stratified by whether genetic variants associated with MTX toxicity. Results: A total of 42 publications that included 28 genes with 88 gene SNPs associated with the transporters, enzymes, and metabolites of MTX or the progression of RA were included in the SR, and 31 studies were included in 7 meta-analyses. The meta-analysis showed a significant association between the toxicity of MTX and the RFC-1 80G > A (rs1051266) polymorphism in the European RA patients. Conclusion: RFC-1 80G > A (rs1051266) polymorphism was associated with MTX toxicity, and larger and more stringent study designs may provide more accurate results for the effect of these SNPs on the MTX toxicity. PMID:28296761

  7. St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats.

    Science.gov (United States)

    Yang, Shih-Ying; Juang, Shin-Hun; Tsai, Shang-Yuan; Chao, Pei-Dawn Lee; Hou, Yu-Chi

    2012-08-15

    St. John's wort (SJW, Hypericum perforatum) is one of the popular nutraceuticals for treating depression. Methotrexate (MTX) is an immunosuppressant with narrow therapeutic window. This study investigated the effect of SJW on MTX pharmacokinetics in rats. Rats were orally given MTX alone and coadministered with 300 and 150 mg/kg of SJW, and 25mg/kg of diclofenac, respectively. Blood was withdrawn at specific time points and serum MTX concentrations were assayed by a specific monoclonal fluorescence polarization immunoassay method. The results showed that 300 mg/kg of SJW significantly increased the AUC(0-t) and C(max) of MTX by 163% and 60%, respectively, and 150 mg/kg of SJW significantly increased the AUC(0-t) of MTX by 55%. In addition, diclofenac enhanced the C(max) of MTX by 110%. The mortality of rats treated with SJW was higher than that of controls. In conclusion, coadministration of SJW significantly increased the systemic exposure and toxicity of MTX. The combined use of MTX with SJW would need to be with caution.

  8. A Comparative Evaluation of Hydroxycamptothecin Drug Nanorods With and Without Methotrexate Prodrug Functionalization for Drug Delivery

    Science.gov (United States)

    Guo, Fuqiang; Fan, Zhongxiong; Yang, Jinbin; Li, Yang; Wang, Yange; Zhao, Hai; Xie, Liya; Hou, Zhenqing

    2016-08-01

    We developed a novel self-targeted multi-drug co-delivery system based on rod-shaped 10-hydroxycamptothecin (CPT) nanoanticancer drug (CPT NRs) followed by a surface functionalization with self-targeting PEGylated lipid-conjugated methotrexate (MTX) pro-anticancer drug. The self-targeting effect and in vitro cell viability of the MTX-PEG-CPT NRs on HeLa cells were demonstrated by comparative cellular uptake and MTT assay of the PEG-CPT NRs. In vitro studies showed the feasibility of using this high drug-loading MTX-PEG-CPT NRs in self-targeted drug delivery, controlled-/sustained-release, and synergistic cancer therapy. More importantly, this work would stimulate interest in the use of PEGylated lipid-conjugated MTX by introducing an early-phase tumor-targeting role and then driving a late-phase anticancer role for the highly convergent design of nanomulti-drug, which may advantageously offer a new and simple strategy for simultaneously targeting and treating FA receptor-overexpressing cancer cells.

  9. Hemocompatibility of liposomes loaded with lipophilic prodrugs of methotrexate and melphalan in the lipid bilayer.

    Science.gov (United States)

    Kuznetsova, Natalia R; Sevrin, Chantal; Lespineux, David; Bovin, Nicolai V; Vodovozova, Elena L; Mészáros, Tamás; Szebeni, Janos; Grandfils, Christian

    2012-06-10

    A panel of in vitro tests intended for evaluation of the nano-sized drug delivery systems' compliance with human blood was applied to liposomal formulations of anticancer lipophilic prodrugs incorporated into the lipid bilayer. Liposomes on the basis of natural phosphatidylcholine (PC) and phosphatidylinositol (PI), 8:1 (mol) were loaded with 10 mol% of either methotrexate or melphalan 1,2-dioleoylglyceride esters (MTX-DOG and Mlph-DOG respectively) and either decorated with 2 mol% of sialyl Lewis X/A (SiaLe(X/A)) tetrasaccharide ligand or not. Hemolysis rate, red blood cells and platelets integrity and size distribution, complement (C) activation, and coagulation cascade functioning were analyzed upon the material incubation with whole blood. Both formulations were negatively charged with the zeta potential value being higher in the case of MTX-DOG liposomes, which also were larger than Mlph-DOG liposomes and more prone to aggregation. Accordingly, in hemocompatibility tests Mlph-DOG liposomes did not provoke any undesirable effects, while MTX-DOG liposomes induced significant C activation and abnormal coagulation times in a concentration-dependent manner. Reactivity of the liposome surface was not affected by the presence of SiaLe(X/A) or PI. Decrease in liposome loading with MTX-DOG from 10 to 2.5% resulted in lower surface charge density, smaller liposome size and considerably reduced impact on C activation and coagulation cascades.

  10. Triethanolamine Stabilization of Methotrexate-β-Cyclodextrin Interactions in Ternary Complexes

    Directory of Open Access Journals (Sweden)

    Jahamunna A. A. Barbosa

    2014-09-01

    Full Text Available The interaction of methotrexate (MTX with beta-cyclodextrin (β-CD in the presence of triethanolamine (TEA was investigated with the aim to elucidate the mechanism whereby self-assembly cyclodextrin systems work in association with this third component. Solubility diagram studies showed synergic increment of the MTX solubility to be about thirty-fold. Experiments using 2D ROESY and molecular modeling studies revealed the inclusion of aromatic ring III of the drug into β-CD cavity, in which TEA contributes by intensifying MTX interaction with β-CD and stabilizes MTX:β-CD:TEA ternary complex by electrostatic interaction. The maintenance of these interactions in solid phase was also studied in ternary MTX:β-CD:TEA and comparisons were made with freeze dried binary MTX:β-CD and physical mixtures. FTIR studies evidenced that MTX–β-CD interaction remained in solid ternary complexes, which was also supported by thermal (differential scanning calorimetry (DSC, thermogravimetric analysis (TG/first derivative of TG analysis (DTG and C,N,H elementary analysis and structural (X-ray diffraction analysis, (XRD studies, mainly regarding the increment of drug stability. The efficient in vitro drug dissolution studies successfully demonstrated the contribution of ternary complexes, which highlights the importance of this possible new raw material for further applications in drug delivery systems.

  11. Mg-Al layered double hydroxide-methotrexate nanohybrid drug delivery system: evaluation of efficacy.

    Science.gov (United States)

    Chakraborty, Jui; Roychowdhury, Susanta; Sengupta, Somoshree; Ghosh, Swapankumar

    2013-05-01

    Mg-Al layered double hydroxide nanoparticles were synthesized by one-pot co-precipitation method and anticancerous drug methotrexate was incorporated into it by in-situ ion exchange. The LDH-MTX nanohybrid produced moderately stable suspension in water, as predicted by zeta potential measurement. X-ray diffraction revealed that the basal spacing increased to nearly twice the same for pristine LDH on MTX intercalation. Thermogravimetric analyses confirmed an increase in thermal stability of the intercalated drug in the LDH framework. A striking enhancement in efficacy/sensitivity of MTX on the HCT-116 cells was obtained when intercalated within the LDH layers, as revealed by the attainment of half maximal inhibitory concentration of LDH-MTX nanohybrid by 48 h, whereas, bare MTX required 72 h for the same. The MTX release from MgAl-LDH-MTX hybrids in phosphate buffer saline at pH7.4 followed a relatively slow, first order kinetics and was complete within 8 days following diffusion and crystal dissolution mechanism.

  12. Synthesis of nanostructured methotrexate/hydroxyapatite: Morphology control, growth mechanism, and bioassay explore.

    Science.gov (United States)

    Dai, Chao-Fan; Li, Shu-Ping; Li, Xiao-Dong

    2015-12-01

    In this study, a new structure of methotrexate/hydroxyapatite (MTX/HAp) nanorods via a facile hydrothermal route was reported. The as-synthesized samples were then characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), thermogravimetric (TG) and differential scanning calorimetry (DSC) analysis. In order to explore the formation mechanism, the effects of reaction time, MTX concentrations and addition of ethylene glycol (PEG) were emphatically examined. The results indicated that, with the increase in reaction time, the fibrous nanoparticles turned to needle-like and then to rod-like. Our study also proved that reaction time of 12h was enough for the full-growth of the nanostructure. Drug-loading capacities (AIn) rose dramatically in the first 12h and reached a plateau afterwards. Importantly, MTX played a critical role in the longitudinal growth of MTX/HAp nanostructure and polyethylene glyco (PEG) was a good dispersing agent to improve the monodispersity. As expected, the functional agent of MTX was served as both the target anticancer drug loaded in HAp and effective complex agents to modify and control the morphologies of MTX/HAp. Lastly, in vitro bioassay tests gave us evidence that obvious tumor inhibition can be achieved when MTX was hybridized with HAp.

  13. Methotrexate Increases Skeletal Muscle GLUT4 Expression and Improves Metabolic Control in Experimental Diabetes

    Directory of Open Access Journals (Sweden)

    Giuseppina T. Russo

    2012-01-01

    Full Text Available Long-term administration of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR mimics the effects of endurance exercise by activating AMP kinase and by increasing skeletal muscle expression of GLUT4 glucose transporter. AICAR is an intermediate in the purine de novo synthesis, and its tissue concentrations can be increased, in vivo, by low doses of methotrexate (MTX through the inhibition of the enzyme AICAR transformylase. We report here the first evidence that, in experimental type 2 diabetes, chronic treatment with low doses of MTX increases skeletal muscle GLUT4 expression and improves metabolic control. MTX (0.5 mg/kg body weight or vehicle was administered intraperitoneally, once a week for 4 weeks, to genetically diabetic female C57BL/KsJ-m+/+Leptdb mice (db+/db+ and their normoglycemic littermates (db+/+m. In the db+/db+ mice, MTX treatment was associated with a ∼2-fold increase in skeletal muscle GLUT4 protein concentration and a >4-fold increase in GLUT4 mRNA expression (P<0.01, all, as compared to vehicle-treated mice; no significant differences were noted in controls. MTX treatment was also associated with a significant reduction of glucose and insulin serum concentrations in diabetic mice (P<0.001, and glucose levels only (P<0.05 in controls. These data indicate a different route to increase skeletal muscle GLUT4 expression, through the potential inhibition of the enzyme AICAR transformylase.

  14. Use of methotrexate in the treatment of psoriasis and psoriatic arthritis

    Directory of Open Access Journals (Sweden)

    Tatiana Viktorovna Korotaeva

    2013-01-01

    Full Text Available Objective: To analyze the results of using methotrexate (MT in the treatment of psoriasis and psoriatic arthritis (PsA. Results. The mechanism of action of MT, the historical aspects of its use in the treatment of psoriasis and PsA, and the data of clinical trials of the efficacy and safety of the drug are considered. MT therapy is shown to cause a high rate of adverse reactions, which requires measures to prevent and treat adverse events. MT has been found to be frequently used in different combinations, including with other disease-modifying antirheumatic drugs (sulfasalazine, prednisolone, and biological agents, such as tumor necrosis factor inhibitors. In accordance with the European S3-guidelines S3 on the systemic treatment of psoriasis, MT (15-22.5 mg weekly should be recommended from the results of randomized clinical trials and the extensive clinical experience with this drug. In terms of the present-day views, the indications for immunosuppressive therapy for PsA may be expanded it should be initiated in the early stage of the disease, particularly in its severe forms, until there are destructive changes in the osteoarticular apparatus. Conclusion. MT is an effective drug to treat psoriasis and PsA. It is recommended for use in moderate and severe peripheral arthritis (Grade B and skin lesions (Grade A.

  15. Smart thermo/pH responsive magnetic nanogels for the simultaneous delivery of doxorubicin and methotrexate.

    Science.gov (United States)

    Salehi, Roya; Rasouli, Sepideh; Hamishehkar, Hamed

    2015-06-20

    Two novel dual temperature/pH-sensitive superparamagnetic nanogels were developed with the aim of simultaneously delivering two different anticancer drugs, doxorubicin (DOX) and methotrexate (MTX). The studied copolymers were characterized by (1)H NMR, SEM, and FTIR spectroscopy. Morphological investigations showed that both blank and drug-loaded nanogels had uniform shapes with a mean diameter of less than 30 nm. The drug storage/release behaviors were investigated. The nanogels showed an encapsulation efficiency of about 95% for both drugs. The cumulative in vitro release of the DOX/MTX-loaded nanogels exhibited an apparent thermo/pH-triggered controlled drug release in a sustained manner that was able to distinguish between tumor tissues. The cytotoxicity assay of a blank carrier to MCF7 and MDA-MB-231 cell lines indicated that the nanogels were suitable as drug carriers. Cell viability experiments further confirmed that the co-administration of DOX with MTX had a superior cytotoxicity to the mentioned cells compared with free dual drug- or single drug-loaded forms. Therefore, dual anticancer drug-loaded thermo/pH-sensitive nanogels have the potential to be used for cancer therapy, because they maintain a low premature drug release during blood circulation while having a rapid release upon reaching tumorous tissue.

  16. Oral to subcutaneous methotrexate dose-conversion strategy in the treatment of rheumatoid arthritis.

    Science.gov (United States)

    Schiff, Michael H; Sadowski, Peter

    2017-02-01

    Both the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) guidelines recommend the use of methotrexate (MTX) for the treatment of rheumatoid arthritis (RA) when there is no contraindication. While MTX is the foundation of RA therapy (Singh et al. in Arthritis Care Res 64:625-639,2012), absorption saturation compromises its oral bioavailability (BA). Differences in the relative BA of oral versus subcutaneous (SC) MTX demonstrate the need for guidance on successful dose-conversion strategies. This study was designed to compare MTX PK profiles as a result of MTX administration via three different treatment administrations: oral, SC MTX administered via an auto-injector (MTXAI) into the abdomen (MTXAIab) and into the thigh (MTXAIth). In this paper, we establish a dose-conversion method based on the BA of MTX from oral and SC administration. SC administration provided higher exposure of MTX than the same dose given orally. Unlike the exposure limitations of oral MTX, dose-proportional exposure was seen with SC MTX.

  17. 1HNMR study of methotrexate serum albumin (MTX SA) binding in rheumatoid arthritis

    Science.gov (United States)

    Sułkowska, A.; Maciążek-Jurczyk, M.; Bojko, B.; Równicka, J.; Sułkowski, W. W.

    2008-11-01

    Rheumatoid arthritis (RA) is an immunologically depended disease. It is characterized by a chronic, progressive inflammatory process. Methotrexate (4-amino-10-methylfolic acid, MTX) is the modifying drug used to treat RA. The aim of the presented studies is to determine the low affinity binding site of MTX in bovine (BSA) and human (HSA) serum albumin with the use of proton nuclear magnetic resonance ( 1HNMR) spectroscopy. The analysis of 1HNMR spectra of MTX in the presence of serum albumin (SA) allows us to observe the interactions between aromatic rings of the drug and the rings of amino acids located in the hydrophobic subdomains of the protein. On the basis of the chemical shifts σ [ppm] and the relaxation times T1 [s] of drug protons the hydrophobic interaction between MTX-SA and the stoichiometric molar ratio of the complex was evaluated. This work is a part of a spectroscopic study on MTX-SA interactions [A. Sułkowska, M. Maciążek, J. Równicka, B. Bojko, D. Pentak, W.W. Sułkowski, J. Mol. Struct. 834-836 (2007) 162-169].

  18. Methotrexate-conjugated magnetic nanoparticles for thermochemotherapy and magnetic resonance imaging of tumor

    Energy Technology Data Exchange (ETDEWEB)

    Gao Fuping, E-mail: gaofp158@gmail.com [Tsinghua University, Key Laboratory of Particle and Radiation Imaging, Ministry of Education, Institute of Medical Physics and Engineering, Department of Engineering Physics (China); Yan Zixing [Shanxi Medical University, Second Hospital (China); Zhou Jing; Cai Yuanyuan; Tang Jintian, E-mail: tangjt@mail.tsinghua.edu.cn [Tsinghua University, Key Laboratory of Particle and Radiation Imaging, Ministry of Education, Institute of Medical Physics and Engineering, Department of Engineering Physics (China)

    2012-10-15

    There is significant interest in recent years in developing magnetic nanoparticles (MNPs) having multifunctional characteristics with complimentary roles. In this study, methotrexate (MTX) was conjugated on the iron oxide magnetic nanoparticles surface via a poly(ethyleneimine) self-assembled monolayer (MTX-MNPs). The novel platform combined cancer chemotherapy, hyperthermia and potential monitoring of the progression of disease through magnetic resonance imaging (MRI). The conjugation of MTX on the magnetite surface was confirmed by Fourier transform infrared spectroscopy and change of zeta potential. Transmission electron microscope (TEM) showed that MTX-MNPs were morphologically spherical. The average diameter of MTX-MNPs was 30.1 {+-} 5.2 nm determined by dynamic light scattering. Magnetic measurements revealed that the saturation magnetization of MTX-MNPs reached 68.8 emu/g and the nanoparticles were superparamagnetic. The MTX-MNPs had good heating properties in an alternating magnetic field. TEM results showed that a larger number of MTX-MNPs were internalized into the MCF-7 cellular cytoplasm compared with the MNPs. The MTX-MNPs demonstrated highly synergistic antiproliferative effects of simultaneous chemotherapy and hyperthermia in MCF-7 breast cancer cells. A significant negative contrast enhancement was observed with magnetic resonance phantom imaging for MCF-7 cells over L929cells, when both were cultured with the nanoconjugate. The MTX-MNPs with combined characteristics of thermochemotherapy and MRI could be of high clinical significance in the treatment of tumor.

  19. Interactions among Low Dose of Methotrexate and Drugs Used in the Treatment of Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Marinella Patanè

    2013-01-01

    Full Text Available Methotrexate (MTX is a nonbiological disease-modifying antirheumatic drug that has shown both a good control of clinical disease and a good safety. Usually drug-drug interactions (DDIs represent the most limiting factor during the clinical management of any disease, in particular when several drugs are coadministered to treat the same disease. In this paper, we report the interactions among MTX and the other drugs commonly used in the management of rheumatoid arthritis. Using Medline, PubMed, Embase, Cochrane libraries, and Reference lists, we searched for the articles published until June 30, 2012, and we reported the most common DDIs between MTX and antirheumatic drugs. In particular, clinically relevant DDIs have been described during the treatment with MTX and NSAIDs, for example, diclofenac, indomethacin, or COX-2 inhibitors, and between MTX and prednisone or immunosuppressant drugs (e.g., leflunomide and cyclosporine. Finally, an increase in the risk of infections has been recorded during the combination treatment with MTX plus antitumor necrosis factor-α agents. In conclusion, during the treatment with MTX, DDIs play an important role in both the development of ADRs and therapeutic failure.

  20. Folate antagonist, methotrexate induces neuronal differentiation of human embryonic stem cells transplanted into nude mouse retina.

    Science.gov (United States)

    Hara, Akira; Taguchi, Ayako; Aoki, Hitomi; Hatano, Yuichiro; Niwa, Masayuki; Yamada, Yasuhiro; Kunisada, Takahiro

    2010-06-25

    Transplanted embryonic stem (ES) cells can be integrated into the retinas of adult mice as well-differentiated neuroretinal cells. However, the transplanted ES cells also have a tumorigenic activity as they have the ability for multipotent differentiation to various types of tissues. In the present study, human ES (hES) cells were transplanted into adult nude mouse retinas by intravitreal injections 20 h after intravitreal N-methyl-D-aspartate (NMDA) administration. After the transplantation of hES cells, the folate antagonist, methotrexate (MTX) was administrated in order to control the differentiation of the transplanted hES cells. Neuronal differentiation and teratogenic potential of hES cells were examined immunohistochemically 5 weeks after transplantation. The proliferative activity of transplanted cells was determined by both the mitotic index and the Ki-67 proliferative index. Disappearance of Oct-4-positive hES cells showing undifferentiated morphology was observed after intraperitoneal MTX treatment daily, for 15 days. Decreased mitotic and Ki-67 proliferative indices, and increased neuronal differentiation were detected in the surviving hES cells after the MTX treatment. These results suggest two important effects of intraperitoneal MTX treatment for hES cells transplanted into nude mouse retina: (1) MTX treatment following transplantation induces neuronal differentiation, and (2) MTX decreases proliferative activity and tumorigenic potential.

  1. Folic acid conjugated guar gum nanoparticles for targeting methotrexate to colon cancer.

    Science.gov (United States)

    Sharma, Monika; Malik, Ritu; Verma, Ashwni; Dwivedi, Pankaj; Banoth, Gabbar Singh; Pandey, Nagendra; Sarkar, Jayant; Mishra, Prabhat Ranjan; Dwivedi, Anil Kumar

    2013-01-01

    It was envisaged to develop surface modified Guar Gum Nanoparticles (GGNP) with Folic acid (FA) charged with methotrexate (MTX) to target the colon specifically. The MTX loaded FA functionalized GGNP (MTX-FA-GGNP) have been prepared by emulsion crosslinking method. These surface modified nanoparticles were compared with unmodified MTX loaded GGNP (MTX-GGNP). The developed formulations were evaluated for size and size distribution, zeta potential, Differential Scanning Calorimetry (DSC), release profile and uptake studies. The nanoparticles have been found to have average size of 325 nm in diameter having polydispersity index (PDI) 0.177 indicating mono-disperse particles. The zeta potential of the particles was found to be -36.9 mV. The percent growth inhibition of Caco 2 cells with MTX-FA-GGNP was found to be better than MTX-GGNP indicating folate receptor mediated uptake. The MTX-GGNP protects the release of MTX in upper gastrointestinal tract while maximum release of MTX occurred in simulated colonic fluids of pH 6.8. The in vivo uptake studies revealed preferential uptake of nanoparticles formulation in the colon. These studies provide evidences that MTX-FA-GGNP holds promise to address colorectal cancer over-expressing folate receptors. This prototype formulation enjoys dual advantage of having propensity to release the drug in the colon and in the conditions of colorectal carcinoma; it could be better localized and targeted with improved therapy due to over-expression of folate receptors.

  2. Localized and systemic scleroderma show different histological responses to methotrexate therapy.

    Science.gov (United States)

    Seyger, M M; van den Hoogen, F H; van Vlijmen-Willems, I M; van de Kerkhof, P C; de Jong, E M

    2001-04-01

    Although morphoea (localized scleroderma) and systemic sclerosis are distinct disease entities, the skin lesions show identical histological characteristics and both diseases respond favourably to low-dose treatment with methotrexate (MTX). The aim of this study was to find out whether MTX treatment induces different histological response patterns in these two diseases. In seven patients with morphoea and eight with systemic sclerosis, skin biopsies were taken before and after 24 weeks of treatment with low-dose MTX. In the centre and active margin of morphoea lesions, a significant reduction in tenascin staining was seen after 24 weeks of treatment, in contrast to systemic sclerosis. The numbers of mast cells decreased in the active margin of morphoea lesions, whereas in systemic sclerosis no significant change was seen after MTX therapy. Epidermal proliferation and staining of heparan sulphate proteoglycans showed no changes. Although skin lesions from both diseases respond clinically to treatment with MTX, systemic sclerosis shows no change in the immunohistochemical parameters investigated, whereas morphoea does. This difference in dynamic pattern suggests that the apparently similar lesions in localized and systemic sclerosis are not identical.

  3. NEW RECOMMENDATIONS FOR THE MANAGEMENT OF RHEUMATOID ARTHRITIS (EULAR, 2013: THE ROLE OF METHOTREXATE

    Directory of Open Access Journals (Sweden)

    Evgeniy L Nasonov

    2014-01-01

    Full Text Available In our previous publication, we reported the main provisions of the new EULAR recommendations (2013 and discussed some debating points of RA pharmacotherapy that require further research. The purpose of this article is to review the present-day knowledge concerning the use of methotrexate (MT, since according to the EULAR recommendations, “MT should be considered as the main component of the strategy of the first-line treatment of active RA”. In the context of EULAR recommendations, special priority was given to the discussion of MT administration in patients with early inflammatory (undifferentiated arthritis (UDA and early RA, efficacy of MT monotherapy and combined therapy, including, along with MT, the standard basic anti-rheumatic drugs (DMARDs and genetically engineered biological drugs (GEBDs, the role of MT in the induction and maintenance of remission, including remission without treatment with GEBDs. A conclusion was drawn that administration of MT is required in all patients with early RA and probably in patients with UDA in case of high risk of the disease transformation into RA. Early administration of the subcutaneous form of MT improves the efficacy of RA treatment and should be a mandatory component of the intensive RA treatment strategies, regardless of the use of glucocorticoids and other standard DMARDs and GEBDs. In patients with high disease activity, who require administration of high dose of MT or different schemes of combined treatment, it is advisable to begin the treatment with the injectable form of MT rather than tablet one.

  4. Dioscin enhances methotrexate absorption by down-regulating MDR1 in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Lijuan, E-mail: jlwang1979@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Wang, Changyuan, E-mail: wangcyuan@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); Peng, Jinyong, E-mail: jinyongpeng2005@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); Liu, Qi, E-mail: llaqii@yahoo.com.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); Meng, Qiang, E-mail: mengq531@yahoo.cn [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); Sun, Huijun, E-mail: sunhuijun@hotmail.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); Huo, Xiaokui, E-mail: huoxiaokui@163.com [Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China); Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning (China); and others

    2014-06-01

    The purpose of this study was to investigate the enhancing effect of dioscin on the absorption of methotrexate (MTX) and clarify the molecular mechanism involved in vivo and in vitro. Dioscin increased MTX chemosensitivity and transepithelial flux in the absorptive direction, significantly inhibiting multidrug resistance 1 (MDR1) mRNA and protein expression and MDR1 promoter and nuclear factor κ-B (NF-κB) activities in Caco-2 cells. Moreover, inhibitor κB-α (IκB-α) degradation was inhibited by dioscin. Dioscin enhanced the intracellular concentration of MTX by down-regulating MDR1 expression through a mechanism that involves NF-κB signaling pathway inhibition in Caco-2 cells. Dioscin strengthened MTX absorption by inhibiting MDR1 expression in rat intestine. In addition, even though MTX is absorbed into the enterocytes, there was no increase in toxicity observed, and that, in fact, decreased toxicity was seen. - Highlights: • Dioscin raised MTX concentration by inhibiting MDR1 in Caco-2 cells. • Dioscin suppresses MDR1 by inhibiting NF-κB signaling pathway in Caco-2 cells. • Dioscin can enhance MTX absorption via inhibiting MDR1 in vivo and in vitro. • Dioscin did not increase MTX-induced gastrointestinal mucosal toxicity.

  5. Preliminary neutron diffraction studies of Escherichia coli dihydrofolate reductase bound to the anticancer drug methotrexate

    Energy Technology Data Exchange (ETDEWEB)

    Bennett, Brad C. [University of Tennessee, Knoxville (UTK); Meilleur, Flora [Institut Laue-Langevin (ILL); Myles, Dean A A [ORNL; Howell, Elizabeth E. [University of Tennessee, Knoxville (UTK); Dealwis, Chris G. [University of Tennessee, Knoxville (UTK)

    2005-01-01

    The contribution of H atoms in noncovalent interactions and enzymatic reactions underlies virtually all aspects of biology at the molecular level, yet their 'visualization' is quite difficult. To better understand the catalytic mechanism of Escherichia coli dihydrofolate reductase (ecDHFR), a neutron diffraction study is under way to directly determine the accurate positions of H atoms within its active site. Despite exhaustive investigation of the catalytic mechanism of DHFR, controversy persists over the exact pathway associated with proton donation in reduction of the substrate, dihydrofolate. As the initial step in a proof-of-principle experiment which will identify ligand and residue protonation states as well as precise solvent structures, a neutron diffraction data set has been collected on a 0.3 mm{sup 3} D{sub 2}O-soaked crystal of ecDHFR bound to the anticancer drug methotrexate (MTX) using the LADI instrument at ILL. The completeness in individual resolution shells dropped to below 50% between 3.11 and 3.48 {angstrom} and the I/{sigma}(I) in individual shells dropped to below 2 at around 2.46 {angstrom}. However, reflections with I/{sigma}(I) greater than 2 were observed beyond these limits (as far out as 2.2 {angstrom}). To our knowledge, these crystals possess one of the largest primitive unit cells (P6{sub 1}, a = b = 92, c = 73 {angstrom}) and one of the smallest crystal volumes so far tested successfully with neutrons.

  6. MRI in methotrexate-related leukoencephalopathy: Disseminated necrotising leukoencephalopathy in comparison with mild leukoencephalopathy

    Energy Technology Data Exchange (ETDEWEB)

    Oka, M. [Department of Radiology, Hokkaido Graduate University School of Medicine, 060-8638, Sapporo (Japan); Department of Radiology, St Luke' s International Hospital, 9-1 Akashi-cho Chuo-ku, 104-8560, Tokyo (Japan); Terae, S.; Kudoh, K.; Tha, K.K.; Miyasaka, K. [Department of Radiology, Hokkaido Graduate University School of Medicine, 060-8638, Sapporo (Japan); Kobayashi, R.; Yoshida, M.; Suzuki, Y. [Department of Paediatrics, Hokkaido Graduate University School of Medicine, 060-8638, Sapporo (Japan); Sawamura, Y.; Kaneda, M. [Department of Neurosurgery, Hokkaido Graduate University School of Medicine, 060-8638, Sapporo (Japan)

    2003-07-01

    We report two fatal cases of methotrexate (MTX)-induced disseminated necrotising leukoencephalopathy (DNL) in which MRI was repeated from the onset. Initial T2-weighted images showed multiple areas of high signal, mainly in deep cerebral white matter, which on follow-up, spread and coalesced to involve the entire white matter. Small irregular low-signal foci on T2-weighted images were seen within the high-signal lesions. Multiple areas of contrast enhancement corresponded to these low-signal foci. The condition of both patients deteriorated and they died. We compared their MRI findings with those of seven patients with mild MTX-related leukoencephalopathy, six of whom were asymptomatic; one had transient neurological symptoms. They showed no contrast enhancement, but rather mild-to-moderate diffuse high signal in deep white matter, which later disappeared. These findings suggest that multiple low-signal foci on T2-weighted images with contrast enhancement may be characteristic of DNL, and that contrast-enhanced imaging is useful to differentiate this condition from mild leukoencephalopathy. (orig.)

  7. Whole brain magnetization transfer histogram analysis of pediatric acute lymphoblastic leukemia patients receiving intrathecal methotrexate therapy

    Energy Technology Data Exchange (ETDEWEB)

    Yamamoto, Akira [Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi Kyoto 606-8507 (Japan)]. E-mail: yakira@kuhp.kyoto-u.ac.jp; Miki, Yukio [Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi Kyoto 606-8507 (Japan)]. E-mail: mikiy@kuhp.kyoto-u.ac.jp; Adachi, Souichi [Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto-shi Kyoto 606-8507 (Japan)]. E-mail: sadachi@kuhp.kyoto-u.ac.jp (and others)

    2006-03-15

    Background and purpose: The purpose of this prospective study was to evaluate the hypothesis that magnetization transfer ratio (MTR) histogram analysis of the whole brain could detect early and subtle brain changes nonapparent on conventional magnetic resonance imaging (MRI) in children with acute lymphoblastic leukemia (ALL) receiving methotrexate (MTX) therapy. Materials and methods: Subjects in this prospective study comprised 10 children with ALL (mean age, 6 years; range, 0-16 years). In addition to conventional MRI, magnetization transfer images were obtained before and after intrathecal and intravenous MTX therapy. MTR values were calculated and plotted as a histogram, and peak height and location were calculated. Differences in peak height and location between pre- and post-MTX therapy scans were statistically analyzed. Conventional MRI was evaluated for abnormal signal area in white matter. Results: MTR peak height was significantly lower on post-MTX therapy scans than on pre-MTX therapy scans (p = 0.002). No significant differences in peak location were identified between pre- and post-chemotherapy imaging. No abnormal signals were noted in white matter on either pre- or post-MTX therapy conventional MRI. Conclusions: This study demonstrates that MTR histogram analysis allows better detection of early and subtle brain changes in ALL patients who receive MTX therapy than conventional MRI.

  8. Folylpolyglutamate synthase is a major determinant of intracellular methotrexate polyglutamates in patients with rheumatoid arthritis

    Science.gov (United States)

    Yamamoto, Tatsuhiro; Shikano, Kotaro; Nanki, Toshihiro; Kawai, Shinichi

    2016-01-01

    We investigated major determinants of the intracellular concentrations of methotrexate polyglutamates (MTXPGs) in patients with rheumatoid arthritis (RA). In 271 RA patients on stable oral low dose weekly pulse MTX therapy, the concentrations of MTXPGs in red blood cells (RBCs) were measured by liquid chromatography-electrospray ionization-tandem mass spectrometry. Polymerase chain reaction-restriction fragment length polymorphism analysis was performed to determine the genotypes of solute carrier family 19 member 1 (SLC19A1), folylpolyglutamate synthase (FPGS), and gamma-glutamyl hydrolase (GGH). The mean total MTXPG concentration and the concentrations of individual MTXPGs increased dose-dependently, but reached a plateau at MTX doses >10 mg weekly. The MTXPG3-5/1-2 ratio was lower in patients with adverse events related to MTX than in patients without adverse events. Three polymorphisms of FPGS significantly influenced the MTXPG3-5/1-2 ratio in RBCs, while polymorphisms of SLC19A1 and GGH had no impact. The minor allele frequencies of 2 FPGS genotypes were significantly increased in our patients compared with a Caucasian population. FPGS may have a major role in regulating intracellular polyglutamation of MTX in RA patients receiving low-dose weekly MTX therapy. PMID:27752107

  9. Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis.

    Science.gov (United States)

    Kolli, V K; Natarajan, K; Isaac, B; Selvakumar, D; Abraham, P

    2014-10-01

    The efficacy of methotrexate (MTX), a widely used chemotherapeutic drug, is limited by its gastrointestinal toxicity and the mechanism of which is not clear. The present study investigates the possible role of mitochondrial damage in MTX-induced enteritis. Small intestinal injury was induced in Wistar rats by the administration of 7 mg kg(-1) body wt. MTX intraperitoneally for 3 consecutive days. MTX administration resulted in severe small intestinal injury and extensive damage to enterocyte mitochondria. Respiratory control ratio, the single most useful and reliable test of mitochondrial function, and 3-(4,5-dimethylthiazol-2-yll)-2,5-diphenyltetrazolium bromide reduction, a measure of cell viability were significantly reduced in all the fractions of MTX-treated rat enterocytes. A massive decrease (nearly 70%) in the activities of complexes II and IV was also observed. The results of the present study suggest that MTX-induced damage to enterocyte mitochondria may play a critical role in enteritis. MTX-induced alteration in mitochondrial structure may cause its dysfunction and decreases the activities of the electron chain complexes. MTX-induced mitochondrial damage can result in reduced adenosine triphosphate synthesis, thereby interfering with nutrient absorption and enterocyte renewal. This derangement may contribute to malabsorption of nutrients, diarrhea, and weight loss seen in patients on MTX chemotherapy.

  10. Primary Hepatic Lymphoma in a Patient with Rheumatoid Arthritis Treated with Methotrexate

    Directory of Open Access Journals (Sweden)

    Goichi Tatsumi

    2014-01-01

    Full Text Available Primary hepatic lymphoma (PHL has rarely been reported in patients with immunosuppression. We herein describe a case of Epstein-Barr virus- (EBV- positive PHL in a 67-year-old Japanese woman receiving methotrexate (MTX treatment for rheumatoid arthritis (RA. The patient, who had been receiving MTX therapy for more than 6 years, presented with low-grade fever and abdominal pain. Initial laboratory tests showed mildly elevated liver enzymes with normal levels of alpha-fetoprotein and carcinoembryonic antigen, and computed tomography scans revealed multiple hepatic tumors with no lymph-node swelling. Examination of liver specimens obtained via ultrasonography-guided needle biopsy indicated EBV-positive diffuse large B cell lymphoma; therefore, she was diagnosed with PHL. MTX was discontinued, and she was carefully monitored thereafter owing to the prolonged history of MTX administration for RA. Rapid progression of PHL was observed; therefore 10 days after the PHL diagnosis, she received 6 cycles of R-THP-COP (rituximab, cyclophosphamide, pirarubicin, vincristine, and prednisolone therapy and achieved complete remission for more than 1 year. Although MTX-associated lymphoproliferative disorders often show remission after withdrawal of MTX, early diagnosis and treatment are essential for PHL in patients with RA treated with MTX, because of the aggressive nature of the disease.

  11. The isobutylene-isobutane alkylation process in liquid HF revisited.

    Science.gov (United States)

    Esteves, P M; Araújo, C L; Horta, B A C; Alvarez, L J; Zicovich-Wilson, C M; Ramírez-Solís, A

    2005-07-07

    Details on the mechanism of HF catalyzed isobutylene-isobutane alkylation were investigated. On the basis of available experimental data and high-level quantum chemical calculations, a detailed reaction mechanism is proposed taking into account solvation effects of the medium. On the basis of our computational results, we explain why the density of the liquid media and stirring rates are the most important parameters to achieve maximum yield of alkylate, in agreement with experimental findings. The ab initio Car-Parrinello molecular dynamics calculations show that isobutylene is irreversibly protonated in the liquid HF medium at higher densities, leading to the ion pair formation, which is shown to be a minimum on the potential energy surface after optimization using periodic boundary conditions. The HF medium solvates preferentially the fluoride anion, which is found as solvated [FHF](-) or solvated F(-.)(HF)(3). On the other hand, the tert-butyl cation is weakly solvated, where the closest HF molecules appear at a distance of about 2.9 Angstrom with the fluorine termination of an HF chain.

  12. Self-Powered Analogue Smart Skin.

    Science.gov (United States)

    Shi, Mayue; Zhang, Jinxin; Chen, Haotian; Han, Mengdi; Shankaregowda, Smitha A; Su, Zongming; Meng, Bo; Cheng, Xiaoliang; Zhang, Haixia

    2016-04-26

    The progress of smart skin technology presents unprecedented opportunities for artificial intelligence. Resolution enhancement and energy conservation are critical to improve the perception and standby time of robots. Here, we present a self-powered analogue smart skin for detecting contact location and velocity of the object, based on a single-electrode contact electrification effect and planar electrostatic induction. Using an analogue localizing method, the resolution of this two-dimensional smart skin can be achieved at 1.9 mm with only four terminals, which notably decreases the terminal number of smart skins. The sensitivity of this smart skin is remarkable, which can even perceive the perturbation of a honey bee. Meanwhile, benefiting from the triboelectric mechanism, extra power supply is unnecessary for this smart skin. Therefore, it solves the problems of batteries and connecting wires for smart skins. With microstructured poly(dimethylsiloxane) films and silver nanowire electrodes, it can be covered on the skin with transparency, flexibility, and high sensitivity.

  13. Dynamic Analogue Initialization for Ensemble Forecasting

    Institute of Scientific and Technical Information of China (English)

    LI Shan; RONG Xingyao; LIU Yun; LIU Zhengyu; Klaus FRAEDRICH

    2013-01-01

    This paper introduces a new approach for the initialization of ensemble numerical forecasting:Dynamic Analogue Initialization (DAI).DAI assumes that the best model state trajectories for the past provide the initial conditions for the best forecasts in the future.As such,DAI performs the ensemble forecast using the best analogues from a full size ensemble.As a pilot study,the Lorenz63 and Lorenz96 models were used to test DAI's effectiveness independently.Results showed that DAI can improve the forecast significantly.Especially in lower-dimensional systems,DAI can reduce the forecast RMSE by ~50% compared to the Monte Carlo forecast (MC).This improvement is because DAI is able to recognize the direction of the analysis error through the embedding process and therefore selects those good trajectories with reduced initial error.Meanwhile,a potential improvement of DAI is also proposed,and that is to find the optimal range of embedding time based on the error's growing speed.

  14. Long-term predictions using natural analogues

    Energy Technology Data Exchange (ETDEWEB)

    Ewing, R.C. [Univ. of New Mexico, Albuquerque, NM (United States)

    1995-09-01

    One of the unique and scientifically most challenging aspects of nuclear waste isolation is the extrapolation of short-term laboratory data (hours to years) to the long time periods (10{sup 3}-10{sup 5} years) required by regulatory agencies for performance assessment. The direct validation of these extrapolations is not possible, but methods must be developed to demonstrate compliance with government regulations and to satisfy the lay public that there is a demonstrable and reasonable basis for accepting the long-term extrapolations. Natural systems (e.g., {open_quotes}natural analogues{close_quotes}) provide perhaps the only means of partial {open_quotes}validation,{close_quotes} as well as data that may be used directly in the models that are used in the extrapolation. Natural systems provide data on very large spatial (nm to km) and temporal (10{sup 3}-10{sup 8} years) scales and in highly complex terranes in which unknown synergisms may affect radionuclide migration. This paper reviews the application (and most importantly, the limitations) of data from natural analogue systems to the {open_quotes}validation{close_quotes} of performance assessments.

  15. Synthesis of 2-substituted tryptophans via a C3- to C2-alkyl migration

    Directory of Open Access Journals (Sweden)

    Michele Mari

    2014-08-01

    Full Text Available The reaction of 3-substituted indoles with dehydroalanine (Dha derivatives under Lewis acid-mediated conditions has been investigated. The formation of 2-substituted tryptophans is proposed to occur through a selective alkylative dearomatization–cyclization followed by C3- to C2-alkyl migration and rearomatization.

  16. The Retention Behaviors of Benzene and Its Alkyl Homologues in Microemulsion Electrokinetic Chromatography

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The retention behaviors of benzene and its alkyl homologues in microemulsion electrokinetic chromatography were investigated in both anionic and cationic surfactant MEEKC systems. The effects of the composition of microemulsion on retention time and selectivity were studied. A good linear relationship was obtained between log k' and the carbon number of alkyl chain.

  17. A new procedure for N1-alkylation of imidazolidin-4-ones and its NMR characterization

    Science.gov (United States)

    Vale, Nuno; Figueiredo, Patrícia

    2016-12-01

    N1-unsubstituted imidazolidin-4-ones of primaquine (PQ) can be stabilized by N1-alkylation under basic conditions. Here we report the development, with our conditions, of peptidomimetic derivatives of PQ with L-amino acid and alkyl derivatives. The new derivatives represent potential new therapeutics for use against protozoan parasites, through enzymatic protection of aminopeptidases.

  18. Catalytic Alkylation of 2-Methylfuran with Formalin Using Supported Acidic Ionic Liquids

    DEFF Research Database (Denmark)

    Li, Hu; Shunmugavel, Saravanamurugan; Yang, Song;

    2015-01-01

    Biphasic alkylation of 2-methylfuran (2-MF) with formalin was carried out with a series of SBA-15 supported acidic ionic liquid catalysts (acidic SILCs) under mild reaction conditions. Acidic SILC with sulfonic acid groups (SO3H) and long alkyl chains was observed to have higher catalytic activity...

  19. The asymmetric alkylation of dimethylhydrazones; intermolecular chirality transfer using sparteine as chiral ligand.

    Science.gov (United States)

    McSweeney, Christina M; Foley, Vera M; McGlacken, Gerard P

    2014-12-01

    The asymmetric alkylation of ketones represents a fundamental transformation in organic chemistry. Chiral auxiliaries have been used almost exclusively for this transformation. Herein we describe a strategy for the generation of enantiomerically enriched α-alkylated ketones up to an er of 83 : 17, using a chiral ligand protocol.

  20. Sources and proxy potential of long chain alkyl diols in lacustrine environments.

    NARCIS (Netherlands)

    Rampen, Sebastiaan W.; Datema, Mariska; Rodrigo-Gámiz, M.; Schouten, Stefan; Reichart, Gert-Jan; Sinninghe Damste, Jaap S.

    2014-01-01

    Long chain 1,13- and 1,15-alkyl diols form the base of a number of recently proposed proxies used for climate reconstruction. However, the sources of these lipids and environmental controls on their distribution are still poorly constrained. We have analyzed the long chain alkyl diol (LCD) compositi