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Sample records for hydroxyurea induces hydroxyl

  1. [Hydroxyurea-induced pneumonia].

    Science.gov (United States)

    Girard, A; Ricordel, C; Poullot, E; Claeyssen, V; Decaux, O; Desrues, B; Delaval, P; Jouneau, S

    2014-05-01

    Hydroxyurea is an antimetabolite drug used in the treatment of myeloproliferative disorders. Common adverse effects include haematological, gastrointestinal cutaneous manifestations, and fever. Hydroxyurea-induced pneumonitis is unusual. A female patient was treated with hydroxyurea for polycythemia vera. She was admitted 20 days after commencing treatment with a high fever, productive cough, clear sputum and nausea. A chest CT-scan showed diffuse ground-glass opacities. Microbiological investigations were negative. The symptoms disappeared a few days after discontinuation of the drug and rechallenge led to a relapse of symptoms. Our case and 15 earlier cases of hydroxyurea-induced pneumonitis are reviewed. Two patterns of this disease may exist: an acute febrile form occurring within 1 month of introduction of hydroxyurea and a subacute form without fever. Even if uncommon, one should be aware of this complication of hydroxyurea. Copyright © 2013. Published by Elsevier Masson SAS.

  2. Hydroxyurea-Induced Replication Stress

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    Kenza Lahkim Bennani-Belhaj

    2010-01-01

    Full Text Available Bloom's syndrome (BS displays one of the strongest known correlations between chromosomal instability and a high risk of cancer at an early age. BS cells combine a reduced average fork velocity with constitutive endogenous replication stress. However, the response of BS cells to replication stress induced by hydroxyurea (HU, which strongly slows the progression of replication forks, remains unclear due to publication of conflicting results. Using two different cellular models of BS, we showed that BLM deficiency is not associated with sensitivity to HU, in terms of clonogenic survival, DSB generation, and SCE induction. We suggest that surviving BLM-deficient cells are selected on the basis of their ability to deal with an endogenous replication stress induced by replication fork slowing, resulting in insensitivity to HU-induced replication stress.

  3. Hydroxyurea-induced oral ulceration.

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    Badawi, Maha; Almazrooa, Soulafa; Azher, Fatima; Alsayes, Fatin

    2015-12-01

    Hydroxyurea is an antimetabolite that is widely used in the treatment of many benign and malignant conditions. This drug is usually well tolerated but has a number of side effects that vary in incidence. In cases of clinically significant adverse events, hydroxyurea is usually discontinued either temporarily or permanently, depending on treatment need versus harm caused by side effects. Here, we report a case of oral ulceration associated with hydroxyurea treatment in a patient who had chronic myelogenous leukemia. The patient rapidly developed an oral ulcer 12 days after administration of the drug. Hydroxyurea was discontinued, and the oral lesion appreciably decreased in size and severity. Physicians and dentists should be aware of the association between hydroxyurea and oral lesions. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. A Cutaneous Lupus Erythematosus-Like Eruption Induced by Hydroxyurea.

    Science.gov (United States)

    Yanes, Daniel A; Mosser-Goldfarb, Joy L

    2017-01-01

    Hydroxyurea is a medication with many well-described cutaneous side effects, notably the dermatomyositis-like eruption known as hydroxyurea dermopathy. Although systemic lupus erythematosus has been reported with hydroxyurea use, cutaneous lupus has not. We report a novel case of chronic cutaneous lupus induced by hydroxyurea and propose that this is a side effect that is distinct from hydroxyurea dermopathy. © 2016 Wiley Periodicals, Inc.

  5. Hydroxyurea

    Science.gov (United States)

    Hydroxyurea (Hydrea) is used alone or with other medications or radiation therapy to treat a certain type ... the mouth, cheek, tongue, throat, tonsils, and sinuses). Hydroxyurea (Droxia, Siklos) is used to reduce the frequency ...

  6. Severe excessive daytime sleepiness induced by hydroxyurea.

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    Revol, Bruno; Joyeux-Faure, Marie; Albahary, Marie-Victoire; Gressin, Remy; Mallaret, Michel; Pepin, Jean-Louis; Launois, Sandrine H

    2017-06-01

    Excessive daytime sleepiness (EDS) has been reported with many drugs, either as an extension of a hypnotic effect (e.g. central nervous system depressants) or as an idiosyncratic response of the patient. Here, we report unexpected and severe subjective and objective EDS induced by hydroxyurea therapy, with a favorable outcome after withdrawal. Clinical history, sleep log, polysomnography, and multiple sleep latency tests confirming the absence of other EDS causes are presented. © 2016 Société Française de Pharmacologie et de Thérapeutique.

  7. A Hydroxyurea-induced Leg Ulcer

    OpenAIRE

    Hwang, Seon-Wook; Hong, Soon-Kwon; Kim, Sang-Hyun; Seo, Jong-Keun; Lee, Deborah; Sung, Ho-Suk

    2009-01-01

    Hydroxyurea is a cytostatic agent that has recently become the drug of choice in the treatment of various myeloproliferative diseases. The cutaneous side effects of hydroxyurea include xerosis, hyperpigmentation, nail discoloration, and scaling. Leg ulcers have only rarely been reported in association with hydroxyurea treatment. A 75-year-old woman presented with leg ulcers, nail discoloration, and xerosis. The leg ulcers were refractory to conventional treatment. She had been taking oral hyd...

  8. [Hydroxyurea (hydroxycarbamide)-induced hepatic dysfunction confirmed by drug-induced lymphocyte stimulation test].

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    Shimizu, Takayuki; Mori, Takehiko; Karigane, Daiki; Kikuchi, Taku; Koda, Yuya; Toyama, Takaaki; Nakajima, Hideaki; Okamoto, Shinichiro

    2014-01-01

    A 62-year-old man with refractory leukemia transformed from myelodysplastic syndrome was placed on hydroxyurea (hydroxycarbamide) at a daily dose of 500 mg. Because of insufficient cytoreductive efficacy, the dose was increased to 1,500 mg five days later. Eight days after the initiation of hydroxyurea, the patient started complaining of chills, fever, and vomiting. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly elevated to 5,098 and 3,880 IU/l from 44 and 59 IU/l in one day, respectively. Tests for hepatitis viruses were all negative. With the discontinuation of hydroxyurea, AST and ALT returned to their former levels within two weeks. A drug-induced lymphocyte stimulation test for hydroxyurea was positive with a stimulating index of 2.0. Hepatic dysfunction has been recognized as one of the side effects of hydroxyurea. However, there have been only a limited number of reports demonstrating drug allergy to have a role in hepatic dysfunction accompanied by fever and gastrointestinal symptoms. The findings of our case strongly suggest that all presentations could be explained by drug allergy. Physicians should be mindful of the potential for acute and severe hepatic dysfunction due to allergic reaction against hydroxyurea.

  9. Hydroxylated PBDEs induce developmental arrest in zebrafish

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    Usenko, Crystal Y., E-mail: Crystal_usenko@baylor.edu; Hopkins, David C.; Trumble, Stephen J., E-mail: Stephen_trumble@baylor.edu; Bruce, Erica D., E-mail: Erica_bruce@baylor.edu

    2012-07-01

    The ubiquitous spread of polybrominated diphenyl ethers (PBDEs) has led to concerns regarding the metabolites of these congeners, in particular hydroxylated PBDEs. There are limited studies regarding the biological interactions of these chemicals, yet there is some concern they may be more toxic than their parent compounds. In this study three hydroxylated PBDEs were assessed for toxicity in embryonic zebrafish: 3-OH-BDE 47, 5-OH-BDE 47, and 6-OH-BDE 47. All three congeners induced developmental arrest in a concentration-dependent manner; however, 6-OH-BDE 47 induced adverse effects at lower concentrations than the other congeners. Furthermore, all three induced cell death; however apoptosis was not observed. In short-term exposures (24–28 hours post fertilization), all hydroxylated PBDEs generated oxidative stress in the region corresponding to the cell death at 5 and 10 ppm. To further investigate the short-term effects that may be responsible for the developmental arrest observed in this study, gene regulation was assessed for embryos exposed to 0.625 ppm 6-OH-BDE 47 from 24 to 28 hpf. Genes involved in stress response, thyroid hormone regulation, and neurodevelopment were significantly upregulated compared to controls; however, genes related to oxidative stress were either unaffected or downregulated. This study suggests that hydroxylated PBDEs disrupt development, and may induce oxidative stress and potentially disrupt the cholinergic system and thyroid hormone homeostasis. -- Highlights: ► OH-PBDEs induce developmental arrest in a concentration-dependent manner. ► Hydroxyl group location influences biological interaction. ► OH-PBDEs induce oxidative stress. ► Thyroid hormone gene regulation was disrupted following exposure. ► To our knowledge, this is the first whole organism study of OH-PBDE toxicity.

  10. Myeloid Sarcoma Developing in Prexisting Hydroxyurea-Induced Leg Ulcer in a Polycythemia Vera Patient

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    Hatim Nafil

    2013-01-01

    Full Text Available Myeloid sarcoma (MS is an extramedullary tumour consisting of myeloblasts or immature myeloid cells located in an extramedullary site. It may occur at presentation of AML, at relapse, or prior to the onset of frank leukemia. We report a rare case of MS developing in prexisting Hydroxyurea-induced leg Ulcer in a 70-year-old woman.

  11. Hydroxyl radical induced degradation of ibuprofen

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    Illés, Erzsébet, E-mail: erzsebet.illes@chem.u-szeged.hu [Institute of Chemistry, Research Group of Environmental Chemistry, University of Szeged, Szeged (Hungary); Institute of Isotopes, Centre for Energy Research, Hungarian Academy of Sciences, Budapest (Hungary); Takács, Erzsébet [Institute of Isotopes, Centre for Energy Research, Hungarian Academy of Sciences, Budapest (Hungary); Dombi, András [Institute of Chemistry, Research Group of Environmental Chemistry, University of Szeged, Szeged (Hungary); Gajda-Schrantz, Krisztina [Institute of Chemistry, Research Group of Environmental Chemistry, University of Szeged, Szeged (Hungary); Department of Inorganic and Analytical Chemistry, University of Szeged, Szeged (Hungary); EMPA, Laboratory for High Performance Ceramics, Duebendorf (Switzerland); Rácz, Gergely; Gonter, Katalin; Wojnárovits, László [Institute of Isotopes, Centre for Energy Research, Hungarian Academy of Sciences, Budapest (Hungary)

    2013-03-01

    Pulse radiolysis experiments were used to characterize the intermediates formed from ibuprofen during electron beam irradiation in a solution of 0.1 mmol dm{sup −3}. For end product characterization {sup 60}Co γ-irradiation was used and the samples were evaluated either by taking their UV–vis spectra or by HPLC with UV or MS detection. The reactions of {sup ·}OH resulted in hydroxycyclohexadienyl type radical intermediates. The intermediates produced in further reactions hydroxylated the derivatives of ibuprofen as final products. The hydrated electron attacked the carboxyl group. Ibuprofen degradation is more efficient under oxidative conditions than under reductive conditions. The ecotoxicity of the solution was monitored by Daphnia magna standard microbiotest and Vibrio fischeri luminescent bacteria test. The toxic effect of the aerated ibuprofen solution first increased upon irradiation indicating a higher toxicity of the first degradation products, then decreased with increasing absorbed dose. Highlights: ► In hydroxyl radical attack on the ring mainly hydroxylated products form ► The hydrated electron attacks the carboxyl group. ► Oxidative conditions are more effective in ibuprofen decomposition than reductive. ► Ecotoxicity of ibuprofen solution first increases then decreases with irradiation.

  12. Hydroxyl radical induced degradation of ibuprofen

    International Nuclear Information System (INIS)

    Illés, Erzsébet; Takács, Erzsébet; Dombi, András; Gajda-Schrantz, Krisztina; Rácz, Gergely; Gonter, Katalin; Wojnárovits, László

    2013-01-01

    Pulse radiolysis experiments were used to characterize the intermediates formed from ibuprofen during electron beam irradiation in a solution of 0.1 mmol dm −3 . For end product characterization 60 Co γ-irradiation was used and the samples were evaluated either by taking their UV–vis spectra or by HPLC with UV or MS detection. The reactions of · OH resulted in hydroxycyclohexadienyl type radical intermediates. The intermediates produced in further reactions hydroxylated the derivatives of ibuprofen as final products. The hydrated electron attacked the carboxyl group. Ibuprofen degradation is more efficient under oxidative conditions than under reductive conditions. The ecotoxicity of the solution was monitored by Daphnia magna standard microbiotest and Vibrio fischeri luminescent bacteria test. The toxic effect of the aerated ibuprofen solution first increased upon irradiation indicating a higher toxicity of the first degradation products, then decreased with increasing absorbed dose. Highlights: ► In hydroxyl radical attack on the ring mainly hydroxylated products form ► The hydrated electron attacks the carboxyl group. ► Oxidative conditions are more effective in ibuprofen decomposition than reductive. ► Ecotoxicity of ibuprofen solution first increases then decreases with irradiation

  13. Dependence of u.v.-induced DNA excision repair on deoxyribonucleoside triphosphate concentrations in permeable human fibroblasts: a model for the inhibition of repair by hydroxyurea

    International Nuclear Information System (INIS)

    Hunting, D.J.; Dresler, S.L.

    1985-01-01

    We have tested the hypothesis that the inhibition by hydroxyurea of repair patch ligation and chromatin rearrangement during u.v.-induced DNA excision repair results from a reduction in cellular deoxyribonucleotide concentrations and not from a direct effect of hydroxyurea on the repair process. Using permeable human fibroblasts, we have shown that hydroxyurea has no direct effect on either repair synthesis or repair patch ligation. We also have shown that by reducing the deoxyribonucleoside triphosphate concentrations in the permeable cell reaction mixture, we can mimic the inhibition of repair patch ligation and chromatin rearrangement seen when u.v.-damaged intact confluent fibroblasts are treated with hydroxyurea. Our results are consistent with the concept that hydroxyurea inhibits DNA repair in intact cells by inhibiting deoxyribonucleotide synthesis through its effect on ribonucleotide reductase and, conversely, that continued deoxyribonucleotide synthesis is required for the excision repair of u.v.-induced DNA damage even in resting cells

  14. Twenty-Nail Transverse Melanonychia Induced by Hydroxyurea: Case Report and Review of the Literature.

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    Osemwota, Osamuede; Uhlemann, John; Rubin, Adam

    2017-08-01

    Twenty-nail transverse melanonychia from hydroxyurea is a rare phenomenon, only reported four times previously. Here we describe a 51-year-old female who presented with 20-nail transverse melanonychia 3 months after initiating hydroxyurea therapy. Transverse melanonychia is a benign process but can cause patients significant distress, and thus is an entity with which dermatologists should recognize. We then review the cutaneous manifestations, differential diagnosis, and clinical considerations when evaluating patients with transverse melanonychia from hydroxyurea or other causes. J Drugs Dermatol. 2017;16(8):814-815..

  15. Hydroxyl radical induced degradation of salicylates in aerated aqueous solution

    International Nuclear Information System (INIS)

    Szabó, László; Tóth, Tünde; Homlok, Renáta; Rácz, Gergely; Takács, Erzsébet; Wojnárovits, László

    2014-01-01

    Ionizing radiation induced degradation of acetylsalicylic acid, its hydrolysis product salicylic acid and a salicylic acid derivative 5-sulpho-salicylic acid, was investigated in dilute aqueous solutions by UV–vis spectrophotometry, HPLC separation and diode-array or MS/MS detection, chemical oxygen demand, total organic carbon content and by Vibrio fischeri toxicity measurements. Hydroxyl radicals were shown to degrade these molecules readily, and first degradation products were hydroxylated derivatives in all cases. Due to the by-products, among them hydrogen peroxide, the toxicity first increased and then decreased with the absorbed dose. With prolonged irradiation complete mineralization was achieved. - Highlights: • In OH induced reactions of salicylates first products are hydroxylated derivatives. • With prolonged irradiation dihydroxy derivatives also form. • In aerated solutions the one-electron oxidant OH induces 3–4 oxidations. • Toxicity first increases and then decreases with dose mainly due to H 2 O 2 formation. • The toxicity in tap water is smaller than in pure water

  16. Hydroxyl-radical induced dechlorination of pentachlorophenol in water

    International Nuclear Information System (INIS)

    He Yongke; Wu Jilan; Fang Xingwang; Sonntag, C. von

    1998-01-01

    The hydroxyl-radical induced dechlorination of pentachlorophenol (PCP) in water has been investigated pulse radiolytically. Hydroxyl radicals react with PCP by both electron transfer and addition. The former process results in pentachlorophenoxyl radicals (PCP-O), the latter process followed by rapid HCl elimination gives birth to deprotonated hydroxytetrachlorophenoxyl radicals ( - O-TCP-O). These phenoxyl radicals exhibit maximum absorption around 452 nm, which hinders the proper estimation of the ratio of the two processes. However, these two processes cause different changes in conductivity. In basic solution, the electron transfer causes a conductivity increase due to the formation of OH - whereas an addition followed by HCl elimination results in a conductivity decrease. The concurrence of these two processes reduces the relative variation in conductivity, from which about 53% electron transfer is deduced

  17. Sustained enhancement of OCTN1 transporter expression in association with hydroxyurea induced gamma-globin expression in erythroid progenitors

    OpenAIRE

    Walker, Aisha L.; Ofori-Acquah, Solomon

    2016-01-01

    The clinical benefits of hydroxyurea treatment in patients with sickle cell disease (SCD) are due largely to increased gamma-globin expression. However, mechanisms that control gamma-globin expression by hydroxyurea in erythroid progenitors are incompletely understood. Here, we investigated the role of two hydroxyurea transporters, urea transporter B (UTB) and organic cation/carnitine transporter 1 (OCTN1), in this process. Endogenous expression of both transporters peaked towards the end of ...

  18. Comparison of fluorescence-based techniques for the quantification of particle-induced hydroxyl radicals

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    Cohn Corey A

    2008-02-01

    Full Text Available Abstract Background Reactive oxygen species including hydroxyl radicals can cause oxidative stress and mutations. Inhaled particulate matter can trigger formation of hydroxyl radicals, which have been implicated as one of the causes of particulate-induced lung disease. The extreme reactivity of hydroxyl radicals presents challenges to their detection and quantification. Here, three fluorescein derivatives [aminophenyl fluorescamine (APF, amplex ultrared, and dichlorofluorescein (DCFH] and two radical species, proxyl fluorescamine and tempo-9-ac have been compared for their usefulness to measure hydroxyl radicals generated in two different systems: a solution containing ferrous iron and a suspension of pyrite particles. Results APF, amplex ultrared, and DCFH react similarly to the presence of hydroxyl radicals. Proxyl fluorescamine and tempo-9-ac do not react with hydroxyl radicals directly, which reduces their sensitivity. Since both DCFH and amplex ultrared will react with reactive oxygen species other than hydroxyl radicals and another highly reactive species, peroxynitite, they lack specificity. Conclusion The most useful probe evaluated here for hydroxyl radicals formed from cell-free particle suspensions is APF due to its sensitivity and selectivity.

  19. Laser Photobiomodulation for a Complex Patient with Severe Hydroxyurea-Induced Oral Ulcerations.

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    Cabras, Marco; Cafaro, Adriana; Gambino, Alessio; Broccoletti, Roberto; Romagnoli, Ercole; Marina, Davide; Arduino, Paolo G

    2016-01-01

    Patients affected by polycythemia vera (PV), a myeloproliferative neoplasm characterized by an elevated red blood cell mass, are at high risk of vascular and thrombotic complications. Conventional therapeutic options aim at reducing vascular and thrombotic risk; low-dose aspirin and phlebotomy are first-line recommendations, for patients at low risk of thrombotic events, whereas cytoreductive therapy, usually hydroxyurea (HU) or interferon alpha, is recommended for high-risk patients. In the present study, we report the case of a patient with persistent oral ulcerations, possibly related to long-lasting HU treatment, firstly treated with topic and systemic corticosteroids and then more effectively with the addition of low-level laser therapy. Laser photobiomodulation has achieved pain control and has contributed to the healing of oral ulcers without any adverse effect; this has permitted a reduction in the dose of systemic corticosteroids and the suspension of the use of the topic ones, due to the long-term stability of oral health, even after the interruption of low-level laser therapy sessions.

  20. Laser Photobiomodulation for a Complex Patient with Severe Hydroxyurea-Induced Oral Ulcerations

    Directory of Open Access Journals (Sweden)

    Marco Cabras

    2016-01-01

    Full Text Available Patients affected by polycythemia vera (PV, a myeloproliferative neoplasm characterized by an elevated red blood cell mass, are at high risk of vascular and thrombotic complications. Conventional therapeutic options aim at reducing vascular and thrombotic risk; low-dose aspirin and phlebotomy are first-line recommendations, for patients at low risk of thrombotic events, whereas cytoreductive therapy, usually hydroxyurea (HU or interferon alpha, is recommended for high-risk patients. In the present study, we report the case of a patient with persistent oral ulcerations, possibly related to long-lasting HU treatment, firstly treated with topic and systemic corticosteroids and then more effectively with the addition of low-level laser therapy. Laser photobiomodulation has achieved pain control and has contributed to the healing of oral ulcers without any adverse effect; this has permitted a reduction in the dose of systemic corticosteroids and the suspension of the use of the topic ones, due to the long-term stability of oral health, even after the interruption of low-level laser therapy sessions.

  1. Hydroxyl radical induced transformation of phenylurea herbicides: A theoretical study

    International Nuclear Information System (INIS)

    Mile, Viktória; Harsányi, Ildikó; Kovács, Krisztina; Földes, Tamás; Takács, Erzsébet; Wojnárovits, László

    2017-01-01

    Aromatic ring hydroxylation reactions occurring during radiolysis of aqueous solutions are studied on the example of phenylurea herbicides by Density Functional Theory calculations. The effect of the aqueous media is taken into account by using the Solvation Model Based on Density model. Hydroxyl radical adds to the ring because the activation free energies (0.4–47.2 kJ mol −1 ) are low and also the Gibbs free energies have high negative values ((−27.4) to (−5.9) kJ mol −1 ). According to the calculations in most of cases the ortho- and para-addition is preferred in agreement with the experimental results. In these reactions hydroxycyclohexadienyl type radicals form. In a second type reaction, when loss of chlorine atom takes place, OH/Cl substitution occurs without cyclohexadienyl type intermediate. - Highlights: • Attack of • OH to aniline, phenol, fenuron, monuron, diuron was studied by DFT. • Ortho-para directing is suggested with –NH 2 , –OH and –NHCON(CH 3 ) 2 groups. • • OH addition to the ring gives hydroxycyclohexadienyl radical. • Attack at C-Cl leads to • OH/Cl substitution without cyclohexadienyl intermediate.

  2. Hydroxyurea Induces Cytokinesis Arrest in Cells Expressing a Mutated Sterol-14α-Demethylase in the Ergosterol Biosynthesis Pathway.

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    Xu, Yong-Jie; Singh, Amanpreet; Alter, Gerald M

    2016-11-01

    Hydroxyurea (HU) has been used for the treatment of multiple diseases, such as cancer. The therapeutic effect is generally believed to be due to the suppression of ribonucleotide reductase (RNR), which slows DNA polymerase movement at replication forks and induces an S phase cell cycle arrest in proliferating cells. Although aberrant mitosis and DNA damage generated at collapsed forks are the likely causes of cell death in the mutants with defects in replication stress response, the mechanism underlying the cytotoxicity of HU in wild-type cells remains poorly understood. While screening for new fission yeast mutants that are sensitive to replication stress, we identified a novel mutation in the erg11 gene encoding the enzyme sterol-14α-demethylase in the ergosterol biosynthesis pathway that dramatically sensitizes the cells to chronic HU treatment. Surprisingly, HU mainly arrests the erg11 mutant cells in cytokinesis, not in S phase. Unlike the reversible S phase arrest in wild-type cells, the cytokinesis arrest induced by HU is relatively stable and occurs at low doses of the drug, which likely explains the remarkable sensitivity of the mutant to HU. We also show that the mutation causes sterol deficiency, which may predispose the cells to the cytokinesis arrest and lead to cell death. We hypothesize that in addition to the RNR, HU may have a secondary unknown target(s) inside cells. Identification of such a target(s) may greatly improve the chemotherapies that employ HU or help to expand the clinical usage of this drug for additional pathological conditions. Copyright © 2016 by the Genetics Society of America.

  3. Effects of hydroxylated benzaldehyde derivatives on radiation-induced reactions involving various organic radicals

    Science.gov (United States)

    Ksendzova, G. A.; Samovich, S. N.; Sorokin, V. L.; Shadyro, O. I.

    2018-05-01

    In the present paper, the effects of hydroxylated benzaldehyde derivatives and gossypol - the known natural occurring compound - on formation of decomposition products resulting from radiolysis of ethanol and hexane in deaerated and oxygenated solutions were studied. The obtained data enabled the authors to make conclusions about the effects produced by the structure of the compounds under study on their reactivity towards oxygen- and carbon-centered radicals. It has been found that 2,3-dihydroxybenzaldehyde, 4,6-di-tert-butyl-2,3-dihydroxybenzaldehyde and 4,6-di-tert-butyl-3-(1,3-dioxane-2-yl)-1,2-dihydroxybenzene are not inferior in efficiency to butylated hydroxytoluene - the industrial antioxidant - as regards suppression of the radiation-induced oxidation processes occurring in hexane. The derivatives of hydroxylated benzaldehydes were shown to have a significant influence on radiation-induced reactions involving α-hydroxyalkyl radicals.

  4. Repair-induced DNA double strand breaks after ultraviolet-light and either aphidocolin or 1-β-D-arabinofuranosylcytosine/hydroxyurea

    International Nuclear Information System (INIS)

    Bradley, M.O.; Taylor, V.I.

    1983-01-01

    A study was performed to determine whether 'repair-induced double strand breaks' (RDSBs) occur in IMR-90 cells at low u.v. doses and whether the RDSBs are themselves repairable by holding open the excision-repair induced gaps by inhibiting nucleotide polymerization after u.v. light with hydroxyurea/ara C or aphidocolin. The results show as little as 2.5 J.m -2 of u.v. light induces RDSBs during repair incubation when repair inhibitors are present. This suggests that 'hot spots' of high lesion frequency occur and the overlapping excision in these areas will produce RDSBs. Removing aphidocolin showed that RDSBs are only partially repairable with between 15 and 40% of the breaks unrepaired at 24 h. Because the lesions are partially repairable they should not always cause toxicity and may be involved in processes such as mutation, transformation, and chromosome or chromatid type aberrations of the sort associated with human tumors. (author)

  5. The yield of fission neutron-induced chromatid aberrations in G[sub 2]-stage human lymphocytes: effect of caffeine, hydroxyurea and cytosine arabinoside post-irradiation

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    Antoccia, A.; Tanzarella, C. (La Sapienza Univ., Rome (Italy)); Palitti, F. (Tuscia Univ., Viterbo (Italy) La Sapienza Univ., Rome (Italy)); Raggi, T. (Tuscia Univ., Viterbo (Italy)); Catena, C. (ENEA, Casaccia (Italy). Centro Ricerche Energia)

    1992-11-01

    To evaluate the influence of inhibitors of DNA synthesis/repair on the yield of chromosomal aberrations in the G[sub 2] phase of the cell cycle, whole-blood cultures of human lymphocytes were exposed to various doses of fission neutrons or X-rays and treated post-irradiation during the last 2.45 h before harvesting, with 5mM hydroxyurea (HU) and 0.05 mM cytosine arabinoside (ara-C). The presence of caffeine and HU strongly potentiated the yield of chromatid-type aberrations induced by both neutrons and X-rays. No potentiating effect, except at the highest dose of neutrons, was observed when irradiated cells were subsequently treated with ara-C. In addition, neutron-induced mitotic delay was shortened by treatment with caffeine, mainly within the first 2 h after irradiation. (Author).

  6. Inducible hydroxylation and demethylation of the herbicide isoproturon by Cunninghamella elegans.

    Science.gov (United States)

    Hangler, Martin; Jensen, Bo; Rønhede, Stig; Sørensen, Sebastian R

    2007-03-01

    A screening of 27 fungal strains for degradation of the phenylurea herbicide isoproturon was performed and yielded 15 strains capable of converting the herbicide to polar metabolites. The zygomycete fungus Cunninghamella elegans strain JS/2 isolated from an agricultural soil converted isoproturon to several known hydroxylated metabolites. In addition, unknown metabolites were produced in minor amounts. Inducible degradation was indicated by comparing resting cells pregrown with or without isoproturon. This shows that strain JS/2 is capable of partially degrading isoproturon and that one or more of the enzymes involved are inducible upon isoproturon exposure.

  7. Use of hydroxyurea in the measurement of DNA repair by the BND cellulose method

    International Nuclear Information System (INIS)

    Irwin, J.; Strauss, B.

    1980-01-01

    Hydroxyurea inhibition is a convenient method of suppressing replicative DNA synthesis for DNA excision-repair measurement by the BND cellulose technique. Nonetheless, hydroxyurea can introduce artefacts by direct reaction with repair-inducing compounds and by long-term inhibition of the overall repair process. A simple technique of overcoming these problems is described. Cells are reacted with repair-inducing compounds in the absence of hydroxyurea, the cells are washed free of inducer, hydroxyurea is added to 2 mM, and after a short period to establish replication inhibition, 3 H dThd is added and repair measured over a one-hour incubation period

  8. Effect of Cytosine Arabinoside, 3-Aminobenzamide and Hydroxyurea on the frequencies of radiation-induced micronuclei and aneuploidy in human lymphocytes

    International Nuclear Information System (INIS)

    Cho, Yoon Hee; Kim, Yang Jee; Ha, Sung Whan; Chung, Hai Won; Kang, Chang Mo

    2005-01-01

    This study was carried out to examine the effect of the DNA repair inhibitors, Cytosine Arabinoside(Ara C), 3-Aminobenzamide(3AB) and Hydroxyurea(HU) on the frequencies of radiation-induced MicroNuclei(MNi) and aneuploidy. Irradiated lymphocytes(1-3Gy) were treated with DNA repair inhibitors, Ara C, 3AB and HU for 3 hours and CBMN assay - FISH technique with DNA probe for chromosome 1 and 4 was performed. The frequencies of x-ray induced MNi and aneuploidy of chromosome 1 and 4 were increased in a dose-dependent manner. Ara C, 3AB and HU enhanced the frequencies of radiation-induced MNi and the frequencies of radiation-induced aneuploidy of chromosome 1 and 4 were enhanced by HU and Ara C while no effect was observed by 3AB. The frequency of radiation-induced aneuploidy of chromosome 1 was higher than that of chromosome 4. These results suggest that there are different mechanisms involved in the formation of MNi and aneuploidy by radiation

  9. Effect of Cytosine Arabinoside, 3-Aminobenzamide and Hydroxyurea on the frequencies of radiation-induced micronuclei and aneuploidy in human lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Yoon Hee; Kim, Yang Jee; Ha, Sung Whan; Chung, Hai Won [Seoul National Univ., Seoul (Korea, Republic of); Kang, Chang Mo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2005-12-15

    This study was carried out to examine the effect of the DNA repair inhibitors, Cytosine Arabinoside(Ara C), 3-Aminobenzamide(3AB) and Hydroxyurea(HU) on the frequencies of radiation-induced MicroNuclei(MNi) and aneuploidy. Irradiated lymphocytes(1-3Gy) were treated with DNA repair inhibitors, Ara C, 3AB and HU for 3 hours and CBMN assay - FISH technique with DNA probe for chromosome 1 and 4 was performed. The frequencies of x-ray induced MNi and aneuploidy of chromosome 1 and 4 were increased in a dose-dependent manner. Ara C, 3AB and HU enhanced the frequencies of radiation-induced MNi and the frequencies of radiation-induced aneuploidy of chromosome 1 and 4 were enhanced by HU and Ara C while no effect was observed by 3AB. The frequency of radiation-induced aneuploidy of chromosome 1 was higher than that of chromosome 4. These results suggest that there are different mechanisms involved in the formation of MNi and aneuploidy by radiation.

  10. Cutaneous ulcers associated with hydroxyurea therapy.

    Science.gov (United States)

    Quattrone, Filippo; Dini, Valentina; Barbanera, Sabrina; Zerbinati, Nicola; Romanelli, Marco

    2013-11-01

    Hydroxyurea is an antitumoral drug mainly used in the treatment of Philadelphia chromosome-negative myeloproliferative syndromes and sickle-cell disease. Ulcers represent a rare but severe long-term adverse effect of hydroxyurea therapy. Hydroxyurea-induced ulcers are often multiple and bilateral, typically developing in the perimalleolar region, although any cutaneous district is potentially affected. They generally look small, well-defined, shallow with an adherent, yellow, fibrinous necrotic base. A constant finding is also an extremely intense, treatment-resistant pain accompanying these ulcerations. Withdrawal of the drug generally leads to spontaneous healing of these lesions. Care providers tend to show insufficient awareness of this highly debilitating cutaneous side effect, and late or missed diagnoses are frequent. Instead, regular dermatologic screening should be performed on hydroxyurea-treated patients. This article will present a comprehensive review of indexed case reports and clinical studies, followed by a discussion about treatment options aiming at increasing knowledge about this specific topic. Copyright © 2013 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.

  11. Hydroxyl radical induced cross-linking of cytosine and tyrosine in nucleohistone

    International Nuclear Information System (INIS)

    Gajewski, E.; Dizdaroglu, M.

    1990-01-01

    Hydroxyl radical induced formation of a DNA-protein cross-link involving cytosine and tyrosine in nucleohistone in buffered aqueous solution is reported. The technique of gas chromatography-mass spectrometry was used for this investigation. A γ-irradiated aqueous mixture of cytosine and tyrosine was first investigated in order to obtain gas chromatographic-mass spectrometric properties of possible cytosine-tyrosine cross-links. One cross-link was observed, and its structure was identified as the product from the formation of a covalent bond between carbon 6 of cytosine and carbon 3 of tyrosine. With the use of gas chromatography-mass spectrometry with selected-ion monitoring, this cytosine-tyrosine cross-link was identified in acidic hydrolysates of calf thymus nucleohistone γ-irradiated in N 2 O-saturated aqueous solution. The yield of this DNA-protein cross-link in nucleohistone was found to be a linear function of the radiation dose in the range of 100-500 Gy (J·kg -1 ). This yield amounted to 0.05 nmol·J -1 . Mechanisms underlying the formation of the cytosine-tyrosine cross-link in nucleohistone were proposed to involve radical-radical and/or radical addition reactions of hydroxyl adduct radicals of cytosine and tyrosine moieties, forming a covalent bond between carbon 6 of cytosine and carbon 3 of tyrosine. When oxygen was present in irradiated solutions, no cytosine-tyrosine cross-links were observed

  12. A Systematic Review of Known Mechanisms of Hydroxyurea-induced Foetal Haemoglobin for Treatment of Sickle Cell Disease

    Science.gov (United States)

    Pule, Gift D.; Mowla, Shaheen; Novitzky, Nicolas; Wiysonge, Charles S.; Wonkam, Ambroise

    2016-01-01

    Aims To report on molecular mechanisms of foetal haemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of Sickle Cell Disease (SCD). Study Design Systematic review. Results Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways, that modulate γ-globin expression (cAMP/cGMP; Giα/JNK/Jun; methylation and microRNA). Three main molecular pathways have been reported: 1) Epigenetic modifications, transcriptional events and signalling pathways involved in HU-mediated response, 2) Signalling pathways involving HU-mediated response and 3) Post-transcriptional pathways (regulation by microRNAs). Conclusions The complete picture of HU-mediated mechanisms of HbF production in SCD remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome. PMID:26327494

  13. A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease.

    Science.gov (United States)

    Pule, Gift D; Mowla, Shaheen; Novitzky, Nicolas; Wiysonge, Charles S; Wonkam, Ambroise

    2015-10-01

    To report on molecular mechanisms of fetal hemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of sickle cell disease. Systematic review. Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways that modulate γ-globin expression (cAMP/cGMP; Giα/c-Jun N-terminal kinase/Jun; methylation and miRNA). Three main molecular pathways have been reported: i) Epigenetic modifications, transcriptional events and signaling pathways involved in HU-mediated response, ii) Signaling pathways involving HU-mediated response and iii) Post-transcriptional pathways (regulation by miRNAs). The complete picture of HU-mediated mechanisms of HbF production in Sickle Cell Disease remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome.

  14. Prolyl hydroxylation regulates protein degradation, synthesis, and splicing in human induced pluripotent stem cell-derived cardiomyocytes.

    Science.gov (United States)

    Stoehr, Andrea; Yang, Yanqin; Patel, Sajni; Evangelista, Alicia M; Aponte, Angel; Wang, Guanghui; Liu, Poching; Boylston, Jennifer; Kloner, Philip H; Lin, Yongshun; Gucek, Marjan; Zhu, Jun; Murphy, Elizabeth

    2016-06-01

    Protein hydroxylases are oxygen- and α-ketoglutarate-dependent enzymes that catalyse hydroxylation of amino acids such as proline, thus linking oxygen and metabolism to enzymatic activity. Prolyl hydroxylation is a dynamic post-translational modification that regulates protein stability and protein-protein interactions; however, the extent of this modification is largely uncharacterized. The goals of this study are to investigate the biological consequences of prolyl hydroxylation and to identify new targets that undergo prolyl hydroxylation in human cardiomyocytes. We used human induced pluripotent stem cell-derived cardiomyocytes in combination with pulse-chase amino acid labelling and proteomics to analyse the effects of prolyl hydroxylation on protein degradation and synthesis. We identified 167 proteins that exhibit differences in degradation with inhibition of prolyl hydroxylation by dimethyloxalylglycine (DMOG); 164 were stabilized. Proteins involved in RNA splicing such as serine/arginine-rich splicing factor 2 (SRSF2) and splicing factor and proline- and glutamine-rich (SFPQ) were stabilized with DMOG. DMOG also decreased protein translation of cytoskeletal and sarcomeric proteins such as α-cardiac actin. We searched the mass spectrometry data for proline hydroxylation and identified 134 high confidence peptides mapping to 78 unique proteins. We identified SRSF2, SFPQ, α-cardiac actin, and cardiac titin as prolyl hydroxylated. We identified 29 prolyl hydroxylated proteins that showed a significant difference in either protein degradation or synthesis. Additionally, we performed next-generation RNA sequencing and showed that the observed decrease in protein synthesis was not due to changes in mRNA levels. Because RNA splicing factors were prolyl hydroxylated, we investigated splicing ± inhibition of prolyl hydroxylation and detected 369 alternative splicing events, with a preponderance of exon skipping. This study provides the first extensive

  15. Effects of hydroxyl radical induced-Injury in atrial versus ventricular myocardium of dog and rabbit

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    Nitisha Hiranandani

    2010-09-01

    Full Text Available Aim: Despite the widespread use of ventricular tissue in the investigation involving hydroxyl-radical (OH* injury, one of the most potent mediators in ischemia-reperfusion injury, little is known about the impact on atrial myocardium. In this study we thus compared the OH*-induced injury response between atrial and right ventricular muscles from both rabbits and dogs under identical experimental conditions. Methods: Small, contracting ventricular and atrial rabbit and dog trabeculae were directly exposed to OH*, and contractile properties were examined and quantified. Results: A brief OH* exposure led to transient rigor like contracture with marked elevation of diastolic tension and depression of developed force. Although the injury response showed similarities between atrial and ventricular myocardium, there were significant differences as well. In rabbit atrial muscles, the development of the contracture and its peak was much faster as compared to ventricular muscles. Also, at the peak of contracture, both rabbit and dog atrial muscles show a lesser degree of contractile dysfunction. Conclusion: These results indicate that both atrial and ventricular muscles develop a rigor like contracture after acute OH*-induced injury, and atrial muscles showed a lesser degree of contractile dysfunction. Comparison of dog versus rabbit tissue shows that the response was similar in magnitude, but slower to develop in dog tissue.

  16. Assessment of genotoxicity associated with hydroxyurea therapy in children with sickle cell anemia

    Science.gov (United States)

    Flanagan, Jonathan M.; Howard, Thad A.; Mortier, Nicole; Avlasevich, Svetlana L.; Smeltzer, Matthew P.; Wu, Song; Dertinger, Stephen D.; Ware, Russell E.

    2018-01-01

    Hydroxyurea induces fetal hemoglobin, improves laboratory parameters, and ameliorates clinical complications of sickle cell anemia (SCA), but its long-term efficacy and safety in this patient population remain incompletely defined. Although generally considered non-DNA reactive, an important safety concern is that hydroxyurea may indirectly cause genotoxic damage. To better address this safety issue of hydroxyurea in patients with SCA, we measured the production of micronuclei (MN) in red blood cells (RBC) as a marker of genotoxicity. Blood samples were collected from children with SCA enrolled in the Hydroxyurea Study of Long-term Effects (ClinicalTrials.gov NCT00305175). Flow cytometry quantified circulating MN-containing erythrocyte sub-populations before and during hydroxyurea exposure. The frequency of micronucleated reticulocytes (MN-CD71+) and micronucleated mature erythrocytes (MN-RBC) were then tested for associations with laboratory and clinical data. In cross-sectional analysis of 293 blood samples from 105 children with SCA and a median of 2 years of hydroxyurea therapy, exposure to hydroxyurea was associated with significantly increased frequencies of MN-CD71+ and MN-RBC compared to baseline. The increases were evident by 3 months of therapy, and did not escalate further with up to 12 years of continuous drug exposure. In prospective longitudinal analysis, substantial inter-individual variation in the effect of hydroxyurea on %MN-CD71+ was observed that was associated with the expected laboratory effects of hydroxyurea. In conclusion, clinically relevant exposure to hydroxyurea is associated with increased MN production consistent with erythroblast genotoxicity but with substantial inter-patient variability. Associations between increased %MN-CD71+ and laboratory benefits suggest that hydroxyurea effects on MN production may be related to individual patient sensitivity to hydroxyurea within the bone marrow. PMID:20230905

  17. Apoptosis of THP-1 derived macrophages induced by sonodynamic therapy using a new sonosensitizer hydroxyl acetylated curcumin.

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    Longbin Zheng

    Full Text Available Curcumin is extracted from the rhizomes of the traditional Chinese herb Curcuma longa. Our previous study indicated curcumin was able to function as a sonosensitizer. Hydroxyl acylated curcumin was synthesized from curcumin to eliminate the unstable hydroxy perssad in our group. The potential use of Hydroxyl acylated curcumin as a sonosensitizer for sonodynamic therapy (SDT requires further exploration. This study investigated the sonodynamic effect of Hydroxyl acylated curcumin on THP-1 macrophage. THP-1 macrophages were cultured with Hydroxyl acylated curcumin at a concentration of 5.0 μg/mL for 4 hours and then exposed to pulse ultrasound irradiation (0.5 W/cm2 with 1.0 MHz for 5 min, 10 min and 15 min. Six hours later, cell viability decreased significantly by CCK-8 assay. After ultrasound irradiation, the ratio of apoptosis and necrosis in SDT group was higher than that in control, Hydroxyl acylated curcumin alone and ultrasound alone. Moreover, the apoptotic rate was higher than necrotic rate with the flow cytometry analysis. Furthermore, Hydroxyl acylated curcumin-SDT induced reactive oxygen species (ROS generation in THP-1 macrophages immediately after the ultrasound treatment while ROS generation was reduced significantly with the scavenger of singlet oxygen Sodium azide (NaN3. Hydroxyl acylated curcumin-SDT led to a conspicuous loss of mitochondrial membrane potential (MMP compared with other groups, while MMP was increased significantly with the scavenger of singlet oxygen Sodium azide (NaN3, ROS inhibitor N-acetyl cysteine (NAC and Mitochondrial Permeability Transition Pore (MPTP inhibitor Cyclosporin A (CsA. The cytochrome C, cleaved-Caspase-9, cleaved-Caspase-3 and cleaved-PARP upregulated after SDT through Western blotting. These findings suggested that Hydroxyl acylated curcumin under low-intensity ultrasound had sonodynamic effect on THP-1 macrophages via generation of intracellular singlet oxygen and mitochondria

  18. Proline-hydroxylated hypoxia-inducible factor 1α (HIF-1α upregulation in human tumours.

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    Cameron E Snell

    Full Text Available The stabilisation of HIF-α is central to the transcriptional response of animals to hypoxia, regulating the expression of hundreds of genes including those involved in angiogenesis, metabolism and metastasis. HIF-α is degraded under normoxic conditions by proline hydroxylation, which allows for recognition and ubiquitination by the von-Hippel-Lindau (VHL E3 ligase complex. The aim of our study was to investigate the posttranslational modification of HIF-1α in tumours, to assess whether there are additional mechanisms besides reduced hydroxylation leading to stability. To this end we optimised antibodies against the proline-hydroxylated forms of HIF-1α for use in formalin fixed paraffin embedded (FFPE immunohistochemistry to assess effects in tumour cells in vivo. We found that HIF-1α proline-hydroxylated at both VHL binding sites (Pro402 and Pro564, was present in hypoxic regions of a wide range of tumours, tumour xenografts and in moderately hypoxic cells in vitro. Staining for hydroxylated HIF-1α can identify a subset of breast cancer patients with poorer prognosis and may be a better marker than total HIF-1α levels. The expression of unhydroxylated HIF-1α positively correlates with VHL in breast cancer suggesting that VHL may be rate-limiting for HIF degradation. Our conclusions are that the degradation of proline-hydroxylated HIF-1α may be rate-limited in tumours and therefore provides new insights into mechanisms of HIF upregulation. Persistence of proline-hydroxylated HIF-1α in perinecrotic areas suggests there is adequate oxygen to support prolyl hydroxylase domain (PHD activity and proline-hydroxylated HIF-1α may be the predominant form associated with the poorer prognosis that higher levels of HIF-1α confer.

  19. Dissociative electron attachment to the radiosensitizing chemotherapeutic agent hydroxyurea

    Science.gov (United States)

    Huber, S. E.; Śmiałek, M. A.; Tanzer, K.; Denifl, S.

    2016-06-01

    Dissociative electron attachment to hydroxyurea was studied in the gas phase for electron energies ranging from zero to 9 eV in order to probe its radiosensitizing capabilities. The experiments were carried out using a hemispherical electron monochromator coupled with a quadrupole mass spectrometer. Diversified fragmentation of hydroxyurea was observed upon low energy electron attachment and here we highlight the major dissociation channels. Moreover, thermodynamic thresholds for various fragmentation reactions are reported to support the discussion of the experimental findings. The dominant dissociation channel, which was observed over a broad range of energies, is associated with formation of NCO-, water, and the amidogen (NH2) radical. The second and third most dominant dissociation channels are associated with formation of NCNH- and NHCONH2-, respectively, which are both directly related to formation of the highly reactive hydroxyl radical. Other ions observed with significant abundance in the mass spectra were NH2-/O-, OH-, CN-, HNOH-, NCONH2-, and ONHCONH2-.

  20. A method for detection of hydroxyl radicals in the vicinity of biomolecules using radiation-induced fluorescence of coumarin

    International Nuclear Information System (INIS)

    Makrigiorgos, G.M.; Baranowska-Kortylewicz, J.; Bump, E.; Sahu, S.K.; Berman, R.M.; Kassis, A.I.

    1993-01-01

    A novel method is described to quantitate radiation-induced hydroxyl radicals in the vicinity of biomolecules in aqueous solutions. Coumarin-3-carboxylic acid (CCA) is a non-fluorescent molecule that, upon interaction with radiation in aqueous solution, produces fluorescent products. CCA was derivatized to its succinimidyl ester (SECCA) and coupled to free primary amines of albumin, avidin, histone-H1, polylysine, and an oligonucleotide. When SECCA-biomolecule conjugates were irradiated, the relationship between induced fluorescence and dose was linear in the dose range examined (0.01-10 Gy). The data indicate that the induction of fluorescence on SECCA-biomolecule conjugates records specifically the presence of the hydroxyl radical in the immediate vicinity of the irradiated biomolecule. The method is rapid and sensitive, uses standard instrumentation, and the sample remains available for further studies. (Author)

  1. Hydroxyurea-resistant vaccinia virus: overproduction of ribonucleotide reductase

    International Nuclear Information System (INIS)

    Slabaugh, M.B.; Mathews, C.K.

    1986-01-01

    Repeated passage of vaccinia virus in increasing concentrations of hydroxyurea followed by plaque purification resulted in the isolation of variants capable of growth in 5 mM hydroxyurea, a drug concentration which inhibited the reproduction of wild-type vaccinia virus 1000-fold. Analyses of viral protein synthesis by using [ 35 S]methionine pulse-labeling at intervals throughout the infection cycle revealed that all isolates overproduced a 34,000-molecular-weight (MW) early polypeptide. Measurement of ribonucleoside-diphosphate reductase activity after infection indicated that 4- to 10-fold more activity was induced by hydroxyurea-resistant viruses than by the wild-type virus. A two-step partial purification resulted in a substantial enrichment for the 34,000-MW protein from extracts of wild-type and hydroxyurea-resistant-virus-infected, but not mock-infected, cells. In the presence of the drug, the isolates incorporated [ 3 H]thymidine into DNA earlier and a rate substantially greater than that of the wild type, although the onset of DNA synthesis was delayed in both cases. The drug resistance trait was markedly unstable in all isolates. In the absence of selective pressure, plaque-purified isolated readily segregated progeny that displayed a wide range of resistance phenotypes. The results of this study indicate that vaccinia virus encodes a subunit of ribonucleotide reductase which is 34,000-MW early protein whose overproduction confers hydroxyurea resistance on reproducing viruses

  2. Epigenetic and molecular profiles of erythroid cells after hydroxyurea treatment in sickle cell anemia

    Science.gov (United States)

    Steward, Shirley; Howard, Thad A.; Mortier, Nicole; Smeltzer, Matthew; Wang, Yong-Dong; Ware, Russell E.

    2011-01-01

    Hydroxyurea has been shown to be efficacious for the treatment of sickle cell anemia (SCA), primarily through the induction of fetal hemoglobin (HbF). However, the exact mechanisms by which hydroxyurea can induce HbF remain incompletely defined, although direct transcriptional effects and altered cell cycle kinetics have been proposed. In this study, we investigated potential epigenetic and alternative molecular mechanisms of hydroxyurea-mediated HbF induction by examining methylation patterns within the Gγ-globin promoter and miRNA expression within primary CD71+ erythrocytes of patients with SCA, both at baseline before beginning hydroxyurea therapy and after reaching maximum tolerated dose (MTD). Using both cross-sectional analysis and paired-sample analysis, we found that the highly methylated Gγ-globin promoter was inversely correlated to baseline HbF levels, but only slightly altered by hydroxyurea treatment. Conversely, expression of several specific miRNAs was significantly increased after hydroxyurea treatment, and expression of miR-26b and miR-151-3p were both associated with HbF levels at MTD. The significant associations identified in these studies suggest that methylation may be important for regulation of baseline HbF, but not after hydroxyurea treatment, whereas changes in miRNA expression may be associated with hydroxyurea-mediated HbF induction. This study was registered at ClinicalTrials.gov (NCT00305175). PMID:21921042

  3. Macrocytosis secondary to hydroxyurea therapy.

    Science.gov (United States)

    Conrado, Francisco O; Weeden, Amy L; Speas, Abbie L; Leissinger, Mary K

    2017-09-01

    A 10-year-old, male neutered Shetland Sheepdog was presented to the University of Florida for evaluation of a well-granulated mast cell tumor. Hydroxyurea therapy was instituted and serial CBCs showed persistent mild anemia and macrocytosis without a corresponding increase in polychromasia. The dog's MCV increased progressively, reaching its highest value of 100.0 fL after 6 months of treatment, and a diagnosis of macrocytosis associated with hydroxyurea therapy was made. The dog's increase in MCV was prominent, and rapidly decreased after the drug was discontinued, consistent with previous observations in human and canine subjects treated with hydroxyurea. Hydroxyurea is a cytotoxic chemotherapeutic agent used in a variety of conditions in human and veterinary medicine, and megaloblastic changes associated with its use have been described in multiple species. This report shows that hydroxyurea treatment is a differential diagnosis for prominent macrocytosis in dogs in the absence of other signs of erythrocyte regeneration. © 2017 American Society for Veterinary Clinical Pathology.

  4. Hydroxyurea for sickle cell anemia: What have we learned and what questions still remain?

    Science.gov (United States)

    McGann, Patrick T.; Ware, Russell E.

    2011-01-01

    Purpose of review Sickle cell anemia (SCA) is a well-characterized severe hematological disorder with substantial morbidity and early mortality. Hydroxyurea is a potent inducer of fetal hemoglobin, and evidence over the past 25 years has documented its laboratory and clinical efficacy for both adults and children with SCA. Recent findings The Phase III study of hydroxyurea in infants (BABY HUG) has just been completed and preliminary results indicate equivocal benefits for organ protection during the two-year treatment period, but significant benefits for pain, acute chest syndrome, hospitalizations, and transfusions. Three new reports document the benefits of hydroxyurea on reducing mortality in SCA: two adult trials (LaSHS and MSH) and one pediatric study (Brazilian cohort). Recent results from the HUSTLE protocol suggest minimal genotoxicity or carcinogenicity with long-term hydroxyurea exposure. Summary The potential utility of hydroxyurea for all patients with SCA is clear and indisputable. With decades of accumulated evidence and documented efficacy with an acceptable long-term safety profile, it is time to consider hydroxyurea treatment the standard of care for all young patients with SCA. Exporting our knowledge and experience with hydroxyurea to developing nations with large medical burdens from SCA can help relieve global suffering from this condition. PMID:21372708

  5. UVA-induced reset of hydroxyl radical ultradian rhythm improves temporal lipid production in Chlorella vulgaris.

    Science.gov (United States)

    Balan, Ranjini; Suraishkumar, G K

    2014-01-01

    We report for the first time that the endogenous, pseudo-steady-state, specific intracellular levels of the hydroxyl radical (si-OH) oscillate in an ultradian fashion (model system: the microalga, Chlorella vulgaris), and also characterize the various rhythm parameters. The ultradian rhythm in the endogenous levels of the si-OH occurred with an approximately 6 h period in the daily cycle of light and darkness. Further, we expected that the rhythm reset to a shorter period could rapidly switch the cellular redox states that could favor lipid accumulation. We reset the endogenous rhythm through entrainment with UVA radiation, and generated two new ultradian rhythms with periods of approximately 2.97 h and 3.8 h in the light phase and dark phase, respectively. The reset increased the window of maximum lipid accumulation from 6 h to 12 h concomitant with the onset of the ultradian rhythms. Further, the saturated fatty acid content increased approximately to 80% of total lipid content, corresponding to the peak maxima of the hydroxyl radical levels in the reset rhythm. © 2014 American Institute of Chemical Engineers.

  6. Hydroxyl radical formation and oxidative DNA damage induced by areca quid in vivo.

    Science.gov (United States)

    Chen, Chiu-Lan; Chi, Chin-Wen; Liu, Tsung-Yun

    2002-02-01

    Chewing areca quid (AQ) has been implicated as a major risk factor for the development of oral squamous-cell carcinoma (OSCC). Recent studies have suggested that AQ-generated reactive oxygen species (ROS) is one of the contributing factors for oral carcinogenesis. However, the AQ used in Taiwan is different from that used in other countries. This study is designed to test whether ROS are generated and the consequent effects in locally prepared AQ in vivo. We measured the hydroxyl radical formation, as represented by the presence of o- and m-tyrosine in saliva from volunteers who chewed AQ containing 20 mg phenylalanine. Their saliva contained significantly higher amounts (p betel leaf. We further tested the oxidative DNA damaging effect of the reconstituted AQ, as evidenced by the elevation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) levels, in hamster buccal pouch. Following daily painting for 14 d, the 8-OH-dG level in hamster buccal pouch is significantly elevated (p < .05) in the AQ-treated group versus the controls. These findings demonstrate that ROS, such as hydroxyl radical, are formed in the human oral cavity during AQ chewing, and chewing such prepared AQ might cause oxidative DNA damage to the surrounding tissues.

  7. Hydroxyurea therapy for sickle cell anemia.

    Science.gov (United States)

    McGann, Patrick T; Ware, Russell E

    2015-01-01

    Sickle cell anemia (SCA) is a severe, inherited hemoglobin disorder affecting 100,000 persons in the US and millions worldwide. Hydroxyurea, a once daily oral medication, has emerged as the primary disease-modifying therapy for SCA. The accumulated body of evidence over 30 years demonstrates that hydroxyurea is a safe and effective therapy for SCA, but hydroxyurea remains underutilized for a variety of reasons. In this review, we summarize the available evidence regarding the pharmacology, clinical, and laboratory benefits, and safety of hydroxyurea therapy for the treatment of SCA. The purpose of this review is to provide the reader a comprehensive understanding of hydroxyurea and to reinforce the fact that hydroxyurea is a safe and effective medication for the treatment of SCA. In our opinion, hydroxyurea therapy should be considered standard-of-care for SCA, representing an essential component of patient management. Early initiation and broader use of hydroxyurea will alter the natural history of SCA, so affected children can live longer and healthier lives. In addition, hydroxyurea use should be extended to low-resource settings such as sub-Saharan Africa, where the burden of SCA and the need for hydroxyurea is arguably the greatest.

  8. Deprenyl Enhances the Teratogenicity of Hydroxyurea in Organogenesis Stage Mouse Embryos

    Science.gov (United States)

    Schlisser, Ava E.; Hales, Barbara F.

    2013-01-01

    Hydroxyurea, an antineoplastic drug, is a model teratogen. The administration of hydroxyurea to CD1 mice on gestation day 9 induces oxidative stress, increasing the formation of 4-hydroxy-2-nonenal adducts to redox-sensitive proteins such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the caudal region of the embryo. GAPDH catalytic activity is reduced, and its translocation into the nucleus is increased. Because the nuclear translocation of GAPDH is associated with oxidative stress–induced cell death, we hypothesized that this translocation plays a role in mediating the teratogenicity of hydroxyurea. Deprenyl (also known as selegiline), a drug used as a neuroprotectant in Parkinson’s disease, inhibits the nuclear translocation of GAPDH. Hence, timed pregnant CD1 mice were treated with deprenyl (10mg/kg) on gestation day 9 followed by the administration of hydroxyurea (400 or 600mg/kg). Deprenyl treatment significantly decreased the hydroxyurea-induced nuclear translocation of GAPDH in the caudal lumbosacral somites. Deprenyl enhanced hydroxyurea-mediated caudal malformations, inducing specifically limb reduction, digit anomalies, tail defects, and lumbosacral vertebral abnormalities. Deprenyl did not augment the hydroxyurea-induced inhibition of glycolysis or alter the ratio of oxidized to reduced glutathione. However, it did dramatically increase cleaved caspase-3 in embryos. These data suggest that nuclear GAPDH plays an important, region-specific, role in teratogen-exposed embryos. Deprenyl exacerbated the developmental outcome of hydroxyurea exposure by a mechanism that is independent of oxidative stress. Although the administration of deprenyl alone did not affect pregnancy outcome, this drug may have adverse consequences when combined with exposures that increase the risk of malformations. PMID:23696560

  9. Original Research: Parvovirus B19 infection in children with sickle cell disease in the hydroxyurea era

    Science.gov (United States)

    Penkert, Rhiannon R; Lavoie, Paul; Tang, Li; Sun, Yilun; Hurwitz, Julia L

    2016-01-01

    Parvovirus B19 infection causes transient aplastic crisis in sickle cell disease (SCD) due to a temporary interruption in the red blood cell production. Toxicity from hydroxyurea includes anemia and reticulocytopenia, both of which also occur during a transient aplastic crisis event. Hydroxyurea inhibits proliferation of hematopoietic cells and may be immunosuppressive. We postulated that hydroxyurea could exacerbate parvovirus B19-induced aplastic crisis and inhibit the development of specific immune responses in children with SCD. We conducted a retrospective review of parvovirus B19 infection in 330 children with SCD. Altogether there were 120 known cases of aplastic crisis attributed to parvovirus B19 infection, and 12% of children were on hydroxyurea treatment during the episode. We evaluated hematological and immune responses. Children with HbSS or HbSβ0-thalassemia treated with hydroxyurea, when compared with untreated children, required fewer transfusions and had higher Hb concentration nadir during transient aplastic crisis. Duration of hospital stays was no different between hydroxyurea-treated and untreated groups. Children tested within a week following aplastic crisis were positive for parvovirus-specific IgG. Immune responses lasted for the duration of the observation period, up to 13 years after transient aplastic crisis, and there were no repeat aplastic crisis episodes. The frequencies of parvovirus-specific antibodies in all children with SCD increased with age, as expected due to the increased likelihood of a parvovirus exposure, and were comparable to frequencies reported for healthy children. Approximately one-third of children had a positive parvovirus B19-specific IgG test without a documented history of transient aplastic crisis, and 64% of them were treated with hydroxyurea. Hydroxyurea may reduce requirements for blood transfusions and may attenuate symptoms during transient aplastic crisis episodes caused by parvovirus B19 infections

  10. Original Research: Parvovirus B19 infection in children with sickle cell disease in the hydroxyurea era.

    Science.gov (United States)

    Hankins, Jane S; Penkert, Rhiannon R; Lavoie, Paul; Tang, Li; Sun, Yilun; Hurwitz, Julia L

    2016-04-01

    Parvovirus B19 infection causes transient aplastic crisis in sickle cell disease (SCD) due to a temporary interruption in the red blood cell production. Toxicity from hydroxyurea includes anemia and reticulocytopenia, both of which also occur during a transient aplastic crisis event. Hydroxyurea inhibits proliferation of hematopoietic cells and may be immunosuppressive. We postulated that hydroxyurea could exacerbate parvovirus B19-induced aplastic crisis and inhibit the development of specific immune responses in children with SCD. We conducted a retrospective review of parvovirus B19 infection in 330 children with SCD. Altogether there were 120 known cases of aplastic crisis attributed to parvovirus B19 infection, and 12% of children were on hydroxyurea treatment during the episode. We evaluated hematological and immune responses. Children with HbSS or HbSβ(0)-thalassemia treated with hydroxyurea, when compared with untreated children, required fewer transfusions and had higher Hb concentration nadir during transient aplastic crisis. Duration of hospital stays was no different between hydroxyurea-treated and untreated groups. Children tested within a week following aplastic crisis were positive for parvovirus-specific IgG. Immune responses lasted for the duration of the observation period, up to 13 years after transient aplastic crisis, and there were no repeat aplastic crisis episodes. The frequencies of parvovirus-specific antibodies in all children with SCD increased with age, as expected due to the increased likelihood of a parvovirus exposure, and were comparable to frequencies reported for healthy children. Approximately one-third of children had a positive parvovirus B19-specific IgG test without a documented history of transient aplastic crisis, and 64% of them were treated with hydroxyurea. Hydroxyurea may reduce requirements for blood transfusions and may attenuate symptoms during transient aplastic crisis episodes caused by parvovirus B19 infections

  11. Supplementary data for the mechanism for cleavage of three typical glucosidic bonds induced by hydroxyl free radical

    Directory of Open Access Journals (Sweden)

    Yujie Dai

    2017-12-01

    Full Text Available The data presented in this article are related to the research article entitled “The mechanism for cleavage of three typical glucosidic bonds induced by hydroxyl free radical” (Dai et al., 2017 [1]. This article includes the structures of three kinds of disaccharides such as maltose, fructose and cellobiose, the diagrammatic sketch of the hydrogen abstraction reaction of the disaccharides by hydroxyl radical, the structure of the transition states for pyran ring opening of moiety A and cleavage of α(1→2 glycosidic bond starting from the hydrogen abstraction of C6–H in moiety A of sucrose, the transition state structure for cleavage of α(1→2 glycosidic bond starting from the hydrogen abstraction of C1′-H in moiety B of sucrose, the transition state structure, sketch for the reaction process and relative energy change of the reaction pathway for direct cleavage of α(1→4 glycosidic bond starting from hydrogen abstraction of C6′–H of moiety B of maltose.

  12. Optimizing hydroxyurea therapy for sickle cell anemia.

    Science.gov (United States)

    Ware, Russell E

    2015-01-01

    Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA. © 2015 by The American Society of Hematology. All rights reserved.

  13. An Anion Conductance, the Essential Component of the Hydroxyl-Radical-Induced Ion Current in Plant Roots

    Directory of Open Access Journals (Sweden)

    Igor Pottosin

    2018-03-01

    Full Text Available Oxidative stress signaling is essential for plant adaptation to hostile environments. Previous studies revealed the essentiality of hydroxyl radicals (HO•-induced activation of massive K+ efflux and a smaller Ca2+ influx as an important component of plant adaptation to a broad range of abiotic stresses. Such activation would modify membrane potential making it more negative. Contrary to these expectations, here, we provide experimental evidence that HO• induces a strong depolarization, from −130 to −70 mV, which could only be explained by a substantial HO•-induced efflux of intracellular anions. Application of Gd3+ and NPPB, non-specific blockers of cation and anion conductance, respectively, reduced HO•-induced ion fluxes instantaneously, implying a direct block of the dual conductance. The selectivity of an early instantaneous HO•-induced whole cell current fluctuated from more anionic to more cationic and vice versa, developing a higher cation selectivity at later times. The parallel electroneutral efflux of K+ and anions should underlie a substantial leak of the cellular electrolyte, which may affect the cell’s turgor and metabolic status. The physiological implications of these findings are discussed in the context of cell fate determination, and ROS and cytosolic K+ signaling.

  14. Hydroxylated polychlorinated biphenyls increase reactive oxygen species formation and induce cell death in cultured cerebellar granule cells

    International Nuclear Information System (INIS)

    Dreiem, Anne; Rykken, Sidsel; Lehmler, Hans-Joachim; Robertson, Larry W.; Fonnum, Frode

    2009-01-01

    Polychlorinated biphenyls (PCBs) are persistent organic pollutants that bioaccumulate in the body, however, they can be metabolized to more water-soluble products. Although they are more readily excreted than the parent compounds, some of the metabolites are still hydrophobic and may be more available to target tissues, such as the brain. They can also cross the placenta and reach a developing foetus. Much less is known about the toxicity of PCB metabolites than about the parent compounds. In the present study, we have investigated the effects of eight hydroxylated (OH) PCB congeners (2'-OH PCB 3, 4-OH PCB 14, 4-OH PCB 34, 4'-OH PCB 35, 4-OH PCB 36, 4'-OH PCB 36, 4-OH PCB 39, and 4'-OH PCB 68) on reactive oxygen species (ROS) formation and cell viability in rat cerebellar granule cells. We found that, similar to their parent compounds, OH-PCBs are potent ROS inducers with potency 4-OH PCB 14 < 4-OH PCB 36 < 4-OH PCB 34 < 4'-OH PCB 36 < 4'-OH PCB 68 < 4-OH PCB 39 < 4'-OH PCB 35. 4-OH PCB 36 was the most potent cell death inducer, and caused apoptotic or necrotic morphology depending on concentration. Inhibition of ERK1/2 kinase with U0126 reduced both cell death and ROS formation, suggesting that ERK1/2 activation is involved in OH-PCB toxicity. The results indicate that the hydroxylation of PCBs may not constitute a detoxification reaction. Since OH-PCBs like their parent compounds are retained in the body and may be more widely distributed to sensitive tissues, it is important that not only the levels of the parent compounds but also the levels of their metabolites are taken into account during risk assessment of PCBs and related compounds.

  15. Hydroxyurea: a radiation potentiator in carcinoma of the uterine cervix. A randomized double-blind study

    International Nuclear Information System (INIS)

    Piver, M.S.; Barlow, J.J.; Vongtama, V.; Blumenson, L.

    1983-01-01

    From June, 1972, to December, 1976, 40 patients with FIGO (International Federation of Gynaecology and Obstetrics) Stage IIB carcinoma of the uterine cervix were entered into a prospective, double-blind, randomized study to evaluate the possible radiation-potentiating properties (i.e., improved survival) of the S-phase cell cycle-specific inhibitor of DNA synthesis, hydroxyurea. All patients were documented to be without aortic lymph node metastasis by pretherapy staging para-aortic lymphadenectomy. All 40 patients were followed up for longer than 5 years (5.2 to 9.2 years) or until death. The double-blind code was not broken until all patients had been followed up for a minimum of 2 to 5 years. Leukopenia (white blood cell count less than 2,500 mm3) was significantly increased in the patients given hydroxyurea as compared to those given placebo (P less than 0.0001). There was no statistically significant difference relative to anemia, thrombocytopenia, radiation-induced skin reaction, and radiation-induced intestinal reaction between the patients given placebo or those given hydroxyurea. Life-table survival for the patients given hydroxyurea was 94% as compared to 53% for the patients given placebo (P . 0.006). Only one (5%) patient given hydroxyurea died of cervical cancer. Of the other patients who died in the group given hydroxyurea, all were confirmed by postmortem examination to have been without recurrent cervical cancer. In contrast, 45% (nine) of the patients given placebo died of cervical cancer

  16. Incorporation of thymidine into onion root meristematic cell nuclei in presence of hydroxyurea and its role in recovery of mitotic activity

    OpenAIRE

    H. Habdas

    2015-01-01

    Hydroxyurea treatment of onion roots induced mitotic block which was released by transfer of bulbs to water, and also to some extent by addition of cold or 3H-thymidine to hydroxyurea solutions. In presence of hydroxyurea there was noted very intense incorporation of 3H-thymidine into cell nuclei, giving labelling index of 40-70%. However, all the mitotic figures appearing in presence of hydroxyurea and 3H-thymidine were unlabelled. On the other hand, labelled mitotic figures were obtained wh...

  17. Characterisation of an inlet pre-injector laser-induced fluorescence instrument for the measurement of atmospheric hydroxyl radicals

    Science.gov (United States)

    Novelli, A.; Hens, K.; Tatum Ernest, C.; Kubistin, D.; Regelin, E.; Elste, T.; Plass-Dülmer, C.; Martinez, M.; Lelieveld, J.; Harder, H.

    2014-10-01

    Atmospheric measurements of hydroxyl radicals (OH) are challenging due to a high reactivity and consequently low concentration. The importance of OH as an atmospheric oxidant has motivated a sustained effort leading to the development of a number of highly sensitive analytical techniques. Recent work has indicated that the laser-induced fluorescence of the OH molecules method based on the fluorescence assay by gas expansion technique (LIF-FAGE) for the measurement of atmospheric OH in some environments may be influenced by artificial OH generated within the instrument, and a chemical method to remove this interference was implemented in a LIF-FAGE system by Mao et al. (2012). While it is not clear whether other LIF-FAGE instruments suffer from the same interference, we have applied this method to our LIF-FAGE HORUS (Hydroxyl Radical Measurement Unit based on fluorescence Spectroscopy) system, and developed and deployed an inlet pre-injector (IPI) to determine the chemical zero level in the instrument via scavenging the ambient OH radical. We describe and characterise this technique in addition to its application at field sites in forested locations in Finland, Spain and Germany. Ambient measurements show that OH generated within the HORUS instrument is a non-negligible fraction of the total OH signal, which can comprise 30 to 80% during daytime and 60 to 100% during the night. The contribution of the background OH varied greatly between measurement sites and was likely related to the type and concentration of volatile organic compounds (VOCs) present at each particular location. Two inter-comparisons in contrasting environments between the HORUS instrument and two different chemical ionisation mass spectrometers (CIMS) are described to demonstrate the efficacy of IPI and the necessity of the chemical zeroing method for our LIF-FAGE instrument in such environments.

  18. Characterisation of an inlet pre-injector laser induced fluorescence instrument for the measurement of ambient hydroxyl radicals

    Science.gov (United States)

    Novelli, A.; Hens, K.; Tatum Ernest, C.; Kubistin, D.; Regelin, E.; Elste, T.; Plass-Dülmer, C.; Martinez, M.; Lelieveld, J.; Harder, H.

    2014-01-01

    Ambient measurements of hydroxyl radicals (OH) are challenging due to a high reactivity and consequently low concentration. The importance of OH as an atmospheric oxidant has resulted in a sustained effort leading to the development of a number of analytical techniques. Recent work has indicated that the laser-induced fluorescence of the OH molecules method based on the fluorescence assay by gas expansion technique (LIF-FAGE) for the measurement of atmospheric OH in some environments may be influenced by artificial OH generated within the instrument, and a chemical method to remove this interference was implemented in a LIF-FAGE system by Mao et al. (2012). We have applied this method to our LIF-FAGE HORUS (HydrOxyl Radical Measurement Unit based on fluorescence Spectroscopy) system, and developed and deployed an inlet pre-injector (IPI) to determine the chemical zero level in the instrument via scavenging the ambient OH radical. We describe and characterise this technique in addition to its application at field sites in forested locations in Finland, Spain, and Germany. Ambient measurements show that OH generated within the HORUS instrument is a non-negligible fraction of the total OH signal, which can comprise 30% to 80% during the day and 60% to 100% during the night. The contribution of the background OH varied greatly between measurement sites and was likely related to the type and concentration of volatile organic compounds (VOCs) present at each particular location. Two inter-comparisons in contrasting environments between the HORUS instrument and two different chemical ionisation mass spectrometers (CIMS) are described to demonstrate the efficacy of the inlet-pre-injector and the necessity of the chemical zeroing method in such environments.

  19. Incorporation of thymidine into onion root meristematic cell nuclei in presence of hydroxyurea and its role in recovery of mitotic activity

    International Nuclear Information System (INIS)

    Habdas, H.

    1977-01-01

    Hydroxyurea treatment of onion roots induced mitotic block which was released by transfer of bulbs to water, and also to some extent by addition of cold or 3 H-thymidine to hydroxyurea solutions. In presence of hydroxyurea there was noted very intense incorporation of 3 H-thymidine into cell nuclei, giving labelling index of 40-70%. However, all the mitotic figures appearing in presence of hydroxyurea and 3 H-thymidine were unlabelled. On the other hand, labelled mitotic figures were obtained when roots incubated with 3 H-thymidine in presence of hydroxyurea had been transferred to water. Incorporation of 3 H-uridine was unaffected by hydroxyurea. The results show that hydroxyurea arrests onion root meristematic cells, either in the S phase and the G 2 phase. Enhanced incorporation of 3 H-thymidine in the presence of hydroxyurea, and release by added thymidine of the mitotic block indicate that hydroxyurea induces in onion root meristematic cells a particular shortage of thymidylate. (author)

  20. Dissociative electron attachment to the radiosensitizing chemotherapeutic agent hydroxyurea

    Energy Technology Data Exchange (ETDEWEB)

    Huber, S. E.; Tanzer, K.; Denifl, S. [Institute for Ion Physics and Applied Physics and Center of Molecular Biosciences Innsbruck, Leopold Franzens University of Innsbruck, Technikerstr. 25, 6020 Innsbruck (Austria); Śmiałek, M. A., E-mail: smialek@pg.gda.pl [Department of Control and Power Engineering, Faculty of Ocean Engineering and Ship Technology, Gdańsk University of Technology, Gabriela Narutowicza 11/12, 80-233 Gdańsk (Poland)

    2016-06-14

    Dissociative electron attachment to hydroxyurea was studied in the gas phase for electron energies ranging from zero to 9 eV in order to probe its radiosensitizing capabilities. The experiments were carried out using a hemispherical electron monochromator coupled with a quadrupole mass spectrometer. Diversified fragmentation of hydroxyurea was observed upon low energy electron attachment and here we highlight the major dissociation channels. Moreover, thermodynamic thresholds for various fragmentation reactions are reported to support the discussion of the experimental findings. The dominant dissociation channel, which was observed over a broad range of energies, is associated with formation of NCO{sup −}, water, and the amidogen (NH{sub 2}) radical. The second and third most dominant dissociation channels are associated with formation of NCNH{sup −} and NHCONH{sub 2}{sup −}, respectively, which are both directly related to formation of the highly reactive hydroxyl radical. Other ions observed with significant abundance in the mass spectra were NH{sub 2}{sup −}/O{sup −}, OH{sup −}, CN{sup −}, HNOH{sup −}, NCONH{sub 2}{sup −}, and ONHCONH{sub 2}{sup −}.

  1. Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea

    Science.gov (United States)

    Green, Nancy S.; Ender, Katherine L.; Pashankar, Farzana; Driscoll, Catherine; Giardina, Patricia J.; Mullen, Craig A.; Clark, Lorraine N.; Manwani, Deepa; Crotty, Jennifer; Kisselev, Sergey; Neville, Kathleen A.; Hoppe, Carolyn; Barral, Sandra

    2013-01-01

    Background Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin. Methodology/Principal Findings In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels. Conclusions/Significance These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease. PMID:23409025

  2. The Zinc Finger of Prolyl Hydroxylase Domain Protein 2 Is Essential for Efficient Hydroxylation of Hypoxia-Inducible Factor α.

    Science.gov (United States)

    Arsenault, Patrick R; Song, Daisheng; Chung, Yu Jin; Khurana, Tejvir S; Lee, Frank S

    2016-09-15

    Prolyl hydroxylase domain protein 2 (PHD2) (also known as EGLN1) is a key oxygen sensor in mammals that posttranslationally modifies hypoxia-inducible factor α (HIF-α) and targets it for degradation. In addition to its catalytic domain, PHD2 contains an evolutionarily conserved zinc finger domain, which we have previously proposed recruits PHD2 to the HSP90 pathway to promote HIF-α hydroxylation. Here, we provide evidence that this recruitment is critical both in vitro and in vivo We show that in vitro, the zinc finger can function as an autonomous recruitment domain to facilitate interaction with HIF-α. In vivo, ablation of zinc finger function by a C36S/C42S Egln1 knock-in mutation results in upregulation of the erythropoietin gene, erythrocytosis, and augmented hypoxic ventilatory response, all hallmarks of Egln1 loss of function and HIF stabilization. Hence, the zinc finger ordinarily performs a critical positive regulatory function. Intriguingly, the function of this zinc finger is impaired in high-altitude-adapted Tibetans, suggesting that their adaptation to high altitude may, in part, be due to a loss-of-function EGLN1 allele. Thus, these findings have important implications for understanding both the molecular mechanism of the hypoxic response and human adaptation to high altitude. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  3. Myelofibrosis-Related Arthritis Successfully Treated with Hydroxyurea

    Directory of Open Access Journals (Sweden)

    Xavier Guillot

    2014-01-01

    Full Text Available A 62-year-old woman suffering from one-year lasting, nonerosive peripheral arthritides with general health impairment and high acute-phase reactant levels was admitted to rheumatology department. The patient had suffered from chronic polyarthralgia and a thrombocytosis had been discovered 9 years before, with a recent increase in platelet count. All immunological blood tests were negative. Corticosteroid and methotrexate treatments improved pain, swollen joint count, and systemic inflammation. However, joints remained stiff and painful with two swollen wrists and persistent thrombocytosis. An iliac bone marrow biopsy was performed, showing primary myelofibrosis. Hydroxyurea treatment (500 mg per day allowed to achieve complete and prolonged clinical and biological remission. After 6 months, a new disease flare occurred. The patient reached remission again after hydroxyurea dose increased to 1500 mg per day. This supports the hypothesis of idiopathic myelofibrosis-associated seronegative polyarthritis. This is the first reported case in which haemopathy-targeted treatment using hydroxyurea induced arthritis remission.

  4. Combination of Hydroxyl Acetylated Curcumin and Ultrasound Induces Macrophage Autophagy with Anti-Apoptotic and Anti-Lipid Aggregation Effects

    Directory of Open Access Journals (Sweden)

    Longbin Zheng

    2016-10-01

    Full Text Available Background/Aims: Sonodynamic therapy (SDT is considered a new approach for the treatment of atherosclerosis. We previously confirmed that hydroxyl acetylated curcumin (HAC was a sonosensitizer. In this study, we investigated the mechanism of THP-1 macrophage apoptosis and autophagy induced by HAC mediated SDT (HAC-SDT. Methods: Cell viability was measured using a CCK-8 assay. Laser scanning confocal microscopy was used to measure the levels of intracellular reactive oxygen species (ROS, sub-cellular HAC localization, BAX and cytochrome C translocation, LC3 expression, monodansylcadaverine staining and Dil-labeled oxidized low density lipoprotein (Dil-ox-LDL uptake. Flow cytometry was used to analyze apoptosis and autophagy via Annexin V/propidium iodide and acridine orange staining, respectively. The expression levels of apoptosis- and autophagy-related proteins were detected by Western blot. Oil red O was used to measure intracellular lipid accumulation. Results: We identified HAC (5.0 μg/mL located in lysosomes, endoplasmic reticulum, Golgi apparatus and mitochondria after 4 h of incubation. Compared with other sonosensitizers (e.g., curcumin and emodin, HAC had a more obvious sonodynamic effect on macrophages. Furthermore, the mitochondrial-caspase pathway was confirmed to play a crucial role in the HAC-SDT-induced apoptosis; BAX translocated from the cytosol to the mitochondria during HAC-SDT. Subsequently, mitochondrial cytochrome C was released into the cytosol, activating the caspase cascade in a time-dependent manner. Furthermore, HAC-SDT could induce PI3K/AKT/mTOR pathway dependent autophagy, accompanied by a decrease in the lipid uptake of THP-1 macrophages. This mechanism was demonstrated by the formation of acidic vesicular organelles, the conversion of LC3 I to LC3 II, the expression of related proteins, and the attenuation of both Dil-ox-LDL and oil red O staining. Moreover, pre-treatment with the autophagy inhibitor 3

  5. Editor's Highlight: Hydroxyurea Exposure Activates the P53 Signaling Pathway in Murine Organogenesis-Stage Embryos.

    Science.gov (United States)

    El Husseini, Nazem; Schlisser, Ava E; Hales, Barbara F

    2016-08-01

    Hydroxyurea, an anticancer agent and potent teratogen, induces oxidative stress and activates a DNA damage response pathway in the gestation day (GD) 9 mouse embryo. To delineate the stress response pathways activated by this drug, we investigated the effect of hydroxyurea exposure on the transcriptome of GD 9 embryos. Timed pregnant CD-1 mice were treated with saline or hydroxyurea (400 mg/kg or 600 mg/kg) on GD 9; embryonic gene and protein expression were examined 3 h later. Microarray analysis revealed that the expression of 1346 probe sets changed significantly in embryos exposed to hydroxyurea compared with controls; the P53 signaling pathway was highly affected. In addition, P53 related family members, P63 and P73, were predicted to be activated and had common and unique downstream targets. Western blot analysis revealed that active phospho-P53 was significantly increased in drug-exposed embryos; confocal microscopy showed that the translocation of phospho-P53 to the nucleus was widespread in the embryo. Furthermore, qRT-PCR showed that the expression of P53-regulated genes (Cdkn1A, Fas, and Trp53inp1) was significantly upregulated in hydroxyurea-exposed embryos; the concentration of the redox sensitive P53INP1 protein was also increased in a hydroxyurea dose-dependent fashion. Thus, hydroxyurea elicits a significant effect on the transcriptome of the organogenesis stage murine embryo, activating several key developmental signaling pathways related to DNA damage and oxidative stress. We propose that the P53 pathway plays a central role in the embryonic stress response and the developmental outcome after teratogen exposure. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Widespread Natural Occurrence of Hydroxyurea in Animals.

    Science.gov (United States)

    Fraser, David I; Liu, Kyle T; Reid, Bryan J; Hawkins, Emily; Sevier, Andrew; Pyle, Michelle; Robinson, Jacob W; Ouellette, Pierre H R; Ballantyne, James S

    2015-01-01

    Here we report the widespread natural occurrence of a known antibiotic and antineoplastic compound, hydroxyurea in animals from many taxonomic groups. Hydroxyurea occurs in all the organisms we have examined including invertebrates (molluscs and crustaceans), fishes from several major groups, amphibians and mammals. The species with highest concentrations was an elasmobranch (sharks, skates and rays), the little skate Leucoraja erinacea with levels up to 250 μM, high enough to have antiviral, antimicrobial and antineoplastic effects based on in vitro studies. Embryos of L. erinacea showed increasing levels of hydroxyurea with development, indicating the capacity for hydroxyurea synthesis. Certain tissues of other organisms (e.g. skin of the frog (64 μM), intestine of lobster (138 μM) gills of the surf clam (100 μM)) had levels high enough to have antiviral effects based on in vitro studies. Hydroxyurea is widely used clinically in the treatment of certain human cancers, sickle cell anemia, psoriasis, myeloproliferative diseases, and has been investigated as a potential treatment of HIV infection and its presence at high levels in tissues of elasmobranchs and other organisms suggests a novel mechanism for fighting disease that may explain the disease resistance of some groups. In light of the known production of nitric oxide from exogenously applied hydroxyurea, endogenous hydoxyurea may play a hitherto unknown role in nitric oxide dynamics.

  7. Widespread Natural Occurrence of Hydroxyurea in Animals.

    Directory of Open Access Journals (Sweden)

    David I Fraser

    Full Text Available Here we report the widespread natural occurrence of a known antibiotic and antineoplastic compound, hydroxyurea in animals from many taxonomic groups. Hydroxyurea occurs in all the organisms we have examined including invertebrates (molluscs and crustaceans, fishes from several major groups, amphibians and mammals. The species with highest concentrations was an elasmobranch (sharks, skates and rays, the little skate Leucoraja erinacea with levels up to 250 μM, high enough to have antiviral, antimicrobial and antineoplastic effects based on in vitro studies. Embryos of L. erinacea showed increasing levels of hydroxyurea with development, indicating the capacity for hydroxyurea synthesis. Certain tissues of other organisms (e.g. skin of the frog (64 μM, intestine of lobster (138 μM gills of the surf clam (100 μM had levels high enough to have antiviral effects based on in vitro studies. Hydroxyurea is widely used clinically in the treatment of certain human cancers, sickle cell anemia, psoriasis, myeloproliferative diseases, and has been investigated as a potential treatment of HIV infection and its presence at high levels in tissues of elasmobranchs and other organisms suggests a novel mechanism for fighting disease that may explain the disease resistance of some groups. In light of the known production of nitric oxide from exogenously applied hydroxyurea, endogenous hydoxyurea may play a hitherto unknown role in nitric oxide dynamics.

  8. Reactions of OH-radicals with hydroxylated and methoxylated benzoic acids and cinnamic acids. Radiation-induced chemical changes in mushrooms

    International Nuclear Information System (INIS)

    Gaisberger, B.

    2001-05-01

    In the first part of this work the radiation induced chemical changes of methoxylated and hydroxylated benzoic acids and cinnamic acids were investigated. Methoxylated compounds were also used as model components for acid derivatives with no free-OH groups. The latter are essentials parts of vegetable foodstuff. A comparison of the radiolytic behaviour of single substituted methoxy- and hydroxybenzoic acids was given at first, data of literature was included. The priority of the investigation was the hydroxylation process induced by OH-radicals. The OH-adduct distribution is generally the same for the hydroxy- as well as for the methoxybenzoic acid isomers. This could be proved by oxidation of these OH-adducts with K 3 Fe(CN) 6 . In the presence of air 68-77 % of the hydroxybenzoic acids are converted into hydroxylation products, whereas with the methoxylated acids this reaction leads only to about 10%. An explanation gives the different decay pathways of the intermediate peroxylradical. The multiple methoxy- and hydroxybenzoic acids show three different reaction possibilities: hydroxylation, replacement of -OCH 3 by -OH and -in case of the cinnamic acids-oxidative decomposition of the rest of the propenic acid under formation of the corresponding benzaldehydes. All these reactions can be expected when irradiating foodstuff, containing these acid compounds. The characteristic formation of these components and their linear dose/concentration relationship make these substrates very promising for the use as markers for irradiation treatment of foodstuff. The second part of this work deals with the gamma-radiation induced chemical changes in mushrooms. The irradiated and non-irradiated samples were freeze-dried and purified from matrix components chromatographically on polyamid columns. In case of the phenolic compounds for 4-hydroxybenzoic acid and three unknown components linear dose/concentration relationships could be obtained. Two of these unknown compounds seem

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

    OpenAIRE

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

    2009-01-01

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

  10. Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

    OpenAIRE

    Walker, Aisha L.; Lancaster, Cynthia S.; Finkelstein, David; Ware, Russell E.; Sparreboom, Alex

    2013-01-01

    Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assess...

  11. Manganese-induced hydroxyl radical formation in rat striatum is not attenuated by dopamine depletion or iron chelation in vivo

    NARCIS (Netherlands)

    W.N. Sloot (W.); J. Korf (Jakob); J.F. Koster (Johan); L.E.A. de Wit (Elly); J.-B.P. Gramsbergen (J. B P)

    1996-01-01

    textabstractThe present studies were aimed at investigating the possible roles of dopamine (DA) and iron in production of hydroxyl radicals (.OH) in rat striatum after Mn2+ intoxication. For this purpose, DA depletions were assessed concomitant with in vivo 2,3- and 2,5-dihydroxybenzoic acid (DHBA)

  12. Limited efficacy of hydroxyurea in lowering of the JAK2 V617F allele burden

    DEFF Research Database (Denmark)

    Larsen, Thomas Stauffer; Pallisgaard, Niels; de Stricker, Karin

    2009-01-01

    Besides being an invaluable marker of clonal disease in chronic myeloproliferative disorders (CMPDs), the JAK2 V617F mutation and the mutated allele burden have an impact on disease phenotype and may provide information on prognosis. Recently, hydroxyurea (HU) has been shown to induce a rapid...

  13. Induction of mitotic recombination by UV and diepoxybutane and its enhancement by hydroxyurea in Saccharomyces cerevisae

    Energy Technology Data Exchange (ETDEWEB)

    Zaborowska, D.; Swietlinska, Z.; Zuk, J. (Polska Akademia Nauk, Warsaw. Inst. Biochemii i Biofizyki)

    1983-04-01

    Mitotic inter- and intra-genic recombination was induced by UV-irradiation and treatment with diepoxybutane (DEB) in 2 heteroallelic diploid strains of Saccharomyces cerevisiae SBTD and D7. Induction of the events tested was strongly potentiated by plating of mutagen-treated cells on growth media containing 0.03 M hydroxyurea (HU).

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

    NARCIS (Netherlands)

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

    2009-01-01

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

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

    NARCIS (Netherlands)

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

    2009-01-01

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

  16. Induction of mitotic recombination by UV and diepoxybutane and its enhancement by hydroxyurea in Saccharomyces cerevisae

    International Nuclear Information System (INIS)

    Zaborowska, D.; Swietlinska, Z.; Zuk, J.

    1983-01-01

    Mitotic inter- and intra-genic recombination was induced by UV-irradiation and treatment with diepoxybutane (DEB) in 2 heteroallelic diploid strains of Saccharomyces cerevisiae SBTD and D7. Induction of the events tested was strongly potentiated by plating of mutagen-treated cells on growth media containing 0.03 M hydroxyurea (HU). (orig.)

  17. Thermodynamic properties of aqueous hydroxyurea solutions

    International Nuclear Information System (INIS)

    Kumar, Shekhar; Sinha, Pranay Kumar; Kamachi Mudali, U.; Natarajan, R.

    2011-01-01

    Hydroxyurea is a novel reductant for uranium-plutonium separation in PUREX process. Little information on its thermophysical properties is available in published literature. In this work, its contributions to aqueous density, apparent molal volume, vapour pressure and thermodynamic water activity values, derived from in-house experiments, are reported. (author)

  18. Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

    Science.gov (United States)

    Lebensburger, Jeffrey D.; Howard, Thad; Hu, Yunming; Pestina, Tamara I.; Gao, Geli; Johnson, Melissa; Zakharenko, Stanislav S.; Ware, Russell E.; Tuomanen, Elaine I.; Persons, Derek A.

    2012-01-01

    Sickle cell anemia is characterized by chronic hemolysis coupled with extensive vascular inflammation. This inflammatory state also mechanistically promotes a high risk of lethal, invasive pneumococcal infection. Current treatments to reduce vaso-occlusive complications include chronic hydroxyurea therapy to induce fetal hemoglobin. Because hydroxyurea also reduces leukocytosis, an understanding of the impact of this treatment on pneumococcal pathogenesis is needed. Using a sickle cell mouse model of pneumococcal pneumonia and sepsis, administration of hydroxyurea was found to significantly improve survival. Hydroxyurea treatment decreased neutrophil extravasation into the infected lung coincident with significantly reduced levels of E-selectin in serum and on pulmonary epithelia. The protective effect of hydroxyurea was abrogated in mice deficient in E-selectin. The decrease in E-selectin levels was also evident in human sickle cell patients receiving hydroxyurea therapy. These data indicate that in addition to induction of fetal hemoglobin, hydroxyurea attenuates leukocyte–endothelial interactions in sickle cell anemia, resulting in protection against lethal pneumococcal sepsis. PMID:22130804

  19. Hydroxyurea (hydroxycarbamide) for sickle cell disease.

    Science.gov (United States)

    Nevitt, Sarah J; Jones, Ashley P; Howard, Jo

    2017-04-20

    Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising fetal haemoglobin. This is an update of a previously published Cochrane Review. To assess the effects of hydroxyurea therapy in people with SCD (all genotypes), of any age, regardless of setting. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries.Date of the most recent search: 16 January 2017. Randomised and quasi-randomised controlled trials, of one month or longer, comparing hydroxyurea with placebo, standard therapy or other interventions for people with SCD. Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias. Seventeen studies were identified in the searches; eight randomised controlled trials were included, recruiting 899 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months.Four studies (577 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; three recruited individuals with only severe disease and one recruited individuals with all disease severities. There were statistically significant improvements in terms of pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use), measures of fetal haemoglobin and neutrophil counts and fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. There were no consistent

  20. Assessment of rotation thromboelastometry parameters in patients with essential thrombocythemia at diagnosis and after hydroxyurea therapy.

    Science.gov (United States)

    Treliński, Jacek; Okońska, Marta; Robak, Marta; Chojnowski, Krzysztof

    2016-03-01

    Patients with essential thrombocythemia suffer from thrombotic complications that are the main source of mortality. Due to its complex pathogenesis, no existing single laboratory method is able to identify the patients at highest risk for developing thrombosis. Twenty patients with essential thrombocythemia at diagnosis, 15 healthy volunteers and 20 patients treated with hydroxyurea were compared with regard to certain rotation thromboelastometry parameters. Clotting time (CT), clot formation time (CFT), α-angle, and maximum clot firmness (MCF) were assessed by using the INTEM, EXTEM, FIBTEM, and NATEM tests. Patients with essential thrombocythemia at diagnosis demonstrated significantly higher mean platelet count and markedly lower mean red blood count than controls. CT and CFT readings were found to be markedly lower in essential thrombocythemia patients at diagnosis than in the control group according to the EXTEM test. Patients at diagnosis had markedly lower CT values (EXTEM, FIBTEM) than patients on hydroxyurea therapy. Alpha angle values were markedly higher in essential thrombocythemia patients at diagnosis than in controls, according to the EXTEM, FIBTEM and NATEM tests. MCF readings were significantly higher in essential thrombocythemia patients at diagnosis than in controls according to EXTEM, INTEM, FIBTEM, and NATEM tests. Patients on hydroxyurea therapy had markedly lower MCF values according to EXTEM test than patients at diagnosis. Patients with essential thrombocythemia demonstrate a prothrombotic state at the time of diagnosis, which is reflected in changes by certain rotation thromboelastometry parameters. The hydroxyurea therapy induces downregulation of the prothrombotic features seen in essential thrombocythemia patients at diagnosis.

  1. A patient case highlighting the myriad of cutaneous adverse effects of prolonged use of hydroxyurea.

    Science.gov (United States)

    Neill, Brett; Ryser, Ted; Neill, John; Aires, Daniel; Rajpara, Anand

    2017-11-15

    Hydroxyurea is an antimetabolite primarily used to treat myeloproliferative disorders, and chronic treatment is associated with many cutaneous adverse effects ranging in severity from ichthyosis to aggressive nonmelanoma skin cancer. We report a 67-year-oldman with a history of polycythemia vera who was referred for management of progressively worsening dorsal hand lesions. The patient presented withhyperpigmentation, ichthyosis, plantar keratoderma, dermatomyositis-like eruptions, two squamous cell carcinomas, and actinic keratoses. The adversereactions observed were acknowledged to be related to chronic hydroxyurea use. The patient underwent Mohs excision of the squamous cell carcinomas and thehydroxyurea was promptly discontinued; subsequent cutaneous improvement of the dermatomyositislike lesions ensued. Another clinically suspicious aggressive squamous cell carcinoma was suspected and the patient was referred to the plastic surgery department for complete excision because of the size of the lesion. The patient remains on periodic dermatology follow up. We report a case that exemplifies the cutaneous adverse effects of chronic hydroxyurea therapy. Although many cases improve after drug discontinuation, strict photoprotection and ongoing surveillance are indicated given the recently proposed premalignant potential of dermatomyositis-like eruptions and the aggressive nature of hydroxyurea-induced nonmelanoma skin cancer.

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

    Science.gov (United States)

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

    2005-12-20

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

  3. Effect of hydroxyurea on the promoter occupancy profiles of tumor suppressor p53 and p73

    Directory of Open Access Journals (Sweden)

    Lu Xin

    2009-06-01

    Full Text Available Abstract Background The p53 tumor suppressor and its related protein, p73, share a homologous DNA binding domain, and mouse genetics studies have suggested that they have overlapping as well as distinct biological functions. Both p53 and p73 are activated by genotoxic stress to regulate an array of cellular responses. Previous studies have suggested that p53 and p73 independently activate the cellular apoptotic program in response to cytotoxic drugs. The goal of this study was to compare the promoter-binding activity of p53 and p73 at steady state and after genotoxic stress induced by hydroxyurea. Results We employed chromatin immunoprecipitation, the NimbleGen promoter arrays and a model-based algorithm for promoter arrays to identify promoter sequences enriched in anti-p53 or anti-p73 immunoprecipitates, either before or after treatment with hydroxyurea, which increased the expression of both p53 and p73 in the human colon cancer cell line HCT116-3(6. We calculated a model-based algorithm for promoter array score for each promoter and found a significant correlation between the promoter occupancy profiles of p53 and p73. We also found that after hydroxyurea treatment, the p53-bound promoters were still bound by p73, but p73 became associated with additional promoters that that did not bind p53. In particular, we showed that hydroxyurea induces the binding of p73 but not p53 to the promoter of MLH3, which encodes a mismatch repair protein, and causes an up-regulation of the MLH3 mRNA. Conclusion These results suggest that hydroxyurea exerts differential effects on the promoter-binding functions of p53 and p73 and illustrate the power of model-based algorithm for promoter array in the analyses of promoter occupancy profiles of highly homologous transcription factors.

  4. Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics.

    Science.gov (United States)

    Walker, Aisha L; Lancaster, Cynthia S; Finkelstein, David; Ware, Russell E; Sparreboom, Alex

    2013-12-15

    Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assessing the role of OATP1B transporters in modulating hydroxyurea PK. Using wild-type and Oatp1b knockout (Oatp1b(-/-)) mice, hydroxyurea PK was analyzed in vivo by measuring [(14)C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled (14)CO2 metabolite. Plasma levels were significantly reduced by 20% in Oatp1b(-/-) mice compared with wild-type (area under the curve of 38.64 or 48.45 μg·h(-1)·ml(-1), respectively) after oral administration, whereas no difference was observed between groups following intravenous administration. Accumulation in the kidney was significantly decreased by twofold in Oatp1b(-/-) mice (356.9 vs. 748.1 pmol/g), which correlated with a significant decrease in urinary excretion. Hydroxyurea accumulation in the liver was also decreased (136.6 vs. 107.3 pmol/g in wild-type or Oatp1b(-/-) mice, respectively) correlating with a decrease in exhaled (14)CO2. These findings illustrate that deficiency of Oatp1b transporters alters the absorption, distribution, and elimination of hydroxyurea thus providing the first in vivo evidence that cell membrane transporters may play a significant role in modulating hydroxyurea PK. Future studies to investigate other transporters and their role in hydroxyurea disposition are warranted for understanding the sources of variation in hydroxyurea's PK.

  5. Hydroxyl-radical-induced oxidation of cyclic dipeptides: Reactions of free peptide radicals and their peroxyl radicals

    International Nuclear Information System (INIS)

    Mieden, O.J.

    1989-01-01

    In the course of this study investigations were carried out into the reactions of hydroxyl radicals and hydrogen atoms with cyclic dipeptides as well as the subsequent reactions of peptide radicals and their peroxyl radicals in aqueous solution. The radiolysis products formed in the absence and presence of oxygen or transient metal complexes were characterized and determined on a quantitative basis. The linking of information from product analyses to the kinetic data for transient species obtained by time-resolving UV/VIS and conductivity measurements (pulse radiolysis) as well as computer-assisted simulations of individual events during the reaction permitted an evaluation of the mechanisms underlying the various processes and an identification of interim products with short life-times, which did or did not belong to the group of radicals. Through the characterization of key reactions of radicals and peroxyl radicals of this substance class a major advance has been made towards a better understanding of the role of radicals in the peptide compound and the mechanisms involved in indirect radiation effects on long-chain peptides and proteins. (orig.) [de

  6. Hydroxyl group induced adsorption of four-nitro benzoic acid on Si(100) 2x1 surface

    International Nuclear Information System (INIS)

    Ihm, K.; Kang, T.-H.; Hwang, C.C.; Kim, K.-J.; Hwang, H.-N.; Kim, H.-D.; Han, J.H.; Moon, S.; Kim, B.; POSTECH

    2004-01-01

    Full text: A number of studies have been conducted on self-assembled monolayers (SAMs) in order to study the adhesion of polymer films on various substrates. Recently, the studies on SAMs on the semiconductor substrate are more motivated because of their possible application to nanoscale devices. For the electronic and chemical properties suitable for various applications, the aromatic ring has been used as a building block of various molecules forming SAMs. Here, we used four-nitro benzoic acid (4-NBA) as a model planar aromatic compound, in which the phenyl ring, the carboxylic functional group, and NO2 are on the same plane. The adsorption mechanism of 4-NBA on the in-situ prepared OH/Si(100) 2x1 surface was investigated using x-ray photoelectron spectroscopy and near-edge x-ray absorption e structure. The results revealed that the 4-NBA molecule reacts with the hydroxyl group on the Si(100) 2x1 surface through deprotonation of the carboxyl group. The saturation coverage of 4-NBA estimated by the O 1s ratio is 1/2 ML. Additionally, we could observe the desorption of the oxygen atom from the NO2 moiety of the 4-NBA upon irradiating the surface by photons of 500 eV

  7. Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma

    OpenAIRE

    Reardon, David A.; Norden, Andrew D.; Desjardins, Annick; Vredenburgh, James J.; Herndon, James E.; Coan, April; Sampson, John H.; Gururangan, Sridharan; Peters, Katherine B.; McLendon, Roger E.; Norfleet, Julie A.; Lipp, Eric S.; Drappatz, Jan; Wen, Patrick Y.; Friedman, Henry S.

    2011-01-01

    We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint wa...

  8. Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase.

    Science.gov (United States)

    Liew, Li Phing; Lim, Zun Yi; Cohen, Matan; Kong, Ziqing; Marjavaara, Lisette; Chabes, Andrei; Bell, Stephen D

    2016-11-01

    In many organisms, hydroxyurea (HU) inhibits class I ribonucleotide reductase, leading to lowered cellular pools of deoxyribonucleoside triphosphates. The reduced levels for DNA precursors is believed to cause replication fork stalling. Upon treatment of the hyperthermophilic archaeon Sulfolobus solfataricus with HU, we observe dose-dependent cell cycle arrest, accumulation of DNA double-strand breaks, stalled replication forks, and elevated levels of recombination structures. However, Sulfolobus has a HU-insensitive class II ribonucleotide reductase, and we reveal that HU treatment does not significantly impact cellular DNA precursor pools. Profiling of protein and transcript levels reveals modulation of a specific subset of replication initiation and cell division genes. Notably, the selective loss of the regulatory subunit of the primase correlates with cessation of replication initiation and stalling of replication forks. Furthermore, we find evidence for a detoxification response induced by HU treatment. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  9. Hydroxyurea therapy in adult Nigerian sickle cell disease: a ...

    African Journals Online (AJOL)

    Background: The clinical prospects of hydroxyurea therapy in the management of sickle cell disease (SCD) require evaluation in the Nigerian setting to develop indigenous guidelines. This survey examines the pattern of hydroxyurea therapy, its clinico-haematologic benefits and safety profile in Nigerian SCD subjects.

  10. Immunologic effects of hydroxyurea in sickle cell anemia.

    Science.gov (United States)

    Lederman, Howard M; Connolly, Margaret A; Kalpatthi, Ram; Ware, Russell E; Wang, Winfred C; Luchtman-Jones, Lori; Waclawiw, Myron; Goldsmith, Jonathan C; Swift, Andrea; Casella, James F

    2014-10-01

    Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea's effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1-S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses. T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG). Compared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use. Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced. Copyright © 2014 by the American Academy of Pediatrics.

  11. Evidence for hydroxyl radical scavenging action of nitric oxide donors in the protection against 1-methyl-4-phenylpyridinium-induced neurotoxicity in rats.

    Science.gov (United States)

    Banerjee, Rebecca; Saravanan, Karuppagounder S; Thomas, Bobby; Sindhu, Kizhake M; Mohanakumar, Kochupurackal P

    2008-06-01

    In the present study we provide evidence for hydroxyl radical (*OH) scavenging action of nitric oxide (NO*), and subsequent dopaminergic neuroprotection in a hemiparkinsonian rat model. Reactive oxygen species are strongly implicated in the nigrostriatal dopaminergic neurotoxicity caused by the parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). Since the role of this free radical as a neurotoxicant or neuroprotectant is debatable, we investigated the effects of some of the NO* donors such as S-nitroso-N-acetylpenicillamine (SNAP), 3-morpholinosydnonimine hydrochloride (SIN-1), sodium nitroprusside (SNP) and nitroglycerin (NG) on in vitro *OH generation in a Fenton-like reaction involving ferrous citrate, as well as in MPP+-induced *OH production in the mitochondria. We also tested whether co-administration of NO* donor and MPP+ could protect against MPP+-induced dopaminergic neurotoxicity in rats. While NG, SNAP and SIN-1 attenuated MPP+-induced *OH generation in the mitochondria, and in a Fenton-like reaction, SNP caused up to 18-fold increase in *OH production in the latter reaction. Striatal dopaminergic depletion following intranigral infusion of MPP+ in rats was significantly attenuated by NG, SNAP and SIN-1, but not by SNP. Solutions of NG, SNAP and SIN-1, exposed to air for 48 h to remove NO*, when administered similarly failed to attenuate MPP+-induced neurotoxicity in vivo. Conversely, long-time air-exposed SNP solution when administered in rats intranigrally, caused a dose-dependent depletion of the striatal dopamine. These results confirm the involvement of *OH in the nigrostriatal degeneration caused by MPP+, indicate the *OH scavenging ability of NO*, and demonstrate protection by NO* donors against MPP+-induced dopaminergic neurotoxicity in rats.

  12. Effects of hydroxyl radical scavengers KCN and CO on ultraviolet light-induced activation of crude soluble guanylate cyclase

    International Nuclear Information System (INIS)

    Karlsson, J.O.; Axelsson, K.L.; Andersson, R.G.

    1985-01-01

    The crude soluble guanylate cyclase (GC) from bovine mesenteric artery was stimulated by ultraviolet (UV) light (366 nm). Addition of free radical scavengers, dimethylsulfoxide or superoxide dismutase and/or catalase to the GC assay did not abolish the stimulatory effect of UV light. On the contrary, the UV light-induced activation was enhanced in the presence of these scavengers. KCN (1 mM) did not affect the UV light-induced activation, while 0.1 mM of CO potentiated the activation. These results may indicate that UV light is operating through a direct interaction with the ferrous form of the GC-heme

  13. Electron paramagnetic resonance evidence of hydroxyl radical generation and oxidative damage induced by tetrabromobisphenol A in Carassius auratus

    Energy Technology Data Exchange (ETDEWEB)

    Shi Huahong [State Key Laboratory of Pollution Control and Resource Reuse, Nanjing University, Nanjing 210093 (China)]. E-mail: huahongshi@tom.com; Wang Xiaorong [State Key Laboratory of Pollution Control and Resource Reuse, Nanjing University, Nanjing 210093 (China); Luo Yi [State Key Laboratory of Pollution Control and Resource Reuse, Nanjing University, Nanjing 210093 (China); Su Yan [State Key Laboratory of Pollution Control and Resource Reuse, Nanjing University, Nanjing 210093 (China)

    2005-09-30

    Tetrabromobisphenol A (TBBPA) is one of the most widely used brominated flame retardants (BFRs). To confirm its putative oxidative stress-inducing activity, freshwater fish Carassius auratus were injected intraperitoneally with TBBPA. One experiment lasted 3 h to 28 days after a single injection of 100 mg/kg TBBPA, and the other lasted 24 h after a single injection of 0-300 mg/kg TBBPA. Reactive oxygen species (ROS) were trapped by phenyl-tert-butyl nitrone (PBN) and detected by electron paramagnetic resonance (EPR). Protein carbonyl (PCO) and lipid peroxidation product (LPO) content were also determined. A six-line EPR spectrum was detected in the sample prepared in air, and a multiple one was obtained in nitrogen. The observed spectrum in nitrogen fits the simulation one with PBN/{center_dot}OCH{sub 3} and PBN/{center_dot}CH{sub 3} quite well. As compared to the control group, TBBPA significantly induced ROS production marked by the intensity of the prominent spectra in liver and bile. TBBPA (100 mg/kg) also significantly increased PCO content in liver starting 24 h and LPO content 3 days after injection. Either PCO or LPO content showed significant relation with ROS production. Based on the hyperfine constants and shape of the spectrum, ROS induced by TBBPA was determined as {center_dot}OH. The results clearly indicated that TBBPA could induce {center_dot}OH generation and result in oxidative damage in liver of C. auratus.

  14. Damage induced by hydroxyl radicals generated in the hydration layer of γ-irradiated frozen aqueous solution of DNA

    International Nuclear Information System (INIS)

    Ohshima, Hideki; Matsuda, Akira; Kuwabara, Mikinori; Iida, Yoshiharu.

    1996-01-01

    Aqueous DNA solutions with or without the spin trap α-phenyl-N-tert-butylnitrone (PBN) were exposed to γ-rays at 77 K. After thawing the solutions, three experiments were carried out to confirm the generation of OH radicals in the hydration layer of DNA and to examine whether they act as an inducer of DNA strand breaks and base alterations. Observation with the EZR-spin tapping method showed ESR signals from PBN-OH adducts in the solution containing PBN and DNA, but there were few signals in the solution containing PBN alone, suggesting that reactive OH radicals were produced in the hydration layer of γ-irradiated DNA and were effectively scavenged by PBN, and that unreactive OH radicals were produced in the free water layer of γ-irradiated DNA. Agarose gel electrophoresis of DNA proved that PBN had no effect on the formation of strand breaks, whereas examination with the high-performance liquid chromatography-eloctrochemical detection (HPLC-ECD) method showed that PBN suppressed the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). From these results it was concluded that OH radicals generated in the hydration layer of γ-irradiated DNA did not induce DNA strand breaks but induced base alterations. (author)

  15. Toxicity of hydroxyurea in rats and dogs.

    Science.gov (United States)

    Morton, Daniel; Reed, Lori; Huang, Wenhu; Marcek, John M; Austin-LaFrance, Robert; Northcott, Carrie A; Schelling, Scott H; Enerson, Bradley E; Tomlinson, Lindsay

    2015-06-01

    The toxicity of hydroxyurea, a treatment for specific neoplasms, sickle-cell disease, polycythemia, and thrombocytosis that kills cells in mitosis, was assessed in repeat-dose, oral gavage studies in rats and dogs and a cardiovascular study in telemetered dogs. Hydroxyurea produced hematopoietic, lymphoid, cardiovascular, and gastrointestinal toxicity with steep dose response curves. In rats dosed for 10 days, 50 mg/kg/day was tolerated; 500 mg/kg/day produced decreased body weight gain; decreased circulating leukocytes, erythrocytes, and platelets; decreased cellularity of thymus, lymph nodes, and bone marrow; and epithelial degeneration and/or dysplasia of the stomach and small intestine; 1,500 mg/kg/day resulted in deaths on day 5. In dogs, a single dose at ≥ 250 mg/kg caused prostration leading to unscheduled euthanasia. Dogs administered 50 mg/kg/day for 1 month had decreased circulating leukocytes, erythrocytes, and platelets; increased bone marrow cellularity with decreased maturing granulocytes; increased creatinine kinase activity; and increased iron pigment in bone marrow and hepatic sinusoidal cells. In telemetered dogs, doses ≥ 15 mg/kg decreased systolic blood pressure (BP); 50 mg/kg increased diastolic BP, heart rate, and change in blood pressure over time (+dP/dt), and decreased QT and PR intervals and maximum left ventricular systolic and end diastolic pressures with measures returning to control levels within 24 hr. © 2014 by The Author(s).

  16. Transformations of dissolved organic matter induced by UV photolysis, Hydroxyl radicals, chlorine radicals, and sulfate radicals in aqueous-phase UV-Based advanced oxidation processes.

    Science.gov (United States)

    Varanasi, Lathika; Coscarelli, Erica; Khaksari, Maryam; Mazzoleni, Lynn R; Minakata, Daisuke

    2018-05-15

    Considering the increasing identification of trace organic contaminants in natural aquatic environments, the removal of trace organic contaminants from water or wastewater discharge is an urgent task. Ultraviolet (UV) and UV-based advanced oxidation processes (AOPs), such as UV/hydrogen peroxide (UV/H 2 O 2 ), UV/free chlorine and UV/persulfate, are attractive and promising approaches for the removal of these contaminants due to the high reactivity of active radical species produced in these UV-AOPs with a wide variety of organic contaminants. However, the removal efficiency of trace contaminants is greatly affected by the presence of background dissolved organic matter (DOM). In this study, we use ultrahigh resolution mass spectrometry to evaluate the transformation of a standard Suwanee River fulvic acid DOM isolate in UV photolysis and UV-AOPs. The use of probe compounds allows for the determination of the steady-state concentrations of active radical species in each UV-AOP. The changes in the H/C and O/C elemental ratios, double bond equivalents, and the low-molecular-weight transformation product concentrations of organic acids reveal that different DOM transformation patterns are induced by each UV-AOP. By comparison with the known reactivities of each radical species with specific organic compounds, we mechanistically and systematically elucidate the molecular-level DOM transformation pathways induced by hydroxyl, chlorine, and sulfate radicals in UV-AOPs. We find that there is a distinct transformation in the aliphatic components of DOM due to HO• in UV/H 2 O 2 and UV/free chlorine. Cl• induced transformation of olefinic species is also observed in the UV/free chlorine system. Transformation of aromatic and olefinic moieties by SO 4 •- are the predominant pathways in the UV/persulfate system. Copyright © 2018 Elsevier Ltd. All rights reserved.

  17. Thermal decomposition studies of aqueous and nitric solutions of hydroxyurea

    International Nuclear Information System (INIS)

    Shekhar Kumar; Pranay Kumar Sinha; Kamachi Mudali, U.; Natarajan, R.

    2012-01-01

    Hydroxyurea and its derivatives are important nonsalt forming reductants in partitioning of uranium and plutonium in the nuclear fuel reprocessing operations. There is no experimental data available in open literature describing pressurization due to the thermal decomposition of aqueous and nitric solutions of hydroxyurea at elevated temperatures. Authors studied thermal decomposition of hydroxyurea-nitric acid system and resultant pressurization at various concentrations of nitric acid in an adiabatic calorimeter in closed-vent conditions. During these experiments, pressurization was observed. In this paper, results of these experiments have been discussed. (author)

  18. Natural montmorillonite induced photooxidation of As(III) in aqueous suspensions: Roles and sources of hydroxyl and hydroperoxyl/superoxide radicals

    International Nuclear Information System (INIS)

    Wang, Yajie; Xu, Jing; Li, Jinjun; Wu, Feng

    2013-01-01

    Highlights: • Natural montmorillonite contributes to photochemical oxidation of arsenite. • Ferrous ions significantly affect photochemical behavior of montmorillonite. • HO· and HO 2 ·/O 2 − · play different roles in this process. -- Abstract: Photooxidation of arsenite(As(III)) in a suspension of natural montmorillonite under the irradiation of metal halide lamp (λ ≥ 313 nm)has been investigated. The results showed that the natural montmorillonite induced the photooxidation of As(III) by generating hydroxyl radicals (HO·) and hydroperoxyl/superoxide radicals (HO 2 ·/O 2 − ·). HO· which was responsible for the As(III) photooxidation. Approximately 38% of HO· was generated by the photolysis of ferric ions, and the formation of the remaining 62% was strongly dependent on the HO 2 ·/O 2 − ·. The presence of free ironions (Fe 2+ and Fe 3+ ), made significant contributions to the photogeneration of these reactive oxygen species (ROS). The photooxidation of As(III) in natural montmorillonite suspensions was greatly influenced by the pH values. The photooxidation of As(III) by natural montmorillonite followed the Langmuir–Hinshelwood equation. In addition, the photooxidation of As(III) could be enhanced by the addition of humic acid. This work demonstrates that photooxidation may be an important environmental process for the oxidation of As(III) and may be a way to remove As(III) from acidic surface water containing iron-bearing clay minerals

  19. Studies on the relationship between the cancer chemotherapeutic agent, hydroxyurea, and DNA repair in mammalian cells

    International Nuclear Information System (INIS)

    Katz, E.J.

    1988-01-01

    To examine the possibility that manipulating DNA repair might lessen drug resistance, we investigated whether depletion of the thymidine triphosphate (TTP) pool or administration of hydroxyurea could interfere with the ability of confluent normal human skin fibroblasts to repair ultraviolet irradiation-induced DNA damage. A method was developed for the quantitation of cellular TTP pools by labeling them with [ 3 H]thymidine. The addition of hydroxyurea, either simultaneously with [ 3 H]thymidine or two hours later, resulted in a dose- and time-dependent increase in the [ 3 H]TTP pool. The capacity of these cells to carry out DNA repair was quantitated by their ability to perform repair replication synthesis of DNA after exposure to ultraviolet irradiation. This radiation produces thymine dimers in DNA, which are repaired by the nucleotide excision repair pathway. The experimental protocol resulted in an 8-10-fold reduction in the [ 3 H]TTP pool. Saturating levels of DNA repair synthesis were observed under these conditions, with no further diminution of the already reduced [ 3 H]TTP pool. Repair replication and [ 3 H]TTP pool measurements were identical in cultures treated with 10 mM hydroxyurea and in those not exposed to the drug

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

    Science.gov (United States)

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

    2009-12-15

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

  1. Assessment of response to therapy with hydroxyurea in patients with functional asplenia

    International Nuclear Information System (INIS)

    Santos A, O.; Demange, M.N.; Severiche, F.A.; Bomediano, V.H.; Silva, V.R.; Anjos, A.C.; Brandalise, S.R.; Etchebehere, E.C.S.C.; Cunha, M.L.; Camargo, E.E.

    1997-01-01

    Full text: Functional asplenia is a chronic complication of sickle cell (SC) disease. As the concentration of fetal hemoglobin (hemoglobin F) increases in the re blood cells (RBCs), the polymerization of hemoglobin S declines. This makes it possible for a therapeutic approach with drugs that induce hemoglobin F synthesis, leading to improvement of the acute and chronic consequences of SC disease. Hydroxyurea is a chemotherapeutic agent capable of increasing the levels of hemoglobin F in RBCs. Its long term use as an anti-sicklemic agent has been proposed recently. The purpose of this investigation was to evaluate the long term effects of hydroxyurea on the recovery of splenic function in pts with SC disease. Six pts with the disease (5 males, 1 female; 4 to 22 yrs; 5 with SS hemoglobinopathy, , 1 with Sβ o hemoglobinopathy; 4 black, 2 white) were studied. All pts received an intravenous injection of 74-185 MBq of [Tc-99m] sulfur colloid and liver-spleen imaging was performed 10 minutes later in the anterior and posterior views, with and without hepatic shielding. Pts were studied before and immediately after 6 months of treatment with hydroxyurea. All studied were submitted to visual and semi-quantitative analysis. Liver/spleen ratios were obtained before and after 6 months of treatment. Baseline images showed functional asplenia both visually and semi-quantitatively in all 5 SS pts and severely impaired splenic function in the Sβ o pt. Follow-up images performed after 6 months of treatment demonstrated significant splenic function improvement in 4 pts while 2 pts did not show any improvement. It was to demonstrate, using liver/spleen scintigraphy, that hydroxyurea is capable of reversing functional asplenia in pts with SC disease. The best results were observed in the youngest pts and in the Sβ o pt, probably because the amount of splenic fibrosis was less significant

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

    Science.gov (United States)

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

    2009-01-01

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

  3. Effects of hydroxyurea treatment for patients with hemoglobin SC disease.

    Science.gov (United States)

    Luchtman-Jones, Lori; Pressel, Sara; Hilliard, Lee; Brown, R Clark; Smith, Mary G; Thompson, Alexis A; Lee, Margaret T; Rothman, Jennifer; Rogers, Zora R; Owen, William; Imran, Hamayun; Thornburg, Courtney; Kwiatkowski, Janet L; Aygun, Banu; Nelson, Stephen; Roberts, Carla; Gauger, Cynthia; Piccone, Connie; Kalfa, Theodosia; Alvarez, Ofelia; Hassell, Kathryn; Davis, Barry R; Ware, Russell E

    2016-02-01

    Although hemoglobin SC (HbSC) disease is usually considered less severe than sickle cell anemia (SCA), which includes HbSS and HbS/β(0) -thalassemia genotypes, many patients with HbSC experience severe disease complications, including vaso-occlusive pain, acute chest syndrome, avascular necrosis, retinopathy, and poor quality of life. Fully 20 years after the clinical and laboratory efficacy of hydroxyurea was proven in adult SCA patients, the safety and utility of hydroxyurea treatment for HbSC patients remain unclear. Recent NHLBI evidence-based guidelines highlight this as a critical knowledge gap, noting HbSC accounts for ∼30% of sickle cell patients within the United States. To date, only 5 publications have reported short-term, incomplete, or conflicting laboratory and clinical outcomes of hydroxyurea treatment in a total of 71 adults and children with HbSC. We now report on a cohort of 133 adult and pediatric HbSC patients who received hydroxyurea, typically for recurrent vaso-occlusive pain. Hydroxyurea treatment was associated with a stable hemoglobin concentration; increased fetal hemoglobin (HbF) and mean corpuscular volume (MCV); and reduced white blood cell count (WBC), absolute neutrophil count (ANC), and absolute reticulocyte count (ARC). Reversible cytopenias occurred in 22% of patients, primarily neutropenia and thrombocytopenia. Painful events were reduced with hydroxyurea, more in patients >15 years old. These multicenter data support the safety and potentially salutary effects of hydroxyurea treatment for HbSC disease; however, a multicenter, placebo-controlled, Phase 3 clinical trial is needed to determine if hydroxyurea therapy has efficacy for patients with HbSC disease. © 2015 Wiley Periodicals, Inc.

  4. Characterization of hydroxyurea resistance in C. elegans

    DEFF Research Database (Denmark)

    Brejning, Jeanette

    The soil nematode Caenorhabditis elegans has become a prominent model organism for studying aging and many age-related diseases. We use C. elegans to study the relationship between cancer and aging. To prevent cancer, cells are equipped with surveillance systems that detect damage and stop cells...... from dividing. These surveillance systems are collectively called cellular checkpoints. We have found that inactivation of certain checkpoint proteins, including p53, also cause resistance to the chemotherapeutic drug hydroxyurea (HU) that stalls replication. We have found that in C. elegans, HU...... inhibits ribonucleotide reductase (RNR). RNR is involved in synthesis of deoxyribonucleotide (dNTP) precursors for DNA replication and repair. Previously we have shown that inactivation of some checkpoint proteins can increase stress resistance and lifespan of C. elegans1. Interestingly, several genes...

  5. Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice

    Directory of Open Access Journals (Sweden)

    Kaushlendra eTripathi

    2012-05-01

    Full Text Available The fungal pathogen Cryptococcus neoformans (Cn is a serious threat to immunocompromised individuals, especially for HIV patients who develop meningoencephalitis. For effective cryptococcal treatment, novel antifungal drugs or innovative combination therapies are needed. Recently, sphingolipids have emerged as important bioactive molecules in the regulation of microbial pathogenesis. Previously we reported that the sphingolipid pathway gene, ISC1, which is responsible for ceramide production, is a major virulence factor in Cn infection. Here we report our studies of the role of ISC1 during genotoxic stress induced by the antineoplastic hydroxyurea (HU and methylmethane sulfonate (MMS, which affect DNA replication and genome integrity. We observed that Cn cells lacking ISC1 are highly sensitive to HU and MMS in a rich culture medium. HU affected cell division of Cn cells lacking the ISC1 gene, resulting in cell clusters. Cn ISC1, when expressed in a Saccharomyces cerevisiae (Sc strain lacking its own ISC1 gene, restored HU resistance. In macrophage-like cells, although HU affected the proliferation of WT Cn cells by 50% at the concentration tested, HU completely inhibited Cn isc1-delta cell proliferation. Interestingly, our preliminary data show that mice infected with WT or Cn isc1-delta cells and subsequently treated with HU had longer lifespans than untreated, infected control mice. Our work suggests that the sphingolipid pathway gene, ISC1, is a likely target for combination therapy with traditional drugs such as HU.

  6. DIFFERENCES IN HEALTH RELATED QUALITY OF LIFE IN CHILDREN WITH SICKLE CELL DISEASE RECEIVING HYDROXYUREA

    OpenAIRE

    Thornburg, Courtney D.; Calatroni, Agustin; Panepinto, Julie A.

    2011-01-01

    Hydroxyurea is a safe and efficacious medication for children with sickle cell disease (SCD). Our objective was to compare health related quality of life (HRQL) between children taking hydroxyurea and those not taking hydroxyurea. We conducted a retrospective cohort study of children with SCD who had completed the PedsQL 4.0 at Duke University Medical Center or the Midwest Sickle Cell Center. Our primary outcome was HRQL in children receiving hydroxyurea therapy compared to those not receivin...

  7. Hydroxyurea revisited: a decade of clinical effects studies

    International Nuclear Information System (INIS)

    Sinclair, W.K.

    1981-01-01

    Over a decade ago hydroxyurea was shown to selectively kill cells in the S phase in a proliferating cell population and to block cells at the G 1 -S border. Consequently, blocked cells became sensitized to irradiation and were further sensitized when the drug was present after exposure. In the ensuing decade, many in vivo studies on hydroxyurea have confirmed that the main properties of hydroxyurea identified in the dish are also evident in vivo. During a period of about ten years, a considerable number of clinical studies have been performed, the results of which have been mixed, ranging from indeterminate to encouraging, depending to some extent on the site treated and whether careful randomized studies were done. The question arises whether the clinical studies have represented adequate tests, by laboratory standards, of the likely effectiveness of the drug in clinical circumstances. The clinical studies with hydroxyurea have been examined in this light, since the results might also bear on the use of many other such agents in combination therapy. This examination revealed that no attempts have been made to determine the concentration of hydroxyurea in the tumor and other relevant tissues as a function of time or to assess the cell kinetic features of the tumor and thus estimate the appropriate dose regimen. It would seem that a wide gap still exists between laboratory research and clinical application

  8. Hydroxyurea could be a good clinically relevant iron chelator.

    Science.gov (United States)

    Italia, Khushnooma; Colah, Roshan; Ghosh, Kanjaksha

    2013-01-01

    Our previous study showed a reduction in serum ferritin of β-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum-ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl's Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination.

  9. Hydroxyurea could be a good clinically relevant iron chelator.

    Directory of Open Access Journals (Sweden)

    Khushnooma Italia

    Full Text Available Our previous study showed a reduction in serum ferritin of β-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum-ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl's Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination.

  10. Phases of crown-gall transformation susceptible to hydroxyurea

    Directory of Open Access Journals (Sweden)

    Aldona Rennert

    2014-01-01

    Full Text Available With the use of bacterial strains, both sensitive and resistant to hydroxyurea the action of this inhibitor on tumour formation on the leaves of Kalanchoe daigremontiana infected with Agrobacterium tumefaciens was tested for five days after inoculation. The results are in agreement with the opinion that the anti-tumour effect of hydroxyurea applied in the induction phase (between 18 and 60 h after inoculation is the result of its direct action on plant cells, whereas inhibition of tumour formation by the inhibitor in the inoculation period depends on its action on the pathogenic bacteria.

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

    Science.gov (United States)

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

    2007-05-01

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

  12. Enhancing Effect of Hydroxyurea on Hb F in Sickle Cell Disease: Ten-Year Egyptian Experience.

    Science.gov (United States)

    Youssry, Ilham; Abdel-Salam, Amina; Ismail, Rania; Bou-Fakhredin, Rayan; Mohamed Samy, Rania; Ezz El-Deen, Fatma; Taher, Ali T

    Patients with sickle cell disease experience hemolytic anemia and vaso-occlusions that result in pain, organ injury, and premature mortality. Several prospective studies have verified the efficacy and tolerability of hydroxyurea (HU), and demonstrated its efficacy in reducing painful vaso-occlusive crises (VOCs) in addition to its ability to increase Hb F levels. We aimed to evaluate the long-term effects of HU therapy on Hb F and assess its long term efficacy and safety in sickle cell disease patients. A retrospective study on 60 sickle cell disease patients was conducted. We studied the laboratory changes, frequency of VOCs per year, frequency of hospital admisions per year and number of transfusions per year, both before and after HU therapy. The follow-up period was 4 to 120 months. Hb F levels after HU therapy positively correlated with the duration of HU therapy, baseline Hb F levels and baseline total hemoglobin (Hb) (r = 0.4, p = 0.04; r = 0.45, p = 0.001; r = 0.5, p = 0.019, respectively) and inversely correlated with baseline total leucocyte count (r = -0.33, p = 0.034). Hydroxyurea therapy was associated with an increase in the total Hb and mean corpuscular volume (MCV) (p = 0.009, p = 0.000; respectively) and with a decrease in total leucocyte count, platelet count and reticulocyte count (p = 0.00, p = 0.03, p = 0.02, respectively). Moreover, a significant reduction in the frequency of VOCs, transfusion frequency and hospital admissions per year after HU therapy was shown in the studied subjects. Hydroxyurea induced an increase in Hb F level, which was maintained over time and was associated with clinical efficacy and acceptable safety.

  13. Synthetic bovine proline-rich-polypeptides generate hydroxyl radicals and fail to protect dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity in mice.

    Science.gov (United States)

    Knaryan, Varduhi H; Samantaray, Supriti; Varghese, Merina; Srinivasan, Ambika; Galoyan, Armen A; Mohanakumar, Kochupurackal P

    2006-08-01

    Proline-rich-polypeptides (PRPs) isolated from bovine hypothalamus have been shown to render protection against neuronal injury of the brain and spinal cord. We examined two PRPs containing 15 and 10 amino acid residues (PRP-1 and PRP-4 synthetic polypeptide) for their effect, if any, on dopaminergic neuronal damage caused by the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Effects of these PRPs on hydroxyl radical ((*)OH) generation in a Fenton-like reaction as well as from isolated mitochondria were monitored, employing a sensitive salicylate hydroxylation procedure. Balb/c mice treated (i.p., twice, 16 h apart) with MPTP (30 mg/kg) or PRP-1 (1.6 mg/kg), but not PRP-4 (1.6 mg/kg) showed significant loss of striatal dopamine and norepinephrine as assayed by an HPLC-electrochemical procedure. Pretreatment with the PRPs, 30 min prior to the neurotoxin administration failed to attenuate MPTP-induced striatal dopamine or norepinephrine depletion, but significantly attenuated the MPTP-induced decrease in dopamine turnover. A significant increase in the generation of (*)OH by the PRPs in a Fenton-like reaction or from isolated mitochondria suggests their pro-oxidant action, and explains their failure to protect against MPTP-induced parkinsonism in mice.

  14. N-Hydroxylation of 4-Aminobiphenyl by CYP2E1 Produces Oxidative Stress in a Mouse Model of Chemically Induced Liver Cancer

    Science.gov (United States)

    Wang, Shuang; Sugamori, Kim S.; Tung, Aveline; McPherson, J. Peter; Grant, Denis M.

    2015-01-01

    4-Aminobiphenyl (ABP) is a trace component of cigarette smoke and hair dyes, a suspected human carcinogen and a potent rodent liver carcinogen. Postnatal exposure of mice to ABP results in a higher incidence of liver tumors in males than in females, paralleling the sex difference in human liver cancer incidence. A traditional model of ABP tumorigenesis involves initial CYP1A2-mediated N-hydroxylation, which eventually leads to production of mutagenic ABP-DNA adducts that initiate tumor growth. However, several studies have found no correlation between sex or CYP1A2 function and the DNA-damaging, mutagenic, or tumorigenic effects of ABP. Oxidative stress may be an important etiological factor for liver cancer, and it has also been linked to ABP exposure. The goals of this study were to identify novel enzyme(s) that contribute to ABP N-oxidation, and to investigate a potential role for oxidative stress in ABP liver tumorigenicity. Isozyme-selective inhibition experiments using liver microsomes from wild-type and genetically modified mice identified CYP2E1 as a major ABP N-hydroxylating enzyme. The N-hydroxylation of ABP by transiently expressed CYP2E1 produced oxidative stress in cultured mouse hepatoma cells. In vivo postnatal exposure of mice to a tumorigenic dose of ABP also produced oxidative stress in male wild-type mice, but not in male Cyp2e1(−/−) mice or in female mice. However, a stronger NRF2-associated antioxidant response was observed in females. Our results identify CYP2E1 as a novel ABP-N-oxidizing enzyme, and suggest that sex differences in CYP2E1-dependent oxidative stress and antioxidant responses to ABP may contribute to the observed sex difference in tumor incidence. PMID:25601990

  15. Comparative studies on antisickling properties of thiocyanate, tellurite and hydroxyurea

    International Nuclear Information System (INIS)

    Oyewole, O.I.; Maloma, S.O.; Adebayo, J.O.

    2008-01-01

    Thiocyanate, hydroxyurea and tellurite are among chemical agents being used as antisickling drugs and currently receiving attention for research. The antisickling properties of these drugs was investigated and compared in this study. Human sickle blood was incubated with the drugs in vitro at concentrations related to the dose used by patients in vivo. Haemoglobin function and specific aspects of the sickling process were then measured by employing standard methods used in screening potential antisickling agents. All the drugs significantly inhibited (P<0.05) sickling of deoxygenated sickle blood and formation of irreversibly sickled cell in a dose and time-dependent manner. Thiocyanate, hydroxyurea and tellurite inhibited sickling optimally at 20 mM, 40 mM and 50 microM respectively. Thiocyanate and hydroxyurea prolonged sickle red blood cell life span as indicated in the significant decrease in haemolysis and osmotic fragility while tellurite increased these blood parameters. The three drugs also caused significant prolongation of delay time of haemoglobin S (HbS) polymerization while thiocyanate and hydroxyurea significantly increased (P<0.05) both solubility ratio and oxygen affinity of HbS. Results obtained in this study suggest that the three drugs have remarkable antisickling potential in vitro with thiocyanate being the most efficient followed by tellurite. (author)

  16. Hydroxyl radical reactivity with diethylhydroxylamine

    International Nuclear Information System (INIS)

    Gorse, R.A. Jr.; Lii, R.R.; Saunders, B.B.

    1977-01-01

    Diethylhydroxylamine (DEHA) reacts with gas-phase hydroxyl radicals on every third collision, whereas the corresponding reaction in aqueous solution is considerably slower. The high gas-phase reactivity explains the predicted inhibitory effect of DEHA in atmospheric smog processes. Results from the studies in the aqueous phase are helpful in predicting the mechanism of the reaction of DEHA with hydroxyl radicals

  17. Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma.

    Science.gov (United States)

    Reardon, David A; Norden, Andrew D; Desjardins, Annick; Vredenburgh, James J; Herndon, James E; Coan, April; Sampson, John H; Gururangan, Sridharan; Peters, Katherine B; McLendon, Roger E; Norfleet, Julie A; Lipp, Eric S; Drappatz, Jan; Wen, Patrick Y; Friedman, Henry S

    2012-01-01

    We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥ 10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.

  18. Effect of N-hydroxyurea, mitomycin C and actinomycin D on tumour formation on the leaves of Kalanchoe daigremontiana

    Directory of Open Access Journals (Sweden)

    Józef Koawalczyk

    2014-01-01

    Full Text Available The leaves of Kalanchoe daigremontiana wounded and infected with Agrobacterium tumefaciens were treated with single doses of inhibitors (hydroxyurea - 190, mitomycin - 0.5, actinomycin - 2 µ,g per leaf. After delaying the time' of dosage of inhibitors during five days after inoculation, changes in susceptibility of the system to antitumorous activity of analysed compounds were observed. In several hours after inoculation (period of the bacteria metabolic activity in wounds all the inhibitors prevent strongly the tumour formation. At the time between 14 and 72 hours after inoculation, including the phase of tumour induction, the system becomes sensitive to the DNA synthesis inhibitors, particularly hydroxyurea. The intensified action of actinomycin appears again only about 60 hours after inoculation and lasts till the end of experiment (the initiation of the transformed plant cell proliferation. According to the literature the antitumorous effect of inhibitors could be connected with their action on the bacteria metabolism inside the host tissue. The activities of hydroxyurea and mitomycin in the second period correspond with the intensive DNA synthesis in plant cells, which is induced by wounding. The effect of actinomycin D in 60 hours after inoculation could depend upon the inhibition of the proliferation of the transformed host cells.

  19. Isotope-dilution gas chromatography-mass spectrometry method for the analysis of hydroxyurea.

    Science.gov (United States)

    Garg, Uttam; Scott, David; Frazee, Clint; Kearns, Gregory; Neville, Kathleen

    2015-06-01

    Hydroxyurea is used in the treatment of various malignancies and sickle cell disease. There are limited studies on the pharmacokinetics of hydroxyurea, particularly in pediatric patients. An accurate, precise, and sensitive method is needed to support such studies and to monitor therapeutic adherence. We describe a novel gas chromatography-mass spectrometry (GC-MS) method for the determination of hydroxyurea concentration in plasma using stable labeled hydroxyurea C N2 as an internal standard. The method involved an organic extraction followed by the preparation of trimethylsilyl (TMS) derivatives of hydroxyurea for GC-MS selected ion-monitoring analysis. The following mass-to-charge (m/z) ratio ions for silated hydroxyurea and hydroxyurea C N2 were monitored: hydroxyurea-quantitative ion 277, qualifier ions 292 and 249; hydroxyurea C N2-quantitative ion 280, qualifier ion 295. This method was evaluated for reportable range, accuracy, within-run and between-run imprecisions, and limits of quantification. The reportable range for the method was 0.1-100 mcg/mL. All results were accurate within an allowable error of 15%. Within-run and between-run imprecisions were hydroxyurea described here is accurate, sensitive, precise, and robust. Its characteristics make the method suitable for supporting pharmacokinetic studies and/or clinical therapeutic monitoring.

  20. [Curative Effects of Hydroxyurea on the Patients with β-thalassaemia Intermadia].

    Science.gov (United States)

    Huang, Li; Yao, Hong-Xia

    2016-06-01

    To investigate the clinical features of β-thalassaemia intermediate (TI) patients and the curative effect and side reactions of hydroxyurea therapys. Twenty nine patients with TI were divided into hydroxyurea therapy group and no hydroxyurea therapy group; the curative effect and side reactions in 2 groups were compared; the situation of blood transfusion in the 2 groups was evaluated. In hydroxyurea therapy group, the hemoglobin level increased after treatment for 3 months; the reticulocyte percentage obviously decreased after treatment for 12 months; the serum ferritin had been maintained at a low level; while in no hydroxyurea therapy group, the levels of hemoglobin and reticulocytes were not significantly improved after treatment, the serum ferritin level gradually increased. In hydroxyurea therapy group, 12 cases were out of blood transfusion after treatment for 12 months, effective rate of treatment was 85.71%; while in no hydroxyurea therapy group, the blood transfusion dependency was not improved after treatment. No serious side reactions were found in all the hydroxyurea treated patients. The hydroxyurea shows a better curative effect on TI patients, no serious side reactions occur in all the patients treated with hydroxyurea, but the long-term curative effect and side reactions should be observed continuously.

  1. Original Research: Use of hydroxyurea and phlebotomy in pediatric patients with hemoglobin SC disease.

    Science.gov (United States)

    Summarell, Carly C Ginter; Sheehan, Vivien A

    2016-04-01

    Hydroxyurea is an excellent therapeutic agent for the pharmacological induction of HbF in patients with sickle cell disease (SCD). However, all completed clinical trials of hydroxyurea have excluded patients with hemoglobin SC (HbSC) disease. HbSC differs significantly in pathophysiology from HbSS, as HbC does not sickle, but instead causes cellular dehydration which potentiates sickling of HbS. Many severely affected HbSC patients have been placed on hydroxyurea on a case by case basis, but there are no large scale prospective data on safety or efficacy of hydroxyurea in this subset of patients with SCD. Here, we report a case series of 14 pediatric patients with HbSC treated to maximum tolerated dose (MTD) with hydroxyurea. Those who failed to show clinical improvement after at least six months at MTD were offered phlebotomy in addition to hydroxyurea. Five out of 11 patients with HbSC who achieved MTD failed to demonstrate clinical improvement on hydroxyurea. Of the four placed on dual hydroxyurea and phlebotomy therapy, all showed at least partial clinical improvement. Percent dense red blood cells (%DRBC) were measured via an ADVIA hematology analyzer. A marked rise in percent dense cells preceded clinical complications in three patients. Dual therapy with hydroxyurea and phlebotomy may be an effective approach to patients with HbSC that do not experience improvement with hydroxyurea alone. Monitoring of %DRBC may predict adverse events and aid in assessing hydroxyurea compliance. Large scale clinical trials are needed to evaluate the safety and efficacy of hydroxyurea and hydroxyurea with phlebotomy in patients with HbSC disease. © 2016 by the Society for Experimental Biology and Medicine.

  2. Acral keratoses and leucocytoclastic vasculitis occurring during treatment of essential thrombocythaemia with hydroxyurea.

    Science.gov (United States)

    Worley, B; Glassman, S J

    2016-03-01

    Hydroxyurea is used in essential thrombocythaemia to lower thromboembolic risk. Cutaneous adverse effects from hydroxyurea are diverse. Small vessel vasculitis has been rarely reported, and the coexistence of several different morphologies has not been described. We report a case of acral keratoses, psoriasiform plaques and leucocytoclastic vasculitis (LCV) in a patient with essential thrombocythaemia. A 69-year-old woman developed a confusing array of skin lesions including keratotic papules, psoriasiform plaques and keratoderma 4 years after commencing hydroxyurea therapy. The initial diagnosis was hand and foot psoriasis, but lesions were resistant to therapy. With an increase in the dose of hydroxyurea, the lesions ulcerated. Skin biopsies taken from different sites indicated different diagnoses, including LCV. Discontinuation of hydroxyurea yielded rapid improvement. Although the most commonly reported cutaneous adverse effect from hydroxyurea is leg ulceration, this can be preceded or accompanied by less dramatic skin lesions. Unless recognized, delayed diagnosis and lesion progression can occur. © 2015 British Association of Dermatologists.

  3. Hydroxyurea does not prevent synchronized G1 Chinese hamster cells from entering the DNA synthetic period

    International Nuclear Information System (INIS)

    Walters, R.A.; Tobey, R.A.; Hildebrand, C.E.

    1976-01-01

    Using very high concentrations of radioactively labeled thymidine, we show that synchronized G 1 cells treated with hydroxyurea entered the DNA synthetic period at a time and rate indistinguishable from that of untreated cells, although the rate of DNA synthesis was greatly reduced in the drug-treated cultures. The DNA synthesized in the presence of hydroxyurea was less than or equal to 1 x 10 7 daltons, all of which could be chased into bulk DNA of approximately 3.5 x 10 8 daltons within 3 hr after removal of hydroxyurea. Hydroxyurea synchronized cells are apparently not blocked at the G 1 /S boundary but in the S phase itself

  4. Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea.

    Science.gov (United States)

    Alvarez-Larrán, Alberto; Pérez-Encinas, Manuel; Ferrer-Marín, Francisca; Hernández-Boluda, Juan Carlos; Ramírez, María José; Martínez-López, Joaquín; Magro, Elena; Cruz, Yasmina; Mata, María Isabel; Aragües, Pilar; Fox, María Laura; Cuevas, Beatriz; Montesdeoca, Sara; Hernández-Rivas, José Angel; García-Gutiérrez, Valentín; Gómez-Casares, María Teresa; Steegmann, Juan Luis; Durán, María Antonia; Gómez, Montse; Kerguelen, Ana; Bárez, Abelardo; García, Mari Carmen; Boqué, Concepción; Raya, José María; Martínez, Clara; Albors, Manuel; García, Francesc; Burgaleta, Carmen; Besses, Carlos

    2017-01-01

    Hematocrit control below 45% is associated with a lower rate of thrombosis in polycythemia vera. In patients receiving hydroxyurea, this target can be achieved with hydroxyurea alone or with the combination of hydroxyurea plus phlebotomies. However, the clinical implications of phlebotomy requirement under hydroxyurea therapy are unknown. The aim of this study was to evaluate the need for additional phlebotomies during the first five years of hydroxyurea therapy in 533 patients with polycythemia vera. Patients requiring 3 or more phlebotomies per year (n=85, 16%) showed a worse hematocrit control than those requiring 2 or less phlebotomies per year (n=448, 84%). There were no significant differences between the two study groups regarding leukocyte and platelet counts. Patients requiring 3 or more phlebotomies per year received significantly higher doses of hydroxyurea than the remaining patients. A significant higher rate of thrombosis was found in patients treated with hydroxyurea plus 3 or more phlebotomies per year compared to hydroxyurea with 0-2 phlebotomies per year (20.5% vs. 5.3% at 3 years; Phydroxyurea was significantly higher in the group requiring 3 or more phlebotomies per year (18.7% vs. 7.1%; P=0.001) mainly due to extrahematologic toxicity. In conclusion, phlebotomy requirement under hydroxyurea therapy identifies a subset of patients with increased proliferation of polycythemia vera and higher risk of thrombosis. Copyright© Ferrata Storti Foundation.

  5. DNA Binding Hydroxyl Radical Probes

    OpenAIRE

    Tang, Vicky J; Konigsfeld, Katie M; Aguilera, Joe A; Milligan, Jamie R

    2012-01-01

    The hydroxyl radical is the primary mediator of DNA damage by the indirect effect of ionizing radiation. It is a powerful oxidizing agent produced by the radiolysis of water and is responsible for a significant fraction of the DNA damage associated with ionizing radiation. There is therefore an interest in the development of sensitive assays for its detection. The hydroxylation of aromatic groups to produce fluorescent products has been used for this purpose. We have examined four different c...

  6. Hydroxyl radicals (·OH) are associated with titanium dioxide (TiO2) nanoparticle-induced cytotoxicity and oxidative DNA damage in fish cells

    International Nuclear Information System (INIS)

    Reeves, James F.; Davies, Simon J.; Dodd, Nicholas J.F.; Jha, Awadhesh N.

    2008-01-01

    TiO 2 nanoparticles ( 2 nanoparticles on goldfish skin cells (GFSk-S1), either alone or in combination with UVA. Whilst neutral red retention (NRR) assay (a measure of lysosomal membrane integrity) was used to evaluate cell viability, a modified Comet assay using bacterial lesion-specific repair endonucleases (Endo-III, Fpg) was employed to specifically target oxidative DNA damage. Additionally, electron spin resonance (ESR) studies with different spin traps were carried out for qualitative analysis of free radical generation. For cell viability, TiO 2 alone (0.1-1000 μg ml -1 ) had little effect whereas co-exposure with UVA (0.5-2.0 kJ m -2 ) caused a significant dose-dependent decrease which was dependent on both the concentration of TiO 2 and the dose of UVA administered. For the Comet assay, doses of 1, 10 and 100 μg ml -1 in the absence of UVA caused elevated levels of Fpg-sensitive sites, indicating the oxidation of purine DNA bases (i.e. guanine) by TiO 2 . UVA irradiation of TiO 2 -treated cells caused further increases in DNA damage. ESR studies revealed that the observed toxic effects of nanoparticulate TiO 2 were most likely due to hydroxyl radical (·OH) formation

  7. Ruxolitinib is effective and safe in Japanese patients with hydroxyurea-resistant or hydroxyurea-intolerant polycythemia vera with splenomegaly.

    Science.gov (United States)

    Kirito, Keita; Suzuki, Kenshi; Miyamura, Koichi; Takeuchi, Masahiro; Handa, Hiroshi; Okamoto, Shinichiro; Gadbaw, Brian; Yamauchi, Kyosuke; Amagasaki, Taro; Ito, Kazuo; Hino, Masayuki

    2018-02-01

    Ruxolitinib, a potent JAK1/JAK2 inhibitor, was found to be superior to the best available therapy (BAT) in controlling hematocrit, reducing splenomegaly, and improving symptoms in the phase 3 RESPONSE study of patients with polycythemia vera with splenomegaly who experienced an inadequate response to or adverse effects from hydroxyurea. We report findings from a subgroup analysis of Japanese patients in RESPONSE (n = 18). The composite response rate (hematocrit control and spleen response) was higher in patients receiving ruxolitinib (50.0%) than in those receiving BAT (8.3%). A total of 50.0% of patients randomized to ruxolitinib achieved a spleen response vs 8.3% of those receiving BAT; 100 and 33.3% of patients in the respective groups achieved hematocrit control, with mean hematocrit in ruxolitinib-treated patients remaining stable at hydroxyurea.

  8. Cyanide, Peroxide and Nitric Oxide Formation in Solutions of Hydroxyurea Causes Cellular Toxicity and May Contribute to its Therapeutic Potency

    OpenAIRE

    Kuong, Kawai J.; Kuzminov, Andrei

    2009-01-01

    Hydroxyurea is a potent remedy against a variety of ailments and an efficient inhibitor of DNA synthesis, yet its pharmacology is unclear. Hydroxyurea acts in Escherichia coli by the same mechanism as it does in eukaryotes, via inhibition of ribonucleotide reductase. When examining a controversy about concentrations of hydroxyurea that prevent thymineless death in E. coli, we found instability in hydroxyurea solutions which avoided prior detection due to its peculiar nature. In contrast to fr...

  9. Hydroxyl radicals ({center_dot}OH) are associated with titanium dioxide (TiO{sub 2}) nanoparticle-induced cytotoxicity and oxidative DNA damage in fish cells

    Energy Technology Data Exchange (ETDEWEB)

    Reeves, James F.; Davies, Simon J.; Dodd, Nicholas J.F. [School of Biological Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA (United Kingdom); Jha, Awadhesh N. [School of Biological Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA (United Kingdom)], E-mail: a.jha@plymouth.ac.uk

    2008-04-02

    TiO{sub 2} nanoparticles (<100 nm diameter) have been reported to cause oxidative stress related effects, including inflammation, cytotoxicity and genomic instability, either alone or in the presence of UVA irradiation in mammalian studies. Despite the fact that the aquatic environment is often the ultimate recipient of all contaminants there is a paucity of data pertaining to the potential detrimental effects of nanoparticles on aquatic organisms. Therefore, these investigations aimed to evaluate the potential cytotoxic and genotoxic effects of TiO{sub 2} nanoparticles on goldfish skin cells (GFSk-S1), either alone or in combination with UVA. Whilst neutral red retention (NRR) assay (a measure of lysosomal membrane integrity) was used to evaluate cell viability, a modified Comet assay using bacterial lesion-specific repair endonucleases (Endo-III, Fpg) was employed to specifically target oxidative DNA damage. Additionally, electron spin resonance (ESR) studies with different spin traps were carried out for qualitative analysis of free radical generation. For cell viability, TiO{sub 2} alone (0.1-1000 {mu}g ml{sup -1}) had little effect whereas co-exposure with UVA (0.5-2.0 kJ m{sup -2}) caused a significant dose-dependent decrease which was dependent on both the concentration of TiO{sub 2} and the dose of UVA administered. For the Comet assay, doses of 1, 10 and 100 {mu}g ml{sup -1} in the absence of UVA caused elevated levels of Fpg-sensitive sites, indicating the oxidation of purine DNA bases (i.e. guanine) by TiO{sub 2}. UVA irradiation of TiO{sub 2}-treated cells caused further increases in DNA damage. ESR studies revealed that the observed toxic effects of nanoparticulate TiO{sub 2} were most likely due to hydroxyl radical ({center_dot}OH) formation.

  10. Impact of hydroxyurea on clinical events in the BABY HUG trial

    Science.gov (United States)

    Files, Beatrice A.; Luo, Zhaoyu; Miller, Scott T.; Kalpatthi, Ram; Iyer, Rathi; Seaman, Phillip; Lebensburger, Jeffrey; Alvarez, Ofelia; Thompson, Bruce; Ware, Russell E.; Wang, Winfred C.

    2012-01-01

    The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of hydroxyurea in infants (beginning at 9-18 months of age) with sickle cell anemia. An important secondary objective of this study was to compare clinical events between the hydroxyurea and placebo groups. One hundred and ninety-three subjects were randomized to hydroxyurea (20 mg/kg/d) or placebo; there were 374 patient-years of on-study observation. Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain, dactylitis, acute chest syndrome, and hospitalization; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea. Despite expected mild myelosuppression, hydroxyurea was not associated with an increased risk of bacteremia or serious infection. These data provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children with sickle cell anemia. This clinical trial is registered with the National Institutes of Health (NCT00006400, www.clinicaltrials.gov). PMID:22915643

  11. DNA Binding Hydroxyl Radical Probes.

    Science.gov (United States)

    Tang, Vicky J; Konigsfeld, Katie M; Aguilera, Joe A; Milligan, Jamie R

    2012-01-01

    The hydroxyl radical is the primary mediator of DNA damage by the indirect effect of ionizing radiation. It is a powerful oxidizing agent produced by the radiolysis of water and is responsible for a significant fraction of the DNA damage associated with ionizing radiation. There is therefore an interest in the development of sensitive assays for its detection. The hydroxylation of aromatic groups to produce fluorescent products has been used for this purpose. We have examined four different chromophores which produce fluorescent products when hydroxylated. Of these, the coumarin system suffers from the fewest disadvantages. We have therefore examined its behavior when linked to a cationic peptide ligand designed to bind strongly to DNA.

  12. Superb hydroxyl radical-mediated biocidal effect induced antibacterial activity of tuned ZnO/chitosan type II heterostructure under dark

    International Nuclear Information System (INIS)

    Podder, Soumik; Halder, Suman; Roychowdhury, Anirban; Das, Dipankar; Ghosh, Chandan Kr.

    2016-01-01

    Reactive oxygen species (ROS) is the most dominating factor for bacteria cell toxicity due to release of oxidative stress. Hydroxyl radical ("·OH) is a strong oxidizing ROS that has high impact on biocidal activity. This present paper highlights "·OH influenced antibacterial activity and biocidal propensity of tuned ZnO/chitosan (ZnO/CS) nanocomposite against Pseudomonas putida (P. putida) in the absence of light for the first time. For this purpose, the CS proportion was increased by 25 % (w/w) of ZnO during the preparation of ZnO/CS nanocomposite and a systematic study of different ROS like superoxide anion (O_2"·"−), hydrogen peroxide (H_2O_2) and "·OH production as well as their kinetics was carried out both under UV irradiation and in dark by UV–Vis spectroscopy using NBT dye, starch and iodine reaction and fluorescence spectroscopy using terephthalic acid. The decoration of ZnO nanoparticles (ZnO·NPs) with CS tuning was characterized by XRD and FTIR spectroscopy, revealing sustained crystallinity and surface coating of ZnO NP (size about ~24 nm) by CS molecule. The hybridization of ZnO nanoparticles with CS@50 wt% (w/w) resulted superior biocidal activity (81 %) within 3 h in dark mediated by optimum production of "·OH among all ROS. Here we have proposed the enhanced production of "·OH in ZnO/CS due to generation of holes by entrapment of electrons in acceptor level formed in nanocomposite for the first time, and the acceptor levels were probed by Positron annihilation lifetime spectroscopy. The increase in non-positronium (non-Ps) formation probability (I_2) in ZnO/CS nanocomposite confirmed the acceptor levels. This work also confirms surface defect-mediated ROS generation in dark, and zinc interstitials are proposed as active defect sites for generation of holes and "·OH for the first time and confirmed by steady-state room temperature photoluminescence spectroscopy. Finally, a plausible mechanism was hypothesized focusing on hole

  13. Superb hydroxyl radical-mediated biocidal effect induced antibacterial activity of tuned ZnO/chitosan type II heterostructure under dark

    Science.gov (United States)

    Podder, Soumik; Halder, Suman; Roychowdhury, Anirban; Das, Dipankar; Ghosh, Chandan Kr.

    2016-10-01

    Reactive oxygen species (ROS) is the most dominating factor for bacteria cell toxicity due to release of oxidative stress. Hydroxyl radical (·OH) is a strong oxidizing ROS that has high impact on biocidal activity. This present paper highlights ·OH influenced antibacterial activity and biocidal propensity of tuned ZnO/chitosan (ZnO/CS) nanocomposite against Pseudomonas putida (P. putida) in the absence of light for the first time. For this purpose, the CS proportion was increased by 25 % (w/w) of ZnO during the preparation of ZnO/CS nanocomposite and a systematic study of different ROS like superoxide anion (O 2 ·- ), hydrogen peroxide (H2O2) and ·OH production as well as their kinetics was carried out both under UV irradiation and in dark by UV-Vis spectroscopy using NBT dye, starch and iodine reaction and fluorescence spectroscopy using terephthalic acid. The decoration of ZnO nanoparticles (ZnO·NPs) with CS tuning was characterized by XRD and FTIR spectroscopy, revealing sustained crystallinity and surface coating of ZnO NP (size about 24 nm) by CS molecule. The hybridization of ZnO nanoparticles with CS@50 wt% (w/w) resulted superior biocidal activity (81 %) within 3 h in dark mediated by optimum production of ·OH among all ROS. Here we have proposed the enhanced production of ·OH in ZnO/CS due to generation of holes by entrapment of electrons in acceptor level formed in nanocomposite for the first time, and the acceptor levels were probed by Positron annihilation lifetime spectroscopy. The increase in non-positronium (non-Ps) formation probability (I2) in ZnO/CS nanocomposite confirmed the acceptor levels. This work also confirms surface defect-mediated ROS generation in dark, and zinc interstitials are proposed as active defect sites for generation of holes and ·OH for the first time and confirmed by steady-state room temperature photoluminescence spectroscopy. Finally, a plausible mechanism was hypothesized focusing on hole generation in ZnO NP and

  14. Superb hydroxyl radical-mediated biocidal effect induced antibacterial activity of tuned ZnO/chitosan type II heterostructure under dark

    Energy Technology Data Exchange (ETDEWEB)

    Podder, Soumik [Jadavpur University, School of Materials Science and Nanotechnology (India); Halder, Suman [Jadavpur University, Department of Pharmaceutical Technology (India); Roychowdhury, Anirban; Das, Dipankar [Kolkata Centre, UGC-DAE Consortium for Scientific Research (India); Ghosh, Chandan Kr., E-mail: chandu-ju@yahoo.co.in [Jadavpur University, School of Materials Science and Nanotechnology (India)

    2016-10-15

    Reactive oxygen species (ROS) is the most dominating factor for bacteria cell toxicity due to release of oxidative stress. Hydroxyl radical ({sup ·}OH) is a strong oxidizing ROS that has high impact on biocidal activity. This present paper highlights {sup ·}OH influenced antibacterial activity and biocidal propensity of tuned ZnO/chitosan (ZnO/CS) nanocomposite against Pseudomonas putida (P. putida) in the absence of light for the first time. For this purpose, the CS proportion was increased by 25 % (w/w) of ZnO during the preparation of ZnO/CS nanocomposite and a systematic study of different ROS like superoxide anion (O{sub 2}{sup ·−}), hydrogen peroxide (H{sub 2}O{sub 2}) and {sup ·}OH production as well as their kinetics was carried out both under UV irradiation and in dark by UV–Vis spectroscopy using NBT dye, starch and iodine reaction and fluorescence spectroscopy using terephthalic acid. The decoration of ZnO nanoparticles (ZnO·NPs) with CS tuning was characterized by XRD and FTIR spectroscopy, revealing sustained crystallinity and surface coating of ZnO NP (size about ~24 nm) by CS molecule. The hybridization of ZnO nanoparticles with CS@50 wt% (w/w) resulted superior biocidal activity (81 %) within 3 h in dark mediated by optimum production of {sup ·}OH among all ROS. Here we have proposed the enhanced production of {sup ·}OH in ZnO/CS due to generation of holes by entrapment of electrons in acceptor level formed in nanocomposite for the first time, and the acceptor levels were probed by Positron annihilation lifetime spectroscopy. The increase in non-positronium (non-Ps) formation probability (I{sub 2}) in ZnO/CS nanocomposite confirmed the acceptor levels. This work also confirms surface defect-mediated ROS generation in dark, and zinc interstitials are proposed as active defect sites for generation of holes and {sup ·}OH for the first time and confirmed by steady-state room temperature photoluminescence spectroscopy. Finally, a

  15. Molecular structures of (3-aminopropyl)trialkoxysilane on hydroxylated barium titanate nanoparticle surfaces induced by different solvents and their effect on electrical properties of barium titanate based polymer nanocomposites

    International Nuclear Information System (INIS)

    Fan, Yanyan; Wang, Guanyao; Huang, Xingyi; Bu, Jing; Sun, Xiaojin; Jiang, Pingkai

    2016-01-01

    Graphical abstract: - Highlights: • The silanization on the surface of hydroxylated barium titanate nanoparticles was introduced by using two kinds of trialkoxysilanes with different solvents (toluene and ethanol), respectively. • Solvents have more remarkable impact on the dielectric properties of the subsequent BT/PVDF nanocomposites than the types of silanes. • The solvents used for BT nanoparticle surface modification exhibit a significant effect on the breakdown strength of the nanocomposites. - Abstract: Surface modification of nanoparticles by grafting silane coupling agents has proven to be a significant approach to improve the interfacial compatibility between inorganic filler and polymer matrix. However, the impact of grafted silane molecular structure after the nanoparticle surface modification, induced by the utilized solvents and the silane alkoxy groups, on the electrical properties of the corresponding nanocomposites, has been seldom investigated. Herein, the silanization on the surface of hydroxylated barium titanate (BT-OH) nanoparticles was introduced by using two kinds of trialkoxysilane, 3-aminopropyltriethoxysilane (AMEO) and 3-aminopropyltrimethoxysilane (AMMO), with different solvents (toluene and ethanol), respectively. Solid-state 13 C, 29 Si nuclear magnetic resonance (NMR) spectroscopy and high-resolution X-ray photoelectron spectroscopy (XPS) were employed to validate the structure differences of alkoxysilane attachment to the nanoparticles. The effect of alkoxysilane structure attached to the nanoparticle surface on the dielectric properties of the BT based poly(vinylidene fluoride) (PVDF) nanocomposites were investigated. The results reveal that the solvents used for BT nanoparticle surface modification exhibit a significant effect on the breakdown strength of the nanocomposites. Nevertheless, the alkoxy groups of silane show a marginal influence on the dielectric properties of the nanocomposites. These research results provide

  16. Predictors of splenic function preservation in children with sickle cell anemia treated with hydroxyurea.

    Science.gov (United States)

    Nottage, Kerri A; Ware, Russell E; Winter, Bryan; Smeltzer, Matthew; Wang, Winfred C; Hankins, Jane S; Dertinger, Stephen D; Shulkin, Barry; Aygun, Banu

    2014-11-01

    More than 90% of children with sickle cell anemia (SCA) lose splenic function by the age of 2 yrs. Splenic function may improve with hydroxyurea, but previous studies are conflicting. We prospectively evaluated the effect of hydroxyurea on splenic filtrative function. Children with SCA enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE-NCT00305175) underwent clinical evaluations including Tc(99) m liver-spleen (LS) scans before hydroxyurea initiation and after 3 yrs of treatment to maximum tolerated dose (MTD). LS scans were classified as follows: no uptake, Hydroxyurea at MTD is associated with preserved or improved splenic filtrative function, with 33% demonstrating LS scan uptake after 3 yrs. Younger age, higher %HbF, and baseline splenic function are associated with a favorable outcome. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Differential effects of hydroxyurea on the survival of UV- and MNNG-treated adenovirus 5

    International Nuclear Information System (INIS)

    Day, R.S. III; Ziolkowski, C.H.J.

    1982-01-01

    The effects of hydroxyurea on plaque formation by UV-irradiated and MNNG-treated adenovirus 5 were investigated. Hydroxyurea blocked the recovery of UV-irradiated viruses in all cases studied, but the effect was less when fibroblasts from a patient with xeroderma pigmentosum were used. This fact supports the notion that hydroxyurea blocks excision repair of UV-produced damage. The recovery of MNNG-treated viruses was not blocked by hydroxyurea when viruses were used to infect normal human fibroblasts, but was blocked if the cell strain used as viral host were deficient in repair of O 6 -methylguanine. To account for these data, we propose that hydroxyurea blocks repair in which DNA polymerases play a role, but does not block repair in which DNA polymerases are not required. (orig.)

  18. Differential effects of hydroxyurea on the survival of UV- and MNNG-treated adenovirus 5

    Energy Technology Data Exchange (ETDEWEB)

    Day, R.S. III; Ziolkowski, C.H.J. (National Inst. for Cancer Research, Bethesda, MD (USA). Nucleic Acid Section)

    1982-01-01

    The effects of hydroxyurea on plaque formation by UV-irradiated and MNNG-treated adenovirus 5 were investigated. Hydroxyurea blocked the recovery of UV-irradiated viruses in all cases studied, but the effect was less when fibroblasts from a patient with xeroderma pigmentosum were used. This fact supports the notion that hydroxyurea blocks excision repair of UV-produced damage. The recovery of MNNG-treated viruses was not blocked by hydroxyurea when viruses were used to infect normal human fibroblasts, but was blocked if the cell strain used as viral host were deficient in repair of O/sup 6/-methylguanine. To account for these data, we propose that hydroxyurea blocks repair in which DNA polymerases play a role, but does not block repair in which DNA polymerases are not required.

  19. Hydroxyurea therapy in UK children with sickle cell anaemia: A single-centre experience.

    Science.gov (United States)

    Phillips, Kate; Healy, Laura; Smith, Louise; Keenan, Russell

    2018-02-01

    Despite the demonstrated efficacy of hydroxyurea therapy, children with sickle cell anaemia in the UK are preferentially managed with supportive care or transfusion. Hydroxyurea is reserved for children with severe disease phenotype. This is in contrast to North America and other countries where hydroxyurea is widely used for children of all clinical phenotypes. The conservative UK practice may in part be due to concerns about toxicity, in particular marrow suppression with high doses, and growth in children. We monitored 37 paediatric patients with sickle cell anaemia who were treated with hydroxyurea at a single UK treatment centre. Therapy was well tolerated and mild transient cytopenias were the only toxicity observed. Comparative analysis of patients receiving ≥26 mg/kg/day versus hydroxyurea as a disease-modifying therapy, which we advocate for all children with sickle cell anaemia. © 2017 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.

  20. Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: implications for drug-induced osteomalacia.

    Science.gov (United States)

    Wang, Zhican; Lin, Yvonne S; Dickmann, Leslie J; Poulton, Emma-Jane; Eaton, David L; Lampe, Johanna W; Shen, Danny D; Davis, Connie L; Shuhart, Margaret C; Thummel, Kenneth E

    2013-05-01

    Long-term therapy with certain drugs, especially cytochrome P450 (P450; CYP)-inducing agents, confers an increased risk of osteomalacia that is attributed to vitamin D deficiency. Human CYP24A1, CYP3A4, and CYP27B1 catalyze the inactivation and activation of vitamin D and have been implicated in the adverse drug response. In this study, the inducibility of these enzymes and monohydroxylation of 25-hydroxyvitamin D3 (25OHD3) were evaluated after exposure to P450-inducing drugs. With human hepatocytes, treatment with phenobarbital, hyperforin, carbamazepine, and rifampin significantly increased the levels of CYP3A4, but not CYP24A1 or CYP27B1 mRNA. In addition, rifampin pretreatment resulted in an 8-fold increase in formation of the major metabolite of 25OHD3, 4β,25(OH)2D3. This inductive effect was blocked by the addition of 6',7'-dihydroxybergamottin, a selective CYP3A4 inhibitor. With human renal proximal tubular HK-2 cells, treatment with the same inducers did not alter CYP3A4, CYP24A1, or CYP27B1 expression. 24R,25(OH)2 D3 was the predominant monohydroxy metabolite produced from 25OHD3, but its formation was unaffected by the inducers. With healthy volunteers, the mean plasma concentration of 4β,25(OH)2D3 was increased 60% (p osteomalacia. Copyright © 2013 American Society for Bone and Mineral Research.

  1. Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea

    Science.gov (United States)

    Alvarez-Larrán, Alberto; Pérez-Encinas, Manuel; Ferrer-Marín, Francisca; Hernández-Boluda, Juan Carlos; Ramírez, María José; Martínez-López, Joaquín; Magro, Elena; Cruz, Yasmina; Mata, María Isabel; Aragües, Pilar; Fox, María Laura; Cuevas, Beatriz; Montesdeoca, Sara; Hernández-Rivas, José Angel; García-Gutiérrez, Valentín; Gómez-Casares, María Teresa; Steegmann, Juan Luis; Durán, María Antonia; Gómez, Montse; Kerguelen, Ana; Bárez, Abelardo; García, Mari Carmen; Boqué, Concepción; Raya, José María; Martínez, Clara; Albors, Manuel; García, Francesc; Burgaleta, Carmen; Besses, Carlos

    2017-01-01

    Hematocrit control below 45% is associated with a lower rate of thrombosis in polycythemia vera. In patients receiving hydroxyurea, this target can be achieved with hydroxyurea alone or with the combination of hydroxyurea plus phlebotomies. However, the clinical implications of phlebotomy requirement under hydroxyurea therapy are unknown. The aim of this study was to evaluate the need for additional phlebotomies during the first five years of hydroxyurea therapy in 533 patients with polycythemia vera. Patients requiring 3 or more phlebotomies per year (n=85, 16%) showed a worse hematocrit control than those requiring 2 or less phlebotomies per year (n=448, 84%). There were no significant differences between the two study groups regarding leukocyte and platelet counts. Patients requiring 3 or more phlebotomies per year received significantly higher doses of hydroxyurea than the remaining patients. A significant higher rate of thrombosis was found in patients treated with hydroxyurea plus 3 or more phlebotomies per year compared to hydroxyurea with 0–2 phlebotomies per year (20.5% vs. 5.3% at 3 years; P<0.0001). In multivariate analysis, independent risk factors for thrombosis were phlebotomy dependency (HR: 3.3, 95%CI: 1.5–6.9; P=0.002) and thrombosis at diagnosis (HR: 4.7, 95%CI: 2.3–9.8; P<0.0001). The proportion of patients fulfilling the European LeukemiaNet criteria of resistance/intolerance to hydroxyurea was significantly higher in the group requiring 3 or more phlebotomies per year (18.7% vs. 7.1%; P=0.001) mainly due to extrahematologic toxicity. In conclusion, phlebotomy requirement under hydroxyurea therapy identifies a subset of patients with increased proliferation of polycythemia vera and higher risk of thrombosis. PMID:27686377

  2. Characterization of hydroxyurea (HYU) S49 T lymphoma cells

    International Nuclear Information System (INIS)

    Albert, D.A.; Gudas, L.J.

    1986-01-01

    This paper tests the hypotheses that in vivo ribonucleotide reductase activity and consequent deoxyribonucleoside triphosphate production is rate-limited by the availability of M2 activity. The authors selected and characterized cell lines with variable resistance to hydroxyurea and comparing them with wild type S49 T-lymphoma cells. Ribonucleotide reductase assay was measured and in the process C 14-CDP was added in the final volume of assay mixture. It is shown that hydroxourea reversibly binds to the tyrosine radical of the M2 subunit of ribonucleotide reductase that is required for catalytic activity

  3. Hydroxyurea derivatives of irofulven with improved antitumor efficacy.

    Science.gov (United States)

    Staake, Michael D; Kashinatham, Alisala; McMorris, Trevor C; Estes, Leita A; Kelner, Michael J

    2016-04-01

    Irofulven is a semi-synthetic derivative of Illudin S, a toxic sesquiterpene isolated from the mushroom Omphalotus illudens. Irofulven has displayed significant antitumor activity in various clinical trials but displayed a limited therapeutic index. A new derivative of irofulven was prepared by reacting hydroxyurea with irofulven under acidic conditions. Acetylation of this new compound with acetic anhydride produced a second derivative. Both of these new derivatives displayed significant antitumor activity in vitro and in vivo comparable to or exceeding that of irofulven. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Anagrelide compared with hydroxyurea in essential thrombocythemia: a meta-analysis.

    Science.gov (United States)

    Samuelson, Bethany; Chai-Adisaksopha, Chatree; Garcia, David

    2015-11-01

    Cytoreductive therapy, with or without low-dose aspirin, is the mainstay of thrombotic risk reduction in patients with essential thrombocythemia (ET), but the optimal choice of agent remains unclear. The aim of this study was to meta-analyze currently available data comparing anagrelide to hydroxyurea for reduction of rates of thrombosis, bleeding and death among patients with ET. A literature search for randomized, controlled trials comparing anagrelide to hydroxyurea among patients with ET revealed two published studies. Statistical analysis was performed using fixed effects meta-analysis. Rates of thrombosis were similar between patients treated with hydroxyurea vs anagrelide (RR 0.86, 95 % CI 0.64-1.16). Rates of major bleeding were lower in patients treated with hydroxyurea (RR 0.37, 95 % CI 0.18-0.75). Rates of progression to acute myeloid leukemia were not statistically different (RR 1.50, 95 % CI 0.43-5.29). The composite of thrombosis, major bleeding and death favored hydroxyurea (RR 0.78, 95 % CI 0.63-0.97). In conclusion, our analysis supports use of hydroxyurea as a first-line cytoreductive agent for patients with ET, based largely on decreased rates of major bleeding. Anagrelide appears to be equally effective for protection against thrombotic events and may be an appropriate alternative for patients who are intolerant of hydroxyurea.

  5. Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

    Science.gov (United States)

    Despotovic, Jenny M.; Mortier, Nicole A.; Flanagan, Jonathan M.; He, Jin; Smeltzer, Matthew P.; Kimble, Amy C.; Aygun, Banu; Wu, Song; Howard, Thad; Sparreboom, Alex

    2011-01-01

    Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal. PMID:21876119

  6. How I use hydroxyurea to treat young patients with sickle cell anemia

    Science.gov (United States)

    2010-01-01

    Hydroxyurea has many characteristics of an ideal drug for sickle cell anemia (SCA) and provides therapeutic benefit through multiple mechanisms of action. Over the past 25 years, substantial experience has accumulated regarding its safety and efficacy for patients with SCA. Early proof-of-principle studies were followed by prospective phase 1/2 trials demonstrating efficacy in affected adults, then adolescents and children, and more recently infants and toddlers. The phase 3 National Heart, Lung and Blood Institute–sponsored Multicenter Study of Hydroxyurea trial proved clinical efficacy for preventing acute vaso-occlusive events in severely affected adults. Based on this cumulative experience, hydroxyurea has emerged as an important therapeutic option for children and adolescents with recurrent vaso-occlusive events; recent evidence documents sustained long-term benefits with prevention or reversal of chronic organ damage. Despite abundant evidence for its efficacy, however, hydroxyurea has not yet translated into effective therapy for SCA. Because many healthcare providers have inadequate knowledge about hydroxyurea, patients and families are not offered treatment or decline because of unrealistic fears. Limited support for hydroxyurea by lay organizations and inconsistent medical delivery systems also contribute to underuse. Although questions remain regarding its long-term risks and benefits, current evidence suggests that many young patients with SCA should receive hydroxyurea treatment. PMID:20223921

  7. From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia.

    Science.gov (United States)

    Hankins, Jane S; Aygun, Banu; Nottage, Kerri; Thornburg, Courtney; Smeltzer, Matthew P; Ware, Russell E; Wang, Winfred C

    2014-12-01

    Despite documented laboratory and clinical benefits of hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of hydroxyurea in infants with SCA. This report describes HUSOFT participants who have continued hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters. Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5-31.2); neutropenia [absolute neutrophil count (ANC)hydroxyurea therapy since infancy appears safe and efficacious in SCA.

  8. Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters

    Science.gov (United States)

    Walker, Aisha L.; Franke, Ryan M.; Sparreboom, Alex; Ware, Russell E.

    2015-01-01

    Objective Hydroxyurea has proven laboratory and clinical therapeutic benefits for sickle cell anemia (SCA) and other diseases, yet many questions remain regarding its in vivo pharmacokinetic and pharmacodynamic profiles. Previous reports suggest that hydroxyurea passively diffuses across cells, but its observed rapid absorption and distribution are more consistent with facilitated or active transport. We investigated the potential role of solute carrier (SLC) transporters in cellular uptake and accumulation of hydroxyurea. Materials and Methods Passive diffusion of hydroxyurea across cell membranes was determined using the parallel artificial membrane permeability assay. SLC transporter screens were conducted using in vitro intracellular drug accumulation and transcellular transport assays in cell lines and oocytes overexpressing SLC transporters. Gene expression of SLC transporters was measured by real-time PCR in human tissues and cell lines. Results Hydroxyurea had minimal diffusion across a lipid bilayer but was a substrate for 5 different SLC transporters belonging to the OCTN and OATP families of transporters and urea transporters A and B. Further characterization of hydroxyurea transport revealed that cellular uptake by OATP1B3 is time and temperature dependent and inhibited by known substrates of OATP1B3. Urea transporters A and B are expressed differentially in human tissues and erythroid cells, and transport hydroxyurea bidirectionally via facilitated diffusion. Conclusions These studies provide new insight into drug transport proteins that may be involved in the in vivo absorption, cellular distribution, and elimination of hydroxyurea. Elucidation of hydroxyurea transcellular movement should improve our understanding of its pharmacokinetics and pharmacodynamics, and may help explain some of the inter-patient drug variability observed in patients with SCA. PMID:21256917

  9. Uranium/plutonium and uranium/neptunium separation by the Purex process using hydroxyurea

    International Nuclear Information System (INIS)

    Zhu Zhaowu; He Jianyu; Zhang Zefu; Zhang Yu; Zhu Jianmin; Zhen Weifang

    2004-01-01

    Hydroxyurea dissolved in nitric acid can strip plutonium and neptunium from tri-butyl phosphate efficiently and has little influence on the uranium distribution between the two phases. Simulating the 1B contactor of the Purex process by hydroxyurea with nitric acid solution as a stripping agent, the separation factors of uranium/plutonium and uranium/neptunium can reach values as high as 4.7 x 10 4 and 260, respectively. This indicates that hydroxyurea is a promising salt free agent for uranium/plutonium and uranium/neptunium separations. (author)

  10. Original Research: Use of hydroxyurea and phlebotomy in pediatric patients with hemoglobin SC disease

    OpenAIRE

    Summarell, Carly C Ginter; Sheehan, Vivien A

    2016-01-01

    Hydroxyurea is an excellent therapeutic agent for the pharmacological induction of HbF in patients with sickle cell disease (SCD). However, all completed clinical trials of hydroxyurea have excluded patients with hemoglobin SC (HbSC) disease. HbSC differs significantly in pathophysiology from HbSS, as HbC does not sickle, but instead causes cellular dehydration which potentiates sickling of HbS. Many severely affected HbSC patients have been placed on hydroxyurea on a case by case basis, but ...

  11. Molecular structures of (3-aminopropyl)trialkoxysilane on hydroxylated barium titanate nanoparticle surfaces induced by different solvents and their effect on electrical properties of barium titanate based polymer nanocomposites

    Science.gov (United States)

    Fan, Yanyan; Wang, Guanyao; Huang, Xingyi; Bu, Jing; Sun, Xiaojin; Jiang, Pingkai

    2016-02-01

    Surface modification of nanoparticles by grafting silane coupling agents has proven to be a significant approach to improve the interfacial compatibility between inorganic filler and polymer matrix. However, the impact of grafted silane molecular structure after the nanoparticle surface modification, induced by the utilized solvents and the silane alkoxy groups, on the electrical properties of the corresponding nanocomposites, has been seldom investigated. Herein, the silanization on the surface of hydroxylated barium titanate (BT-OH) nanoparticles was introduced by using two kinds of trialkoxysilane, 3-aminopropyltriethoxysilane (AMEO) and 3-aminopropyltrimethoxysilane (AMMO), with different solvents (toluene and ethanol), respectively. Solid-state 13C, 29Si nuclear magnetic resonance (NMR) spectroscopy and high-resolution X-ray photoelectron spectroscopy (XPS) were employed to validate the structure differences of alkoxysilane attachment to the nanoparticles. The effect of alkoxysilane structure attached to the nanoparticle surface on the dielectric properties of the BT based poly(vinylidene fluoride) (PVDF) nanocomposites were investigated. The results reveal that the solvents used for BT nanoparticle surface modification exhibit a significant effect on the breakdown strength of the nanocomposites. Nevertheless, the alkoxy groups of silane show a marginal influence on the dielectric properties of the nanocomposites. These research results provide important insights into the fabrication of advanced polymer nanocomposites for dielectric applications.

  12. 21 CFR 172.814 - Hydroxylated lecithin.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Hydroxylated lecithin. 172.814 Section 172.814 Food... Multipurpose Additives § 172.814 Hydroxylated lecithin. The food additive hydroxylated lecithin may be safely... obtained by the treatment of lecithin in one of the following ways, under controlled conditions whereby the...

  13. NTP-CERHR monograph on the potential human reproductive and developmental effects of hydroxyurea.

    Science.gov (United States)

    2008-10-01

    The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for hydroxyurea to cause adverse effects on reproduction and development in humans. Hydroxyurea is a drug used to treat cancer, sickle cell disease, and thalassemia. It is the only treatment for sickle cell disease in children, aside from blood transfusion and, in severe cases, hematopoietic stem cell transplantation. Hydroxyurea is FDA-approved for use in adults with sickle cell anemia to reduce the frequency of painful crises and the need for blood transfusions. Hydroxyurea may be given to children and adults with sickle cell disease for an extended period of time or for repeated cycles of therapy. Treatment with hydroxyurea is associated with known side effects such as cytotoxicity and myelosuppression, and hydroxyurea is genotoxic (can damage DNA). CERHR selected hydroxyurea for evaluation because of: its increasing use for treatment of sickle cell disease in children and adults, knowledge that it inhibits DNA synthesis and is cytotoxic, and published evidence of reproductive and developmental toxicity in rodents. The results of this evaluation are published in the NTP-CERHR Monograph on Hydroxyurea, which includes the NTP Brief and Expert Panel Report on the Reproductive and Developmental Toxicity of Hydroxyurea. Additional information related to the evaluation process, including public comments received on the draft NTP Brief and the final expert panel report, are available on the CERHR website (http:// cerhr.niehs.nih.gov/). See hydroxyurea under "CERHR Chemicals" on the homepage or go directly to http://cerhr.niehs.nih.gov/chemicals/hydroxyurea/hydroxyurea-eval.html). The NTP reached the following conclusions on the possible effects of exposure to hydroxyurea on human reproduction or development. The possible levels of concern, from lowest to highest, are negligible concern, minimal concern, some concern, concern

  14. Variation in Gamma-Globin Expression before and after Induction with Hydroxyurea Associated with BCL11A, KLF1 and TAL1.

    Directory of Open Access Journals (Sweden)

    Amanda J Grieco

    Full Text Available The molecular mechanisms governing γ-globin expression in a subset of fetal hemoglobin (α2γ2: HbF expressing red blood cells (F-cells and the mechanisms underlying the variability of response to hydroxyurea induced γ-globin expression in the treatment of sickle cell disease are not completely understood. Here we analyzed intra-person clonal populations of basophilic erythroblasts (baso-Es derived from bone marrow common myeloid progenitors in serum free cultures and report the level of fetal hemoglobin production in F-cells negatively correlates with expression of BCL11A, KLF1 and TAL1. We then examined the effects of hydroxyurea on these three transcription factors and conclude that a successful induction of γ-globin includes a reduction in BCL11A, KLF1 and TAL1 expression. These data suggests that expression changes in this transcription factor network modulate γ-globin expression in F-cells during steady state erythropoiesis and after induction with hydroxyurea.

  15. In Vitro/In Vivo Evaluation of Radiolabeled [(99m)Tc(CO)3](+)-Hydroxyurea and Fluorescein Isothiocyanate-Hydroxyurea.

    Science.gov (United States)

    Yilmaz, Baris; Teksoz, Serap; Kilcar, Ayfer Yurt; Ucar, Eser; Ichedef, Cigdem; Medine, Emin Ilker; Ari, Kadir

    2016-02-01

    The aim of current study is to examine hydroxyurea (HU), which is an antineoplastic drug used for the treatment of leukemia, sickle-cell disease, HIV, psoriasis, thrombocythemia, and various neoplastic diseases in two aspects. The active ingredient hydroxyurea was obtained by purification of the capsule form drug, commercially named as HYDREA. Then, [(99m)Tc(CO)3](+)core radiolabeling with HU was performed as first aspect. Quality control studies of (99m)Tc(CO)3-HU complex were performed by thin-layer radiochromatography and high-performance liquid radiochromatography methods. The results demonstrated that the radiolabeling yield was quite high (98.43% ± 2.29%). Also, (99m)Tc(CO)3-HU complex has good stability during the 24-hour period. Biological behavior of (99m)Tc(CO)3-HU complex is evaluated by biodistribution studies on Wistar Albino rats. Fluorescein isothiocyanate (FITC) labeling of HU was performed as second aspect. Fluorometric evaluation of binding efficacy and fluorescence imaging studies on MCF7 and Hela cell lines were carried out. It was thought that the knowledge achieved in this study would contribute to using (99m)Tc(CO)3-HU complex as an imaging agent, which inhibits the DNA synthesis selectively, by inhibiting ribonucleotide reductase enzyme. It was observed that FITC-HU has noteworthy incorporation on both cell lines.

  16. Roles of Fragile X Mental Retardation Protein in Dopaminergic Stimulation-induced Synapse-associated Protein Synthesis and Subsequent α-Amino-3-hydroxyl-5-methyl-4-isoxazole-4-propionate (AMPA) Receptor Internalization*

    Science.gov (United States)

    Wang, Hansen; Kim, Susan S.; Zhuo, Min

    2010-01-01

    Fragile X syndrome, the most common form of inherited mental retardation, is caused by the absence of the RNA-binding protein fragile X mental retardation protein (FMRP). FMRP regulates local protein synthesis in dendritic spines. Dopamine (DA) is involved in the modulation of synaptic plasticity. Activation of DA receptors can regulate higher brain functions in a protein synthesis-dependent manner. Our recent study has shown that FMRP acts as a key messenger for DA modulation in forebrain neurons. Here, we demonstrate that FMRP is critical for DA D1 receptor-mediated synthesis of synapse-associated protein 90/PSD-95-associated protein 3 (SAPAP3) in the prefrontal cortex (PFC). DA D1 receptor stimulation induced dynamic changes of FMRP phosphorylation. The changes in FMRP phosphorylation temporally correspond with the expression of SAPAP3 after D1 receptor stimulation. Protein phosphatase 2A, ribosomal protein S6 kinase, and mammalian target of rapamycin are the key signaling molecules for FMRP linking DA D1 receptors to SAPAP3. Knockdown of SAPAP3 did not affect surface expression of α-amino-3-hydroxyl-5-methyl-4-isoxazole-4-propionate (AMPA) GluR1 receptors induced by D1 receptor activation but impaired their subsequent internalization in cultured PFC neurons; the subsequent internalization of GluR1 was also impaired in Fmr1 knock-out PFC neurons, suggesting that FMRP may be involved in subsequent internalization of GluR1 through regulating the abundance of SAPAP3 after DA D1 receptor stimulation. Our study thus provides further insights into FMRP involvement in DA modulation and may help to reveal the molecular mechanisms underlying impaired learning and memory in fragile X syndrome. PMID:20457613

  17. Roles of fragile X mental retardation protein in dopaminergic stimulation-induced synapse-associated protein synthesis and subsequent alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-4-propionate (AMPA) receptor internalization.

    Science.gov (United States)

    Wang, Hansen; Kim, Susan S; Zhuo, Min

    2010-07-09

    Fragile X syndrome, the most common form of inherited mental retardation, is caused by the absence of the RNA-binding protein fragile X mental retardation protein (FMRP). FMRP regulates local protein synthesis in dendritic spines. Dopamine (DA) is involved in the modulation of synaptic plasticity. Activation of DA receptors can regulate higher brain functions in a protein synthesis-dependent manner. Our recent study has shown that FMRP acts as a key messenger for DA modulation in forebrain neurons. Here, we demonstrate that FMRP is critical for DA D1 receptor-mediated synthesis of synapse-associated protein 90/PSD-95-associated protein 3 (SAPAP3) in the prefrontal cortex (PFC). DA D1 receptor stimulation induced dynamic changes of FMRP phosphorylation. The changes in FMRP phosphorylation temporally correspond with the expression of SAPAP3 after D1 receptor stimulation. Protein phosphatase 2A, ribosomal protein S6 kinase, and mammalian target of rapamycin are the key signaling molecules for FMRP linking DA D1 receptors to SAPAP3. Knockdown of SAPAP3 did not affect surface expression of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-4-propionate (AMPA) GluR1 receptors induced by D1 receptor activation but impaired their subsequent internalization in cultured PFC neurons; the subsequent internalization of GluR1 was also impaired in Fmr1 knock-out PFC neurons, suggesting that FMRP may be involved in subsequent internalization of GluR1 through regulating the abundance of SAPAP3 after DA D1 receptor stimulation. Our study thus provides further insights into FMRP involvement in DA modulation and may help to reveal the molecular mechanisms underlying impaired learning and memory in fragile X syndrome.

  18. Massive Accidental Overdose of Hydroxyurea in a Young Child with Sickle Cell Anemia

    Science.gov (United States)

    Miller, Scott T.; Rey, Kathy; He, Jin; Flanagan, Jonathan; Fish, Billie J.; Rogers, Zora R.; Wang, Winfred C.; Ware, Russell E.

    2011-01-01

    The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) confirmed safety and efficacy of hydroxyurea therapy for infants with sickle cell anemia. Treatment was associated with reduction in rates of pain, acute chest syndrome, hospitalizations and blood transfusions; improved hematologic values; and, perhaps, preservation of organ function. During the study, a two year-old ingested at one time an entire 35-day supply of hydroxyurea (612 mg/kg body-weight). Despite a serum level of 7,756 μM four hours post-ingestion, the only toxicity was transient mild myelosuppression. With wider usage of hydroxyurea anticipated, conservative management of future overdoses seems reasonable. (ClinicalTrials.gov NCT00006400) PMID:21744485

  19. Hydroxyurea therapy contributes to infertility in adult men with sickle cell disease: a review.

    Science.gov (United States)

    DeBaun, Michael R

    2014-12-01

    Hydroxyurea therapy, a chemotherapeutic agent, is the only US FDA approved therapy for the prevention of vaso-occlusive pain in sickle cell disease (SCD). The National Institutes of Health has sponsored two Phase III randomized, placebo-controlled trials, initially in adults, and subsequently in children with sickle cell anemia (SCA). Despite the overwhelming evidence that hydroxyurea therapy is beneficial to children and adults with SCA, individuals with SCA and their families express reservations about its use, in part because of the concerns about fertility, particularly in men. As adolescent boys with SCD are now expected to reach their reproductive years, a new concern is emerging about the role of hydroxyurea therapy as a barrier to their progeny. This review will systemically evaluate compromised fertility in men with SCD, and the evidence that hydroxyurea therapy is associated with further decreasing fertility in men with SCD.

  20. Hydroxyurea is associated with lower prevalence of albuminuria in adults with sickle cell disease.

    Science.gov (United States)

    Laurin, Louis-Philippe; Nachman, Patrick H; Desai, Payal C; Ataga, Kenneth I; Derebail, Vimal K

    2014-06-01

    Albuminuria is an early manifestation of sickle cell nephropathy. Prior small case series suggests benefit of hydroxyurea in reducing albuminuria, with a similar trend noted in pediatric studies. We aimed to comprehensively evaluate hydroxyurea use and prevalence of albuminuria in adult sickle cell patients. We performed a cross-sectional study of 149 adult patients followed between 2000 and 2011 in a comprehensive sickle cell clinic. All patients were assessed for albuminuria either by direct measurement or by urinary chemical strip (dipstick) testing. Urinary albumin-to-creatinine ratios (UACRs) were available for 112 patients. Hydroxyurea exposure was defined as ≥3 months of therapy before the assessment of albuminuria. Albuminuria was defined as either UACR ≥30 mg/g or ≥1+ proteinuria on two separate dipsticks. We constructed a multivariate logistic regression model to assess the association between hydroxyurea and albuminuria. The prevalence of albuminuria was lower among patients on hydroxyurea (34.7 versus 55.4%; P = 0.01) as was median albumin excretion (17.9 versus 40.5 mg/g; P = 0.04). In multivariate analysis, hydroxyurea was associated with a lower likelihood of albuminuria (odds ratio 0.28, 95% CI: 0.11-0.75, P = 0.01), adjusting for age, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, tricuspid regurgitant jet velocity, hypertension and acute chest syndrome. In our population of sickle cell patients, those using hydroxyurea were less than one-third as likely to exhibit albuminuria. Hydroxyurea use may prevent development of overt nephropathy or the progression of sickle cell disease nephropathy to end-stage renal disease, and its use for this indication merits further investigation. © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  1. Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia.

    Science.gov (United States)

    Wang, Winfred C; Oyeku, Suzette O; Luo, Zhaoyu; Boulet, Sheree L; Miller, Scott T; Casella, James F; Fish, Billie; Thompson, Bruce W; Grosse, Scott D

    2013-10-01

    In the BABY HUG trial, young children with sickle cell anemia randomized to receive hydroxyurea had fewer episodes of pain, hospitalization, and transfusions. With anticipated broader use of hydroxyurea in this population, we sought to estimate medical costs of care in treated versus untreated children. The BABY HUG database was used to compare inpatient events in subjects receiving hydroxyurea with those receiving placebo. Unit costs were estimated from the 2009 MarketScan Multi-state Medicaid Database for children with sickle cell disease, aged 1 to 3 years. Inpatient costs were based on length of hospital stay, modified by the occurrence of acute chest syndrome, splenic sequestration, or transfusion. Outpatient expenses were based on the schedule required for BABY HUG and a "standard" schedule for 1- to 3-year-olds with sickle cell anemia. There were 232 hospitalizations in the subjects receiving hydroxyurea and 324 in those on placebo; length of hospital stay was similar in the 2 groups. Estimated outpatient expenses were greater in those receiving hydroxyurea, but these were overshadowed by inpatient costs. The total estimated annual cost for those on hydroxyurea ($11 072) was 21% less than the cost of those on placebo ($13 962; P = .038). Savings on inpatient care resulted in a significantly lower overall estimated medical care cost for young children with sickle cell anemia who were receiving hydroxyurea compared with those receiving placebo. Because cost savings are likely to increase with age, these data provide additional support for broad use of hydroxyurea treatment in this population.

  2. Hydroxyurea reaction with HNO2 and Pu(III) stabilization

    International Nuclear Information System (INIS)

    Zhu Zhaowu; He Jianyu; Zhang Zefu; Zheng Weifang; Song Tianbao; Lin Min

    2004-01-01

    Reaction kinetics of hydroxyurea (HU) with HNO 2 in nitric acid solution is studied. The results show that the reaction rate follows the equation as: -dc(HNO 2 )/dt=k 0 c(HNO 2 )c 1.1 (HNO 3 ) c 0 (HU), where k 0 =(0.18±0.01)L 1.1 ·mol -1.1 ·s -1 at 10 degree C and c(HNO 2 )=5 mmol/L; the activation energy is deduced to be about 63 kJ/mol. The reaction appears zero order relative to HU. Kinetic study performed at various NaNO 3 solutions shows that salt ions have little effect on the reaction rate. Excess HU can stabilize Pu(III) well in nitric solutions

  3. Evidence review of hydroxyurea for the prevention of sickle cell complications in low-income countries.

    Science.gov (United States)

    Mulaku, Mercy; Opiyo, Newton; Karumbi, Jamlick; Kitonyi, Grace; Thoithi, Grace; English, Mike

    2013-11-01

    Hydroxyurea is widely used in high-income countries for the management of sickle cell disease (SCD) in children. In Kenyan clinical guidelines, hydroxyurea is only recommended for adults with SCD. Yet many deaths from SCD occur in early childhood, deaths that might be prevented by an effective, disease modifying intervention. The aim of this review was to summarise the available evidence on the efficacy, effectiveness and safety of hydroxyurea in the management of SCD in children below 5 years of age to support guideline development in Kenya. We undertook a systematic review and used the Grading of Recommendations Assessment, Development and Evaluation system to appraise the quality of identified evidence. Overall, available evidence from 1 systematic review (n=26 studies), 2 randomised controlled trials (n=354 children), 14 observational studies and 2 National Institute of Health reports suggest that hydroxyurea may be associated with improved fetal haemoglobin levels, reduced rates of hospitalisation, reduced episodes of acute chest syndrome and decreased frequency of pain events in children with SCD. However, it is associated with adverse events (eg, neutropenia) when high to maximum tolerated doses are used. Evidence is lacking on whether hydroxyurea improves survival if given to young children. Majority of the included studies were of low quality and mainly from high-income countries. Overall, available limited evidence suggests that hydroxyurea may improve morbidity and haematological outcomes in SCD in children aged below 5 years and appears safe in settings able to provide consistent haematological monitoring.

  4. Mutagenicity of hydroxyurea in lymphocytes from patients with sickle cell disease

    Directory of Open Access Journals (Sweden)

    Khayat André Salim

    2004-01-01

    Full Text Available Hydroxyurea is commonly used in the treatment of myeloproliferative diseases and in patients with sickle cell disease (SCD. The use of this antineoplastic agent in patients with SCD is justified because of the drug's ability to increase fetal hemoglobin levels, thereby decreasing the severity of SCD. However, high doses or prolonged treatment with hydroxyurea can be cytotoxic or genotoxic for these patients, with an increased risk of developing acute leukemia. This danger can be avoided by monitoring the lymphocytes of patients treated with hydroxyurea. Cytogenetic tests are important endpoints for monitoring the physiological effects of physical and chemical agents, including drugs. In this work, we assessed the genotoxicity of hydroxyurea in short-term cultures of lymphocytes from SCD patients. Hydroxyurea was not cytotoxic or genotoxic at the concentrations tested in the G2 phase of the cell cycle. These results support the use of hydroxyurea in the treatment of SCD, although further work is necessary to understand the effects of this drug in vivo.

  5. Blood transfusion versus hydroxyurea in beta-thalassemia in Iran: a cost-effectiveness study.

    Science.gov (United States)

    Ravangard, Ramin; Mirzaei, Zahra; Keshavarz, Khosro; Haghpanah, Sezaneh; Karimi, Mehran

    2017-11-21

    Thalassemia intermedia is a type of anemia which has several treatments modalities. We aimed to study the cost effectiveness of two treatments, including blood transfusion and hydroxyurea, in patients with beta-thalassemia intermedia in south of Iran referred to a referral center affiliated to Iran, Shiraz University of Medical Sciences in 2015. This was a cost-effectiveness study which was conducted on 122 patients with beta-thalassemia intermedia. The indicator of effectiveness in this study was the reduction of growth disorder (normal BMI). Data analysis was done using SPSS 21, Excel 2010 and Treeage 2011. Finally, the one-way sensitivity analysis was performed to determine the robustness of the results. The average annual costs of blood transfusion and the use of hydroxyurea in 2015 were 20733.27 purchasing power parity (PPP)$ and 7040.29 PPP$, respectively. The effectiveness of blood transfusion was57.4% while in hydroxyurea group was 60.7%. The results showed that the cost effectiveness of using hydroxyurea was more than that of blood transfusion. Therefore, it is recommended that the use of hydroxyurea in the treatment of patients with beta-thalassemia intermedia would become the first priority, and more basic and supplementary insurance coverage for treating such patients using hydroxyurea should be considered.

  6. NTP-CERHR expert panel report on the reproductive anddevelopmental toxicity of hydroxyurea

    Energy Technology Data Exchange (ETDEWEB)

    Liebelt, E.L.; Balk, S.J.; Faber, W.; Fisher, J.W.; Hughes, C.L.; Lanzkron, S.M.; Lewis, K.M.; Marchetti, F.; Mehendale, H.M.; Rogers,J.M.; Shad, A.T.; Skalko, R.G.; Stanek, E.J.

    2007-01-01

    The National Toxicology Program (NTP) and the National Institute of Environmental Health Sciences (NIEHS) established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in June 1998. The purpose of CERHR is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects on reproduction and development caused by agents to which humans may be exposed. Hydroxyurea was selected for evaluation by a CERHR expert panel because of (1) its increasing use in the treatment of sickle cell disease in children and adults, (2) knowledge that it inhibits DNA synthesis and is cytotoxic, and (3) published evidence of its reproductive and developmental toxicity in rodents. Hydroxyurea is FDA-approved for reducing the frequency of painful crises and the need for blood transfusions in adults with sickle cell anemia who experience recurrent moderate-to-severe crises. Hydroxyurea is used in the treatment of cancer, sickle cell disease, and thalassemia. It is the only treatment for sickle cell disease aside from blood transfusion used in children. Hydroxyurea may be used in the treatment of children and adults with sickle cell disease for an extended period of time or for repeated cycles of therapy. Treatment with hydroxyurea may be associated with cytotoxic and myelosuppressive effects, and hydroxyurea is mutagenic.

  7. Prolyl hydroxylation in elastin is not random.

    Science.gov (United States)

    Schmelzer, Christian E H; Nagel, Marcus B M; Dziomba, Szymon; Merkher, Yulia; Sivan, Sarit S; Heinz, Andrea

    2016-10-01

    This study aimed to investigate the prolyl and lysine hydroxylation in elastin from different species and tissues. Enzymatic digests of elastin samples from human, cattle, pig and chicken were analyzed using mass spectrometry and bioinformatics tools. It was confirmed at the protein level that elastin does not contain hydroxylated lysine residues regardless of the species. In contrast, prolyl hydroxylation sites were identified in all elastin samples. Moreover, the analysis of the residues adjacent to prolines allowed the determination of the substrate site preferences of prolyl 4-hydroxylase. It was found that elastins from all analyzed species contain hydroxyproline and that at least 20%-24% of all proline residues were partially hydroxylated. Determination of the hydroxylation degrees of specific proline residues revealed that prolyl hydroxylation depends on both the species and the tissue, however, is independent of age. The fact that the highest hydroxylation degrees of proline residues were found for elastin from the intervertebral disc and knowledge of elastin arrangement in this tissue suggest that hydroxylation plays a biomechanical role. Interestingly, a proline-rich domain of tropoelastin (domain 24), which contains several repeats of bioactive motifs, does not show any hydroxyproline residues in the mammals studied. The results show that prolyl hydroxylation is not a coincidental feature and may contribute to the adaptation of the properties of elastin to meet the functional requirements of different tissues. The study for the first time shows that prolyl hydroxylation is highly regulated in elastin. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Kinetics of hemopoietic stem cells and survival of mice treated with hydroxyurea and exposed to prolonged γ-radiation

    International Nuclear Information System (INIS)

    Chertkov, K.S.; Rogozkin, V.D.; Dikovenko, E.A.; Mosina, Z.M.

    1979-01-01

    A study was made of radioprotective efficiency of hydroxyurea in relation to mice exposed to prolonged 137 Cs-γ-radiation. It was found that a 30-day survival rate, under optimal conditions of treatment with hydroxyurea, was more than 40 per cent higher than that of the controls. The protective effect of hydroxyurea was manifested at the level of hemopoietic stem cells due to a quicker onset and accelerated rate of the repopulation process

  9. Prolyl hydroxylation in elastin is not random

    DEFF Research Database (Denmark)

    Schmelzer, Christian E H; Nagel, Marcus B M; Dziomba, Szymon

    2016-01-01

    BACKGROUND: This study aimed to investigate the prolyl and lysine hydroxylation in elastin from different species and tissues. METHODS: Enzymatic digests of elastin samples from human, cattle, pig and chicken were analyzed using mass spectrometry and bioinformatics tools. RESULTS: It was confirmed...... at the protein level that elastin does not contain hydroxylated lysine residues regardless of the species. In contrast, prolyl hydroxylation sites were identified in all elastin samples. Moreover, the analysis of the residues adjacent to prolines allowed the determination of the substrate site preferences...... of prolyl 4-hydroxylase. It was found that elastins from all analyzed species contain hydroxyproline and that at least 20%-24% of all proline residues were partially hydroxylated. Determination of the hydroxylation degrees of specific proline residues revealed that prolyl hydroxylation depends on both...

  10. Modification of the heat response and thermotolerance by cycloheximide, hydroxyurea, and lucanthone in CHO cells

    International Nuclear Information System (INIS)

    Henle, K.J.; Leeper, D.B.

    1982-01-01

    Exposure of Chinese hamster ovary cells to cycloheximide for 2 hr immediately prior to 45 0 C hyperthemia increased cell survival by a factor of 1.8. The increase in cell survival was independent of the heating time for heat treatments longer than 10 min at 45 0 C and was similar with cycloheximide concentrations of 1 and 10 μg/ml. Thermotolerance was induced by an initial treatment of 10 min at 45 0 C (conditioning), developed during a 7-hr incubation period at 37 0 C, and was defined by the hyperthermia dose response with a second 45 0 C heat treatment. When cycloheximide (1μg/ml) was added to the medium after heat conditioning and removed prior to the second heat treatment, the degree of thermotolerance was 50% less than that in medium controls. A 3-hr exposure to 10 μg/ml cycloheximide at 37 0 C by itself did not result in the progressive development of thermotolerance which occurs after a conditioning heat treatment. In contrast to the effects of cycloheximide, hydroxyurea (1 mM) and lucanthone (5 μg/ml) showed little effect on the heat sensitivity and the development of thermotolerance after heat conditioning. Although the results can be interpreted that the development of thermotolerance requires the synthesis of new proteins, but not that of DNA and RNA, alternate interpretations are possible based on known cycloheximide effects aside from its primary inhibition of protein synthesis

  11. Cytotoxicity and DNA damage in the neutrophils of patients with sickle cell anaemia treated with hydroxyurea

    Directory of Open Access Journals (Sweden)

    Alano Martins Pedrosa

    2014-04-01

    Full Text Available Hydroxyurea (HU is the most important advance in the treatment of sickle cell anaemia (SCA for preventing complications and improving quality of life for patients. However, some aspects of treatment with HU remain unclear, including their effect on and potential toxicity to other blood cells such as neutrophils. This study used the measurement of Lactate Dehydrogenase (LDH and Methyl ThiazolTetrazolium (MTT and the comet assay to investigate the cytotoxicity and damage index (DI of the DNA in the neutrophils of patients with SCA using HU.In the LDH and MTT assays, a cytoprotective effect was observed in the group of patients treated, as well as an absence of toxicity. When compared to patients without the treatment, the SS group (n=20, 13 women and 07 men, aged 18-69 years, and the group of healthy individuals (AA used as a control group (n=52, 28 women and 24 men, aged 19-60 years, The SSHU group (n=21, 11 women and 10 men, aged 19-63 years showed a significant reduction (p20 months, demonstrating that despite the cytoprotective effects in terms of cell viability, the use of HU can induce DNA damage in neutrophils.

  12. HYDROXYUREA TREATMENT DECREASES GLOMERULAR HYPERFILTRATION IN CHILDREN WITH SICKLE CELL ANEMIA

    Science.gov (United States)

    Aygun, Banu; Mortier, Nicole A.; Smeltzer, Matthew P.; Shulkin, Barry L.; Hankins, Jane S.; Ware, Russell E.

    2015-01-01

    Background Glomerular hyperfiltration and microalbuminuria/proteinuria are early manifestations of sickle nephropathy. The effects of hydroxyurea therapy on these renal manifestations of sickle cell anemia (SCA) are not well defined. Objective To investigate the effects of hydroxyurea on glomerular filtration rate (GFR) measured by 99mTc-DTPA clearance, and on microalbuminuria/proteinuria in children with SCA. Study Design Hydroxyurea Study of Long-Term Effects (HUSTLE) is a prospective study (NCT00305175) with the goal of describing the long-term cellular, molecular, and clinical effects of hydroxyurea therapy in SCA. Glomerular filtration rate, urine microalbumin, and serum cystatin C were measured before initiating hydroxyurea therapy and then repeated after 3 years. Baseline and Year 3 values for HUSTLE subjects were compared using the Wilcoxon Signed Rank test. Associations between continuous variables were evaluated using Spearman correlation coefficient. Results Twenty-three children with SCA (median age 7.5 years, range 2.5–14.0 years) received hydroxyurea at maximum tolerated dose (MTD, 24.4 ± 4.5 mg/kg/day, range 15.3–30.6 mg/kg/day). After three years of treatment, GFR measured by 99mTc-DTPA decreased significantly from 167 ± 46 mL/min/1.73m2 to 145 ± 27 mL/min/1.73m2 (p=0.016). This decrease in GFR was significantly associated with increase in fetal hemoglobin (p= 0.042) and decrease in lactate dehydrogenase levels (p=0.035). Urine microalbumin and cystatin C levels did not change significantly. Conclusions Hydroxyurea at MTD is associated with a decrease in hyperfiltration in young children with SCA. PMID:23255310

  13. A multicenter randomised controlled trial of hydroxyurea (hydroxycarbamide) in very young children with sickle cell anaemia

    Science.gov (United States)

    Wang, Winfred C; Ware, Russell E; Miller, Scott T; Iyer, Rathi V; Casella, James F; Minniti, Caterina P; Rana, Sohail; Thornburg, Courtney D; Rogers, Zora R; Kalpatthi, Ram V; Barredo, Julio C; Brown, R Clark; Sarnaik, Sharada A; Howard, Thomas H; Wynn, Lynn W; Kutlar, Abdullah; Armstrong, F Daniel; Files, Beatrice A; Goldsmith, Jonathan C; Waclawiw, Myron A; Huang, Xiangke; Thompson, Bruce W

    2011-01-01

    Background Sickle cell anaemia (SCA) is associated with significant morbidity from acute complications and organ dysfunction beginning in the first year of life. In the first multicenter randomised double-blinded trial in very young children with SCA, the impact of hydroxyurea (hydroxycarbamide) therapy on organ dysfunction, clinical complications, and laboratory findings, and its toxicity, were examined. Methods Eligible subjects had HbSS or Sβ0thalassaemia, were age 9–18 months at randomisation, and were not selected for clinical severity. Subjects received liquid hydroxyurea, 20 mg/kg/day, or placebo for two years. Primary study endpoints were splenic function (qualitative uptake on 99Tc spleen scan) and renal function (glomerular filtration rate by 99mTc-DTPA clearance). Additional evaluations included: blood counts, HbF, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every two to four weeks. Findings Ninety-six subjects received hydroxyurea and 97 placebo; 86% completed the study. Significant differences were not seen for the primary endpoints, but suggestive benefit was noted in quantitative measures of spleen function. Hydroxyurea significantly decreased pain and dactylitis with trends for decreased acute chest syndrome, hospitalisation and transfusion. Hydroxyurea increased haemoglobin and HbF and decreased WBC count. Toxicity was limited to mild-moderate neutropaenia. Interpretation Although hydroxyurea treatment did not reduce splenic and renal dysfunction assessed by primary endpoint measures, it resulted in major clinical benefit because of diminished acute complications, favorable haematologic results, and a lack of unexpected toxicities. Based on the safety and efficacy data from this trial, hydroxyurea can now be considered for all very young children with SCA. PMID:21571150

  14. Hydroxyurea Use in Young Children With Sickle Cell Anemia in New York State.

    Science.gov (United States)

    Anders, David G; Tang, Fei; Ledneva, Tatania; Caggana, Michele; Green, Nancy S; Wang, Ying; Sturman, Lawrence S

    2016-07-01

    This study examined hydroxyurea usage in young children with sickle cell anemia within New York State (NYS). The cohort was 273 children with sickle cell anemia born in NYS in 2006-2009 and enrolled essentially continuously in Medicaid for the first 4 years of life. Medicaid data were used to examine hydroxyurea usage in this group by age at first prescription fill, persistence, region, treatment institution, and year. Log-binomial regression models were used to estimate the likelihood of receiving hydroxyurea treatment. Data from birth through 2014 for all members of the study group were assembled and analyzed in 2015. About 25% of the cohort had at least one filled hydroxyurea prescription by their fifth birthday, and nearly 40% by the end of the study period. The mean proportion of days covered for the first year of therapy was 56.3%. Adherence was also assessed by calculating medication possession ratios for individual treatment periods. Slightly more than one third of treated children showed 80% coverage by these measures. There was a consistent, but not statistically significant, trend toward younger age at first fill. Significant regional and treatment center differences in initiation of hydroxyurea use, but not in persistence after initiation, were noted among NYS centers. Subsequent to clinical studies demonstrating safety, current NYS-wide use of hydroxyurea in young children with sickle cell anemia appears to be widespread and increasing. However, practice differences between treatment centers and inadequate adherence may limit the full disease-modifying effects of hydroxyurea. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

  15. Hydroxyurea-Lactose Interaction Study: In Silico and In Vitro Evaluation.

    Science.gov (United States)

    Bachchhao, Kunal B; Patil, R R; Patil, C R; Patil, Dipak D

    2017-11-01

    The Maillard reaction between hydroxyurea (a primary amine-containing drug) and lactose (used as an excipient) was explored. The adduct of these compounds was synthesized by heating hydroxyurea with lactose monohydrate at 60 °C in borate buffer (pH 9.2) for 12 h. Synthesis of the adduct was confirmed using UV-visible spectroscopy and Fourier transform infrared, differential scanning calorimetry, high-pressure liquid chromatography, and liquid chromatography-mass spectrometry studies. An in silico investigation of how the adduct formation affected the interactions of hydroxyurea with its biological target oxyhemoglobin, to which it binds to generate nitric oxide and regulates fetal hemoglobin synthesis, was carried out. The in silico evaluations were complemented by an in vitro assay of the anti-sickling activity. Co-incubation of hydroxyurea with deoxygenated blood samples reduced the percentage of sickled cells from 38% to 12 ± 1.6%, whereas the percentage of sickled cells in samples treated with the adduct was 17 ± 1.2%. This indicated loss of anti-sickling activity in the case of the adduct. This study confirmed that hydroxyurea can participate in a Maillard reaction if lactose is used as a diluent. Although an extended study at environmentally feasible temperatures was not carried out in the present investigation, the partial loss of the anti-sickling activity of hydroxyurea was investigated along with the in silico drug-target interactions. The results indicated that the use of lactose in hydroxyurea formulations needs urgent reconsideration and that lactose must be replaced by other diluents that do not form Maillard adducts.

  16. Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide

    DEFF Research Database (Denmark)

    Dresemann, G.; Weller, M.; Ostenfeld-Rosenthal, Ann Maria

    2010-01-01

    A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor...

  17. Minimal doses of hydroxyurea for sickle cell disease

    Directory of Open Access Journals (Sweden)

    C.S.P. Lima

    1997-08-01

    Full Text Available The use of hydroxyurea (HU can improve the clinical course of sickle cell disease. However, several features of HU treatment remain unclear, including the predictability of drug response and determination of adequate doses, considering positive responses and minimal side effects. In order to identify adequate doses of HU for treatment of sickle cell disease, 10 patients, 8 with sickle cell anemia and 2 with Sß thalassemia (8SS, 2Sß, were studied for a period of 6 to 19 months in an open label dose escalation trial (10 to 20 mg kg-1 day-1. Hemoglobin (Hb, fetal hemoglobin (Hb F and mean corpuscular volume (MCV values and reticulocyte, neutrophil and platelet counts were performed every two weeks during the increase of the HU dose and every 4 weeks when the maximum HU dose was established. Reduction in the number of vasoocclusive episodes was also considered in order to evaluate the efficiency of the treatment. The final Hb and Hb F concentrations, and MCV values were significantly higher than the initial values, while the final reticulocyte and neutrophil counts were significantly lower. There was an improvement in the concentration of Hb (range: 0.7-2.0 g/dl at 15 mg HU kg-1 day-1, but this concentration did not increase significantly when the HU dose was raised to 20 mg kg-1 day-1. The concentration of Hb F increased significantly (range: 1.0-18.1% when 15 mg HU was used, and continued to increase when the dose was raised to 20 mg kg-1 day-1. The final MCV values increased 11-28 fl (femtoliters. However, reticulocyte (range: 51-205 x 109/l and neutrophil counts (range: 9.5-1.3 x 109/l obtained at this dose were significantly lower than those obtained with 15 mg kg-1 day-1. All patients reported a decrease in frequency or severity of vasoocclusive episodes. These results suggest that a hydroxyurea dose of 15 mg kg-1 day-1 seems to be adequate for treatment of sickle cell disease in view of the minimal side effects observed and the improvement

  18. Quantification of hydroxyl radical produced during phacoemulsification.

    Science.gov (United States)

    Gardner, Jonathan M; Aust, Steven D

    2009-12-01

    To quantitate hydroxyl radicals produced during phacoemulsification with various irrigating solutions and conditions used in cataract surgery. Chemistry and Biochemistry Department, Utah State University, Logan, Utah, USA. All experiments were performed using an Infiniti Vision System phacoemulsifier with irrigation and aspiration. Hydroxyl radicals were quantitated using electron spin resonance spectroscopy and a spectrophotometric assay for malondialdehyde, which is formed by the oxidation of deoxyribose by the hydroxyl radical. Hydroxyl radical production increased during longitudinal-stroking phacoemulsification as power levels were increased in a nonlinear, nonexponential fashion. The detection of hydroxyl radical was reduced in irrigating solutions containing organic molecules (eg, citrate, acetate, glutathione, dextrose) and further reduced in Navstel, an irrigating solution containing a viscosity-modifying agent, hydroxypropyl methylcellulose. Hydroxyl radicals produced in settings representative of those used in phacoemulsification cataract surgery were quantitated using the deoxyribose method. Hydroxyl radical production was dependent on the level of ultrasound power applied and the irrigating solution used. Oxidative stress on the eye during phacoemulsification may be minimized by using irrigating solutions that contain organic molecules, including the viscosity-modifying agent hydroxypropyl methylcellulose, that can compete for reaction with hydroxyl radicals.

  19. Improved hydroxyurea effect with the use of text messaging in children with sickle cell anemia.

    Science.gov (United States)

    Estepp, Jeremie H; Winter, Bryan; Johnson, Margery; Smeltzer, Matthew P; Howard, Scott C; Hankins, Jane S

    2014-11-01

    In children with sickle cell anemia (SCA), hydroxyurea reduces morbidity, but adherence is frequently suboptimal. Because most families of children with SCA have access to cellular telephone services, we assessed the impact of text messaged reminders as a tool to improve adherence to hydroxyurea. All patients hydroxyurea at a maximal tolerated dosage (MTD) at St. Jude Children's Research Hospital Comprehensive Pediatric Sickle Cell Program and who received automated text message reminders (SIMON®) were retrospectively identified. Laboratory parameters, hospitalizations, and medication possession ratios (MPR) prior to and after initiation of SIMON® were compared to assess the impact of SIMON®. Of the 97.3% of families with access to a cell phone, 91% elected to receive text message reminders. Among 55 children receiving hydroxyurea at MTD, laboratory parameters reflected waning medication compliance during the 12 months prior to SIMON®. Following initiation of SIMON®, children had higher mean corpuscular volumes, hemoglobin levels and fetal hemoglobin percentages and lower absolute reticulocyte counts and bilirubin levels, suggesting improved medication adherence. Hospitalizations were uncommon before and after SIMON®, and medication possession ratios (MPRs) were high before and after SIMON®, neither was significantly changed. SIMON® was feasible and improved hematologic parameters in children with SCA receiving hydroxyurea at a MTD. Future work will include extension of this technology to children with other chronic medical conditions who require daily use of medication. © 2014 Wiley Periodicals, Inc.

  20. The influence of hydroxyurea on oxidative stress in sickle cell anemia

    Directory of Open Access Journals (Sweden)

    Lidiane de Souza Torres

    2012-01-01

    Full Text Available OBJECTIVE: The oxidative stress in 20 sickle cell anemia patients taking hydroxyurea and 13 sickle cell anemia patients who did not take hydroxyurea was compared with a control group of 96 individuals without any hemoglobinopathy. METHODS: Oxidative stress was assessed by thiobarbituric acid reactive species production, the Trolox-equivalent antioxidant capacity and plasma glutathione levels. RESULTS: Thiobarbituric acid reactive species values were higher in patients without specific medication, followed by patients taking hydroxyurea and the Control Group (p < 0.0001. The antioxidant capacity was higher in patients taking hydroxyurea and lower in the Control Group (p = 0.0002 for Trolox-equivalent antioxidant capacity and p < 0.0292 for plasma glutathione. Thiobarbituric acid reactive species levels were correlated with higher hemoglobin S levels (r = 0.55; p = 0.0040 and lower hemoglobin F concentrations(r = -0.52; p = 0.0067. On the other hand, plasma glutathione levels were negatively correlated with hemoglobin S levels (r = -0.49; p = 0.0111 and positively associated with hemoglobin F values (r = 0.56; p = 0.0031. CONCLUSION: Sickle cell anemia patients have high oxidative stress and, conversely, increased antioxidant activity. The increase in hemoglobin F levels provided by hydroxyurea and its antioxidant action may explain the reduction in lipid peroxidation and increased antioxidant defenses in these individuals.

  1. Survival and mortality among users and non-users of hydroxyurea with sickle cell disease.

    Science.gov (United States)

    de Araujo, Olinda Maria Rodrigues; Ivo, Maria Lúcia; Ferreira Júnior, Marcos Antonio; Pontes, Elenir Rose Jardim Cury; Bispo, Ieda Maria Gonçalves Pacce; de Oliveira, Eveny Cristine Luna

    2015-01-01

    to estimate survival, mortality and cause of death among users or not of hydroxyurea with sickle cell disease. cohort study with retrospective data collection, from 1980 to 2010 of patients receiving inpatient treatment in two Brazilian public hospitals. The survival probability was determined using the Kaplan-Meier estimator, survival calculations (SPSS version 10.0), comparison between survival curves, using the log rank method. The level of significance was p=0.05. of 63 patients, 87% had sickle cell anemia, with 39 using hydroxyurea, with a mean time of use of the drug of 20.0±10.0 years and a mean dose of 17.37±5.4 to 20.94±7.2 mg/kg/day, raising the fetal hemoglobin. In the comparison between those using hydroxyurea and those not, the survival curve was greater among the users (p=0.014). A total of 10 deaths occurred, with a mean age of 28.1 years old, and with Acute Respiratory Failure as the main cause. the survival curve is greater among the users of hydroxyurea. The results indicate the importance of the nurse incorporating therapeutic advances of hydroxyurea in her care actions.

  2. Inhibition of DNA repair in ultraviolet-irradiated human cells by hydroxyurea

    International Nuclear Information System (INIS)

    Francis, A.A.; Carrier, W.L.; Smith, D.P.; Regan, J.D.; Blevins, R.D.

    1979-01-01

    The effect on DNA repair in ultraviolet-irradiated human skin fibroblasts by hydroxyurea has been examined in this study using three independent methods for measuring DNA repair: the 5-bromodeoxyuridine photolysis assay which measures DNA repair replication, chromatographic measurement of thymine-containing dimers, and measurement of specific ultraviolet-endonuclease-sensitive sites in irradiated DNA. Little effect on hydroxyurea was observed at the concentration of 2mM, which is often used to inhibit semiconservative DNA synthesis; however, 10 mM hydroxyurea resulted in marked inhibition (65-70%) of excision repair. This inhibition was accompanied by a possible doubling in the size of the repaired region. The accumulation of large numbers of single-strand breaks following ultraviolet irradiation and hydroxyurea incubation seen by other investigators was not observed with the normal skin fibroblasts used in this study. A comparison of hydroxyurea effects on the different DNA repair assays indicates inhibition of one step in DNA repair also results in varying degrees of inhibition of other steps as well. (Auth.)

  3. Inhibition of DNA repair in ultraviolet-irradiated human cells by hydroxyurea

    Energy Technology Data Exchange (ETDEWEB)

    Francis, A.A. (Oak Ridge National Lab., TN); Blevins, R.D.; Carrier, W.L.; Smith, D.P.; Regan, J.D.

    1979-01-01

    The effect on DNA repair in ultraviolet-irradiated human skin fibroblasts by hydroxyurea has been examined in this study using three independent methods for measuring DNA repair: the 5-bromodeoxyuridine photolysis assay which measures DNA repair replication, chromatographic measurement of thymine-containing dimers, and measurement of specific ultraviolet-endonuclease-sensitive sites in irradiated DNA. Little effect of hydroxyurea was observed at the concentration of 2 mM, which is often used to inhibit semiconservative DNA synthesis; however, 10 mM hydroxyurea resulted in marked inhibition (65 to 70%) of excision repair. This inhibition was accompanied by a possible doubling in the size of the repaired region. The accumulation of large numbers of single-strand breaks following ultraviolet irradiation and hydroxyurea incubation seen by other investigators was not observed with the normal skin fibroblasts used in this study. A comparison of hydroxyurea effects on the different DNA repair assays indicates inhibition of one step in DNA repair also results in varying degrees of inhibition of other steps as well.

  4. Hydroxyurea effectiveness in children and adolescents with sickle cell anemia: A large retrospective, population-based cohort.

    Science.gov (United States)

    Quarmyne, Maa-Ohui; Dong, Wei; Theodore, Rodney; Anand, Sonia; Barry, Vaughn; Adisa, Olufolake; Buchanan, Iris D; Bost, James; Brown, Robert C; Joiner, Clinton H; Lane, Peter A

    2017-01-01

    The clinical efficacy of hydroxyurea in patients with sickle cell anemia (SCA) has been well established. However, data about its clinical effectiveness in practice is limited. We evaluated the clinical effectiveness of hydroxyurea in a large pediatric population using a retrospective cohort, pre-post treatment study design to control for disease severity selection bias. The cohort included children with SCA (SS, Sβ 0 thalassemia) who received care at Children's Healthcare of Atlanta (CHOA) and who initiated hydroxyurea in 2009-2011. Children on chronic transfusions, or children with inadequate follow up data and/or children who had taken hydroxyurea in the 3 years prior were excluded. For each patient healthcare utilization, laboratory values, and clinical outcomes for the 2-year period prior to hydroxyurea initiation were compared to those 2 years after initiation. Of 211 children with SCA who initiated hydroxyurea in 2009-2011, 134 met eligibility criteria. After initiation of hydroxyurea, rates of hospitalizations, pain encounters, and emergency department visits were reduced by 47% (Hydroxyurea effectiveness was similar across gender, insurance types and age, although there was a slightly greater reduction in hospitalizations in younger children. Am. J. Hematol. 92:77-81, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. Replication in hydroxyurea: it's a matter of time.

    Science.gov (United States)

    Alvino, Gina M; Collingwood, David; Murphy, John M; Delrow, Jeffrey; Brewer, Bonita J; Raghuraman, M K

    2007-09-01

    Hydroxyurea (HU) is a DNA replication inhibitor that negatively affects both the elongation and initiation phases of replication and triggers the "intra-S phase checkpoint." Previous work with budding yeast has shown that, during a short exposure to HU, MEC1/RAD53 prevent initiation at some late S phase origins. In this study, we have performed microarray experiments to follow the fate of all origins over an extended exposure to HU. We show that the genome-wide progression of DNA synthesis, including origin activation, follows the same pattern in the presence of HU as in its absence, although the time frames are very different. We find no evidence for a specific effect that excludes initiation from late origins. Rather, HU causes S phase to proceed in slow motion; all temporal classes of origins are affected, but the order in which they become active is maintained. We propose a revised model for the checkpoint response to HU that accounts for the continued but slowed pace of the temporal program of origin activation.

  6. Hydroxyurea inhibits parvovirus B19 replication in erythroid progenitor cells.

    Science.gov (United States)

    Bonvicini, Francesca; Bua, Gloria; Conti, Ilaria; Manaresi, Elisabetta; Gallinella, Giorgio

    2017-07-15

    Parvovirus B19 (B19V) infection is restricted to erythroid progenitor cells (EPCs) of the human bone marrow, leading to transient arrest of erythropoiesis and severe complications mainly in subjects with underlying hematological disorders or with immune system deficits. Currently, there are no specific antiviral drugs for B19V treatment, but identification of compounds inhibiting B19V replication can be pursued by a drug repositioning strategy. In this frame, the present study investigates the activity of hydroxyurea (HU), the only disease-modifying therapy approved for sickle cell disease (SCD), towards B19V replication in the two relevant cellular systems, the UT7/EpoS1 cell line and EPCs. Results demonstrate that HU inhibits B19V replication with EC 50 values of 96.2µM and 147.1µM in UT7/EpoS1 and EPCs, respectively, providing experimental evidence of the antiviral activity of HU towards B19V replication, and confirming the efficacy of a drug discovery process by drug repositioning strategy. The antiviral activity occurs in vitro at concentrations lower than those affecting cellular DNA replication and viability, and at levels measured in plasma samples of SCD patients undergoing HU therapy. HU might determine a dual beneficial effect on SCD patients, not only for the treatment of the disease but also towards a virus responsible for severe complications. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Time dependence of intestinal proliferative cell risk vs. stem cell risk to radiation or colcemid cytotoxicity following hydroxyurea

    International Nuclear Information System (INIS)

    Hanson, W.R.; Henninger, D.L.; Fry, R.J.M.

    1979-01-01

    A comparison of the time dependence between intestinal crypt damage by hydroxyurea (HU) and crypt cell or clonogenic cell risk to colcemid (COL) cytotoxicity was made to determine if rapidly cycling cells are clonogenic or if crypt damage by HU induces clonogenic cells into rapid cycle. B6CF 1 /An1 mice were given 15 mg HU 15 min before or after increments of 137 Csγ-irradiation for the crypt colony assay. HU reduced the crypt cells from 254 + - 11 to 170 + - 8; however, the clonogenic cell survival curve was unaltered. At 2 hours after administration of HU, the dose for clonogenic cell survival giving rise to 10 microcolonies/circumference was reduced from 1625 rad in controls to 1375 rad; but at 6 hours after HU, the dose was 2200 rad. Hydroxyurea appears to stimulate stem cells from G 1 into rapid cycle. To test this, groups of mice were given HU and at 6, 12, 18, 24, and 30 hr, a 12 hr treatment of COL was given to kill cells in M phase of the cell cycle. At 3 hr after the last COL injection, mice were killed for crypt cell counts or given 1100 rad 137 Csγ for the microcolony assay. The greatest clonogenic cell risk (38/40) occurred when COL was begun 12 hr after HU, but the greatest total crypt cell risk (183/254) occurred when COL was begun 24 hr after HU at a time when clonogenic cell risk was 10/40. The data suggest that the cell cycle kinetics of clonogenic and rapidly proliferating cells are different. Further, damage to crypts by HU stimulates G 1 clonogenic cells into rapid cycle

  8. Key endothelial cell angiogenic mechanisms are stimulated by the circulating milieu in sickle cell disease and attenuated by hydroxyurea

    Science.gov (United States)

    Lopes, Flavia C. M.; Traina, Fabiola; Almeida, Camila B.; Leonardo, Flavia C.; Franco-Penteado, Carla F.; Garrido, Vanessa T.; Colella, Marina P.; Soares, Raquel; Olalla-Saad, Sara T.; Costa, Fernando F.; Conran, Nicola

    2015-01-01

    As hypoxia-induced inflammatory angiogenesis may contribute to the manifestations of sickle cell disease, we compared the angiogenic molecular profiles of plasma from sickle cell disease individuals and correlated these with in vitro endothelial cell-mediated angiogenesis-stimulating activity and in vivo neovascularization. Bioplex demonstrated that plasma from patients with steady-state sickle cell anemia contained elevated concentrations of pro-angiogenic factors (angiopoietin-1, basic fibroblast growth factor, vascular endothelial growth factor, vascular endothelial growth factor-D and placental growth factor) and displayed potent pro-angiogenic activity, significantly increasing endothelial cell proliferation, migration and capillary-like structure formation. In vivo neovascularization of Matrigel plugs was significantly greater in sickle cell disease mice than in non-sickle cell disease mice, consistent with an up-regulation of angiogenesis in the disease. In plasma from patients with hemoglobin SC disease without proliferative retinopathy, anti-angiogenic endostatin and thrombospondin-2 were significantly elevated. In contrast, plasma from hemoglobin SC individuals with proliferative retinopathy had a pro-angiogenic profile and more significant effects on endothelial cell proliferation and capillary formation than plasma from patients without retinopathy. Hydroxyurea therapy was associated with significant reductions in plasma angiogenic factors and inhibition of endothelial cell-mediated angiogenic mechanisms and neovascularization. Thus, individuals with sickle cell anemia or hemoglobin SC disease with retinopathy present a highly angiogenic circulating milieu, capable of stimulating key endothelial cell-mediated angiogenic mechanisms. Combination anti-angiogenic therapy to prevent the progression of unregulated neovascularization and associated manifestations in sickle cell disease, such as pulmonary hypertension, may be indicated; furthermore, the

  9. Sensitization of a transplantable murine fibrosarcoma by partial synchronization with hydroxyurea

    International Nuclear Information System (INIS)

    Kummermehr, J.; Trott, K.R.; Gesellschaft fuer Strahlen- und Umweltforschung m.b.H., Neuherberg/Muenchen

    1977-01-01

    A C3H fibrosarcoma was synchronized by an injection schedule of hydroxyurea adjusted to its proliferation kinetics. By imposing an 8 h block, 70% of the proliferating non-S-phase cells were accumulated and entered the S-phase synchronously between 2 and 3 h after the last injection. Progression of S-phase cells exposed to hydroxyurea was severely disturbed whereas progression of the synchronized population was nearly normal. Tumours were given a local irradiation with single doses of 300kV X-rays either 2 h after the last hydroxyurea injection, when the synchronized population was still at the G 1 /S-border, or 6 h after the last injection, when cells had proceeded into mid S-phase. Doses ranged from 600 rad to 2400 rad and were given under ambient or hypoxic conditions. The tumour volume was measured at regular intervals. The median regrowth delay of tumours irradiated in air without hydroxyurea displayed a typical biphasic dose/response curve. Tumours irradiated 6 h after hydroxyurea injection showed the same response. For tumours irradiated 2 h after hydroxyurea injection, a significant increase in delay time was found after 600 rad had been given in air, but not after higher doses. A similar sensitizing effect could be detected after 2400 rad had been given under hypoxic conditions. The sensitizing effect of synchronization could be repeated 2 days after a first dose of 600 rad but not after 3 or 4 days. Repeating the synchronization and 600 rad irradiation schedule three times was less effective than irradiating with 3 fractions of 600 rad in 4 days. (author)

  10. Hydroxyurea as a radiation sensitizer in malignancies of the head and neck

    International Nuclear Information System (INIS)

    Mohanta, P.K.; Singhal, R.M.; Jindel, R.; Sharma, R.L.; Julka, P.K.

    1992-01-01

    A prospective randomized trail was undertaken to assess the efficacy of hydroxyurea as a radiation sensitizer. Disease control rates achieved significance (p<0.01) values only at 2 and 3 months post-radiation. At the end of 2 years of follow-up there was no significant difference in the disease control rate between the control and the experimental group. The toxicity in the experimental group was acceptable. One patient had severe vomiting; 13% showed severe mucositis, 4.5% had erythema of the treatment area and 40% showed dry desquamation. There seems to be no added advantage of hydroxyurea and radiation over radiation alone. (author). 12 refs., 2 tabs

  11. Ultrastructural comparison of single dose hydroxyurea and ionizing radiation on mouse hair roots

    Energy Technology Data Exchange (ETDEWEB)

    Pearson, R.W.; Malkinson, F.D.

    1986-01-01

    Growing mouse vibrissae were investigated by light and electron microscopy to compare the effects of hydroxyurea (1500 mgkg/sup -1/ intraperitoneally) and gamma radiation (10 Gy). In the case of the drug, specimens were obtained from 30 min to 9 days post-treatment. Irradiated specimens were taken at intervals up to 1.5 years post-irradiation. The morphological alterations were similar for both types of insult, but the time sequences of events were quite different. The post-irradiation recovery period was vastly extended compared with that of the hydroxyurea treated hair roots.

  12. Ultrastructural comparison of single dose hydroxyurea and ionizing radiation on mouse hair roots

    International Nuclear Information System (INIS)

    Pearson, R.W.; Malkinson, F.D.

    1986-01-01

    Growing mouse vibrissae were investigated by light and electron microscopy to compare the effects of hydroxyurea (1500 mgkg -1 intraperitoneally) and gamma radiation (10 Gy). In the case of the drug, specimens were obtained from 30 min to 9 days post-treatment. Irradiated specimens were taken at intervals up to 1.5 years post-irradiation. The morphological alterations were similar for both types of insult, but the time sequences of events were quite different. The post-irradiation recovery period was vastly extended compared with that of the hydroxyurea treated hair roots. (UK)

  13. Hydroxyurea for the Treatment of Sickle Cell Disease: Efficacy, Barriers, Toxicity, and Management in Children

    Science.gov (United States)

    Strouse, John J.; Heeney, Matthew M.

    2012-01-01

    Hydroxyurea is the only approved medication in the United States for the treatment of sickle cell anemia (HbSS) and is widely used in children despite an indication limited to adults. We review the evidence of efficacy and safety in children with reference to pivotal adult studies. This evidence and expert opinion form the basis for recommended guidelines for the use of hydroxyurea in children including indications, dosing, therapeutic and safety monitoring, and interventions to improve adherence. However, there are substantial gaps in our knowledge to be addressed by on-going and planned studies in children. PMID:22517797

  14. Second malignancies in hydroxyurea and interferon-treated Philadelphia-negative myeloproliferative neoplasms

    DEFF Research Database (Denmark)

    Hansen, Iben Onsberg; Sørensen, Anders Lindholm; Hasselbalch, Hans Carl

    2017-01-01

    OBJECTIVE: In an era of controversy in regard to 'hydroxyurea-leukaemogenicity' and when interferon-alfa2 (IFN) is being revived in the treatment of Philadelphia-negative myeloproliferative neoplasms (MPNs), we aim in this single-centre observational study to describe the frequencies of second...... malignancies in a cohort of MPN patients treated with hydroxyurea (HU) or IFN monotherapy or the combination of these agents. PATIENTS AND METHODS: Records of a MPN cohort of 196 patients were reviewed, and a retrospective analysis was performed on 90 patients treated with HU, 38 patients treated with IFN...

  15. Genomic variants in the ASS1 gene, involved in the nitric oxide biosynthesis and signaling pathway, predict hydroxyurea treatment efficacy in compound sickle cell disease/β-thalassemia patients.

    Science.gov (United States)

    Chalikiopoulou, Constantina; Tavianatou, Anastasia-Gerasimoula; Sgourou, Argyro; Kourakli, Alexandra; Kelepouri, Dimitra; Chrysanthakopoulou, Maria; Kanelaki, Vasiliki-Kaliopi; Mourdoukoutas, Evangelos; Siamoglou, Stavroula; John, Anne; Symeonidis, Argyris; Ali, Bassam R; Katsila, Theodora; Papachatzopoulou, Adamantia; Patrinos, George P

    2016-03-01

    Hemoglobinopathies exhibit a remarkable phenotypic diversity that restricts any safe association between molecular pathology and clinical outcomes. Herein, we explored the role of genes involved in the nitric oxide biosynthesis and signaling pathway, implicated in the increase of fetal hemoglobin levels and response to hydroxyurea treatment, in 119 Hellenic patients with β-type hemoglobinopathies. We show that two ASS1 genomic variants (namely, rs10901080 and rs10793902) can serve as pharmacogenomic biomarkers to predict hydroxyurea treatment efficacy in sickle cell disease/β-thalassemia compound heterozygous patients. These markers may exert their effect by inducing nitric oxide biosynthesis, either via altering splicing and/or miRNA binding, as predicted by in silico analysis, and ultimately, increase γ-globin levels, via guanylyl cyclase targeting.

  16. Mutations of the resistance to 6-thioguanine after exposure of Chinese hamster cells at G1 phase to x-radiation and subsequent treatment with cytosine arabinoside combined with hydroxyurea

    International Nuclear Information System (INIS)

    Elisova, T.V.; Feoktistova, T.P.; Stavrakova, N.M.

    1988-01-01

    A study was made of the effect of two-hour treatment of Chinese hamster cells with cytosine arabinoside (AraC) combined with hydroxyurea (HU) at the G 1 phase of the cell cycle on lethal and mutagenic effects of X-radiation (50 to 400 cGy). The inhibitors were shown to increase a spontaneous mutation level of the resistance to 6-thioguanine: this increase augmented by 3 times as the time the treatment increased from 1-2 to 6 h. However, while shorply enhancing the inactivating effect of X-radiation (the enhancement coefficient was 2.6) Arac+HU caused an additive, or a somewhat lesser, effect as estimated by the yield of mutations. It is suggested that AraC combined with hydroxyurea fail to modify the radiation-induced premutation damages

  17. Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia.

    Science.gov (United States)

    Opoka, Robert O; Ndugwa, Christopher M; Latham, Teresa S; Lane, Adam; Hume, Heather A; Kasirye, Phillip; Hodges, James S; Ware, Russell E; John, Chandy C

    2017-12-14

    Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%; P = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical

  18. Functionalization of hydroxyl terminated polybutadiene with ...

    Indian Academy of Sciences (India)

    CBDT), has been covalently attached at the terminal carbon atoms of the hydroxyl terminated polybutadiene (HTPB) backbone. The modification of HTPB backbone by CBDT molecule does not affect the unique physico-chemical properties such ...

  19. Hydroxyurea for reducing blood transfusion in non-transfusion dependent beta thalassaemias.

    Science.gov (United States)

    Foong, Wai Cheng; Ho, Jacqueline J; Loh, C Khai; Viprakasit, Vip

    2016-10-18

    Non-transfusion dependent beta thalassaemia is a subset of inherited haemoglobin disorders characterised by reduced production of the beta globin chain of the haemoglobin molecule leading to anaemia of varying severity. Although blood transfusion is not a necessity for survival, it is required when episodes of chronic anaemia occur. This chronic anaemia can impair growth and affect quality of life. People with non-transfusion dependent beta thalassaemia suffer from iron overload due to their body's increased capability of absorbing iron from food sources. Iron overload becomes more pronounced in those requiring blood transfusion. People with a higher foetal haemoglobin level have been found to require fewer blood transfusions. Hydroxyurea has been used to increase foetal haemoglobin level; however, its efficacy in reducing transfusion, chronic anaemia complications and its safety need to be established. To assess the effectiveness, safety and appropriate dose regimen of hydroxyurea in people with non-transfusion dependent beta thalassaemia (haemoglobin E combined with beta thalassaemia and beta thalassaemia intermedia). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of relevant journals. We also searched ongoing trials registries and the reference lists of relevant articles and reviews.Date of last search: 30 April 2016. Randomised or quasi-randomised controlled trials of hydroxyurea in people with non-transfusion dependent beta thalassaemia comparing hydroxyurea with placebo or standard treatment or comparing different doses of hydroxyurea. Two authors independently applied the inclusion criteria in order to select trials for inclusion. Both authors assessed the risk of bias of trials and extracted the data. A third author verified these assessments. No trials comparing hydroxyurea with placebo or standard care were found. However, we included

  20. Hydroxyurea responses in clinically varied beta, HbE-beta thalassaemia and sickle cell anaemia patients of Eastern India.

    Science.gov (United States)

    Chatterjee, Tridip; Chakravarty, Amit; Chakravarty, Sudipa

    2018-05-01

    The haematological and clinical response to hydroxyurea was estimated in HbE-beta, beta thalassaemia and sickle cell anaemia patients of Eastern India, with variable clinical severity and transfusion requirement to determine whether hydroxyurea can help these patients to maintain their steady haemoglobin level without blood transfusions. Three hundred patients (189 HbE-beta thalassaemia, 95 beta thalassaemia and 16 other haemoglobinopathies including sickle cell anaemia) were selected for hydroxyurea therapy and were followed up for 48-60 months. Results suggest significant response to hydroxyurea therapy in 19 beta and 99 HbE-beta patients in the transfusion-dependent group (GR-I). All of them became transfusion-independent while on hydroxyurea therapy. The majority of responding patients were IVS1-5(G-C) in one of their alleles in HbE-beta cases (83 out of 119). Though IVS1-5(G-C) was found to be the commonest mutation in our selected patients, the mutational background of the patients does not found to have any significant correlation with the response category towards hydroxyurea as per the results observed in our study. But, the drug works pretty well in most of the transfusion-dependent patients, as these patients were withdrawn from regular blood transfusion. At the same time, partial or no response to the drug hydroxyurea was also recorded in our study.

  1. Hydroxyurea therapy in adult Nigerian sickle cell disease: a monocentric survey on pattern of use, clinical effects and patient's compliance.

    Science.gov (United States)

    Adewoyin, Ademola Samson; Oghuvwu, Omokiniovo Sunday; Awodu, Omolade Augustina

    2017-03-01

    The clinical prospects of hydroxyurea therapy in the management of sickle cell disease (SCD) require evaluation in the Nigerian setting to develop indigenous guidelines. This survey examines the pattern of hydroxyurea therapy, its clinico-haematologic benefits and safety profile in Nigerian SCD subjects. A cross sectional pilot survey was carried out among 60 adult SCD subjects over 3 months. Data on clinical phenotypes, relevant haematological parameters and details of hydroxyurea therapy were obtained using a structured questionnaire through an interview process and case file review. The median age was 30 years. Thirty-four (56.7%) of the subjects are aware of hydroxyurea therapy in SCD. Twenty-four (40%) SCD patients had previously used hydroxyurea. Only 4 subjects were fully compliant. Reasons for non-compliance included poor knowledge and lack of funds. In particular, hydroxyurea reduced leucocyte count and increased mean red cell volume (MCV) in compliant subjects. Hydroxyurea use is low among Nigerian SCD subjects despite its proven efficacy/clinical prospects in the developed nations. Large scale multicenter studies and clinical trials are needed to form a basis for developing standard local treatment protocol for its use.

  2. Therapeutic superiority and safety of combined hydroxyurea with recombinant human erythropoietin over hydroxyurea in young β-thalassemia intermedia patients.

    Science.gov (United States)

    Elalfy, Mohsen S; Adly, Amira A M; Ismail, Eman A; Elhenawy, Yasmine I; Elghamry, Islam R

    2013-12-01

    To assess the efficacy and safety of combined hydroxyurea (HU) and recombinant human erythropoietin (rHuEPO) in β-thalassemia intermedia (TI) patients compared with single HU therapy. An interventional prospective randomized study registered in the ClinicalTrials.gov (NCT01624038) was performed on 80 TI patients (≤ 18 yr) divided into group A (40 patients received combined HU and rHuEPO) and group B (40 patients received single HU therapy). Baseline serum EPO levels were measured, and both groups were followed up for a mean period of 1 yr with regular assessment of transfusion requirements, blood pressure, ferritin, liver and renal functions, hemoglobin, and HbF. Quality of life (QoL) was assessed at the start and end of the study. Transfusion frequency and index were significantly decreased, while QoL was increased in group A compared with group B where 85% of patients showed improvement on combined therapy compared with 50% of patients on HU. Hemoglobin and HbF were significantly increased in both TI groups; however, this was more evident in group A than in group B. Also, 37.5% of patients in group A became transfusion-independent compared with 15% in group B. EPO levels were negatively related to increments of hemoglobin and HbF. Splenectomized patients and those with initial HbF% >40% had the best response to combined therapy. No serious adverse events necessitating discontinuation of therapy in both groups. HU was effective in management of TI; however, combination with rHuEPO gave a superior therapeutic effect resulting in the best clinical and hematological responses without adverse events. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Hydroxyurea for Treatment of Nephrotic Syndrome Associated With Polycythemia Vera.

    Science.gov (United States)

    Hundemer, Gregory L; Rosales, Ivy A; Chen, Yi-Bin; Colvin, Robert B; Tolkoff-Rubin, Nina E

    2016-09-01

    Myeloproliferative disorders are a rare cause of focal segmental glomerulosclerosis (FSGS), although the mechanism is unclear. Hydroxyurea is commonly used in these disorders for its cytoreductive properties; however, the effect of this treatment on proteinuria or kidney function remains unclear in cases of myeloproliferative disorder-associated FSGS. We describe the clinical course of a patient with polycythemia vera and nephrotic-range proteinuria, demonstrated to have FSGS on biopsy. The patient had a distant history of granulomatosis with polyangiitis (Wegener's), for which he routinely had his kidney function and proteinuria measured, allowing for early detection of nephrotic syndrome soon after being diagnosed with polycythemia vera. Treatment with hydroxyurea resulted in rapid improvement in proteinuria that correlated with a decrease in hematocrit. This response was replicated 2 additional times when the patient was taken off and then restarted on hydroxyurea therapy. He now maintains a steady dose of hydroxyurea with favorable kidney measures (proteinuria with <1g/d of protein excretion and serum creatinine of 1.27mg/dL [corresponding to estimated glomerular filtration rate of 56mL/min/1.73 m(2)]). This case suggests that early screening and treatment for myeloproliferative disorder-associated FSGS may lead to improved long-standing kidney function. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  4. Hydroxyurea with Radiation Therapy of the Carcinoma of the Cervix IIA, IIB

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jin Hee; Youn, Seon Min; Kim, Ok Bae [Keimyung University College of Medicine, Taegu (Korea, Republic of)

    1995-12-15

    Purpose : To evaluate the efficacy of hydroxyurea with radiation in carcinoma of the cervix, huge exophytic or endophytic stage IIa and Iib. Materials and Methods : Sixty four patients with carcinoma of the cervix stage IIA(29 patients) with exophytic({>=}3cm in diameter) or huge endophytic mass and IIB(35 patients) treated with radiation and hydroxyurea at the Department of Radiation Oncology, Dongsan Hospital, Keimyung University, School of Medicine from Aug, 1989 to May, 1991. The maximum and mean follow up durations were 68 and 57 months respectively. The radiation therapy consisted of external irradiation to the whole pelvis(3600-5400cGy) shield (4X10 cm), and combined with intracavitary irradiation (3000-3500cGy to point A). Hydroxyurea was to be taken in a single oral dose of 1.0gm/day during radiation therapy. Results : The control rate was 89.1%. The actuarial overall five year survival rate was 78.8% for stage IIA and 72.8% for stage IIB. The overall recurrence rate was 25%(16/64). Twenty-three percent of the patients developed or greater thrombocytopenia. Grade 3 or greater GI, GU complication and anemia were not noted. There was no treatment related death noted. Conclusion : We considered that hydroxyurea and radiation therapy may improve survival rate in huge exophytic and endophytic stage IIa cervical carcinoma with acceptible morbidity.

  5. A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy.

    Science.gov (United States)

    Estepp, Jeremie H; Smeltzer, Matthew P; Kang, Guolian; Li, Chen; Wang, Winfred C; Abrams, Christina; Aygun, Banu; Ware, Russell E; Nottage, Kerri; Hankins, Jane S

    2017-12-01

    Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P 20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%. © 2017 Wiley Periodicals, Inc.

  6. Hydroxyurea with Radiation Therapy of the Carcinoma of the Cervix IIA, IIB

    International Nuclear Information System (INIS)

    Kim, Jin Hee; Youn, Seon Min; Kim, Ok Bae

    1995-01-01

    Purpose : To evaluate the efficacy of hydroxyurea with radiation in carcinoma of the cervix, huge exophytic or endophytic stage IIa and Iib. Materials and Methods : Sixty four patients with carcinoma of the cervix stage IIA(29 patients) with exophytic(≥3cm in diameter) or huge endophytic mass and IIB(35 patients) treated with radiation and hydroxyurea at the Department of Radiation Oncology, Dongsan Hospital, Keimyung University, School of Medicine from Aug, 1989 to May, 1991. The maximum and mean follow up durations were 68 and 57 months respectively. The radiation therapy consisted of external irradiation to the whole pelvis(3600-5400cGy) shield (4X10 cm), and combined with intracavitary irradiation (3000-3500cGy to point A). Hydroxyurea was to be taken in a single oral dose of 1.0gm/day during radiation therapy. Results : The control rate was 89.1%. The actuarial overall five year survival rate was 78.8% for stage IIA and 72.8% for stage IIB. The overall recurrence rate was 25%(16/64). Twenty-three percent of the patients developed or greater thrombocytopenia. Grade 3 or greater GI, GU complication and anemia were not noted. There was no treatment related death noted. Conclusion : We considered that hydroxyurea and radiation therapy may improve survival rate in huge exophytic and endophytic stage IIa cervical carcinoma with acceptible morbidity

  7. Clinical Course of Two Children with Unstable Hemoglobins : The Effect of Hydroxyurea Therapy

    NARCIS (Netherlands)

    Loovers, Harriet M.; Tamminga, Nienke; Mulder, Andre B.; Tamminga, Rienk Y. J.

    Case reports on the effect of hydroxyurea (HU) therapy for unstable hemoglobins (Hbs) are sparse; only three adult cases have been reported. We report for the first time on the effect of HU therapy in children carrying unstable Hbs. The first case concerns a female child with a familial history of

  8. Hematological differences between patients with different subtypes of sickle cell disease on hydroxyurea treatment

    Directory of Open Access Journals (Sweden)

    Fabia Neves

    2012-01-01

    Full Text Available OBJECTIVE: Sickle cell anemia and the interaction S/Beta thalassemia differ in hematological values due to microcytosis and hypochromia caused by the thalassemic mutation. The clinical benefit of long-term hydroxyurea treatment is undeniable in sickle cell disease with monitoring of the biological action of the drug being by the complete blood count. The objective of this work is to compare changes in some of the erythrocytic indexes between S/Beta thalassemia and sickle cell anemia patients on long-term hydroxyurea treatment. METHODS: The values of erythrocyte indexes (mean corpuscular volume and mean corpuscular hemoglobin were compared in a retrospective study of two groups of patients (Sickle cell anemia and S/Beta thalassemia on hydroxyurea treatment over a mean of six years. RESULTS: The quantitative values of the two parameters differed between the groups. Increases in mean corpuscular volume and reductions in mean corpuscular hemoglobin delay longer in S/Beta thalassemia patients (p-value = 0.018. CONCLUSION: Hematological changes are some of the beneficial effects of hydroxyurea in sickle cell disease as cellular hydration increases and the hemoglobin S concentration is reduced. The complete blood count is the best test to monitor changes, but the interpretation of the results in S/Beta thalassemia should be different.

  9. Interaction of N-hydroxyurea with strong proton donors: HCl and HF

    Science.gov (United States)

    Sałdyka, Magdalena

    2014-11-01

    An infrared spectroscopic and MP2/6-311++G(2d,2p) study of strong hydrogen bonded complexes of N-hydroxyurea (NH2CONHOH) with hydrogen halides (HCl and HF) trapped in solid argon matrices is reported. 1:1 and 1:2 complexes between N-hydroxyurea and hydrogen chloride, hydrogen fluoride have been identified in the NH2CONHOH/HCl/Ar, NH2CONHOH/HF/Ar matrices, respectively; their structures were determined by comparison of the spectra with the results of calculations. In the 1:1 complexes, identified for both hydrogen halide molecules, the cyclic structure stabilized by the X-H⋯O and N-H⋯X bonds is present; for the NH2CONHOH⋯HF system another isomeric 1:1 complex is also observed. Two 1:2 complexes were identified for the N-hydroxyurea-hydrogen chloride system characterised by the Cl-H⋯O and N-H⋯Cl bonds. The results of the study evidence that N-hydroxyurea is an oxygen base in the gas-phase with the carbonyl group as the strongest proton acceptor centre in the molecule.

  10. Hydroxyurea as a radiation sensitizer in women with carcinoma of the uterine cervix

    International Nuclear Information System (INIS)

    Piver, M.S.; Barlow, J.J.; Vongtama, V.; Blumenson, L.

    1977-01-01

    Hydroxyurea was evaluated as a possible radiation sensitizer in 130 evaluable women with Stages IIB and IIIB (International Federation of Gynecology and Obstetrics) carcinoma of the uterine cervix. This was a prospective double-blind randomized study in which hydroxyurea or placebo was compared in conjunction with continuous or split-course radiation therapy. Of all patients with Stage IIB cancer without biopsy proof of aortic node metastasis, a significant improvement in survival (P < 0.01) was achieved in the hydroxyurea group (74.0 per cent) as compared to the patients receiving placebo (43.5 per cent). In women with Stage IIIB cervical cancer there was a trend toward longer survival in those receiving hydroxyurea (52.1 per cent) as compared to those receiving placebo (33.3 per cent). However, there was a statistically significant improvement in survival in those women with Stage IIIB cervical cancer who had staging done at operation, were found to have negative para-aortic nodes, and subsequently received continuous radiation therapy (90.9 per cent) as compared to those receiving split-course therapy (29.4 per cent)

  11. Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis

    International Nuclear Information System (INIS)

    Hreshchyshyn, M.M.; Aron, B.S.; Boronow, R.C.; Franklin, E.W. III; Shingleton, H.M.; Blessing, J.A.

    1979-01-01

    In a prospective study by the Gynecologic Oncology Group (GOG), 104 evaluable patients with cervical squamous cell carcinoma Stages IIIB and IVA were randomly assigned to treatment with hydroxyurea or placebo in combination with radiation. There were no deaths resulting from the treatment. Hematologic toxicity was more common and more severe in patients who received hydroxyurea. Response was evaluated in terms of complete tumor regression, duration of progression-free interval, and survival probability. By all those parameters the response was significantly better in the groups of patients receiving hydroxyurea

  12. Interaction of N-hydroxyurea with strong proton donors: HCl and HF

    International Nuclear Information System (INIS)

    Sałdyka, Magdalena

    2014-01-01

    Highlights: • 1:1 and 1:2 N-hydroxyurea complexes with HCl and HF are trapped in argon matrices. • The complexes are stabilized by strong X–H⋯O bond. • Hydrogen bonds in the cyclic 1:2 complexes show strong cooperativity. • The C=O group is the strongest proton acceptor centre in the N-hydroxyurea molecule. - Abstract: An infrared spectroscopic and MP2/6-311++G(2d,2p) study of strong hydrogen bonded complexes of N-hydroxyurea (NH 2 CONHOH) with hydrogen halides (HCl and HF) trapped in solid argon matrices is reported. 1:1 and 1:2 complexes between N-hydroxyurea and hydrogen chloride, hydrogen fluoride have been identified in the NH 2 CONHOH/HCl/Ar, NH 2 CONHOH/HF/Ar matrices, respectively; their structures were determined by comparison of the spectra with the results of calculations. In the 1:1 complexes, identified for both hydrogen halide molecules, the cyclic structure stabilized by the X–H⋯O and N–H⋯X bonds is present; for the NH 2 CONHOH⋯HF system another isomeric 1:1 complex is also observed. Two 1:2 complexes were identified for the N-hydroxyurea–hydrogen chloride system characterised by the Cl–H⋯O and N–H⋯Cl bonds. The results of the study evidence that N-hydroxyurea is an oxygen base in the gas-phase with the carbonyl group as the strongest proton acceptor centre in the molecule

  13. Interaction of N-hydroxyurea with strong proton donors: HCl and HF

    Energy Technology Data Exchange (ETDEWEB)

    Sałdyka, Magdalena, E-mail: magdalena.saldyka@chem.uni.wroc.pl

    2014-11-24

    Highlights: • 1:1 and 1:2 N-hydroxyurea complexes with HCl and HF are trapped in argon matrices. • The complexes are stabilized by strong X–H⋯O bond. • Hydrogen bonds in the cyclic 1:2 complexes show strong cooperativity. • The C=O group is the strongest proton acceptor centre in the N-hydroxyurea molecule. - Abstract: An infrared spectroscopic and MP2/6-311++G(2d,2p) study of strong hydrogen bonded complexes of N-hydroxyurea (NH{sub 2}CONHOH) with hydrogen halides (HCl and HF) trapped in solid argon matrices is reported. 1:1 and 1:2 complexes between N-hydroxyurea and hydrogen chloride, hydrogen fluoride have been identified in the NH{sub 2}CONHOH/HCl/Ar, NH{sub 2}CONHOH/HF/Ar matrices, respectively; their structures were determined by comparison of the spectra with the results of calculations. In the 1:1 complexes, identified for both hydrogen halide molecules, the cyclic structure stabilized by the X–H⋯O and N–H⋯X bonds is present; for the NH{sub 2}CONHOH⋯HF system another isomeric 1:1 complex is also observed. Two 1:2 complexes were identified for the N-hydroxyurea–hydrogen chloride system characterised by the Cl–H⋯O and N–H⋯Cl bonds. The results of the study evidence that N-hydroxyurea is an oxygen base in the gas-phase with the carbonyl group as the strongest proton acceptor centre in the molecule.

  14. Whole exome sequencing identifies novel genes for fetal hemoglobin response to hydroxyurea in children with sickle cell anemia.

    Science.gov (United States)

    Sheehan, Vivien A; Crosby, Jacy R; Sabo, Aniko; Mortier, Nicole A; Howard, Thad A; Muzny, Donna M; Dugan-Perez, Shannon; Aygun, Banu; Nottage, Kerri A; Boerwinkle, Eric; Gibbs, Richard A; Ware, Russell E; Flanagan, Jonathan M

    2014-01-01

    Hydroxyurea has proven efficacy in children and adults with sickle cell anemia (SCA), but with considerable inter-individual variability in the amount of fetal hemoglobin (HbF) produced. Sibling and twin studies indicate that some of that drug response variation is heritable. To test the hypothesis that genetic modifiers influence pharmacological induction of HbF, we investigated phenotype-genotype associations using whole exome sequencing of children with SCA treated prospectively with hydroxyurea to maximum tolerated dose (MTD). We analyzed 171 unrelated patients enrolled in two prospective clinical trials, all treated with dose escalation to MTD. We examined two MTD drug response phenotypes: HbF (final %HbF minus baseline %HbF), and final %HbF. Analyzing individual genetic variants, we identified multiple low frequency and common variants associated with HbF induction by hydroxyurea. A validation cohort of 130 pediatric sickle cell patients treated to MTD with hydroxyurea was genotyped for 13 non-synonymous variants with the strongest association with HbF response to hydroxyurea in the discovery cohort. A coding variant in Spalt-like transcription factor, or SALL2, was associated with higher final HbF in this second independent replication sample and SALL2 represents an outstanding novel candidate gene for further investigation. These findings may help focus future functional studies and provide new insights into the pharmacological HbF upregulation by hydroxyurea in patients with SCA.

  15. Functionalization of hydroxyl terminated polybutadiene with ...

    Indian Academy of Sciences (India)

    Administrator

    The hydroxyl terminated polybutadiene (HTPB) used in this work was prepared by free radical polymerization using hydrogen peroxide as initiator and was received from HEMRL Pune, India, as a gift sample. The molecu- lar weight and polydispersity of the HTPB was deter- mined by using gel permeable chromatography ...

  16. Presence of hydrogen peroxide, a source of hydroxyl radicals, in acid electrolyzed water.

    Directory of Open Access Journals (Sweden)

    Takayuki Mokudai

    Full Text Available BACKGROUND: Acid electrolyzed water (AEW, which is produced through the electrolysis of dilute sodium chloride (NaCl or potassium chloride solution, is used as a disinfectant in various fields because of its potent antimicrobial activity. The hydroxyl radical, an oxygen radical species, is often suggested as a putative active ingredient for AEW antimicrobial activity. METHODOLOGY/PRINCIPAL FINDINGS: The aim of the present study is to detect hydroxyl radicals in AEW. The hydroxyl radicals in AEW prepared under different conditions were determined using an electron spin resonance (ESR technique. A signal from 5,5-dimethyl-1-pyrroline N-oxide (DMPO-OH, an adduct of DMPO and the hydroxyl radical, was detected in AEW prepared by double or triple electrolyses of 1% NaCl but not of 0.1% NaCl solution. Then the presence of hydrogen peroxide as a proposed source of hydroxyl radicals was examined using a combination of ESR and a Fenton reaction. The DMPO-OH signal was clearly detected, even in AEW prepared by single electrolysis of 0.1% NaCl solution, when ferrous sulfate was added to induce a Fenton reaction, indicating the presence of hydrogen peroxide in the AEW. Since sodium formate, a hydroxyl radical scavenger, did not affect the bactericidal activity of AEW, it is concluded that the radical is unlikely to contribute to the antimicrobial activity of AEW, although a small amount of the radical is produced from hydrogen peroxide. Dimethyl sulfoxide, the other hydroxyl radical scavenger used in the present study, canceled the bactericidal activity of AEW, accompanied by complete depletion of free available chlorine, suggesting that hypochlorous acid is probably a major contributor to the antimicrobial activity. CONCLUSIONS: It is strongly suggested that although hydrogen peroxide is present in AEW as a source of hydroxyl radicals, the antimicrobial activity of AEW does not depend on these radicals.

  17. Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide

    DEFF Research Database (Denmark)

    Dresemann, G.; Weller, M.; Ostenfeld-Rosenthal, Ann Maria

    2010-01-01

    A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor...... activity compared with HU monotherapy in the treatment of recurrent GBM. The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0-2 who had completed previous treatment comprising surgical resection, irradiation therapy...

  18. A predictable but life-threatening complication of hydroxyurea in a patient with sickle cell anaemia: an experience learned from a Jehovah's Witness.

    Science.gov (United States)

    Tun, Aung Myint; Naing, Ei Ei; Tun, Nay Min; Guevara, Elizabeth

    2015-09-30

    It is well known that hydroxyurea can cause pancytopaenia secondary to bone marrow suppression, which is reversible with short-term discontinuation of the therapy. However, it is important to note that bone marrow suppressive effects caused by hydroxyurea could be easily potentiated in patients with sickle cell anaemia complicated by chronic kidney disease (CKD). We present a case of a Jehovah's Witness with sickle cell anaemia, who developed severe bone marrow suppression due to the combined effects of hydroxyurea and CKD, resulting in a prolonged recovery period after discontinuation of hydroxyurea. 2015 BMJ Publishing Group Ltd.

  19. Adherence to hydroxyurea, health-related quality of life domains, and patients' perceptions of sickle cell disease and hydroxyurea: a cross-sectional study in adolescents and young adults.

    Science.gov (United States)

    Badawy, Sherif M; Thompson, Alexis A; Lai, Jin-Shei; Penedo, Frank J; Rychlik, Karen; Liem, Robert I

    2017-07-05

    Sickle cell disease (SCD) patients have impaired domains of health-related quality of life (HRQOL). Hydroxyurea is safe and efficacious in SCD; however, adherence is suboptimal, and patients' perceptions are poorly understood amongst adolescents and young adults (AYA). Study objectives were to: (1) examine patients' perceptions of SCD and hydroxyurea; and (2) explore the relationship of their perceptions to clinical characteristics, HRQOL domains and hydroxyurea adherence. Thirty-four SCD patients on hydroxyurea (≥6 months) participated in a single-institution study. Study measures included Brief-Illness Perceptions Questionnaire, ©Modified Morisky Adherence Scale 8-items, and Patient Reported Outcomes Measurement Information System (PROMIS®). We assessed the relationship of patients' perceptions to hydroxyurea adherence using Wilcoxon rank-sum test, the number of hospitalizations using Kruskal-Wallis test, and the number of ED visits, adherence level, HRQOL domain scores using Spearman's rho correlations. We conducted a sub-analysis in HbSS patients to evaluate the relationship of patients' perceptions to laboratory markers of hydroxyurea adherence. Participants were 59% male and 91% Black, and had a median age of 13.5 (range 12-18) years. Participants with ≥4 hospitalizations over 1-year prior (using electronic medical chart review) reported more negative perceptions of SCD-related symptoms and emotional response, and perceived hydroxyurea as less beneficial; all p-values ≤0.01. Most participants (74%) reported low hydroxyurea adherence. Participants with higher hydroxyurea adherence perceived more hydroxyurea benefits (r s  = 0.44, p hydroxyurea positively correlated with HbF (r s  = 0.37, p = 0.05) and MCV values (r s  = 0.35, p = 0.05). Participants with more negative perceptions of SCD-related consequences, concerns, and emotional response, and fewer perceived hydroxyurea benefits reported worse fatigue (r s  = 0.68; r s  = 0.44; r s

  20. Clinical and hematological response to hydroxyurea in a patient with Hb Lepore/beta-thalassemia.

    Science.gov (United States)

    Rigano, P; Manfré, L; La Galla, R; Renda, D; Renda, M C; Calabrese, A; Calzolari, R; Maggio, A

    1997-05-01

    The possibility of increasing Hb F in vivo using drugs like 5-azacytidine, hydroxyurea, and butyrate has been established. However, in many cases this does not entail an increase in total hemoglobin. We report on a patient with Hb Lepore/beta-thalassemia being treated with hydroxyurea (30 mg/Kg/day) because of the presence of erythroid extramedullary masses with severe neurological abnormalities. During therapy the patient showed a remarkable improvement in neurological signs due to the reduction in extra-medullary masses, a significant increase in both total hemoglobin (from 5.8 to 9.7 g/dl) and Hb F (from 4.9 g/dl to 9.1 g/dl). The marked improvement in hemoglobin level in our patient with Hb Lepore/beta-thalassemia suggests gamma-globin gene activation due to the DNA structure determined by the crossover event.

  1. EPR detection of hydroxyl radical generation and its interaction with antioxidant system in Carassius auratus exposed to pentachlorophenol

    Energy Technology Data Exchange (ETDEWEB)

    Luo Yi [Key Laboratory of Pollution Processes and Environmental Criteria (Nankai University), Ministry of Education, College of Environmental Sciences and Engineering, Nankai University, Tianjin 300071 (China); Wang Xiaorong, E-mail: yiyluo@gmail.com [State Key Laboratory of Pollution Control and Resources Reuse, School of Environment, Nanjing University, Nanjing 210093 (China); Ji Liangliang; Su Yan [State Key Laboratory of Pollution Control and Resources Reuse, School of Environment, Nanjing University, Nanjing 210093 (China)

    2009-11-15

    In the present study, direct evidence of hydroxyl radical production in livers of Carassius auratus exposed to pentachlorophenol (PCP) was provided using electron paramagnetic resonance (EPR) with spin-trapping. A dose-effect relationship was obtained between hydroxyl radical intensities and PCP exposure. It was observed that hydroxyl radical was significantly induced by 0.001 mg l{sup -1} (below the criteria for Chinese fishery water quality) of PCP exposure. A strong positive correlation (r = 0.9581, p < 0.001) was observed between PCP liver concentrations and hydroxyl radical intensities within 7 d of PCP exposure, which suggests that hydroxyl radical are mainly produced from PCP itself. However, no correlation was observed between PCP liver concentrations and hydroxyl radical intensities after 7 d, and a higher intensity of hydroxyl radical could still be observed when the PCP liver concentrations decreased to a lower level, which suggests that other mechanisms may possibly contribute to hydroxyl radical production after 7 d. The glutathione/oxidized glutathione (GSH/GSSG) ratio decreased below that of the control level during the entire period of PCP exposure (0.05 mg l{sup -1}), which suggested oxidative stress occurred.

  2. Alpha-thalassaemia and response to hydroxyurea in sickle cell anaemia.

    Science.gov (United States)

    Darbari, Deepika S; Nouraie, Mehdi; Taylor, James G; Brugnara, Carlo; Castro, Oswaldo; Ballas, Samir K

    2014-04-01

    Hydroxyurea (HU) reduces vaso-occlusive crises (VOC) and other complications of sickle cell anaemia (SCA). Alpha-thalassaemia is a known modifier of SCA. Studies on the efficacy of HU in SCA patients with α-thalassaemia have yielded varying results. To determine the effect of α-thalassaemia in response to HU therapy in the Multicenter Study of Hydroxyurea (MSH) cohort. We compared the laboratory parameters and VOC incidence in the MSH cohort stratified by the presence or the absence of α-thalassaemia. Hydroxyurea showed significant (P = 0.001 for all baseline vs. follow-up comparisons) treatment effect on red cell indices irrespective of α-globin gene deletion. The magnitude of the HU-related changes was similar for mean corpuscular volume (MCV) (no α-thalassaemia 13 fl and α-thalassaemia 13 fl) and mean corpuscular haemoglobin (MCH) (no α-thalassaemia 4 pg and α-thalassaemia 4 pg) in both groups. Foetal haemoglobin (HbF) and F-cells also increased significantly with HU treatment in both groups. Total haemoglobin increased after HU treatment in both groups, but the increase was smaller and not statistically significant in patients with α-thalassaemia. In contrast, HU-related reduction in VOCs was more pronounced in patients with α-thalassaemia (VOC incidence rate ratio HU/placebo: 0.63 for α-thalassaemia and 0.54 for no α-thalassaemia (P for interaction 0.003). Hydroxyurea decreases VOCs in SCA patients with and without α-thalassaemia, and the degree of VOC reduction was more pronounced in the patients with alpha-thalassaemia. Despite the lower baseline values, changes in standard laboratory parameters such as MCV and HbF percent remain useful in monitoring HU therapy in the presence of α-thalassaemia. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. The effect of hydroxyurea on synchronized Chinese hamster ovary cells irradiated by ultraviolet light

    International Nuclear Information System (INIS)

    Burg, K.; Collins, A.R.S.; Johnson, R.T.

    1979-01-01

    The effect of hydroxyurea (HU) on cell survival was investigated in Chinese hamster ovary cells after different radiation doses of UV light (254 nm) during the individual phases of the cell cycle. HU inhibits the repair DNA replication by mediation through the DNA precursor pool. These results are supported by the absence of the effect of HU both in the G2 phase possessing high levels of precursors and in supplying the 4 deoxyribonucleosides together with HU after irradiation

  4. Treatment with hydroxyurea in thalassemia intermedia with paravertebral pseudotumors of extramedullary hematopoiesis.

    Science.gov (United States)

    Cario, H; Wegener, M; Debatin, K-M; Kohne, E

    2002-08-01

    Excessive ineffective erythropoiesis in thalassemia intermedia may cause paravertebral pseudotumors of extramedullary hematopoiesis. Due to the proximity to the spinal canal, these paravertebral masses carry the risk of severe neurological damage. Treatment strategies include hypertransfusion, radiotherapy, and laminectomy. Hydroxyurea, stimulating fetal hemoglobin synthesis, may represent an alternative therapeutic approach. We report on a 26-year-old patient suffering from thalassemia intermedia with progressive anemia symptoms and presenting multiple intrathoracic paravertebral pseudotumors of extramedullary hematopoiesis. Hypertransfusion therapy and splenectomy were followed by regular transfusion (baseline hemoglobin 10 g/dl) and chelation with desferrioxamine. With this treatment, clinical symptoms disappeared, paravertebral hematopoietic masses did not progress, but severe hemosiderosis developed within a few years. Hydroxyurea therapy was initiated to increase the efficacy of erythropoiesis, thereby reducing the required transfusion volume but suppressing concomitantly further expansion of extramedullary hematopoiesis, and finally leading to a reduction of transfusional iron load. Treatment was started with 4 mg/kg per day and stepwise increased to 12.5 mg/kg per day. The fetal hemoglobin concentration increased from 4.5 to 5.5 g/dl after 1 year and to 9.9 g/dl after 2 years of treatment. The yearly transfusion volume was halved during the 1st year of treatment. At present, after 26 months of treatment, the patient has been transfusion-independent for 10 months. Serum ferritin levels decreased from 2844 to 1335 ng/ml. Size and shape of paravertebral hematopoietic pseudotumors remained stable. No side effects of hydroxyurea have been observed. In thalassemia intermedia patients with extramedullary hematopoiesis, hydroxyurea may lead to independence from regular transfusion therapy without further expansion of ectopic hematopoietic tissue.

  5. The in Vivo Toxicity of Hydroxyurea Depends on Its Direct Target Catalase*

    OpenAIRE

    Juul, Trine; Malolepszy, Anna; Dybk?r, Karen; Kidmose, Rune; Rasmussen, Jan Trige; Andersen, Gregers Rom; Johnsen, Hans Erik; J?rgensen, Jan-Elo; Andersen, Stig Uggerh?j

    2010-01-01

    Hydroxyurea (HU) is a well tolerated ribonucleotide reductase inhibitor effective in HIV, sickle cell disease, and blood cancer therapy. Despite a positive initial response, however, most treated cancers eventually progress due to development of HU resistance. Although RNR properties influence HU resistance in cell lines, the mechanisms underlying cancer HU resistance in vivo remain unclear. To address this issue, we screened for HU resistance in the plant Arabidopsis thaliana and identified ...

  6. Hydroxyurea therapy in sickle cell anemia patients aids to maintain oral fungal colonization balance.

    Science.gov (United States)

    Salvia, Ana Carolina Rodrigues Danzi; Figueiredo, Maria Stella; Braga, Josefina Aparecida Pellegrini; Pereira, Daniel Freitas Alves; Brighenti, Fernanda Lourenção; Koga-Ito, C Y

    2013-08-01

    The aim of this study was to evaluate the frequency of Candida species and presence of lesions in the oral cavity of patients with sickle cell anemia (SS). The study included 30 patients diagnosed with sickle cell anemia and taking hydroxyurea for at least 90 days (SS/HU+); and 39 patients with sickle cell anemia and without hydroxyurea therapy (SS/HU-). Two control groups were constituted by healthy individuals matched to the test groups in age, gender, and oral conditions (C/HU+ for SS/HU+ and C/HU- for SS/HU-). Oral clinical examination and anamnesis were performed. Yeasts were collected by oral rinses and identified by API system. Antifungal susceptibility evaluation was performed according to the CLSI methodology. Data obtained for microorganisms counts were compared by Student's t test (SS/HU+ vs. C/HU+ and SS/HU- vs. C/HU-) using MINITAB for Windows 1.4. Significance level was set at 5%. No oral candidosis lesions were detected. Significant differences in yeasts counts were observed between SS/HU- group and the respective control, but there were no differences between SS/HU+ and C/HU+. Candida albicans was the most prevalent species in all groups. Candida famata was observed both in SS and control groups. Candida dubliniensis, Candida glabrata, Candida krusei, Candida tropicalis, Candida pelliculosa, and Candida parapsilosis were observed only in SS groups. Most strains were susceptible to all antifungal agents. Hydroxyurea therapy seems to decrease candidal counts and resistance rate in sickle cell anemia patients. However, further studies should be conducted in the future to confirm this finding. Hydroxyurea therapy in sickle cell anemia patients maintains fungal species balance in oral cavity. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease.

    Science.gov (United States)

    Wiczling, Paweł; Liem, Robert I; Panepinto, Julie A; Garg, Uttam; Abdel-Rahman, Susan M; Kearns, Gregory L; Neville, Kathleen A

    2014-09-01

    The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222 hour. The typical apparent volume of distribution was 21.8 L and the apparent systemic clearance was 6.88 L/h for an average weight patient of 30.7 kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6 hours post-dose and AUC with the most significant (R(2)  = 0.71) observed at 1.5 hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 hours after an oral dose of the drug were highly predictive of systemic drug exposure. © 2014, The American College of Clinical Pharmacology.

  8. Hydroxyurea in Pediatric Patients With Sickle Cell Disease: What Nurses Need to Know.

    Science.gov (United States)

    Rees, Allison L

    2016-09-01

    Sickle cell disease (SCD) is an inherited disorder in which sickled red blood cells occlude the small vessels of the body, reducing oxygen delivery to tissues and ultimately negatively affecting many of the body's major organs. Hydroxyurea has proven beneficial in the treatment of SCD and prevention of disease-related complications. The 2014 guidelines put forth by the National Heart, Lung, and Blood Institute recommend hydroxyurea treatment in infants 9 months and older, children, and adolescents with SCD-SS or SCD-Sβ(0) thalassemia regardless of clinical severity. This is a change from the 2002 guidelines in which hydroxyurea was recommended for adolescents and children with SCD-SS or SCD-Sβ(0) thalassemia with frequent episodes of pain, a history of acute chest syndrome, severe and symptomatic anemia or other severe vaso-occlusive events. Nurses play a critical role in working with patients and families to provide education, guidance, and support to improve compliance to mitigate the long-term effects of SCD. © 2015 by Association of Pediatric Hematology/Oncology Nurses.

  9. Clinic Attendance of Youth With Sickle Cell Disease on Hydroxyurea Treatment.

    Science.gov (United States)

    Ingerski, Lisa M; Arnold, Trisha L; Banks, Gabrielle; Porter, Jerlym S; Wang, Winfred C

    2017-07-01

    The objective of this study is to describe rates of clinic attendance of youth with sickle cell disease prescribed hydroxyurea and examine potential demographic and medical factors related to consistent clinic attendance. Participants included 148 youth diagnosed with sickle cell disease and prescribed hydroxyurea during a single calendar year. Clinic attendance and potential demographic and medical factors related to attendance were extracted via systematic retrospective medical chart review. Youth attended 90.3% of scheduled appointments and 85.1% of youth attended at least 80% of scheduled clinic appointments during the study window. Adjusting for other factors, multivariate analysis revealed families with fewer children in the household, families with private insurance, youth experiencing fever, and youth not experiencing pain during the calendar year were more likely to consistently attend clinic visits. Adherence to clinic appointments is critical to optimizing health outcomes for youth with sickle cell disease and integral for adequate monitoring of youth prescribed hydroxyurea, in particular. Findings may aid providers in appropriately identifying possible barriers to clinic attendance to develop attendance promotion interventions.

  10. TiO(2) doping by hydroxyurea at the nucleation stage: towards a new photocatalyst in the visible spectral range.

    Science.gov (United States)

    Azouani, R; Tieng, S; Chhor, K; Bocquet, J-F; Eloy, P; Gaigneaux, E M; Klementiev, K; Kanaev, A V

    2010-10-07

    We report an original method of preparation of OCN-doped TiO(2) for photocatalysis in the visible spectral range. The preparation is achieved by a sol-gel route using titanium tetraisopropoxide precursor. Special attention was paid to fluid micromixing, which enables homogeneous reaction conditions in the reactor bulk and monodispersity of the produced clusters/nanoparticles. The dopant hydroxyurea (HyU, CH(4)N(2)O(2)) is injected into the reactive fluid at the nucleation stage, which lasts tens of milliseconds. The doping results in a strong yellow coloration of the nanocolloids due to the absorption band in the spectral range 380-550 nm and accelerates the aggregation kinetics of both nuclei at the induction stage and sub-nuclei units (clusters) at the nucleation stage. FTIR, Raman and UV-visible absorption analyses show the formation of a stable HyU-TiO(2) complex. EXAFS spectra indicate no appreciable changes of the first-shell Ti atom environment. The doping agent takes available surface sites of TiO(2) clusters/nanoparticles attaining ∼10% molar loading. The reaction kinetics then accelerates due to a longer collisional lifetime between nanoparticles induced by the formation of a weak [double bond, length as m-dash]OTi bond. The OCN-group bonding to titanium atoms produces a weakening of the C[double bond, length as m-dash]O double bond and a strengthening of the C-N and N-O bonds.

  11. Effects of hydroxyurea on blood rheology in sickle cell anemia: A two-years follow-up study.

    Science.gov (United States)

    Lemonne, Nathalie; Möckesch, Berenike; Charlot, Keyne; Garnier, Yohann; Waltz, Xavier; Lamarre, Yann; Antoine-Jonville, Sophie; Etienne-Julan, Maryse; Hardy-Dessources, Marie-Dominique; Romana, Marc; Connes, Philippe

    2017-01-01

    The aim of the present study was to test the effects of hydroxyurea (HU) therapy on clinical, hematological and hemorheological parameters in adult patients with sickle cell anemia (SCA). Hematological and hemorheological parameters were measured in 28 SCA patients before HU therapy (i.e., baseline) and at 6, 12 and 24 months of treatment. RBC deformability was determined by ektacytometry at 30 Pa. RBC aggregation properties were investigated by light-backscatter method. Blood viscosity was measured at 225 s-1 by a cone-plate viscometer. The rates of vaso-occlusive crises and acute chest syndrome were lower at 1 and 2 years of HU therapy compared to baseline. The proportion of patients with leg ulcers tended to decrease after 2 years of treatment. Hemoglobin oxygen saturation improved with HU therapy. HU therapy induced a decrease of platelet and white blood cell counts and a rise in fetal hemoglobin level and mean cell volume. While hemoglobin concentrations increased under HU, blood viscosity remained unchanged all along the study. RBC deformability increased over baseline values at 6 months of HU therapy and continued to rise until the end of the follow-up period. In conclusion, the improvement in RBC deformability probably compensates the increase of hemoglobin on blood viscosity and participates to the improvement of the clinical status of patients.

  12. Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub‐Saharan Africa: Rationale and Design of the REACH Trial

    Science.gov (United States)

    Tshilolo, Léon; Santos, Brigida; Tomlinson, George A.; Stuber, Susan; Latham, Teresa; Aygun, Banu; Obaro, Stephen K.; Olupot‐Olupot, Peter; Williams, Thomas N.; Odame, Isaac; Ware, Russell E.

    2015-01-01

    Background Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease‐modifying therapy for SCA, and has proven safety and efficacy in high‐resource countries. In sub‐Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence‐based guidelines, and inexperience among healthcare providers. Procedure A partnership was established between investigators in North America and sub‐Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA. Results The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open‐label dose escalation study of hydroxyurea that will treat a total of 600 children age 1–10 years with SCA: 150 at each of four different clinical sites within sub‐Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed‐dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose. Conclusions REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub‐Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc. PMID:26275071

  13. Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial.

    Science.gov (United States)

    McGann, Patrick T; Tshilolo, Léon; Santos, Brigida; Tomlinson, George A; Stuber, Susan; Latham, Teresa; Aygun, Banu; Obaro, Stephen K; Olupot-Olupot, Peter; Williams, Thomas N; Odame, Isaac; Ware, Russell E

    2016-01-01

    Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease-modifying therapy for SCA, and has proven safety and efficacy in high-resource countries. In sub-Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence-based guidelines, and inexperience among healthcare providers. A partnership was established between investigators in North America and sub-Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA. The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open-label dose escalation study of hydroxyurea that will treat a total of 600 children age 1-10 years with SCA: 150 at each of four different clinical sites within sub-Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed-dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose. REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub-Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa. © 2015 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.

  14. Modeling and Proposed Molecular Mechanism of Hydroxyurea Through Docking and Molecular Dynamic Simulation to Curtail the Action of Ribonucleotide Reductase.

    Science.gov (United States)

    Iman, Maryam; Khansefid, Zeynab; Davood, Asghar

    2016-01-01

    Ribonucleotide Reductase (RNR) is an important anticancer chemotherapy target. It has main key role in DNA synthesis and cell growth. Therefore several RNR inhibitors, such as hydroxyurea, have entered the clinical trials. Based on our proposed mechanism, radical site of RNR protein reacts with hydroxyurea in which hydroxyurea is converted into its oxidized form compound III, and whereby the tyrosyl radical is converted into a normal tyrosine residue. In this study, docking and molecular dynamics simulations were used for proposed molecular mechanism of hydroxyurea in RNR inhibition as anticancer agent. The binding affinity of hydroxyurea and compound III to RNR was studied by docking method. The docking study was performed for the crystal structure of human RNR with the radical scavenger Hydroxyurea and its oxidized form to inhibit the human RNR. hydroxyurea and compound III bind at the active site with Tyr-176, which are essential for free radical formation. This helps to understand the functional aspects and also aids in the development of novel inhibitors for the human RNR2. To confirm the binding mode of inhibitors, the molecular dynamics (MD) simulations were performed using GROMACS 4.5.5, based upon the docked conformation of inhibitors. Both of the studied compounds stayed in the active site. The results of MD simulations confirmed the binding mode of ligands, accuracy of docking and the reliability of active conformations which were obtained by AutoDock. MD studies confirm our proposed mechanism in which compound III reacts with the active site residues specially Tyr-176, and inhibits the radical generation and subsequently inhibits the RNR enzyme.

  15. Elevated glucocorticoid receptor binding in cultured human lymphoblasts following hydroxyurea treatment: lack of effect on steroid responsiveness

    International Nuclear Information System (INIS)

    Littlefield, B.A.; Hoagland, H.C.; Greipp, P.R.

    1986-01-01

    While studying the effects of chemotherapy on glucocorticoid receptor (GR) binding levels in hematological malignancies, we observed a sizable increase in nuclear GR binding of [ 3 H]dexamethasone in peripheral leukocytes from a chronic basophilic leukemia patient following treatment with hydroxyurea plus prednisone, but not after prednisone alone. This apparent clinical effect of hydroxyurea led to an examination of hydroxyurea effects on GR binding and sensitivity in the glucocorticoid-sensitive human lymphoblast cell line GM4672A. GR binding levels in GM4672A cells were measured following a 3-day exposure to 50 microM hydroxyurea, a concentration chosen to have a minimal but measurable effect on cellular growth rates with little or no effect on cellular viability. Under these conditions, nuclear [ 3 H]dexamethasone receptor binding measured by Scatchard analysis using a whole-cell assay was elevated 2.4-fold over control values (P less than 0.05), while cytosolic residual receptor binding (measured at 37 0 C) remained unchanged. Thus, the total cellular content of measurable GR was increased, and this increase was totally accounted for by GR capable of nuclear binding. Hydroxyurea treatment of GM4672A cells had no effect on the affinity of nuclear or cytosolic GR for [ 3 H]dexamethasone. The increase in measurable nuclear-bound receptors occurred in a time-dependent manner over a period of 3 days and was fully reversible within 3 days following removal of hydroxyurea. The increase in receptor binding could not be explained by the slight alterations in cell cycle kinetics which occur at this low level of hydroxyurea. Despite increased receptor binding, cellular glucocorticoid responsiveness was unaltered as assessed by dexamethasone inhibition of cell growth and dexamethasone inhibition of a urokinase-like plasminogen activator

  16. Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less Organ Damage and Longer Survival in Adults with Sickle Cell Anemia.

    Science.gov (United States)

    Fitzhugh, Courtney D; Hsieh, Matthew M; Allen, Darlene; Coles, Wynona A; Seamon, Cassie; Ring, Michael; Zhao, Xiongce; Minniti, Caterina P; Rodgers, Griffin P; Schechter, Alan N; Tisdale, John F; Taylor, James G

    2015-01-01

    Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea. We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010. An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648. Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003-1.006, phydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34-0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17-0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels. Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings.

  17. Thermophysical properties of hydroxyl ammonium ionic liquids

    International Nuclear Information System (INIS)

    Kurnia, K.A.; Wilfred, C.D.; Murugesan, T.

    2009-01-01

    The thermophysical properties of hydroxyl ammonium ionic liquids: density ρ, T = (293.15 to 363.15) K; dynamic viscosity η, T = (298.2 to 348.2) K; and refractive indices n D , T = (293.15 to 333.15) K have been measured. The coefficients of thermal expansion α, values were calculated from the experimental density results using an empirical correlation for T = (293.15 to 363.15) K. The variation of volume expansion of ionic liquids studied was found to be independent of temperature within the range covered in the present work. The thermal decomposition temperature 'T d ' for all the six hydroxyl ammonium ionic liquids is also investigated using thermogravimetric analyzer (TGA)

  18. The effect of 60Co γ-radiation and hydroxyurea on the in vivo chain growth of DNA in crypt cells of the small intestine of the mouse

    International Nuclear Information System (INIS)

    Johanson, K.J.; Rydberg, B.

    1977-01-01

    DNA chain growth has been studied in small intestinal crypt cells of the mouse in vivo using a sensitive method. The method was designed primarily to study radiation-induced DNA-breaks and their repair; but since there were breaks in DNA at the replicating fork, it was also possible to study DNA chain growth after a 3 H-thymidine pulse. It was found that DNA chain growth was not depressed by 200 rad of 60 Co γ-radiation. This finding supports the hypothesis that irradiation interferes mainly with the initiation of new replicons in mammalian cells affecting DNA chain growth only at higher doses. Hydroxyurea at sufficient dosage, however, depressed or even stopped DNA chain growth in mouse crypt cells in vivo. (author)

  19. Involvement of hydroxyl radicals in the release by ionizing radiation of a cell surface nuclease from Micorcoccus radiodurans

    International Nuclear Information System (INIS)

    Mitchel, R.E.J.

    1975-01-01

    The ionizing radiation-induced release of a surface exonuclease from Micrococcus radiodurans is to a large extent inhibited by the removal of water. Irradiation of a cell suspension saturated with O 2 (an effective aqueous electron and hydrogen atom scavenger) allows the same release as irradiation in the presence of N 2 . Ethanol (a good hydroxyl radical scavenger) protects the enzyme from release. These data suggest that hydroxyl radicals produced by the radiolysis of water are important releasing agents. Hydroxyl radicals produced by the ultraviolet decomposition of H 2 O 2 were effective in releasing the enzyme

  20. Hydroxyl tagging velocimetry in a supersonic flow over a cavity

    International Nuclear Information System (INIS)

    Pitz, Robert W.; Lahr, Michael D.; Douglas, Zachary W.; Wehrmeyer, Joseph A.; Hu Shengteng; Carter, Campbell D.; Hsu, Kuang-Yu; Lum, Chee; Koochesfahani, Manoochehr M.

    2005-01-01

    Hydroxyl tagging velocimetry (HTV) measurements of velocity were made in a Mach 2 (M 2) flow with a wall cavity. In the HTV method, ArF excimer laser (193 nm) beams pass through a humid gas and dissociate H2O into H + OH to form a tagging grid of OH molecules. In this study, a 7x7 grid of hydroxyl (OH) molecules is tracked by planar laser-induced fluorescence. The grid motion over a fixed time delay yields about 50 velocity vectors of the two-dimensional flow in the plane of the laser sheets. Velocity precision is limited by the error in finding the crossing location of the OH lines written by the excimer tag laser. With a signal-to-noise ratio of about 10 for the OH lines, the determination of the crossing location is expected to be accurate within ±0.1 pixels. Velocity precision within the freestream, where the turbulence is low, is consistent with this error. Instantaneous, single-shot measurements of two-dimensional flow patterns were made in the nonreacting M 2 flow with a wall cavity under low- and high-pressure conditions. The single-shot profiles were analyzed to yield mean and rms velocity profiles in the M 2 nonreacting flow

  1. Activity of Oligoresveratrols from Stem Bark of Hopea mengarawan (Dipterocarpaceae as Hydroxyl Radical Scavenger

    Directory of Open Access Journals (Sweden)

    SRI ATUN

    2006-06-01

    Full Text Available Four oligoresveratrols ranging from dimer to tetramer, isolated from stem bark of Hopea mengarawan (Dipterocarpaceae plants were tested for their activity as hydroxyl radical scavenger. The activity of these compounds was evaluated against the 2-deoxyribose degradation induced by the hydroxyl radical generated via a Fenton-type reaction. Result showed that balanocarpol, heimiol A, vaticanol G, and vaticanol B had IC50 3.83; 15.44; 2.01; and 4.71 µM, respectively. These results suggest that oligoresveratrols from stem bark of H. mengarawan maybe useful as potential sources of natural antioxidants.

  2. - Hydroxylated Anthraquinones Produced by Geosmithia species

    Czech Academy of Sciences Publication Activity Database

    Stodůlková, Eva; Kolařík, Miroslav; Křesinová, Zdena; Kuzma, Marek; Šulc, Miroslav; Man, Petr; Novák, Petr; Maršík, Petr; Landa, Přemysl; Olšovská, Jana; Chudíčková, Milada; Pažoutová, Sylvie; Černý, J.; Bella, J.; Flieger, Miroslav

    2009-01-01

    Roč. 54, č. 3 (2009), s. 179-187 ISSN 0015-5632 R&D Projects: GA AV ČR KAN200200651; GA MŠk LC07017; GA MŠk 1M0506; GA ČR GP203/05/P575 Grant - others:CZ(CZ) 205/2004 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z50380511 Keywords : hydroxylated anthraquinones * staphylococcus aureus * mammalian cell lines Subject RIV: EE - Microbiology, Virology Impact factor: 0.978, year: 2009

  3. Development of a pharmacokinetic‐guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia

    Science.gov (United States)

    Dong, Min; McGann, Patrick T.; Mizuno, Tomoyuki; Ware, Russell E.

    2016-01-01

    AIMS Hydroxyurea has emerged as the primary disease‐modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic‐guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Methods Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non‐linear mixed effects modelling (nonmem 7.2). A D‐optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration–time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. Results PK profiles were best described by a one compartment with Michaelis–Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre‐dose (baseline), 15–20 min, 50–60 min and 3 h after an initial 20 mg kg–1 oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l–1 h. Conclusion We developed a PK model‐based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly. PMID:26615061

  4. Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia.

    Science.gov (United States)

    Dong, Min; McGann, Patrick T; Mizuno, Tomoyuki; Ware, Russell E; Vinks, Alexander A

    2016-04-01

    Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non-linear mixed effects modelling (nonmem 7.2). A D-optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. PK profiles were best described by a one compartment with Michaelis-Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre-dose (baseline), 15-20 min, 50-60 min and 3 h after an initial 20 mg kg(-1) oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l(-1)  h. We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly. © 2015 The British Pharmacological Society.

  5. PREVENTION OF CONVERSION TO ABNORMAL TCD WITH HYDROXYUREA IN SICKLE CELL ANEMIA: A PHASE III INTERNATIONAL RANDOMIZED CLINICAL TRIAL

    Science.gov (United States)

    Hankins, Jane S.; McCarville, M. Beth; Rankine-Mullings, Angela; Reid, Marvin E.; Lobo, Clarisse L.C.; Moura, Patricia G.; Ali, Susanna; Soares, Deanne; Aldred, Karen; Jay, Dennis W.; Aygun, Banu; Bennett, John; Kang, Guolian; Goldsmith, Jonathan C.; Smeltzer, Matthew P.; Boyett, James M.; Ware, Russell E.

    2015-01-01

    Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was an NHLBI-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ0-thalassemia (1), and HbSD (1), median age 5.4 years (range, 2.7-9.8)]. Due to slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI 0 to 35%) in the hydroxyurea arm and 47% (95% CI 6 to 81%) in observation arm at 15 months (p=0.16). In post-hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities, compared to observation (0% versus 50%, p=0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (−15.5 versus +10.2 cm/sec, p=0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities. PMID:26414435

  6. Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial.

    Science.gov (United States)

    Hankins, Jane S; McCarville, Mary Beth; Rankine-Mullings, Angela; Reid, Marvin E; Lobo, Clarisse L C; Moura, Patricia G; Ali, Susanna; Soares, Deanne P; Aldred, Karen; Jay, Dennis W; Aygun, Banu; Bennett, John; Kang, Guolian; Goldsmith, Jonathan C; Smeltzer, Matthew P; Boyett, James M; Ware, Russell E

    2015-12-01

    Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ(0) -thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7-9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0-35%) in the hydroxyurea arm and 47% (95% CI = 6-81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (-15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities. © 2015 Wiley Periodicals, Inc.

  7. Perturbation of the Developmental Potential of Preimplantation Mouse Embryos by Hydroxyurea

    Directory of Open Access Journals (Sweden)

    Edward R. Hills

    2010-04-01

    Full Text Available Women are advised not to attempt pregnancy while on hydroxyurea (HU due to the teratogenic effects of this agent, based on results obtained from animal studies. Several case reports suggest that HU may have minimal or no teratogenic effects on the developing human fetus. Fourteen cases of HU therapy in pregnant patients diagnosed with acute or chronic myelogenous leukemia, primary thrombocythemia, or sickle cell disease (SCD have been reported. Three pregnancies were terminated by elective abortion; 1 woman developed eclampsia and delivered a phenotypically normal stillborn infant. All other patients delivered live, healthy infants without congenital anomalies. We contend that case studies such as these have too few patients and cannot effectively address the adverse effect of HU on preimplantation embryo or fetuses. The objective of this study was to assess the risks associated with a clinically relevant dose of HU used for the treatment of SCD, on ovulation rate and embryo development, using adult C57BL/6J female mice as a model. In Experiment 1, adult female mice were randomly assigned to a treatment or a control group (N = 20/group. Treatment consisted of oral HU (30 mg/kg for 28 days; while control mice received saline (HU vehicle. Five days to the cessation of HU dosing, all mice were subjected to folliculogenesis induction with pregnant mare serum gonadotropin (PMSG. Five mice/group were anesthetized at 48 hours post PMSG to facilitate blood collection via cardiac puncture for estradiol-17β (E2 measurement by RIA. Ovulation was induced in the remaining mice at 48 hours post PMSG with human chorionic gonadotropin (hCG and immediately caged with adult males for mating. Five plugged female mice/group were sacrificed for the determination of ovulation rate. The remaining mated mice were sacrificed about 26 hours post hCG, ovaries excised and weighed and embryos harvested and cultured in Whitten’s medium (WM supplemented with CZBt. In

  8. Survival among children and adults with sickle cell disease in Belgium: Benefit from hydroxyurea treatment.

    Science.gov (United States)

    Lê, Phu Quoc; Gulbis, Béatrice; Dedeken, Laurence; Dupont, Sophie; Vanderfaeillie, Anna; Heijmans, Catherine; Huybrechts, Sophie; Devalck, Christine; Efira, André; Dresse, Marie-Françoise; Rozen, Laurence; Benghiat, Fleur Samantha; Ferster, Alina

    2015-11-01

    To evaluate the survival of patients with sickle cell disease (SCD) recorded in the Belgian SCD Registry and to assess the impact of disease-modifying treatments (DMT). The Registry created in 2008 included patients of eight centers. All available data in 2008 were retrospectively encoded in the database. After 2008 and until 2012, all data were recorded prospectively for already registered patients as well as newly diagnosed subjects. Data were registered from neonatal screening or from diagnosis (first contact) until last follow-up or death. Data included diagnosis, demography, and outcome data. We collected data from 469 patients over a 5,110 patient years (PY) follow-up period. The global mortality rate was low (0.25/100 PY), although 13 patients died (2.8%) and was similar between children, adolescents (10-18 years), and young adults (P = 0.76). Out of the cohort, 185 patients received hydroxyurea at last follow-up (median duration of treatment: 10.3 years), 90 underwent hematopoietic stem cell transplantation (HSCT), 24 were chronically transfused, and 170 had never had any DMT. Hydroxyurea showed significant benefit on patients outcome as reflected by a lower mortality rate compared to transplanted individuals or people without DMT (0.14, 0.36, and 0.38 per 100 PY, respectively) and by higher Kaplan-Meier estimates of 15 year survival (99.4%) compared to HSCT (93.8%; P = 0.01) or no DMT groups (95.4%; P = 0.04). SCD mortality in Belgium is low with no increase observed in young adults. Patients treated with hydroxyurea demonstrate a significant benefit in survival when compared to those without DMT or transplanted. © 2015 Wiley Periodicals, Inc.

  9. Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less Organ Damage and Longer Survival in Adults with Sickle Cell Anemia.

    Directory of Open Access Journals (Sweden)

    Courtney D Fitzhugh

    Full Text Available Adults with sickle cell anemia (HbSS are inconsistently treated with hydroxyurea.We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010.An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648.Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003-1.006, p<0.0.0001, kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00-1.27, p = 0.043, and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23-4.02, p = 0.0082. Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34-0.97, p = 0.040. This effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17-0.73, p = 0.0050. Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004. While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively, other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels.Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose

  10. α:Non–α and Gγ:Aγ globin chain ratios in thalassemia intermedia patients treated with hydroxyurea

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    Abbas Najjari

    2014-05-01

    Conclusions: Improvement in α:non-α ratio and consequent decrease of free α-globin chain might be the cause of beneficial effects of hydroxyurea therapy. Two patients who felt better didn't show significant increase in their fetal hemoglobin level, and this is in contradiction with the hypothesis claiming that the HbF level increase is the cause of such therapeutic effect. In spite of the unclear mechanism of action of this drug, hydroxyurea therapy had noticeable impacts on thalassemia intermedia and also sickle cell disease and even patients suffering from thalassemia major.

  11. Partitioning of plutonium and uranium in aqueous medium using hydroxyurea as reducing agent

    International Nuclear Information System (INIS)

    Sivakumar, P.; Subba Rao, R.V.; Meenakshi, S.

    2012-01-01

    A new process for the partitioning of plutonium and uranium during the reprocessing of spent fuel discharged from fast reactor was optimised using hydroxyurea (HU) as a reductant. Stoichiometric ratio of HU required for the reduction of Pu(IV) was studied. The effect of concentration of uranium, plutonium and acidity on the distribution ratio (Kd) of Pu in the presence of HU was studied. The effect of HU in further purification of Pu such as solvent extraction and precipitation of plutonium as oxalate was also studied. The results of the study indicate that Pu and U can be separated from each other using HU as reductant. (author)

  12. Moderate dose of hydroxyurea in children with sickle cell disease and stroke. Preliminary results

    OpenAIRE

    Machín-García, Sergio; Menéndez-Veitía, Andrea; Scherle-Matamoros, Claudio; Svarch, Eva; González-Otero, Alejandro; Arencibia-Núñez, Alberto; Gutiérrez-Díaz, Adys; Lam-Díaz, Rosa M

    2014-01-01

    Twenty children with sickle cell anemia, two with SC hemoglobinopathy and one with S/â0 thalassemia were treated, with a previous stroke or abnormal ultrasound transcranial Doppler (TCD) flow velocities more than 170 cm/s. The mean follow-up was of 41 ± 19 months. Hydroxyurea (HU) at a dose of 25 mg/kg/day associated with chronic transfusion therapy, was administrated during one year to patients with stroke. Patients with abnormal TCD received only HU at the same dose. There was a significant...

  13. An Ulceronecrotic Foot Lesion in a Patient with Essential Thrombocythemia: Successful Treatment with Hydroxyurea

    Directory of Open Access Journals (Sweden)

    Tokue Kato

    2012-01-01

    Full Text Available The patient was a 47-year-old woman with a painful ulcer that had appeared on the right 5th toe two weeks before she visited our hospital. Histopathological examination showed that thrombi were present in small blood vessels in the dermis and pancytosis was detected in a blood test, suggesting polycythemia-associated ulceration of the toe. Essential thrombocythemia was diagnosed based on bone marrow puncture and chromosomal test findings. Platelet count and the ulcer were improved by oral hydroxyurea.

  14. Hydroxyurea Therapy Mobilises Arachidonic Acid from Inner Cell Membrane Aminophospholipids in Patients with Homozygous Sickle Cell Disease

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    A. A. Daak

    2011-01-01

    Full Text Available The cytotoxic compound hydroxyurea (HU is effective therapy for sickle cell disease. However, its effect on unsaturated membrane lipids is unknown. Red cell fatty acids were investigated in HU-treated (n=19 and HU-untreated (n=17 sickle cell patients and controls (n=20. The HU-treated compared with the HU-untreated patients had lower arachidonic (AA acid level in ethanolamine, physphoglycerids (EPG (22.9±1.2   versus   24.0±1.1%,  P<0.05 serine SPG (22.13±2.2   versus   24.9±2.3%,  P<0.01 phosphoglycerides. The treated patients and controls had comparable levels of docosahexaenoic (DHA and total n-3 fatty acids in EPG and choline phosphoglycerides (CPG. In contrast, the untreated group had significantly (P<0.05 lower DHA and total n-3 compared with the controls in EPG (2.7±0.4   versus   3.2±0.6% and 4.6±0.5   versus   5.2±0.7% and CPG (0.7±0.2   versus   1.0±0.2% and 1.2±0.2   versus   1.4±0.3. HU is known to activate cytosolic phospholipase A2 and cyclooxygenase 2, and from this study, it appears to induce mobilisation of AA from the inner cell membrane EPG and SPG. Hence, eicosanoids generated from the released AA may play a role in clinical improvements which occur in HU-treated patients.

  15. Effect of hydroxyurea and vinblastine on the proliferation of the pluripotential stem cells

    International Nuclear Information System (INIS)

    Necas, E.; Neuwirt, J.

    1977-01-01

    The population of the pluripotential hemopoietic stem cells in mice, i.e., cells forming colonies in the spleens of lethally irradiated mice (colony forming cells CFc) proliferates relatively slowly. After partial damage the population regenerates which is achieved by an increased proliferation rate. The effect of damage caused by different doses of hydroxyurea or vinblastine to the proliferation of the CFc was investigated. CFc population was measured in femur bone marrow after the grafting of a bone marrow sample into lethally irradiated mice recipients (spleen colony method). The proliferation rate was estimated either according to the magnitude of the fraction of cells synthesizing DNA in the S phase of the cell cycle, or according to the sensitivity of the population to repeated injections of vinblastine. Data showed that even after very minute damage by hydroxyurea the stem cells started to proliferate intensively. The effect was dose dependent. The comparable damage caused by vinblastine had a significantly weaker effect on the proliferation of the stem cells. It is concluded from the results that the proliferation response of the pluripotential stem cells depends on two factors: the extent of the damage caused to the hemopoietic tissue and the position of the killed cells in the cell cycle. (author)

  16. Changes of the proliferation kinetics of human bone marrow in vivo through hydroxyurea

    International Nuclear Information System (INIS)

    Ertl, E.

    1982-01-01

    A 10-hour oral continuous infusion with hydroxyurea (HU) at a non-toxic concentration was performed in 20 malignoma patients with undisturbed bone marrow. Bone marrow taken before, during and after HU-administration was examined for 3H-TdR incorporation by means of autoradiography and liquid scintimetry, for cell phase distribution by means of flow cytophotometry, morphologically and by means of CFUc. 3H-TdR incorporation into bone marrow cells dropped to 16% of the initial value under HU and rose to 156% 10 h after HU-effect terminated. Cytophotometry did not furnish any proof of a decrease of S-phase cells or increase of cells in G 1 -to-S-transition during HU. S-cells rise to 129% of the initial value 10 h after having fallen below minimum inhibition concentration. Under HU, there is an equal number of cells in S which incorporate much less 3H-thymidine; after HU more S-cells incorporate more 3H-thymidine than before HU. During HU action, DNA synthesis activity is reduced to 17% and reaches the initial value with 105% afterwards. In human bone marrow, hydroxyurea in non-toxic concentration causes a temporary DNA synthesis inhibition in terms of activity reduction and partial arrest in S. A stop-and-go of the cell cycle effected by HU does not occur; the effect is rather a slow-down of DNA synthesis. (orig./MG) [de

  17. Acidification of the parasitophorous vacuole containing Toxoplasma gondii in the presence of hydroxyurea

    Directory of Open Access Journals (Sweden)

    Cristiane S. Carvalho

    2006-09-01

    Full Text Available Toxoplasma gondii multiplies within parasitophorous vacuole that is not recognized by the primary no oxidative defense of host cells, mainly represented by the fusion with acidic organelles. Recent studies have already shown that hydroxyurea arrested the intracellular parasites leading to its destruction. In the present work we investigated the cellular mechanism involved in the destruction of intracellular Toxoplasma gondii. Fluorescent vital stains were used in order to observe possible acidification of parasitophorous vacuole-containing Toxoplasma gondii in presence of hydroxyurea. Vero cells infected with tachyzoites were treated with hydroxyurea for 12, 24 or 48 hours. Fluorescence, indicative of acidification, was observed in the parasitophorous vacuole when the cultures were incubated in presence of acridine orange. LysoTracker red was used in order to determine whether lysosomes were involved in the acidification process. An intense fluorescence was observed after 12 and 24 hours of incubation with hydroxyurea, achieving it is highly intensity after 48 hours of treatment. Ultrastructural cytochemistry for localization of the acid phosphatase lysosomal enzyme was realized. Treated infected cultures showed reaction product in vesicles fusing with vacuole or associated with intravacuolar parasites. These results suggest that fusion with lysosomes and acidification of parasitophorous vacuole leads to parasites destruction in the presence pf hydroxyurea.Toxoplasma gondii se multiplica dentro do vacúolo parasitóforo que não é reconhecido pela defesa primária não oxidativa de células hospedeiras: a fusão com organelas ácidas. Estudos anteriores mostraram que hidroxiuréia interrompeu a multiplicação dos parasitos intracelulares causando sua eliminação. No presente trabalho nós investigamos o mecanismo celular envolvido na destruição do Toxoplasma gondii intracelular. Marcadores vitais fluorescentes foram usados para observar a

  18. Barriers to hydroxyurea adherence and health-related quality of life in adolescents and young adults with sickle cell disease.

    Science.gov (United States)

    Badawy, Sherif M; Thompson, Alexis A; Penedo, Frank J; Lai, Jin-Shei; Rychlik, Karen; Liem, Robert I

    2017-06-01

    To identify barriers to hydroxyurea adherence (negative beliefs, access, and/or recall barriers), and their relationship to adherence rates and health-related quality of life (HRQOL) among adolescents and young adults (AYA) with sickle cell disease (SCD). A cross-sectional survey was administered to 34 AYAs (12-22 years old) in SCD clinics from January to December 2015. Study measures included Brief Medication Questionnaire, Modified Morisky Adherence Scale 8-items, visual analog scale, and Patient Reported Outcomes Measurement Information System. Participants (59% male; 91% Black) had a median age of 13.5 years (IQR 12-18). Participants reported negative beliefs (32%), recall barriers (44%), and access barriers (32%). Participants with recall barriers reported worse pain (P=.02), fatigue (P=.05), and depression (P=.05). The number of adherence barriers inversely correlated with adherence level using ©MMAS-8 (r s =-.38, P=.02) and VAS dose (r s =-.25, P=.14) as well as MCV (r s =-.45, P=.01) and HbF% (r s =-.36, P=.05), suggesting higher hydroxyurea adherence in patients with fewer barriers. Patients with fewer barriers to hydroxyurea adherence were more likely to have higher adherence rates and better HRQOL scores. Routine assessment of hydroxyurea adherence and its related barriers could provide actionable information to improve adherence rates, HRQOL, and other clinical outcomes. © 2017 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.

  19. Evaluation of nevirapine and/or hydroxyurea with nucleoside reverse transcriptase inhibitors in treatment-naive HIV-1-infected subjects

    NARCIS (Netherlands)

    Blanckenberg, Daniel H.; Wood, Robin; Horban, Andrzej; Beniowski, Marek; Boron-Kaczmarska, Anna; Trocha, Hanna; Halota, Waldemar; Schmidt, Reinhold E.; Fatkenheuer, G.; Jessen, Heiko; Lange, Joep M. A.

    2004-01-01

    Objective: To examine the effect of adding nevirapine (NVP) and/or hydroxyurea (HU) to a triple nucleoside analogue reverse transcriptase inhibitor (NRTI) regimen in terms of efficacy and tolerability. Methods: HIV-1-infected, treatment-naive adults were randomized, using a factorial design, to add

  20. Toxic death of mouse small intestinal enterocytes as a function of intervals between injections of the S-phase-specific agent hydroxyurea

    International Nuclear Information System (INIS)

    Churikova, L.I.; Krinskaya, A.V.; Dibrov, B.F.; Zhabotinskii, A.M.; Neifakh, Yu.A.; Gel'fand, E.V.

    1986-01-01

    The authors study optimal conditions for administration of hydroxyurea to mice to ensure minimal damage to intestinal enterocytes. Before receiving an injection of hydroxyurea the mice were irradiated in a dose of 200 rads from a 137 Cs source to activate proliferation of the epithelial cells. The morphometric parameters of the epithelium after injection of hydroxyurea are given. A resonance increase in the survival rate of the enterocytes was revealed if the cytostatic was injected with a period close to the average duration of the cell cycle of the regenerating intestinal cells

  1. The dynamics of histone H2A ubiquitination in HeLa cells exposed to rapamycin, ethanol, hydroxyurea, ER stress, heat shock and DNA damage.

    Science.gov (United States)

    Nakata, Shiori; Watanabe, Tadashi; Nakagawa, Koji; Takeda, Hiroshi; Ito, Akihiro; Fujimuro, Masahiro

    2016-03-25

    Polyubiquitination plays key roles in proteasome-dependent and independent cellular events, whereas monoubiquitination is involved in gene expression, DNA repair, protein-protein interaction, and protein trafficking. We previously developed an FK2 antibody, which specifically recognizes poly-Ub moieties but not free Ub. To elucidate the role of Ub conjugation in response to cellular stress, we used FK2 to investigate whether chemical stress (rapamycin, ethanol, or hydroxyurea), ER stress (thapsigargin or tunicamycin), heat shock or DNA damage (H2O2 or methyl methanesulfonate) affect the formation of Ub conjugates including histone H2A (hH2A) ubiquitination. First, we found that all forms of stress tested increased poly-ubiquitinated proteins in HeLa cells. Furthermore, rapamycin and hydroxyurea treatment, and ER stress increased ubiquitination of hH2A, while methyl methanesulfonate (MMS) treatment induced deubiquitination of hH2A. The ethanol and H2O2 treatments, and heat shock transiently induced hH2A de-ubiquitination, although deubiquitinated hH2A were ubiquitinated again by subsequent cultivation. We also revealed that FK2 reacts with not only polyubiquitinated proteins but also mono-ubiquitinated hH2A. With the exception of MMS, all forms of stress tested increased the acetylation of K5-hH2A, K9-hH3 and K8-hH4 in addition to ubiquitination. K118 and K119 of hH2A were ubiquitinated in cells under normal conditions, and K119 was the major ubiquitination site. The MMS-treatment and heat shock induced the deubiquitination of both K118 and K119-histone H2A. Interestingly, MMS treatment did not affect cell HeLa cell viability expressing double-mutant hH2A (KK118,119AA-hH2A), while heat shock slightly but significantly decreased viability of double-mutant hH2A expressing cells, indicating that ubiquitination of both sites associates with recovery from heat shock but not MMS treatment. Thus, we characterized FK2 reactivity and demonstrated that various stresses alter

  2. Autoradiography of DNA from Hela cells under normal conditions and after treatment with hydroxyurea

    International Nuclear Information System (INIS)

    Martinova, Y.S.; Angelova, P.A.; Roeva, I.G.

    1984-01-01

    The results are presented of the first stage of the elaboration of the novel autoradiographic technique for studying the replication of DNA fibers from nonsynchronized Hela cell cultures under normal conditions and after treatment with hydroxyurea. The preparations were covered with liquid nuclear emulsion Ilford L 4 . Exposure was carried out for 3 months at 4 deg C. After development, the autoradiograms were recorded quantitatively, and the length of the individual replicative segments was measured by means of an object micrometers. For each group (control and experimental) 100 segments from different cells were recorded. The results obtained were subjected to mathematical-statistical processing for determining the standard deviation. The application of hidroxyurea highly reduces the replicative elements, i.e. it actually inhibits DNA synthesis. This inhibition is due to reduction in the production of the four endogenous deoxynucleotides and affects the length of growth of the DNA chain, but the interreplicative distance as well

  3. Kinetics of the reduction of plutonium(IV) by hydroxyurea, a novel salt-free agent

    International Nuclear Information System (INIS)

    Zhu Zhaowu; He Jianyu; Zhang Zefu; Zhang Yu; Zheng Weifang

    2004-01-01

    The kinetics of the reduction of plutonium(IV) by hydroxyurea (HU), a novel salt free reductant, in nitric acid solutions has been studied. The observed reaction rate can be expressed as: -d[Pu(IV)]/dt=k 0 [Pu(IV)] 2 [HU]/[H + ] 0.9 , where k 0 = 5853 ± 363 (l 1.1 x mol -1.1 x s -1 ) at t = 13 deg C. The activation energy is about 81.2 kJ/mol. It was also shows that uranium(VI) has no appreciable influence on the reaction rate. Compared with other organic reductants our experiments indicate that HU is a very fast reductant for plutonium(IV). (author)

  4. Irradiation of solid Walker carcino-sarcomas after synchronisation with hydroxyurea

    International Nuclear Information System (INIS)

    Wayss, K.; Mattern, J.; Volm, M.

    1980-01-01

    Sprague-Dawley rats with solid Walker carcino-sarcomas were synchronized with hydroxyurea (HU; 6 x 50 mg and 1 x 300 mg HU/kg body weight) and then irradiated at different time points ( 60 Co). The synchronized tumors showed a significant delay of growth when irradiation was applied in the late G1 phase, at the transition G1/S and in the early S phase. The remaining phases of the cell cycle, especially the S phase showed the same sensitivity as the non-synchronized controls. Improvement of therapy by irradiation after HU application was largely due to the synchronization of tumor cells. Only the increased therapeutic effect of irradiation shortly after application of HU can be explained also by combination of both HU and irradiation. (orig.) 891 MG/orig. 892 MKO [de

  5. Cellular normoxic biophysical markers of hydroxyurea treatment in sickle cell disease.

    Science.gov (United States)

    Hosseini, Poorya; Abidi, Sabia Z; Du, E; Papageorgiou, Dimitrios P; Choi, Youngwoon; Park, YongKeun; Higgins, John M; Kato, Gregory J; Suresh, Subra; Dao, Ming; Yaqoob, Zahid; So, Peter T C

    2016-08-23

    Hydroxyurea (HU) has been used clinically to reduce the frequency of painful crisis and the need for blood transfusion in sickle cell disease (SCD) patients. However, the mechanisms underlying such beneficial effects of HU treatment are still not fully understood. Studies have indicated a weak correlation between clinical outcome and molecular markers, and the scientific quest to develop companion biophysical markers have mostly targeted studies of blood properties under hypoxia. Using a common-path interferometric technique, we measure biomechanical and morphological properties of individual red blood cells in SCD patients as a function of cell density, and investigate the correlation of these biophysical properties with drug intake as well as other clinically measured parameters. Our results show that patient-specific HU effects on the cellular biophysical properties are detectable at normoxia, and that these properties are strongly correlated with the clinically measured mean cellular volume rather than fetal hemoglobin level.

  6. Where to Turn for Second-Line Cytoreduction After Hydroxyurea in Polycythemia Vera?

    Science.gov (United States)

    Nazha, Aziz; Gerds, Aaron T

    2016-04-01

    The goals of therapy in patients with polycythemia vera (PV) are to improve disease-related symptoms, prevent the incidence or recurrence of thrombosis, and possibly delay or prevent the transformation into myelofibrosis or acute myeloid leukemia (AML). Cytoreductive therapies have been used in older patients and those with a history of thrombosis to achieve these goals. Hydroxyurea (HU) remains the first-line cytoreductive choice; however, up to one in four patients treated with HU over time will develop resistance or intolerance to HU. More importantly, patients who fail HU have a 5.6-fold increase in mortality and a 6.8-fold increase risk of transformation to myelofibrosis or AML; therefore, alternative therapies are needed for these patients. Interferon-α has been used in PV and has shown significant activity in achieving hematologic responses and decreasing JAK2 V617F mutation allele burden. JAK inhibition has also been investigated and recently garnered regulatory approval for this indication. In this review, we will discuss the current treatment options that are available for patients after HU and the novel therapies that are currently under investigation. The outcomes of PV patients who fail or who are intolerant of hydroxyurea are poor. Although pegylated interferon can be considered in younger patients, currently, ruxolitinib is the only U.S. Food and Drug Administration-approved agent in this setting, representing a viable option, leading to hematocrit control and a reduction in spleen size and constitutional symptoms. Although a small number of patients will achieve a molecular response with continuous treatment, the implications of such response on the clinical outcomes are still unknown. Patients whose disease is not adequately controlled with ruxolitinib, or who lose their response, can be treated with low-dose busulfan or pipobroman; however, they should be encouraged to participate in trials with novel therapies. ©AlphaMed Press.

  7. Role of hydroxylation modification on the structure and property of reduced graphene oxide/TiO{sub 2} hybrids

    Energy Technology Data Exchange (ETDEWEB)

    Cao, Shiyi [College of Physics and Electronic Science, Changsha University of Science and Technology, Changsha 410114 (China); Liu, Tiangui, E-mail: tianguiliu@gmail.com [College of Physics and Microelectronics Science, Hunan University, Changsha 410082 (China); Tsang, Yuenhong [Department of Applied Physics, The Hong Kong Polytechnic University, Hong Kong, 999077 (China); Chen, Chuansheng, E-mail: 1666423158@qq.com [College of Physics and Electronic Science, Changsha University of Science and Technology, Changsha 410114 (China)

    2016-09-30

    Graphical abstract: The structure model and enhancement mechanism of hydroxylation treatment on adsorbability and photocatalytic activity. - Highlights: • Highly-hydroxylated TiO{sub 2}/rGO hybrids can be obtained by UV pre-excitation and microwave method. • Surface hydroxylation induces many defects (Ti{sup 3+}, O vacancy and Ti-OH) and changes color into yellow. • Hydroxylation expands the light absorption up to about 600 nm and benefits to adsorb organic dyes. • ESR reveals the self-accumulation of hydroxyl radicals under the irradiation of UV and visible light. • The photoinduced defects and rGO/TiO{sub 2}@OH-TiO{sub 2} heterojunctions enable the excellent applicability. - Abstract: To extend the spectra response of TiO{sub 2} and enhance its photocatalytic activity, surface modification and catalyst supporter have attracted great attention. In this report, a simple and versatile approach has been developed to hydroxylate the reduced graphene oxide/TiO{sub 2} hybrids (OH-rGO/TiO{sub 2}) by UV-microwave method, and the enhanced mechanisms of hydroxylation were analyzed in details. Experimental results show that TiO{sub 2} nanocrystals@OH-TiO{sub 2} heterojunctions formed on rGO sheets in situ by UV/H{sub 2}O{sub 2} process. Hydroxylation not only can induce many surface defects (Ti{sup 3+}, O vacancy and Ti-OH) on the surface of TiO{sub 2}, but also change the color into yellow and strengthen the interaction between rGO and TiO{sub 2}. OH-rGO/TiO{sub 2} hybrids showed excellent durability for high-concentration dyes, and exhibited strong adsorbability and photocatalytic activity. These enhancements are attributed to the excellent property of rGO and surface defects of TiO{sub 2} induced by hydroxylation, which expand the light absorption up to 600 nm, benefit to the self-dispersion of hybrids, and improve the adsorption dynamic and charge transfer with lower carrier’s recombination.

  8. Hydroxyl radical-modified fibrinogen as a marker of thrombosis: the role of iron.

    Science.gov (United States)

    Lipinski, B; Pretorius, E

    2012-07-01

    Excessive free iron in blood and in organ tissues (so called iron overload) has been observed in degenerative diseases such as atherosclerosis, cancer, neurological, and certain autoimmune diseases, in which fibrin-like deposits are also found. Although most of the body iron is bound to hemoglobin and myoglobin in a divalent ferrous form, a certain amount of iron exists in blood as a trivalent (ferric) ion. This particular chemical state of iron has been shown to be toxic to the human body when not controlled by endogenous and/or dietary chelating agents. Experiments described in this paper show for the first time that ferric ions (Fe(3+)) can generate hydroxyl radicals without participation of any redox agent, thus making it a special case of the Fenton reaction. Ferric chloride was also demonstrated to induce aggregation of purified fibrinogen at the same molar concentrations that were used for the generation of hydroxyl radicals. Iron-aggregated fibrinogen, by contrast to native molecule, could not be dissociated into polypeptide subunit chains as shown in a polyacrylamide gel electrophoresis. The mechanism of this phenomenon is very likely based on hydroxyl radical-induced modification of fibrinogen tertiary structure with the formation of insoluble aggregates resistant to enzymatic and chemical degradations. Soluble modified fibrinogen species can be determined in blood of thrombotic patients by the reaction with protamine sulfate and/or by scanning electron microscopy. In view of these findings, it is postulated that iron-induced alterations in fibrinogen structure is involved in pathogenesis of certain degenerative diseases associated with iron overload and persistent thrombosis. It is concluded that the detection of hydroxyl radical-modified fibrinogen may be utilized as a marker of a thrombotic condition in human subjects.

  9. Hydroxyl free radical production during torsional phacoemulsification.

    Science.gov (United States)

    Aust, Steven D; Hebdon, Thomas; Humbert, Jordan; Dimalanta, Ramon

    2010-12-01

    To quantitate free radical generation during phacoemulsification using an ultrasonic phacoemulsification device that includes a torsional mode and evaluate tip designs specific to the torsional mode. Chemistry and Biochemistry Department, Utah State University, Logan, Utah, USA. Experimental study. Experiments were performed using the Infiniti Vision System and OZil handpiece. Hydroxyl radical concentrations in the aspirated irrigation solution during torsional phacoemulsification were quantitated as nanomolar malondialdehyde (nM MDA) and determined spectrophotometrically using the deoxyribose assay. The mean free radical production during phacoemulsification with torsional modality at 100% amplitude was 30.1 nM MDA ± 5.1 (SD) using a 0.9 mm 45-degree Kelman tapered ABS tip. With other tip designs intended for use with the torsional modality, free radical production was further reduced when fitted with the 0.9 mm 45-degree Kelman mini-flared ABS tip (13.2 ± 5.6 nM MDA) or the 0.9 mm 45-degree OZil-12 mini-flared ABS tip (14.3 ± 6.7 nM MDA). Although the measurements resulting from the use of the latter 2 tips were not statistically significantly different (P ≈ .25), they were different from those of the tapered tip (P<.0001). The MDA concentration in the aspirated irrigation solution using the torsional modality was approximately one half that reported for the handpiece's longitudinal modality in a previous study using the same bent-tip design (Kelman tapered, P<.0001). The level of MDA was further reduced approximately one half with torsional-specific tips. Copyright © 2010 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  10. Regioselective alkane hydroxylation with a mutant AlkB enzyme

    Science.gov (United States)

    Koch, Daniel J.; Arnold, Frances H.

    2012-11-13

    AlkB from Pseudomonas putida was engineered using in-vivo directed evolution to hydroxylate small chain alkanes. Mutant AlkB-BMO1 hydroxylates propane and butane at the terminal carbon at a rate greater than the wild-type to form 1-propanol and 1-butanol, respectively. Mutant AlkB-BMO2 similarly hydroxylates propane and butane at the terminal carbon at a rate greater than the wild-type to form 1-propanol and 1-butanol, respectively. These biocatalysts are highly active for small chain alkane substrates and their regioselectivity is retained in whole-cell biotransformations.

  11. Synthesis and preliminary scintigraphic evaluation of in vivo distribution of 11C-hydroxyurea/isohydroxyurea and 11C-cyanate

    International Nuclear Information System (INIS)

    Winstead, M.B.; Chern, C.-I.; Lin, T.-H.; Khentigan, A.; Lamb, J.F.; Winchell, H.S.

    1978-01-01

    H 11 CN, produced directly from proton bombardment of 99% N 2 -1% H 2 [ 14 N(p, α) 11 C], was oxidized by KMn0 4 to 11 C-cyanate which was added to hydroxylamine at -5 to 0 0 C to yield a mixture of hydroxyurea and isohydroxyurea. Scintigraphic evaluation of in vivo distribution in a dog following administration of K0 11 CN showed diffuse whole-body distribution, apparently including brain, with greater activity seen in regions of the heart, liver, and kidneys. Similar evaluation of a dog given 11 C-hydroxyurea/isohydroxyurea showed early localization of activity in the region of the heart which appeared to be due to activity in the myocardium. However, tissue activity measured in rats after administration of this material failed to demonstrate concentration in the myocardium. (author)

  12. Analysis of the Involvement of Different Ceramide Variants in the Response to Hydroxyurea Stress in Baker's Yeast.

    Directory of Open Access Journals (Sweden)

    Po-Wei Chen

    Full Text Available Sphingolipids have been identified as important signaling compounds in stress responses. However, it is not always clear how different sphingolipid profiles are achieved in a particular stress situation. Here we propose a detailed mass action model, containing 42 dependent variables and 137 reactions, that offers explanations of the roles of variant ceramides species, which differ in the lengths of their fatty acyl chains and their saturation state, in the response to hydroxyurea stress. The simulations demonstrate that the cells manage to achieve hydroxyurea tolerance through a well-coordinated, differential usage of the variant ceramide species. Moreover, the results suggest that key enzymes have different affinities toward saturated and unsaturated fatty acyl chains, which implies that the saturation state affords the cells with an additional mode of regulation that had not been recognized so far. These conclusions from our computational analysis are yet to be validated experimentally.

  13. Relationship of colony-stimulating activity to apparent kill of human colony-forming cells by irradiation and hydroxyurea

    International Nuclear Information System (INIS)

    Broxmeyer, H.E.; Galbraith, P.R.; Baker, F.L.

    1976-01-01

    Suspensions of human bone marrow cells were subjected to 137 Cs irradiation in vitro and then cultured in semisolid agar medium. Cultures of irradiated cells were stimulated with colony-stimulating activity (CSA) of different potencies, and it was found that the amount of stimulation applied to cultures influenced the apparent kill of colony-forming cells (CFC). It was also found that the effects of irradiation on colony formation were not confined to CFC kill since medium conditioned by cells during irradiation exhibited stimulatory and inhibitory properties after treatment by 600 and 1000 rads, respectively. Studies in which irradiated cells were pretreated with hydroxyurea indicated that CFC in the DNA synthetic phase of the cell cycle were particularly sensitive to low doses of irradiation. The proliferative capacity of CFC surviving 1000 rads was undiminished as judged by their ability to form large colonies. Estimates of CFC kill by hydroxyurea were also affected by the level of CSA

  14. Hydroxyl radical production in plasma electrolysis with KOH electrolyte solution

    Energy Technology Data Exchange (ETDEWEB)

    Saksono, Nelson; Febiyanti, Irine Ayu, E-mail: irine.ayu41@ui.ac.id; Utami, Nissa; Ibrahim [Department of Chemical Engineering, Universitas Indonesia, Depok 16424, Indonesia Phone: +62217863516, Fax: +62217863515 (Indonesia)

    2015-12-29

    Plasma electrolysis is an effective technology for producing hydroxyl radical (•OH). This method can be used for waste degradation process. This study was conducted to obtain the influence of applied voltage, electrolyte concentration, and anode depth in the plasma electrolysis system for producing hydroxyl radical. The materials of anode and cathode, respectively, were made from tungsten and stainless steel. KOH solution was used as the solution. Determination of hydroxyl radical production was done by measuring H{sub 2}O{sub 2} amount formed in plasma system using an iodometric titration method, while the electrical energy consumed was obtained by measuring the electrical current throughout the process. The highest hydroxyl radical production was 3.51 mmol reached with 237 kJ energy consumption in the power supply voltage 600 V, 0.02 M KOH, and 0.5 cm depth of anode.

  15. Effect of curcumin against oxidation of biomolecules by hydroxyl radicals.

    Science.gov (United States)

    Borra, Sai Krishna; Mahendra, Jaideep; Gurumurthy, Prema; Jayamathi; Iqbal, Shabeer S; Mahendra, Little

    2014-10-01

    Among various reactive oxygen species, hydroxyl radicals have the strongest chemical activity, which can damage a wide range of essential biomolecules such as lipids, proteins, and DNA. The objective of this study was to investigate the beneficial effects of curcumin on prevention of oxidative damage of biomolecules by hydroxyl radicals generated in in vitro by a Fenton like reaction. We have incubated the serum, plasma and whole blood with H2O2/Cu2+/ Ascorbic acid system for 4 hours at 37 0C and observed the oxidation of biomolecules like albumin, lipids, proteins and DNA. Curcumin at the concentrations of 50,100 and 200 μmoles, prevented the formation of ischemia modified albumin, MDA, protein carbonyls, oxidized DNA and increased the total antioxidant levels and GSH significantly. These observations suggest the hydroxyl radical scavenging potentials of curcumin and protective actions to prevent the oxidation of biomolecules by hydroxyl radicals.

  16. Clinical and Hematological Evaluation of Patients with Sickle Cell Anemia Before and After Four Years of Using Hydroxyurea

    Directory of Open Access Journals (Sweden)

    Ieda Maria Gonçalves Pacce Bispo

    2017-06-01

    Full Text Available Objective: Evaluating clinical and hematological-clinical parameters of patients with sickle cell anemia (SCA before and after four years of using hydroxyurea (HU.  Method: A retrospective cohort study implementing a quantitative, descriptive and analytical approach developed in two public teaching hospitals located in the Central-West region of Brazil, from November 2010 to October 2011. Data collection was performed through medical records of 32 patients with SCA to assess clinical and hematological parameters before and after HU treatment. The study was approved by the UFMS Ethics Committee under protocol number 1890/2010. Results: All of the 32 patients were homozygous with a mean age in the prescription of hydroxyurea of 19.72±7.58 years, an initial dose of 15.59±4.27 mg/kg/day, and 22.48±5.35 mg/kg/day in the fourth year of treatment. Regarding the use of HU, average values of some hematological parameters presented a significant difference in the fourth year compared to the mean values prior to HU use, such as fetal hemoglobin (14.49±7.52%, red blood cells (2.54±0.38x1012/L, hematocrit (25.30±4.03% and hemoglobin (9.22±3.34g/dL.  Conclusion: Treatment with hydroxyurea showed a significant increase in fetal hemoglobin levels, increased hemoglobin, hematocrit and average corpuscular hemoglobin concentration, with reduced episodes of pain, infection and acute chest syndrome in such a way as to reaffirm its efficiency in treating these patients. Keywords: Hemoglobin; Sickle Cell Anemia; Hydroxyurea.

  17. Anaerobic Dehalogenation of Hydroxylated Polychlorinated Biphenyls by Desulfitobacterium dehalogenans

    OpenAIRE

    Wiegel, Juergen; Zhang, Xiaoming; Wu, Qingzhong

    1999-01-01

    Ten years after reports on the existence of anaerobic dehalogenation of polychlorinated biphenyls (PCBs) in sediment slurries, we report here on the rapid reductive dehalogenation of para-hydroxylated PCBs (HO-PCBs), the excreted main metabolites of PCB in mammals, which can exhibit estrogenic and antiestrogenic activities in humans. The anaerobic bacterium Desulfitobacterium dehalogenans completely dehalogenates all flanking chlorines (chlorines in ortho position to the para-hydroxyl group) ...

  18. Scintigraphic follow-up of the effects of therapy with hydroxyurea on splenic function in patients with sickle cell disease

    Energy Technology Data Exchange (ETDEWEB)

    Santos, Allan [Division of Nuclear Medicine, Department of Radiology, Campinas State University (UNICAMP), Campinas (Brazil); Servico de Medicina Nuclear, Hospital das Clinicas da UNICAMP, Campina (Brazil); Pinheiro, Vitoria; Anjos, Ana Claudia; Brandalise, Silvia [Centro Infantil Domingos A. Boldrini, Campinas (Brazil); Fahel, Fernanda; Lima, Mariana; Etchebehere, Elba; Ramos, Celso; Camargo, Edwaldo E. [Division of Nuclear Medicine, Department of Radiology, Campinas State University (UNICAMP), Campinas (Brazil)

    2002-04-01

    Patients with sickle cell disease (SCD) may develop functional asplenia as a chronic complication, secondary to repeated episodes of polymerisation of haemoglobin S. It is known that increased plasma concentrations of fetal haemoglobin (HbF) reduce the polymerisation of haemoglobin S. Hydroxyurea is a chemotherapeutic agent capable of increasing HbF levels in the red blood cells and its use has recently been proposed in the treatment of SCD. The objective of this study was to evaluate the effects of long-term therapy with hydroxyurea on recovery of splenic function. Twenty-one patients (aged 3-22 years; 14 with SS haemoglobinopathy, 7 with S{beta}{sup 0} haemoglobinopathy) were studied with liver/spleen scintigraphy before and after 6 and 12 months of treatment. All studies were submitted to visual inspection and semi-quantitative analyses using spleen/liver ratios. Imaging prior to treatment demonstrated functional asplenia in nine SS patients and one S{beta}{sup 0} patient and impaired splenic function in five SS patients and six S{beta}{sup 0} patients. After treatment, splenic function improved in ten patients, remained unchanged in eight and worsened in three. Using liver/spleen imaging, it was possible to demonstrate that hydroxyurea is capable of improving splenic function in some SCD patients. Improvement is not always possible and frequently does not lead to a normal splenic function even after 1 year of treatment. (orig.)

  19. Scintigraphic follow-up of the effects of therapy with hydroxyurea on splenic function in patients with sickle cell disease

    International Nuclear Information System (INIS)

    Santos, Allan; Pinheiro, Vitoria; Anjos, Ana Claudia; Brandalise, Silvia; Fahel, Fernanda; Lima, Mariana; Etchebehere, Elba; Ramos, Celso; Camargo, Edwaldo E.

    2002-01-01

    Patients with sickle cell disease (SCD) may develop functional asplenia as a chronic complication, secondary to repeated episodes of polymerisation of haemoglobin S. It is known that increased plasma concentrations of fetal haemoglobin (HbF) reduce the polymerisation of haemoglobin S. Hydroxyurea is a chemotherapeutic agent capable of increasing HbF levels in the red blood cells and its use has recently been proposed in the treatment of SCD. The objective of this study was to evaluate the effects of long-term therapy with hydroxyurea on recovery of splenic function. Twenty-one patients (aged 3-22 years; 14 with SS haemoglobinopathy, 7 with Sβ 0 haemoglobinopathy) were studied with liver/spleen scintigraphy before and after 6 and 12 months of treatment. All studies were submitted to visual inspection and semi-quantitative analyses using spleen/liver ratios. Imaging prior to treatment demonstrated functional asplenia in nine SS patients and one Sβ 0 patient and impaired splenic function in five SS patients and six Sβ 0 patients. After treatment, splenic function improved in ten patients, remained unchanged in eight and worsened in three. Using liver/spleen imaging, it was possible to demonstrate that hydroxyurea is capable of improving splenic function in some SCD patients. Improvement is not always possible and frequently does not lead to a normal splenic function even after 1 year of treatment. (orig.)

  20. Phase II study of Gleevec® plus hydroxyurea in adults with progressive or recurrent low-grade glioma1

    Science.gov (United States)

    Reardon, David A.; Desjardins, Annick; Vredenburgh, James J.; Herndon, James E.; Coan, April; Gururangan, Sridharan; Peters, Katherine B.; McLendon, Roger; Sathornsumetee, Sith; Rich, Jeremy N.; Lipp, Eric S.; Janney, Dorothea; Friedman, Henry S.

    2013-01-01

    Background We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low-grade glioma. Methods A total of 64 patients with recurrent/progressive low-grade glioma were enrolled in this single-center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression-free survival at 12 months (PFS-12) and secondary endpoints were safety, median progression-free survival and radiographic response rate. Results Thirty-two patients were enrolled into each cohort. Eleven patients (17%) had prior radiotherapy and 24 (38%) had received prior chemotherapy. The median PFS and PFS-12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%) and diarrhea (3%). Conclusions Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible anti-tumor activity. PMID:22371319

  1. The effect of hydroxyurea on compound heterozygotes for sickle cell-hemoglobin D-Punjab--a single centre experience in eastern India.

    Science.gov (United States)

    Patel, Siris; Purohit, Prasanta; Mashon, Ranjeet Singh; Dehury, Snehadhini; Meher, Satyabrata; Sahoo, Sulia; Dash, Subhransu Sekhar; Das, Kishalaya; Das, Padmalaya; Patel, Dilip Kumar

    2014-08-01

    Although hydroxyurea is the only effective agent for the treatment of sickle cell disease, published experience with this drug is limited to treatment of homozygous sickle cell anemia and HbS/β thalassemia. The role of hydroxyurea in the treatment of patients with HbSD-Punjab, a rare hemoglobinopathy with phenotypic expression similar to that of sickle cell anemia is unknown. Over a period of 10 years, we followed 42 patients with HbSD-Punjab, of which 20 presented with severe clinical manifestations (≥3 episodes of VOC and/or ≥2 units of blood transfusion in the previous 12 months). These 20 patients were enrolled for treatment with hydroxyurea at a dose of 10 mg/kg/day and followed prospectively for a period of 24 months. The frequency of VOC decreased significantly and none of them required blood transfusion while receiving hydroxyurea. The HbF, total hemoglobin, MCV, MCH, and MCHC levels increased significantly, whereas HbS, WBC, platelet count, total serum bilirubin, and LDH levels decreased significantly in all the patients. No short-term drug toxicity was observed. This study describes the use of hydroxyurea therapy in patients with HbSD-Punjab. Low dose hydroxyurea (10 mg/kg/day) was found to be effective in reducing the clinical severity in patients with HbSD-Punjab without any short-term toxicity. In view of easy affordability amongst poor patients, widespread acceptability by patients and doctors, the need of infrequent monitoring and its potential effectiveness, low dose hydroxyurea is suitable for treatment of patients with HbSD-Punjab. © 2014 Wiley Periodicals, Inc.

  2. Cytochrome P450-dependent N-hydroxylation of an aminoguanidine (amidinohydrazone) and microsomal retroreduction of the N-hydroxylated product.

    Science.gov (United States)

    Clement, B; Schultze-Mosgau, M H; Richter, P H; Besch, A

    1994-07-01

    1. The first example of a P450-dependent N-hydroxylation of an aminoguanidine (amidinohydrazone) is reported for 2-amino-5-chlorobenzophenone amidinohydrazone 1 (G 256) as substrate. 2. The N-hydroxylated metabolite 2 (2-amino-5-chlorobenzophenone N-hydroxyamidinohydrazone NOH-G256) and a further metabolite of 1, the phenol 3, were identified by tlc and ms analysis. 3. The microsomal reduction of an N-hydroxyaminoguanidine (N-hydroxy-amidino-hydrazone) was also demonstrated for the transformation of 2 to 1. 4. Both the N-hydroxylation of the aminoguanidine and the retroreduction of the N-hydroxyaminoguanidine were characterized by quantitative hplc analysis. 5. The conversion of the aminoguanidine 1 to N-hydroxyaminoguanidine 2 may be considered as an analogue of the physiological N-hydroxylation of arginine to N-hydroxyarginine by NO synthases.

  3. Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub-Saharan Africa.

    Science.gov (United States)

    McGann, Patrick T; Williams, Thomas N; Olupot-Olupot, Peter; Tomlinson, George A; Lane, Adam; Luís Reis da Fonseca, José; Kitenge, Robert; Mochamah, George; Wabwire, Ham; Stuber, Susan; Howard, Thad A; McElhinney, Kathryn; Aygun, Banu; Latham, Teresa; Santos, Brígida; Tshilolo, Léon; Ware, Russell E

    2018-08-01

    Despite its well-described safety and efficacy in the treatment of sickle cell anemia (SCA) in high-income settings, hydroxyurea remains largely unavailable in sub-Saharan Africa, where more than 75% of annual SCA births occur and many comorbidities exist. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) is a prospective, Phase I/II open-label trial of hydroxyurea designed to evaluate the feasibility, safety, and benefits of hydroxyurea treatment for children with SCA in four sub-Saharan African countries. Following comprehensive training of local research teams, REACH was approved by local Ethics Committees and achieved full enrollment ahead of projections with 635 participants enrolled over a 30-month period, despite half of families living >12 km from their clinical site. At enrollment, study participants (age 5.4 ± 2.4 years) had substantial morbidity, including a history of vaso-occlusive pain (98%), transfusion (68%), malaria (85%), and stroke (6%). Significant differences in laboratory characteristics were noted across sites, with lower hemoglobin concentrations (P < .01) in Angola (7.2 ± 1.0 g/dL) and the DRC (7.0 ± 0.9 g/dL) compared to Kenya (7.4 ± 1.1 g/dL) and Uganda (7.5 ± 1.1 g/dL). Analysis of known genetic modifiers of SCA demonstrated a high frequency of α-thalassemia (58.4% with at least a single α-globin gene deletion) and G6PD deficiency (19.7% of males and 2.4% of females) across sites. The CAR β-globin haplotype was present in 99% of participants. The full enrollment to REACH confirms the feasibility of conducting high-quality SCA research in Africa; this study will provide vital information to guide safe and effective dosing of hydroxyurea for children with SCA living in Africa. © 2018 Wiley Periodicals, Inc.

  4. Hydroxyurea decreases hospitalizations in pediatric patients with Hb SC and Hb SB+ thalassemia

    Directory of Open Access Journals (Sweden)

    Lebensburger JD

    2015-12-01

    Full Text Available Jeffrey D Lebensburger, Rakeshkumar J Patel, Prasannalaxmi Palabindela, Christina J Bemrich-Stolz, Thomas H Howard, Lee M HilliardDivision of Pediatric Hematology Oncology, University of Alabama at Birmingham, Birmingham, AL, USAPurpose: Patients with hemoglobin SC (Hb SC and hemoglobin SB+ (Hb SB+ thalassemia suffer from frequent hospitalizations yet strong evidence of a clinical benefit of hydroxyurea (HU in this population is lacking. Patients with recurrent hospitalizations for pain crisis are offered HU at our institution based on small cohort data and anecdotal benefit. This study identifies outcomes from a large cohort of patients with Hb SC and SB+ thalassemia who were treated with HU for 2 years.Materials and methods: A retrospective review was conducted of 32 patients with Hb SC and SB+ thalassemia who were treated with HU. We reviewed the number, and reasons for hospitalization in the 2 years prior to, and 2 years post-HU treatment as well as laboratory changes from baseline, over 1 year.Results: Patients with Hb SC and SB+ thalassemia started on HU for frequent pain, had a significant reduction in hospitalizations over 2 years as compared to the 2 years prior to HU initiation (mean total hospitalizations/year: pre-HU: 1.6 vs post-HU 0.4 hospitalizations, P<0.001; mean pain hospitalizations/year: pre-HU 1.5 vs post-HU 0.3 hospitalizations, P<0.001. Patients demonstrated hematologic changes including an increase in percent fetal hemoglobin (%HbF pre–post HU (4.5% to 7.7%, P=0.002, mean corpuscular volume (74 to 86 fL, P<0,0001, and decrease in absolute neutrophil count (5.0 to 3.2×109/L, P=0.007. Patients with higher doses of HU demonstrated the greatest reduction in hospitalizations but this was unrelated to absolute neutrophil count.Conclusion: This cohort of patients with Hb SC and SB+ thalassemia provides additional support for using HU in patients with recurrent hospitalizations for pain. A large randomized multicenter trial of

  5. FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1.

    Directory of Open Access Journals (Sweden)

    Carsten C Scholz

    2016-01-01

    Full Text Available The asparagine hydroxylase, factor inhibiting HIF (FIH, confers oxygen-dependence upon the hypoxia-inducible factor (HIF, a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1 is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit.

  6. Survival of nonsurgically staged patients with negative lymphangiograms who had Stage IIB carcinoma of the cervix treated by pelvic radiation plus hydroxyurea

    International Nuclear Information System (INIS)

    Piver, M.S.; Krishnamsetty, R.M.; Emrich, L.J.

    1985-01-01

    Twenty patients with Stage IIB carcinoma of the cervix who did not undergo pretherapy para-aortic lymphadenectomy, but who had negative preradiation therapy lymphangiograms, were treated with pelvic radiation plus hydroxyurea. Patients received a median of 5020 rads of pelvic radiation plus 4000 rads of radium to point A. During radiation therapy and for a total of 12 weeks, patients received hydroxyurea administered at a dose of 80 mg/kg of body weight every 3 days if the white blood cell count was greater than or equal to 2,500/mm3 and platelets were greater than or equal to 75,000/mm3. The median follow-up time was 28 months (6 to 83 months). The estimated 5-year survival rate was 92%. Seventeen patients are alive with no evidence of disease (median, 28 months); one died of intercurrent disease with no evidence of disease (17 months); one is alive with no evidence of disease after recurrence (18 months); and one died of cervical cancer (22 months). The survival rate of patients with nonsurgically staged negative pretherapy lymphangiograms who had Stage IIB cervical cancer treated by pelvic radiation therapy plus hydroxyurea approximated the improved survival rate reported for patients with negative pretherapy para-aortic lymphadenectomy who were treated with pelvic radiation therapy plus hydroxyurea. Both studies would suggest that pelvic radiation plus hydroxyurea improves the rate of survival in patients with Stage IIB cervical cancer

  7. Cyclical thrombocytosis, acquired von Willebrand syndrome and aggressive non-melanoma skin cancers are common in patients with Philadelphia-negative myeloproliferative neoplasms treated with hydroxyurea.

    Science.gov (United States)

    Verner, Emma; Forsyth, Cecily; Grigg, Andrew

    2014-05-01

    Abstract Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea complications have been reported in Philadelphia-negative myeloproliferative neoplasms (MPNs), but their incidence and clinical consequences have not been defined in a large cohort of patients. We conducted a retrospective analysis of 188 consecutive patients with MPNs specifically addressing the incidence of these complications. Cyclical thrombocytosis was documented in 29 patients (15%), the majority of whom were receiving hydroxyurea. Acquired von Willebrand syndrome was identified in 17 of the 84 screened patients (20%), but was not associated with any major bleeding complications. Non-melanoma skin cancers were reported in 51 patients (27%). Hydroxyurea-related fever occurred in nine of 149 patients (6%) who received hydroxyurea. Seventy-three patients (39%) experienced a total of 98 major thrombotic events, with the majority of these occurring prior to or within 3 months of the diagnosis. Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea-related complications are not infrequent in MPNs and have important clinical consequences for management.

  8. Development of Hydroxyl Tagging Velocimetry for Low Velocity Flows

    Science.gov (United States)

    Andre, Matthieu A.; Bardet, Philippe M.; Burns, Ross A.; Danehy, Paul M.

    2016-01-01

    Hydroxyl tagging velocimetry (HTV) is a molecular tagging technique that relies on the photo-dissociation of water vapor into OH radicals and their subsequent tracking using laser induced fluorescence. Velocities are then obtained from time-of-flight calculations. At ambient temperature in air, the OH species lifetime is relatively short (<50 µs), making it suited for high speed flows. Lifetime and radicals formation increases with temperature, which allows HTV to also probe low-velocity, high-temperature flows or reacting flows such as flames. The present work aims at extending the domain of applicability of HTV, particularly towards low-speed (<10 m/s) and moderate (<500 K) temperature flows. Results are compared to particle image velocimetry (PIV) measurements recorded in identical conditions. Single shot and averaged velocity profiles are obtained in an air jet at room temperature. By modestly raising the temperature (100-200 degC) the OH production increases, resulting in an improvement of the signal-to-noise ratio (SNR). Use of nitrogen - a non-reactive gas with minimal collisional quenching - extends the OH species lifetime (to over 500 µs), which allows probing of slower flows or, alternately, increases the measurement precision at the expense of spatial resolution. Instantaneous velocity profiles are resolved in a 100degC nitrogen jet (maximum jet-center velocity of 6.5 m/s) with an uncertainty down to 0.10 m/s (1.5%) at 68% confidence level. MTV measurements are compared with particle image velocimetry and show agreement within 2%.

  9. Genomic mapping of single-stranded DNA in hydroxyurea-challenged yeasts identifies origins of replication.

    Science.gov (United States)

    Feng, Wenyi; Collingwood, David; Boeck, Max E; Fox, Lindsay A; Alvino, Gina M; Fangman, Walton L; Raghuraman, Mosur K; Brewer, Bonita J

    2006-02-01

    During DNA replication one or both strands transiently become single stranded: first at the sites where initiation of DNA synthesis occurs (known as origins of replication) and subsequently on the lagging strands of replication forks as discontinuous Okazaki fragments are generated. We report a genome-wide analysis of single-stranded DNA (ssDNA) formation in the presence of hydroxyurea during DNA replication in wild-type and checkpoint-deficient rad53 Saccharomyces cerevisiae cells. In wild-type cells, ssDNA was first observed at a subset of replication origins and later 'migrated' bi-directionally, suggesting that ssDNA formation is associated with continuously moving replication forks. In rad53 cells, ssDNA was observed at virtually every known origin, but remained there over time, suggesting that replication forks stall. Telomeric regions seemed to be particularly sensitive to the loss of Rad53 checkpoint function. Replication origins in Schizosaccharomyces pombe were also mapped using our method.

  10. Novel electroanalysis of hydroxyurea at glassy carbon and gold electrode surfaces

    Directory of Open Access Journals (Sweden)

    Keerti M. Naik

    2014-09-01

    Full Text Available A simple and a novel electroanalysis of hydroxyurea (HU drug at glassy carbon and gold electrode was investigated for the first time using cyclic, linear sweep and differential pulse voltammetric techniques. The oxidation of HU was irreversible and exhibited a diffusion controlled process on both electrodes. The oxidation mechanism was proposed. The dependence of the current on pH, the concentration, nature of buffer, and scan rate was investigated to optimize the experimental conditions for the determination of HU. It was found that the optimum buffer pH was 7.0, a physiological pH. In the range of 0.01 to 1.0 mM, the current measured by differential pulse voltammetry showed a linear relationship with HU concentration with limit of detection of 0.46 µM for glassy carbon electrode and 0.92 µM for gold electrode. In addition, reproducibility, precision and accuracy of the method were checked as well. The developed method was successfully applied to HU determination in pharmaceutical formulation and human biological fluids. The method finds its applications in quality control laboratories and pharmacokinetics.

  11. Hydroxyurea for nontransfusion-dependent β-thalassemia: A systematic review and meta-analysis.

    Science.gov (United States)

    Algiraigri, Ali H; Wright, Nicola A M; Paolucci, Elizabeth Oddone; Kassam, Aliya

    2017-09-01

    Nontransfusion-dependent β-thalassemia (NTDβT) syndromes consist of β-thalassemia intermedia and moderate hemoglobin E/β thalassemias. They are characterized by varying degrees of chronic anemia and a wide spectrum of complications due to ineffective erythropoiesis and iron overload from chronic transfusions. Hydroxyurea (HU), an oral chemotherapeutic drug, is anticipated to decrease disease severity. We performed a meta-analysis to evaluate the clinical efficacy and safety of HU in NTDβT patients of any age. MEDLINE, EMBASE, Cochrane databases, and major conference proceedings for studies that assessed HU in NTDβT patients were searched. Qualities of eligible studies were assessed by National Institutes of Health tools. Seventeen studies, collectively involving 709 patients, fulfilled the eligibility criteria. HU was associated with a significant decrease in transfusion need in severe NTDβT with complete and overall (≥50%) response rates of 42% and 79%, respectively. For mild NTDβT, HU was effective in raising hemoglobin by 1g/L in 64% of patients. HU appears to be effective, well tolerated, and associated with mild and transient adverse events. NTDβT patients may benefit from a trial of HU, although large randomized clinical trials assessing its efficacy should be conducted to confirm the findings of this meta-analysis and to assess its long-term toxicity and response sustainability. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

  12. Essential Thrombocythemia in a Two-year-old Child, Responsive to Hydroxyurea but Not Aspirin

    Directory of Open Access Journals (Sweden)

    Tariq N. Aladily

    2017-06-01

    Full Text Available Essential thrombocythemia (ET is a myeloproliferative neoplasm that occurs mostly in patients above the age of 50 years. Its incidence in children is very rare, with around 100 cases reported in the literature. High-risk patients are defined by previous life threatening major thrombotic or severe hemorrhagic complication or age > 60. Those patients probably benefit from cytoreductive therapy. On the other hand, antiplatelet drugs are recommended for patients with low risk group. Although rare, ET should be considered in the differential diagnosis of persistent thrombocytosis in children, even at a very young age. A constellation of clinical, pathologic ,and molecular testing are essential for diagnosis. Given the rarity of these cases, there is currently no consensus for treatment guidelines in children, especially in asymptomatic patients. We describe a case of a two-year old girl who presented with unexplained, isolated thrombocytosis which persisted for eight years. Bone marrow biopsy demonstrated typical features of ET. Over the course of the disease, hydroxyurea, but not aspirin, showed better control of symptoms and lowered the platelets level.

  13. Determination of hydroxyurea in human plasma by HPLC-UV using derivatization with xanthydrol.

    Science.gov (United States)

    Legrand, Tiphaine; Rakotoson, Marie-Georgine; Galactéros, Frédéric; Bartolucci, Pablo; Hulin, Anne

    2017-10-01

    A simple and rapid high performance liquid chromatography (HPLC) method using ultraviolet (UV) detection was developed to determine hydroxyurea (HU) concentration in plasma sample after derivatization with xanthydrol. Two hundred microliters samples were spiked with methylurea (MeU) as internal standard and proteins were precipitated by adding methanol. Derivatization of HU and MeU was immediately performed by adding 0.02M xanthydrol and 1.5M HCl in order to obtain xanthyl-derivatives of HU and MeU that can be further separated using HPLC and quantified using UV detection at 240nm. Separation was achieved using a C18 column with a mobile phase composed of 20mM ammonium acetate and acetonitrile in gradient elution mode at a flow rate of 1mL/min. The total analysis time did not exceed 18min. The method was found linear from 5 to 400μM and all validation parameters fulfilled the international requirements. Between- and within-run accuracy error ranged from -4.7% to 3.2% and precision was lower than 12.8%. This simple method requires small volume samples and can be easily implemented in most clinical laboratories to develop pharmacokinetics studies of HU and to promote its therapeutic monitoring. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Hydroxyurea for hemoglobin E/β-thalassemia: a systematic review and meta-analysis.

    Science.gov (United States)

    Algiraigri, Ali H; Kassam, Aliya

    2017-12-01

    Hemoglobin E-beta thalassemia (Hb E/β-thalassemia) is a distinct, yet common, type of β-thalassemia, in which the patient co-inherits a β-thalassemia allele from one parent, and a structural variant, Hb E, from the other parent. This co-inheritance leads to remarkable clinical heterogeneity, varying degrees of chronic anemia, and a wide spectrum of complications due to ineffective erythropoiesis and iron overload. Hydroxyurea (HU), an oral chemotherapeutic drug, is expected to decrease disease severity. To assess the clinical efficacy and safety of HU in Hb E/β-thalassemia patients. We searched MEDLINE, EMBASE, Cochrane databases, and major preceding conferences for studies that assessed HU in Hb E/β-thalassemias patients. The effect size was estimated as a proportion (responder/sample size). Qualities of eligible studies were assessed using NIH tools. A total of five [one randomized clinical trial (RCT) and four observational] studies involving 106 patients were included. HU was associated with a significant RR of 46% with no statistical heterogeneity. No serious adverse effects were reported. Patients with Hb E/β-thalassemia may benefit from a trial of HU, though large RCTs assessing efficacy should be conducted to confirm the findings of this meta-analysis and to assess long-term toxicity and response sustainability.

  15. Pu(IV) reduction with hydroxyurea and its application in U/Pu separation

    International Nuclear Information System (INIS)

    Zhu Zhaowu; He Jianyu; Zhang Zefu; Song Tianbao; Zhang Yu; Zheng Weifang

    2004-01-01

    The reduction of Pu(IV) with hydroxyurea (HU) in the mixed phase of 30% TBP/OK-HNO 3 system was studied. The study results show that HU can reduce Pu(IV) to Pu(III) and the reduction rate can be expressed as -dc(Pu(IV))/dt=kc(HU)c -3.2 (HNO 3 )c mix 2 (Pu(IV))c mix -1 (Pu(III)), where k is the rate constant, and k=(896 ± 59) mol 2.3 ·L -2.3 ·min -1 at 15 degree C. With HU serves as a reductant, 16 stages count-current cascade experiment was performed using centrifugal tube to simulate U/Pu separation in the 1B contactor of Purex process. The separation factor of Pu from U and the separation factor of U from Pu reach to 5.4 x 10 4 and 1.8 x 10 5 , respectively. The amount of Pu is about 11 μg in per kg U product. (authors)

  16. The in vivo toxicity of hydroxyurea depends on its direct target catalase.

    Science.gov (United States)

    Juul, Trine; Malolepszy, Anna; Dybkaer, Karen; Kidmose, Rune; Rasmussen, Jan Trige; Andersen, Gregers Rom; Johnsen, Hans Erik; Jørgensen, Jan-Elo; Andersen, Stig Uggerhøj

    2010-07-09

    Hydroxyurea (HU) is a well tolerated ribonucleotide reductase inhibitor effective in HIV, sickle cell disease, and blood cancer therapy. Despite a positive initial response, however, most treated cancers eventually progress due to development of HU resistance. Although RNR properties influence HU resistance in cell lines, the mechanisms underlying cancer HU resistance in vivo remain unclear. To address this issue, we screened for HU resistance in the plant Arabidopsis thaliana and identified seventeen unique catalase mutants, thereby establishing that HU toxicity depends on catalase in vivo. We further demonstrated that catalase is a direct HU target by showing that HU acts as a competitive inhibitor of catalase-mediated hydrogen peroxide decomposition. Considering also that catalase can accelerate HU decomposition in vitro and that co-treatment with another catalase inhibitor alleviates HU effects in vivo, our findings suggests that HU could act as a catalase-activated pro-drug. Clinically, we found high catalase activity in circulating cells from untreated chronic myeloid leukemia, offering a possible explanation for the efficacy of HU against this malignancy.

  17. New insights into the aquatic photochemistry of fluoroquinolone antibiotics: Direct photodegradation, hydroxyl-radical oxidation, and antibacterial activity changes

    Energy Technology Data Exchange (ETDEWEB)

    Ge, Linke; Na, Guangshui [Key Laboratory for Ecological Environment in Coastal Areas (SOA), National Marine Environmental Monitoring Center, Dalian 116023 (China); Zhang, Siyu [Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang 110016 (China); Li, Kai [Key Laboratory for Ecological Environment in Coastal Areas (SOA), National Marine Environmental Monitoring Center, Dalian 116023 (China); Zhang, Peng, E-mail: pzhang@nmemc.org.cn [Key Laboratory for Ecological Environment in Coastal Areas (SOA), National Marine Environmental Monitoring Center, Dalian 116023 (China); Ren, Honglei; Yao, Ziwei [Key Laboratory for Ecological Environment in Coastal Areas (SOA), National Marine Environmental Monitoring Center, Dalian 116023 (China)

    2015-09-15

    The ubiquity and photoreactivity of fluoroquinolone antibiotics (FQs) in surface waters urge new insights into their aqueous photochemical behavior. This study concerns the photochemistry of 6 FQs: ciprofloxacin, danofloxacin, levofloxacin, sarafloxacin, difloxacin and enrofloxacin. Methods were developed to calculate their solar direct photodegradation half-lives (t{sub d,E}) and hydroxyl-radical oxidation half-lives (t{sub ·OH,E}) in sunlit surface waters. The t{sub d,E} values range from 0.56 min to 28.8 min at 45° N latitude, whereas t{sub ·OH,E} ranges from 3.24 h to 33.6 h, suggesting that most FQs tend to undergo fast direct photolysis rather than hydroxyl-radical oxidation in surface waters. However, a case study for levofloxacin and sarafloxacin indicated that the hydroxyl-radical oxidation induced risky photochlorination and resulted in multi-degradation pathways, such as piperazinyl hydroxylation and clearage. Changes in the antibacterial activity of FQs caused by photodegradation in various waters were further examined using Escherichia coli, and it was found that the activity evolution depended on primary photodegradation pathways and products. Primary intermediates with intact FQ nuclei retained significant antibacterial activity. These results are important for assessing the fate and risk of FQs in surface waters. - Highlights: • It is first reported on hydroxyl-radical oxidation of 6 fluoroquinolone antibiotics. • Methods were developed to assess photolysis and oxidation fate in surface waters. • The neutral form reacted faster with hydroxyl radical than protonated forms. • The main oxidation intermediates and transformation pathways were clarified. • The antibacterial activity changes depend on dominant photolysis pathways.

  18. New insights into the aquatic photochemistry of fluoroquinolone antibiotics: Direct photodegradation, hydroxyl-radical oxidation, and antibacterial activity changes

    International Nuclear Information System (INIS)

    Ge, Linke; Na, Guangshui; Zhang, Siyu; Li, Kai; Zhang, Peng; Ren, Honglei; Yao, Ziwei

    2015-01-01

    The ubiquity and photoreactivity of fluoroquinolone antibiotics (FQs) in surface waters urge new insights into their aqueous photochemical behavior. This study concerns the photochemistry of 6 FQs: ciprofloxacin, danofloxacin, levofloxacin, sarafloxacin, difloxacin and enrofloxacin. Methods were developed to calculate their solar direct photodegradation half-lives (t d,E ) and hydroxyl-radical oxidation half-lives (t ·OH,E ) in sunlit surface waters. The t d,E values range from 0.56 min to 28.8 min at 45° N latitude, whereas t ·OH,E ranges from 3.24 h to 33.6 h, suggesting that most FQs tend to undergo fast direct photolysis rather than hydroxyl-radical oxidation in surface waters. However, a case study for levofloxacin and sarafloxacin indicated that the hydroxyl-radical oxidation induced risky photochlorination and resulted in multi-degradation pathways, such as piperazinyl hydroxylation and clearage. Changes in the antibacterial activity of FQs caused by photodegradation in various waters were further examined using Escherichia coli, and it was found that the activity evolution depended on primary photodegradation pathways and products. Primary intermediates with intact FQ nuclei retained significant antibacterial activity. These results are important for assessing the fate and risk of FQs in surface waters. - Highlights: • It is first reported on hydroxyl-radical oxidation of 6 fluoroquinolone antibiotics. • Methods were developed to assess photolysis and oxidation fate in surface waters. • The neutral form reacted faster with hydroxyl radical than protonated forms. • The main oxidation intermediates and transformation pathways were clarified. • The antibacterial activity changes depend on dominant photolysis pathways

  19. Characterization of the Ornithine Hydroxylation Step in Albachelin Biosynthesis

    Directory of Open Access Journals (Sweden)

    Kendra Bufkin

    2017-10-01

    Full Text Available N-Hydroxylating monooxygenases (NMOs are involved in siderophore biosynthesis. Siderophores are high affinity iron chelators composed of catechol and hydroxamate functional groups that are synthesized and secreted by microorganisms and plants. Recently, a new siderophore named albachelin was isolated from a culture of Amycolatopsis alba growing under iron-limiting conditions. This work focuses on the expression, purification, and characterization of the NMO, abachelin monooxygenase (AMO from A. alba. This enzyme was purified and characterized in its holo (FAD-bound and apo (FAD-free forms. The apo-AMO could be reconstituted by addition of free FAD. The two forms of AMO hydroxylate ornithine, while lysine increases oxidase activity but is not hydroxylated and display low affinity for NADPH.

  20. Serum Hydroxyl Radical Scavenging Capacity as Quantified with Iron-Free Hydroxyl Radical Source

    Science.gov (United States)

    Endo, Nobuyuki; Oowada, Shigeru; Sueishi, Yoshimi; Shimmei, Masashi; Makino, Keisuke; Fujii, Hirotada; Kotake, Yashige

    2009-01-01

    We have developed a simple ESR spin trapping based method for hydroxyl (OH) radical scavenging-capacity determination, using iron-free OH radical source. Instead of the widely used Fenton reaction, a short (typically 5 seconds) in situ UV-photolysis of a dilute hydrogen peroxide aqueous solution was employed to generate reproducible amounts of OH radicals. ESR spin trapping was applied to quantify OH radicals; the decrease in the OH radical level due to the specimen’s scavenging activity was converted into the OH radical scavenging capacity (rate). The validity of the method was confirmed in pure antioxidants, and the agreement with the previous data was satisfactory. In the second half of this work, the new method was applied to the sera of chronic renal failure (CRF) patients. We show for the first time that after hemodialysis, OH radical scavenging capacity of the CRF serum was restored to the level of healthy control. This method is simple and rapid, and the low concentration hydrogen peroxide is the only chemical added to the system, that could eliminate the complexity of iron-involved Fenton reactions or the use of the pulse-radiolysis system. PMID:19794928

  1. Rate constant for reaction of hydroxyl radicals with bicarbonate ions

    International Nuclear Information System (INIS)

    Buxton, G.V.; Elliot, A.J.

    1986-01-01

    The rate constant for reaction of hydroxyl radicals with the bicarbonate ion has been determined to be 8.5 x 10 6 dm 3 mol -1 s -1 . This value was calculated from: the measured rate of formation of the CO 3 - radical in pulsed electron irradiation of bicarbonate solutions over the pH range 7.0 to 9.4; the pK for the equilibrium HCO 3 - = CO 3 2- + H + ; and the rate constant for hydroxyl radicals reacting with the carbonate ion. (author)

  2. Effect of hydroxyurea on mitotic activity 3H-thymidine and 3H-phenylalanine incorporation in the antheridial filament cells of Chara vulgaris

    International Nuclear Information System (INIS)

    Bielecka, A.

    1979-01-01

    Hydroxyurea inhibits mitotic activity in cells of the antheridial filaments of Chara vulgaris by blocking phase S and phase G 2 . Blocking of cells in phase G 2 also occurs in the case of the root meristem cells of Helianthus annuus and Vicia faba var. minor. 3 H-thine incorporation confirmed autoradiographically the blocking of cells of the antheridial filaments in Chara vulgaris at phase S and slowing down of the rate of DNA replication. Incubation with 3 H-phenylalanine demonstrated that hydroxyurea inhibits protein synthesis. (author)

  3. The cytogenetic effect of radiation and postirradiation treatment of Chinese hamster cells with arabinoside cytosine and hydroxyurea

    International Nuclear Information System (INIS)

    Elisova, T.V.; Stavrakova, N.M.; Feoktistova, T.P.

    1988-01-01

    A two-hour treatment of Chinese hamster cells at the G 1 stage of the cell cycle with arabinoside cytocine combined with hydroxyurea after X-irradiation (50-300 cGy) produced a 2- to 4-fold increase in the frequency of chromosome aberrations. The mitotic selection method was used to synchronize the cells. The potentiating effect of inhibitors was estimated by the yield of centric exchanges decreased with increasing radiation dose. It is suggested that DNA repair processes determining a linear component of the dose-response curve are modified within the dose-range under study

  4. Hydroxyurea as a first-line treatment of extramedullary hematopoiesis in patients with beta thalassemia: Four case reports.

    Science.gov (United States)

    Karimi, Mehran; Cohan, Nader; Pishdad, Parisa

    2015-01-01

    Extramedullary hematopoiesis (EMH) is evidenced by erythropoietic masses, which occurs as a compensatory mechanism to overcome hypoxia during chronic anemia. EMH masses in spinal cord could lead to cord compression and neurological symptoms. Besides transfusion, radiotherapy, and surgery, hydroxyurea (HU) is also a treatment strategy in EMH. We described four cases of beta thalassemia with EMH who were treated with HU as a monotherapy. INTERVENTION (AND TECHNIQUE): HU therapy was done in all patients without any transfusion during therapy. HU is a good treatment option for patients with EMH and it could be a substitute for radiotherapy and invasive surgery or regular blood transfusion.

  5. Sequential Oral Hydroxyurea and Intravenous Cytosine Arabinoside in Refractory Childhood Acute Leukemia: A Pediatric Oncology Group Phase I Study

    OpenAIRE

    Dubowy, Ronald; Graham, Michael; Hakami, Nasrollah; Kletzel, Morris; Mahoney, Donald; Newman, Edward; Ravindranath, Yaddanapudi; Camitta, Bruce

    2008-01-01

    At concentrations >0.1 mM, Hydroxyurea (HU) enhances the accumulation of cytosine arabinoside (ara-C) in leukemia cells in vitro. This study of children with refractory acute leukemia was designed to take advantage of this biochemical modulation. A fixed dose of HU and an escalating dose of ara-C were used. Oral HU, 1200 mg/m2 was followed 2 hours later by ara-C, 250-3100 mg/m2 intravenously in 15 minutes. The combination was given on days 1,2,3 and 8,9,10. Thirty-three children (26 ALL, 7 AN...

  6. Health-related quality of life and adherence to hydroxyurea in adolescents and young adults with sickle cell disease.

    Science.gov (United States)

    Badawy, Sherif M; Thompson, Alexis A; Lai, Jin-Shei; Penedo, Frank J; Rychlik, Karen; Liem, Robert I

    2017-06-01

    Complications related to sickle cell disease (SCD) result in significant declines in health-related quality of life (HRQOL). While hydroxyurea reduces SCD complications, adherence remains suboptimal. The study's objectives were to assess the feasibility of Internet-based electronic assessment of HRQOL in SCD clinic and to examine the relationship between HRQOL and hydroxyurea adherence in adolescents and young adults (AYAs) with SCD. A cross-sectional survey was administered on tablets to 34 AYAs (12-22 years old) in a SCD clinic from January through December 2015. Study measures included Patient Reported Outcomes Measurement Information System (PROMIS ® ) computerized adaptive testing and ©Modified Morisky Adherence Scale 8-items (©MMAS-8). Participants (59% male, 91% Black) had median age of 13.5 (range 12-18) years. Ninety-one percent completed PROMIS® measures electronically in the clinic, meeting our feasibility criterion of ≥85% completion rate. ©MMAS-8 scores positively correlated with fetal hemoglobin (HbF) (r s = 0.34, P = 0.04) and mean corpuscular volume (MCV) (r s = 0.42, P = 0.01) and inversely correlated with fatigue (r s = -0.45, P = 0.01), depression (r s = -0.3, P = 0.08), and social isolation (r s = -0.78, P = 0.02). Low ©MMAS-8 scores, indicating poor adherence, were associated with worse fatigue (P = 0.001) and trended toward significance for pain (P = 0.07) and depression (P = 0.06). Homozygous hemoglobin S disease patients with low HbF (<16%) had worse social isolation (P = 0.04) and those with low MCV (<102 fl) reported worse fatigue (P = 0.001), pain (P = 0.01), mobility (P = 0.01), and social isolation (P = 0.04). HRQOL assessment in the SCD clinic is feasible. SCD patients with low hydroxyurea adherence and/or low HbF or MCV levels had worse HRQOL scores, particularly fatigue. Future prospective studies examining the relationship between HRQOL and hydroxyurea adherence are warranted. © 2016 Wiley Periodicals, Inc.

  7. Infrared absorption characteristics of hydroxyl groups in coal tars

    Energy Technology Data Exchange (ETDEWEB)

    Cannon, S A; Chu, C J; Hange, R H; Margrave, J L

    1987-01-01

    Tar evolution was observed over a temperature range of 150-600 C for four coals. Pittsburgh bituminous, Illinois No.6, Rawhide subbituminous, and Texas lignite. Isolation of the evolved tars in a nitrogen matrix at 15 degrees K produced better resolved infrared spectra than those in a coal matrix, thus enhancing structural characterization of the tar molecules. Two distinct hydroxyl functional groups in the tar molecules free of hydrogen bonding were identified for the first time without interference from H/sub 2/O absorptions. These absorptions at 3626.5 cm/sup -1/ have been assigned to phenolic hydroxyls. It is suggested that carboxylic and aliphatic hydroxyl groups do not survive the vaporization process. Tars from Illinois No.6 were found to contain the largest amount of phenolic hydroxyl; Pittsburgh No. 8 tar contains approximately half of that for Illinois No.6 while Rawhide and Texas lignite contain much less phenolic than either of the other coals. 10 references, 6 figures, 1 table.

  8. Hydroxyl radical reactivity at the air-ice interface

    Directory of Open Access Journals (Sweden)

    T. F. Kahan

    2010-01-01

    Full Text Available Hydroxyl radicals are important oxidants in the atmosphere and in natural waters. They are also expected to be important in snow and ice, but their reactivity has not been widely studied in frozen aqueous solution. We have developed a spectroscopic probe to monitor the formation and reactions of hydroxyl radicals in situ. Hydroxyl radicals are produced in aqueous solution via the photolysis of nitrite, nitrate, and hydrogen peroxide, and react rapidly with benzene to form phenol. Similar phenol formation rates were observed in aqueous solution and bulk ice. However, no reaction was observed at air-ice interfaces, or when bulk ice samples were crushed prior to photolysis to increase their surface area. We also monitored the heterogeneous reaction between benzene present at air-water and air-ice interfaces with gas-phase OH produced from HONO photolysis. Rapid phenol formation was observed on water surfaces, but no reaction was observed at the surface of ice. Under the same conditions, we observed rapid loss of the polycyclic aromatic hydrocarbon (PAH anthracene at air-water interfaces, but no loss was observed at air-ice interfaces. Our results suggest that the reactivity of hydroxyl radicals toward aromatic organics is similar in bulk ice samples and in aqueous solution, but is significantly suppressed in the quasi-liquid layer (QLL that exists at air-ice interfaces.

  9. Hydroxyl radical scavenging activity of peptide from sea cucumber ...

    African Journals Online (AJOL)

    enzyme complex, sea cucumber protein hydrolysis was carried out to obtain hydrolysates that have hydroxyl-radical-scavenging activity (HRSA). The hydrolytic process was monitored by HRSA and conditions for this process were optimized as follows: pH 6.5, temperature 35°C, 12 mg enzyme complex in a reaction solution ...

  10. Iron-functionalized Al-SBA-15 for benzene hydroxylation

    NARCIS (Netherlands)

    Li, Y.; Xia, H.; Fan, F.; Feng, Z.; Santen, van R.A.; Hensen, E.J.M.; Li, Can

    2008-01-01

    For the first time an ordered mesoporous silica (Fe–Al-SBA-15) with catalytically active isolated Fe surface species for the hydroxylation of benzene with nitrous oxide is prepared by introduction of Fe3+ in the synthesis gel of Al-SBA-15. Graphical abstract image for this article (ID: b717079c)

  11. 11 µ-Hydroxylation of cortexolone using immobilized ...

    African Journals Online (AJOL)

    Transformation of cortexolone to cortisol and prednisolone by the filamentous fungus Cunninghamella elegans protoplasts as a research tool was studied. The immobilized protoplasts of the fungus hydroxylated cortexolone at 11β -position had significantly higher activity than the free protoplasts. Sucrose as an osmotic ...

  12. Decomposition of water into highly combustible hydroxyl gas used in ...

    African Journals Online (AJOL)

    The method proposed involves the decomposition of water into highly combustible hydroxyl gas via electrolysis, which is used in internal combustion engines of electrical generators for electricity generation. The by-product obtained from combustion of this gas is water vapour and oxygen to replenish the atmosphere.

  13. Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia.

    Science.gov (United States)

    Estepp, Jeremie H; Melloni, Chiara; Thornburg, Courtney D; Wiczling, Paweł; Rogers, Zora; Rothman, Jennifer A; Green, Nancy S; Liem, Robert; Brandow, Amanda M; Crary, Shelley E; Howard, Thomas H; Morris, Maurine H; Lewandowski, Andrew; Garg, Uttam; Jusko, William J; Neville, Kathleen A

    2016-03-01

    Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSβspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open-label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight-based dosing schemes provide consistent drug exposure; and age-based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA. © 2015, The American College of Clinical Pharmacology.

  14. Hydroxyurea lowers transcranial Doppler flow velocities in children with sickle cell anaemia in a Nigerian cohort.

    Science.gov (United States)

    Lagunju, IkeOluwa; Brown, Biobele J; Sodeinde, Olugbemiro

    2015-09-01

    Sickle cell anaemia (SCA) is the leading genetic disorder in Nigeria. Elevated velocities ≥170 cm/sec occur in about a third of Nigerian children with SCA. Chronic blood transfusion for stroke prevention is faced with a myriad of challenges in our practice. To evaluate the effectiveness of hydroxyurea (HU) in reducing flow velocities in a cohort of Nigerian children with SCA and elevated velocities treated with HU. An observational study was carried out on a cohort of Nigerian children with SCA and elevated velocities identified on routine transcranial Doppler (TCD) screening. HU was recommended in those with TCD velocities ≥ 170cm/sec as stipulated in our hospital protocol. Outcomes were compared after ≥12 months of observation. Fifty children with elevated TCD velocities were studied; 31 consented to HU therapy and 19 declined. Children on HU showed a statistically significant decline in mean velocities from 199.7 [17.1] cm/sec to 165.8 [20.7] cm/sec (P < 0.001) with a significant increase in mean packed cell volume from 21.1 [3.4] to 25.0 [2.8]%. Children without treatment had a significant rise in mean velocities from 190.2 [10.8] cm/sec to 199.7 [14.9] cm/sec (P = 0.003). Children with conditional risk velocities on HU were less likely to convert to abnormal risk (P < 0.001). Two stroke events occurred, one in each group. No adverse effects of HU were recorded in the cohort. HU appears to significantly reduce TCD velocities in Nigerian children with SCA and elevated velocities ≥170 cm/sec with beneficial effect on the haematological profile. HU may provide an effective approach to primary stroke prevention, particularly in Africa. © 2015 Wiley Periodicals, Inc.

  15. Hydroxyurea appears beneficial in patients with beta-thalassaemia major and intermedia

    Directory of Open Access Journals (Sweden)

    S. F.S.A. Abdul Wahid

    2007-06-01

    Full Text Available Patients with severe inherited β-globin chain disorders may have milder illness if they produce high levels of fetal hemoglobin (HbF. Hydroxyurea (HU has been shown to enhance HbF levels in patients with sickle cell disease and may be useful in β-thalassemias. We administered HU to 13 patients with β-thalassemia intermedia or major, including 6 splenectomized patients. The patients received escalating doses (10 to 25 mg/kg/d of HU for around 2 years (median: 21 months, range: 8 - 55 months. Eleven patients responded with an increase in the pre-transfusion HbF levels, from a base line median of 8.0% (2.5 - 61.3% to 28.0% (6.6 - 49.2% and 40.7% (4.8 - 72.3% at 3 months and 18 months post-HU, respectively. A concomitant increment in median hemoglobin levels was noted at 1, 3 and 18 months of HU therapy. Six of 7 transfusion-dependent patients who had an increment of HbF (one with β-thalassemia major also had reduced transfusion requirement over the 2-year period of HU therapy. Response to HU was also shown by a reduction in spleen size. Apart from oral ulcers that resolved upon dose reduction of HU, no significant toxicity was noted. We conclude that increased HbF production in β-thalassemia patients, with an improvement in erythropoiesis, can be achieved using HU with minimal toxicity. (Med J Indones 2007; 16:78-83 Keywords: fetal hemoglobin (HbF, erythropoiesis, toxicity

  16. Efeitos colaterais cutâneos após uso prolongado de hidroxiuréia na Policitemia Vera Cutaneous effects after prolongaded use of hydroxyurea in Polycythemia Vera

    Directory of Open Access Journals (Sweden)

    Emmanuel Rodrigues de França

    2011-08-01

    Full Text Available A hidroxiureia é um derivado hidroxilado da ureia utilizado em diversas desordens hematológicas. Inúmeras alterações cutâneas, porém raras, são relatadas após seu uso prolongado. A patogênese das mesmas não está bem esclarecida, porém, sugere-se que a droga tenha uma ação tóxica direta sobre a pele. Descrevemos um homem de 75 anos, branco, com diagnóstico de Policitemia Vera que, ao longo de 11 anos de tratamento com hidroxiureia, evoluiu com várias lesões cutâneas: hiperpigmentação da pele, lesões atróficas em antebraços, melanoníquia longitudinal das 20 unhas, úlcera em antebraço direito, xerose cutânea, ictiose em pernas e carcinoma espinocelular no pavilhão auricular direito. Até o momento, os relatos na literatura descrevem pouca diversidade de lesões nos pacientes acometidosHydroxyurea is an hydroxylated urea derivative used in many myeloproliferative disorders. Many, but unusual cutaneous disorders are related after its prolonged use. Their pathogenesis is not clear, but it is suggested that there is direct toxicity of the drug on the skin. We described a white, 75-year old man with diagnosis of Polycythemia Vera that in 11 years of treatment developed many cutaneous lesions: skin hyperpigmentation, atrophic lesions on forearms, longitudinal melanonychia of 20 nails, right forearm ulcer, cutaneous xerosis, ichthyosis and auricular spinocellular carcinoma. At this moment, the literature reports describe little diversity of lesions in affected patients

  17. New insights into the aquatic photochemistry of fluoroquinolone antibiotics: Direct photodegradation, hydroxyl-radical oxidation, and antibacterial activity changes.

    Science.gov (United States)

    Ge, Linke; Na, Guangshui; Zhang, Siyu; Li, Kai; Zhang, Peng; Ren, Honglei; Yao, Ziwei

    2015-09-15

    The ubiquity and photoreactivity of fluoroquinolone antibiotics (FQs) in surface waters urge new insights into their aqueous photochemical behavior. This study concerns the photochemistry of 6 FQs: ciprofloxacin, danofloxacin, levofloxacin, sarafloxacin, difloxacin and enrofloxacin. Methods were developed to calculate their solar direct photodegradation half-lives (td,E) and hydroxyl-radical oxidation half-lives (tOH,E) in sunlit surface waters. The td,E values range from 0.56 min to 28.8 min at 45° N latitude, whereas tOH,E ranges from 3.24h to 33.6h, suggesting that most FQs tend to undergo fast direct photolysis rather than hydroxyl-radical oxidation in surface waters. However, a case study for levofloxacin and sarafloxacin indicated that the hydroxyl-radical oxidation induced risky photochlorination and resulted in multi-degradation pathways, such as piperazinyl hydroxylation and clearage. Changes in the antibacterial activity of FQs caused by photodegradation in various waters were further examined using Escherichia coli, and it was found that the activity evolution depended on primary photodegradation pathways and products. Primary intermediates with intact FQ nuclei retained significant antibacterial activity. These results are important for assessing the fate and risk of FQs in surface waters. Copyright © 2015. Published by Elsevier B.V.

  18. Hydroxyl migration disorders the surface structure of hydroxyapatite nanoparticles

    Science.gov (United States)

    Cheng, Xiajie; Wu, Hong; Zhang, Li; Ma, Xingtao; Zhang, Xingdong; Yang, Mingli

    2017-09-01

    The surface structure of nano-hydroxyapatite (HAP) was investigated using a combined simulated annealing and molecular dynamics method. The stationary structures of nano-HAP with 4-7 nm in diameter and annealed under different temperatures were analyzed in terms of pair distribution function, structural factor, mean square displacement and atomic coordination number. The particles possess different structures from bulk crystal. A clear radial change in their atomic arrangements was noted. From core to surface the structures change from ordered to disordered. A three-shell model was proposed to describe the structure evolution of nano-HAP. Atoms in the core zone keep their arrangements as in crystal, while atoms in the surface shell are in short-range order and long-range disorder, adopting a typically amorphous structure. Atoms in the middle shell have small displacements and/or deflections but basically retain their original locations as in crystal. The disordered shell is about 1 nm in thickness, in agreement with experimental observations. The disordering mainly stems from hydroxyl migration during which hydroxyls move to the surface and bond with the exposed Ca ions, and their left vacancies bring about a rearrangement of nearby atoms. The disordering is to some extent different for particles unannealed under different temperatures, resulting from fewer number of migrated hydroxyls at lower temperatures. Particles with different sizes have similar surface structures, and their surface energy decreases with increasing size. Moreover, the surface energy is reduced by hydroxyl migration because the exposed Ca ions on the surface are ionically bonded with the migrated hydroxyls. Our calculations proposed a new structure model for nano-HAP, which indicates a surface structure with activities different from those without surface reorganization. This is particularly interesting because most bioactivities of biomaterials are dominated by their surface activity.

  19. Comparison of MicroRNAs Mediated in Reactivation of the γ-Globin in β-Thalassemia Patients, Responders and Non-Responders to Hydroxyurea.

    Science.gov (United States)

    Hojjati, Mohammad T; Azarkeivan, Azita; Pourfathollah, Ali A; Amirizadeh, Naser

    2017-03-01

    Drug induction of Hb F seems to be an ideal therapy for patients with hemoglobin (Hb) disorders, and many efforts have been made to reveal the mechanism behind it. Thus, we examined in vivo expression of some microRNAs (miRNAs) that are thought to be involved in this process. Among β-thalassemia (β-thal) patients who were undergoing hydroxyurea (HU) therapy in the past 3 months and five healthy individuals, five responders and five non-responders, were also included in the study. Erythroid progenitors were isolated by magnetic activated cell sorting (MACS) and miRNA expression analyzed using reverse transcription-polymerase chain reaction (RT-PCR). We showed that γ-globin, miR-210 and miR-486-3p had higher levels in the responders than the non-responders group. Moreover, miR-150 and miR-320 had higher levels in the healthy group than both non-responders and responders groups, but the expression of miR-96 did not show any significant difference between the study groups. To the best of our knowledge, this is the first study proposing that 'induction of cellular hypoxic condition by Hb F inducing agents' could be the milestone of possible mechanisms that explain why responders are able to reactivate γ-globin genes and subsequently, more production of Hb F, in response to these agents in comparison to non-responders. However, further investigations need to be performed to verify this hypothesis.

  20. Randomized feasibility trial to improve hydroxyurea adherence in youth ages 10-18 years through community health workers: The HABIT study.

    Science.gov (United States)

    Green, Nancy S; Manwani, Deepa; Matos, Sergio; Hicks, April; Soto, Luisa; Castillo, Yina; Ireland, Karen; Stennett, Yvonne; Findley, Sally; Jia, Haomiao; Smaldone, Arlene

    2017-12-01

    The main therapeutic intervention for sickle cell disease (SCD) is hydroxyurea (HU). The effect of HU is largely through dose-dependent induction of fetal hemoglobin (HbF). Poor HU adherence is common among adolescents. Our 6-month, two-site pilot intervention trial, "HABIT," was led by culturally aligned community health workers (CHWs). CHWs performed support primarily through home visits, augmented by tailored text message reminders. Dyads of youth with SCD ages 10-18 years and a parent were enrolled. A customized HbF biomarker, the percentage decrease from each patients' highest historical HU-induced HbF, "Personal best," was used to qualify for enrollment and assess HU adherence. Two primary outcomes were as follows: (1) intervention feasibility and acceptability and (2) HU adherence measured in three ways: monthly percentage improvement toward HbF Personal best, proportion of days covered (PDC) by HU, and self-report. Twenty-eight dyads were enrolled, of which 89% were retained. Feasibility and acceptability were excellent. Controlling for group assignment and month of intervention, the intervention group improved percentage decrease from Personal best by 2.3% per month during months 0-4 (P = 0.30), with similar improvement in adherence demonstrated using pharmacy records. Self-reported adherence did not correlate. Dyads viewed CHWs as supportive for learning about SCD and HU, living with SCD and making progress in coordinated self-management responsibility to support a daily HU habit. Most parents and youth appreciated text message HU reminders. The HABIT pilot intervention demonstrated feasibility and acceptability with promising effect toward improved medication adherence. Testing in a larger multisite intervention trial is warranted. © 2017 Wiley Periodicals, Inc.

  1. Hydroxyurea with or without imatinib in the treatment of recurrent or progressive meningiomas: a randomized phase II trial by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

    Science.gov (United States)

    Mazza, Elena; Brandes, Alba; Zanon, Silvia; Eoli, Marika; Lombardi, Giuseppe; Faedi, Marina; Franceschi, Enrico; Reni, Michele

    2016-01-01

    Hydroxyurea (HU) is among the most widely used salvage therapies in progressive meningiomas. Platelet-derived growth factor receptors are expressed in virtually all meningiomas. Imatinib sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism. The combination of HU with imatinib yielded intriguing results in recurrent malignant glioma. The current trial addressed the activity of this association against meningioma. Patients with recurrent or progressive WHO grade I-III meningioma, without therapeutic indication for surgery, radiotherapy, or stereotactic radiosurgery, aged 18-75 years, ECOG performance status 0-2, and not on enzyme-inducing anti-epileptic drugs were randomized to receive HU 500 mg BID ± imatinib 400 mg QD until progression, unacceptable toxicity, or patient's refusal. The primary endpoint was progression-free survival rate at 9 months (PFS-9). Between September 2009 and February 2012, 15 patients were randomized to receive HU + imatinib (N = 7; Arm A) or HU alone (N = 8; Arm B). Afterward the trial was prematurely closed due to slow enrollment rate. PFS-9 (A/B) was 0/75%, and median PFS was 4/19.5 months. Median and 2-year overall survival (A/B) rates were: 6/27.5 months; 28.5/75%, respectively. Main G3-4 toxicities were: G3 neutropenia in 1/0, G4 headache in 1/1, and G3 vomiting in 1/0. The conduction of a study in recurrent or progressive meningioma remains a challenge. Given the limited number of patients enrolled, no firm conclusions can be drawn about the combination of imatinib and HU. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified.

  2. Amphiphilic lipid derivatives of 3'-hydroxyurea-deoxythymidine: preparation, properties, molecular self-assembly, simulation and in vitro anticancer activity.

    Science.gov (United States)

    Li, Miao; Qi, Shuo; Jin, Yiguang; Yao, Weishang; Zhang, Sa; Zhao, Jingyu

    2014-11-01

    Lipid derivatives of nucleoside analogs and their nanoassemblies have become the research hotspot due to their unique function in cancer therapy. Six lipid derivatives of 3'-hydroxyurea-deoxythymidine were prepared with zidovudine as the raw material. The 5'-substituted lipid chains in the derivatives were from the various fatty acids including octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid and octadecanoic acid corresponding to the derivatives OHT, DHT, DDHT, TDHT, HDHT and ODHT. The amphiphilic derivatives formed Langmuir monolayers at the air/water interface with different surface pressure-molecular area isotherms depending on the length of lipid chains. The nanoassemblies of OHT, DHT, DDHT, TDHT and HDHT and the nanoscale precipitates of ODHT were obtained after we injected their tetrahydrofuran solutions doped with hydrophilic long chained polymers into water. Electron microscopy showed that the morphology of nanoassemblies may be vesicles or nanotubes depending on the length of lipid chains. The shorter the lipid chains were, the softer the nanoassemblies. Computer simulation supported the experimental results. The nanoassemblies and the nanoscale precipitates showed much higher anticancer effects on SW620 cells than the parent drug hydroxyurea. The nanostructures of the derivatives are promising anticancer nanomedicines. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Differential effects of collagen prolyl 3-hydroxylation on skeletal tissues.

    Directory of Open Access Journals (Sweden)

    Erica P Homan

    2014-01-01

    Full Text Available Mutations in the genes encoding cartilage associated protein (CRTAP and prolyl 3-hydroxylase 1 (P3H1 encoded by LEPRE1 were the first identified causes of recessive Osteogenesis Imperfecta (OI. These proteins, together with cyclophilin B (encoded by PPIB, form a complex that 3-hydroxylates a single proline residue on the α1(I chain (Pro986 and has cis/trans isomerase (PPIase activity essential for proper collagen folding. Recent data suggest that prolyl 3-hydroxylation of Pro986 is not required for the structural stability of collagen; however, the absence of this post-translational modification may disrupt protein-protein interactions integral for proper collagen folding and lead to collagen over-modification. P3H1 and CRTAP stabilize each other and absence of one results in degradation of the other. Hence, hypomorphic or loss of function mutations of either gene cause loss of the whole complex and its associated functions. The relative contribution of losing this complex's 3-hydroxylation versus PPIase and collagen chaperone activities to the phenotype of recessive OI is unknown. To distinguish between these functions, we generated knock-in mice carrying a single amino acid substitution in the catalytic site of P3h1 (Lepre1(H662A . This substitution abolished P3h1 activity but retained ability to form a complex with Crtap and thus the collagen chaperone function. Knock-in mice showed absence of prolyl 3-hydroxylation at Pro986 of the α1(I and α1(II collagen chains but no significant over-modification at other collagen residues. They were normal in appearance, had no growth defects and normal cartilage growth plate histology but showed decreased trabecular bone mass. This new mouse model recapitulates elements of the bone phenotype of OI but not the cartilage and growth phenotypes caused by loss of the prolyl 3-hydroxylation complex. Our observations suggest differential tissue consequences due to selective inactivation of P3H1 hydroxylase

  4. Low and fixed dose of hydroxyurea is effective and safe in patients with HbSβ(+) thalassemia with IVS1-5(G→C) mutation.

    Science.gov (United States)

    Dehury, Snehadhini; Purohit, Prasanta; Patel, Siris; Meher, Satyabrata; Kullu, Bipin Kishore; Sahoo, Lulup Kumar; Patel, Nayan Kumar; Mohapatra, Alok Kumar; Das, Kishalaya; Patel, Dilip Kumar

    2015-06-01

    Despite compelling evidence that hydroxyurea is safe and effective in sickle cell disease, it is prescribed sparingly due to several barriers like knowledge gaps in certain genotypes, apprehension about its safety and toxicity, and limited resources. We undertook this study to find out the efficacy and safety of HU in patients with HbSβ(+) -thalassemia with IVS1-5(G→C) mutation. We registered 318 patients with HbSβ(+) -thalassemia with IVS1-5(G→C) mutation. Of these, 203 were enrolled for hydroxyurea treatment at a low and fixed dose of 10 mg/kg/day. One hundred four patients (Group-I: 37 children and Group-II: 67 adults) with ≥2 years of hydroxyurea treatment were studied. The rate of vaso-occlusive crises, requirement of blood transfusion and rate of hospitalization reduced from 3 to 0.5, 1 to 0 and 1 to 0 in Group-I and 3 to 0, 1 to 0 and 0.5 to 0 in Group-II respectively after HU therapy (P hydroxyurea is suitable for treatment of patients with HbSβ(+) -thalassemia in resource poor setting. © 2014 Wiley Periodicals, Inc.

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

    Science.gov (United States)

    Edesa, Wael Abdelgawad; Abdel-malek, Raafat Ragaey

    2015-06-01

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

  6. Radiation plus adjuvant CCNU (1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea) vs CCNU, hydroxyurea and vincristine in the treatment of malignant glioma

    International Nuclear Information System (INIS)

    Costanza, M.; Buechler, M.; Munzenreider, J.

    1979-01-01

    Following maximal surgery, 25 patients with malignant glioma were randomized to receive either radiation therapy and CCNU or radiation therapy and CCNU, hydroxyurea, and vincristine. Radiation therapy included 4000 rad to whole brain followed by 1500 rad to the primary. Chemotherapy was either: CCNU alone 130 mg/m 2 PO every 6 weeks or triple drug chemotherapy given in 6 week cycles of CCNU 90 mg/m 2 PO (one dose), vincristine 1 mg/m 2 IV (one dose), and hydroxyurea 1.5 gm/m 2 PO every 3 days x 7 doses. Thirteen patients received CCNU alone. Of these, 8 are dead, 2 are alive with progressive disease and 3 are alive with stable disease at 10, 22, and 23 months. Median survival is 10 months. Twelve patients received CCNU, vincristine and hydroxyurea. Of these, 8 are dead, 1 is alive with progressive disease and 3 are stable. Median survival is 9.5 months +. Toxicity included nausea, which was common, leukopenia < 3000 in 7 patients and thrombocytopenia in 9 patients. There were no episodes of bleeding or infection attributable to chemotherapy. Although toxicity was tolerable, no additional benefit could be demonstrated for triple agent chemotherapy with CCNU, vincristine and hydroxyurea compared to CCNU alone. Median survival for both groups was similar at 42 to 44 weeks

  7. Hydroxyurea responsiveness in β-thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity

    NARCIS (Netherlands)

    F. Pourfarzad, F. (Farzin); M.M. von Lindern (Marieke); A. Azarkeivan (Azita); J. Hou (Jun); S.K. Kia; F. Esteghamat (Fatemehsadat); W.F.J. van IJcken (Wilfred); J.N.J. Philipsen (Sjaak); H. Najmabadi (Hossein); F.G. Grosveld (Frank)

    2013-01-01

    textabstractβ-thalassemia is caused by mutations in the β-globin locus resulting in loss of, or reduced, hemoglobin A (adult hemoglobin, HbA, α2β2) production. Hydroxyurea treatment increases fetal γ-globin (fetal hemoglobin, HbF, α2γ2) expression in postnatal life substituting for the missing adult

  8. Hydroxyurea responsiveness in β-thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity

    NARCIS (Netherlands)

    Pourfarzad, Farzin; von Lindern, Marieke; Azarkeivan, Azita; Hou, Jun; Kia, Sima Kheradmand; Esteghamat, Fatemehsadat; van Ijcken, Wilfred; Philipsen, Sjaak; Najmabadi, Hossein; Grosveld, Frank

    2013-01-01

    β-thalassemia is caused by mutations in the β-globin locus resulting in loss of, or reduced, hemoglobin A (adult hemoglobin, HbA, α2β2) production. Hydroxyurea treatment increases fetal γ-globin (fetal hemoglobin, HbF, α2γ2) expression in postnatal life substituting for the missing adult β-globin

  9. KLF10 gene expression is associated with high fetal hemoglobin levels and with response to hydroxyurea treatment in β-hemoglobinopathy patients

    NARCIS (Netherlands)

    Borg, Joseph; Phylactides, Marios; Bartsakoulia, Marina; Tafrali, Christina; Lederer, Carsten; Felice, Alexander E.; Papachatzopoulou, Adamantia; Kourakli, Alexandra; Stavrou, Eleana F.; Christou, Soteroula; Hou, Jun; Karkabouna, Sophia; Lappa-Manakou, Christina; Ozgur, Zeliha; van Ijcken, Wilfred; von Lindern, Marieke; Grosveld, Frank G.; Georgitsi, Marianthi; Kleanthous, Marina; Philipsen, Sjaak; Patrinos, George P.

    2012-01-01

    In humans, fetal hemoglobin (HbF) production is controlled by many intricate mechanisms that, to date, remain only partly understood. Pharmacogenomic analysis of the effects of hydroxyurea (HU) on HbF production was undertaken in a collection of Hellenic β-thalassemia and sickle cell disease (SCD)

  10. A sequential analysis of meiosis in the male mouse using a restricted spermatocyte population obtained by a hydroxyurea/triaziquone treatment

    NARCIS (Netherlands)

    Oud, J. L.; de Jong, J. H.; de rooij, D. G.

    1979-01-01

    A method is described to restrict the spermatocyte population in mice and other rodents using hydroxyurea (HU) and triaziquone (T). HU affects cells in S-phase, whereas T is an agent especially active on spermatogonia and not on spermatocytes. An application of three i.p. HU injections with 12 h

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

    Directory of Open Access Journals (Sweden)

    Wael Abdelgawad Edesa

    2015-06-01

    Conclusion: Duration of prior hydroxyurea had no impact on response or progression free survival, while patients regular on imatinib had statistically significant difference with respect to major molecular response, complete molecular response and progression free survival compared to those who had periods of drug interruption, thus we need more governmental support to supply the drug without interruption to improve the outcome of therapy.

  12. Hydroxyl-dependent Evolution of Oxygen Vacancies Enables the Regeneration of BiOCl photocatalyst

    KAUST Repository

    Wu, Sujuan; Xiong, Jiawei; Sun, Jianguo; Hood, Zachary D.; Zeng, Wen; Yang, Zhenzhong; Gu, Lin; Zhang, Xixiang; Yang, Shize

    2017-01-01

    irradiation in the sample with surface hydroxyl groups, while variable changes were observed in samples without surface hydroxyls. Density functional theory (DFT) calculations reveal that the binding energy of Bi-O is drastically influenced by surficial

  13. Trimeric Hydrogen Bond in Geometrically Frustrated Hydroxyl Cobalt Halogenides

    International Nuclear Information System (INIS)

    Xiao-Dong, Liu; Masato, Hagihala; Xu-Guang, Zheng; Dong-Dong, Meng; Wan-Jun, Tao; Sen-Lin, Zhang; Qi-Xin, Guo

    2011-01-01

    The mid-infrared absorption spectra of geometrically frustrated hydroxyl cobalt halogenides Co 2 (OH) 3 Cl and Co 2 (OH) 3 Br are measured by FTIR spectrometers, and the stretching vibrational modes of hydroxyl groups are found to be 3549cm −1 and 3524cm −1 respectively. Through finding their true terminal O-H group stretching vibration frequencies, we obtain 107cm −1 and 99cm −1 red shift caused by the corresponding O-H···Cl and O-H···Br hydrogen bonds. Rarely reported trimeric hydrogen bonds (Co 3 ≡O-H) 3 ···Cl/Br are pointed out to demonstrate the relative weakness of this kind of hydrogen bond which may have a critical effect on the lattice symmetry and magnetic structures. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

  14. On the spatial coincidence of hydroxyl and methanol masers

    Science.gov (United States)

    Hartquist, T. W.; Menten, K. M.; Lepp, S.; Dalgarno, A.

    1995-01-01

    We argue that purely gas-phase chemical models for the production of OH in hydroxyl masers around ultracompact H II regions such as W3(OH) cannot account for the CH_3OH in the methanol masers that are found to coincide with the hydroxyl masers in these sources. We suggest that the CH_3OH in the masers is injected into the gas phase by evaporation of the grain mantles, the grains being heated by the passage of weak shocks. Gas evaporation also injects H_2O into the gas. Photodissociation of H_2O, CH_3OH and OH occur at similar rates, and substantial abundances of CH_3OH and OH coexist.

  15. The Influence of Hydroxylated Carbon Nanotubes on Epoxy Resin Composites

    Directory of Open Access Journals (Sweden)

    Jiaoxia Zhang

    2012-01-01

    Full Text Available Hydroxylated multiwall carbon nanotubes (MWNTs/epoxy resin nanocomposites were prepared with ultrasonic dispersion and casting molding. The effect of hydroxylated MWNTs content on reactive activity of composites is discussed. Then the flexural and electrical properties were studied. Transmission electron microscope was employed to characterize the microstructure of nanocomposites. As a result, the reactive activity of nanocomposites obtained increases with the increasing content of MWNTs. When MWNTs content of the composites is 1 wt%, as compared to neat resin, the flexural strength increases from 143 Mpa to 156 MPa, the modulus increases from 3563 Mpa to 3691 MPa, and the volume and surface resistance of nanocomposites decrease by two orders of magnitude, respectively.

  16. Novel denture-cleaning system based on hydroxyl radical disinfection.

    Science.gov (United States)

    Kanno, Taro; Nakamura, Keisuke; Ikai, Hiroyo; Hayashi, Eisei; Shirato, Midori; Mokudai, Takayuki; Iwasawa, Atsuo; Niwano, Yoshimi; Kohno, Masahiro; Sasaki, Keiichi

    2012-01-01

    The purpose of this study was to evaluate a new denture-cleaning device using hydroxyl radicals generated from photolysis of hydrogen peroxide (H2O2). Electron spin resonance analysis demonstrated that the yield of hydroxyl radicals increased with the concentration of H2O2 and light irradiation time. Staphylococcus aureus, Pseudomonas aeruginosa, and methicillin-resistant S aureus were killed within 10 minutes with a > 5-log reduction when treated with photolysis of 500 mM H2O2; Candida albicans was killed within 30 minutes with a > 4-log reduction with photolysis of 1,000 mM H2O2. The clinical test demonstrated that the device could effectively reduce microorganisms in denture plaque by approximately 7-log order within 20 minutes.

  17. Efecto de la hidroxiurea en hemoglobina S Effect of hydroxyurea on hemoglobin S

    Directory of Open Access Journals (Sweden)

    A. Feliu Torres

    2003-04-01

    Full Text Available Estudios preliminares han determinado las modificaciones en la clínica, el laboratorio y la toxicidad del tratamiento con hidroxiurea (HU en pacientes con drepanocitosis y complicaciones clínicas severas. Se presenta la eficacia del tratamiento con HU en la prevención de las crisis vaso-oclusivas en un niño de 11 años de edad con drepanocitosis y manifestaciones graves. El número de crisis vaso-oclusivas, los días de internación y el número de transfusiones en el año previo al inicio del tratamiento con HU fueron comparados con los mismos parámetros a 6,12, 24, 36 y 72 meses de tratamiento. Se observó una disminución en la frecuencia de las crisis vaso-oclusivas, las transfusiones y los días de internación durante el tratamiento con HU comparado con el período previo. Las respuestas clínica y de laboratorio obtenidas le permitieron al paciente su inserción escolar y social. Los efectos adversos fueron leves y revirtieron al suspender la HU transitoriamente. Concluimos que el tratamiento crónico con HU en pacientes con drepanocitosis y manifestaciones graves parece posible y libre de efectos tóxicos serios.Previous studies have determined the laboratory alterations, clinical efficacy and toxicity profile associated with hydroxyurea (HU therapy in patients with severe sickle cell anemia. We report the efficacy of HU treatment in the prevention of vaso-occlusive crises in an 11-years-old boy with severe sickle cell disease. The number of vaso-occlusive crises, hospital days and blood transfusions in the year before HU treatment were compared with the same parameters at 6,12, 24, 36 and 72 months of treatment. A decrease in the frequency of vaso-occlusive crises, blood transfusions and days spent in hospital were demonstrated during the HU treatment period compared to the same period before hand. The clinical and laboratory response to HU was dramatic in this severely affected patient, allowing him a normal schooling and social

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

    International Nuclear Information System (INIS)

    Edesa, W.A.; Abdel-malek, R.R.

    2015-01-01

    Background: Optimal response requires that patients should be maintained on the drug continuously. Objectives: To evaluate the influence of imatinib interruption and prior hydroxyurea use on the outcome of patients with chronic myeloid leukemia. Materials and methods: Between January 2010 and November 2013, patients with chronic phase who received imatinib at the Kasr Al-ainy Center of Clinical Oncology were included. Results: Sixty patients were included in this study, thirty three patients (55%) received imatinib upfront, while 27 (45%) received imatinib post hydroxyurea. Imatinib was not given regularly in 50% of patients. In terms of response, only major molecular response and complete molecular response were statistically significant in favor of patients who were receiving imatinib regularly compared to those who had interruption (ρ < 0.001, ρ < 0.001, respectively) , while there was no difference in patients stratified according to prior hydroxyurea. The median progression free survival was 30.3 months (95% CI 24.3–36.3). Among the group of patients who received imatinib regularly, progression free survival was longer (ρ = 0.049), there was no difference between those who received prior hydroxyurea versus those who did not (ρ = 0.67). Conclusion: Duration of prior hydroxyurea had no impact on response or progression free survival, while patients regular on imatinib had statistically significant difference with respect to major molecular response, complete molecular response and progression free survival compared to those who had periods of drug interruption, thus we need more governmental support to supply the drug without interruption to improve the outcome of therapy

  19. The Haber Process Made Efficient by Hydroxylated Graphene

    OpenAIRE

    Chaban, Vitaly; Prezhdo, Oleg

    2016-01-01

    The Haber-Bosch process is the main industrial method for producing ammonia from diatomic nitrogen and hydrogen. Very demanding energetically, it uses an iron catalyst, and requires high temperature and pressure. Any improvement of the Haber process will have an extreme scientific and economic impact. We report a significant increase of ammonia production using hydroxylated graphene. Exploiting the polarity difference between N2/H2 and NH3, as well as the universal proton acceptor behavior of...

  20. Structure, electronic properties, and aggregation behavior of hydroxylated carbon nanotubes

    Energy Technology Data Exchange (ETDEWEB)

    López-Oyama, A. B.; Silva-Molina, R. A.; Ruíz-García, J.; Guirado-López, R. A., E-mail: guirado@ifisica.uaslp.mx [Instituto de Física “Manuel Sandoval Vallarta,” Universidad Autónoma de San Luis Potosí, Álvaro Obregón 64, 78000 San Luis Potosí, San Luis Potosí (Mexico); Gámez-Corrales, R. [Departamento de Física, Universidad de Sonora, Apartado Postal 5-088, 83190, Hermosillo, Sonora (Mexico)

    2014-11-07

    We present a combined experimental and theoretical study to analyze the structure, electronic properties, and aggregation behavior of hydroxylated multiwalled carbon nanotubes (OH–MWCNT). Our MWCNTs have average diameters of ∼2 nm, lengths of approximately 100–300 nm, and a hydroxyl surface coverage θ∼0.1. When deposited on the air/water interface the OH–MWCNTs are partially soluble and the floating units interact and link with each other forming extended foam-like carbon networks. Surface pressure-area isotherms of the nanotube films are performed using the Langmuir balance method at different equilibration times. The films are transferred into a mica substrate and atomic force microscopy images show that the foam like structure is preserved and reveals fine details of their microstructure. Density functional theory calculations performed on model hydroxylated carbon nanotubes show that low energy atomic configurations are found when the OH groups form molecular islands on the nanotube's surface. This patchy behavior for the OH species is expected to produce nanotubes having reduced wettabilities, in line with experimental observations. OH doping yields nanotubes having small HOMO–LUMO energy gaps and generates a nanotube → OH direction for the charge transfer leading to the existence of more hole carriers in the structures. Our synthesized OH–MWCNTs might have promising applications.

  1. Regioselective hydroxylation of isoflavones by Streptomyces avermitilis MA-4680.

    Science.gov (United States)

    Roh, Changhyun; Seo, Su-Hyun; Choi, Kwon-Young; Cha, Minho; Pandey, Bishnu Prasad; Kim, June-Hyung; Park, Jun-Seong; Kim, Duck Hee; Chang, Ih Seop; Kim, Byung-Gee

    2009-07-01

    Screening of bacterial whole cells was performed for regioselective hydroxylation of daidzein and genistein. Among the strains examined, Streptomyces avermitilis MA-4680 showed high ortho-dihydroxylation activity to produce 3',4',7-trihydroxyisoflavone and 3',4',5,7-tetrahydroxyisoflavone from daidzein (4',7-dihydroxyisoflavone) and genistein (4',5,7-trihydroxyisoflavone), respectively. Using 100 mg cells (wet wt.) and 1% (v/v) Triton X100 in 1 ml of total reaction volume, where 100 microl of the substrate solution (0.5 mM in 10% (v/v) mixed solvent of DMSO:MeOH = 3:7) was added to 900 microl of potassium phosphate buffer (100 mM, pH 7.2), a 16% molar conversion yield of 3',4',7-trihydroxyisoflavone was obtained from 0.5 mM daidzein after 24 h of reaction time at 28 degrees C and 200 rpm. Ketoconazole significantly (ca. 90%) inhibited the ortho-hydroxylation activity of daidzein, suggesting that cytochrome P450 enzymes putatively play roles in regiospecific daidzein hydroxylation. The analysis of the reaction products was determined by gas chromatography/mass spectrometry (GC/MS) and (1)H NMR.

  2. Synthesis and properties evaluation of sulfobetaine surfactant with double hydroxyl

    Science.gov (United States)

    Zhou, Ming; Luo, Gang; Zhang, Ze; Li, Sisi; Wang, Chengwen

    2017-09-01

    A series of sulfobetaine surfactants {N-[(3-alkoxy-2-hydroxyl)propoxy] ethyl-N,N-dimethyl-N-(2-hydroxyl)propyl sulfonate} ammonium chloride were synthesized with raw materials containing linear saturated alcohol, N,N-dimethylethanolamine, sodium 3-chloro-2-hydroxyl propane sulfonic acid and epichlorohydrin. The molecule structures of sulfobetaine surfactants were characterized by FTIR, 1HNMR and elemental analysis. Surface tension measurements can provide us information about the surface tension at the CMC (γCMC), pC20, Γmax and Amin. The pC20 values of sulfobetaine surfactants increase with the hydrophobic chain length increasing. Amin values of the surfactants decrease with increasing hydrophobic chain length from 10 to 14. The critical micelle concentration (CMC) and surface tension (γCMC) values of the sulfobetaine surfactants decrease with increasing hydrophobic chain length from 10 to 16. The lipophilicity of surfactant was enhanced with the increase of the carbon chain, however, the ability of anti-hard water was weakened. The minimum oil/water interfacial tension of four kinds of sulfobetaine surfactants is 10-2-10-3 mN/m magnitude, which indicates that the synthesized bis-hydroxy sulfobetaine surfactants have a great ability to reduce interfacial tension in the surfactant flooding system. The surface tension (γCMC) values of synthesized surfactants were lower compared with conventional anionic surfactant sodium dodecyl sulfonate.

  3. Tratamiento con dosis moderada de hidroxiurea en la drepanocitosis Treatment with moderate doses of hydroxyurea in drepanocytosis

    Directory of Open Access Journals (Sweden)

    Sergio Machín García

    2008-08-01

    Full Text Available En el período comprendido entre junio del 2003 y junio del 2005 se trataron con hidroxiurea 45 pacientes con anemia drepanocítica; 16 niños y 29 adultos, al menos con una de las manifestaciones siguientes: más de 3 crisis vasooclusivas (CVO dolorosas al año en los 3 años previos al estudio, uno o más episodios de síndrome torácico agudo (STA al año en los 2 años previos al estudio, o accidente vascular encefálico (AVE en el año anterior. La hidroxiurea se administró en dosis de 15mg/kg/día. El número de CVO dolorosas, STA, AVE, ingresos y transfusiones disminuyó significativamente (pFrom June 2003 to June 2005, 45 patients with drepanocytic anemia, 16 children and 29 adults, with at least one of the following manifestations were treated with hydroxyurea: more than 3 painful vasoocclusive crises (VOC at a year and 3 years before the study, one or more episodes of acute thoracic syndrome (ATS at a year and 2 years previous to the study, or vascular encephalic accident (VEA in the previous year. Hydroxyurea was administered at doses of 15mg/kg/day. The number of painful VOC, ATS, VEA, admissions and transfusions decreased significantly (p<0.001. There was not either reduction of the hematological parameters or increase of creatinin or alanine aminotransferase. An important rise of fetal hemoglobin values (p<0.008 was reported. There were no toxic manifestations and the fulfilment was good. It was proved in this paper that it is not necessary to take the maximum tolerated dose of hydroxyurea to improve the clinical picture in drepanocytic anemia. Two of its advantages are its lower toxicity and the less expensive treatment. This would make possible that a greater amount of children in those countries with scarce resources may benefit from the treatment.

  4. Secondary benefit of maintaining normal transcranial Doppler velocities when using hydroxyurea for prevention of severe sickle cell anemia.

    Science.gov (United States)

    Ghafuri, Djamila Labib; Chaturvedi, Shruti; Rodeghier, Mark; Stimpson, Sarah-Jo; McClain, Brandi; Byrd, Jeannie; DeBaun, Michael R

    2017-07-01

    In a retrospective cohort study, we tested the hypothesis that when prescribing hydroxyurea (HU) to children with sickle cell anemia (SCA) to prevent vaso-occlusive events, there will be a secondary benefit of maintaining low transcranial Doppler (TCD) velocity, measured by imaging technique (TCDi). HU was prescribed for 90.9% (110 of 120) of children with SCA ≥5 years of age and followed for a median of 4.4 years, with 70% (n = 77) receiving at least one TCDi evaluation after starting HU. No child prescribed HU had a conditional or abnormal TCDi measurement. HU initiation for disease severity prevention decreases the prevalence of abnormal TCDi velocities. © 2016 Wiley Periodicals, Inc.

  5. Can hydroxyurea serve as a free radical scavenger and reduce iron overload in β-thalassemia patients?

    Science.gov (United States)

    Italia, Khushnooma; Chandrakala, S; Ghosh, Kanjaksha; Colah, Roshan

    2016-09-01

    In this study, we hypothesize that hydroxyurea could provide an additional benefit as a free radical scavenger and/or iron chelator in β-thalassemia patients with iron overload. Twenty-one β-thalassemia intermedia patients who presented between 3 and 17 years but later required regular blood transfusions were enrolled for hydroxyurea therapy for a year. Fourteen patients responded to the therapy with hemoglobin levels maintained above 7.5 g/dl without transfusions. Hydroxyurea was discontinued after 6 months in seven patients who did not respond to the therapy and had to be continued on regular blood transfusions. We observed a statistically significant decrease in serum ferritin levels from 4194 ± 4850 ng/ml to 2129 ± 2380 ng/ml among the responders and from 2955 ± 2909 ng/ml to 2040 ± 2432 ng/ml among the non-responders and statistically significant decrease in labile iron pool from 18678.7 ± 10067.4 mean fluorescence intensity (MFI) to 14888.5 ± 5284.0 MFI among responders and from 17986.3 ± 9079.8 MFI to 15634.8 ± 8976.9 MFI among the non-responders after therapy. Phosphatidylserine externalization also showed a statistically significant decrease from 44.2 ± 22.2 MFI to 16.6 ± 6.7 MFI among the responders and from 46.9 ± 33.1 MFI to 39.8 ± 7.4 MFI among the non-responders along with a statistically significant decrease in the levels of reactive oxygen species from 72.8 ± 35.5 MFI to 29.0 ± 8.3 MFI among the responders and from 80.9 ± 41.4 MFI to 40.5 ± 15.8 MFI among the non-responders after therapy. A statistically significant increase in reduced glutathione levels was also observed from 430.8 ± 201.1 MFI to 715.5 ± 292.4 MFI among the responders and from 359.6 ± 165.6 MFI to 450.3 ± 279.5 MFI among the non-responders after therapy. This suggests the possible additional role of hydroxyurea as a free radical scavenger and

  6. Simultaneous production of buds on mother and daughter cells of Saccharomyces cerevisiae in the presence of hydroxyurea

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, K; Michio, I

    1979-12-01

    Individual budding yeast cells, Saccharomyces cerevisiae, enclosed in small culture chambers were observed through two budding cycles to examine their behavior during growth and division. In the nutrient medium (YHG medium), the duration of the budding cycles was 77 minutes for mother cells and 90 minutes for daughter cells. Continuous exposure of cells to 16 or 32 mm hydroxyurea extended the duration of the cycles and increased the volume of cells, resulting in the formation of abnormally large and equal-sized mother-daughter pairs. Each cell of these pairs subsequently produced buds simultaneously. Stained cell nuclei showed simultaneous nuclear division. This synchronous budding on mother-daughter pairs was repeated in the next budding cycle. The coordination of growth with division is discussed in relation to these results.

  7. Hydroxyurea prescription, availability and use for children with sickle cell disease in Italy: Results of a National Multicenter survey.

    Science.gov (United States)

    Colombatti, Raffaella; Palazzi, Giovanni; Masera, Nicoletta; Notarangelo, Lucia Dora; Bonetti, Elisa; Samperi, Piera; Barone, Angelica; Perrotta, Silverio; Facchini, Elena; Miano, Maurizio; Del Vecchio, Giovanni Carlo; Guerzoni, Maria Elena; Corti, Paola; Menzato, Federica; Cesaro, Simone; Casale, Maddalena; Rigano, Paolo; Forni, Gian Luca; Russo, Giovanna; Sainati, Laura

    2018-02-01

    The number of patients with sickle cell disease (SCD) has increased in Italy in the past decade due to immigration. In spite of the established efficacy of hydroxyurea (HU) in childhood, population-based data regarding its prescription and effectiveness come mainly from studies performed in adults or outside Europe. The Hydroxyurea in SCD: A Large Nation-wide Cohort Study from Italy was a retrospective cohort study of adult and pediatric patients with SCD attending 32 centers. Pediatric data are analyzed separately. Out of 504 children followed in 11 centers, 206 (40%) were on HU (194 SS/Sβ°, 12 SC/Sß+); 74% came from Sub-Saharian Africa and 18% from Europe. HU therapy indications for SS/Sβ° patients were as follows: 57% painful vaso-occlusive crisis, acute chest syndrome or both, 24% anemia, 8% anemia, and other reasons (the majority had Hb ≤ 8-8.5 g/dl, revealing scarce acceptance of low Hb values by pediatric hematologist). Mean starting dose was 15.5 mg/kg, and dose at full regimen was 17.1 mg/kg. Mean age at HU therapy was 7.68 years, although it was lower for SS/Sβ° patients. Only 10% started HU before 3 years. In 92%, 500 mg capsule was used; in 6%, the galenic was used; and in 2%, 100 mg tablet was used. Significant reduction of clinical events and inpatients admissions, with improvement in hematological parameters, was observed for SS/Sβ° patients and a trend toward improvement for SC/Sß+ patients was also observed. HU effectiveness is demonstrated in a national cohort of children with SCD living in Italy, even at a lower dose than recommended, revealing good adherence to a treatment program by a socially vulnerable group of patients such as immigrants. © 2017 Wiley Periodicals, Inc.

  8. The interaction of hydroxyurea and ionizing radiation in human cervical carcinoma cells.

    Science.gov (United States)

    Kuo, M L; Kunugi, K A; Lindstrom, M J; Kinsella, T J

    1997-01-01

    The results from prior in vitro and in vivo studies and recent phase 3 clinical trials suggest a significant potential role for hydroxyurea (HU) as a clinical radiosensitizer for cervix cancer. However, a detailed study of possible cellular mechanisms of radiosensitization in human cervix cancer cells as a consequence of dose and timing of HU and ionizing radiation (IR) has not been performed. This in vitro study analyses the interactions of HU and IR in a human cervical carcinoma cell line, Caski. Exponentially growing Caski cells were continuously exposed to clinically achievable but minimally cytotoxic concentrations of HU (0.3-3.0 mM) for various time intervals (6, 12, 18, 24, and 30 hours) up to one population doubling time either prior to or immediately following IR (2-8 Gy). The radiation survival data were analyzed using our modification of the linear-quadratic model to test for an interaction (greater than additive). The effects of HU alone, IR alone, and the combination on cell cycle progression and on apoptotic cell death in exponentially growing Caski cells were measured. We report a significant HU-IR interaction (radiosensitization) based on the sequence of HU exposure (post- > pre-IR) and with increasing concentrations of HU (0.3-3.0 mM), but no effect on radiosensitization with the duration of exposure to HU for up to one cell population doubling (6-30 hours). HU concentration has a significant effect on both alpha and beta linear-quadratic values in the post-IR sequences. Exposures of exponentially growing Caski cells to 1 mM and 3 mM HU alone result in a complete block in early S phase throughout the 30-hour exposure, while 0.3 mM HU causes a transient early S-phase block over the initial 12 to 18 hours of exposure. HU alone has no effect on cell cycle progression in G1 or G2/M populations but results in a large apoptotic population (31% following 1 mM HU x 30 hours), which appears to be the principal mechanism of drug cytotoxicity in these cells

  9. Virus-induced polyclonal T cell activation is followed by apoptosis: partitioning of CD8+ T cells based on alpha 4 integrin expression

    DEFF Research Database (Denmark)

    Christensen, Jan Pravsgaard; Röpke, C; Thomsen, Allan Randrup

    1996-01-01

    that LCMV-induced activation of T cells is followed by apoptosis of many of the activated cells. Those CD8+VLA-4hi cells which do persist in LCMV immune mice are more sensitive to treatment with the cell-cycle-specific drug hydroxyurea than are phenotypically naive T cells. Our results therefore indicate...

  10. Anticancer system created by acrolein and hydroxyl radical generated in enzymatic oxidation of spermine and other biochemical reactions.

    Science.gov (United States)

    Alarcon, R A

    2012-10-01

    A hypothesis suggesting the existence of a ubiquitous physiological anticancer system created by two highly reactive oxidative stress inducers with anticancer properties, acrolein and hydroxyl radical, is reported in this communication. Both components can originate separately or together in several biochemical interactions, among them, the enzymatic oxidation of the polyamine spermine, which appear to be their main source. The foundations of this hypothesis encompass our initial search for growth-inhibitors or anticancer compounds in biological material leading to the isolation of spermine, a polyamine that became highly cytotoxic through the generation of acrolein, when enzymatically oxidized. Findings complemented with pertinent literature data by other workers and observed anticancer activities by sources capable of producing acrolein and hydroxyl radical. This hypothesis obvious implication: spermine enzymatic oxidations or other biochemical interactions that would co-generate acrolein and hydroxyl radical, the anticancer system components, should be tried as treatments for any given cancer. The biochemical generation of acrolein observed was totally unexpected, since this aldehyde was known; as a very toxic and highly reactive xenobiotic chemical produced in the pyrolysis of fats and other organic material, found as an atmospheric pollutant, in tobacco smoke and car emissions, and mainly used as a pesticide or aquatic herbicide. Numerous studies on acrolein, considered after our work a biological product, as well, followed. In them, acrolein widespread presence, its effects on diverse cellular proteins, such as, growth factors, and its anticancer activities, were additionally reported. Regarding hydroxyl radical, the second component of the proposed anticancer system, and another cytotoxic product in normal cell metabolism, it co-generates with acrolein in several biochemical interactions, occurrences suggesting that these products might jointly fulfill some

  11. Determining the local origin of hydroxyl radical generation during phacoemulsification.

    Science.gov (United States)

    Aust, Steven D; Terry, Scott; Hebdon, Thomas; Gunderson, Broc; Terry, Michael; Dimalanta, Ramon

    2011-06-01

    To determine the local origin of hydroxyl radicals during phacoemulsification using an ultrasonic phacoemulsification device that includes longitudinal and torsional modalities. Chemistry and Biochemistry Department, Utah State University, Logan, Utah, USA. Experimental study. Experiments were conducted using the Infiniti Vision System and Ozil handpiece. Hydroxyl radical concentrations during longitudinal and torsional phacoemulsification were quantitated as malondialdehyde (MDA) determined spectrophotometrically using the deoxyribose assay. The difference between the total concentration found in the aspirated solution at steady-state concentrations and the pre-aspirate levels deductively determined the concentration of MDA formed along the interior of the sonicating tip. The time to reach 50% of steady state as a function of reaction vessel volume was determined. The mean maximum for torsional ultrasound at 100% amplitude was 7.70 nM ± 0.38 (SD), 91.1% of which was generated outside the tip. During longitudinal ultrasound at 100% power, MDA concentration in the aspirated solution was 29.5 ± 0.3 nM, 71.6% of which was generated outside the tip. The time (seconds) to reach 50% of maximum for longitudinal ultrasound using 5 mL, 10 mL, and 20 mL reaction vessels was 12.6 ± 1.5, 21.0 ± 1.5, and 25.3 ± 3.4, respectively. Although a significantly greater proportion of the hydroxyl radicals generated during ultrasound modality were formed outside the phaco tip (91.1% torsional; 71.6% longitudinal), torsional ultrasound generated only about one-fourth the amount of MDA as longitudinal ultrasound in total and about one-third that generated outside the tip (7.02 nM versus 21.1 nM). No author has a financial or proprietary interest in any material or method mentioned. Additional disclosures are found in the footnotes. Copyright © 2011 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  12. Formation of Hydroxylamine from Ammonia and Hydroxyl Radicals

    Science.gov (United States)

    Krim, Lahouari; Zins, Emilie-Laure

    2014-06-01

    In the interstellar medium, as well as in icy comets, ammonia may be a crucial species in the first step toward the formation of amino-acids and other prebiotic molecules such as hydroxylamine (NH2OH). It is worth to notice that the NH3/H2 ratio in the ISM is 3 10-5 compared the H2O/H2 one which is only 7 10-5. Using either electron-UV irradiations of water-ammonia ices or successive hydrogenation of solid nitric oxide, laboratory experiments have already shown the feasibility of reactions that may take place on the surface of ice grains in molecular clouds, and may lead to the formation of this precursor. Herein is proposed a new reaction pathway involving ammonia and hydroxyl radicals generated in a microwave discharge. Experimental studies, at 3 and 10 K, in solid phase as well as in neon matrix have shown that this reaction proceed via a hydrogen abstraction, leading to the formation of NH2 radical, that further recombine with hydroxyl radical to form hydroxylamine, under non-energetic conditions.

  13. From cation to oxide: hydroxylation and condensation of aqueous complexes

    International Nuclear Information System (INIS)

    Jolivet, J.P.

    1997-01-01

    Hydroxylation, condensation and precipitation of metal cations in aqueous solution are briefly reviewed. Hydroxylation of aqueous complexes essentially depends on the format charge (oxidation state), the size and the pH of the medium. It is the step allowing the condensation reaction. Depending on the nature of complexes (aqua-hydroxo, oxo-hydroxo), the. mechanism of condensation is different, olation or ox-olation respectively. The first one leads to poly-cations or hydroxides more or less stable against dehydration. The second one leads to poly-anions or oxides. Oligomeric species (poly-cations, poly-anions) are form from charged monomer complexes while the formation of solid phases requires non-charged precursors. Because of their high lability, charged oligomers are never the precursors of solids phases. The main routes for the formation of solid phases from solution are studied with two important and representative elements, Al and Si. For Al 3+ ions, different methods (base addition in solution, thermo-hydrolysis, hydrothermal synthesis) are discussed in relation to the crystal structure of the solid phase obtained. For silicic species condensing by ox-olation, the role of acid or base catalysis on the morphology of gels is studied. The influence of complexing ligands on the processes and on the characteristics of solids (morphology of particles, basic salts and polymetallic oxides formation) is studied. (author)

  14. Hydroxylated ceramic waste forms and the absurdity of leach tests

    Energy Technology Data Exchange (ETDEWEB)

    Roy, R; Odoj, R; Merz, E [eds.

    1981-06-01

    The repository pressure and temperature conditions during the thermal period projected in US repositories have been drastically lowered in the last year or two to new values of say 175 +- 50/sup 0/K. Using the argument that the evidence from natural models indicates the most stable mineral (= ceramic) hosts for radionuclides, one finds that under these new repository conditions such crystalline assemblages would be micas, clays, zeolites and other hydrated minerals, plus the tetravalent anhydrous oxide families. A waste form consisting of specific hydroxylated candidate phases can be made via a simple in-can technology (demonstrated by Oak Ridge) by reacting liquid wastes with precursor gels or phyllo or tektosilicates at <200/sup 0/C under modest pressure within the final disposal canister. The data on the rate of reaction of typical oxide materials to yield hydroxylated phases under these conditions show that the typical leach test (at 25 to 100/sup 0/C in deionized water) does not provide a simulation of the reactions which will occur. Hence such tests are not only totally meaningless with respect to qualifying a waste form for its role in a repository, they can be downright misleading.

  15. Hydroxylated ceramic waste forms and the absurdity of 'leach tests'

    Energy Technology Data Exchange (ETDEWEB)

    Roy, R; Odoj, R; Merz, E [eds.

    1981-06-01

    The repository pressure and temperature conditions during the thermal period projected in U.S. repositories have been drastically lowered in the last year or two to new values of say 175 +- 50 K. Using the argument that the evidence from natural models indicates the most stable mineral (= ceramic) hosts for radionuclides, one finds that under these new repository conditions such crystalline assemblages would be micas, clays, zeolites, and other hydrated minerals, plus the tetravalent anhydrous oxide families. A waste form consisting of specific hydroxylated candidate phase can be made via a simple in-can technology (demonstrated by Oak Ridge) by reacting liquid wastes with precursor gels or phyllo or tektosilicates at <200/sup 0/C under modest pressure within the final disposal canister. The data on the rate of reaction of typical oxide materials to yield hydroxylated phases under these conditions show that the typical leach test (at 25-100/sup 0/C in deionized water) does not provide a simulation of the reactions which will occur. Hence such tests are not only totally meaningless with respect to qualifying a waste form for its role in a repository, they can be downright misleading.

  16. Influence of hydroxyurea on nucleic acids content and 3H-uridine incorporation in callus and tumorous tobacco tissues cultured in vitro

    Directory of Open Access Journals (Sweden)

    A. Bielecka

    2015-01-01

    Full Text Available In callus and tumor tissues of Nicotiana tabacum cultured for 39 days in media supplemented with various concentrations of hydroxyurea (1.3 x 10-4 M - 1.3 x 10-3 M a decrease of DNA content (ca. 24 per cent in callus tissue and ca. 23 per cent in tumour tissue and a decrease of RNA content (over 10 per cent and ca. 9 per cent in callus and tumour tissue, respectively was observed. The autoradiographic method showed that a long-lasting action of this com-pound inhibits RNA synthesis. A stronger inhibitory influence of hydroxyurea upon incorporation of 3H-uridine from the incubation medium was revealed.

  17. Response of resting L5178Y-S and L5178Y-R cells with different radiosensitivity to radiation and hydroxyurea

    International Nuclear Information System (INIS)

    Afanas'ev, G.G.; Shumel', I.; Valitska, M.; Nekokojchitska, Eh.; Beer, Ya. Z.; Pelevina, I.I.

    1981-01-01

    A study was made of cloning capacity of radiosensitive L5178YS and radioresjstant L5J78YR cells of mouse leukaemia suspension culture after X-irradiation and postradiation treatment with hydroxyurea at 37 deg and 34 deg C. It was shown that both cell lines possess a good cloning capacity at the stationary phase of growth; they are more radiosensitive than cells at the logarithmic phase of growth and cannot repair potentially lethal damages either after decreasing the temperature or the administration of h droxyurea. The postradiation treatment with hydroxyurea enhances the effect of radiation by 2 times in the case of R cells, and by 2 and 1.3 times, depending on the incubation temperature, in the case of S cells

  18. Real-life experience with hydroxyurea in sickle cell disease: A multicenter study in a cohort of patients with heterogeneous descent.

    Science.gov (United States)

    Rigano, Paolo; De Franceschi, Lucia; Sainati, Laura; Piga, Antonio; Piel, Frédéric B; Cappellini, Maria Domenica; Fidone, Carmelo; Masera, Nicoletta; Palazzi, Giovanni; Gianesin, Barbara; Forni, Gian Luca

    2018-03-01

    We conducted the first nation-wide cohort study of sickle cell disease (SCD) in Italy, a Southern European country exposed to intense recent flux migration from endemic areas for SCD. We evaluate the impact of hydroxyurea on a total of 652 pediatric and adult patients from 33 Reference Centers for SCD (mean age 24.5±15years, 51.4% males). Hydroxyurea median treatment duration was 7years (range: crisis (-34.1%, p<0.001), hospitalization (-53.2%, p<0.001), and bone necrosis (-6.9%, p<0.001). New silent cerebral infarction (SCI) occurred during treatment (+42.4%, p<0.001) but not stroke (+0.5%, p=0.572). These observations were generally consistent upon stratification for age, descent (Caucasian or African), genotype (βS/βS, βS/β 0 or βS/β + ) and duration of treatment (< or ≥10years). There were no new safety concerns observed compared to those commonly reported in the literature. Our study, conducted on a large population of patients with different descent and compound state supports the benefits of hydroxyurea therapy as a treatment option. Registered at clinical trials.gov (NCT02709681). Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Tissue specificity for incorporation of [3H]thymidine by the 10- to 12-somite mouse embryo: alteration by acute exposure to hydroxyurea

    International Nuclear Information System (INIS)

    Miller, S.A.; Runner, M.N.

    1978-01-01

    Radioautograms from 10- to 12-somite mouse embryos labelled for 30 min in vitro with [ 3 H]thymidine were examined for frequency and intensity of incorporation. Results from ten tissues showed that values ranged from 82% of nuclei with a mean of 16.6 grains for visceral yolk sac to 17% of nuclei labelled with a mean of 4.4 grains for epithelium of the anterior gut tube. Labelling in the ten tissues indicated (1) a tissue-specific spectrum of incorporation of [ 3 H]thymidine, (2) close correlation between frequency and intensity of labelling within a tissue and (3) asymmetrical quantities of incorporation between right and left somatopleure. Treatment with hydroxyurea in vitro reduced the frequency of labelled nuclei by 85% to 17% of control values. Mean numbers of grains over treated nuclei, 3.3 to 4.6 grains, were well above background but were clustered below the low end of the control range. Tissues exposed to hydroxyurea showed (1) labelling of significant numbers of nuclei, (2) inhibition of labelling in selected tissues and (3) equalization of bilateral asymmetry in quantity (frequency and intensity) of incorporation in somatopleure. The selective reduction of thymidine incorporation and equalization of asymmetrical rates of proliferation may constitute mechanisms by which hydroxyurea causes abnormal morphogenesis. (author)

  20. Tuning the Slide-Roll Motion Mode of Carbon Nanotubes via Hydroxyl Groups

    Science.gov (United States)

    Li, Rui; Wang, Shiwei; Peng, Qing

    2018-05-01

    Controlling the motion of carbon nanotubes is critical in manipulating nanodevices, including nanorobots. Herein, we investigate the motion behavior of SWCNT (10,10) on Si substrate utilizing molecular dynamics simulations. We show that hydroxyl groups have sensitive effect on the carbon nanotube's motion mode. When the hydroxyl groups' ratio on carbon nanotube and silicon substrate surfaces is larger than 10 and 20%, respectively, the motion of carbon nanotube transforms from sliding to rolling. When the hydroxyl groups' ratio is smaller, the slide or roll mode can be controlled by the speed of carbon nanotube, which is ultimately determined by the competition between the interface potential energy and kinetic energy. The change of motion mode holds true for different carbon nanotubes with hydroxyl groups. The chirality has little effect on the motion behavior, as opposed to the diameter, attributed to the hydroxyl groups' ratio. Our study suggests a new route to control the motion behavior of carbon nanotube via hydroxyl groups.

  1. The stability of the hydroxylated (0001) surface of alpha-Al2O3

    DEFF Research Database (Denmark)

    Lodziana, Zbigniew; Nørskov, Jens Kehlet; Stoltze, Per

    2003-01-01

    Self-consistent density functional calculations of the hydroxylated (0001) corundum surfaces are presented. It is demonstrated that the hydroxylated surfaces are the most stable under most, but not all, conditions. Hydroxylation significantly lowers the surface free energy of alpha-alumina. The s......Self-consistent density functional calculations of the hydroxylated (0001) corundum surfaces are presented. It is demonstrated that the hydroxylated surfaces are the most stable under most, but not all, conditions. Hydroxylation significantly lowers the surface free energy of alpha......-alumina. The stability of the hydrated surface resolves the discrepancies between the morphology of the alpha-alumina (0001) surface observed under ultra-high vacuum, and at ambient conditions. A method for the calculation of the equilibrium surface stoichiometry is proposed. The proposed approach provides a valuable...

  2. Self-hydroxylation of the splicing factor lysyl hydroxylase, JMJD6

    DEFF Research Database (Denmark)

    Mantri, M.; Webby, C.J.; Loik, N.D.

    2012-01-01

    The lysyl 5S-hydroxylase, JMJD6 acts on proteins involved in RNA splicing. We find that in the absence of substrate JMJD6 catalyses turnover of 2OG to succinate. H-NMR analyses demonstrate that consumption of 2OG is coupled to succinate formation. MS analyses reveal that JMJD6 undergoes self......-hydroxylation in the presence of Fe(ii) and 2OG resulting in production of 5S-hydroxylysine residues. JMJD6 in human cells is also found to be hydroxylated. Self-hydroxylation of JMJD6 may play a regulatory role in modulating the hydroxylation status of proteins involved in RNA splicing. This journal is...

  3. Synthesis of hydroxylated and methoxylated polybrominated diphenyl ethers

    Institute of Scientific and Technical Information of China (English)

    ZHENG Ke-wen; GAO Li-ping; CAO Jie; YU Hai-wen; ZHANG Zhang

    2009-01-01

    Hydroxylated/methoxylated polybrominated diphenyl ethers (OH/MeO-PBDEs) are not only detected as natural products, but also regarded as metabolites formed from polybrominated diphenyl ethers (PBDEs), which are widely used as flame-retardants in various materials. The aim of the present study was to synthesize authentic OH-PBDEs and MeO-PBDEs, as reference standards for environmental exploration. Twenty OH-PBDEs and their corresponding MeO-PBDEs containing three to six bromine atoms were synthesized via a trial of reactions including coupling, oxidation, bromination, methylation, etc. The products were characterized by GC-MS and 1H-NMR spectroscopy in the work. As results show, all compounds synthesized were up to 99% on purity and be reqarded as authentic standards for detecting the chemical pollutants in the emvironment.

  4. [Epimerization of hydroxyl group in the lupan series of triterpenes].

    Science.gov (United States)

    Symon, A V; Kaplun, A P; Vlasenkova, N K; Gerasimova, G K; Shon, Le Bang; Litvin, E F; Kozlova, L M; Surkova, E L; Shvets, V I

    2003-01-01

    Two methods of obtaining of 3 alpha-betulinic acid and related compounds from their 3 beta-epimers were studied: the reaction of bimolecular substitution and the stereoselective reduction of 3-ketoderivatives. The substitution of acyloxy by formyloxy group in 3-O-tosyllupeol or of the betulin hydroxyl by benzoyloxy group resulted only in delta 2, 3-elimination products, with none of the expected products of bimolecular substitution being found. The catalytic hydrogenation of betulonic acid over Raney nickel resulted only in reduction of the isopropenyl double bond, whereas the use of 5% Ru/C gave a 60:40 mixture of epimers of dihydrobetulinic acid. Practically the same mixture of betulinic acid epimers was obtained when reducing betulonic acid with L-Selectride. The cytotoxic activity of 3 alpha-betulinic acid increased toward melanoma Bro cells and decreased toward melanoma MS cells.

  5. Chemical models of chains electron transfer in hydroxylating ferment systems

    International Nuclear Information System (INIS)

    Akhrem, A.A.; Kiselev, P.A.; Metelitsa, D.I.

    1977-01-01

    The rate constants are measured of consumption of nicotineamidedinucleotide (NAD-N) during its oxidation by molecular oxygen with the participation of Ti 4+ , Sn 4+ , Cu 2+ , Fe 3+ , VO 2+ , and Ce 4+ ions in mixtures of acetonitrile with water and of dioxane with water taken in a volume ratio of 1:1 (46 deg C). The kinetics of oxidation of NAD-N with the participation of Ti 4+ at 37 deg C in a water-acetonitrile medium is studied in detail. The hydroxylating capacity of the system NAD-N - Ti 4+ - O 2 with respect to naphthalene is proved. The reaction mechanism and its relationship with the microsomal chains of electron transport are discussed

  6. Kinetics of hydrogen peroxide decomposition by catalase: hydroxylic solvent effects.

    Science.gov (United States)

    Raducan, Adina; Cantemir, Anca Ruxandra; Puiu, Mihaela; Oancea, Dumitru

    2012-11-01

    The effect of water-alcohol (methanol, ethanol, propan-1-ol, propan-2-ol, ethane-1,2-diol and propane-1,2,3-triol) binary mixtures on the kinetics of hydrogen peroxide decomposition in the presence of bovine liver catalase is investigated. In all solvents, the activity of catalase is smaller than in water. The results are discussed on the basis of a simple kinetic model. The kinetic constants for product formation through enzyme-substrate complex decomposition and for inactivation of catalase are estimated. The organic solvents are characterized by several physical properties: dielectric constant (D), hydrophobicity (log P), concentration of hydroxyl groups ([OH]), polarizability (α), Kamlet-Taft parameter (β) and Kosower parameter (Z). The relationships between the initial rate, kinetic constants and medium properties are analyzed by linear and multiple linear regression.

  7. Spectroscopy and reaction dynamics of collision complexes containing hydroxyl radicals

    Energy Technology Data Exchange (ETDEWEB)

    Lester, M.I. [Univ. of Pennsylvania, Philadelphia (United States)

    1993-12-01

    The DOE supported work in this laboratory has focused on the spectroscopic characterization of the interaction potential between an argon atom and a hydroxyl radical in the ground X{sup 2}II and excited A {sup 2}{summation}{sup +} electronic states. The OH-Ar system has proven to be a test case for examining the interaction potential in an open-shell system since it is amenable to experimental investigation and theoretically tractable from first principles. Experimental identification of the bound states supported by the Ar + OH (X {sup 2}II) and Ar + OH(A {sup 2}{summation}{sup +}) potentials makes it feasible to derive realistic potential energy surfaces for these systems. The experimentally derived intermolecular potentials provide a rigorous test of ab initio theory and a basis for understanding the dramatically different collision dynamics taking place on the ground and excited electronic state surfaces.

  8. Effective L-Tyrosine Hydroxylation by Native and Immobilized Tyrosinase.

    Directory of Open Access Journals (Sweden)

    Małgorzata Cieńska

    Full Text Available Hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (L-DOPA by immobilized tyrosinase in the presence of ascorbic acid (AH2, which reduces DOPA-quinone to L-DOPA, is characterized by low reaction yields that are mainly caused by the suicide inactivation of tyrosinase by L-DOPA and AH2. The main aim of this work was to compare processes with native and immobilized tyrosinase to identify the conditions that limit suicide inactivation and produce substrate conversions to L-DOPA of above 50% using HPLC analysis. It was shown that immobilized tyrosinase does not suffer from partitioning and diffusion effects, allowing a direct comparison of the reactions performed with both forms of the enzyme. In typical processes, additional aeration was applied and boron ions to produce the L-DOPA and AH2 complex and hydroxylamine to close the cycle of enzyme active center transformations. It was shown that the commonly used pH 9 buffer increased enzyme stability, with concomitant reduced reactivity of 76%, and that under these conditions, the maximal substrate conversion was approximately 25 (native to 30% (immobilized enzyme. To increase reaction yield, the pH of the reaction mixture was reduced to 8 and 7, producing L-DOPA yields of approximately 95% (native enzyme and 70% (immobilized. A three-fold increase in the bound enzyme load achieved 95% conversion in two successive runs, but in the third one, tyrosinase lost its activity due to strong suicide inactivation caused by L-DOPA processing. In this case, the cost of the immobilized enzyme preparation is not overcome by its reuse over time, and native tyrosinase may be more economically feasible for a single use in L-DOPA production. The practical importance of the obtained results is that highly efficient hydroxylation of monophenols by tyrosinase can be obtained by selecting the proper reaction pH and is a compromise between complexation and enzyme reactivity.

  9. Effective L-Tyrosine Hydroxylation by Native and Immobilized Tyrosinase

    Science.gov (United States)

    Lewańczuk, Marcin; Koźlecki, Tomasz; Liesiene, Jolanta; Bryjak, Jolanta

    2016-01-01

    Hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (L-DOPA) by immobilized tyrosinase in the presence of ascorbic acid (AH2), which reduces DOPA-quinone to L-DOPA, is characterized by low reaction yields that are mainly caused by the suicide inactivation of tyrosinase by L-DOPA and AH2. The main aim of this work was to compare processes with native and immobilized tyrosinase to identify the conditions that limit suicide inactivation and produce substrate conversions to L-DOPA of above 50% using HPLC analysis. It was shown that immobilized tyrosinase does not suffer from partitioning and diffusion effects, allowing a direct comparison of the reactions performed with both forms of the enzyme. In typical processes, additional aeration was applied and boron ions to produce the L-DOPA and AH2 complex and hydroxylamine to close the cycle of enzyme active center transformations. It was shown that the commonly used pH 9 buffer increased enzyme stability, with concomitant reduced reactivity of 76%, and that under these conditions, the maximal substrate conversion was approximately 25 (native) to 30% (immobilized enzyme). To increase reaction yield, the pH of the reaction mixture was reduced to 8 and 7, producing L-DOPA yields of approximately 95% (native enzyme) and 70% (immobilized). A three-fold increase in the bound enzyme load achieved 95% conversion in two successive runs, but in the third one, tyrosinase lost its activity due to strong suicide inactivation caused by L-DOPA processing. In this case, the cost of the immobilized enzyme preparation is not overcome by its reuse over time, and native tyrosinase may be more economically feasible for a single use in L-DOPA production. The practical importance of the obtained results is that highly efficient hydroxylation of monophenols by tyrosinase can be obtained by selecting the proper reaction pH and is a compromise between complexation and enzyme reactivity. PMID:27711193

  10. Effective L-Tyrosine Hydroxylation by Native and Immobilized Tyrosinase.

    Science.gov (United States)

    Cieńska, Małgorzata; Labus, Karolina; Lewańczuk, Marcin; Koźlecki, Tomasz; Liesiene, Jolanta; Bryjak, Jolanta

    2016-01-01

    Hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (L-DOPA) by immobilized tyrosinase in the presence of ascorbic acid (AH2), which reduces DOPA-quinone to L-DOPA, is characterized by low reaction yields that are mainly caused by the suicide inactivation of tyrosinase by L-DOPA and AH2. The main aim of this work was to compare processes with native and immobilized tyrosinase to identify the conditions that limit suicide inactivation and produce substrate conversions to L-DOPA of above 50% using HPLC analysis. It was shown that immobilized tyrosinase does not suffer from partitioning and diffusion effects, allowing a direct comparison of the reactions performed with both forms of the enzyme. In typical processes, additional aeration was applied and boron ions to produce the L-DOPA and AH2 complex and hydroxylamine to close the cycle of enzyme active center transformations. It was shown that the commonly used pH 9 buffer increased enzyme stability, with concomitant reduced reactivity of 76%, and that under these conditions, the maximal substrate conversion was approximately 25 (native) to 30% (immobilized enzyme). To increase reaction yield, the pH of the reaction mixture was reduced to 8 and 7, producing L-DOPA yields of approximately 95% (native enzyme) and 70% (immobilized). A three-fold increase in the bound enzyme load achieved 95% conversion in two successive runs, but in the third one, tyrosinase lost its activity due to strong suicide inactivation caused by L-DOPA processing. In this case, the cost of the immobilized enzyme preparation is not overcome by its reuse over time, and native tyrosinase may be more economically feasible for a single use in L-DOPA production. The practical importance of the obtained results is that highly efficient hydroxylation of monophenols by tyrosinase can be obtained by selecting the proper reaction pH and is a compromise between complexation and enzyme reactivity.

  11. Effects of aphidicolin on repair replication and induced chromosomal aberrations in mammalian cells

    International Nuclear Information System (INIS)

    Zeeland, A.A. van; Filon, A.R.; Natarajan, A.T.; Bussmann, C.J.M.; Degrassi, F.; Kesteren-van Leeuwen, A.C. van; Palitti, F.; Rome Univ.

    1982-01-01

    The influence of aphidicolin, an inhibitor of polymerase α, on UV-induced repair replication in human skin fibroblasts, as well as in HeLa cells, was determined. In growing fibroblasts and in HeLa cells, aphidicolin had a potentiating effect on UV-induced repair replication, whereas in fibroblasts grown to confluency, aphidicolin had an inhibitory effect. This inhibitory effect was stronger when measured in the presence of hydroxyurea. In HeLa cells the presence of both aphidicolin and hydroxyurea also had an inhibitory effect, but in the presence of hydroxyurea alone, UV-induced repair replication was enhanced. The results of these studies can be explained on the basis of differences in deoxyribonucleotide triphosphate pool sizes in growing and confluent cells. Post-treatment of X-irradiated human lymphocytes in the G 0 and G 1 stages with aphidicolin increased the frequencies of X-ray-induced chromosomal aberrations. Such an increase was not observed in G 1 cells of CHO after similar treatment with X-rays and aphidicolin. However, treatment with aphidicolin, in the G 2 stage, increased the frequencies of induced chromatid breaks. The significance of these results is discussed. (orig.)

  12. Immuno-chemistry of hydroxyl radical modified GAD-65: A possible role in experimental and human diabetes mellitus.

    Science.gov (United States)

    Moinuddin; Ansari, Nadeem A; Shahab, Uzma; Habeeb, Safia; Ahmad, Saheem

    2015-10-01

    The repertoire of known auto-antigens is limited to a very small proportion of all human proteins, and the reason why only some proteins become auto-antigens is unclear. The 65 kDa isoform of the enzyme glutamic acid decarboxylase (GAD-65) is a major auto-antigen in type I diabetes, and in various neurological diseases. Most patients with type I diabetes (70-80%) have auto-antibodies against GAD-65, which often appear years before clinical onset of the autoimmune diabetes. Thus, the aim of the study is to focus on the immunogenicity of GAD65 and its reactive oxygen species (ROS) conformer in STZ-induced diabetic rats and on human diabetic patients. In the present study, GAD-65 was modified by hydroxyl radical following Fenton's reaction. The modifications in the structure of the GAD-65 are supported by UV-vis and fluorescence spectral studies. Immunogenicity of both native and hydroxyl radical modified GAD-65 (ROS-GAD-65) was studied in experimental rabbits and was confirmed by inducing type I diabetes in experimental male albino rats using streptozotocin (45 mg/kg). We found that ROS-GAD-65 was a better immunogen as compared to the native GAD-65. A considerable high binding to ROS-GAD-65 was observed as compared to native GAD-65 in both the serum antibodies from diabetes animal models and as well as in the serum samples of type I diabetes. Hydrogen peroxide under the exposure of UV light produces hydroxyl radical (·OH) which is most potent oxidant, and could cause protein damage (GAD-65) to the extent of generating neo-epitopes on the molecule, thus making it immunogenic. © 2015 International Union of Biochemistry and Molecular Biology.

  13. Studies on 16α-Hydroxylation of Steroid Molecules and Regioselective Binding Mode in Homology-Modeled Cytochrome P450-2C11

    Directory of Open Access Journals (Sweden)

    Hamed I. Ali

    2011-01-01

    Full Text Available We investigated the 16α-hydroxylation of steroid molecules and regioselective binding mode in homology-modeled cytochrome P450-2C11 to correlate the biological study with the computational molecular modeling. It revealed that there was a positive relationship between the observed inhibitory potencies and the binding free energies. Docking of steroid molecules into this homology-modeled CYP2C11 indicated that 16α-hydroxylation is favored with steroidal molecules possessing the following components, (1 a bent A-B ring configuration (5β-reduced, (2 C-3 α-hydroxyl group, (3 C-17β-acetyl group, and (4 methyl group at both the C-18 and C-19. These respective steroid components requirements were defined as the inhibitory contribution factor. Overall studies of the male rat CYP2C11 metabolism revealed that the above-mentioned steroid components requirements were essential to induce an effective inhibition of [3H]progesterone 16α-hydroxylation. As far as docking of homology-modeled CYP2C11 against investigated steroids is concerned, they are docked at the active site superimposed with flurbiprofen. It was also found that the distance between heme iron and C16α-H was between 4 to 6 Å and that the related angle was in the range of 180±45∘.

  14. Adherence to hydroxyurea medication by children with sickle cell disease (SCD) using an electronic device: a feasibility study.

    Science.gov (United States)

    Inoue, Susumu; Kodjebacheva, Gergana; Scherrer, Tammy; Rice, Gary; Grigorian, Matthew; Blankenship, Jeremy; Onwuzurike, Nkechi

    2016-08-01

    Adherence to hydroxyurea (HU) is a significant modifying factor in sickle cell vaso-occlusive pain. We conducted a study using an electronic medication container-monitor-reminder device (GlowCap™) to track adherence and determine whether use of this device affected rates of HU adherence. Subjects were regular attendees to our clinic. They were given a 37-item questionnaire and were asked to use a GlowCap containing HU. When the device cap is opened, it makes a remote "medication taken" record. The device also provides usage reminder in the form of lights and alarm sounds if the cap opening is delayed. Nineteen subjects participated in the survey, and 17 in the intervention phase. Of the 17, 12 had reliable adherence data. Seventeen caregivers of patients and two patients completed the survey. Two most common barriers to adherence identified were lack of reminders and absence of medicine home delivery. The intervention component of this study, which used both the electronic (GlowCap) method and medication possession ratio showed that the median adherence rate for the 12 patients evaluated was 85 %. The GlowCap device accurately kept a record of adherence rates. This device may be an effective tool for increasing HU medication adherence.

  15. Cell growth state determines susceptibility of repair DNA synthesis to inhibition by hydroxyurea and 1-beta-D-arabinofuranosylcytosine

    International Nuclear Information System (INIS)

    Mullinger, A.M.; Collins, A.R.; Johnson, R.T.

    1983-01-01

    The effects of inhibitors of replicative DNA synthesis on repair DNA synthesis have been examined by autoradiography in several different cell types and in cells in different growth states. Hydroxyurea (HU) and 1-beta-D-arabinofuranosylcytosine (ara C), administered together, influence unscheduled DNA synthesis (UDS) in a manner which is independent of the status of the cell culture (normal or transformed) and of the species, but which is strongly affected by whether the cells are proliferating or quiescent. In proliferating human, Chinese hamster and Microtus cell cultures, UDS is not inhibited by HU and ara C, and may even appear to be stimulated. In quiescent cultures of these cells UDS is reduced by HU and ara C. In cells reseeded from a confluent culture and followed during proliferation and back to quiescence the effect of inhibitors parallels the growth pattern. The results are interpreted in terms of changes in the sizes of endogenous DNA precursor pools; they underline the potential problems associated with quantitating UDS in the presence of inhibitors

  16. Molecular structure, vibrational spectra and quantum chemical MP2/DFT studies toward the rational design of hydroxyurea imprinted polymer

    Science.gov (United States)

    Prasad, Bhim Bali; Rai, Garima

    2013-03-01

    In this study, both experimental and theoretical vibrational spectra of template (hydroxyurea, HU), monomer (N-(4,6-bisacryloyl amino-[1,3,5] triazine-2-yl-)-acryl amide, TAT), and HU-TAT complexes were compared and these were respectively found to be in good agreement. Binding energies of HU, when complexed with different monomers, were computed using second order Moller Plesset theory (MP2) at 6-311++G(d,p) level both in the gas as well as solution phases. HU is an antineoplastic agent extensively being used in the treatment of polycythaemia Vera and thrombocythemia. It is also used to reduce the frequency of painful attacks in sickle cell anemia. It has antiretroviral property in disease like AIDS. All spectral characterizations were made using Density Functional Theory (DFT) at B3LYP employing 6-31+g(2d, 2p) basis set. The theoretical values for 13C and 1H NMR chemical shifts were found to be in accordance with the corresponding experimental values. Of all different monomers studied for the synthesis of molecularly imprinted polymer (MIP) systems, the monomer TAT (2 mol) was typically found to have a best binding score requisite for complexation with HU (1 mol) at the ground state.

  17. Standardization method for measurement of hydroxyurea by Ultra High Efficiency Liquid Chromatography in plasma of patients with sickle cell disease

    Directory of Open Access Journals (Sweden)

    Darcielle Bruna Dias Elias

    2014-09-01

    Full Text Available Sickle cell anemia (SCA is a recessively inherited disease characterized by chronic hemolytic anemia, chronic inflammation, and acute episodes of hemolysis. Hydroxyurea (HU is widely used to increase the levels of fetal hemoglobin (HbF. The objective of this study was to standardize and validate a method for the quantification of HU in human plasma by using ultra high performance liquid chromatography (UPLC in order to determine the plasma HU levels in adult patients with SCA who had been treated with HU. We used an analytical reverse phase column (Nucleosil C18 with a mobile phase consisting of acetonitrile/water (16.7/83.3. The retention times of HU, urea, and methylurea were 6.7, 7.7, and 11.4 min, respectively. All parameters of the validation process were defined. To determine the precision and accuracy of quality controls, HU in plasma was used at concentrations of 100, 740, and 1600 µM, with methylurea as the internal standard. Linearity was assessed in the range of 50-1600 µM HU in plasma, obtaining a correlation coefficient of 0.99. The method was accurate and precise and can be used for the quantitative determination of HU for therapeutic monitoring of patients with SCA treated with HU.

  18. Biomineralization-Inspired Synthesis of Cerium-Doped Carbonaceous Nanoparticles for Highly Hydroxyl Radical Scavenging Activity

    Science.gov (United States)

    Zou, Shenqiang; Zhu, Xiaofang; Zhang, Lirong; Guo, Fan; Zhang, Miaomiao; Tan, Youwen; Gong, Aihua; Fang, Zhengzou; Ju, Huixiang; Wu, Chaoyang; Du, Fengyi

    2018-03-01

    Cerium oxide nanoparticles recently have received extensive attention in biomedical applications due to their excellent anti-oxidation performance. In this study, a simple, mild, and green approach was developed to synthesize cerium-doped carbonaceous nanoparticles (Ce-doped CNPs) using bio-mineralization of bull serum albumin (BSA) as precursor. The resultant Ce-doped CNPs exhibited uniform and ultrasmall morphology with an average size of 14.7 nm. XPS and FTIR results revealed the presence of hydrophilic group on the surface of Ce-doped CNPs, which resulted in excellent dispersity in water. The CCK-8 assay demonstrated that Ce-doped CNPs possessed favorable biocompatibility and negligible cytotoxicity. Using H2O2-induced reactive oxygen species (ROS) as model, Ce-doped CNPs showed highly hydroxyl radical scavenging capability. Furthermore, flow cytometry and live-dead staining results indicated that Ce-doped CNPs protected cells from H2O2-induced damage in a dose-dependent effect, which provided a direct evidence for anti-oxidative performance. These findings suggest that Ce-doped CNPs as novel ROS scavengers may provide a potential therapeutic prospect in treating diseases associated with oxidative stress.

  19. Mechanism of aromatic hydroxylation of lidocaine at a Pt electrode under acidic conditions

    NARCIS (Netherlands)

    Gul, Turan; Bischoff, Rainer; Permentier, Hjalmar P.

    2017-01-01

    Aromatic hydroxylation reactions, which are mainly catalyzed by cytochrome P450 (CYP) enzymes in vivo, are some of the most important reactions of Phase I metabolism, because insertion of a hydroxyl group into a lipophilic drug compound increases its hydrophilicity and prepares it for subsequent

  20. Formation of hydroxyl radicals in the human lens is related to the severity of nuclear cataract

    DEFF Research Database (Denmark)

    Garner, B; Davies, Michael Jonathan; Truscott, R J

    2000-01-01

    Recent studies have identified specific hydroxylated amino acid oxidation products which strongly suggest the presence of hydroxyl radical (HO.)-damaged proteins in human cataractous lenses. In the present study, the ability of early stage (type II) and advanced (type IV) nuclear cataractous lens...

  1. Testosterone 15β-hydroxylation by solvent tolerant Pseudomonas putida S12

    NARCIS (Netherlands)

    Ruijssenaars, H.J.; Sperling, E.M.G.M.; Wiegerinck, P.H.G.; Brands, F.T.L.; Wery, J.; Bont, J.A.M.de

    2007-01-01

    A steroid 15β-hydroxylating whole-cell solvent tolerant biocatalyst was constructed by expressing the Bacillus megaterium steroid hydroxylase CYP106A2 in the solvent tolerant Pseudomonas putida S12. Testosterone hydroxylation was improved by a factor 16 by co-expressing Fer, a putative Fe-S protein

  2. The effect of adenosine A(2A) receptor antagonists on hydroxyl radical, dopamine, and glutamate in the striatum of rats with altered function of VMAT2.

    Science.gov (United States)

    Gołembiowska, Krystyna; Dziubina, Anna

    2012-08-01

    It has been shown that a decreased vesicular monoamine transporter (VMAT2) function and the disruption of dopamine (DA) storage is an early contributor to oxidative damage of dopamine neurons in Parkinson's disease (PD). In our previous study, we demonstrated that adenosine A(2A) receptor antagonists suppressed oxidative stress in 6-hydroxydopamine-treated rats suggesting that this effect may account for neuroprotective properties of drugs. In the present study, rats were injected with reserpine (10 mg/kg sc) and 18 h later the effect of the adenosine A(2A) receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on extracellular DA, glutamate and hydroxyl radical formation was studied in the rat striatum using in vivo microdialysis. By disrupting VMAT2 function, reserpine depleted DA stores, and increased glutamate and hydroxyl radical levels in the rat striatum. CSC (1 mg/kg) but not ZM 241385 (3 mg/kg) increased extracellular DA level and production of hydroxyl radical in reserpinised rats. Both antagonists decreased the reserpine-induced increase in extracellular glutamate. L-3,4-Dihydroxyphenylalanine (L-DOPA) (25 mg/kg) significantly enhanced extracellular DA, had no effect on reserpine-induced hydroxyl radical production and decreased extracellular glutamate concentration. CSC but not ZM 241385 given jointly with L-DOPA increased the effect of L-DOPA on extracellular DA and augmented the reserpine-induced hydroxyl radical production. CSC and ZM 241385 did not influence extracellular glutamate level, which was decreased by L-DOPA. It seems that by decreasing the MAO-dependent DA metabolism rate, CSC raised cytosolic DA and by DA autoxidation, it induced hydroxyl radical overproduction. Thus, the methylxanthine A(2A) receptor antagonists bearing properties of MAO-B inhibitor, like CSC, may cause a risk of oxidative stress resulting from dysfunctional DA storage

  3. Cisplatin enhances the formation of DNA single- and double-strand breaks by hydrated electrons and hydroxyl radicals.

    Science.gov (United States)

    Rezaee, Mohammad; Sanche, Léon; Hunting, Darel J

    2013-03-01

    The synergistic interaction of cisplatin with ionizing radiation is the clinical rationale for the treatment of several cancers including head and neck, cervical and lung cancer. The underlying molecular mechanism of the synergy has not yet been identified, although both DNA damage and repair processes are likely involved. Here, we investigate the indirect effect of γ rays on strand break formation in a supercoiled plasmid DNA (pGEM-3Zf-) covalently modified by cisplatin. The yields of single- and double-strand breaks were determined by irradiation of DNA and cisplatin/DNA samples with (60)Co γ rays under four different scavenging conditions to examine the involvement of hydrated electrons and hydroxyl radicals in inducing the DNA damage. At 5 mM tris in an N2 atmosphere, the presence of an average of two cisplatins per plasmid increased the yields of single- and double-strand breaks by factors of 1.9 and 2.2, respectively, relative to the irradiated unmodified DNA samples. Given that each plasmid of 3,200 base pairs contained an average of two cisplatins, this represents an increase in radiosensitivity of 3,200-fold on a per base pair basis. When hydrated electrons were scavenged by saturating the samples with N2O, these enhancement factors decreased to 1.5 and 1.2, respectively, for single- and double-strand breaks. When hydroxyl radicals were scavenged using 200 mM tris, the respective enhancement factors were 1.2 and 1.6 for single- and double-strand breaks, respectively. Furthermore, no enhancement in DNA damage by cisplatin was observed after scavenging both hydroxyl radicals and hydrated electrons. These findings show that hydrated electrons can induce both single- and double-strand breaks in the platinated DNA, but not in unmodified DNA. In addition, cisplatin modification is clearly an extremely efficient means of increasing the formation of both single- and double-strand breaks by the hydrated electrons and hydroxyl radicals created by ionizing

  4. Vacuum ultraviolet photoionization cross section of the hydroxyl radical

    Science.gov (United States)

    Dodson, Leah G.; Savee, John D.; Gozem, Samer; Shen, Linhan; Krylov, Anna I.; Taatjes, Craig A.; Osborn, David L.; Okumura, Mitchio

    2018-05-01

    The absolute photoionization spectrum of the hydroxyl (OH) radical from 12.513 to 14.213 eV was measured by multiplexed photoionization mass spectrometry with time-resolved radical kinetics. Tunable vacuum ultraviolet (VUV) synchrotron radiation was generated at the Advanced Light Source. OH radicals were generated from the reaction of O(1D) + H2O in a flow reactor in He at 8 Torr. The initial O(1D) concentration, where the atom was formed by pulsed laser photolysis of ozone, was determined from the measured depletion of a known concentration of ozone. Concentrations of OH and O(3P) were obtained by fitting observed time traces with a kinetics model constructed with literature rate coefficients. The absolute cross section of OH was determined to be σ(13.436 eV) = 3.2 ± 1.0 Mb and σ(14.193 eV) = 4.7 ± 1.6 Mb relative to the known cross section for O(3P) at 14.193 eV. The absolute photoionization spectrum was obtained by recording a spectrum at a resolution of 8 meV (50 meV steps) and scaling to the single-energy cross sections. We computed the absolute VUV photoionization spectrum of OH and O(3P) using equation-of-motion coupled-cluster Dyson orbitals and a Coulomb photoelectron wave function and found good agreement with the observed absolute photoionization spectra.

  5. Vacuum ultraviolet photoionization cross section of the hydroxyl radical.

    Science.gov (United States)

    Dodson, Leah G; Savee, John D; Gozem, Samer; Shen, Linhan; Krylov, Anna I; Taatjes, Craig A; Osborn, David L; Okumura, Mitchio

    2018-05-14

    The absolute photoionization spectrum of the hydroxyl (OH) radical from 12.513 to 14.213 eV was measured by multiplexed photoionization mass spectrometry with time-resolved radical kinetics. Tunable vacuum ultraviolet (VUV) synchrotron radiation was generated at the Advanced Light Source. OH radicals were generated from the reaction of O( 1 D) + H 2 O in a flow reactor in He at 8 Torr. The initial O( 1 D) concentration, where the atom was formed by pulsed laser photolysis of ozone, was determined from the measured depletion of a known concentration of ozone. Concentrations of OH and O( 3 P) were obtained by fitting observed time traces with a kinetics model constructed with literature rate coefficients. The absolute cross section of OH was determined to be σ(13.436 eV) = 3.2 ± 1.0 Mb and σ(14.193 eV) = 4.7 ± 1.6 Mb relative to the known cross section for O( 3 P) at 14.193 eV. The absolute photoionization spectrum was obtained by recording a spectrum at a resolution of 8 meV (50 meV steps) and scaling to the single-energy cross sections. We computed the absolute VUV photoionization spectrum of OH and O( 3 P) using equation-of-motion coupled-cluster Dyson orbitals and a Coulomb photoelectron wave function and found good agreement with the observed absolute photoionization spectra.

  6. Hydroxylated PCBs in abiotic environmental matrices. Precipitation and surface waters

    Energy Technology Data Exchange (ETDEWEB)

    Darling, C.; Alaee, M.; Campbell, L.; Pacepavicius, G.; Ueno, D.; Muir, D. [National Water Research Institute, Burlington, ON (Canada)

    2004-09-15

    Hydroxylated PCBs (OH-PCBs) are of great interest environmentally because of their potential thyroidogenic effects. OH-PCBs can compete with thyroxine for binding sites on transthyretin, one of the three main thyroid hormone transport proteins in mammals1. The chemical structures of some OH-PCBs with a para OH group and adjacent chlorine atoms, particularly 4-OH-CB109, 4- OH-CB146, and 4-OH-CB187, share a similar structure to the thyroid hormones (T3 and T4), which have a para OH with adjacent iodine atoms. A number of OH-PCBs have been identified in the blood of humans and biota during the last 5 to 10 years, however, reports on the identity, presence and levels of OH-PCBs are limited. This presentation describes preliminary studies on the presence of OH-PCBs in abiotic samples and comparisons of congener patterns with biological samples. We have previously shown that OHPCBs were present in lake trout from the Great Lakes and nearby large lakes as well as in nearshore environments. We hypothesized that some of the OH-PCB present in fish might be from abiotic formation in water or the atmosphere, or from microbial oxidation of PCBs and/or deconjugation of PCB metabolites in waste treatment plants.

  7. Detecting irradiated foods: use of hydroxyl radical biomarkers

    International Nuclear Information System (INIS)

    Karam, L.R.; Simic, M.G.

    1988-01-01

    Recent legislation in the United States has increased the probability of using ionizing radiation for preserving food. The possible increased use of food irradiation in this country, in addition to current use of the technique in other countries, makes it important to develop a method whereby the extent of irradiation of foods can be determined. Both opponents and proponents of this particular food-processing technique support postirradiation dosimetry (PID) as a way to measure the extent of changes in irradiated products. To prevent tampering and alteration of the dosimeters, the best postirradiation dosimeters are those that are inherent in the product exposed to the ionizing radiation. Therefore detection of the intermediates and subsequent products arising from the interaction of ionizing radiation with biomolecules in food should be a viable means by which the irradiated status of a food sample can be determined. To be useful as biomarkers, however, the products formed by irradiation must be detectable by routine analytical methods, formed exclusively by ionizing radiation (unless formation from alternate methods can be readily determined), and stable for the duration of the expected shelf life of the food product. In this article Lisa R. Karam and Michael G. Simic of the National Institute of Standards and Technology describe methodology developed to identify the irradiated status of foods using hydroxyl radical biomarkers

  8. Replicative Stress Induces Intragenic Transcription of the ASE1 Gene that Negatively Regulates Ase1 Activity

    OpenAIRE

    McKnight, Kelly; Liu, Hong; Wang, Yanchang

    2014-01-01

    Intragenic transcripts initiate within the coding region of a gene, thereby producing shorter mRNAs and proteins. Although intragenic transcripts are widely expressed [1], their role in the functional regulation of genes remains largely unknown. In budding yeast, DNA replication stress activates the S-phase checkpoint that stabilizes replication forks and arrests cells in S-phase with a short spindle [2-4]. When yeast cells were treated with hydroxyurea (HU) to block DNA synthesis and induce ...

  9. Adverse Effects of a Clinically Relevant Dose of Hydroxyurea Used for the Treatment of Sickle Cell Disease on Male Fertility Endpoints

    Directory of Open Access Journals (Sweden)

    Donald Bruce

    2009-03-01

    Full Text Available Two experiments were conducted to determine: 1 whether the adult male transgenic sickle cell mouse (Tg58 × Tg98; TSCM, exhibits the patterns of reproductive endpoints (hypogonadism characteristic of men with sickle cell disease (SCD and 2 whether hydroxyurea (HU exacerbates this condition. In Experiment 1, blood samples were collected from adult age-matched TSCM and ICR mice (ICRM (N = 10/group for plasma testosterone measurements. Subsequently, mice were sacrificed, testes excised and weighed and stored spermatozoa recovered for the determination of sperm density, progressive motility and percentage of spermatozoa with normal morphology. In experiment 2, adult male TSCM were orally treated with 25 mg HU/kg body weight/day for 28 or 56 days. Control mice received the vehicle for HU (saline as described above. At the end of the treatment periods, blood samples were collected for quantification of circulating testosterone. Subsequently, mice were sacrificed, testes and epididymides were recovered and weighed and one testis per mouse was subjected to histopathology. Stored spermatozoa were recovered for the determination of indices of sperm quality mentioned in Experiment 1. Testis weight, stored sperm density, progressive motility, percentage of spermatozoa with normal morphology and plasma testosterone concentrations of TSCM were significantly lower by 40, 65, 40, 69 and 66%, respectively than those of ICRM. These data indicate that adult TSCM used in this study suffered from hypogonadism, characteristically observed among adult male SCD patients. In Experiment 2, HU treatment significantly decreased testis weight on day 28, (0.09 ± 0.004g that was further decreased on day 56 (0.06 ± 0.003g; treatment x time interaction compared with controls (day 28, 0.15 ± 0.01g; day 56, 2, 0.16 ± 0.01g. Concomitant with a 52% shrinkage (P<0.001 in area of testes in 56 days of HU treatment, testes from HU-treated TSCM exhibited significant atrophic

  10. Effects of natural water constituents on the photo-decomposition of methylmercury and the role of hydroxyl radical

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Moon-Kyung; Zoh, Kyung-Duk, E-mail: zohkd@snu.ac.kr

    2013-04-01

    Photo-decomposition of methylmercury (MeHg) in surface water is thought to be an important process that reduces the bioavailability of mercury (Hg) to aquatic organisms. In this study, photo-initiated decomposition of MeHg was investigated under UVA irradiation in the presence of natural water constituents including NO{sub 3}{sup −}, Fe{sup 3+}, and HCO{sub 3}{sup −} ions, and dissolved organic matter such as humic and fulvic acid. MeHg degradation followed the pseudo-first-order kinetics; the rate constant increased with increasing UVA intensity (0.3 to 3.0 mW cm{sup −2}). In the presence of NO{sub 3}{sup −}, Fe{sup 3+}, and fulvic acid, the decomposition rate of MeHg increased significantly due to photosensitization by reactive species such as hydroxyl radical. The presence of humic acid and HCO{sub 3}{sup −} ions lowered the degradation rate through a radical scavenging effect. Increasing the pH of the solution increased the degradation rate constant by enhancing the generation of hydroxyl radicals. Hydroxyl radicals play an important role in the photo-decomposition of MeHg in water, and natural constituents in water can affect the photo-decomposition of MeHg by changing radical production and inhibition. - Highlights: ► The abiotic photodecomposition of methylmercury (MeHg) in water was examined. ► UVA light is a primary factor inducing MeHg photodecomposition in water. ► Fulvic acid, NO{sub 3}{sup −}, and Fe{sup 3+} ion increased MeHg photo-decomposition rate significantly. ► Humic acid and HCO{sub 3}{sup −} ions inhibited photodecomposition through radical scavenging. ► OH radical is an important compound affecting photodecomposition of MeHg in water.

  11. Accessibility of nucleic acid-complexed biomolecules to hydroxyl radicals correlates with their conformation: a fluorescence polarization spectroscopy study

    International Nuclear Information System (INIS)

    Makrigiorgos, G.M.; Bump, E.; Huang, C.; Kassis, A.I.; Baranowska-Kortylewicz, J.

    1994-01-01

    A fluorescence methodology has been developed to examine the relationship between the conformational state of specific biomolecules in simple chromatin models and their accessibility to hydroxyl radicals ( . OH). Polylysine and histone H1 were labelled with SECCA, the succinimidyl ester of coumarin-3-carboxylic acid, which generates the fluorescent derivative 7-OH-SECCA following its interaction with radiation-induced . OH in aqueous solution. The fluorescence induced per unit γ-ray dose reflecting the accessibility of . OH to such SECCA-conjugated biomolecules was recorded. The biomolecules were also labelled with the fluorescent derivative 7-OH-SECCA in trace amounts to study their conformation under identical conditions via fluorescence polarization spectroscopy. (author)

  12. Role of XmnIgG Polymorphism in Hydroxyurea Treatment and Fetal Hemoglobin Level at Isfahanian Intermediate β-Thalassemia Patients.

    Science.gov (United States)

    Motovali-Bashi, Majid; Ghasemi, Tayyebeh

    2015-01-01

    β-thalassemia is the most common monogenic disorder in human. The (C-->T) polymorphism at -158 upstream region of the γG-globin gene and pharmacological factors such as hydroxyurea have been reported to influence γ-globin gene expression and the severity of clinical symptoms of β-thalassemia. In the present study, 51 β-thalassemia intermediate patients were studied. Xmn1γG polymorphism genotype was determined using Tetra-Primer ARMS-PCR technique. Hemoglobin (Hb) and fetal hemoglobin (HbF) levels were determined by gel electrophoresis. Of 51 patients, 35 (68.6%) patients were heterozygous (CT) and 16 (31.4%) patients were homozygous (CC). Of 30 patients under treatment by hydroxyurea, 20 (66.7%) patients were heterozygous (CT) and 10 (33.3%) patients were homozygous (CC). Our results demonstrated that in the heterozygous (CT) genotype, the Hb (9.58 ± 1.25 gm/dl) and HbF (89.30 ± 21.87) levels were significantly higher in comparison with homozygous (CC) genotype (7.94 ± 1.34 gm/dl and 70.32 ± 40.56, respectively). Furthermore, we observed that after drug usage, the Hb and HbF levels in patients with heterozygous (CT) genotype (0.7 ± 1.26 gm/dl and 5.95 ± 14.8, respectively) raised more in comparison with homozygous (CC) genotype (0.26 ± 1.43 gm/dl and 0.8 ± 1.31, respectively). Hb and HbF levels in the patients carrying T allele are increased significantly, and they also response to hydroxyurea treatment.

  13. Hydroxyurea enhances the activity of acyclovir and cidofovir against herpes simplex virus type 1 resistant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes.

    Science.gov (United States)

    Sergerie, Yan; Boivin, Guy

    2008-01-01

    Drug-resistant herpes simplex virus type 1 (HSV-1) recombinant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes were evaluated for their susceptibility to various antivirals in the presence of 25 microg/ml of hydroxyurea (HyU). The latter compound decreased the 50% inhibitory concentrations of acyclovir by 1.5-3.8-fold and that of cidofovir by 2.7-14.4-fold. However, HyU did not affect the susceptibilities of the various recombinant mutants to foscarnet. Hydroxyurea, a ribonucleotide reductase inhibitor, can increase the activity of nucleoside/nucleotide analogues against drug-resistant viruses.

  14. Measurement of hydroxyl radical production in ultrasonic aqueous solutions by a novel chemiluminescence method.

    Science.gov (United States)

    Hu, Yufei; Zhang, Zhujun; Yang, Chunyan

    2008-07-01

    Measurement methods for ultrasonic fields are important for reasons of safety. The investigation of an ultrasonic field can be performed by detecting the yield of hydroxyl radicals resulting from ultrasonic cavitations. In this paper, a novel method is introduced for detecting hydroxyl radicals by a chemiluminescence (CL) reaction of luminol-hydrogen peroxide (H2O2)-K5[Cu(HIO6)2](DPC). The yield of hydroxyl radicals is calculated directly by the relative CL intensity according to the corresponding concentration of H2O2. This proposed CL method makes it possible to perform an in-line and real-time assay of hydroxyl radicals in an ultrasonic aqueous solution. With flow injection (FI) technology, this novel CL reaction is sensitive enough to detect ultra trace amounts of H2O2 with a limit of detection (3sigma) of 4.1 x 10(-11) mol L(-1). The influences of ultrasonic output power and ultrasonic treatment time on the yield of hydroxyl radicals by an ultrasound generator were also studied. The results indicate that the amount of hydroxyl radicals increases with the increase of ultrasonic output power (< or = 15 W mL(-1)). There is a linear relationship between the time of ultrasonic treatment and the yield of H2O2. The ultrasonic field of an ultrasonic cleaning baths has been measured by calculating the yield of hydroxyl radicals.

  15. Hydroxyl-dependent Evolution of Oxygen Vacancies Enables the Regeneration of BiOCl photocatalyst

    KAUST Repository

    Wu, Sujuan

    2017-05-02

    Photoinduced oxygen vacancies (OVs) are widely investigated as a vital point defect in wide-band-gap semiconductors. Still, the formation mechanism of OVs remains unclear in various materials. To elucidate the formation mechanism of photoinduced OVs in bismuth oxychloride (BiOCl), we synthesized two surface hydroxyl discrete samples in light of the discovery of the significant variance of hydroxyl groups before and after UV light exposure. It is noted that OVs can be obtained easily after UV light irradiation in the sample with surface hydroxyl groups, while variable changes were observed in samples without surface hydroxyls. Density functional theory (DFT) calculations reveal that the binding energy of Bi-O is drastically influenced by surficial hydroxyl groups, which is intensely correlated to the formation of photoinduced OVs. Moreover, DFT calculations reveal that the adsorbed water molecules are energetically favored to dissociate into separate hydroxyl groups at the OV sites via proton transfer to a neighboring bridging oxygen atom, forming two bridging hydroxyl groups per initial oxygen vacancy. This result is consistent with the experimental observation that the disappearance of photoinduced OVs and the recovery of hydroxyl groups on the surface of BiOCl after exposed to a H2O(g)-rich atmosphere, and finally enables the regeneration of BiOCl photocatalyst. Here, we introduce new insights that the evolution of photoinduced OVs is dependent on surface hydroxyl groups, which will lead to the regeneration of active sites in semiconductors. This work is useful for controllable designs of defective semiconductors for applications in photocatalysis and photovoltaics.

  16. Hydroxylation of the herbicide isoproturon by fungi isolated from agricultural soil.

    Science.gov (United States)

    Rønhede, Stig; Jensen, Bo; Rosendahl, Søren; Kragelund, Birthe B; Juhler, René K; Aamand, Jens

    2005-12-01

    Several asco-, basidio-, and zygomycetes isolated from an agricultural field were shown to be able to hydroxylate the phenylurea herbicide isoproturon [N-(4-isopropylphenyl)-N',N'-dimethylurea] to N-(4-(2-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea and N-(4-(1-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea. Bacterial metabolism of isoproturon has previously been shown to proceed by an initial demethylation to N-(4-isopropylphenyl)-N'-methylurea. In soils, however, hydroxylated metabolites have also been detected. In this study we identified fungi as organisms that potentially play a major role in the formation of these hydroxylated metabolites in soils treated with isoproturon. Isolates of Mortierella sp. strain Gr4, Phoma cf. eupyrena Gr61, and Alternaria sp. strain Gr174 hydroxylated isoproturon at the first position of the isopropyl side chain, yielding N-(4-(2-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea, while Mucor sp. strain Gr22 hydroxylated the molecule at the second position, yielding N-(4-(1-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea. Hydroxylation was the dominant mode of isoproturon transformation in these fungi, although some cultures also produced traces of the N-demethylated metabolite N-(4-isopropylphenyl)-N'-methylurea. A basidiomycete isolate produced a mixture of the two hydroxylated and N-demethylated metabolites at low concentrations. Clonostachys sp. strain Gr141 and putative Tetracladium sp. strain Gr57 did not hydroxylate isoproturon but N demethylated the compound to a minor extent. Mortierella sp. strain Gr4 also produced N-(4-(2-hydroxy-1-methylethyl)phenyl)-N'-methylurea, which is the product resulting from combined N demethylation and hydroxylation.

  17. Hydroxyl temperature and intensity measurements during noctilucent cloud displays

    Directory of Open Access Journals (Sweden)

    M. J. Taylor

    1995-10-01

    Full Text Available Two Fourier transform spectrometers have been used to investigate the properties of the near-infrared hydroxyl (OH nightglow emission under high-latitude summertime conditions and any association with noctilucent clouds (NLCs. The measurements were made from Poker Flat Research Range, Alaska (65.1°N, 147.5°W, during August 1986. Simultaneous photographic observations of the northern twilight sky were made from Gulkana, Alaska (62.2°N, 145.5°W, approximately 340 km to the south to establish the presence of NLCs over the spectrometer site. Data exhibiting significant short-term variations in the relative intensity (as much as 50–100% and rotational temperature (typically 5–15 K were recorded on six occasions when NLCs were observed. Joint measurements were also obtained on several "cloud-free" nights. No obvious relationship was found linking the mean OH intensity or its variation with the occurrence of NLCs. However, a clear tendency was found for the mean OH temperature to be lower on NLC nights than on cloud-free nights. In particular, a significant fraction of the OH(3–1 band spectra recorded by each instrument (16–57% exhibited temperatures below ~154 K on NLC nights compared with <3% on cloud-free nights. This result is qualitatively consistent with current models for ice particle nucleation and growth, but the mean OH temperature on NLC nights (~156 K was significantly higher than would be expected for long-term particle growth in this region. These observations raise questions concerning the expected proximity of the high-latitude, summertime OH layer and the NLC growth region.

  18. Hydroxyl temperature and intensity measurements during noctilucent cloud displays

    Directory of Open Access Journals (Sweden)

    M. J. Taylor

    Full Text Available Two Fourier transform spectrometers have been used to investigate the properties of the near-infrared hydroxyl (OH nightglow emission under high-latitude summertime conditions and any association with noctilucent clouds (NLCs. The measurements were made from Poker Flat Research Range, Alaska (65.1°N, 147.5°W, during August 1986. Simultaneous photographic observations of the northern twilight sky were made from Gulkana, Alaska (62.2°N, 145.5°W, approximately 340 km to the south to establish the presence of NLCs over the spectrometer site. Data exhibiting significant short-term variations in the relative intensity (as much as 50–100% and rotational temperature (typically 5–15 K were recorded on six occasions when NLCs were observed. Joint measurements were also obtained on several "cloud-free" nights. No obvious relationship was found linking the mean OH intensity or its variation with the occurrence of NLCs. However, a clear tendency was found for the mean OH temperature to be lower on NLC nights than on cloud-free nights. In particular, a significant fraction of the OH(3–1 band spectra recorded by each instrument (16–57% exhibited temperatures below ~154 K on NLC nights compared with <3% on cloud-free nights. This result is qualitatively consistent with current models for ice particle nucleation and growth, but the mean OH temperature on NLC nights (~156 K was significantly higher than would be expected for long-term particle growth in this region. These observations raise questions concerning the expected proximity of the high-latitude, summertime OH layer and the NLC growth region.

  19. Hydroxyl radical modify amino acids and prevent E. coli growth

    International Nuclear Information System (INIS)

    Zhang, Y.; Davies, K.J.A.

    1986-01-01

    The authors report that hydroxyl radical (/sup ./OH) damage to amino acids (AA) affects their incorporation into E. coli proteins. Modification of AA (Try, Trp, Met, Cys, His, Lys, Asn, Gln) by /sup ./OH was achieved by exposure to 60 Co radiation (1-100 krads at 600 rads/min) in N 2 O saturated water. Following exposure to /sup ./OH, the modified AA were added to suspensions of 8 AA requiring E. coli mutants in M9 medium + glucose. Mutants incubated with the /sup ./OH modified AA underwent less growth than those incubated with unmodified AA; with a declining exponential relationship between /sup ./OH exposure of AA and cell growth. The sensitivity of each AA to modification by /sup ./OH was as follows: Tyr > Trp > Met > Cys > His > Lys > Asn > Gln. Essentially the same pattern was observed for inhibition of mutant growth, which was proportional to the concentration of remaining unmodified (i.e. native) AA. Furthermore, cell growth was restored to normal levels by replenishment of native AA. When AA were irradiated at 50μM and then diluted to concentrations expected to support exponential growth (different for each AA) the radiation doses at which mutant growth was inhibited by 63% were as follows (in krad): Tyr 41, Trp 48, Met 53, Cys 56, His 57, Lys 68, Asn 80, Gln 116. /sup ./OH-modified 3 H-Trp was not a substrate for protein synthesis in Trp requiring mutants but was taken up by the cells. Modified Trp was also not incorporated in cell-free synthesis experiments. No toxicity was observed when wild type E. coli, in M9 medium + glucose, were supplemented with any of the/sup ./OH-modified AA. Thus /sup ./OH-modified AA do not support E. coli growth

  20. Measurement of hydroxylated PCB metabolites for Slovakia maternal blood serums

    Energy Technology Data Exchange (ETDEWEB)

    Park, J.S.; Athanasiadou, M; Bergman, A. [Stockholm Univ., Stockholm (Sweden); Charles, J.; Zhao, G.; Hertz-Picciotto, I. [California Univ., Sacramento, CA (United States); Petrik, J.; Kocan, A; Trnovec, T. [Bratislava Inst. of Preventive and Clinical Medicine, Bratislava (Slovakia)

    2005-07-01

    Although it is known that polychlorinated biphenyls (PCBs) have adverse impacts on human health, it is not clear if human health impacts are caused by the PCBs or their related hydroxylated (OH) PCB metabolite compounds. This study measured OH-PCB metabolites in the maternal blood serum specimens from the Svidnik and Michalovce areas in eastern Slovakia where PCBs were intensively produced and inadequately disposed. The aim of the study was to characterize and quantify levels of specific OH-PCB metabolites in Slovakian maternal serums exposed to high environmental PCB levels. All specimens were analyzed for PCBs, and a subset of the samples was analyzed for OH-PCB metabolites. The Wallenburg blood extraction method was adopted to separate the OH-PCBs from the blood serums. Final eluates and calibration standards were spiked with PCB209 as an injection standard before gas chromatography (GC) analysis. OH-PCBs in the samples range from 75{+-}9 per cent to 101{+-}11 per cent. Median concentrations of OH-PCB metabolites of Michalovce samples were approximately twice as high as for the Svidnik samples. Concentrations of OH-PCBs of Michalovce blood samples were comparable to samples obtained from northern Canadian female Inuit and Faroe Island females, and were considered to be among the highest OH-PCB concentrations obtained in human blood. It was concluded that further research is needed to understand the placental transfer of OH-PCBs to the fetus, as well as epidemiological approaches to determine the relationship between the exposure of OH-PCB metabolites and child development. 12 refs., 2 figs.

  1. Di-hydroxyurea-a Promising Reducing Reagent for the U/Pu split in the PUREX process

    Energy Technology Data Exchange (ETDEWEB)

    Taihong, Yan; Weifang, Zheng; Guoan, Ye; Yu, Zhang; Liang, Xian; Ying, Di; Xiaoyan, Bian [Department of Radiochemistry, China Institute of Atomic Energy - CIAE, Beijing 102413 (China)

    2009-06-15

    In the reprocessing of spent nuclear fuel by the Purex process, the separation of U and Pu is a major stage. This is commonly achieved by a redox process, in which a reducing agent (e.g. U(IV) or (FeII)) and a stabiliser (e.g. N{sub 2}H{sub 4} or NH{sub 2}SO{sub 3}H) are added to reduce extractable Pu{sup 4+} to un-extractable Pu{sup 3+}. The stabiliser prevents the nitrous acid catalysed re-oxidation of Pu(III) back to Pu(IV). One of the key objectives is to reduce both the number of solvent extraction cycles and the waste stream volumes [1]. One option for Advanced Purex flowsheets is to adopt a new salt-free reductant in the U/Pu split. Di-hydroxyurea(DHU)-a new Reducing reagent was synthesized with tri-associated solid phosgene (Bis(trichloromethyl)Carbonate) solved in dioxane and hydroxylamine hydrochloride solved in potassium acetate solution. The Reduction of Pu(IV) by DHU was investigated using UV-Vis spectrophotometer. The reduction back-extraction behavior of Pu(IV) in 30%TBP /OK was firstly investigated under conditions of different temperature, different concentration of DHU and HNO{sub 3} and various phase contract time respectively.The results showed that Pu(IV) in organic phase can be stripped rapidly to aqueous phase by DHU. Simulating the 1B contactor of the Purex process by DHU with nitric acid solution as the stripping agent,the separation factors of uranium/plutonium can reach 2.1 10{sup 4}. This indicates that DHU is a promising salt free agent for uranium/plutonium separation. (authors)

  2. A reappraisal of the benefit-risk profile of hydroxyurea in polycythemia vera: A propensity-matched study.

    Science.gov (United States)

    Barbui, Tiziano; Vannucchi, Alessandro Maria; Finazzi, Guido; Finazzi, Maria Chiara; Masciulli, Arianna; Carobbio, Alessandra; Ghirardi, Arianna; Tognoni, Gianni

    2017-11-01

    The use of hydroxyurea (HU) as first line therapy in polycythemia vera (PV) has been criticized because no solid demonstration that this drug prevents thrombosis or prolongs survival has been so far produced. Here we present the outcomes of a large cohort of patients with PV included in the European Collaborative Low-dose Aspirin (ECLAP) study. We selected 1,042 patients who, during the follow-up, had received only phlebotomy (PHL) or HU to maintain the hematocrit level < 45%. To assure comparability, we conducted a propensity score matching analysis. The two groups (PHL n = 342 and HU n = 681) were well balanced for the parameters included in the propensity score (overall balance: χ 2  = 2.44, P = 0.964). Over a comparable period of follow-up (PHL = 29.9 vs. HU = 34.7 months), we documented an advantage of HU over PHL consistently significant with respect to the incidence of fatal/non-fatal cardiovascular (CV) events (5.8 vs. 3.0 per 100 person-years in PHL vs. HU group, P = 0.002) and myelofibrosis transformation that was only experienced by patients of PHL group. Evolution to acute leukemia was registered in three patients (two in PHL and one in HU group). The excess of mortality and total CV events in the PHL patients was restricted to the high-risk group, and, compared with HU cases, was significant higher in the PHL patients who failed to reach the hematocrit target < 0.45% (P = 0.000). In conclusion, this analysis provides reliable and qualified estimates of the therapeutic profile of HU and PHL treatments for future experimental studies and for the management of PV in clinical practice. © 2017 Wiley Periodicals, Inc.

  3. Can Homeopathy Bring Additional Benefits to Thalassemic Patients on Hydroxyurea Therapy? Encouraging Results of a Preliminary Study

    Directory of Open Access Journals (Sweden)

    Antara Banerjee

    2010-01-01

    Full Text Available Several homeopathic remedies, namely, Pulsatilla Nigricans (30th potency, Ceanothus Americanus (both mother tincture and 6th potency and Ferrum Metallicum (30th potency selected as per similia principles were administered to 38 thalassemic patients receiving Hydroxyurea (HU therapy for a varying period of time. Levels of serum ferritin (SF, fetal hemoglobin (HbF, hemoglobin (Hb, platelet count (PC, mean corpuscular volume (MCV, mean corpuscular hemoglobin concentration (MCHC, mean corpuscular hemoglobin (MCH, white blood cell (WBC count, bilirubin content, alanine amino transferase (ALT, aspartate amino transferase (AST and serum total protein content of patients were determined before and 3 months after administration of the homeopathic remedies in combination with HU to evaluate additional benefits, if any, derived by the homeopathic remedies, by comparing the data with those of 38 subjects receiving only HU therapy. Preliminary results indicated that there was a significant decrease in the SF and increase in HbF levels in the combined, treated subjects. Although the changes in other parameters were not so significant, there was a significant decrease in size of spleen in most patients with spleenomegaly and improvement in general health conditions along with an increased gap between transfusions in most patients receiving the combined homeopathic treatment. The homeopathic remedies being inexpensive and without any known side-effects seem to have great potentials in bringing additional benefits to thalassemic patients; particularly in the developing world where blood transfusions suffer from inadequate screening and fall short of the stringent safety standards followed in the developed countries. Further independent studies are encouraged.

  4. Study of hydroxylation of benzene and toluene using a micro-DBD plasma reactor

    International Nuclear Information System (INIS)

    Sekiguchi, H; Ando, M; Kojima, H

    2005-01-01

    The hydroxylation behaviour of benzene and toluene were studied using a micro-plasma reactor, where an atmospheric non-thermal plasma was generated by a dielectric barrier discharge (DBD). The results indicated that oxidation products primarily consisted of phenol and C 4 -compounds for benzene hydroxylation, whereas cresol, benzaldehyde, benzylalcohol and C 4 -compounds were detected for toluene hydroxylation. By taking into consideration the reaction mechanism in the plasma reactor, these products were classified into (1) oxidation of the aromatic ring and functional group on the ring and (2) cleavage of the aromatic ring or dissociation of the functional group on the ring

  5. Microbial hydroxylation and glycosidation of oleanolic acid by Circinella muscae and their anti-inflammatory activities.

    Science.gov (United States)

    Yan, Sensen; Lin, Haijun; Huang, Huilian; Yang, Min; Xu, Bohui; Chen, Guangtong

    2018-05-29

    Biotransformation of oleanolic acid (OA) by Circinella muscae AS 3.2695 was investigated. Nine hydroxylated and glycosylated metabolites (1-9) were obtained. Their structures were elucidated as 3β,7β-dihydroxyolean-12-en-28-oic acid (1), 3β,7β,21β-trihydroxyolean-12-en-28-oic acid (2), 3β,7α,21β-trihydroxyolean-12-en- 28-oic acid (3), 3β,7β,15α-trihydroxyolean-12-en-28-oic acid (4), 7β,15α-dihydroxy- 3-oxo-olean-12-en-28-oic acid (5), 7β-hydroxy-3-oxo-olean-12-en-28-oic acid (6), oleanolic acid-28-O-β-D-glucopyranosyl ester (7), 3β,21β-dihydroxyolean-12-en-28- oic acid-28-O-β-D-glucopyranosyl ester (8), and 3β,7β,15α-trihydroxyolean-12-en- 28-oic acid-28-O-β-D-glucopyranosyl ester (9) by spectroscopic analysis. Among them, compounds 4 and 9 were new compounds. In addition, anti-inflammatory activities were assayed and evaluated for the isolated metabolites. Most of the metabolites exhibited significant inhibitory activities on lipopolysaccharides-induced NO production in RAW 264.7 cells.

  6. Photoproduction of hydroxyl radicals in aqueous solution with algae under high-pressure mercury lamp.

    Science.gov (United States)

    Liu, Xianli; Wu, Feng; Deng, Nansheng

    2004-01-01

    Photoproduction of hydroxyl radicals (*OH) could be induced in aqueous solution with algae (Nitzschia hantzschiana, etc.) and (or not) Fe3+ under high-pressure mercury lamp with an exposure time of 4 h. *OH was determined by HPLC using benzene as a probe. The photoproduction of *OH increased with increasing algae concentration. Fe3+ could enhance the photoproduction of *OH in aqueous solution with algae. The results showed that the photoproduction of *OH in algal solution with Fe3+ was greater than that in algal solution without Fe3+. The light intensity and pH affected the photoproduction of *OH in aqueous solution with algae with/without Fe3+. The photoproduction of *OH in aqueous solution with algae and Fe3+ under 250 W was greater than that under 125 W HPML. The photoproduction of *OH in algal solution (pH ranged from 4.0 to 7.0) with (or not) Fe3+ at pH 4 was the greatest.

  7. Possible involvement of G-proteins and cAMP in the induction of progesterone hydroxylating enzyme system in the vascular wilt fungus Fusarium oxysporum.

    Science.gov (United States)

    Poli, Anna; Di Pietro, Antonio; Zigon, Dusan; Lenasi, Helena

    2009-02-01

    Fungi present the ability to hydroxylate steroids. In some filamentous fungi, progesterone induces an enzyme system which converts the compound into a less toxic hydroxylated product. We investigated the progesterone response in the vascular wilt pathogen Fusarium oxysporum, using mass spectrometry and high performance liquid chromatography (HPLC). Progesterone was mainly transformed into 15alpha-hydroxyprogesterone, which was found predominantly in the extracellular medium. The role of two conserved fungal signaling cascades in the induction of the progesterone-transforming enzyme system was studied, using knockout mutants lacking the mitogen-activated protein kinase Fmk1 or the heterotrimeric G-protein beta subunit Fgb1 functioning upstream of the cyclic adenosine monophosphate (cAMP) pathway. No steroid hydroxylation was induced in the Deltafgb1 strain, suggesting a role for the G-protein beta subunit in progesterone signaling. Exogenous cAMP restored the induction of progesterone-transforming activity in the Deltafgb1 strain, suggesting that steroid signaling in F. oxysporum is mediated by the cAMP-PKA pathway.

  8. Endoscopic treatment of vesicoureteral reflux using calcium hydroxyl apatite in dogs

    Directory of Open Access Journals (Sweden)

    Tavakoli Azin

    2011-01-01

    Full Text Available Abstract Background Injection of biomaterial to suburetral region, using minimally invasive procedure, has become an interesting topic for urologists to treat vesicoureteral reflux. The objective of this study was to evaluate the feasibility of injecting newly introduced calcium hydroxyl apatite to suburetral region, for treating an experimentally induced vesicoureteral reflux in dogs. Findings Bilateral vesicoureteral refluxed (VUR mixed breed dogs (n = 12; 10-15 kg live weight, 3-6 months of age were selected for this study. The presence and grade of the reflux were determined using cystography. Accordingly, 6 dogs displayed grade 1 & 2 and the other 6 showed grade 3 & 4 bilateral VUR. Every single dog, with bilateral VUR, underwent endoscopic treatment and received an injection of calcium hydroxyl apatite (an Iranian made product into the left (treated side and an injection of the similar volume of normal saline in to the right (control side subureteric space. One week, 3 and 6 months after treatment, cystography was performed. On each occasion, 4 dogs were euthanized by gas inhalation and biopsy samples were collected for histopathological study from ureter, bladder, kidney, lung and spleen in order to investigate the biomaterial migration into different organs. Data were analyzed using Chi-squared test. In control sides, radiographs confirmed the same grade of VUR, found at the initiation of the study. VUR was resolved in 100% (6/6 of Grade 1 & 2 and 83.33% (5/6 of Grade 3 & 4 in treated side. Therefore, the total success rate of this study was 91.67% (11/12. Macroscopic examination of the vesicouretral region of the treated side revealed a firm and consistent biomaterial mass at the site of injection. Histological findings confirmed inflammation at treated side. In contrast, there was no tissue reaction on control side. There was no evidence for biomaterial migration in macroscopic and microscopic observations in this study. Conclusion In

  9. Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition

    Science.gov (United States)

    Frost, Julianty; Galdeano, Carles; Soares, Pedro; Gadd, Morgan S.; Grzes, Katarzyna M.; Ellis, Lucy; Epemolu, Ola; Shimamura, Satoko; Bantscheff, Marcus; Grandi, Paola; Read, Kevin D.; Cantrell, Doreen A.; Rocha, Sonia; Ciulli, Alessio

    2016-11-01

    Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.

  10. Inhibition of polymerases-alpha and -beta completely blocks DNA repair induced by UV irradiation in cultured mouse neuronal cells

    International Nuclear Information System (INIS)

    Licastro, F.; Sarafian, T.; Verity, A.M.; Walford, R.L.

    1985-01-01

    The effects of hydroxyurea, aphidicolin and dideoxythymidine on UV-induced DNA repair of mouse neuronal granular cells were studied. Aphidicolin, which is considered a specific inhibitor of polymerase-alpha, decreased spontaneous DNA synthesis by 93% and totally suppressed DNA repair. Dideoxythymidine, an inhibitor of polymerase-beta, was more potent in decreasing scheduled DNA synthesis than aphidicolin, and also completely blocked the UV-induced DNA repair. Hydroxyurea, a specific inhibitor of ribonucleotide reductase, inhibited scheduled DNA synthesis, but unscheduled DNA synthesis after UV irradiation was always well detectable. Our data suggest that in neuronal cells from 5 to 10 days old mice both polymerases-alpha and -beta are required for both DNA synthesis and repair. These two enzymes may act jointly in filling up the gaps along the DNA molecule and elongating the DNA chain

  11. Scattering of State-Selected and Oriented Hydroxyl Radicals by Halogen Hydrides and Xenon

    NARCIS (Netherlands)

    Moise, A.V.

    2007-01-01

    The interaction of the OH radical with atoms and other molecules is relevant for many physical and chemical processes involved in atmospheric, combustion and interstellar chemistry. Various experimental and theoretical studies have revealed information concerning the interaction of the hydroxyl

  12. Atmospheric hydroxyl radical production from electronically excited NO2 and H2O.

    Science.gov (United States)

    Li, Shuping; Matthews, Jamie; Sinha, Amitabha

    2008-03-21

    Hydroxyl radicals are often called the "detergent" of the atmosphere because they control the atmosphere's capacity to cleanse itself of pollutants. Here, we show that the reaction of electronically excited nitrogen dioxide with water can be an important source of tropospheric hydroxyl radicals. Using measured rate data, along with available solar flux and atmospheric mixing ratios, we demonstrate that the tropospheric hydroxyl contribution from this source can be a substantial fraction (50%) of that from the traditional O(1D) + H2O reaction in the boundary-layer region for high solar zenith angles. Inclusion of this chemistry is expected to affect modeling of urban air quality, where the interactions of sunlight with emitted NOx species, volatile organic compounds, and hydroxyl radicals are central in determining the rate of ozone formation.

  13. Hydroxylation of benzene to phenol over magnetic recyclable nanostructured CuFe mixed-oxide catalyst

    CSIR Research Space (South Africa)

    Makgwane, PR

    2015-03-01

    Full Text Available A highly active and magnetically recyclable nanostructured copper–iron oxide (CuFe) catalyst has been synthesized for hydroxylation of benzene to phenol under mild reaction conditions. The obtained catalytic results were correlated with the catalyst...

  14. MLS/Aura L2 Hydroxyl (OH) Mixing Ratio V002

    Data.gov (United States)

    National Aeronautics and Space Administration — ML2OH is the EOS Aura Microwave Limb Sounder (MLS) standard product for hydroxyl derived from radiances measured by the THz radiometer. The current version is 2.2....

  15. Stereoselective and regiospecific hydroxylation of ketamine and norketamine.

    Science.gov (United States)

    Desta, Zeruesenay; Moaddel, Ruin; Ogburn, Evan T; Xu, Cong; Ramamoorthy, Anuradha; Venkata, Swarajya Lakshmi Vattem; Sanghvi, Mitesh; Goldberg, Michael E; Torjman, Marc C; Wainer, Irving W

    2012-11-01

    The objective was to determine the cytochrome P450s (CYPs) responsible for the stereoselective and regiospecific hydroxylation of ketamine [(R,S)-Ket] to diastereomeric hydroxyketamines, (2S,6S;2R,6R)-HK (5a) and (2S,6R;2R,6S)-HK (5b) and norketamine [(R,S)-norKet] to hydroxynorketamines, (2S,6S;2R,6R)-HNK (4a), (2S,6R;2R,6S)-HNK (4b), (2S,5S;2R,5R)-HNK (4c), (2S,4S;2R,4R)-HNK (4d), (2S,4R;2R,4S)-HNK (4e), (2S,5R;2R,5S)-HNK (4f). The enantiomers of Ket and norKet were incubated with characterized human liver microsomes (HLMs) and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site Michaelis-Menten, Hill or substrate inhibition equation. 5a was predominantly formed from (S)-Ket by CYP2A6 and N-demethylated to 4a by CYP2B6. 5b was formed from (R)- and (S)-Ket by CYP3A4/3A5 and N-demethylated to 4b by multiple enzymes. norKet incubation produced 4a, 4c and 4f and minor amounts of 4d and 4e. CYP2A6 and CYP2B6 were the major enzymes responsible for the formation of 4a, 4d and 4f, and CYP3A4/3A5 for the formation of 4e. The 4b metabolite was not detected in the norKet incubates. 5a and 4b were detected in plasma samples from patients receiving (R,S)-Ket, indicating that 5a and 5b are significant Ket metabolites. Large variations in HNK concentrations were observed suggesting that pharmacogenetics and/or metabolic drug interactions may play a role in therapeutic response.

  16. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea.

    Science.gov (United States)

    Verstovsek, Srdan; Passamonti, Francesco; Rambaldi, Alessandro; Barosi, Giovanni; Rosen, Peter J; Rumi, Elisa; Gattoni, Elisabetta; Pieri, Lisa; Guglielmelli, Paola; Elena, Chiara; He, Shui; Contel, Nancy; Mookerjee, Bijoyesh; Sandor, Victor; Cazzola, Mario; Kantarjian, Hagop M; Barbui, Tiziano; Vannucchi, Alessandro M

    2014-02-15

    Polycythemia vera (PV) is a myeloproliferative neoplasm associated with somatic gain-of-function mutations of Janus kinase-2 (JAK2). Therapeutic options are limited in patients with advanced disease. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is active in preclinical models of PV. The long-term efficacy and safety of ruxolitinib in patients with advanced PV who are refractory or intolerant to hydroxyurea were studied in a phase 2 trial. Response was assessed using modified European LeukemiaNet criteria, which included a reduction in hematocrit to cell and platelet counts, and reduction in PV-associated symptoms. Thirty-four patients received ruxolitinib for a median of 152 weeks (range, 31 weeks-177 weeks) or 35.0 months (range, 7.1 months-40.7 months). Hematocrit night sweats, and bone pain were observed within 4 weeks of the initiation of therapy and maintained with continued treatment. Ruxolitinib treatment also reduced elevated levels of inflammatory cytokines and granulocyte activation. Thrombocytopenia and anemia were the most common adverse events.Thrombocytopenia of grade 3 or anemia of grade 3 (according to National Cancer Institute Common Terminology Criteria for Adverse Events,version 3.0) occurred in 3 patients each (9%) (1 patient had both) and were managed with dose modification. Ruxolitinib was generally well tolerated and provided rapid and durable clinical benefits in patients with advanced PV who were refractory or intolerant to hydroxyurea.

  17. Hydroxylation of the Herbicide Isoproturon by Fungi Isolated from Agricultural Soil

    OpenAIRE

    Rønhede, Stig; Jensen, Bo; Rosendahl, Søren; Kragelund, Birthe B.; Juhler, René K.; Aamand, Jens

    2005-01-01

    Several asco-, basidio-, and zygomycetes isolated from an agricultural field were shown to be able to hydroxylate the phenylurea herbicide isoproturon [N-(4-isopropylphenyl)-N′,N′-dimethylurea] to N-(4-(2-hydroxy-1-methylethyl)phenyl)-N′,N′-dimethylurea and N-(4-(1-hydroxy-1-methylethyl)phenyl)-N′,N′-dimethylurea. Bacterial metabolism of isoproturon has previously been shown to proceed by an initial demethylation to N-(4-isopropylphenyl)-N′-methylurea. In soils, however, hydroxylated metaboli...

  18. 4-Substituted-2-Methoxyphenol: Suitable Building Block to Prepare New Bioactive Natural-like Hydroxylated Biphenyls.

    Science.gov (United States)

    Dettori, Maria Antonietta; Fabbri, Davide; Pisano, Marina; Rozzo, Carla; Palmieri, Giuseppe; Dess, Alessandro; Dallocchio, Roberto; Delogu, Giovanna

    2015-02-01

    A small collection of eugenol- and curcumin-analog hydroxylated biphenyls was prepared by straightforward methods starting from natural 4-substituted-2-methoxyphenols and their antitumoral activity was evaluated in vitro . Two curcumin-biphenyl derivatives showed interesting growth inhibitory activities on different malignant melanoma cell lines with IC 50 ranging from 13 to 1 µM. Preliminary molecular modeling studies were carried out to evaluate conformations and dihedral angles suitable for antiproliferative activity in hydroxylated biphenyls bearing a side aliphatic chain.

  19. The hydroxyl species and acid sites on diatomite surface: a combined IR and Raman study

    Science.gov (United States)

    Yuan, P.; Wu, D. Q.; He, H. P.; Lin, Z. Y.

    2004-04-01

    Diffuse reflectance infrared Fourier transform spectroscopy (DRIFT), Raman spectroscopy of adsorbed pyridine molecules (Py-Raman) and in situ Py-IR have been used to investigate the hydroxyl species and acid sites on diatomite surfaces. The Lewis (L) and Brønsted (B) acid sites, and various hydroxyl species, including isolated hydroxyl groups, H-bonded hydroxyl groups and physically adsorbed water, are identified. The L acid sites in diatomite samples are resulted from the clay impurities, and the B acid sites are resulted from some moderate strength H-bonded hydroxyl groups. At room temperature, both of the isolated and H-bonded silanols associate with the physically adsorbed water by hydrogen bond. After calcination treatment, physically adsorbed water will be desorbed from the silanols, and the silanols will condense with the increase of temperature. Generally, the H-bonded silanols condense more easily than the isolated ones. The properties of surface hydroxyl species of diatomaceous silica are more similar to precipitated silica rather than fumed silica.

  20. CATALYTIC PERFORMANCES OF Fe2O3/TS-1 CATALYST IN PHENOL HYDROXYLATION REACTION

    Directory of Open Access Journals (Sweden)

    Didik Prasetyoko

    2010-07-01

    Full Text Available Hydroxylation reaction of phenol into diphenol, such as hydroquinone and catechol, has a great role in many industrial applications. Phenol hydroxylation reaction can be carried out using Titanium Silicalite-1 (TS-1 as catalyst and H2O2 as an oxidant. TS-1 catalyst shows high activity and selectivity for phenol hydroxylation reaction. However, its hydrophobic sites lead to slow H2O2 adsorption toward the active site of TS-1. Consequently, the reaction rate of phenol hydroxylation reaction is tends to be low. Addition of metal oxide Fe2O3 enhanced hydrophilicity of TS-1 catalyst. Liquid phase catalytic phenol hydroxylation using hydrogen peroxide as oxidant was carried out over iron (III oxide-modified TS-1 catalyst (Fe2O3/TS-1, that were prepared by impregnation method using iron (III nitrate as precursor and characterized by X-ray diffraction, infrared spectroscopy, nitrogen adsorption, pyridine adsorption, and hydrophilicity techniques. Catalysts 1Fe2O3/TS-1 showed maximum catalytic activity of hydroquinone product. In this research, the increase of hydroquinone formation rate is due to the higher hydrophilicity of Fe2O3/TS-1 catalysts compare to the parent catalyst, TS-1.   Keywords: Fe2O3/TS-1, hydrophilic site, phenol hydroxylation

  1. Intracrystalline fractionation of oxygen isotopes between hydroxyl and non-hydroxyl sites in kaolinite measured by thermal dehydroxylation and partial fluorination

    Science.gov (United States)

    Girard, Jean-Pierre; Savin, Samuel M.

    1996-02-01

    Thermal dehydroxylation and partial fluorination techniques were used to measure intracrystalline fractionation of oxygen isotopes between hydroxyl and non-hydroxyl sites in kaolinite. Several aliquots of a well characterized, fine-grained (rates, and target temperatures. Measured δ18O values of both the liberated water and the dehydroxylated residue are consistent over a wide range of temperatures (550 850°C) when dehydroxylation is performed in a single-step fashion at a rapid heating rate (>50°C/min.). Similar dehydroxylation experiments indicate that brucite dehydroxylation occurs without any significant isotopic fractionation of the oxygen isotopes. By extrapolation we postulate that no significant fractionation occurs during single-step thermal dehydroxylation of fine-grained kaolinite, provided that dehydroxylation is performed under well controlled conditions. In contrast, gibbsite dehydroxylation is accompanied by substantial isotopic fractionation. This is probably the result of the complex, multi-pathway dehydroxylation reaction of this mineral. Similarly, thermal dehydroxylation of coarsegrained (>1 μm) kaolinites and dickites of weathering and hydrothermal origin yield results that are dependent on the temperature of dehydroxylation. We suggest that this effect may be caused by isotopic exchange during diffusion of water molecules through coarse particles. Partial fluorination of fine-grained kaolinite in the presence of excess F2 at low temperatures (rate of reaction of hydroxyl oxygen than of non-hydroxyl oxygen, but examination of the isotopic data as well as XRD and IR analyses of the residues after partial fluorination indicates that the separation between the two types of oxygen is not complete. The results, therefore, do not yield a reliable δ18O value of the hydroxyl oxygen. The results of this study suggest that the thermal dehydroxylation technique may be appropriate for analysis of OH groups in fine-grained kaolinite. The partial

  2. Insights into the Structures of DNA Damaged by Hydroxyl Radical: Crystal Structures of DNA Duplexes Containing 5-Formyluracil

    Directory of Open Access Journals (Sweden)

    Masaru Tsunoda

    2010-01-01

    Full Text Available Hydroxyl radicals are potent mutagens that attack DNA to form various base and ribose derivatives. One of the major damaged thymine derivatives is 5-formyluracil (fU, which induces pyrimidine transition during replication. In order to establish the structural basis for such mutagenesis, the crystal structures of two kinds of DNA d(CGCGRATfUCGCG with R = A/G have been determined by X-ray crystallography. The fU residues form a Watson-Crick-type pair with A and two types of pairs (wobble and reversed wobble with G, the latter being a new type of base pair between ionized thymine base and guanine base. In silico structural modeling suggests that the DNA polymerase can accept the reversed wobble pair with G, as well as the Watson-Crick pair with A.

  3. Preliminary study on the photoproduction of hydroxyl radicals in aqueous solution with Aldrich humic acid, algae and Fe(III) under high-pressure mercury lamp irradiation.

    Science.gov (United States)

    Liu, Xianli; Xu, Dong; Wu, Feng; Liao, Zhenhuan; Liu, Jiantong; Deng, Nansheng

    2004-03-01

    Under a high-pressure mercury lamp (HPML) and using an exposure time of 4 h, the photoproduction of hydroxyl radicals (*OH) could be induced in an aqueous solution containing humic acid (HA). Hydroxyl radicals were determined by high-performance liquid chromatography using benzene as a probe. The results showed that *OH photoproduction increased from 1.80 to 2.74 microM by increasing the HA concentration from 10 to 40 mg L(-1) at an exposure time of 4 h (pH 6.5). Hydroxyl radical photoproduction in aqueous solutions of HA containing algae was greater than that in the aqueous solutions of HA without algae. The photoproduction of *OH in the HA solution with Fe(III) was greater than that of the solution without Fe(III) at pH ranging from 4.0 to 8.0. The photoproduction of *OH in HA solution with algae with or without Fe(III) under a 250 W HPML was greater than that under a 125 W HPML. The photoproduction of *OH in irradiated samples was influenced by the pH. The results showed that HPML exposure for 4 h in the 4-8 pH range led to the highest *OH photoproduction at pH 4.0.

  4. The Effect of Hydroxylated Fullerene Nanoparticles on Antioxidant Defense System in Brain Ischemia Rat

    Directory of Open Access Journals (Sweden)

    2017-05-01

    Full Text Available Background and Objectives: According to the previous findings, brain ischemia attenuates the brain antioxidant defense system. This study aimed to investigate the effect of hydroxylated fullerene nanoparticle on antioxidant defense system in ischemic brain rat. Methods: In this Experimental study, rats were divided into three groups (n=6 in each group: sham, ischemic control, and ischemic treatment group. Brain ischemia was induced by middle cerebral artery (MCA occlusion for 90 minutes followed by a 24-hour reperfusion. Ischemic treatment animals received fullerene nanoparticles intraperitoneally at a dose of 10mg/kg immediately after the end of MCA occlusion. After 24-h reperfusion period, brain catalase and superoxide dismutase (SOD, and glutathione activities were assessed by biochemical methods. The data were analyzed using one-way ANOVA and Tukey post-hoc test. Results: The mean glutathione level and catalase and SOD activities in sham animals were 1±0.18%, 1±0.20%, and 1±0.04%, respectively. Induction of brain ischemia decreased the value of glutathione level and catalase and SOD activities in control ischemic rats and their values were obtained to be 0.55±0.09%, 0.44±0.05%, and 0.86±0.02%, respectively. Fullerene significantly increased the activities of catalase (0.93±0.29% and SOD (1.33±0.22% in ischemic treatment group compared to ischemic control rats, but did not change the glutathione level (0.52±0.25%. Conclusion: The results of this study showed that treatment with fullerene nanoparticles improves the brain antioxidant defense system, which is weakened during brain ischemia, through increasing catalase and SOD activities.

  5. Hydroxyl and Hydroperoxy Radical Chemistry during the MCMA-2006 Field Campaign: Measurement and Model Comparison

    Science.gov (United States)

    Dusanter, S.; Vimal, D.; Stevens, P. S.; Volkamer, R.; Molina, L. T.

    2007-12-01

    The Mexico City Metropolitan Area (MCMA) field campaign, held in March 2006, was a unique opportunity to collect data in one of the most polluted megacities in the world. Such environments exhibit a complex oxidation chemistry involving a strong coupling between odd hydrogen radicals (HOX=OH+HO2) and nitrogen oxides species (NOX=NO+NO2). High levels of volatile organic compounds (VOCs) and NOX control the HOX budget and lead to elevated tropospheric ozone formation. The HOX-NOX coupling can be investigated by comparing measured and model-predicted HOx concentrations. Atmospheric HOX concentrations were measured by the Indiana University laser-induced fluorescence instrument and data were collected at the Instituto Mexicano del Petroleo between 14 and 31 March. Measured hydroxyl radical (OH) concentrations are comparable to that measured in less polluted urban environments and suggest that the OH concentrations are highly buffered under high NOX conditions. In contrast, hydroperoxy radical (HO2) concentrations are more sensitive to the NOX levels and are highly variable between different urban sites. Enhanced levels of OH and HO2 radicals were observed on several days between 9h30-11h00 AM and suggest an additional HOX source for the morning hours and/or a fast HOX cycling under the high NOX conditions of the MCMA. A preliminary investigation of the HOX chemistry occurring in the MCMA urban atmosphere was performed using a photochemical box model based on the Regional Atmospheric Chemistry Mechanism (RACM). Model comparisons will be presented and the agreement between measured and predicted HOX concentrations will be discussed.

  6. Measurements of hydroxyl and hydroperoxy radicals during CalNex-LA: Model comparisons and radical budgets

    Science.gov (United States)

    Griffith, S. M.; Hansen, R. F.; Dusanter, S.; Michoud, V.; Gilman, J. B.; Kuster, W. C.; Veres, P. R.; Graus, M.; de Gouw, J. A.; Roberts, J.; Young, C.; Washenfelder, R.; Brown, S. S.; Thalman, R.; Waxman, E.; Volkamer, R.; Tsai, C.; Stutz, J.; Flynn, J. H.; Grossberg, N.; Lefer, B.; Alvarez, S. L.; Rappenglueck, B.; Mielke, L. H.; Osthoff, H. D.; Stevens, P. S.

    2016-04-01

    Measurements of hydroxyl (OH) and hydroperoxy (HO2*) radical concentrations were made at the Pasadena ground site during the CalNex-LA 2010 campaign using the laser-induced fluorescence-fluorescence assay by gas expansion technique. The measured concentrations of OH and HO2* exhibited a distinct weekend effect, with higher radical concentrations observed on the weekends corresponding to lower levels of nitrogen oxides (NOx). The radical measurements were compared to results from a zero-dimensional model using the Regional Atmospheric Chemical Mechanism-2 constrained by NOx and other measured trace gases. The chemical model overpredicted measured OH concentrations during the weekends by a factor of approximately 1.4 ± 0.3 (1σ), but the agreement was better during the weekdays (ratio of 1.0 ± 0.2). Model predicted HO2* concentrations underpredicted by a factor of 1.3 ± 0.2 on the weekends, while measured weekday concentrations were underpredicted by a factor of 3.0 ± 0.5. However, increasing the modeled OH reactivity to match the measured total OH reactivity improved the overall agreement for both OH and HO2* on all days. A radical budget analysis suggests that photolysis of carbonyls and formaldehyde together accounted for approximately 40% of radical initiation with photolysis of nitrous acid accounting for 30% at the measurement height and ozone photolysis contributing less than 20%. An analysis of the ozone production sensitivity reveals that during the week, ozone production was limited by volatile organic compounds throughout the day during the campaign but NOx limited during the afternoon on the weekends.

  7. Comparison of Simultaneous PIV and Hydroxyl Tagging Velocimetry in Low Velocity Flows

    Science.gov (United States)

    Andre, Matthieu A.; Bardet, Philippe M.; Burns, Ross A.; Danehy, Paul M.

    2016-01-01

    Hydroxyl tagging velocimetry (HTV) is a molecular tagging velocimetry (MTV) technique that relies on the photo- dissociation of water vapor into OH radicals and their subsequent tracking using laser-induced fluorescence. At ambient temperature in air, the OH species lifetime is about 50 micro-s. The feasibility of using HTV for probing low- speed flows (a few m/s) is investigated by using an inert, heated gas as a means to increase the OH species lifetime. Unlike particle-based techniques, MTV does not suffer from tracer settling, which is particularly problematic at low speeds. Furthermore, the flow needs to be seeded with only a small mole fraction of water vapor, making it safer for both the user and facilities than other MTV techniques based on corrosive or toxic chemical tracers. HTV is demonstrated on a steam-seeded nitrogen jet at approximately 75 C in the laminar (Umean=3.31 m/s, Re=1,540), transitional (Umean=4.48 m/s, Re=2,039), and turbulent (Umean=6.91 m/s, Re=3,016) regimes at atmospheric pressure. The measured velocity profiles are compared with particle image velocimetry (PIV) measurements performed simultaneously with a second imager. Seeding for the PIV is achieved by introducing micron-sized water droplets into the flow with the steam; the same laser sheet is used for PIV and HTV to guarantee spatial and temporal overlap of the data. Optimizing each of these methods, however, requires conflicting operating conditions: higher temperatures benefit the HTV signals but reduce the available seed density for the PIV through evaporation. Nevertheless, data are found to agree within 10% for the instantaneous velocity profiles and within 5% for the mean profiles and demonstrate the feasibility of HTV for low-speed flows at moderate to high temperatures.

  8. Hydrogen bonding analysis of hydroxyl groups in glucose aqueous solutions by a molecular dynamics simulation study

    International Nuclear Information System (INIS)

    Chen, Cong; Li, Wei Zhong; Song, Yong Chen; Weng, Lin Dong; Zhang, Ning

    2012-01-01

    Molecular dynamics simulations have been performed to investigate hydrogen bonding characteristics of hydroxyl groups in glucose aqueous solutions with different concentrations. The hydrogen bonding abilities and strength of different O and H atom types have been calculated and compared. The acceptor/donor efficiencies have been predicted and it has been found that: (1) O2-HO2 and O3-HO3 are more efficient intramolecular hydrogen bonding acceptors than donors; (2) O1-HO1, O4-HO4 and O6-HO6 are more efficient intramolecular hydrogen bonding donors than acceptors; (5) O1-HO1 and O6-HO6 are more efficient intermolecular hydrogen bonding acceptors than donors while hydroxyl groups O2-HO2 and O4-HO4 are more efficient intermolecular hydrogen bonding donors than acceptors. The hydrogen bonding abilities of hydroxyl groups revealed that: (1) the hydrogen bonding ability of OH2-H w is larger than that of hydroxyl groups in glucose; (2) among the hydroxyl groups in glucose, the hydrogen bonding ability of O6-HO6 is the largest and the hydrogen bonding ability of O4-HO4 is the smallest; (3) the intermolecular hydrogen bonding ability of O6-HO6 is the largest; (4) the order for intramolecular hydrogen bonding abilities (from large to small) is O2-HO2, O1-HO1, O3-HO3, O6-HO6 and O4-HO4

  9. Mechanism of aromatic hydroxylation of lidocaine at a Pt electrode under acidic conditions

    International Nuclear Information System (INIS)

    Gul, Turan; Bischoff, Rainer; Permentier, Hjalmar P.

    2017-01-01

    Aromatic hydroxylation reactions, which are mainly catalyzed by cytochrome P450 (CYP) enzymes in vivo, are some of the most important reactions of Phase I metabolism, because insertion of a hydroxyl group into a lipophilic drug compound increases its hydrophilicity and prepares it for subsequent Phase II metabolic conjugation reactions as a prerequisite to excretion. Aromatic hydroxylation metabolites of pharmaceuticals may be obtained through various synthetic and enzymatic methods Electrochemical oxidation is an alternative with advantages in terms of mild reaction conditions and less hazardous chemicals. In the present study, we report that aromatic hydroxylation metabolites of lidocaine can be readily obtained electrochemically under aqueous acidic conditions at platinum electrodes. Our results show that the dominant N-dealkylation reaction can be suppressed by decreasing the solution pH below 0.5 resulting in selective 3-hydroxylidocaine, which is an in vivo metabolite of lidocaine. Experiments in 18 O labelled water indicated that water is the primary source of oxygen, while dissolved molecular oxygen contributes to a minor extent to the hydroxylation reaction.

  10. N-hydroxyurea, mitomycin C and actinomycin D activity in the process of tumour formation on the primary leaves of the 'Pinto' bean

    Directory of Open Access Journals (Sweden)

    Aldona Rennert

    2014-01-01

    Full Text Available Mitomycin C (MC, N-hydroxyurea (HU and actinomycin D (AD inhibit tumour formation on the primary leaves of Pinto beans. Agrobacterium tumefaciens was inoculated into bean leaves with application of the above named inhibitors at various times. It was found that MC action is strongest during inoculation and immediately after it, the maximal effect of HU take place within 12 h after inoculation, whereas the antitumour action of AD starts as late as 12 h after leaf inoculation. In view of the different degree of susceptibility of bacteria and plant cells to the inhibitors applied, the above described results allowed to distinguish three critical periods in the process of tumour formation in the tested host-pathogen system.

  11. Hydroxylative activity of Aspergillus niger towards androst-4-ene and androst-5-ene steroids.

    Science.gov (United States)

    Świzdor, Alina; Panek, Anna; Milecka-Tronina, Natalia

    2017-10-01

    Aspergillus niger, one of fungal species most frequently used for experimental and industrial-scale biotransformations of various organic compounds, is generally known to transform steroids at 16β position. In this work, application of the strain A. niger KCH910 to bioconversion of dehydroepiandrosterone (DHEA), androstenediol and testosterone is described, with emphasis on the metabolic steps leading to the products. Evidence from this study indicated that incubated 5-ene steroids underwent bioconversion within two metabolic pathways: oxidation by the action of 3β-HSD (3β-hydroxysteroid dehydrogenase) to 4-ene steroids, and minor allylic hydroxylation to epimeric 7-alcohols. Further transformation of the 3-oxo-4-ene metabolites resulted in non-selective 16-hydroxylation. It is the first report on an A. niger strain able to introduce not only 16β- but also 16α-hydroxyl function into steroids. Copyright © 2017. Published by Elsevier Inc.

  12. Structure and Dynamics of Hydroxyl-Functionalized Protic Ammonium Carboxylate Ionic Liquids.

    Science.gov (United States)

    Thummuru, Dhileep Nagi Reddy; Mallik, Bhabani S

    2017-10-26

    We performed classical molecular dynamics simulations to investigate the structure and dynamics of protic ionic liquids, 2-hydroxy ethylammonium acetate, ethylammonium hydroxyacetate, and 2-hydroxyethylammonium hydroxyacetate at ambient conditions. Structural properties such as density, radial distribution functions, spatial distribution functions, and structure factors have been calculated. Dynamic properties such as mean square displacements, as well as residence and hydrogen bond dynamics have also been calculated. Hydrogen bond lifetimes and residence times change with the addition of hydroxyl groups. We observe that when a hydroxyl group is present on the cation, dynamics become very slow and it forms a strong hydrogen bond with carboxylate oxygen atoms of the anion. The hydroxyl functionalized ILs show more dynamic diversity than structurally similar ILs.

  13. Electrolytic coloration and spectral properties of hydroxyl-doped potassium chloride single crystals

    International Nuclear Information System (INIS)

    Gu Hongen; Wu Yanru

    2011-01-01

    Hydroxyl-doped potassium chloride single crystals are colored electrolytically at various temperatures and voltages using a pointed cathode and a flat anode. Characteristic OH - spectral band is observed in the absorption spectrum of uncolored single crystal. Characteristic O - , OH - , U, V 2 , V 3 , O 2- -V a + , F, R 2 and M spectral bands are observed simultaneously in absorption spectra of colored single crystals. Current-time curve for electrolytic coloration of hydroxyl-doped potassium chloride single crystal and its relationship with electrolytic coloration process are given. Production and conversion of color centers are explained. - Highlights: → Expanded the traditional electrolysis method. → Hydroxyl-doped potassium chloride crystals were colored electrolytically for the first time. → Useful V, F and F-aggregate color centers were produced in colored crystals. → V color centers were produced directly and F and F-aggregate color centers indirectly.

  14. SU-F-T-676: Measurement of Hydroxyl Radicals in Radiolized Water Systems

    Energy Technology Data Exchange (ETDEWEB)

    Ouyang, Z; Ngwa, W [University of Massachusetts Lowell, Lowell, MA (United States); Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (United States); Strack, G; Sajo, E [University of Massachusetts Lowell, Lowell, MA (United States)

    2016-06-15

    Purpose: Hydroxyl radicals can be produced within tissue by radiation therapy, and they are largely responsible for DNA damage and cell killing. Coumarin-3-carboxylic acid (3-CCA) and crystal violet are reported to react with hydroxyl radicals and can be used for fluorescence and absorbance measurements, respectively. This study assesses the ability of hydroxyl measurement for both 3-CCA and crystal violet in radiolized water systems in order to provide dosimetric information in radiation chemistry and radiation biology experiments. Methods: 3-CCA and crystal violet were both dissolved in phosphate buffered saline (PBS, pH 7.4) with final concentrations 0.5 mg/mL and 0.05 mg/mL. 3-CCA and control solutions (PBS only) were loaded in black bottom 96-well plates. Crystal violet and control solutions were loaded in clear bottom 96-well plates. The prepared solutions were irradiated at 2 Gy using a small animal radiation research platform. Fluorescence reading with 360 nm excitation wavelength and 485 nm emission wavelength was done for 3-CCA, and absorbance reading at wavelength 580 nm was done for crystal violet before and after radiation. Results: 3-CCA showed clear difference in fluorescence before and after radiation, which suggested hydroxyl production during radiation. However, crystal violet absorbance at 580 nm was not changed significantly by radiation. Conclusion: The overall conclusion is that 3-CCA can be used for hydroxyl measurement in radiolized water systems, while crystal violet cannot, although crystal violet is reported widely to react with hydroxyl radicals produced in Fenton reactions. Possible reasons could relate to reaction pH.

  15. Comprehensive database of Manufactured Gas Plant tars. Part C. Heterocyclic and hydroxylated polycyclic aromatic hydrocarbons.

    Science.gov (United States)

    Gallacher, Christopher; Thomas, Russell; Lord, Richard; Kalin, Robert M; Taylor, Chris

    2017-08-15

    Coal tars are a mixture of organic and inorganic compounds that were by-products from the manufactured gas and coke making industries. The tar compositions varied depending on many factors such as the temperature of production and the type of retort used. For this reason a comprehensive database of the compounds found in different tar types is of value to understand both how their compositions differ and what potential chemical hazards are present. This study focuses on the heterocyclic and hydroxylated compounds present in a database produced from 16 different tars from five different production processes. Samples of coal tar were extracted using accelerated solvent extraction (ASE) and derivatized post-extraction using N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane (TMCS). The derivatized samples were analysed using two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GCxGC/TOFMS). A total of 865 heterocyclic compounds and 359 hydroxylated polycyclic aromatic hydrocarbons (PAHs) were detected in 16 tar samples produced by five different processes. The contents of both heterocyclic and hydroxylated PAHs varied greatly with the production process used, with the heterocyclic compounds giving information about the feedstock used. Of the 359 hydroxylated PAHs detected the majority would not have been be detected without the use of derivatization. Coal tars produced using different production processes and feedstocks yielded tars with significantly different heterocyclic and hydroxylated contents. The concentrations of the individual heterocyclic compounds varied greatly even within the different production processes and provided information about the feedstock used to produce the tars. The hydroxylated PAH content of the samples provided important analytical information that would otherwise not have been obtained without the use of derivatization and GCxGC/TOFMS. Copyright © 2017 John Wiley & Sons, Ltd.

  16. Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen

    Directory of Open Access Journals (Sweden)

    Galactéros Frédéric

    2011-05-01

    Full Text Available Abstract Background Hydroxyurea (HU is the first approved pharmacological treatment of sickle cell anemia (SCA. The objectives of this study were to develop population pharmacokinetic(PK-pharmacodynamic(PD models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment. Methods The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF% and mean corpuscular volume (MCV were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months. Results The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV of clearance was 11.6 L/h (30%, the central volume was 45.3 L (35%. PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%; the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients. Conclusions The high variability of response to HU was related in part to pharmacokinetics and

  17. Hidroxiuréia em pacientes com síndromes falciformes acompanhados no Hospital Hemope, Recife, Brasil Hydroxyurea in sickle cell disease patients in Recife, Brazil

    Directory of Open Access Journals (Sweden)

    Flavia M. G. C. Bandeira

    2004-01-01

    Full Text Available O uso de hidroxiuréia promove a elevação dos níveis de hemoglobina fetal (Hb F em pacientes portadores de síndromes falciformes (SF e o medicamento vem sendo estudado em vários grupos de pacientes, incluindo adultos e crianças. O presente trabalho analisou a eficácia e tolerabilidade do uso de hidroxiuréia em crianças na faixa etária entre 5 e 17 anos de idade e em adultos jovens acima de 18 anos, portadores de hemoglobinopatia SS ou Sbeta0 que foram acompanhados regularmente no ambulatório do Hospital Hemope. Os pacientes pediátricos foram tratados com dose inicial de hidroxiuréia de 10 mg/kg/dia, a qual era aumentada em 5 mg/kg por dia em intervalos de oito semanas, até a dose máxima de 25 mg/kg/dia. Para os adultos, o tratamento foi iniciado com 500 mg/dia de hidroxiuréia até a dose máxima de 1g/dia. Foi observada redução do número de crises álgicas assim como do número de internações hospitalares, elevação do nível de Hb F e do Volume Corpuscular Médio, no grupo pediátrico. Entre os pacientes maiores de 18 anos, também se observou melhora clínica e significância estatística com aumento dos valores da hemoglobina e redução dos valores de reticulócitos, leucócitos e plaquetas. Não foram observados sinais ou sintomas sugestivos de toxicidade medicamentosa em ambos os grupos. O uso de hidroxiuréia em todos os pacientes parece ser seguro e eficaz e assegura melhora da qualidade de vida e benefícios a seus familiares. Ademais, as doses preconizadas de hidroxiuréia aparentemente não foram mielotóxicas, não tendo sido necessária a suspensão do tratamento em nenhum dos pacientes.The use of hydroxyurea increases concentrations of fetal hemoglobin (Hb F in sickle cell disease patients. It has been used in adults and in trials with children with the aim of preventing events such as episodes of pain or stokes. The objective of this study was to analyze the efficacy and side effects of Hydroxyurea in

  18. Effects of Hydroxylation on PbS Quantum Dot Sensitized TiO2 Nanotube Array Photoelectrodes

    International Nuclear Information System (INIS)

    Liu, Zhongqing; Wang, Bin; Wu, Jianchun; Dong, Qiang; Zhang, Xiaoming; Xu, He

    2016-01-01

    ABSTRACT: The contact state at the heterojunction interfaces greatly influences the interfacial kinetics of the photoinduced charge carriers. In this study, we used a facile NaOH pretreatment to replenish the hydroxyl groups lost during the heat treatment for crystallization of TiO 2 nanotube arrays (TNAs) prepared via anodic oxidization. By reacting the carboxylic acid groups of thioglycolic acid (TGA) with the TiO 2 surface hydroxyl groups, TGA molecules were covalently linked to the TiO 2 surface and then PbS quantum dots (QDs) were anchored onto the TNAs via the successive ionic layer adsorption and reaction (SILAR) method. The sample microstructure and photoelectrochemical properties were analyzed with X-ray diffraction (XRD), transmission electron microscopy (TEM), field-emission scanning electron microscopy (FE-SEM),current–voltage characteristics (J–V), electrochemical impedance spectroscopy (EIS), transient photovoltage plots and Mott-Schottky curves. The contact state and electrostatic potential distribution between TiO 2 {1 0 1} and PbS {1 1 1} planes were estimated by using first principle simulation. It was found that the NaOH pretreatment could enhance the crystallization degree of PbS QDs, decrease the crystal face mismatch, dangling bond density and the interfacial resistance between PbS QDs and TiO 2 , and accelerate the interfacial separation and transfer of photoinduced charge carriers. The first principle calculations demonstrated that the PbS QDs and TiO 2 interfacial contact was strengthened, and the built-in electric field was induced from TiO 2 {1 0 1} towards PbS {1 1 1}. These combined effects apparently improved the device photoelectrochemical performance. Compared to the sample without pretreatment, the specimen pretreated with NaOH demonstrated 19.96% and 29.93% increases in peak photoconversion efficiency after five and ten cycles of SILAR deposition, respectively.

  19. Reactivity of hydropersulfides toward the hydroxyl radical unraveled: disulfide bond cleavage, hydrogen atom transfer, and proton-coupled electron transfer.

    Science.gov (United States)

    Anglada, Josep M; Crehuet, Ramon; Adhikari, Sarju; Francisco, Joseph S; Xia, Yu

    2018-02-14

    Hydropersulfides (RSSH) are highly reactive as nucleophiles and hydrogen atom transfer reagents. These chemical properties are believed to be key for them to act as antioxidants in cells. The reaction involving the radical species and the disulfide bond (S-S) in RSSH, a known redox-active group, however, has been scarcely studied, resulting in an incomplete understanding of the chemical nature of RSSH. We have performed a high-level theoretical investigation on the reactions of the hydroxyl radical (˙OH) toward a set of RSSH (R = -H, -CH 3 , -NH 2 , -C(O)OH, -CN, and -NO 2 ). The results show that S-S cleavage and H-atom abstraction are the two competing channels. The electron inductive effect of R induces selective ˙OH substitution at one sulfur atom upon S-S cleavage, forming RSOH and ˙SH for the electron donating groups (EDGs), whereas producing HSOH and ˙SR for the electron withdrawing groups (EWGs). The H-Atom abstraction by ˙OH follows a classical hydrogen atom transfer (hat) mechanism, producing RSS˙ and H 2 O. Surprisingly, a proton-coupled electron transfer (pcet) process also occurs for R being an EDG. Although for RSSH having EWGs hat is the leading channel, S-S cleavage can be competitive or even dominant for the EDGs. The overall reactivity of RSSH toward ˙OH attack is greatly enhanced with the presence of an EDG, with CH 3 SSH being the most reactive species found in this study (overall rate constant: 4.55 × 10 12 M -1 s -1 ). Our results highlight the complexity in RSSH reaction chemistry, the extent of which is closely modulated by the inductive effect of the substituents in the case of the oxidation by hydroxyl radicals.

  20. V color centers in electrolytically colored hydroxyl-doped sodium chloride crystals

    International Nuclear Information System (INIS)

    Gu Hongen; Song Cuiying; Han Li

    2006-01-01

    Hydroxyl-doped sodium chloride crystals were successfully colored electrolytically by using pointed anode and flat cathode at various temperatures and under various electric field strengths. V 2 and V 3 color centers were produced in the colored crystals. Current-time curves for the electrolytic colorations were given, and activation energy for the V 2 and V 3 color center migration was determined. Production of the V 2 and V 3 color centers and formation of current zones for the electrolytic colorations of the hydroxyl-doped sodium chloride crystals are explained

  1. Regioselective alkane hydroxylation with a mutant CYP153A6 enzyme

    Science.gov (United States)

    Koch, Daniel J.; Arnold, Frances H.

    2013-01-29

    Cytochrome P450 CYP153A6 from Myobacterium sp. strain HXN1500 was engineered using in-vivo directed evolution to hydroxylate small-chain alkanes regioselectively. Mutant CYP153A6-BMO1 selectively hydroxylates butane and pentane at the terminal carbon to form 1-butanol and 1-pentanol, respectively, at rates greater than wild-type CYP153A6 enzymes. This biocatalyst is highly active for small-chain alkane substrates and the regioselectivity is retained in whole-cell biotransformations.

  2. Mechanism of the N-Hydroxylation of Primary and Secondary Amines by Cytochrome P450

    DEFF Research Database (Denmark)

    Seger, Signe T.; Rydberg, Patrik; Olsen, Lars

    2015-01-01

    Cytochrome P450 enzymes (CYPs) metabolize alkyl- and arylamines, generating several different products. For the primary and secondary amines, some of these reactions result in hydroxylated amines, which may be toxic. Thus, when designing new drugs containing amine groups, it is important to be able...... to predict if a given compound will be a substrate for CYPs, in order to avoid toxic metabolites, and hence to understand the mechanism that is utilized by CYPs. Two possible mechanisms, for the N-hydroxylation of primary and secondary amines mediated by CYPs, are studied by density functional theory (DFT...

  3. Effect of Hydroxyl Concentration on Chemical Sensitivity of Polyvinyl Alcohol/Carbon-Black Composite Chemiresistors

    International Nuclear Information System (INIS)

    Hughes, Robert C.; Patel, Sanjay V.; Yelton, W. Graham

    1999-01-01

    The sensitivity and selectivity of polyvinyl alcohol (PVA) / carbon black composite films have been found to vary depending upon the hydroxylation percentage (''-OH'') of the polymer. These chemiresistors made from PVA films whose polymer backbone is 88% hydroxylated (PVA88) have a high sensitivity to water, while chemiresistors made from PVA75 have a higher sensitivity to methanol. The minor differences in polymer composition result in films with different Hildebrand volubility parameters. The relative responses of several different PVA-based chemiresistors to solvents with different volubility parameters are presented. In addition, polyvinyl acetate (PVAC) films with PVA88 are used in an array to distinguish the responses to methanol-water mixtures

  4. Hydroxylation of the Herbicide Isoproturon by Fungi Isolated from Agricultural soil

    DEFF Research Database (Denmark)

    Rønhede, S.; Jensen, Bo; Rosendahl, Søren

    2005-01-01

    Several asco-, basidio-, and zygomycetes isolated from an agricultural field were shown to be able to hydroxylate the phenylurea herbicide isoproturon [N-(4-isopropylphenyl)-N',N'-dimethylurea] to N-(4-(2-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea and N-(4-(1-hydroxy-1-methylethyl)phenyl)-N......Several asco-, basidio-, and zygomycetes isolated from an agricultural field were shown to be able to hydroxylate the phenylurea herbicide isoproturon [N-(4-isopropylphenyl)-N',N'-dimethylurea] to N-(4-(2-hydroxy-1-methylethyl)phenyl)-N',N'-dimethylurea and N-(4-(1-hydroxy-1-methylethyl...

  5. Diatomite as high performance and environmental friendly catalysts for phenol hydroxylation with H2O2

    Directory of Open Access Journals (Sweden)

    Yuxin Jia et al

    2007-01-01

    Full Text Available A series of diatomite catalysts were treated and characterized. For the first time, the resulting materials were used in catalysis for the hydroxylation of phenol with H2O2 and showed very high hydroxylation activity due to the Fe species in the diatomite. The effect of HCl treatment, contents of catalysts and H2O2 were investigated and the active components of diatomite were discussed. The results show that diatomite is the promising candidate for industrial output due to their high catalytic activity, easy physical separation and very low costs.

  6. DMSO does not protect against hydroxyl radical induced peroxidation in model membranes

    Energy Technology Data Exchange (ETDEWEB)

    Raleigh, J A; Kremers, W [Atomic Energy of Canada Ltd., Pinawa, Manitoba. Whiteshell Nuclear Research Establishment

    1981-04-01

    Dimethylsulphoxide (DMSO) promoted peroxidation in both linolenate and linoleate micelles. The promotional effect was most evident at concentrations of DMSO above 0.3 M with 0.012 M fatty acid. This was well above the DMSO concentration at which all the OH was scavenged by DMSO on the basis of the relative rate constants recorded. It was also found that DMSO did not decrease the yield of lipid hydroperoxide in a concentration range (0.01 to 0.1 M) where DMSO scavenges OH in competition with the unsaturated fatty acids. The sustaining mechanism could be accounted for in terms of CHsup(.)/sub 3/ and CH/sub 3/OOsup(.) being as effective as OH in initiating lipid peroxidation. A possible alternative explanation for the absence of protection by DMSO is that OH scavenging by DMSO is equivalent to lowering the dose-rate. The promotion of peroxidation at high DMSO concentration (> 1.0 M) was more difficult to account for, but may be analogous to the promotional effect of caesium and rubidium counterions.

  7. Computational mechanistic investigation of radiation damage of adenine induced by hydroxyl radicals

    Science.gov (United States)

    Tan, Rongri; Liu, Huixuan; Xun, Damao; Zong, Wenjun

    2018-02-01

    Not Available Project supported by the National Natural Science Foundation of China (Grant Nos. 11564015 and 61404062), the Research Fund for the Doctoral Program of China (Grant No. 3000990110), and the Fund for Distinguished Young Scholars of Jiangxi Science & Technology Normal University (Grant Nos. 2015QNBJRC002 and 2016QNBJRC006).

  8. Synthesis of hydroxyl liquid polybutadiene by photochemical decomposition of hydrogen peroxide

    International Nuclear Information System (INIS)

    Moutinho, Marcus Tadeu Moura

    1995-01-01

    The synthesis of hydroxyl terminated polybutadienes (HTPB) by photochemical decomposition (λ=254 nm) of hydrogen peroxide (H 2 O 2 ) in alcoholic medium was studied. The influence of reaction time, H 2 O 2 and alcohol concentrations, type of alcohol and radiation intensity on the polymerization rate was determined. Higher polymerization rates were attained when t-butyl alcohol was used as the compatibilizing agent (19% conversion after 8 hours). The HTPBs were characterized by hydroxyl content (acetylation), functionality, IR microstructure and types of hydroxyl groups ( 1 H-NMR and 13 C-NMR), 2-vinyl cyclohexene (VCH) content and viscosity. The polymers showed molecular weights (Mn) in the range of 458 to 1,099, molecular weight distribution (Mw/Mn) in the range of 1.20 to 1.46 and functionality between 1.2 and 3.2 depending on the alcohol used. NMR results 1 H and 13 C) revealed low cis content for the polybutadienes and identified primary and secondary hydroxyl groups, depending on the alcohol employed as compatibilizing agent. The incorporation of alcohol in polymer chain ends was evidenced. The produced HTPBs presented viscosities in the range of 850 to 1,250 cP (at 25 deg C) and were VCH free. (author)

  9. New model system for testing effects of flavonoids on doxorubicin-related formation of hydroxyl radicals

    Czech Academy of Sciences Publication Activity Database

    Souček, P.; Kondrová, E.; Heřmánek, J.; Stopka, Pavel; Boumendjel, A.; Ueng, YF.; Gut, I.

    2011-01-01

    Roč. 22, č. 2 (2011), s. 176-184 ISSN 0959-4973 Institutional research plan: CEZ:AV0Z40320502 Keywords : doxorubicin * electron spin resonance * flavonoids hydroxyl radicals Subject RIV: FD - Oncology ; Hematology Impact factor: 2.407, year: 2011

  10. Fetal exposure to PCBs and their hydroxylated metabolites in a Dutch cohort

    NARCIS (Netherlands)

    Soechitram, S.D.; Athanasiadou, M.; Hovander, L.; Bergman, A.; Sauer, P. J. J.

    2004-01-01

    Polychlorinated biphenyls (PCBs) are still the most abundant pollutants in wildlife and humans. Hydroxylated PCB metabolites (OH-PCBs) are known to be formed in humans and wildlife. Studies in animals show that these metabolites cause endocrine-related toxicity. The health effects in humans have not

  11. Hydroxylation of nitro-(pentafluorosulfanyl)benzenes via vicarious nucleophilic substitution of hydrogen

    Czech Academy of Sciences Publication Activity Database

    Beier, Petr; Pastýříková, Tereza

    2011-01-01

    Roč. 52, č. 34 (2011), s. 4392-4394 ISSN 0040-4039 R&D Projects: GA ČR GAP207/11/0344 Institutional research plan: CEZ:AV0Z40550506 Keywords : pentafluorosulfanyl group * vicarious nucleophilic substitution * hydroxylation Subject RIV: CC - Organic Chemistry Impact factor: 2.683, year: 2011

  12. Biological production of hydroxylated aromatics : Optimization strategies for Pseudomonas putida S12

    NARCIS (Netherlands)

    Verhoef, A.

    2010-01-01

    To replace environmentally unfriendly petrochemical production processes, the demand for bio-based production of organic chemicals is increasing. This thesis focuses on the biological production of hydroxylated aromatics from renewable substrates by engineered P. putida S12 including several cases

  13. Prediction of hydroxyl concentrations in cement pore water using a numerical cement hydration model

    NARCIS (Netherlands)

    Eijk, van R.J.; Brouwers, H.J.H.

    2000-01-01

    In this paper, a 3D numerical cement hydration model is used for predicting alkali and hydroxyl concentrations in cement pore water. First, this numerical model is calibrated for Dutch cement employing both chemical shrinkage and calorimetric experiments. Secondly, the strength development of some

  14. Formation of 5,6-dihydroxydihydrothymine-type products in DNA by hydroxyl radicals

    International Nuclear Information System (INIS)

    Remsen, J.F.; Roti, J.L.R.

    1977-01-01

    The purpose of the study is to determine whether 5,6-dihydroxydihydrothymine type products in purified DNA and in intact cells results from direct or indirect action and, if indirect, which radical species is primarily responsible. It is concluded that hydroxyl radical is primarily responsible. (U.K.)

  15. Modeling the thermostability of surface functionalisation by oxygen, hydroxyl, and water on nanodiamonds.

    Science.gov (United States)

    Lai, Lin; Barnard, Amanda S

    2011-06-01

    Understanding nanodiamond functionalisation is of great importance for biological and medical applications. Here we examine the stabilities of oxygen, hydroxyl, and water functionalisation of the nanodiamonds using the self-consistent charge density functional tight-binding simulations. We find that the oxygen and hydroxyl termination are thermodynamically favourable and form strong C–O covalent bonds on the nanodiamond surface in an O2 and H2 gas reservoir, which confirms previous experiments. Yet, the thermodynamic stabilities of oxygen and hydroxyl functionalisation decrease dramatically in a water vapour reservoir. In contrast, H2O molecules are found to be physically adsorbed on the nanodiamond surface, and forced chemical adsorption results in decomposition of H2O. Moreover, the functionalisation efficiency is found to be facet dependent. The oxygen functionalisation prefers the {100} facets as opposed to alternative facets in an O2 and H2 gas reservoir. The hydroxyl functionalisation favors the {111} surfaces in an O2 and H2 reservoir and the {100} facets in a water vapour reservoir, respectively. This facet selectivity is found to be largely dependent upon the environmental temperature, chemical reservoir, and morphology of the nanodiamonds.

  16. Glutathione--hydroxyl radical interaction: a theoretical study on radical recognition process.

    Directory of Open Access Journals (Sweden)

    Béla Fiser

    Full Text Available Non-reactive, comparative (2 × 1.2 μs molecular dynamics simulations were carried out to characterize the interactions between glutathione (GSH, host molecule and hydroxyl radical (OH(•, guest molecule. From this analysis, two distinct steps were identified in the recognition process of hydroxyl radical by glutathione: catching and steering, based on the interactions between the host-guest molecules. Over 78% of all interactions are related to the catching mechanism via complex formation between anionic carboxyl groups and the OH radical, hence both terminal residues of GSH serve as recognition sites. The glycine residue has an additional role in the recognition of OH radical, namely the steering. The flexibility of the Gly residue enables the formation of further interactions of other parts of glutathione (e.g. thiol, α- and β-carbons with the lone electron pair of the hydroxyl radical. Moreover, quantum chemical calculations were carried out on selected GSH/OH(• complexes and on appropriate GSH conformers to describe the energy profile of the recognition process. The relative enthalpy and the free energy changes of the radical recognition of the strongest complexes varied from -42.4 to -27.8 kJ/mol and from -21.3 to 9.8 kJ/mol, respectively. These complexes, containing two or more intermolecular interactions, would be the starting configurations for the hydrogen atom migration to quench the hydroxyl radical via different reaction channels.

  17. Hydroxyl pyridine containing polybenzimidazole membranes for proton exchange membrane fuel cells

    DEFF Research Database (Denmark)

    Yang, Jingshuai; Xu, Yixin; Zhou, Lu

    2013-01-01

    A polybenzimidazole variant polymer containing hydroxyl pyridine groups, termed as OHPyPBI, was synthesized from 3,3'-diaminobenzidine tetrahydrochloride and 4-hydroxy-2,6-pyridinedicarboxylic acid. The thermal-oxidative stability of the OHPyPBI polymer was as high as that of poly[2,2'-(m-phenyle...

  18. Effects of partial hydrogenation, epoxidation, and hydroxylation on the fuel properties of fatty acid methyl esters

    Energy Technology Data Exchange (ETDEWEB)

    Wadumesthrige, Kapila; Salley, Steven O.; Ng, K.Y. Simon [Department of Chemical Engineering and Materials Science, Wayne State University, 5050 Anthony Wayne Drive, Detroit, MI 48202 (United States)

    2009-10-15

    The properties of biodiesel depend on the chemical structure of individual fatty acid methyl esters (FAME). In this work the chemical structure of fatty acid chains was modified by catalytic hydrogenation, epoxidation and hydroxylation under controlled conditions. Hydrolysis of ester functionality or oxidation of fatty acid chain was not observed during these reactions. The properties of hydrogenated FAME strongly depend on the hydrogenation time. The total saturated fatty acid (SFA) percentage increased from 29.3% to 76.2% after 2 h of hydrogenation. This hydrogenated FAME showed higher oxidation stability and higher cetane number but poor cold flow properties. Formation of trans FAME was observed during hydrogenation. Both hydroxylation and epoxidation resulted in a decrease of unsaturated fatty acid methyl ester (UFA) fraction. The percentages of total unsaturated FAME decreased 39% in the epoxidation reaction and 44% in the hydroxylation reaction. The addition of hydroxyl groups to the unsaturated regions of the fatty acid chain yields biodiesel with better cold flow properties, increased lubricity and slightly increased oxidative stability. However, epoxy FAME shows some interesting properties such as higher oxidation stability, higher cetane number and acceptable cold flow properties, which met the limits of ASTM D6751 biodiesel specifications. (author)

  19. Infrared Emission Spectrum of the Hydroxyl Radical: A Novel Experiment in Molecular Spectroscopy.

    Science.gov (United States)

    Henderson, Giles; And Others

    1982-01-01

    Describes an experiment in which parameters from an "ab-initio" potential are used to calculate vibrational-rotational energy levels and construct a "stick spectrum" for the overtone emission of the hydroxyl radical. Provides background information on ab-initio spectrum, experimental procedures, and analysis of data. (Author/JN)

  20. Hydrotreating of compounds and mixtures of compounds having mercapto and hydroxyl groups

    Energy Technology Data Exchange (ETDEWEB)

    Viljava, T.R.; Krause, A.O.I. [Helsinki University of Technology, Espoo (Finland)

    1997-07-01

    Simultaneous hydrodesulfurization (HDS) and hydrodeoxygenation (HDO) of mercapto and hydroxyl group containing benzenes was studied using a commercial presulfided CoMo/{gamma}- Al{sub 2}O{sub 3} catalyst under hydrotreating conditions (150-280 deg C, 7 MPa). Mercaptobenzene, phenol and 4-mercaptophenol were used as model compounds, and CS{sub 2} was used as precursor for H{sub 2}S. The HDS rate of a mercapto group in the presence of a hydroxyl substituent in the para position was higher than that for the molecule containing only a mercapto group. When the hydroxyl group was present as phenol, the HDS rate of the mercapto group was about 30% lower than that for mercaptobenzene without an oxygen-containing additive. The decrease in the HDS rate was independent of the initial molar ratio of sulfur and oxygen within the ratios studied (5:1-1:1). The HDO rate of a hydroxyl group was suppressed by the mercapto group present either in the same or in a separate molecule. HDO reactions did not start until HDS conversion was almost complete. CS{sub 2} also decreased the HDO rate of phenol. When compared to the reactions of phenol alone, the rate of the hydrogenolysis route to benzene was decreased in the presence of a sulfur additive more than the hydrogenolysis- hydrogenation route to cyclohexane. 19 refs.

  1. Gold-catalyzed Alkyne Hydroxylation: Synthesis of 2-Substituted Benzo[b]furan Compounds

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yuan; XIN Zhi-Jun; XUE Ji-Jun; LI Ying

    2008-01-01

    A strategy concerning the synthesis of 2-substituted benzo[b]furan compounds from o-alkynyl phenols via a gold-catalyzed alkyne hydroxylation is described, which allows the rapid synthesis of various 2-substituted benzo[b]furan derivatives in excellent yields under mild conditions. The o-alkynyl phenol precursors were readily prepared with a Sonogashira coupling reaction.

  2. DNA radiolysis in DNA-protein complex: a stochastic simulation of attack by hydroxyl radicals

    Czech Academy of Sciences Publication Activity Database

    Běgusová, Marie; Giliberto, S.; Gras, J.; Sy, D.; Charlier, M.; Spotheim Maurizot, M.

    2003-01-01

    Roč. 79, č. 6 (2003), s. 385-391 ISSN 0955-3002 R&D Projects: GA AV ČR IAA1048103 Institutional research plan: CEZ:AV0Z1048901 Keywords : radiolysis * DNA-protein complexes * hydroxyl radicals Subject RIV: BO - Biophysics Impact factor: 2.165, year: 2003

  3. Progress modelling of aqueous electrons and hydroxyl radicals in RAIM code

    Energy Technology Data Exchange (ETDEWEB)

    Kim, A Yeong; Kim, Han-Chul; Lee, Jongseong [Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of)

    2015-10-15

    In this paper, the RAIM code was revised minutely with regards to aqueous electrons and hydroxyl radicals, and simulated the P10T2 test. The recent study indicated that the RAIM had the potential for improvement of simulating the iodine behavior influenced by water radiolysis products such as aqueous electrons and hydroxyl radicals. In the existing RAIM modelling, it was considered that aqueous electrons only interacted with oxygen as a consumption reaction, but the reaction with hydrogen peroxide also could be major contributor to the iodine behavior as well as the consumption reaction of aqueous electrons. In case of hydroxyl radicals, RAIM took no notice of the pH impact. In other words, it dealt with the consumption reaction constants but not as a variable of pH. In this communication, the procedures to develop the model related to aqueous electrons and hydroxyl radicals in RAIM will be addressed. And the upgraded RAIM (RAIM-1, 2, 3) codes were applied to OECD-BIP P10T2 test which showed the effect of pH on the iodine behavior and compared with the existing RAIM1.8.3 code. Comparing with the existing RAIM, the improvement reduced the difference about 10%. However, the absolute difference values that is about one order at pH 10 could not be reduced by this approach.

  4. An experimental study of hydroxyl in quartz using infrared spectroscopy and ion microprobe techniques

    Energy Technology Data Exchange (ETDEWEB)

    Rovetta, M. R.; Blacic, J. D.; Hervig, R. L.; Holloway, J. R.

    1989-05-10

    We have measured the concentrations of hydroxyl, deuterium, Al, Fe, Li,Na, K, and Rb in a natural quartz crystal before and after hydrothermaltreatment at 1.5 GPa and 800/degree/--1050 /degree/C. We employed microbeam infraredspectroscopy and ion probe techniques to avoid impurities trapped in healedcracks and fluid inclusions that might bias a normal bulk analysis.The /ital f//sub H/sub 2// of our experiments were buffered to thehematite-magnetite-(OH)fluid, nickel-nickel oxide-(OH)fluid, oriron-wustite-(OH)fluid phase assemblages. After hydrothermal treatment,the samples contained local concentrations of hydrogen or deuterium ofseveral hundred atoms/10/sup 6/ Si (the starting crystal contained 45 H/10/sup 6/ Si).We did several experiments with Al/sub 2/O/sub 3/ or RbCl added to the sample chargeand found local Al enrichment where the deuterium concentration was highbut no Rb enrichment. Finally, we measured trace elements and hydroxyl in aquartz sample after plastic deformation in a talc furnace assembly; inregions of the sample containing basal and prismatic deformation lamellae(but no visible healed microcracks at 400/times/ optical magnification)hydroxyl had increased to /similar to/200 oO/10/sup 6/ Si with no increase in Al or Fe.Samples enriched in hydroxyl but not Al (including the plastically strainedsample) gave infrared spectra resembling natural amethyst crystals.

  5. Structural Mass Spectrometry of Proteins Using Hydroxyl Radical Based Protein Footprinting

    OpenAIRE

    Wang, Liwen; Chance, Mark R.

    2011-01-01

    Structural MS is a rapidly growing field with many applications in basic research and pharmaceutical drug development. In this feature article the overall technology is described and several examples of how hydroxyl radical based footprinting MS can be used to map interfaces, evaluate protein structure, and identify ligand dependent conformational changes in proteins are described.

  6. Oxygen activation at the plasma membrane: relation between superoxide and hydroxyl radical production by isolated membranes.

    Science.gov (United States)

    Heyno, Eiri; Mary, Véronique; Schopfer, Peter; Krieger-Liszkay, Anja

    2011-07-01

    Production of reactive oxygen species (hydroxyl radicals, superoxide radicals and hydrogen peroxide) was studied using EPR spin-trapping techniques and specific dyes in isolated plasma membranes from the growing and the non-growing zones of hypocotyls and roots of etiolated soybean seedlings as well as coleoptiles and roots of etiolated maize seedlings. NAD(P)H mediated the production of superoxide in all plasma membrane samples. Hydroxyl radicals were only produced by the membranes of the hypocotyl growing zone when a Fenton catalyst (FeEDTA) was present. By contrast, in membranes from other parts of the seedlings a low rate of spontaneous hydroxyl radical formation was observed due to the presence of small amounts of tightly bound peroxidase. It is concluded that apoplastic hydroxyl radical generation depends fully, or for the most part, on peroxidase localized in the cell wall. In soybean plasma membranes from the growing zone of the hypocotyl pharmacological tests showed that the superoxide production could potentially be attributed to the action of at least two enzymes, an NADPH oxidase and, in the presence of menadione, a quinone reductase.

  7. Structure-based engineering of steroidogenic CYP260A1 for stereo- and regioselective hydroxylation of progesterone

    NARCIS (Netherlands)

    Khatri, Yogan; Jóźwik, Ilona K; Ringle, Michael; Ionescu, Irina Alexandra; Litzenburger, Martin; Hutter, Michael Christopher; Thunnissen, Andy-Mark W H; Bernhardt, Rita

    The production of regio- and stereoselectively hydroxylated steroids is of high pharmaceutical interest and can be achieved by cytochrome P450-based biocatalysts. CYP260A1 from Sorangium cellulosum strain So ce56 catalyzes hydroxylation of C19 or C21 steroids at the very unique 1-position. However,

  8. Urocanic acid isomers are good hydroxyl radical scavengers: a comparative study with structural analogues and with uric acid

    NARCIS (Netherlands)

    Kammeyer, A.; Eggelte, T. A.; Bos, J. D.; Teunissen, M. B.

    1999-01-01

    UV-exposure of the epidermis leads to the isomerisation of trans-UCA into cis-UCA as well as to the generation of hydroxyl radicals. This study shows by means of the deoxyribose degradation test that UCA isomers are more powerful hydroxyl radical scavengers than the other 4-(5-)substituted imidazole

  9. Evidence for formation of hydroxyl radicals during reperfusion after global cerebral ischaemia in rats using salicylate trapping and microdialysis

    DEFF Research Database (Denmark)

    Christensen, Thomas; Bruhn, T; Balchen, T

    1994-01-01

    Systemic administration of salicylate (SA) to rats (100 mg kg-1 i.p. ) was used as an in vivo trap of hydroxyl radicals (.OH). In the brain SA reacts with hydroxyl radicals to form the stable adducts 2, 3- and 2,5 dihydroxybenzoic acid (DHBAs) which can thus be taken as an index of .OH formation...

  10. The effect of hydroxylation on CNT to form Chitosan-CNT composites: A DFT study

    International Nuclear Information System (INIS)

    Yu, Rui; Ran, Maofei; Wen, Jie; Sun, Wenjing; Chu, Wei; Jiang, Chengfa; He, Zhiwei

    2015-01-01

    Graphical abstract: - Highlights: • The effect of hydroxylation on CNT to form Chitosan-CNT composites was studied. • The adsorption of Chitosan on CNTs is very weak by electrostatic interactions. • Chitosan loads onto CNT-OH_n via hydrogen-bond interactions. • Chitosan transfers electron to CNT-OH_n and thus improves the reactivity of CNT. - Abstract: The effect of types of CNTs (pristine and hydroxylated) on the synthesis of Chitosan-CNT (CS-CNT) composites was investigated theoretically. The adsorption energy (E_a_d_s) of CS on the pristine CNT and hydroxylated CNTs (CNT-OH_n, n = 1–6) as well as the structural and electronic properties of said composites have been investigated. Results show that the adsorption of CS on CNT and CNT-OH_n is thermodynamically favored. The E_a_d_s of CS on CNTs was calculated to be −20.387 kcal/mol from electrostatic interactions. For CS adsorbed into CNT-OH_n, E_a_d_s ranges from −20.612 to −37.567 kcal/mol. Hydroxyl groups on CNT are the main adsorption sites for CS loading onto CNT-OH_n via hydrogen-bond interactions. The CS-CNT-OH_3 is the most sable composite among tested complexes. The energy gap (ΔE_g_a_p) of CS-CNT-OH_3 was calculated less than pristine CNT and CNT-OH_3, indicative of the composites being more reactive than that of pristine CNTs and CNT-OH_3. It was proved that CS can transfer electron to the hydroxylated CNTs, thus overcoming the drawbacks of CNTs being chemically inert.

  11. The effect of hydroxylation on CNT to form Chitosan-CNT composites: A DFT study

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Rui [China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan, Guangdong 523808 (China); Department of Chemical Engineering, Sichuan University, Chengdu 610065 (China); Ran, Maofei [College of Chemistry & Environment Protection Engineering, Southwest University for Nationalities, Chengdu 610041, Sichuan (China); Wen, Jie [College of Chemistry and Chemical Engineering, Southwest Petroleum University, Chengdu 610500, Sichuan (China); Sun, Wenjing, E-mail: swj_gdmc@163.com [China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan, Guangdong 523808 (China); Chu, Wei; Jiang, Chengfa [Department of Chemical Engineering, Sichuan University, Chengdu 610065 (China); He, Zhiwei, E-mail: zhiweihe688@yahoo.com [China-America Cancer Research Institute, Key Laboratory for Medical Molecular Diagnostics of Guangdong Province, Guangdong Medical University, Dongguan, Guangdong 523808 (China)

    2015-12-30

    Graphical abstract: - Highlights: • The effect of hydroxylation on CNT to form Chitosan-CNT composites was studied. • The adsorption of Chitosan on CNTs is very weak by electrostatic interactions. • Chitosan loads onto CNT-OH{sub n} via hydrogen-bond interactions. • Chitosan transfers electron to CNT-OH{sub n} and thus improves the reactivity of CNT. - Abstract: The effect of types of CNTs (pristine and hydroxylated) on the synthesis of Chitosan-CNT (CS-CNT) composites was investigated theoretically. The adsorption energy (E{sub ads}) of CS on the pristine CNT and hydroxylated CNTs (CNT-OH{sub n}, n = 1–6) as well as the structural and electronic properties of said composites have been investigated. Results show that the adsorption of CS on CNT and CNT-OH{sub n} is thermodynamically favored. The E{sub ads} of CS on CNTs was calculated to be −20.387 kcal/mol from electrostatic interactions. For CS adsorbed into CNT-OH{sub n}, E{sub ads} ranges from −20.612 to −37.567 kcal/mol. Hydroxyl groups on CNT are the main adsorption sites for CS loading onto CNT-OH{sub n} via hydrogen-bond interactions. The CS-CNT-OH{sub 3} is the most sable composite among tested complexes. The energy gap (ΔE{sub gap}) of CS-CNT-OH{sub 3} was calculated less than pristine CNT and CNT-OH{sub 3}, indicative of the composites being more reactive than that of pristine CNTs and CNT-OH{sub 3}. It was proved that CS can transfer electron to the hydroxylated CNTs, thus overcoming the drawbacks of CNTs being chemically inert.

  12. Steroid hydroxylations: A paradigm for cytochrome P450 catalyzed mammalian monooxygenation reactions

    International Nuclear Information System (INIS)

    Estabrook, Ronald W.

    2005-01-01

    The present article reviews the history of research on the hydroxylation of steroid hormones as catalyzed by enzymes present in mammalian tissues. The report describes how studies of steroid hormone synthesis have played a central role in the discovery of the monooxygenase functions of the cytochrome P450s. Studies of steroid hydroxylation reactions can be credited with showing that: (a) the adrenal mitochondrial enzyme catalyzing the 11β-hydroxylation of deoxycorticosterone was the first mammalian enzyme shown by O 18 studies to be an oxygenase; (b) the adrenal microsomal enzyme catalyzing the 21-hydroxylation of steroids was the first mammalian enzyme to show experimentally the proposed 1:1:1 stoichiometry (substrate:oxygen:reduced pyridine nucleotide) of a monooxygenase reaction; (c) application of the photochemical action spectrum technique for reversal of carbon monoxide inhibition of the 21-hydroxylation of 17α-OH progesterone was the first demonstration that cytochrome P450 was an oxygenase; (d) spectrophotometric studies of the binding of 17α-OH progesterone to bovine adrenal microsomal P450 revealed the first step in the cyclic reaction scheme of P450, as it catalyzes the 'activation' of oxygen in a monooxygenase reaction; (e) purified adrenodoxin was shown to function as an electron transport component of the adrenal mitochondrial monooxygenase system required for the activity of the 11β-hydroxylase reaction. Adrenodoxin was the first iron-sulfur protein isolated and purified from mammalian tissues and the first soluble protein identified as a reductase of a P450; (f) fractionation of adrenal mitochondrial P450 and incubation with adrenodoxin and a cytosolic (flavoprotein) fraction were the first demonstration of the reconstitution of a mammalian P450 monooxygenase reaction

  13. Relationship between cell cycle stage in the fertilized egg of mice and repair capacity for X-ray-induced damage in the sperm

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, Y.; Maemori, M.; Tobari, I. (National Inst. of Radiological Sciences, Chiba (Japan))

    1989-09-01

    The potentiation effects of 3-aminobenzamide, caffeine, hydroxyurea and arabinofuranosyl cytosine on the yield of X-ray-induced chromosome aberrations of mouse sperm were examined at the first-cleavage metaphase, to clarify a correlation between chromosome aberrations and cell cycle dependency of repair capacity of the fertilized egg. The result provided evidence that there are two major types of DNA damage in X-irradiated sperm: (1) short-lived DNA lesions; the lesions are subject to repair inhibitions by agents added in G{sub 1} and are converted into chromosome-type aberrations during G{sub 1}, and (2) long-lived DNA lesions; the lesions persist until S phase and repair of the lesions is inhibited by caffeine, hydroxyurea and arabinofuranosyl cytosine in G {sub 2}. (author).

  14. Relationship between cell cycle stage in the fertilized egg of mice and repair capacity for X-ray-induced damage in the sperm

    International Nuclear Information System (INIS)

    Matsuda, Y.; Maemori, M.; Tobari, I.

    1989-01-01

    The potentiation effects of 3-aminobenzamide, caffeine, hydroxyurea and arabinofuranosyl cytosine on the yield of X-ray-induced chromosome aberrations of mouse sperm were examined at the first-cleavage metaphase, to clarify a correlation between chromosome aberrations and cell cycle dependency of repair capacity of the fertilized egg. The result provided evidence that there are two major types of DNA damage in X-irradiated sperm: (1) short-lived DNA lesions; the lesions are subject to repair inhibitions by agents added in G 1 and are converted into chromosome-type aberrations during G 1 , and (2) long-lived DNA lesions; the lesions persist until S phase and repair of the lesions is inhibited by caffeine, hydroxyurea and arabinofuranosyl cytosine in G 2 . (author)

  15. FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress

    DEFF Research Database (Denmark)

    Fugger, Kasper; Chu, Wai Kit; Haahr, Peter

    2013-01-01

    The molecular events occurring following the disruption of DNA replication forks are poorly characterized, despite extensive use of replication inhibitors such as hydroxyurea in the treatment of malignancies. Here, we identify a key role for the FBH1 helicase in mediating DNA double-strand break...... formation following replication inhibition. We show that FBH1-deficient cells are resistant to killing by hydroxyurea, and exhibit impaired activation of the pro-apoptotic factor p53, consistent with decreased DNA double-strand break formation. Similar findings were obtained in murine ES cells carrying...... of replication stress. Our data suggest that FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA double-strand breaks....

  16. Reaction Mechanisms and Structural and Physicochemical Properties of Caffeic Acid Grafted Chitosan Synthesized in Ascorbic Acid and Hydroxyl Peroxide Redox System.

    Science.gov (United States)

    Liu, Jun; Pu, Huimin; Chen, Chong; Liu, Yunpeng; Bai, Ruyu; Kan, Juan; Jin, Changhai

    2018-01-10

    The ascorbic acid (AA) and hydroxyl peroxide (H 2 O 2 ) redox pair induced free radical grafting reaction is a promising approach to conjugate phenolic groups with chitosan (CS). In order to reveal the exact mechanisms of the AA/H 2 O 2 redox pair induced grafting reaction, free radicals generated in the AA/H 2 O 2 redox system were compared with hydroxyl radical ( • OH) produced in the Fe 2+ /H 2 O 2 redox system. Moreover, the structural and physicochemical properties of caffeic acid grafted CS (CA-g-CS) synthesized in these two redox systems were compared. Results showed that only ascorbate radical (Asc •- ) was produced in the AA/H 2 O 2 system. The reaction between Asc •- and CS produced novel carbon-centered radicals, whereas no new free radicals were detected when • OH reacted with CS. Thin layer chromatography, UV-vis, Fourier transform infrared, and nuclear magnetic resonance spectroscopic analyses all confirmed that CA was successfully grafted onto CS through Asc •- . However, CA could be hardly grafted onto CS via • OH. CA-g-CS synthesized through Asc •- exhibited lower thermal stability and crystallinity than the reaction product obtained through • OH. For the first time, our results demonstrated that the synthesis of CA-g-CS in the AA/H 2 O 2 redox system was mediated by Asc •- rather than • OH.

  17. Modeling nitrous acid and its impact on ozone and hydroxyl radical during the Texas Air Quality Study 2006

    Directory of Open Access Journals (Sweden)

    B. H. Czader

    2012-08-01

    Full Text Available Nitrous acid (HONO mixing ratios for the Houston metropolitan area were simulated with the Community Multiscale Air Quality (CMAQ Model for an episode during the Texas Air Quality Study (TexAQS II in August/September 2006 and compared to in-situ MC/IC (mist-chamber/ion chromatograph and long path DOAS (Differential Optical Absorption Spectroscopy measurements at three different altitude ranges. Several HONO sources were accounted for in simulations, such as gas phase formation, direct emissions, nitrogen dioxide (NO2 hydrolysis, photo-induced formation from excited NO2 and photo-induced conversion of NO2 into HONO on surfaces covered with organic materials. Compared to the gas-phase HONO formation there was about a tenfold increase in HONO mixing ratios when additional HONO sources were taken into account, which improved the correlation between modeled and measured values. Concentrations of HONO simulated with only gas phase chemistry did not change with altitude, while measured HONO concentrations decrease with height. A trend of decreasing HONO concentration with altitude was well captured with CMAQ predicted concentrations when heterogeneous chemistry and photolytic sources of HONO were taken into account. Heterogeneous HONO production mainly accelerated morning ozone formation, albeit slightly. Also HONO formation from excited NO2 only slightly affected HONO and ozone (O3 concentrations. Photo-induced conversion of NO2 into HONO on surfaces covered with organic materials turned out to be a strong source of daytime HONO. Since HONO immediately photo-dissociates during daytime its ambient mixing ratios were only marginally altered (up to 0.5 ppbv, but significant increase in the hydroxyl radical (OH and ozone concentration was obtained. In contrast to heterogeneous HONO formation that mainly accelerated morning ozone formation, inclusion of photo-induced surface chemistry

  18. Hidroxiurea en el tratamiento de niños y adolescentes con depranocitosis Hydroxyurea in the treatment of children and adolescents with sickle cell anemia

    Directory of Open Access Journals (Sweden)

    Gretel González Gilart

    2012-06-01

    Full Text Available Se realizó un estudio de intervención terapéutica, a fin de determinar la mejoría clínica y de los resultados de laboratorio en 163 niños afectados por drepanocitosis y tratados con hidroxiurea, los cuales fueron atendidos en el Hospital Infantil Sur de Santiago de Cuba desde septiembre de 2009 hasta igual mes de 2010. Para ello se seleccionó una muestra intencional de 22 pacientes, teniendo en cuenta criterios de inclusión y exclusión, número de eventos clínicos, parámetros de laboratorio, transfusiones e ingresos al año con el uso del medicamento; meses después de iniciado el tratamiento, fueron comparados con los mismos indicadores. Al finalizar la investigación se constató que la hidroxiurea había aumentado los niveles de hemoglobina fetal y disminuido la aparición de eventos clínicos, entre los cuales se encontraban: crisis vasooclusivas y del sistema nervioso central, síndrome torácico agudo e infecciones.A study of therapeutic intervention was carried out, in order to determine the clinical improvement and laboratory results in 163 children affected by sickle cell anemia and who were treated with hydroxyurea, and who were assisted in the Southern Children Hospital in Santiago de Cuba from September, 2009 to the same month of 2010. For this, an intentional sample of 22 patients was selected, taking into account the inclusion and exclusion criteria, number of clinical events, laboratory parameters, transfusions and admissions in a year with the use of the medication. After some months of initiating the treatment, they were compared with the same indicators. When concluding the investigation it was verified that hydroxyurea had increased the fetal hemoglobin levels and decreased the occurrence of clinical events, among which there were: vasoocclusive and central nervous system crisis, acute thoracic syndrome and infections.

  19. RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck

    International Nuclear Information System (INIS)

    Spencer, S.A.; Harris, J.; Wheeler, R.H.; Machtay, M.; Schultz, C.; Spanos, W.; Rotman, M.; Meredith, R.

    2001-01-01

    Purpose: Patients with recurrent squamous cell cancer of the head and neck (SCH and N) are generally treated with systemic chemotherapy. Improvement in survival has not occurred, despite an increased objective response rate. This study was undertaken to explore the feasibility and toxicity, and estimate the therapeutic impact of, reirradiation (RRT) with concurrent hydroxyurea and 5-fluorouracil. Methods and Materials: The eligibility requirements included SCH and N presenting as a second primary or recurrence ≥6 months after definitive RT to ≥45 Gy, with ≥75% of the tumor volume within the previous field. The cumulative spinal cord dose was limited to 50 Gy, and measurable disease was required. Four weekly cycles were given, each separated by 1 week of rest. A cycle consisted of 5 days, Monday through Friday, of 1.5-Gy twice-daily repeated RT, with the fractions separated by ≥6 h, with 1.5 g of hydroxyurea given 2 h and 300 mg/m 2 of a 5-fluorouracil IV bolus given 30 min before each second daily fraction. Results: Eighty-six patients were entered; 81 patients were assessable. The median prior radiation dose was 61.2 Gy. The 4 planned cycles were delivered in 79% of patients. Grade 3 mucositis occurred in 14% of patients, and Grade 4 in 5%. Grade 3 acute pharyngeal toxicity was seen in 17%. Grade 3 neutropenia occurred in 9%, Grade 4 in 10%, and Grade 5 in 7%. Six patients died of treatment-related toxicity. Two died of hemorrhage from the tumor site without thrombocytopenia. With a median follow-up of 16.3 months for living patients, the estimated median overall survival was 8.2 months and the estimated 1-year survival rate 41.7%. Patients treated >3 years after the previous RT had a 1-year survival rate of 48% compared with 35% for patients treated within 3 years (p=0.017). The 1-year survival rate for patients with a second primary was 54% compared with 38% for patients with recurrence (p=0.083). Conclusion: Repeated RT with concurrent chemotherapy as

  20. HABIT, a Randomized Feasibility Trial to Increase Hydroxyurea Adherence, Suggests Improved Health-Related Quality of Life in Youths with Sickle Cell Disease.

    Science.gov (United States)

    Smaldone, Arlene; Findley, Sally; Manwani, Deepa; Jia, Haomiao; Green, Nancy S

    2018-06-01

    To examine the effect of a community health worker (CHW) intervention, augmented by tailored text messages, on adherence to hydroxyurea therapy in youths with sickle cell disease, as well as on generic and disease-specific health-related quality of life (HrQL) and youth-parent self-management responsibility concordance. We conducted a 2-site randomized controlled feasibility study (Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment [HABIT]) with 2:1 intervention allocation. Youths and parents participated as dyads. Intervention dyads received CHW visits and text message reminders. Data were analyzed using descriptive statistics, the Wilcoxon signed-rank test, and growth models adjusting for group assignment, time, and multiple comparisons. Changes in outcomes from 0 to 6 months were compared with their respective minimal clinically important differences. A total of 28 dyads (mean age of youths, 14.3 ± 2.6 years; 50% Hispanic) participated (18 in the intervention group, 10 in the control group), with 10.7% attrition. Accounting for group assignment, time, and multiple comparisons, at 6 months intervention youths reported improved generic HrQL total score (9.8 points; 95% CI, 0.4-19.2) and Emotions subscale score (15.0 points; 95% CI, 1.6-28.4); improved disease-specific subscale scores for Worry I (30.0 points; 95% CI, 8.5-51.5), Emotions (37.0 points, 95% CI, 9.4-64.5), and Communication I (17.8 points; 95% CI, 0.5-35.1); and 3-month dyad self-management responsibility concordance (3.5 points; 95% CI, -0.2 to 7.1). There were no differences in parent proxy-reported HrQL measures at 6 months. These findings add to research examining effects of behavioral interventions on HrQL outcomes in youths with sickle cell disease. ClinicalTrials.gov: NCT02029742. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Study on the surface hydroxyl group on solid breeding materials by infrared absorption spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Satoru; Taniguchi, Masaki [Tokyo Univ. (Japan). Faculty of Engineering

    1996-10-01

    Hydroxyl groups on the surface of Li{sub 2}O were studied by using a diffuse reflectance method with Fourier transform infrared absorption spectroscopy at high temperature up to 973K under controlled D{sub 2}O or D{sub 2} partial pressure. It was found that hydroxyl groups could exist on Li{sub 2}O surface up to 973K under Ar atmosphere. Under D{sub 2}O containing atmosphere, only the sharp peak at 2520cm{sup -1} was observed at 973K in the O-D stretching vibration region. Below 973K, multiple peaks due to the surface -OD were observed and they showed different behavior with temperature or atmosphere. Multiple peaks mean that surface is not homogeneous for D{sub 2}O adsorption. Assignment of the observed peaks to the surface bonding structure was also discussed. (author)

  2. Stability, electrochemical behaviors and electronic structures of iron hydroxyl-phosphate

    International Nuclear Information System (INIS)

    Wang Zhongli; Sun Shaorui; Li Fan; Chen Ge; Xia Dingguo; Zhao Ting; Chu Wangsheng; Wu Ziyu

    2010-01-01

    Iron hydroxyl-phosphate with a uniform spherical particle size of around 1 μm, a compound of the type Fe 2-y □ y (PO 4 )(OH) 3-3y (H 2 O) 3y-2 (where □ represents a vacancy), has been synthesized by hydrothermal methods. The particles are composed of spheres of diameter -1 and 120 mAh g -1 at current densities of 170 mA g -1 and 680 mA g -1 , respectively. The stability of crystal structure of this material was studied by TGA and XRD which show that the material remains stable at least up to the temperature 200 deg. C. Investigation of the electronic structure of the iron hydroxyl-phosphate by GGA + U calculation has indicated that it has a better electronic conductivity than LiFePO 4 .

  3. Effect of nitrogen doping of graphene oxide on hydrogen and hydroxyl adsorption

    Energy Technology Data Exchange (ETDEWEB)

    Min, Byeong June; Jeong, Hae Kyung [Daegu University, Kyungsan (Korea, Republic of)

    2014-05-15

    We investigate how nitrogen-doping affects the hydrogen (H) and the hydroxyl (OH) adsorption on graphene oxide (GO) and on nitrogen-doped GO (NGO) via pseudopotential plane wave density functional calculations within the local spin density approximation. We find that the nitrogen doping brings about drastic changes in the hydrogen and the hydroxyl adsorption energetics, but its effects depend sensitively on the nitrogen configuration in NGO. The H and the OH adsorption energies are comparable only for pyrrolic NGO. In GO and quarternary NGO, the H adsorption energy is greater than the OH adsorption energy while the trend is reversed in pyridinic NGO. Also, the OH adsorption process is less affected by nitrogen-doping than the H adsorption is.

  4. Effect of Bulky and Hydroxyl Groups on Gas Separation Performance of Polyimide Membranes.

    Science.gov (United States)

    Lee, Bo Mi; Kim, Deuk Ju; Nam, Sang Yong

    2015-03-01

    A series of polyimides were synthesized by a polycondensation reaction using various aromatic dianhydrides and diamines containing bulky cardo and hydroxyl groups. The imidization and chemical structure of the polyimides were confirmed by NMR and FT-IR. The thermal and gas properties of the polyimides were measured by time-lag, XRD, TGA, and DSC studies. The polyimides showed excellent solubility in common organic solvents and high thermal stability. The CO2 selectivity of HPI membrane was higher than traditional polyimides. In particular, the incorporation of hydroxyl groups improved the CO2 permeability of the polyimide due to increased carbon dioxide solubility. The HPI was thermally converted to polybenzoxazole (PBO) at 450 °C.

  5. Properties of the Nafion membrane impregnated with hydroxyl ammonium based ionic liquids

    International Nuclear Information System (INIS)

    Garaev, Valeriy; Pavlovica, Sanita; Vaivars, Guntars; Kleperis, Janis

    2012-01-01

    In this work, the Nafion 112 membrane impregnated with nine various hydroxyl ammonium based ionic liquids have been investigated. The used ionic liquids were combined from hydroxyl ammonium cations (2-hydroxyethylammonium/HEA, bis(2- hydroxyethyl)ammonium/BHEA, tris(2-hydroxyethyl)ammonium/THEA) and carboxylate anions (formate, acetate, lactate). The membranes are characterized by conductivity and thermal stability measurements. It was found, that almost all composites have 10 times higher ion conductivity than a pure Nafion 112 at 90 °C in ambient environment due to the higher thermal stability. The thermal stability of Nafion membrane was increased by all studied nine ionic liquids. In this work, only biodegradable ionic liquids were used for composite preparation.

  6. Study on the plasma reaction process of hydroxyl generation by strong electric field ionization discharge

    International Nuclear Information System (INIS)

    Bai Mindi; Deng Shufang; Bai Xiyao; Zhang Zhitao

    2004-01-01

    Considering the change in the structure of reaction room, dielectric materials and process technology, authors have specifically studied the plasma reaction process of creating hydroxyl radical OH * and e aq - from ionization of O 2 and H 2 O through a strong electric field discharge. The production volume of hydroxyl radical OH * is up to the project application level, and process technology meets the 12 laws of green chemistry, free from environmental pollution from the source. The authors have emphatically researched on the green method of flue gas desulfurization, which will ionize SO 2 , H 2 O and O 2 in the flue gas to synthesis H 2 SO 4 in molecular level within 0.8 s without absorbent and catalyst. (author)

  7. Microbial carbonylation and hydroxylation of 20(R)-panaxadiol by Aspergillus niger.

    Science.gov (United States)

    Yan, Bin; Chen, Zhihua; Zhai, Xuguang; Yin, Guibo; Ai, Yafei; Chen, Guangtong

    2018-04-01

    20(R)-panaxadiol (PD) was metabolised by the fungus Aspergillus niger AS 3.3926 to its C-3 carbonylated metabolite and five other hydroxylated metabolites (1-6). Their structures were elucidated as 3-oxo-20(R)-panaxadiol (1), 3-oxo-7β-hydroxyl- 20(R)-panaxadiol (2), 3-oxo-7β,23α-dihydroxyl-20(R)-panaxadiol (3), 3,12-dioxo- 7β,23β-dihydroxyl-20(R)-panaxadiol (4), 3-oxo-1α,7β-dihydroxyl-20(R)-panaxadiol (5) and 3-oxo-7β,15β-dihydroxyl-20(R)-panaxadiol (6) by spectroscopic analysis. Among them, compounds 2-6 were new compounds. Pharmacological studies revealed that compound 6 exhibited significant anti-hepatic fibrosis activity.

  8. Study of the hydroxyl radical: Experimental advances in microwave spectroscopy, theoretical model and astrophysical consequences

    International Nuclear Information System (INIS)

    Destombes, Jean-Luc

    1978-01-01

    This research thesis mainly addresses the experimental and theoretical study of the hydroxyl radical, and the consequences of the obtained results in astrophysics which are studied with a model of pumping by the far infrared. After a recall of notions related to microwave spectroscopy and to molecular radio-astronomy, the author more particularly discusses different aspects of microwave spectroscopy in the interstellar environment and in laboratory. He also reviews different types of spectrometers for unsteady molecules. In the second part, he addresses issues related to the hydroxyl radical (OH): presentation of spectrometers, study of the reaction environment, study of the radical microwave spectrum, identification of transitions by frequency measurements. In the last parts, the author addresses some aspects of interstellar OH masers, and reports the application of some results to simple models of pumping by the far infra red

  9. Steroid Hydroxylation by Basidiomycete Peroxygenases: a Combined Experimental and Computational Study

    Science.gov (United States)

    Babot, Esteban D.; del Río, José C.; Cañellas, Marina; Sancho, Ferran; Lucas, Fátima; Guallar, Víctor; Kalum, Lisbeth; Lund, Henrik; Gröbe, Glenn; Scheibner, Katrin; Ullrich, René; Hofrichter, Martin; Martínez, Angel T.

    2015-01-01

    The goal of this study is the selective oxyfunctionalization of steroids under mild and environmentally friendly conditions using fungal enzymes. With this purpose, peroxygenases from three basidiomycete species were tested for the hydroxylation of a variety of steroidal compounds, using H2O2 as the only cosubstrate. Two of them are wild-type enzymes from Agrocybe aegerita and Marasmius rotula, and the third one is a recombinant enzyme from Coprinopsis cinerea. The enzymatic reactions on free and esterified sterols, steroid hydrocarbons, and ketones were monitored by gas chromatography, and the products were identified by mass spectrometry. Hydroxylation at the side chain over the steroidal rings was preferred, with the 25-hydroxyderivatives predominating. Interestingly, antiviral and other biological activities of 25-hydroxycholesterol have been reported recently (M. Blanc et al., Immunity 38:106–118, 2013, http://dx.doi.org/10.1016/j.immuni.2012.11.004). However, hydroxylation in the ring moiety and terminal hydroxylation at the side chain also was observed in some steroids, the former favored by the absence of oxygenated groups at C-3 and by the presence of conjugated double bonds in the rings. To understand the yield and selectivity differences between the different steroids, a computational study was performed using Protein Energy Landscape Exploration (PELE) software for dynamic ligand diffusion. These simulations showed that the active-site geometry and hydrophobicity favors the entrance of the steroid side chain, while the entrance of the ring is energetically penalized. Also, a direct correlation between the conversion rate and the side chain entrance ratio could be established that explains the various reaction yields observed. PMID:25862224

  10. The Juxtaposition of Ribose Hydroxyl Groups: The Root of Biological Catalysis and the RNA World?

    Science.gov (United States)

    Bernhardt, Harold S.

    2015-06-01

    We normally think of enzymes as being proteins; however, the RNA world hypothesis suggests that the earliest biological catalysts may have been composed of RNA. One of the oldest surviving RNA enzymes we are aware of is the peptidyl transferase centre (PTC) of the large ribosomal RNA, which joins amino acids together to form proteins. Recent evidence indicates that the enzymatic activity of the PTC is principally due to ribose 2 '-OHs. Many other reactions catalyzed by RNA and/or in which RNA is a substrate similarly utilize ribose 2 '-OHs, including phosphoryl transfer reactions that involve the cleavage and/or ligation of the ribose-phosphate backbone. It has recently been proposed by Yakhnin (2013) that phosphoryl transfer reactions were important in the prebiotic chemical evolution of RNA, by enabling macromolecules composed of polyols joined by phosphodiester linkages to undergo recombination reactions, with the reaction energy supplied by the phosphodiester bond itself. The almost unique juxtaposition of the ribose 2'-hydroxyl and 3'-oxygen in ribose-containing polymers such as RNA, which gives ribose the ability to catalyze such reactions, may have been an important factor in the selection of ribose as a component of the first biopolymer. In addition, the juxtaposition of hydroxyl groups in free ribose: (i) allows coordination of borate ions, which could have provided significant and preferential stabilization of ribose in a prebiotic environment; and (ii) enhances the rate of permeation by ribose into a variety of lipid membrane systems, possibly favouring its incorporation into early metabolic pathways and an ancestral ribose-phosphate polymer. Somewhat more speculatively, hydrogen bonds formed by juxtaposed ribose hydroxyl groups may have stabilized an ancestral ribose-phosphate polymer against degradation (Bernhardt and Sandwick 2014). I propose that the almost unique juxtaposition of ribose hydroxyl groups constitutes the root of both biological

  11. Hydroxyl and water molecule orientations in trypsin: Comparison to molecular dynamics structures

    Energy Technology Data Exchange (ETDEWEB)

    McDowell, R.S.; Kossiakoff, A.A. [Genentech, Inc., South San Francisco, CA (United States)

    1994-12-31

    A comparison is presented of experimentally observed hydroxyl and water hydrogens in trypsin determined from neutron density maps with the results of a 140ps molecular dynamics (MD) simulation. Experimental determination of hydrogen and deuterium atom positions in molecules as large as proteins is a unique capability of neutron diffraction. The comparison addresses the degree to which a standard force-field approach can adequately describe the local electrostatic and van der Waals forces that determine the orientations of these hydrogens. Neutron densities, derived from 2.1{Angstrom} D{sub 2}O-H{sub 2}O difference Fourier maps, provide a database of 27 well-ordered hydroxyl hydrogens. Most of the simulated hydroxyl orientations are within a standard deviation of the experimentally-observed positions, including several examples in which both the simulation and the neutron density indicate that a hydroxyl group is shifted from a {open_quote}standard{close_quote} rotamer. For the most highly ordered water molecules, the hydrogen distributions calculated from the trajectory were in good agreement with neutron density; simulated water molecules that displayed multiple hydrogen bonding networks had correspondingly broadened neutron density profiles. This comparison was facilitated by development of a method to construct a pseudo 2{Angstrom} density map based on the hydrogen atom distributions from the simulation. The degree of disorder of internal water molecules is shown to result primarily from the electrostatic environment surrounding that water molecule as opposed to the cavity size available to the molecule. A method is presented for comparing the discrete observations sampled in a dynamics trajectory with the time- averaged data obtained from X-ray or neutron diffraction studies. This method is particularly useful for statically-disordered water molecules, in which the average location assigned from a trajectory may represent a site of relatively low occupancy.

  12. Monolayer arrangement of fatty hydroxystearic acids on graphite: Influence of hydroxyl groups

    Energy Technology Data Exchange (ETDEWEB)

    Medina, S. [Laboratorio de Rayos-X, Centro de Investigación Tecnología e Innovación, de la Universidad de Sevilla (CITIUS), Universidad de Sevilla, Avenida Reina Mercedes, 4B. 41012, Sevilla (Spain); Benítez, J.J.; Castro, M.A. [Instituto de Ciencia de Materiales de Sevilla, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla, Avenida Américo Vespucio, 49. 41092, Sevilla (Spain); Cerrillos, C. [Servicio de Microscopía, Centro de Investigación Tecnología e Innovación, de la Universidad de Sevilla (CITIUS), Universidad de Sevilla, Avenida Reina Mercedes, 4B. 41012, Sevilla (Spain); Millán, C. [Instituto de Ciencia de Materiales de Sevilla, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla, Avenida Américo Vespucio, 49. 41092, Sevilla (Spain); Alba, M.D., E-mail: alba@icmse.csic.es [Instituto de Ciencia de Materiales de Sevilla, Consejo Superior de Investigaciones Científicas-Universidad de Sevilla, Avenida Américo Vespucio, 49. 41092, Sevilla (Spain)

    2013-07-31

    Previous studies have indicated that long-chain linear carboxylic acids form commensurate packed crystalline monolayers on graphite even at temperatures above their melting point. This study examines the effect on the monolayer formation and structure of adding one or more secondary hydroxyl, functional groups to the stearic acid skeleton (namely, 12-hydroxystearic and 9,10-dihydroxystearic acid). Moreover, a comparative study of the monolayer formation on recompressed and monocrystalline graphite has been performed through X-ray diffraction (XRD) and Scanning Tunneling Microscopy (STM), respectively. The Differential Scanning Calorimetry (DSC) and XRD data were used to confirm the formation of solid monolayers and XRD data have provided a detailed structural analysis of the monolayers in good correspondence with obtained STM images. DSC and XRD have demonstrated that, in stearic acid and 12-hydroxystearic acid adsorbed onto graphite, the monolayer melted at a higher temperature than the bulk form of the carboxylic acid. However, no difference was observed between the melting point of the monolayer and the bulk form for 9,10-dihydroxystearic acid adsorbed onto graphite. STM results indicated that all acids on the surface have a rectangular p2 monolayer structure, whose lattice parameters were uniaxially commensurate on the a-axis. This structure does not correlate with the initial structure of the pure compounds after dissolving, but it is conditioned to favor a) hydrogen bond formation between the carboxylic groups and b) formation of hydrogen bonds between secondary hydroxyl groups, if spatially permissible. Therefore, the presence of hydroxyl functional groups affects the secondary structure and behavior of stearic acid in the monolayer. - Highlights: • Hydroxyl functional groups affect structure and behavior of acids in the monolayer. • Acids on the surface have a rectangular p2 monolayer structure. • Lattice parameters of acids are uniaxially

  13. A Brief Review on Electro-generated Hydroxyl Radical for Organic Wastewater Mineralization

    Directory of Open Access Journals (Sweden)

    Ervin Nurhayati

    2016-05-01

    Full Text Available Hydroxyl radical is a highly reactive oxidizing agent that can be electrochemically generated on the surface of Boron doped diamond (BDD anode. Once generated, this radical will non-selectively mineralize organic pollutants to carbon dioxide, water and organic anions as the oxidation products. Its application in Advanced Oxidation Process (AOP to degrade nonbiodegradable even the recalcitrant pollutants in wastewater has been increasingly studied and even applied.

  14. Hydroxyl group as IR probe to detect the structure of ionic liquid-acetonitrile mixtures

    Science.gov (United States)

    Xu, Jing; Deng, Geng; Zhou, Yu; Ashraf, Hamad; Yu, Zhi-Wu

    2018-06-01

    Task-specific ionic liquids (ILs) are those with functional groups introduced in the cations or anions of ILs to bring about specific properties for various tasks. In this work, the hydrogen bonding interactions between a hydroxyl functionalized IL 1-(2-hydroxylethyl)-3-methylimidazolium tetrafluoroborate ([C2OHMIM][BF4]) and acetonitrile were investigated in detail by infrared spectroscopy, excess spectroscopy, two-dimensional correlation spectroscopy, combined with hydrogen nuclear magnetic resonance and density functional theory calculations (DFT). The hydroxyl group rather than C2sbnd H is found to be the main interaction site in the cation. And the ν(Osbnd H) is more sensitive than v(C-Hs) to the environment, which has been taken as an intrinsic probe to reflect the structural change of IL. Examining the region of ν(Osbnd H), by combining excess spectroscopy and DFT calculation, a number of species were identified in the mixtures. Other than the hydrogen bond between a cation and an anion, the hydroxyl group allows the formation of a hydrogen bond between two like-charged cations. The Osbnd H⋯O hydrogen bonding interactions in the hydroxyl-mediated cation-cation complexes are cooperative, while Osbnd H⋯F and C2sbnd H⋯F hydrogen bonding interactions in cation-anion complexes are anti-cooperative. These in-depth studies on the properties of the ionic liquid-acetonitrile mixtures may shed light on exploring their applications as mixed solvents and understanding the nature of doubly ionic hydrogen bonds.

  15. Lewis base catalyzed enantioselective allylic hydroxylation of Morita-Baylis-Hillman carbonates with water

    KAUST Repository

    Zhu, Bo

    2011-08-19

    A Lewis base catalyzed allylic hydroxylation of Morita-Baylis-Hillman (MBH) carbonates has been developed. Various chiral MBH alcohols can be synthesized in high yields (up to 99%) and excellent enantioselectivities (up to 94% ee). This is the first report using water as a nucleophile in asymmetric organocatalysis. The nucleophilic role of water has been verified using 18O-labeling experiments. © 2011 American Chemical Society.

  16. Fabrication and characterisation of fluidic based memristor sensor for liquid with hydroxyl group

    Directory of Open Access Journals (Sweden)

    Nor Shahanim Mohamad Hadis

    2017-06-01

    Full Text Available Two types of memristor sensor were fabricated using two different TiO2 deposition methods of sputtering and sol-gel spin coating. The surface morphology of the sensors and the behaviour of the sensors were analysed by using scanning electron microscopy with energy dispersive x-ray system and I-V characterisation system respectively. The sensors were applied with liquid with hydroxyl group to check the capability of this sensor in sensing different concentration of hydroxyl ion inside the liquid. For that purpose, d-glucose liquid with four concentrations of 10mM, 20mM, 30mM and 40mM were chosen. The liquids dispensed onto the TiO2 surface to act as sensing material. The TiO2 surface was initially covered with polydimethylsiloxane to control the liquid. The sensing capability of the sensors was determined via the current-voltage measurement and off-on resistance ratio. The sensitivity of the sensors was analysed from the off-on resistance ratio analysis. Type II memristor sensor which was fabricated using sol-gel spin coating technique recorded high sensitivity of 120.65 (mM−1, while Type I sensor fabricated using the sputtering technique recorded low sensitivity of 0.035 (mM−1. However, SEM-EDX image illustrated that th